JPS5910588A - Carbapenem antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new carbapenem antibiotic [wherein A represents a straight-chain or branched alkylene group or a cyclopentylene or cyclohexylene group;
a) an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, aryl, arylaliphatic, heteroaryl, heteroarylaliphatic, heterocyclyl or heterocyclyl-aliphatic residue; Divalent phenylene or C which together form a cross-linked polycyclic group
! ˜represents a C4 alkylene group; represents a quaternary compound nitrogen non-aromatic heterocyclic ring.

Several β-lactam derivatives with a carbapenem nucleus 1 have been disclosed in the literature. These carbapenem derivatives are reported to have utility as antibacterial agents and/or β-laccumase inhibitors.

It was a natural product such as the formula chenamycin (US Pat. No. 5,950,357) obtained by fermentation of Torreya. Chenamycin is a particularly broad-spectrum antibiotic and has significant activity against various Pseudomonas strains, a bacterium that has been noted to be resistant to β-lactac antibiotics.

Other natural products with carbapenem cores include US Pat.
Formula 0 disclosed in No. 113,856 % Antibiotics of the formula shown MM17880, U.S. Pat.
Antibiotic MM4550A of the formula disclosed in No. 9 and U.S. Pat. No. 4,264,7
Included are oripanoic acid derivatives such as the antibiotic 89 U A9 of the formula disclosed in No. 55. In addition to natural products, the compound deacetylated 890 Aio of the formula is disclosed in US Pat. No. 4,264,734 as being prepared by enzymatic deacylation of the corresponding N-acetyl compound. Various derivatives of natural oripanoic acid, such as European Patent Application 8
885 [wherein CO, R, is free,
It is a salt type or ester type carboxyl group, n is 0 or 1, and R2 is H, an acyl group, or a formula R303S (
However, R3 is a salt-forming ion or a methyl or ethyl group] has also been synthesized.

US Pat. No. 4,235,922 (also referenced to European Patent Application No. 2058) discloses carbapenem derivatives of the formula, while reporting the isolation of the British patent application.

Carbapenems that are unsaturated at the 6-position have also been synthesized.

Thus, U.S. Pat. No. 4,210,661 provides a compound of the formula (
where R2 is phenyl or substituted phenyl), and U.S. Pat. No. 4,267,177 discloses compounds of the formula (wherein R,
is an optionally substituted pyridyl group), and U.S. Pat. No. 4,225,441 discloses compounds of the formula [wherein R
2 and R3 are H or argyl, and R4 is NH-CO
nRg (provided that 8 companies are alkyl, phenyl or substituted phenyl, and n is 1 or 2)],
U.S. Pat. No. 4,282,256 discloses compounds of the formula [wherein R1 is H or alkyl and R2 is C
or CO2R3, where R3 is H1 alkyl, aryl or aralkyl].

Carbapenems of the general formula (wherein R1 is H or acyl, R
8 is 11 or substituted or unsubstituted: alkyl, alkenyl,
alkynyl, cycloalkyl, p-p-■p-■, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) in U.S. Pat. No. 4,218,465 It is disclosed inside. There is no disclosure of the heterocyclylalkyl R8 substituent of the type (where A is alkylene and is a quaternary nitrogen non-aromatic heterocyclic ring).

The natural product chenamycin has an absolute coordination of SR, 68,8R. This isomer, sequence 1 (the remaining 7-chainamycin isomers, can be obtained by total synthesis as disclosed in U.S. Pat. No. 4,234,596. 4.28
7.125.4, 269.772.4, 282,148
．． No. 4,273,709.4.290,947 and European Patent Application No. 7973.

The key intermediate of the disclosed synthesis method is (where pNB stands for p-nitrobenzyl).

Due to the unusual biological activity of chenamycin, numerous derivatives have been prepared and disclosed in the literature. Among these are (1) N-formimidoylchenamycin of the formula disclosed in European Patent Application 6639; (2) disclosed in U.S. Pat. No. 4,18z493 of the formula (wherein the difunctional ring is There may be further unsaturation in the ring;
When n is an integer from 1 to 6, P is 0, 1 or 2; R1 is Hl alkyl or aryl; 2 is imino, oxo, ■, amine or alkyl). (5) Formula disclosed in U.S. Pat. No. 4,194,047 [wherein X and Y are H, R, OR, SR, or G;
IR"(7'c and R is substituted or unsubstituted: alkyl,
and R1 and R2 are
H or R] k [wherein R3 is aryl, alkyl, acyl or aralkyl, R1
and R2 are selected from H and acyl of acyl BGu-C-rt'' (with R11 inter alia containing a quaternary ammonium group); a compound of formula (5) [wherein R3 is H, acyl or monovalent I is a soft white substituted hydrocarbon residue; R1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl; R2 is acyl (
Compounds of the type 〇- and -R (including acyl, for example, where R is an alkyl substituted by a quaternary ammonium group) - disclosed in British Patent No. 1.604.276 ( see also U.S. Pat. No. 4,235,917);
(6) The formula disclosed in U.S. Pat. No. 4,235,920 (wherein R5, R' and R7 are H and substituted and unsubstituted:
Alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl) [wherein each of R1 and R2 is independently selected from R a hydrogen atom, or a nitro, hydroxyl, cl-c, alkoxyl, amine, C1-C6 alkylamino, di(Cl-4 alkyl)amino or tri(C,~6 alkylamino residue) and in the latter case another anion is present: or R1
and R2 together with the nitrogen atom to which they are connected form a substituted or unsubstituted monocyclic or bicyclic heteroaryl or heterocyclyl residue having 4 to 10 ring atoms, and one of the ring atoms or more may be another heteroatom selected from oxygen, sulfur and nitrogen; R is a cyano group or a substituted or unsubstituted carbamoyl, carboxyl, (C1-1o alkoxy)carbonyl, 01-1o alkyl , C2~, 0 alkenyl, C2~,. Alkynyl, C3~1o cycloalkyl, C4~1□cycloalkylalkyl, C5~1□cycloalkylalkenyl, C
3-1o cycloalkenyl, C, 1□cycloalkenylalkenyl, C4-1□cycloalkenylalkyl, C
,10 aryl, C7-16 aralkyl, c, 16
Ralkenyl, C8-16aralkynyl or monocyclic or 211 heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl (4-1
Consisting of 0 ring atoms, one or more of which is oxygen,
a heteroatom selected from sulfur and nitrogen, the alkyl residue of the heteroaralkyl or heterocyclylalkyl residue having 1 to 6 carbon atoms): R, R
', Substituents on R2 or on the ring formed by combining R and R2 are chlorine; bromine; iodo; fluorine;
Azide; C1-4 alkyl; mercapto; sulfo; phosphono; cyanothio (-8CN); nitro; cyano; amino; hydrazino; amino or hydrazino (01 up to 3
~6 alkyl substitutions); hydroxy; c? 4 alkoxy; C1-6 alkylthio: carboxyl; oxo; (C□-6 alkoxy) carbonyl; C2-1o acyloxy; carbamoyl: (C1-4 alkylcarbamoyl or di(C1-4 alkyl)carbamoyl;
R3 is a hydrogen atom, an acyl residue or a residue of the type as defined for R4: R4 is C1-1o alkyl; substituted carbonylmethyl; (C=6al)key/)
-(C,-,,,furkyl), (c3-6 cycloalkoxy)-(C1-6 alkyl); C2-□2 alkanoyloxyalkyl; partially or fully halogenated c1-6 alkyl (however, halogen is chlorine, bromine or fluorine)
Niaminoalkyl; C alkenyl; C2-1o alkynyl 2-10; acyl; C alkoxycarbonylalkyl: C4-2
13-14 dialkylaminoacetoxyalkyl; C2-13 alkanoylaminoalkyl; R-(C1-3 alkyl) (with the proviso that the R residue has 6 to 10 carbon atoms); 4 to 10 ring atoms, alkyl Monocyclic or 21! with 1 to 6 carbon atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and/or carboxyl in the residue. ! A-type heteroaralkyl or heterocyclylalkyl: nuclear-substituted aralkyl or heteroaralkyl (wherein the substituent is chlorine, fluorine, bromine, iodo or 01-6 alkyl); having 6 to 10 ring carbon atoms; Aryl or nuclear-substituted aryl in which the moiety is hydroxy, C1-6 alkyl, chlorine, fluorine or bromine; Ralkoxyalkyl; C2-1□alkylthioalkyl; 04-1
2cycloalkylthioalkyl; (C2~,.acylthio)-(C,~6alkyl); or phenylalkenyl, where alkenyl has 2 to 6 carbon atoms: R5 is substituted or unsubstituted 01-1o alkyl ;C2
~1o alkenyl or alkynyl; ring-substituted and unsubstituted cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl (having 3 to 6 ring carbon atoms and up to 6 carbon atoms in the chain); C6-I
0 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 (4 to 6 carbon atoms in the alkyl chain);
has 10 ring atoms, one or more of which is oxygen,
nitrogen or sulfur and having 1 to 6 carbon atoms in the alkyl chain); the ring or optional moiety can be chlorine, bromine, iodo, fluorine, azide, cyano, amino, Cel6alkyamino, di(C1-6 alkyl)amino or tri(C, ~6 alkylamino) - in the latter case another anion is present, hydroxy, C alkoxy, C1-6 alkyl, 1-6 alkyl; carboxyl; oxo: (C, ~ 6alkoxy)carbonyl; C2-1o acyloxy; carbamoyl; (C1-4alkyl)carbamoyl; di(01-4thylkyl)carbamoyl; cyanothio (-8CN) or nitro; R6 is hydrogen, hydroxy, mercapto,
R, -OR, -8R or NR'ft" (However, R, R
1 and R2 are as defined above; or hydroxy, mercapto, amine, acyloxy-
OR', -8R', -NHR', -NR', -0M
, OQ, or 4 is -0- (in which case 8- is not present) when this compound is not in zwitterionic form; A is the opposite ion when this compound is not in zwitterionic form; M is , a pharmaceutically usable cation; Q is a blocking group as defined herein; and (8) a compound of the formula disclosed in European Patent Application 21082 in which chenamycin connected to the amine nitrogen atom represents a mono- or polycyclic N-containing heterocyclic group, and R
is H1 substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclylalkenyl, aralkenyl,
heterocyclylalkyl, ralkyl, -NR2,
C0OR.

C0NR2, -OR, or CN]. Rice (where A is a medicinally usable anion) is also described in Royal Society Op Chemistry, London, 1981, pp. 240-254, where the antibacterial activity is on average higher than that of chenamycin. It has been reported that approximately % to % of

In addition to those mentioned above, carbapenem derivatives having various 6-position moieties have also been synthesized. Thus, for example, (1)
a-Rotupa Patent Application 4Q408 is based on the formula (wherein R1 is H, methyl or hydroxyl, R
(2) European Patent Application 8514 discloses compounds of the formula [wherein R is optionally substituted]; pyrimidinyl, and R2 is hydrogen or a group CR3R4R5 (but R3
is hydrogen or hydroxy, 84 is hydrogen or alkyl, R6 is hydrogen, alkyl, benzyl or phenyl, or B5 and R4 together form a carbocyclic ring). (3) European Patent Application No. 38869 discloses V [where R6, R7, and R8 are hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl
cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl (having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 0 carbon atoms in the alkyl moiety);
6 carbon atoms); aryl such as phenyl;
ralkyl, aralkenyl, and aralkynyl (wherein the aryl portion is phenyl and the aliphatic portion has 1 to 6 carbon atoms); heteroaryl;
independently selected from the group consisting of heteroaralkyl, heterocyclyl and heterocyclylalkyl; where the substituents related to the above residues are monotehalo(chloro, ppmo, 700)-OHhydroxy-oa'alkoxy , aryloxy-CNR'R2carbamoyloxy-CNR'R2carbamoyl-NRIR2amino1-NO2nitro-N(R'')3)-substituted amine (R' group independently selected)R'-C=NOR2oximino-S R"Alkyl and Arylthio-8O2NR'R"Sulfonamide-NHCNR"R2UreidoR'CNR2-Amido-CO2H Carboxy-Co, R'Carboxylate-CLL'Acyl-0CR"Acyloxy-8H Mercapto-S R'Alkyl and Aryl Sulfinyl-SR
1 alkyl and hyarylsulfonyl-CN cyano-N3 azide;
8. Regarding the above substituents, the groups R1 and R2 are hydrogen,
Alkyl, alkenyl, and alkynyl (having 1 to 10 carbon atoms); cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl (having 5 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety); aryl such as phenyl; aralkyl, aralkenyl, and aralkynyl (wherein the aryl portion is phenyl and the aliphatic portion has 1 to 6 carbon atoms); heteroaryl, heteroaralkyl, Heterocyclyl and heterocyclylalkyl (wherein the heterocyclic partial heteroatoms mentioned above are selected from the group consisting of 1 to 4 oxygen, 9 atoms or sulfur atoms, and the alkyl moiety attached to the heterocyclic moiety is 1 to 6 carbon atoms) are disclosed.

(Also European patent applications 1627, 1628.
10317.17992.37080.37081 and 57082); (4) European patent application 24
832 is a compound of the formula [wherein R1 is H or OH, 08O3H or a group thereof or
1-4 alkyl ester, OR2, SR3,0COR2
, OCO,R” or 0CONHR3 (however, R2 is c
, ~6 alkyl group or optionally substituted benzyl, R3 is cI~6 alkyl group or optionally substituted benzyl or phenyl), B+2 is C3_6 alkyl, C2-6 alkenyl, C
3-6 alkynyl (however, there is no three-bundle bond on the carbon adjacent to the sulfur), aralkyl, C1-6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, and each of the R12 groups is optionally substituted. ] is disclosed as an antibacterial agent.

European Patent Application No. 44170 describes the formula [wherein R3 is hydrogen or an organic group bonded to the carbapenem ring via a carbon atom, n is 0 or 1, and X is a saturated or unsaturated hydrocarbon residue (optional is substituted by bromo or chloro), R4 is a q-6 alkyl, C2-6 alkenyl, C1-10 aralkyl or aryl group, and any of the above groups R4 are optionally substituted. discloses carbapenem derivatives. However, no compound is disclosed in which the tetrazole ring is polymerized to X via a quaternary nitrogen atom, ie, a positively charged nitrogen that is not connected to a hydrogen atom.

The above-mentioned European patent application 38,869 is based on the general formula (
In the formula, ♂ and R7 are as defined above, and R2
/ is an easily removable carboxyl protecting group). Also disclosed as intermediates are compounds of the formula in which X is described as a leaving group.

As indicated above, the prior art provides carbapenem derivatives having a 2-substituted moiety of the general formula %, where human represents an alkyl group and Het represents a heterocyclic or heteroaromatic group. However, Het is represented by the formula [in the formula R
5 is (a) optionally substituted aliphatic, alicyclic,
Alicyclic - is an aliphatic, aryl, aliphatic, hederoaryl, heteroalaliphatic, heterocyclyl or heterocyclyl aliphatic residue, or ←) a divalent phenylene that combines with the ring to form a bridged polycyclic group, or There is no disclosure that teaches carbapenems that are the residue of a C1-C4 alkylene group, and represents a quaternized nitrogen-containing non-aromatic heterocyclic ring bonded to the alkylene carbon via a quaternary nitrogen atom. The applicant knows that. Carbapenems having 9.2-W moiety as mentioned above have also been reported.

Although a large number of carbapenem derivatives have been disclosed in the literature,
as it can improve the spectrum of activity, potency, stability and/or toxic side effects of known compounds;
There is a need for unique carbapenems.

(The inclusion in the formula represents a straight chain or branched chain alkylene group, cyclobenzene or cyclohexylene group; R5 is (
a) Optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-
aliphatic, aryl, aliphatic, heteroaryl, heteroalliphatic, heterocyclyl or heterocyclyl-aliphatic residue or divalent phenylene or C which is combined with 0)) to form a bridged polycyclic group
! provides a novel series of carbapenem derivatives characterized by a 2-substitution moiety (representing a quaternized nitrogen-containing non-aromatic heterocyclic ring).

More particularly, the present invention provides carbapenem derivatives of the formula [wherein R8 is hydrogen and R1 is hydrogen; substituted and unsubstituted: alkyl, alkenyl and alkynyl (having 1 to 10 carbon atoms); cycloalkyl and cycloalkylalkyl (having 5 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety); phenyl; aralkyl, aralkenyl and hyaralkynyl (wherein the aryl part is phenyl and aliphatic group moiety has 1 to 6 carbon atoms)
; heteroaryl, heteroallalkyl, heterocyclyl and hiheterocyclylalkyl (provided that the heteroatoms in the above heterocyclic moiety are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms; The associated alkyl moiety is selected from the group consisting of C1-C6 alkyl (optionally an amine). , hydroxy or carboxyl) nohro〇R3 10CNR'R4 〇-6N R3R'-NR"R'- \-N R"R' -S O,N R"R'-NHCNR"R' R3CN R'-coza" N0 10CR' -S R"-SR' 1μR9 1 CN N3 108OsR" 1080!R3 -N R" S ox R'-NR"C=NR4 3 -NR3CO2R' - No2 independently selected from the group consisting of; where with respect to the above moieties, R3 and R4 are hydrogen; alkyl, alkenyl and alkynyl (having 1 to 1 o 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 moiety); phenyl; phenyl and the aliphatic moiety has 1 to 6 carbon atoms); and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl (provided that the heteroatoms in the above heterocyclic moieties include 1 to 4 oxygen, independently selected from the group consisting of nitrogen or sulfur atoms, the alkyl moiety associated with the heterocyclic moiety having from 1 to 6 carbon atoms, or R3 and R4 are at least one may form a 5- or 6-membered nitrogen-containing heterocyclic ring with the nitrogen to which it is linked; R9 is as defined for R3, except that it must not be hydrogen; or in which R1 and R8 together represents C2-CIO alkylidene or C2-CIO alkylidene substituted by hydroxy; R5 is substituted and unsubstituted: alkyl, alkenyl and alkynyl (having 1 to 10 carbon atoms); cycloalkyl and cycloalkylalkyl (
cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety; having carbon atoms); heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl (
However, the heteroatoms in the above heterocyclic moiety are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl moiety associated with the heterocyclic moiety has 1 to 6 carbon atoms. wherein the R5 residue above is: 01-C6 alkyl (optionally substituted by amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl); fluoro, chloro or bromo; 10R3; 10C02R3; - ocoR3; -0CONR"R';-oso2R3;-oxo;-NR3R':R3C0NR'-"-NR3CO2R';-NR3CONR3R';-NR3SO2R';-8R3;-CONR3R'.

-CN; or phenyl (optionally 1 to 3 fluoro, chloro, bromo,
Cl-C6furkyl, -OR'', -NR'R', -8
O3R3, -Coz R3 or -CON R"R'
) (However, in the above R6 substitution, R
3, R4 and R9 are as defined above; or R5 is divalent phenylene or CI''-C4 which joins the ring to form a bridging polycyclic group;
may represent a fulkylene group; A is cyclopentylene, cyclohexylene or c2-c6 alkylene (optionally substituted by one or more c1-c4 alkyl groups); R2 is hydrogen, anionically charged or a conventional easily removable carboxyl protecting group (
However, when L R2 is hydrogen or a protecting group, the opposite ion is also present); has at least one nitrogen in the ring,
or a pharmaceutically usable salt thereof; The compounds of formula I provided are potent antimicrobial agents or useful intermediates in their preparation.

The present invention also encompasses the novel carbapenem derivative preparation described above and pharmaceutical compositions containing a biologically active carbapenem derivative in combination with a pharmaceutically acceptable carrier or diluent.

The novel compound of general formula (1) above has a carbapenem nucleus and can therefore be named a 1-carb-2-benem-5-carboxylic acid derivative. Alternatively, these compounds can be considered to have the basic structure, 7-oxo-1-azabicyclo (&2
．． O) hept-2-ene-2-carboxylic acid derivatives. In the present invention, the relative stereochemistry of the 5.6-proton is ? ? as well as trans, but preferred compounds are the same as for chenamycin (
It has 5R,6S (trans) stereochemistry.

Compounds of formula (1) may be unsubstituted or substituted at the 6-position with substituents previously disclosed for other carbapenam derivatives. More specifically, R8 may be six hydrogens, R'G, hydrogen or non-hydrogen (e.g. European Patent Application 5 C869
(see definition of Rs).

Alternatively, R8 and R1 are together substituted by C2-CIO alkylidene or e.g. hydroxy,
It may be a C2-CIO alkylidene.

To elaborate on the definitions for R1 and 18: (a) aliphatic "alkyl", "alkenyl" and "alkynyl";
The stalk may be straight or branched with 1 to 1 carbon atoms; preferred is 1 to 6, most preferably 1 to 4 carbon atoms; for example, cycloalkynogelkyl, or hetero When it is part of another moiety, as in ralkyl or haaralganyl, alkyl,
Alkenyl and alkynyl groups preferably have 1 to 6, most preferably 1 to 4 carbon atoms.

Φ) "Heteroaryl" includes mono-, bi-, and polycyclic aromatic radicals having 1 to 4 O, N or S atoms; preferred are chenyl, furyl, thiadiazolyl, oxadiazolyl, "triazolyl, It is a 5- or 6-membered heterocyclic ring such as isothiazolyl, thiazolyl, imidazolyl, isoxazolyl, tetrazolyl, oxasilyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, and the like.

(C) "Heterocyclyl" includes mono-, bi- and polycyclic saturated or unsaturated non-aromatic heterocyclics having from 1 to 4 O, N or S atoms; preferred are morpholinyl, piperazinyl, piperidinyl, It is a 5- or 6-membered heterocyclic ring such as pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolinyl L, pyrrolinyl, pyrrolidinyl, and the like.

(d) rHalo J Lt, chloro, bromo, fluoro and hyodo are included, preferably chloro, fluoro or bromo.

The term "commonly removable carboxyl protecting group" refers to a group used to block a carboxyl group during the chemical reaction steps described below and, if desired, to result in appreciable decomposition of the remainder of the molecule. By the method that does not
Examples of protecting groups removed, for example, by chemical or enzymatic hydrolysis, treatment with chemical reducing agents under mild conditions, ultraviolet auyp irradiation or catalytic hydrogenation are benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethyl , benzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxybenzyl, acetonyl, 0
-2[ropei, sil, 4-pyridylmethyl and methyl,
Includes C1-C6 alkyl such as ethyl or t-butyl. Included among the aforementioned protecting groups are those that are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. Particularly preferred carboxyl protecting groups are p-nitrobenzyl (which can be easily removed by catalytic hydrolysis) and allyl (which can be easily removed by Pd(Pφ) 3 catalytic reaction).

- Pharmaceutically usable salts include non-toxic acid addition salts, such as salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, etc., and salts with mineral acids such as maleic acid, acetic acid, etc. , citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid.

Compounds of formula 1 in the form of acid addition salts can be written as R2=H or a protecting group, where Xo represents an acid anion. The counter ion X0 may be selected to provide a pharmaceutically acceptable salt for therapeutic administration, although in the case of intermediate compounds of formula I, Xo may be a toxic anion. In such cases, the ion can be removed or replaced with a pharmaceutically acceptable anion to produce an active end product for therapeutic use.

When present, the present invention provides suitable base or acid salts of these functional groups, e.g., acid addition salts in the case of basic groups. , and in the case of acidic groups metal salts (e.g. sodium, potassium, calcium and aluminium), ammonium salts and salts with non-toxic amines (e.g. trialkylamines, protriamines,
Dibenzylamine, Efenamine, N-benzyl-
β-phenethylamine, N-dibenzylethylenediamine, etc.).

Compounds of formula I which are hydrogen, anionic or physiologically hydrolysable ester groups, together with their pharmaceutically acceptable salts, are useful as antimicrobial agents.The remainder of formula The compounds are valuable as intermediates and can be converted into the biologically active compounds mentioned above.

A preferred embodiment of the present invention is that R8 is hydrogen and R1
is hydrogen, CH3CH2-1 The compound has absolute coordinations 5R, 6S, 8R.

Another preferred embodiment consists of compounds of formula 1, wherein R' and R8 are taken together to form an alkylidene residue of formula.

The alkylene or cycloalkylene substituent A in the compound of formula (I) is 02-C optionally substituted by one or more (preferably 1 or 2) C1-C4 alkyl groups.
6 alkylene (straight 41), or cyclopentylene or cyclohexylene. Alkylene A is preferably a straight or branched chain alkylene of 2 to 6 carbon atoms. Cycloalkylene It detection,
Preferably cyclobenzene of the formula or H2CCH2\. /2 cyclohexylene. A preferred embodiment is that eight-
(CH2)n- (where n is 2.3 or 4), and a particularly preferred embodiment is A
is (a) optionally substituted Ct-Cs alkyl, C2-CIG alkenyl, C2
~CIO alkynyl, C3~CI! cycloalkyl, C
3-C6 cycloalkyl-C1-C6 alkyl, phenyl, phenyl-c, -C, alkyl, phenyl-C2
~Cs alkenyl, phenyl-02~C6 furkynyl,
heteroaryl, heteroallalkyl (wherein the alkyl portion has 1 to 6 carbon atoms), heterocyclyl or heterocyclylalkyl (wherein the alkyl portion has 1 to 6 carbon atoms)
divalent phenylene or C! having ~6 carbon atoms) or combined with the ring to form a polycyclic group, such as a quinuclidine group! ~C4 alkylene group] is linked to an N-substituted quaternized non-aromatic heterocyclic ring. .

Hegeloaryl (or the heteroaryl portion of heteroallalkyl) is 1-4 0. may be a mono-, bi- or polycyclic aromatic heterocyclic group having N or S atoms;
Preferred are 5 or 6 such as chenyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazolyl, inxazolyl, tetrazolyl, oxasilyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl and pyrazolyl.
It is a member heterocyclic ring. Heterocyclyl (or the heterocyclyl part of heterocyclylalkyl) is a mono-, bi- or polycyclic saturated or unsaturated non-aromatic heterocyclic group having 1 to 4 0, N or S atoms; preferred is morpholinyl, piperazinyl. , piperidyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyrrolinyl or pyrrolidinyl.

When the R5 substituent is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylalkenyl, phenylalkynyl, heteroaryl, heteroalkyl, heterocyclyl or heterocyclylalkyl group, These groups optionally include (a) Cs-Cs alkyl (optionally, preferably 1
substituted by ~5 amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl groups);
(b) Fluoro, chloro or habromo; (c) -0
R3; (d) -0C02R3; (e) -0COR3; C) -0SO2R"; ()1) -oxo; (i) -NR3R'; ) -NR3CONR3R'; (Q -NR
3SO2R'; (n) -8R": (0) -8OR'; ([)) -8O,R'; (b) -8O3R3: (r) -CO2R3; (S) -CONR3R4; (li -CN; or (b)phenyl (optionally fluoro, chloro, bromo, C
1-C6 alkyl, -0R3, -NR"R', -S o
s R3, -Co2R3 or -CONR3R4 (with respect to the above R5 substituents, groups R3 and R4 are hydrogen;
Alkyl, alkenyl and alkynyl (having 1 to 10 carbon atoms); cycloalkyl, cycloalkynogelkyl and alkylcycloalkyl (having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety) phenyl; earalkyl, earalkenyl and hyalalkynyl (with the exception that the outer portion is phenyl and the aliphatic portion has 1 to 6 carbon atoms)
; and Hiniheteroaryl, heteroallalkyl, heterocyclyl and heterocyclylalkyl (however, the heteroaryl and heterocyclyl group or part of the group is Bli
as defined above and the alkyl moiety associated with the heterocyclic moiety has 1 to 6 carbon atoms; or R3 and R4 are independently selected from tR9, which together with the linking nitrogen may form a 5- or 6-membered nitrogen-containing heterocyclic ring (as defined above for R5), is as defined above for R3, except that it must not be hydrogen. That's right. The most preferred all substitutions are 1-C6 alkyl, especially methyl.

When R5 is a divalent phenylene or c, -Ca alkylene group, these groups are bonded to one other atom of to form a bridged polycyclic ring, such as a quaternized quiscridine R4 of the formula.

The unsubstituted elements of formula 1 are linked to the unsubstituted A through the ring nitrogen atom, thereby forming a quaternary ammonium group; represents a mono-, bi- or polycyclic nitrogen-containing heterocyclic residue (which may be fused). The heterocyclic residue may be saturated or 6-saturated (having 1-2 double bonds) and may contain up to 2 other heteroatoms in addition to the quaternary nitrogen. The other heteroatoms may include 0, S(0)m,
N1NRlO or NRI5R'' (where m is 0.1 or 2 and RIG is hydrogen, optionally substituted C
m -c, alkyl or optionally substituted phenyl, and R15 and R16 are each independently optionally substituted C, -C6 alkyl or optionally substituted phenyl.

is 0 to 202 double bonds and bonds, 5(0), n, N1NR
10 or NR15RIB (where m is 0.1 or 2, RIO is hydrogen, C, -C, alkyl (optionally 10R3, -NR3R', -CO2R3, oxo, phenyl, fluoro, chloro, bromo, -8O3R3 and -C
ONR3R') or phenyl (optionally C,
-c6 alkyl, -0R3, -NR3R', fluoro, chloro, bromo, -8O3R3, -CO2R2 and -CO
and RI5 and R16 are each independently C1-C6 alkyl (optionally -OR'', -
N R3R', -C02R'', oxo, phenyl, fluoro, chloro, bromo, -8O3R and -CONR3R
') or phenyl (optionally substituted with 1 to 2 non-substitutes independently selected from cl-C, alkyl, -0R3, -NR3R', fluoro, chloro, bromo, -8O3R3, -CO2R) ” and -CONR3R', with the proviso that the heterocyclic N RlG and N R15R16 groups are as defined for the R5 substituent. non-aromatic 4- to 7-membered (preferably 5 or 6) containing O~2 other heteroatoms selected from
(membered ring) represents an N-containing heterocyclic ring. In the above preferred embodiments, upstream is optionally (a) Cs-C6 alkyl (optionally fluoro, chloro, bromo, -0R3, -0COR3, -0CONR3)
R', oxo, -NR3R', -NR3COR',
-NR3CONR3R', -NR3SO2R', -8R
” , -8O3R3, -C02R3 and -CONR3R
(b) C2-C6 alkenyl (K stands for Kct fluoro,
Chloro, bromo, -0R3, -0COR3, -0CON
R3R', oxo, -Ntζ3R', -NR3CON
R3R', -NR3SO2R', -S R3, -8O3
R3, -CO2R3 and -CONR3R';
(C) C2-C6 alkynyl (optionally fluoro, chloro, bromo, -〇R3, -c o R3, -0CON
R3R', oxo, -N R3R', -Na3coR'
, -Na3coR3R', -NR3S02R', -8
R3, -8OsR3, -CO2R3 and -CON R3
(d) C3-C6 cycloalkyl (optionally fluoro, chloro, bromo, -0R3, -0COIζ3.-0C
ONR3R', oxo, -N R3R', -NR3C
OR', -NR3CONR3R', -NR3SO,R
' , -8R3, -8O3R", -comR" and -C
(e) cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl moiety; (optionally fluoro, chloro, bromo, -OR3
, -0COR3, -0CONR3R', oxo, -NR
3R4, -NR3COR', -NR3CONR3R',
-NFL3SO2R4, -8R", -8O3R", -
C02R'' and -〇〇NR3R'); (f)
Heteroaryl selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms (optionally fluoro,
rioo, pu0mo, -OR3, -0COR3, -0CON
R"R', oxo, -NR"R', -NR"C0R
4, -NR3CONR"R', -NR'5O2R',
-8R", -803R", -COIR" and -CONR
3R'); Preferred heteroaryl residues are 5- or 6-membered aromatic heterocycles; (b) 1-2 heteroatoms are substituted by heteroalkyl selected from the group consisting of 4 oxygen, nitrogen or sulfur atoms, in which the alkyl moiety has 1 to 6 carbon atoms (optionally fluoro, chloro, 7"Clmo, -OR', -0COR") , -〇C
0NR3R', oxo, -NR3R', -NR3CO
R', -NR3CONR3R', -NR3C02
B', -8R3, -8O3R3, -C02R3 and -C
ONR3R'); Preferred heteroaralkyls are those in which the heteroaryl residue is a 5- or 6-membered aromatic heterocyclic ring and the alkyl moiety is ~2 carbon atoms; Φ) heterocyclyls in which the heteroatoms are selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms (optionally fluoro, nitrogen, promo, -0R3, -0COR", -0
CONR'R', oxo, -NR''R', -NR
3COR', -NR"C0NR3R', -NR"5O
2R', -8R", -803R', -CO2R3 and -CON R384. Preferred heterocyclyls are 5- or 6-membered saturated or unsaturated rings (i) heteroalkyl (optionally fluoro, chloro, Bromo, -0R3, -0COR3, -oco
NRsa', oxo, -NR"R', -NR"COR
', -NR" CON R"R',-NR"5O
zR4, -S R3, -5OsR', -COzR"
1~ independently selected from and U-C0NR"R'
0) fluoro, chloro or bromo; (k) -OR''; (1) -0CO,R3; ■ -ocoa3; (n) -0CONR3R'; (0) -0S (h R": dispute)oxo; (q) -NR3R': (r) R"C0NR' -: ( s) -NR3C02B'; (t) -NR3CON[1L3R': (u) -
NR'5O1R'; (V) -8R8: (b) -1-Rg: (y) -S 031R3; (z) -C02R3; (aa) -CONR3R'; (1) b) -CN; or (cc ) Phenyl (1 to 3 fluoro in 19Lt,
Chlo a, 7” lomo, C1=C5 alkyl, -0R3,-
NR"R', -803R3, -CO, R3 or -CO
NR3R') The R3, R4 and R9 substitutions G and R1 are as defined above.

The ring defined in -H is a non-aromatic heterocyclic group. However, this ring G1, other rings preferably include a C4 to C7 carbocyclic ring, a phenyl ring, a 4 to 7 membered heterocyclic ring (saturated or unsaturated) (0,5(0)rr, , N,
with 1 to 3 heteroatoms selected from NRIo or NRI5RI6) or a 5- or 6-membered heteroaromatic ring (0,
S(0) having 1 to 3 heteroatoms selected from m, N, NRI' or NR15Ra6) (with the proviso that m,
R", R15 and R16 are as defined above. The fused carbocycle, phenyl, heterocycle or heteroaromatic ring can be c, -Coalkyl, -0R3, -NR
3IiL', fluoro, chloro, bromo, -S o, F
L3, -CO2R'' and -CONR''R' may be optionally substituted by 1 to 3 moieties independently selected from L3, -C02R'' and -CONR''R'.

- Among the preferred embodiments mentioned above, preferred compounds are A
(wherein n is 2.5 or 4), most preferably represents H3 or R8 is hydrogen, and R'75E hydrogen, CH3CH2-. Particularly preferred are compounds in which Ra is hydrogen;
It is a compound having 8R.

A particularly preferred embodiment of the invention is a formula of (n is 2.6 or 4), most preferably A is -CR2CR2-, and (a) R' and R8 taken together are C) R3 or (b) C8 is hydrogen, a' is hydrogen,
There is CHs CR2-1. Particularly preferred is Ll, where R8 is hydrogen and R1 is ? Compounds which are H H3CH-, especially compounds having the absolute configuration 5R16S, 8R.

Among these preferred compounds, preferred compounds are those in which A is -(CH2). - (wherein n is 2.3 or 4), more preferably A is CR3, and (a) R' and R8 together represent, or (b) R8 is hydrogen. , R1 force; hydrogen, CH3CH
It is 2-1. Particularly preferred is when R8 is hydrogen and R
1 is a compound having.

(However, Y is hydrogen, C1-C6 alkyl, hydroxy,
-5-C! ~C6 alkyl, carboxyl, carbamoyl, chloro, bromo, iodo, fluoro or phenyl). Within this preferred subclass, preferred compounds are those in which A is -(CHz)n-, where n is 2.3 or 4, most preferably A is -CH2CH2-, and ( a) R' and R8 taken together represent R3 or (I)) compounds in which R8 is hydrogen and R1 is hydrogen, CR3CR2-1♀H CH3CH-, in particular the absolute configuration 5R16S,
It is a compound having BR.

The most preferred embodiment of the invention consists of compounds of formula I. Among this preferred group of compounds, preferred compounds are those in which A is -(CH2)n-', where n is 2.3 or 4; most preferably, A is -
CH2CH2-, and (a) jt' and R8 taken together represent 0CH2\C=Hs, or (b) R' is hydrogen and R1 is hydrogen, CH3CH2-1H CH3CH-, particularly Distribution @: sR, 6B
, 8R.

The most preferred embodiment of the present invention is a compound of the formula: a charged or conventionally removable carboxyl protecting group (provided that when R2 is hydrogen or a holding group, a reverse ion is also present) , as well as its acid addition salts which can be used as pharmaceuticals.

It is recognized that some products within Formula 1 may be produced as optical isomers as well as epimeric mixtures.

The present invention includes within its scope all of the aforementioned optical isomers and epimeric mixtures. For example, when the 6-substituent is hydroxyethyl, this substitution R
or S configuration, and the resulting isomers and epimer mixtures thereof are included in the present invention.

Carbapenem derivatives of the general formula 1 are prepared from starting materials of the formula (1) where R' and R' are defined above, and R' represents a conventional readily removable carboxyl protecting group. Compound (1) can be prepared, for example, by the general method disclosed and described in European Patent Application No. 38.869 (Compound 7).

One method for preparing compound I from the starting material (1) can be summarized by the following reaction scheme: Elaborating the above method, starting material (1m) is converted into methylene chloride, acetonitrile or dimethyl Intermediate (1) is obtained by reacting F in an inert organic solvent such as formamide with a base such as diisopropyletheramine, triethylamine, 4-dimethylaminopyridine, etc., with approximately equimolar amounts of 1-wave diphenyl chlorophosphorus.

This acylation leaving an oxy leaving group in the 2-position of the intermediate ① is advantageously carried out at about -2o0→40'
C, most preferably about D'C.

Intermediate (1) can be isolated if desired, but can conveniently be used in the next step without isolation or purification. -IJ intermediate (■) is then converted to intermediate (2) by a conventional substitution reaction. Thus, intermediate (1) contains approximately equimolar amounts of the formula % (wherein is cyclopencarene, cyclohexylene or C1-C11 optionally substituted by one or more 01-C4 alkyl groups). (representing alkylene) in the presence of a base such as diisopropylethylamine, triethylamine, sodium bicarbonate, potassium carbonate or dimethylaminopyridine in an inert organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile. let The temperature of this displacement reservoir is not critical, but an advantageous temperature 1
The f range is about -40°C to 25°C. Most conveniently, this reaction is carried out under cooling, for example at about 0°C.

Intermediate V is then acylated with methanesulfonyl chloride or its functional acylating equivalent such as methanesulfonic anhydride in the presence of a base in an inert organic solvent to form the methanesulfonyl intermediate Obtain the roxy leaving group. The acylation can be carried out using diisopropylethylamine, triethylamine,
It is carried out in the presence of a suitable base such as 4-dimethylaminopyridine and the like. This reaction can be carried out over a wide temperature range, e.g.
Although it can be carried out over a temperature of 40°C to +40°C,
Most advantageously chilled, e.g. from about -60'C to -40°C.
Kg.

Intermediate (1) is then subjected to reaction reaction 1.6 to obtain intermediate (2) A-iodo leaving group. This particular group has been found to greatly facilitate the construction of the final carbapenem product of formula II.

Displacement of the methanesulfonyloxy leaving group is carried out by reacting intermediate 1 with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Compounds which ionize to give iodide ions in the solvent used can be used, for example alkali metal iodides such as NaI or KI. Although warm IW for this substitution is not critical, temperatures at or above room temperature are most advantageous to drive the reaction to completion in a reasonable time. The iodide ion source is an intermediate ■
An amount is used that provides approximately an equivalent or excess of iodide ions.

Preparation of the desired carbapenem derivative of II is carried out by nucleophilic displacement of the iodo leaving group of the intermediate with the desired nitrogen-containing heterocyclic nucleophile. Intermediate (1) is reacted with at least an equivalent amount, preferably an excess, of the desired amine reagent in the presence of -ion F in an inert organic solvent.

Suitable inert organic solvents include, for example, tetrahydrofuran, diochitin, methylene chloride, diglyme, dimethoxyethane, and the like. A salt compound, such as Ag01, which substantially ionizes in this solvent to give silver ions and inert ions.
0. can be used as a silver ion source. Generally, it is preferred to use approximately equivalent amounts (1 to intermediate II) of sickle ion to facilitate substitution. This reaction can be carried out over a wide temperature range, for example from about -250°C to about +25°C, but is most preferably carried out at around 0°C. Intermediate 1' has an associated counter ion (e.g. derived from the silver salt used)
, which can be replaced at this stage with another counterion, such as one capable of pharmaceutical use, in a conventional manner. Alternatively, this counterion can then be removed during a deblocking step.

The deblocking step to remove the carboxyl protecting group of intermediate I' is carried out by conventional operations such as solvolysis, chemical reduction or bulk addition of water. p-nitrobenzyl, benzyl, which can be removed by catalytic hydrogenation
When a protecting group such as benzhydryl or 2-caftylmethyl is used, dioxane-water-ethanol, tetrahydro7-diether ether buffer, tetrahydro7-water, potassium hydrogen phosphate-impropanol 1 to 4 of the intermediate ■' in a suitable solvent such as
The treatment can be carried out in the presence of a hydrogenation catalyst such as palladium on charcoal, palladium hydroxide, platinum oxide, etc. at a hydrogen pressure of 0 to 50°C for 0 to 4 hours.

Photolysis can also be used for deblocking when R is a group such as 0-nitrobenzyl. 2.2.2
-) Protecting groups such as dichloroether can be removed by mild zinc reduction. Allyl protecting groups can be removed by a catalyst such as a mixture of a palladium compound and triphenyl phosphine in an aprotic solvent such as tetrahydrofuran, diethyl ether or mebrene chloride. Similarly, other Conventional carboxyl protecting groups can be removed by methods known to those skilled in the art.Most importantly, when Compounds of formula 1', which are physiologically hydrolyzable esters, are hydrolyzed in vivo under physiological conditions and can therefore be administered directly to fd without deblocking.

The preparation of some compounds of general formula (1) may involve one additional reaction step immediately before or after the deblocking reaction.

Thus, for example, when the desired heterocyclic ring contains a sulfoxide group, the corresponding compound having a sulfur-containing heterocyclic ring is first prepared by the above method, and then this compound is subjected to carboxyl deblocking. The former can then be subjected to oxidation to produce the corresponding sulfoxide end product.

Although the above-described method is suitable for preparing the compounds of the present invention, the inventor's co-worker Vinyl Dequinutrase has shown that the preparatory test A is cyclobentelene, cyclohexylene or We have invented a new process that can be used to prepare compounds of formula 1 where each R is independently the amount of hydrogen C8-C4 alkyl. This process, disclosed and claimed in US Pat.

A, cyclopentelene, cyclohexylene, or C (where R, 几, R and 几 are each independently hydrogen or 01-
An alternative method for preparing compounds of the formula I, where C, alkyl are The intermediate (which is an inexpensive carboxyl protecting group) is reacted with a thiol compound of the formula (where Xe is an inverse ion) under the presence of a base F in an inert solvent. to prepare a carbapenem product of formula 1), if desired, by removing the carboxyl protecting group R2, or to prepare a deblocked compound of formula 1, or its pharmaceutically usable carbapenem product. Consists of obtaining salt.

In this alternative method 3, the carbapenem intermediate 1=EIV can be converted to the formula [where A is cyclopentene, cyclohexylene or
However, R, R, 几 and R are each independently hydrogen or C.
8-C4 alkyl), Xe is 0l-1Br
-1 acid is the opposite ion associated with the quaternary amine thiol of S, as defined above, and anti-L6. This anti-L6 is acetonitrile, acetonitrile-H,0, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran-H
The process is carried out in the presence of a base in an inert bath medium such as 1O2 or acetone. The type of base is not critical. However, diisopropyletheramine, 1.8-i;/azabicyclo[
5,4,0]undec-7-ene, 1,5-diazabicyclo(4,5,0)non-5-ene or triethylamines such as triethylamine, triethylamine or tripropylamine. Best results are obtained when using (01-C1) alkyl amines. The reaction of intermediate (■) with thiol (■) can be carried out over a wide temperature range, e.g. -15°C.
~ room temperature, but preferably about -
It can be carried out at a temperature of 15°C to +15'C, most preferably around 0'C.

The carbapenem product produced by the reaction of the quaternary amine kaol (■) with the intermediate (■) has an associated anion (i.e. (0,1(,O),PO,'',
anion associated with fd-/l/), which is present at this stage and, by routine manipulation, has a different counter ion,
For example, it can be replaced with something that can be used as a medicine. Alternatively, this counterion can be removed during the subsequent deblocking step. If the quaternized carbapenem compound and the inverse ion form an insoluble product, the product can be crystallized as it forms and concentrated in pure form by filtration.

If the desired carbapeutic compound is not produced according to the reaction steps described above, the carboxyl protecting group of the compound can optionally be removed by the conventional procedure described above with respect to the general synthetic method. can do.

The thiol intermediate of the formula ■ is, for example, the formula ■a 4b )(,”
)t”Vm.

(wherein R, 几 , 几 and R are each independently hydrogen or 01-C, alkyl) is reacted with a heterocyclic amine of the formula (υ as defined above) and a strong acid. It can be manufactured by This reaction can be carried out in the absence or presence of inert organic solvents, such as solvents Id, UfalKId, non-polar organic solvents such as methylene chloride, benzene, xylene, toluene, and the like. When the amine and oxidized vIJ reagent are liquid or when the solid amine is soluble in the liquid sulfide reagent, it is preferred to carry out the reaction without additional solvent.

The strong acid used during this reaction is not particularly critical and may be, for example, a strong hydrochloric or organic acid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc. It's fine.

The formation of the quaternary amine hexol intermediate (1) can be carried out at temperatures ranging from about -20C to about 100'C. Suitable temperatures generally range from about 50 to 70'C.

The sulfide reagent, aromatic amine and acid are preferably used such that approximately equimolar amounts of sulfide and acid are used and an excess of amine, eg 2 to 6 moles of cyamine per mole of sulfide or acid. be.

The quaternary amine hexaol intermediate has an associated counterion, which is determined by the particular acid used. Of course, it is convenient to replace the carbapenem intermediate with a different counterion at this point by conventional procedures for use in the subsequent reaction with the carbapenem intermediate.

If the different JJ4 ring nucleophile linked to R1 and/or Rs moiety or moiety A has a functional group that may interfere with the desired reaction process, this The group can be protected with a conventional blocking group and then deblocked to regenerate the desired functional group. Persistent blocking groups and procedures for introducing and removing such groups are well known to those skilled in the art.

In the case of some compounds of formula I with a cycloalkylene or branched alkylene A moiety, one or more additional asymmetric carbons are created, which may give rise to diastereoisomers. be. The present invention encompasses mixtures of the aforementioned isomers as well as individual purified diastereoA1 organisms.

As in the case of the β-lactam antibiotic VJ of 110, compounds of general formula I can be converted by known procedures into pharmaceutically usable salts, which for the purposes of the present invention are non-containing. Substantially equivalent to salt compounds. Thus, for example, a compound of 2 in which R' is anionically charged can be dissolved in a suitable inert solvent and then used as an equivalent drug.
T-capable acids can be added.

The desired acid addition salt can be prepared by application procedures such as solvent precipitation,
It can be recovered by freeze-drying or the like. If other basic or acidic functional groups are present in the compound of formula 1, pharmaceutically usable base salts or acid addition salts can be similarly prepared by known methods.

Compounds of formula 1 in which R is hydrogen or anionically charged, or salts of 7 capable of being used as pharmaceuticals, can be converted by conventional procedures into the corresponding compounds in which R3 is a physiologically hydrolyzable ester group. Alternatively, compounds of formula I in which IL'' is a conventional carboxyl pupil group may be substituted with a corresponding compound in which R1 is hydrogen, anionically charged or a physiologically hydrolyzed p/4=r-H ester group. or a pharmaceutically usable salt thereof.

Is R hydrogen or an anion charge? The novel carbapenem derivatives of general formula I, which are 4 or physiologically hydrolyzable ester groups, or their salts capable of being used as pharmaceuticals, are potent compounds active against a variety of Durham-positive and Gram-negative bacteria. As antibiotics, they are used, for example, as growth-promoting animal feed additives, food preservatives, for industrial purposes, e.g. in water-based paints to inhibit the growth of harmful bacteria and in the white liquor of paper mills. It can be used as a sterilizer to destroy or inhibit the growth of harmful bacteria on medical or dental equipment. However, they are particularly useful in the treatment of infections in humans and other organisms caused by Durham-positive or Durham-negative bacteria.

The pharmaceutically active compounds of the invention may be used alone or in addition to the active carbapenem component for pharmaceutical use.
It can be formulated as a pharmaceutical composition with a suitable carrier or diluent.

These compounds can be administered by a variety of means;
Those of primary interest include transdermal, topical or parenteral (intravenous or intramuscular). The pharmaceutical composition includes capsules,
It may be in solid form, such as tablets, powders, etc., or in liquid form, such as solutions, suspensions, and emulsions. Injectable formulations can be prepared in either a favorable or unfavorable delivery route, in an angular or multi-dose medium unit form, and contain prescriptive agents such as suspending, stabilizing and dispersing agents. It's okay to stay. These compositions may be in the form of ready-to-use cedars or powders for reconstitution at the time of application with a suitable solvent such as sterile water.

The dosage will depend to a large extent on the particular compound employed, the particular composition formulated, the route of administration, the condition and the particular site and fungus being treated. Selection of a particular suitable dose and route of application is then undertaken at the discretion of the practitioner. However, in general, these compounds can be administered non-mineral or oral to the mammal in an amount of about 5 to 200 g/97H.

To illustrate the potent broad-spectrum antibacterial activity (both in vitro and in vitro) of the carbapenems of the present invention and the low S content of these compounds, biological data regarding the presently preferred carbapenem compounds of the present invention are presented. is shown below.

In vitro activity -11 carbapenem compounds have molar activity against the indicated microorganisms as determined by making them into aqueous solutions and incubating overnight at 37°C after dilution with nutrient broth. c Next minimum LIZ$1f (M
IO). N-formidoylbu-
Enamycin is included as a comparison compound (of course).

The in vitro therapeutic effects of the compounds of series 1 and N-formidolekaenamycin (after intramuscular administration to macus infected with the cylindrical fungus) are shown in the following table. PJ), o (5 of infected mice)
9 units of mW/dose to protect 0%).

Preventive effect during intramuscular administration of infected mice *Material data Treatment schedule: Infect mice and 2 #
The toxicity of the compound of formula I was determined (dk for intracephalic administration) using 5 mice per dose for each test;
Shown in the table below.

*LD Compound of Example 1 with no clinical signs of toxicity >10 >10* 25/
The urinary collection of the compound proboscis of the average IJi of mouse/compound was administered intramuscularly to mice (
20"19/9) After that, I will show it to the next friend.

Recovery dose percent post-administration time column 1 compound man 18.8 0.6 0.1
195±3.2 compounds are 0.1M phosphorus tea of pi(7)
Stabilized in buffer solution.

Spit is from one test; compound (of course 4 makus).

A sample of the carbapenem compound (identified by column number) shown in the test sample was made into an aqueous solution and diluted with nutrient broth, and then kept at 37°C by tube dilution overnight to determine the presence of the indicated bacteria. Minimum inhibition fsIf of mcg/lnt rate for (
MIO). N-formidoylteenamycin served as a comparison compound.

S, Pneumoniae A-9585S, Pyogenes A-9604S, Faecalis
A20<588S, Aureus A-95
! 17I -50% serum A-9537S, Auretus A-9606 (penicillin resistance) E, Coli A15119E, Coli A20341-IK, Pneumoniae A2046BE, Croace
A-9659E, Croace A-965t
5P, Mirapiris A-9900P, Vulgaris A21559M1 Morganii
A15153P, Rettgeri A22
424S, 7 Lucescence A20019P,
A. aeruginosa A-9843aP, A. aeruginona A21213* N-Formidoylthemycin compound (column number) 0, 05 0.0020.03
0.0020, 5
0.50.03
0.0040.13
0.0160.05 0
．． 00B0.03 0.01
60.03 0.030.1
3 0.060.25
0.13 0.25 0.060.5
0,060.13
0.060.03
0.030.13
0,150.5
0.130.015 0.
0! +63 1 8 025 1 fiyo LS
, Newmonier A-95850,0048,
Pyogenes A-96040,0048, Faecalis A20688 2S, Olewas A-95370,031-50%
Serum A-95370,068, Aureus
A-9606o, o6 (penicillin resistance) E, Kohli A15119
0.13E, Kohli A20341
-1 On 0.13, New Monier A-9
6640, 25K, New Monier A2046
8 Q, 5E, Croace A-
96591E, Croace A-96562
P, Mirabilis A-99000,2SP, Vulgaris A21559 0.25
M1 Morgany A15153
iP, Rettgeri A22424
1S, Ma, Lucescens A20019
0.25P, Aeruginosa A-9b4
3a 16P, Aeruginosa A212
13 1* N-formidoylteenamycin MIO (μ9/-) 0.0.04 0.00.4
0.0010.008 0.004
0.00110.05 0
．． 25 0.03' 0.01 6
0. O[]20, (360,030,004 0,060,030,004 0,130,030,016 0,130,050,016 0,250,060,03 0,50,130,06 0,50, 130,0(S O,250,130,06 0,250,130,03 0,250,060,016 0,50,130,06 10,250,13 o,25 0,060,0363
32 132
16 0.13 In vivo activity The in vivo healing effects of some compounds of the present invention and N-formidoylchenamycin (MKO787) were lowered (after intramuscular administration to mice experimentally infected with various bacteria). Shown below. PD, · (rr! dose in w/Kp required to protect 50% of A-stained mice) is shown.

Example 2 4.7 33 [172Example 4 2.7 - 16MKO787
1α4 0.0710° bacteria (A9606)
, or 2 x 10” A9843A and A204
For compounds 4 and 5, mice were infected ip with 81 ~9X10' bacteria (A9606) or ~8X10
' (A9843). Mice are infected with 0
and treated im with drugs at 2 hours.

Blood Concentrations and Urinary Recovery The blood concentrations and half-lives of several compounds of the invention (after 20 to 9 intramuscular administration in mice) are shown below. Urinary recovery in mice is also shown.

Pharmacokinetic Parameters in Mice After Intramuscular Administration of 201v/9 in Blood Urine compounds were stabilized in 0.1 Mm acid buffer at pH 7.

Values based on a single test; 4 mice per compound.

Mine: T1/2d, half-life in minutes.

Next season's AUG refers to the area under the one-hour blood concentration curve.

Recovery based on 110-6 hour harvest.

Example 1 p-nitrobenzyl 6a-(1
-(R)-hydroxyethyl)-47-thioxo 1-
A solution of 169 g (4.85 mmol) of azabicyclo(x2.o)hept-2-ene-2-carboxylate (1) was cooled to 0 DEG C. in a stream of nitrogen. A solution of 726~(7,18 mmol) of diisopropylethylamine in 2~ acetonitrile is added, followed by 1.51 p (5,6 mmol) of diisopropylethylamine in 12 ml of acetonitrile.
0 mmol was added dropwise over 3 minutes. The resulting solution was stirred for 20 min at - to give p-nitrobenzyl 5-
(diphenylphosphoryloxy)-6α-(1-(R)
-Hydroxyethyl]-7-oxo-1-azabicyclo(&2.0)heft-2-ene-2-carboxylate was obtained. To this solution was added a solution of 726 μm (7.18 mmol) of diisopropylethylamine in 2-acetonitrile, followed by a solution of 4399 μm (5.65 mmol) of 2-mercaptoethanol in 2-acetonitrile. The reaction solution was stirred for 3 hours at 0°C, then diluted with 200 ml of ethyl acetate, 200 td of water, and 20% aqueous H,P.
Washed with O4 as well as Prine. Dried (Mg80
4) The solution was evaporated to give a semi-solid which was triturated with methylene chloride and filtered through p-filtration to give a yield of the title compound 2121 (61%) as a white amorphous solid.

NMR (DM80-d6) δ: 1.20 (3H, d, J
Seven & OHsu, 2.9-5.2 (9H, m), 5
．． 22 (IH, d, J-8, 5H and &23 (
2N, d, J=8.5Hz) Hir(KBr)γmax
:3500,1770 and 17 [) Calculated value as OCII S analysis Cxs Hso Nx Ot 8:
c, 52.93:H, 4,94:N, 6.86
: 8, 7.85° Experimental value: C, 52, 83: H, 4,
90:N, 6.42:8,1131°3 14. in tetrahydrofuran 200- 13.9 (113 mmol) of methanesulfonyl chloride were added to a solution of 1 (10.3 mmol) at -40° C. and then 1.26.9 (12
, 4 mmol) was added dropwise. The reaction mixture was placed in a nitrogen stream.
Stir for 2 hours at 30°C, then add ethyl acetate (700
td) and 5% aqueous phosphorus #(1000-). The organic layer was washed with prine, dried over MgS04, filtered, concentrated to give a syrup, and purified by silica gel chromatography [methylene chloride-ethyl acetate (
3:1 v/ml] to give the title compound 155.9 (75% yield) as a white amorphous solid.

NMR (CDCIm) δ: 125 (
3H,d, J-6,0Hz).

&05 (5H,s), 3.06-5.40 (5H
, m), 4.05-4.40 (4H, m), 5.25
(1H, d, J=14.0Hri.

5.50 (IH, d, J-14, 0H, 7.70
(2H, d.

J = 8.5 Hz) and 8.25 (2H,d
, J-8,5Hz):Ir(KBr)rmax:3
400, 1770 and 16001 O Analysis C19H! Calculated value as Goose Nl 09 S-: C
, 46, 90', H.

4.56: N, 'p, 76° Experimental value: C, 46, 52;
H, 4,32; N, 5.91° acetone 20 - intermediate 3350~ (0,72 mmol) and sodium iodide 216WI9 (14 mmol)
The solution was heated under reflux for 4 hours and the acetone was evaporated to give a white amorphous solid, which was mixed with ether (1otR1)-water (
101Rt).

The white solid was filtered and dried under vacuum to obtain 3 ooW kg (yield: 8α%) of the title compound 4 as a white amorphous solid.

NMR (DM80-d 6) δ: t1B (3H, d,
J=6.0Hz), 120-3.60 (7H, m),
5.80-4.25 (2H, m), 5.10 (IH,
d, J=5.5Hz), 5.25(IH, d, J-1
2,0Hz), 5.45 (IH, d, J=12.0H
z), 7.70 (2H, d, J=8.5H, and 8.27 (2H, d, J=8.5Hz); i r
(KBr) rmax: 5500, 1768 and 170
0cm-'; analysis cts Hte N! os I
Calculated value as: C, 4171: H, 5, 70: N, 5
．． 41: I, 24.4B. Experimental value 20.

42.10:H, 3,75:N, 5.97:I, 25.
200 P-nitrobenzyl 3-(2-iodoethylthio)-6α-C1-CR in dry tetrahydrofuran 60d
)-hydroxyethyl]-7-oxo-1-azabicyclo(3,2,0)hept-2-ene-2-carboxylate) (728119: l mmol) under cooling (5
°C) N-methylpyrrolidine (301 da; &5 mmol)
, followed by tetrahydro7lane 5-dropped silver chlorate (560
Wv, 2.8° C. remol) was added. The reaction mixture was heated to 5°C.
The mixture was stirred for 60 minutes. The solvent is then evaporated under vacuum to form a yellow gum-like compound! I got it. This gum was digested with Celite 2I to obtain an amorphous solid. IR(K
Br) rmax: 3400, 1775, 1700 and 1
100cm.

Without further purification, 50 m of nitrogen diethyl ether and 100 m of tetrahydrofuran were hydrogenated as follows.
1 water 125 - medium potassium carbonate (
&2 mmol) and dibasic potassium phosphate (
280q: 1.6 mmol) was added, and then 1
111 0% palladium on charcoal was added and the mixture was hydrogenated for 60 minutes at 40 ps+ on a Pal shaker. The mixture was then filtered and the catalyst was washed with water (2 x 10 liters). Combine the p solution and washing solution and add diethyl ether (2x2
oo-) and then freeze-dried to obtain a brown powder. This crude product was transferred to a CIS Pondapak reverse phase column (8,9
) (Waters Associates) Qps
Eluted with water under pressure of i. Each fraction (2(ld
) was screened by high pressure liquid chromatography and the fractions with ultraviolet absorption λmJLX 500 mm were collected and lyophilized to give the title compound 6 as a white solid.
5 (14% yield based on compound appearance).

NMR (DsO) δ 2 123 (3H, d
, J=6.0Hz).

2.1-2.4 (4H, m), 5.10 (3H,
s), lj~5.4 (12H, m), 3.95-4.3
0 (2H, m): IRUVλmax (CHs C
HlOH) 297 nm (B=7S877).

Example 2 Boxylate To precooled (water bath) N-methylthiomorpholine 0 (5,00 g, 42.7 mmol) was added methanesulfonic acid (147 m, 20.5 mmol) and ethylene sulfide (130 m, 214 mmol). The mixture was stirred at 65°C for 24 hours and diluted with water (25m). The aqueous solution was washed with diethyl ether (3 x 25m), pumped under vacuum and poured onto a silica gel reverse phase column; the title compound was dissolved in water. Thiols (4,80,9,
A yield of 86%) was obtained.

ir (film) ν: 2550cIR (w, S
R):ax Heavy Hmr (DMSOds) δ: 3.2
5-2.95 (SH, m#CH*N”),
3.32 (3H,8,CH,N">, 52a-2
, 6s (7H, m, CH, S, 8H) and 2.52 P
I)m (3H#”tCHs 803).

Na J, M, Lane and J, Wagner-1 TetrBh.
edron.

26.4227 (1970) B, para-nitrobenzyl 3-(2-(N-methyl-thiomorphonium diphenylphosphate)ethylthio)
-6α-(1'-(R)-hydroxyethyl]-7
-oxo-1-azabicyclo(3,2,0)hept-2
-ene-2-carboxylate 1■C 4) B t N (-ri)! I CHs CN (8m) paranitrobenzyl 6 a
++ (1F -(R)-hydroxyethyl) -
5,7-thioxo 1-azabicyclo[3,2,0]butane-2-carboxylate (557111fl, 1
．． A cold (water bath) solution of diisopropylethylamide 7 (0,536 m, 192 mmol) and diphenylchlorophosphate (0,400 ml, 1.60 mmol) was added.
One boat at a time was treated with 92 mmol) and stirred for 30 minutes.

The reaction mixture was purified with N-methyl-N in CHsCN (4m).
-(2-mercaptoethyl)thiomorpholinium methanesulfone) (8931n?, 2.29 mmol) and diisopropylethylamine (α356m1°192
mmol) and stirred for 30 minutes. The solution was washed with water (20g) and poured onto a silica gel reverse phase column. The desired compound was eluted with 50% acetonitrile-water. Appropriate fractions were combined, pumped under vacuum for 2 hours, and lyophilized to give the title compound (toll, 85% yield).

Mi [ (nujol) ν : 1760 (s, β-lactam) a x da) δ: 8.25 (2H, d, J = 8.8 Hz, H
- aromatic), 7.70 (2H, d, J=8.8Hz,
H-aromatic), 7.33-6.84 (10H,m,H
- aromatic), 5.37 (center of 2H, ABq, J=1
4.2Hz, CH*)y5.14 (IH, d, J=4
．． 5Hz, OH), 4.35-3.80 (2H, m
, H-1' and H-5), 175-3.45 (6H,
m, CHxN)y3.51 (3H,!!,C
HBN), 3.45-2.75 (9H.

”p CHz8 p H-6 and H-4) and 115
ppm (AH.

d, J=6.2Hz, CH3).

Q, I M pH 7,4 phosphate buffer (48,8d
), 2-nitrobenzyl 5-(2-(N-
Methylthiomorpholinium diphenyl phosphate) ethylthio]-6α-(1'-(R)-hydroxyethyl)-7-oxo-1-azabicyclo[&2.0]hept-2-ene-carboxylate (t31.9゜1 10% Pd/c (ts#
) was hydrogenated for 1 hour at 40 ps+. The reaction mixture was diluted with diethyl ether (40m/), the phases were separated and the organic phase was washed with water (2XS-). Combine the aqueous phase with LA
P-per-1 diethyl ether (
2×20 m) and pumped under vacuum. The aqueous solution was poured onto a silica gel reverse phase column, the desired carbapenem was eluted with 5% acetonitrile-water and the appropriate fractions were combined and lyophilized to yield the title compound (205"&t31%) as an amorphous solid. .

ir (nujol) ν: 1750 (s, β-lactam B z C=O and hj 590 crs-1 (s, C-0)
: ”Hmr (D 0) δ: 4.25-3.9
5 (2H, m#H-1', H-5), 5.70-3
．． 40 (5H, m, HzN), 3.35
(1H, dd.

No&jHz, Jx2.6Hz, H-6), 10B
(3H,s.

CHsN), &25-2.75 (8H, CH!8
．． H-4).

and t24ppm (5H, d, J=6.4H2, CH
s'):UV (Hs Ot CO,062)λ
:299 (11Q, 962)ll TI/2 17.7 hours (0.1M pH7m acid buffer y
57℃).

Example 3 1 in N-methylmorpholine (&29m, α060 mol)
Trifluoromethanesulfonic acid (1327
ml.

0.015 mol), then ethylene sulfide (0.89 mol,
0.015 mol) was added. The resulting tan solution was heated at 50-60 C (oil bath) under N2 for 18 hours. The volatiles were then removed in vacuo and the residue was taken up in H,010-. The aqueous solution was washed with diethyl ether (SXS-) and residual organic solvent was removed in vacuo. The resulting aqueous solution was applied to a CtS reverse phase column and eluted with N20, then 5% acetonitrile-H,0, and finally 10% acetonitrile-H,0. Evaporation of the appropriate fractions gave a white solid, which was dried under vacuum (P20S) to give the product (1,
92.9.41%).

! r (KBr) W: 2560 (-8H
) on-' : a x "Hnmr (d6-acetone) δ: t2s-3,
6(m,5H)e149 (s,5H,N-Me),
3.35-2.7 (m, 5l().

P-nitrobenzyl (5R) in phenyl phosphate dry acetonitrile 25-
.

6)-6-((dan)-1-hydroxyethyl)-5,
Diisopropylethylamine (a, 1tp
1d, t 1 mmol), then diphenylchlorophosphate) (0,228+d, 11 mmol) in N!
It was added dropwise at 0°C. After stirring for 1 h at 0 °C, the resulting enol phosphate was treated with diisopropylethylamine (0,226 mm, t s mmol), followed by 1-methyl-1-(2-mercaptoethyl)morpholinium trifluoromethanesulfone). (0,3731
! , 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, then concentrated in vacuo. The residue is H,
0 and applied to a 018 reverse phase column.

H,0, then 20% acetonitrile-H,0, and finally 3
Elution with 0% acetonitrile-H,0 and then lyophilization of the appropriate fractions yielded the product (
0,360Ii.

40%).

ir (film) 33oo (-OH), 177
0 (β-lactam CO), 1700 (-C
(h PNB) cv+-':'II n m r
(d@-acetone) δ: 8.25, 7.8
0 (ABq.

J==8.6Hz, 4H, aromatic), 7.4-
6.8 (m, 10H.

diphenyl phosphate) v 5-56 y 5.
27 (AB Q t l ”14.2Hz, 2H
, Benjirik), 4.42 (d of t, positive' = 2.7H
z, IH, H-5), 4.1-2.7 (m, 17H
), 3.40 (s, 3H, N-Me), 12
2 (d, J=6.2Hz.

3H, -CHMe).

CjlO) 2PO ts acid buffer ([105M pH7:4) 13-p-2) obydyl (May, 6β)-5-(2-(1-methylmorpholino)ethylt)-6-( (dan)-1-hydroxyethyl]-7-oxo-1-azabicyclo(3,2
, o) hept-2-ene-2-carboxylate diphenyl phosphate (α56011°0.49 mmol)
To the solution was added 10% palladium on charcoal, 0.3611 tetrahydro-7, 20% and diethyl ether, 20%.

The mixture was hydrogenated at 32 psi for 1 hour and the mixture was filtered through Celite and the filter pad was washed with hydrogen and diethyl ether. Separate the aqueous phase and adjust the pH to 7 with a phosphate buffer of pH 14.
．． Adjusted to 0.

After removing the residual organic solvent in vacuo, the aqueous solution was applied to a CtS reverse phase column. Elution with H,0 and lyophilization of the appropriate 7-lactone gave an amorphous solid, 0.13011, which was repurified by reverse phase bplcK to give the pure product (0,0
58 g, 34%) was obtained as an amorphous solid.

1r (KBr) ν :3420 (br, OH
).

B x 1750 (β-lactam Co), 1590 (-Co
Goose) Bei 1”Hnmr (D! 0) δ: 4.5
5-2.77 (m, 17H).

5.18 (s, 3H, N-Me), 123 (d
, Positive = 65H2.

5H, CHMe): UV (Hz O) λ:
3oo (g B x 6544) nm: t1/2 (pH 7, 4, 56, 8°C
) 1a5 hours.

Example 4 Preparation of [l]-7-oxo-1-azabicyclo(+,2.0)hept-2-ene-2-carboxylate H Radinium bromide in acetone (4-) in thiol vinegar/! A solution of "I2-bromoethyl" (2°20g, α012 mol) and 1,4-dimethylpiperazine (195m, α014 mol) was heated at 50°C.
The mixture was stirred for 65 hours. After cooling to 25° C., the liquid phase was decanted from the gum and it was triturated twice in dimethyl ether; 42 g (90%) of a hygroscopic yellowish powder was obtained: ir (Nujol) ν :ax -1.

1685 (C=O of thioester) 3, Otori H
mr (Dlo)1 δ: 2.37, 2.39 (2g, 6H, ClmuCO.

Shin B, hay sef, Acta chem, 8c4nd
, l 1゜537-40 (1957) 1-(2-acetylthioethyl)- in 6N hydrochloric acid (4-)
14-dimethylpiperazinium bromide (11 g, 3.7
(mmol) was heated at 80° C. for 1 hour in a nitrogen stream. This solution was concentrated under reduced pressure to give a white powder (1,4
19 (38%) was obtained.

Analysis C@HH, 2% 5BrCI ・Calculated value as H2O: C, 3103:H, 716:N, 905:S, 10
．． 35° Experimental value 20.

3162:I(,7,46:N,?,19:S,10.
19° in acetonitrile (2d) kept in a nitrogen stream (
SR, June) Valanitrobenzyl +5-(1-(R)
Cold (0"C
) solution with diimpropylethylamine (α278d, 1
59 mmol) and diphenylchlorophosphate (1
33m, 159 mmol) to reduce the reaction mixture to 30
4-Dimethyl-1-(2-mercaptoethyl)piperazinium bromide hydrochloride (0,41,t 37 mmol) and diisopropylethylamine (0,278 ml) in a mixture of setonitrile (3-)-water (1-) with a stir bar for min.
, 159 mmol). After stirring for 18 hours at 5° C., cold water (15 ne) was added to the mixture.

The resulting solution was applied to a Gleppakku 500/C (Waters Associates) column (2.5 x 7.5 cm).
Chromatography using eluting solvent at 25-35% in water - after lyophilization yellowish powder α5oII (50%
) was obtained.

ir (KBr)v: 1765 (C=O of β-lactam), ax 1690 (C=O of PNBxxf), 1585 (
yx=4.1512 (Now) #875
(NOx)'N j Breath Hmr (
nMso, ds) δ: 116,118 (2d, J-
61OH), 5.59 (center of ABq, J=15Hz
, PNB's C14,), 6.6-7.4 (m, 10
H, Hoss 7! −) of 7 z = le), 171 (d
, J=8.8H! , 2H, PNB Ho ), 8.2
6 (d, , J=8.8Hz, Hm of PNB
).

'COO'' - in wet tetrahydrofugin (2sy) (5R, 6d)
8 Ranitrobenzyl 3-(2-(1,4-dimethyl-1
-piperazinium)ethylthio)-6-(1-(R)
-Hydroxyethyl]-7-oxo-1-azabicyclo(3,2,0)hept-2-ene-2-, carboxylate diphenyl phosphate (0,4711,0,62
diethyl ether (25v), -
Basic calcium phosphate-caustic soda buffer (13d,
pH 222) and 10% palladium on charcoal (o, 47N) were added and the resulting mixture was hydrogenated at 23° C. under 40 psi for 1 hour. Separate the two layers and add the organic layer to water (2X7
The aqueous layers extracted with After chromatography using water and freeze-drying, a, oq
71 (a3%) was obtained.

1r (KBr) shin1ax:3000-3700 (O
H).

1750 (C=0 of β-lactam), 1585
(carboxylate) OR, “Hm r (DtO
) δ:t24(d, J=6.4Hz, 3H, CH
s CHOH), 2.53 (s, 38°4, 5 (
m e H-5z CI(s CHOH) e U V
(Ho O)λma! :296 (19476), (
a) F36t1° (c o, 26° H2O), t 1/
2-12.4 hours (S# at pH 14 at 56.8 °C
(measured at a concentration of 10 M in buffer).

Example 5 OH in a 1:1 mixture of acetonitrile-water (9-)
68)-3-(2-(N-methyl-thiomorpholinium)ethylthio)-6-(1-(亙)-hydroxyedyl]-7-oxo-1-azabicyclo(3,2,0)hept -2-ene-2-carboxylene) (608q, 1
m-chloroperbenzoic acid (33
4,B■, 165 mmol) was added in small portions over 1 hour. The mixture was then diluted with water (15-) and washed with diethyl ether (3X151 nt).

The aqueous phase was pumped under vacuum and the reverse phase silica gel column (H,
0) to obtain a solid consisting of a mixture of compounds. This mixture was separated by reverse phase H1LC to give 7-lactone A32-4 (yield, 1112 da) and 7-lactone B.
23.6q (yield 6) was obtained as the diastereoisomer of the title compound.

7 RakshiyoyA:ir (Nujoor) v:17
50a x O2β-lactam C=0) and 1585cll+
(@.

C=0): 'Hmr (D!O) δ:5.86
-2.90 (17H.

m, I(-4, H-5, H-6, Il-1', CH,
8, CH, S-0, CH 鵞N), 5.25 (
311,s, C) Is N+) and 124 ppm
(50, d, positive = 6.4 Hz, C1i@)
:UV (Hz O, c O, 05) λm, X: 2.
99 (ε6517); T1/2: 10.75 hours (0,
065M, pH 74 buffer, 37°C).

Example 6 A suspension of 1-(2-acetylthioethyl)-1,4-dimethylpiperazinium bromide (148Ii, 5,0 mmol) in isopropyl alcohol (10m) was added to methyl iodide (0,575d, 6 Treatment with .rJ mmol)1.
．． It was treated at 55-60°C for 30 hours. The solvent was evaporated under reduced pressure: the residue was triturated in hexane, the solid was filtered, the 7'Co 185 go solid was dissolved in hot water (8d), and the solution was diluted with acetone until cloudy (70-80-
). Two successive crystallizations yielded the title compound t5J', "1
ir (KBr
)ν: 1692” (C-0):
'Hmrax (IhO) δ: 2.40 (s, 3H, CH
sC00), 3.37(1,N-CH3),
3.59 (8, N-CH5), 3.99 (s
) : UV (Hz O)λ :226 (!1
3144).

a x analysis C11Iba N! Calculated value as 08Br I: c, 3o, oa:H, 5, 51:N, 6.38
: Experimental value: C, 30, 48: H.

5.53:N, 6.86゜1-(2-acetylthioethyl)-L4.4-)limethylpiperadiium bromide miuride (t84.f, 4.1
9 mmol) and 6N hydrochloric acid (1S-) at 57°C.
The mixture was heated for 2.5 hours in a nitrogen stream. This solution was concentrated to dryness under reduced pressure, the solid was suspended in water (10 g), and the suspension was stirred well until a solution was obtained (palm) f!
After treatment with II-I CI, this solution was applied to a column of Palmchit 8-I CI'' (t 2 x 60c
m) poured on top. The column was eluted with water (15 d/min). Appropriate fractions were combined and lyophilized to produce a white powder, 0.
．． 95g, m9190-191°C, 85% was obtained.

ir (nujol) ν: 2460 (8H)
: ”Hm ra x (D! 0) δ: 3.4 (S, N-CH5), 3.4
5 (1,N-CH3), 4.07 (s).

Analysis ct H Ito Nx5C1, 0.75H! Calculated value is 20 as O.

59.34:H, 8,62:N, 10.20:8
．． 1 ts7° Experimental value: C, 59, 48: H, 8, 39
:N, 10.55 :S, 1115°-trimethyl-11-piperazinium)ethylthio-6 Valanitrobenzyl 6-(1m-hydroxyethyl)- in acetonitrile (3-) maintained in a nitrogen stream (SR, 6°) 3,
Diisopropylethylamine (0,557 m, 3.2 mmol) and diphenyl tetrarophosphate (n663m.

3.2 mmol) was added. The reaction mixture was stirred for 30 min at 5°C and diisopropylethylamine (0,5
99m.

1.25 After an hour, diisopropylethylamine (0.1*/, 0.57 mmol) was added LA. Stirring was continued for 2 hours. Part of the acetonitrile was removed under reduced pressure and the resulting red mixture was mixed with Prekpac-5007C.
Chromatographed on a K11 (Waters Associates) column using 25-75% acetonitrile in water as the eluent and lyophilized as a yellowish powder (14F).
I got it. Dissolve this powder in water and make the solution
-ICI column (t2x5Bcm) and water was used as the eluent.

Appropriate fractions were lyophilized to yield 117 g of powder (repurified on Pregpack-500/Cts column). Lyophilize appropriate fractions to obtain yellowish powder α80.9
(55%) obtained 0 ir (KBr) ν : 3400 (br, OH).

B X 1770 (C=0 of β-lactam), 1690 (PN
B ester C=O), 1605 (aromatic), 151
5 (No.

-1.

1345 (NOI)> , Sumire Hmr (Ih
O) a: t26(d, J=6.5H2,5H,C
Hs CHOH), 3.39 (s.

NCHs), 4.00 (1), 5.57 (br, s
, PNB CH2).

21 (d, J = &tSHz, 2H, Ho of PNB) 8
．． 20 (d, J=&7Hz, 2H, Hm of PNB)
: UV(HsO)λ :276ax (ε12094), 306 (gl 0752).

Calculated value as C, sH3, N, O, SC1, @ 5H, O: C946,51:H,5,65:N, 8.68
:8, 4.97 :C1.

10.98; Experimental value: C, 4S, 31: H26, 18
:N, 8.57:8.5.56゜0O- (5 and 6 times) balanitrobenzyl 5-(2-(1,4
,4-trimethyl-1-piperazinium)ethylthio)
-6(IR-hydroxyethyl)-7-oxo-1-azabicyclo(32,0)hept-2-ene-2-carboxylate bischloride (α40,9, 0.68 mmol), phosphate buffer (30 zu.

0.05M, I)H7,0), tethodihydrofuran (t
o-), ether (soy) and 10% palladium on charcoal (
0,4C119') at 23°C at 35ps
Hydrogenation was carried out under i for 1 hour.

The two phases were separated. The organic phase was extracted with water (1 oe). The aqueous phase was washed with diluted ether (IDmt) on a Celite pad, concentrated under vacuum to 10 ml, and prepack-500
/C, using water as the eluent on a column (equipped with 2,2X 11), treated with 77 ml of r:1-r thorn, and after freeze-drying, obtained 70 ml (25 ml).

1r (KBr) ν: 3400 (br, OH).

IL
0) δ :124(?lH,d.

J=6.3Hz, C11z CH(H(), 5
．． 36 (s, NCHI) *3.9 B (s
) : UV (Hz O)λ :296 ($7
98ax 3 7); [α) 35.9° (c, 0.50,
H20) s T1/2 days = 98 hours (phosphorus!!!? buffer p at 36.8°C
(measured at a concentration of 10 −4 M in H7,4).

Claims (1)

[Claims] 1. A compound of the formula [wherein 148 is hydrogen, R1 is hydrogen;
Substituted and unsubstituted, substituted: alkyl, alkenyl and alkynyl
(having 1 to 10 carbon atoms); cycloalkyl and
Cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
having carbon atoms and having 1 to 6 carbon atoms in the alkyl moiety
phenyl; Ralkyl, Ralkenyl
and hyalalkynyl (however, the aryl part is phenyl)
aliphatic moiety has 1 to 6 carbon atoms);
Teroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl (however, the above heterocyclyl alkyl
The heteroatoms in the moiety include 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of children and associated with the hetero moiety.
The alkyl moiety has 1 to 6 carbon atoms)
selected from the group; where the substitutions related to the above residues are
, C1%C6 alkyl (optionally amine, halo, hydro
(substituted by R9 convex CN N5 -OS O, R3 -OS O, R3 -NR"SO, R'-NR3CO2R'No2; independently selected from the group consisting of;
with respect to which the groups R3 and R4 are hydrogen; alkyl, alkenyl;
and alkynyl (having 1 to 10 carbon atoms);
Chloalkyl, cycloalkylalkyl and hyalkyl
Chloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
and 1 to 6 carbon atoms in the alkyl moiety]; phenyl
R; Ralkyl, Ralkenyl and Hyalal
quinyl (however, the aryl part is phenyl, aliphatic
moiety has 1 to 6 carbon atoms); and heteroaryl
heteroalkyl, heteroalkyl, heterocyclyl and hihete
Rosyclylalkyl (but in the heterocyclic moiety above)
Telo atoms consist of 1 to 4 oxygen, nitrogen or sulfur atoms
an alkyl selected from the group and associated with said heterothyroid moiety;
having 1 to 6 carbon atoms)
or at least one of R3 and R4 is connected
Forms a penta- or hexakinetic nitrogen-containing heterocyclic ring with nitrogen
may be used; except that R″ must not be hydrogen.
, as defined for R3; or in which R
1 and R8 together represent C2-CIO alkylidene or hydrogen.
C2-C1■ alkylide di-substituted by droxy
Rs represents substituted and unsubstituted: alkyl, alkyl;
Kenyl and alkynyl (carrying 1 to 10 carbon atoms)
;cycloalkyl and cycloalkylalkyl (cyclo
3 to 6 carbon atoms in the alkyl term and 1 to 6 carbon atoms in the alkyl moiety
having 6 carbon atoms); phenyl; aralkyl;
Ralkenyl and Ralkynyl (However, R
moiety is phenyl υ, aliphatic moiety is 1 to 6 carbon atoms
); heteroaryl, heteroaralkyl,
Heterocyclyl and heterocyclylalkyl (but above)
The heteroatoms in the heterocyclic moiety are 1 to 4 oxygen, nitrogen,
the heterocyclic group selected from the group consisting of
having carbon atoms of the alkyl moiety Fi1-6 accompanying the moiety
selected from the group consisting of
is optionally one to three substitutions selected from:
Thus substituted: C, -C, alkyl (l!111, meaning amino, fluoro
, chloro, carboxyl, hydroxy or carbamoyl
Fluoro, chloro or haplomo; -OR";1000R3;10COR3;-0CONR3R';10302R";OXO;-NRIR4;;-NR3CONR'R';-NR"SO!R';-5lt"; ↑ -8-R9; -CO2R3; -CONR3R4; -CN;
, C1-C6 alkyl, -〇R3, -NR$R', -S
03 I'L", -Co2R3 or -CONR'R'
) (However, the above R11 position
During the conversion, R3, R4, and R9 are as specified above.
); or Hli is a bridged polycyclic group attached to the ring.
Divalent phenylene or C1-C4 alkylene group forming
may represent; A may represent cyclobenzene, cyclohexane;
Silene or td, C2-C6 alkylene (, optionally Fi
substituted by l or more C1-C4 alkyl groups
R2 is hydrogen, anionically charged or
easily removable carboxyl protecting group (with the exception of R2
When is hydrogen or a protecting group, the opposite ion also exists
]; contains at least one nitrogen in the instep, and through further nitrogen
A is linked to A, thereby forming a four-edge ammonium group.
Substituted or unsubstituted mono-, bi- or po-93Jl non-aromatic
[represents a heterocyclic ring residue]; Compound. 5. The compound according to claim 1, wherein R" and R8 are together. 4. The compound according to claim 1, wherein R1 is ?1 C) I3C) l-. 5. “R”? 1 CR3CH- and the absolute configuration is 5R16S, 8R.
A compound according to Range 1, 2, 3, 4 or 5. Compounds of the formula I [wherein R8 is hydrogen, R1 is a soapstock; substituted
and non-%'P: alkyl, alkenyl and alkynyl (
having 1 to 10 carbon atoms); cycloalkyl and cycloalkyl
Chloalkylalkyl (cycloalkyl 3-6 charcoal)
having 1 to 6 carbon atoms in the elementary atoms and alkyl moieties)
；Phenyl；Ralkyl, Ralkenyl Shiohia
alkynyl (however, the aryl part is phenyl)
, having carbon atoms in the aliphatic moiety Fi1-6); hetero
Aryl, heteroaralkyl, heterocyclyl and
Heterocyclylalkyl (but the heterocyclic moiety above)
Medium heteroatoms are from 1 to 4 oxygen, nitrogen, or atom atoms
selected from the group consisting of
The kill moiety has 1 to 6 carbon atoms.
selected; where the substitutions related to the above residues are C1
~C6 alkyl←optionally amino, halo, hydroxyl
is substituted by carboxyl) NO10 OR3 1 -OCNR3R4 1 -CNR3R4 -N R3R4 -S o2N R3R4 1 -NHCNR3R4 1 R3CNR'- -Co2R3 =0 S R3 1 S R9 MR9 1 CN N3 -0803R3 -OS o2 R3- NR3SO2R'-NR3C=NR' 3 -N 13C02R' No2 where the above substitutions
Regarding the components, the groups R3 and R4 are hydrogen; alkyl, alkyl
Kenyl and alkynyl (having 1 to 10 carbon atoms)
;cycloalkyl, cycloalkylalkyl and alkyl
cycloalkyl (cycloalkyl, 3 to 6 carbon atoms)
(having 1 to 2 carbon atoms in the child and alkyl moiety);
phenyl; aralkyl, arkenyl and ar
Alkynyl (However, L2 aryl part is phenyl,
the aliphatic moiety has 1 to 6 carbon atoms;
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (j: i+,
Heteroatoms U, 1 to 4 oxygen, nitrogen or sulfur atoms in the loit moiety
selected from the group consisting of yellow atoms and associated with the heterocyclic moiety.
The accompanying alkyl moiety has 1 to 2 carbon atoms)
or R3 and R4 are selected from the group consisting of:
5-pronged 6-negative nitrogen with at least one linked nitrogen
may form a containing heterocyclic ring; R9 must not be a hydrocarbon.
Other than that, it is as fixed for R3.
R1 and R8 together represent C2 to C10 atom;
C replaced by alkylidene or hydroxy
2~represents CIO alkylidene; R5, substituted and unsubstituted
Substituted alkyl, alkenyl and alkynyl (1 to 10
carbon atoms); cycloalkyl and cycloalkyl
rualkyl (3 to 6 carbon atoms in the cycloalkyl ring and
having 1 to 6 carbon atoms in the alkyl moiety); heteroa
Ryl, heteroaralkyl, heterocyclyl and hetero
Terocyclylalkyl (but in the above heterocyclic moiety)
Heteroatoms include 1 to 4 oxygen, nitrogen or sulfur atoms, and
an alkyl group selected from the group consisting of
R5 has 1 to 6 carbon atoms]:
The residues are optionally independently selected from 1-
Substituted by 3 substituents: C1-C6 alkyl (optionally amino, fluoro, chloro
, by carboxyl, hydroxy or carbamoyl
-OR";-OC02R';-0COR3;-CONR3R4;-0802R3;-oxo;-NR3R';R3C0NR'-;-NR3CO,R4;-NR3coNa"g';-NR3SOtomiR4;18R";-803R";-C02R3;-CONR3R';-CN;
Fromo, C8-C6 alkyl, -〇R3, -NR3R'
, -S 03 R3, -CO,R3 or -CONR3R
4); R3 in the above R5 substituents
, R4 and R9 are as defined above; or
R6 is a divalent phenyl group that is combined with the ring to form a bridging multifunctional group.
A may represent ren or a C1-C4 alkylene group;
, cyclobenzene, cyclohexylene or 1fi C2
~C6 alkylene (optionally one or more C1-C
(substituted by 4 alkyl groups); R2 is
, hydrogen, anionically charged or commonly used easily removable hydrogen.
Roxyl protecting group (however, when R2 is hydrogen or a protecting group)
has 0 to 2 double bonds and 0. s(0)m, N,
NR10 or NRI"R16 (where m is 0.1 or 2
, RIG is hydrogen, C1-C6 alkyl (@intentionally
10R", -NR3R', -COHR", Oxo s
Phenyl, fluoro, chloro, fluoro, -S o318 and
and 1 to 2 positions independently selected from CONR3R4.
) or phenyl (substituted by substitution) or phenyl (substituted by
C1-C6 alkyl, -0R3, -NR"R'. Fluoro, chloro, bromo, -S 03 R3, -Co,
1 independently selected from R2 and -CONR3R4
~5 substitutions); Hl
s and R16 are each independently C1-C6 alkyl (optional
-0R3, -NR3R', -Co2R3, oxo,
Phenyl, fluoro, chloro, bromo, -8o, R3 and
1 to 3 independently selected from
) or phenyl (optional)
C, -c6 alkyl, -0R3, -NR3R',
Rolo, chloro, bromo, -5o3re3, -C02R
1-3 independently selected from 2 and -CONR3R4
is replaced by the permutation position of
non-aromatic 4~ containing 0~2 additional heteroatoms
Represents a 7-membered N-containing heterocycle; R3 in the above heterocycle
and R4 are as defined above, and the heterocyclic ring is
Through nitrogen atoms? is connected to A, thereby
form a class ammonium group, and the heterocyclic ring optionally has the following:
substituted by 1 to 3 substitutions independently selected from
Substituted with: C1-C6 alkyl (optionally fluoro, chloro, bromo)
, -OR3, -0COR3, -0CONR3R4, OKI
6-NR3R4, -NR3COR4, -NR3CONR
3R4, -NR3S o2R', -S R3, -S 0
3 R3, -Co, R3 and -CONR3R4 to Germany
substituted by 1 to 2 substituents selected according to
]; C2-C6 alkenyl (@in particular fluoro, chloro, bromine);
-OR3, -0COR3, -0CONR3R4,
xo, -NR3R4, -NR3COR4, -NR3C'
(1) NR3R4, -NR3S03R4, -S R3,
-8o3R3, -Co, R3 and -CONR3R4?
P is pressed by one or two substitution positions selected independently from
C2-C6 alkynyl (optionally +-t fluoro, chloro,
Bromo, -OR3, -0COR3, -0CONR"R'
, oxo, -NR3R4, -NR3COR4, -NR3
COR4-NR3SO2R4, -S R3, -S 03
R3, -CO, R" and -CONR3, independent of R4
(substituted by 1 to 2 substitutions selected)
; 03-C6 cycloalkyl (optionally fluoro, chloro,
Bromo, -OR3, -0COR3, -0C'0NR3R
4, Okiroku-NR"R', -NR3COR4, -NR3
CONR3R', -NR3COR4, -S R3, -8
Independent from OjR", -CO,R" and -CONR"R4
is substituted with 1 to 2 substituents selected as
); Cycloalkylalkyl (3 to 6 in the cycloalkyl ring);
having 1 to 6 carbon atoms in the carbon atoms and alkyl moieties;
Optionally fluoro, chloro, bromo, -OR3, -0CO
R3, -0CONR3R4, oxo, -NR'R', -
NR3COR4, -NR3CONR3R', NR35o
, R4, -8R3, -S 03 R3, -Co2R"
, and 1 to 1 independently selected from -CONR''R4
(substituted by 2 substituents); heteroaryl
(However, heteroatoms include 1 to 4 oxygen, nitrogen, or sulfur atoms.
Selected from the group ``Children'', optionally including Fluoro, Chloro,
, bromo, -OR3, -0COR3, -0CONR3R
4, oxo, -N R3R4, -NR"C0R4, -N
R3CONR"R', -NR3SO, R4, -S R
3, -S o, 13, -Co, R3 and -CONR
"by 1 to 2 substituents independently selected from R4
substituted); heteroaralkyl (but heterosubstituted);
Atom is a group of 1 to 4 oxygen, nitrogen, or sulfur atoms.
selected from, optionally fluoro, chloro, bromo, -
OR3, -0COR", -0CONR3R', oxo,
-NR"R4, -NR"COR', -NR3C0NR3
R', -NR3so2R4, -8R3, -S 03R3
, -Co2R3 and -CONR3R4
[substituted with 1 to 2 substituents];
Rosyclyl (heteroatoms include 1 to 4 oxygen, nitrogen
or sulfur atoms, optionally)o
o, rioo, bromo, -〇R3, -0COR3,0CO
NR"R4, O#6-NR3R4, -NR3COR',
-NR3C0NR3R4, -NR3SO,R4, -S
R3, -S o3R3, -Co2R3 and -CONR3
substituted by 1 to 2 substituents independently selected from R4.
); heterocyclylalkyl (but heterocyclyl alkyl);
b atom is a group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms;
selected from, the alkyl moiety having 1 to 6 carbon atoms;
, optionally fluoro, chloro, p0-E-1-〇R3,
-0COR3, -0CONR3R4, Oxo, -NR
3R4, -NR3COR', -NR3CONR3R',
-NR3SO,R', -S R3, -S o, R3,
Select from -C02R3 and -CONR3R4 groups.
(substituted by 1 to 2 substitutions);
-OS 02 R3; Oxony NR"R4;R"C0NR'-;-NR'C02R';-CO2R3;-CONR''R4;-CN; or phenyl (optionally 1 to 3 fluoro, chloro, bromo,
CI~C6 alkyl, -〇R3, -NR3R4, -s
By O, R3, -Co2R3 or -CONR''R4
substituted) (with the exception that R3 in the above heterocyclic ring substituents,
R4 and R9 are as defined above; or
The non-aromatic nitrogen-containing heterocyclic ring is C4-C? Carbocycle, Fe
Nyl ring, o, S(0)m, N, NRIO and NR16
4- to 7-membered heteroatoms containing heteroatoms selected from BII
term ring or 0.5(o)rn, N, NRIO and NR
Containing 1 to 3 heteroatoms selected from ISR16
may be fused to a 5- to 6-membered heteroaromatic ring (only
sim, BIG, Hls and 116 are defined above.
), the fused carbocycle, phenyl, heterocycle or
is a heteroaromatic ring, optionally C1-C6 alkyl, -
013, -NR"R', fluoro, chloro, bromo, -
So3R3, -Co, Ra and -CONR"R'
(However, R3 and R4 in the above fused ring are defined above.
1 to 5 permutations independently selected from
]:9, R1 and R8 are substituted by
The compound according to claim 7, which represents the combination of: 10. The compound according to claim 7, which is R1''゛.□ H3CH-. 11. The compound according to claim 7, in which R1 is ?
Compounds of Range 7. 12, A is -CH2CH, -1-CR2CR2CHz-
1-CHCH*-1 statement H3 7.8,? , 10 or 11 Compounds of formula 15 [wherein R8 is hydrogen and R1 is hydrogen;
and unsubstituted: alkyl, alkenyl and alkynyl (1
~10 carbon atoms); cycloalkyl and cyclo
loalkylalkyl (3 to 6 carbons in the cycloalkyl ring)
having 1 to 6 carbon atoms in the atom and alkyl moiety;
Phenyl; Ralkyl, Ralkenyl and Hir
rualkynyl (however, the aryl part is phenyl υ,
aliphatic moiety has 1 to 6 carbon atoms); heteroaryl
heteroalkyl, heteroalkyl, heterocyclyl and hihete
Rosyclylalkyl (but for the above heterocyclic partial derivatives)
Telo atoms consist of 1 to 4 oxygen, nitrogen or sulfur atoms
The alkyl dialyzed from the group and associated with the heterocyclic moiety
having 1 to 6 carbon atoms); in which the above residues have
The relevant trade components are: C1-C6 alkyl C optionally amino, no, hydro
substituted by xy or carboxyl)/10 10R3? 10CNR3R'12NR'R' -N RF R' -S ox N R8R' -Nu! NR"R4 R3 NR4- -Co, R3 =0 S R3 19 CN -N. -OS o3R8 -OS ox R3 -NR35O, R'-NR3C=NR' 3 -NR3CO2R4 -No2 independently from the group consisting of selected (but the above replacements
Regarding the position, the groups R3 and R4 are hydrogen; alkyl, alkyl;
Kenyl and alkynyl (having 1 to 10 carbon atoms)
;Cycloalkyl, cycloalkylalkyl and hyalkyl
cycloalkyl, (3 to 2 carbon atoms in the cycloalkyl ring)
having 1 to 2 carbon atoms in the atom and alkyl moiety);
Phenyl; Ralkyl, Ralkenyl and Aralkyl;
arginyl (however, the aryl part is phenyl)
, the aliphatic moiety has 1 to 6 carbon atoms);
Teroaryl, Heteroboolalkyl, Hederocyclyl
and heterocyclylalkyl (the above heterocyclic
Is the moiety a group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms?
an alkyl moiety selected from
have 1 to 6 carbon eggs) are independently selected from
or at least one of R3 and R4 is connected
together with nitrogen, form a 5- or 6-negative nitrogen-containing anomaly.
Yes; R9 is similar to R3 except that it must not be hydrogen.
or R1 and R8 are as defined for
, together with C2-CIO alkylidene or hydroxy
represents a C2-CIO alkylidene substituted with
; A is cyclobenzene, cyclohexylene or it C
2-C6 alkylene (in particular one or more
(substituted by a C1-C4 alkyl group)
Was; R2 is hydrogen, anionically charged or commonly used easily removed
Possible carboxyl protecting group (provided that R3 is hydrogen or
When is a logical group, the opposite ion also exists); (Y is hydrogen, C1-C6 alkyl, hydroxy,
-5C1-C6 alkyl, carboxyl, carbamoyl
, chloro, bromo, iodo, fluoro or phenyl
); or a salt thereof that can be used as a medicine. ? 1 or CH3CH-
Compound. 15. The compound according to claim 13, wherein R' and 8 collectively represent. 16. R'? 14. The compound according to claim 13, which is 1 H3CH-. 17. R'? 1 H3CH- and the absolute configuration of the patent claim is SR, 6S, 8R.
A compound according to Range 13. 15.14.15.16 or 17 Compounds. Compound of formula 19 [wherein R8 is hydrogen, R1 is hydrogen; substitution
and unsubstituted; alkyl, alkenyl and alkynyl (1
~1D carbon atoms); cycloalkyl and cycloalkyl
loalkylalkyl (6 to 6 carbons in the cycloalkyl ring)
having 1 to 6 carbon atoms in the atoms and alkyl moieties);
phenyl, aralkyl, arkenyl and here
Rualkynyl (however, the aryl part is phenyl,
aliphatic moiety has 1 to 6 carbon atoms); heteroaryl
Heteroalkyl, heterocyclyl and heteroaryl
Rosyclylalkyl (however, the above-mentioned
Heteroatoms include 1 to 4 oxygen, nitrogen or yellow atoms.
an alkyl group selected from the group consisting of
moiety having 1 to 6 carbon atoms); in which the above residues
Substituents related to C1-C6-alkyl (VB meaning amine, halo, hydro)
(substituted by roxy or carboxyl)-
〇R3 1 -OCNR3R4 1 -CNR3R' + N R3H4 -8O+NR'R' 1 -NHCNR"R' R3I!: NR4- -Co2R3 N0 1 0CR1 -s its? sne Ichinobu R9 〇CN N3 -0.8 os lζ3 - OS 02R3 -NR'' S o2R4 -NR3Co, R'N02;
KIH, the groups R3 and R4 are hydrogen; alkyl, alkyl;
Kenyl and alkynyl (having 1 to 10 carbon atoms)
;cycloalkyl, cycloalkylalkyl and alkyl
cycloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
having 1 to 6 carbon atoms in the child and alkyl moiety];
phenyl; aralkyl, aralkenyl and fur
Alkynyl (however, the aryl part is phenyl, and the fatty acid
aliphatic moieties have 1 to 6 carbon atoms); and hetero
Ari-A/, heteroaralkyl, heterocyclyl
and heterocyclylalkyl (only 1.7 of the above hetero)
The heterosynthesis in the annular part is 1 to 4 oxygen, 9 elements or
selected from the group consisting of atoms associated with the heterocyclic moiety
The alkyl moiety has 1 to 6 carbon atoms) to
or R3 and R4 are at least
5- or 16-membered nitrogen-containing heterogeneity along with the ♀ element in which one is connected
may form a ring; R9 must not be hydrogen
except that it is as defined for R3; or
In the formula, R1 and R8 together represent 02-CIO alkylide
C2-CIO substituted by carbon or hydroxy
Represents alkylidene; Adcyclopentylene, cyclo
Hexylene or C2-C6 alkylene (optionally 1 or
Substituted with more C1-C4 alkyl groups
R2 is hydrogen, anionically charged or conventionally removed.
is a carboxyl protecting group (provided that R2 is hydrogen or
When is a protecting group, the opposite ion is also present); or a pharmaceutically usable salt thereof. Claim 19, which is H or CH,, CH-
Compounds listed. 21 The compound according to claim 19, in which R'' and R8 collectively represent 22. The compound according to claim 19, in which R1 is ?1 H3CH-. 25 R1 is ?H CH , CH-, the absolute configuration of the patent claim is 5R, 6S, 8R.
A compound according to Range 19. 24, A is -CH2CR2-1-CHz CHz CH
z-1-CHCH,-. CH3 Compound described in item 19. 25, a compound having the formula [wherein R8 is hydrogen and R1 is hydrogen]
;Substituted and non-W substituted: alkyl, alkenyl and alkynyl
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; aralkyl, aralkenyl and
Hyalalkynyl (however, the aryl part is phenyl)
aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (with the exception of the above heterocyclic group)
Condensing heteroatoms include 1 to 4 oxygen, elemental, or sulfur atoms.
selected from the group consisting of:
the lukyl moiety has 1 to 6 carbon atoms); in the formula
The W portion of the residue is C1-C6 alkyl (optionally amine, halo, hydroxy).
V-substituted by C or carboxyl) No mouth -〇R3 10 and NR3R4 1 δNR3R'-NR"R' 18o, NR"R'-NHCNR'R' -002R3 =0 1 0CR3 SR3 1 SR9 δ CN N3 - OS 03R3 -OS O,R8 -NR3S O2R' -NR3C=NR4 3 -NR3C02R' NO2 where the above substituted moieties
, the groups R3 and R4 are hydrogen; alkyl, pulque
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and hyalkyl
Cycloalkyl (6 to 6 carbon atoms in the cycloalkyl term)
and having 1 to 6 carbon atoms in the alkyl moiety];
Nyl; Ralkyl, Ralkenyl and Hialua
ruquinyl (however, the aryl part is phenyl, and the fat
group moieties have 1 to 6 carbon atoms); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hetero
Terocyclylalkyl (but in the above heterocyclic moiety)
Heteroatoms include from 1 to 4 oxygen, nitrogen or yellow atoms.
an alkyl group selected from the group consisting of
independently selected from (having 1 to 6 carbon atoms)
or at least one of R3 and R4 is connected.
Formation of 5- or 6-negative nitrogen-containing heterocycles with attached nitrogens
may be used; except that R9 must not be hydrogenated)
is as defined for R3; or in the formula
R1 and R8 together represent C2-CIO alkylene or hydrogen.
C2-CtO alkyl substituted by droxy
A represents cyclobenzene, cyclohexylene
or C, ~C6 alkylene (optionally one or more)
) is substituted by a C4 alkyl group of
;R2 is hydrogen, anionically charged or easily removable
carboxyl retaining group (provided that Rz is hydrogen or retaining group)
When it is a protecting group, a reverse ion also exists); Y is hydrogen,
C1-C6 alkyl, hydroxy, -5-C, ~C6 a
Lucyl, carboxyl, carbamoyl, chloro, bromo
, iodine, fluoro, or haphenyl]; or pharmaceutical
Its salt can be used as salt. ? ■I or CH3CH- as described in claim 25
compound. 27. The compound according to claim 25, wherein R1 and R8 collectively represent. 28. The compound according to claim 25, wherein R1 is (i) H CH3CH-. 29R1? 1 H3CH-, and the absolute configuration is 5R16s, 8R.
A compound according to Range 25. 30, A is -CR2CR2-,'-CR2CR2CR2
-1-CHCH2-No. 25.26.27.28 or 29
Compounds described in Section. 31, a compound having the formula [wherein R8 is hydrogen and 1+, R1 is hydrogen]
; Saturated and unsaturated: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; aralkyl, aralkenyl and
and aralkynyl (however, the aryl part is phenyl)
6p, the aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (however, the above heterocyclylalkyl
Conidial heteroatoms include 1 to 4 oxygen, nitrogen, or amber atoms.
selected from the group consisting of:
the group consisting of 1 to 6 carbon atoms)
selected from; in which the substituents related to the above residues are
, -C, alkyl (optionally amine, halo, hydroxy
or substituted by carboxyl ] no 10 10R3 0-nuR3R4 NR3R4 -S o, NR3R4 1 R3CNR'- -C02R3 =0 SR3 1 SR9 CN N3 -OS o3R3 -OS o2B3 . -NR3SO2R'-NR3CO2R'N02;
, the groups R3 and R4 are hydrogen; alkyl, alkenyl and
Alkynyl (having 1 to 10 carbon atoms); cycloa
alkyl, cycloalkylalkyl and alkylcycloa
(6 to 6 carbon atoms and alkyl in the cycloalkyl ring)
having 1 to 6 carbon atoms in the kill moiety]; phenyl;
ralkyl, aralkenyl and hyaralkynyl
(However, the aryl part is phenyl, and the aliphatic part is
having 1 to 6 carbon atoms); and heteroaryl;
heteroaralkyl, heterocyclyl and hheterosykyl
lylalkyl (but the heterogen in the heterothyroid part mentioned above)
Is the child a group consisting of 1 to 4 IP elements, nitrogen or yellow atoms?
an alkyl moiety selected from and associated with the heterocyclic moiety;
(having 1 to 6 carbon atoms)
or, at least one of R3 and R4 is connected [7
forms a 5- or 6-membered nitrogen-containing heterocyclic ring with nitrogen
Good; I19 must not be hydrogen, except that
as defined for R3; or in which R1
and R8 together represent C2-CIO alkylidene or hydride.
C2~CIG alkylide substituted by roxy
A represents cyclobenzene, cyclohexylene
Also 1ri, C* to C6 alkylene (optionally 1 or more)
Substituted with the above C, -c, alkyl group]
R2 is hydrogen, anionically charged or commonly used easily removed
It is a carboxyl protecting group that can be removed (provided that R2 is hydrogen).
or when it is a p-holding group, an inverse ion also exists);
or a combination of R' and R8 that can be used as a medicine.
34. The compound according to claim 31, which represents
R'? 1 C)], CH-. 35, R1? 1 Ct13C1(-, and the absolute configuration is 5R16S, 8R! I!l
: Compound according to claim 31. 36, A is -CH2C) 12-1-CH2Cl, CH2
-1-CHCH2-1H3 31, 32, 33, 34 or 35 Compound 3Z
A compound of the formula (wherein R2 is hydrogen, anionically charged or a conventional
Easily removable carboxyl protecting group (with the exception of R2
When is hydrogen or a positive radical, the opposite ion also exists)
]; Or, it can be used as a medicine. 3a Claims in which R” is p-nitrobenzyl
A compound according to item 37. Claim 37, wherein 39R2 is anionically charged.
Compounds described. A compound having the formula 40 [wherein R8 is hydrogen and R1 is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(containing 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 in cycloalkylffl)
~6 carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; Ralkyl, Ralkeni
and hyalalkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms];
heteroaryl, heteroaralkyl, heterocycli
and hheterocyclylalkyl (heterocyclic moieties listed above)
Intermediate heteroatoms include 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of
The kill moiety has 1 to 6 carbon atoms.
selected; in the formula C1-C6 alkyl related to the above residues (optionally amino, halo, hydroxy);
)10 OR3 ? -0CNIζ3R4 NR3R4 -8O2NR"R4 -Co, R3 ;0 ? 0CR3 S R3 ? SR9 ? SR9 CN N3 -08OsR3 -os o, R5 -NR"SO,R' -NR3C=NR4 3 -NR3C0,R' From No2 independently selected from the group consisting of;
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 1 o carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
and having 1 to 6 carbon atoms in the alkyl moiety);
Nyl; Ralkyl, Ralkenyl and Hialua
ruquinyl (however, the aryl part is phenyl, and the fat
group moieties have 1 to 6 carbon atoms]; and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (but in the above heterocyclic moiety)
Heteroatoms include 1 to 4 oxygen, nitrogen or sulfur atoms.
an alkyl group selected from the group consisting of
independently selected from [1 to 6 carbon atoms]
or R3 and R4 are at least one in series.
Combines with the nine linked elements to form a 5- or 6-membered nitrogen-containing heterocyclic ring
may be formed; Re must not be hydrogen;
is as defined for R3; or the formula
In the middle, R1 and Re together represent 02-C1o alkylidene or
is C2-CIO a substituted by hydroxyl
represents alkylidene; R2 is hydrogen, anionically charged or
It is an easily removable carboxyl retention group (only
When R2 is hydrogen or a protecting group, a reverse ion also exists.
]; Y is hydrogen, C1-C6 alkyl, hydroxy,
-5-c, ~C6 alkyl, carboxyl, carbamoy
chloro, bromo, iodo, fluoro or phenyl.
]: Or its salt that can be used as a medicine. Claim 40, which is H or CH3CH-
42. The compound according to claim 40, wherein R1 and R8 together represent. 43. R1? 41. The compound according to claim 40, which is 1 CH,C)L-. 44. R1? 1 H3CH- and the absolute configuration is 5R16S, 8R.
A compound according to Range 40. 45, A is -CHz CR2-1-CH, CH, CH,
-1-CHCH2-1H3 The shrimp compound according to item 40, 41, 42, 43 or 44. 46, a compound having the formula [wherein R8 is hydrogen, R1 is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; aralkyl, arbrukenyl and
Hyalalkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms];
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (however, the above heterocyclic part
Condensing heteroatoms include 1 to 4 oxygen, nitrogen or yellow atoms.
is selected from the group consisting of:
The alkyl moiety has 1 to 6 carbon atoms)
selected from the group; in which the moieties related to the above residues are
, C4-C6 alkyl (F18 meaning amine, halo, hydrogen)
substituted by droxy or carboxyl)
10 OR3? 10CNR"R'01δNR"R4-NR"R4 -S o, N R"R' 0 R3δNR'- -C02R3 =0 S R3 1 -8R' CN NS -OS os R3 -OS ot R3 -NR35O2R4 - NR3 Stomach NR' 3 -NR3C0,R' -NO. independently selected from the group υ; in which the above substitutions
Regarding the groups R3 and R' Ir1s hydrogen, alkyl, a
alkenyl and alkynyl (having 1 to 10 carbon atoms)
); cycloalkyl, cycloalkylalkyl and alkyl
Kylcycloalkyl (3 to 6 carbons in the cycloalkyl ring)
having 1 to 6 carbon atoms in the atom and alkyl moiety];
Phenyl; aralkyl, aralkenyl and ar
Rualkynyl (however, the aryl part is phenyl,
the aliphatic moiety has 1 to 6 carbon atoms;
Loary Loupete 1 R Alkyl, Heterocyclyl and
Hiheterocyclylalkyl (with the exception of the above heterocyclic group)
Heteroatoms in the fraction include 1 to 4 oxygen, nitrogen or detrital atoms.
selected from the group consisting of
(having 1 to 6 carbon atoms)
selected, or R3 and R4 are at least one
a 5- or 6-membered nitrogen-containing heterocyclic ring together with the nitrogen to which it is linked.
may be formed; R11 must not be hydrogen
as defined for R3; or
In the formula, R1 and R8 together represent C2-CIO alkylidene
or C2-CIO a substituted by hydroxy
represents alkylidene; t-;A hacyclopentylene, cyclo
Hexylene or Cz-C6 alkylene (optionally 1 or
Substituted with more C1-C4 alkyl groups
); R2 is hydrogen, anionically charged, or
(provided that R3 is
When it is hydrogen or a protecting group, a reverse ion is also present)]
or as a medicament, the compound according to claim 46, wherein fecal compound W4B, R1 and R8 collectively represent. 49. R Otori? 46. The compound according to claim 46, which is 1 CH,C)1-. 5Q, R1 is CH H3CH-, and the absolute configuration is 5R16S, 8R.
A compound according to Range 46. 51, A is -CH,CH,-1-CH鵞CH,CH,-
1-CHCR3, H3 46.47.48.49 or 50 compounds. Compound of formula 528 [wherein R2 is hydrogen, anionically charged or a commonly used capacitor]
Easily removable carboxyl protecting group (with the exception of R2
When is hydrogen or a protective group, the opposite ion also exists)
]; or a salt thereof that can be used as a medicine. 53. Claims in which R1 is p-nitrobenzyl
A compound according to item 52. Claim 52, wherein 54R2 is anionically charged.
Compounds described. 55, a compound having the formula [wherein R8 is hydrogen, R1 is hydrogen;
Substituted and unsubstituted; alkyl, alkenyl and alkynyl
(having 1 to 10 carbon atoms); cycloalkyl and
Cycloalkylalkyl (3 to O in the cycloalkyl ring)
having 1 to 6 carbon atoms in the carbon atoms and alkyl moieties
); phenyl; aralkyl, aralkenyl and
Aralkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms); hetero
Aryl, heteroaralkyl, heterocyclyl and
Heterocyclylalkyl (however, the above heterocyclylalkyl
Native heteroatoms include 1 to 4 oxygen, nitrogen or valent, yellow atoms, etc.
Dialyzed from different groups and associated with the heterogait part.
The alkyl moiety has 1 to 6 carbon atoms;
The moiety related to the residue is C1-C6 argyl (Izukura has amino, /, mouth, hydro
11 by xy or carboxyl)NO10 OR3 10δNR"R' 0-8N R"R' NR3R4 -8o2N R" R4 -Nu crystal N R" R4 π R3CNR4- -Co, R3 =0 0CR3 -8R ``〇１HAI79♂ CN -N. １０８O,R'' -OS O,R3 -NR3S o2R4 -NR3CO2R'-N02; in which the above substituents
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (6 to 6 carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety);
Nyl; Ralkyl, Ralkenyl and Hialua
Luquinyl (the aryl part is phenyl, fatty
group moieties have 1 to 6 carbon atoms); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (in the above heterocyclic moiety)
Heteroatoms consist of 1 to 4 oxygen, sulfur or sulfur atoms.
an alkyl group selected from the group consisting of
independently selected from (having 1 to 6 carbon atoms)
or R3 and R4 are at least one in series.
Forms a 5- or 6-membered nitrogen-containing heterocyclic ring with the connecting space
may be used; except that R9 must not be hydrogen.
, as defined for R3; or in which R
1 and R8 together represent C2-CIO alkylidene or hydrogen.
02~CIO alkyry substituted by droxy
represents den; AFi cyclopentylene, cyclohe
Xylene or C2-C6 alkylene (optionally one or more)
fPf is substituted by more than one C1-C4 alkyl group.
]; R2 is hydrogen, anionic charge or
Easily removable carboxyl binding group (just
When R2 is hydrogen or a saccharide group, a reverse ion also exists.
); Y is hydrogen, C1-C6 alkyl, hydroxy,
-5-C, ~C6 sialkyl, carboxyl, carbamo
yl, chloro, bromo, iodo, fluoro or phenyl
or a compound that can be used as a pharmaceutical. 57. The compound of Claim #1, wherein R' and R8 collectively represent. 5a R'? 1 H3CH- Compound 059, 1 according to claim 55
'but? 1 H3CH- and the absolute configuration is 5R16S, 8R.
A compound according to Range 55. 60, A is -CH2CR2-1-CR2CR2CR2-
1-CHCH2-1H3 Compound according to item 55, 56, 57, 58 or 59. 61, a compound having the formula [wherein R8 is hydrogen, R1 is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; Ralkyl, Ralkenyl 7
Mffuralkynyl (however, the aryl part is phenyl)
aliphatic moiety having 1 to 6 carbon atoms);
Teroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl (in the above heterocyclic moieties)
Heteroatoms are more than 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
The rukyl moiety has 1 to 6 carbon atoms.
The substitutions related to the residues of the formula are selected from C1
-C6 alkyl (optionally amino,), hydroxy
or substituted by carboxyl) nor~roOR3 -CNR3R4 1 -CNR3R'-NR"R' -S o, NR3R' 〇-NHSaNR3R4 -Co, R3 = 〇S R3 -R9 1 SR9 δ CN - N. -OS Oa R3 -NR35O2R'-NR''CO2R4 No2 where the above substituents
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
and phenylene having 1 to 6 carbon atoms in the alkyl moiety.
Nyl; Ralkyl, Ralkenyl and Hialua
Ruquinyl (Aryl part is phenyl, aliphatic part
has 1 to 6 carbon atoms); and heteroary
, heteroaralkyl, heterocyclyl and hhetero
Cyclylalkyl (a heteroatom in the heterocyclic moiety above)
is selected from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms
and the alkyl moiety accompanying the heterologous moiety is 1 to
independently selected from [having 6 carbon atoms], or
Or R3 and R4 are nitrogen atoms in which at least one is connected.
may form a 5- or 6-nitrogen nitrogen-containing ring with the element;
R9 is the same as R3 except that it must not be hydrogen.
or as defined in the formula; or in which R1 and R8
are collectively C2-C1o alkylidene or hydroxy
Therefore, it represents a substituted C2~CSO alkylidene.
A is cyclopentylene, cyclohexylene or UC2
~C6 alkylene (optionally one or more C plates ~C
(substituted by 4 alkyl groups); R2 is
hydrogen, anion, or commonly used easily removable carboxylic acid.
It is a xyl protecting group (only 1.R2 is water is a protecting group)
Sometimes the opposite ion also exists);
It can be used conveniently on the spot. ? 1 or 11: The enclosure 6 of the patent claim which is CH2Cl-
Compounds listed in J. 63. The compound according to claim 61, wherein R' and R8 collectively represent. 64. The compound of Claim 61, wherein R" is 11 CH3Cl-. 65. The compound of Claim 61, wherein R" is H CH3Cl- and the absolute configuration is 5R16S, 8R.
A compound according to Range 61. 66, A is -CII□C)12-1- CR2CR2
CR2-1-CHCH2-1H3 Compound according to item 61, 62, 63, 64 or 65. 6Z formula [In the formula, R2 is hydrogen, anionically charged or commonly used easily removed
Possibly a carboxyl protecting group (provided that R2 is hydrogen or
When is a protective group, an inverse ion also exists)
or its salts that can be used as pharmaceuticals. Claim No. 6&R2 is p-nitrobenzyl
A compound according to item 67. 69, Claim 6 in which R2 is anionically charged
Compound according to item 7. A compound having the formula 70 [wherein R8 is hydrogen and R1 is hydrogen;
Substituted and unsubstituted: alkyl, alkenyl and alkynyl
(having 1 to 10 carbon atoms); cycloalkyl and
Cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
having 1 to 6 carbon atoms in the carbon atoms and alkyl moieties
); phenyl; aralkyl, aralkenyl and
Furoalkynyl (however, the aryl part is phenyl)
cy, aliphatic moiety having 1 to 6 carbon atoms]; hetero
Aryl, heteroaralkyl, heterocyclyl and
Heterocyclylalkyl (but the heterocyclic moiety above)
Intermediate heteroatoms include 1 to 4 oxygen, nitrogen, or Fiben yellow atoms.
selected from the group consisting of
having 1 to 6 atoms in the alkyl moiety);
Substitution positions relating to residues include C, % c, alkyl (optionally amino, halo, hydro
OR3 1 -OCNR3R' 1 -CNR3R' NR3R4 18o, NR"R' -NHdNR3R4 0 R3 NR4- -Co2R" N0 0gR3 -S R" CN N3 108O3R" - OS o2R” -NR3S o, R4 -NR”COOR1 4N02 independently selected from the group;
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety);
Nyl; aralkyl, arkenyl and hyar
Alkynyl (however, the aryl part is phenyl, fat
aliphatic moieties have 1 to 6 carbon atoms]; and hetero
Aryl, heteroaralkyl, heterocyclyl and
Heterocyclylalkyl (heterocyclic moiety mentioned above)
B atoms consist of 1 to 4 #N atoms, nitrogen or sulfur atoms.
selected from the group, to which the atom accompanying the terrorist ring is selected.
The rukyl moiety has from 1 to
selected, or R3 and R4 are at least one
Forms a 5- or 6-membered nitrogen-containing variant with linked nitrogen.
except that R9 must not be hydrogen;
is as defined for R3; or in the formula
R1 and R8 together are C2-CtO alkylidene or
C2-CIO alkyl substituted by hydroxy
Represents lidene; Ai cyclopentylene, cyclohexy
Ren or C2-C6 alkylene (optionally one or more)
substituted by a C1-C4 alkyl group);
R2 is hydrogen, anionically charged or commonly used easily removable
It is a carboxyl-binding group (provided that R2 is hydrogen or
When it is a group, a reverse ion also exists); Y is hydrogen, C
1-C6 alkyl, hydroxy, -5-C, ~C6 alkyl
Kill, carboxyl, carbamoyl, chloro, bromo,
iodine, fluoro or phenyl]; or as a medicine.
and more available. ? 1 or -CH3CH-
72. The compound according to claim 70, wherein R1 and R8 collectively represent. 73. R1? 71. The compound according to claim 70, which is 1 CH, CH-. 74. R'? 1 H3CH, and the patent claim whose absolute configuration is 5R16S, 8R
A compound according to Range 70. 75. A is -CHz CN2-1 CH2CHz CH
z -1CHCHt-170, 71, 72, 73 or 7
Compound according to item 4. 76, compound having the formula [wherein R8 is hydrogen, R8 is hydrogen]
; Substituted and non-substituted: alkyl, alkenyl and alkini
(carrying 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl term)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl; aralkyl, aralkenyl and
Hyalalkynyl (however, the aryl part is phenyl)
aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
Hihete rosyclylalkyl (but the above heterocyclic
Heteroatoms in the moiety are 1 to 4 oxygen, nitrogen or sulfur atoms
selected from the group consisting of:
The alkyl moiety has 1 to 6 carbon atoms.
substituted moieties related to the above-mentioned residues in the formula
is C1-C6 alkyl (optionally amino, halo, hydro)
(substituted by roxy or carboxyl) -〇
R3 -CNR"R' 1 -CNR3R4 NR3R4 -S o, NR" R4 R'(!'NR4- -CO,R" N0 10δR3 S R3? S R1 1 CN N3 - OS o, R3 -0802R3 -NR3802R ' -NR3CO, R4 -N0°
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
and having 1 to 6 carbon atoms in the alkyl moiety);
nil, aralkyl, arkenyl and hyalur
Luquinyl (however, the aryl part is phenyl, fatty
group moieties have 1 to 6 carbon atoms); and heteroa
Reel, heteroaralkyl, heterocyclyl and
＼Terocyclylalkyl (However, the heterothyroid region of superior officer e
Heteroatoms in a minute are 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
the alkyl moiety having from 1 to 6 carbon atoms)
or R3 and I R4 are selected as
Contains 5- or 6-membered nitrogen with both nitrogens linked together
May form a heterogeneous element; R9 must not be hydrogen.
except as defined for R3;
Alternatively, in the formula, R1 and R8 together represent C2-CIO alkyl
C2-C substituted by lydene or hydroxy
IO alkylidene; A is cyclopentylene,
Chlohexylene or C2-C6 alkylene (optionally 1
or substituted with more C1-C4 alkyl groups
]; R2 is hydrogen, anionically charged or easily
is a removable carboxyl protecting group (provided that R2 is water)
When it is an element or a protective group, a reverse ion also exists]];
Alternatively, the compound according to claim 76, wherein R1 and R8 together represent a compound that can be used as a medicine. 79R1? 76. The compound according to claim 76, which is 1 CH, CH-. 80, R1,...? ■ CH, CH-, the absolute configuration is 5R16s, 8R in the patent claim.
A compound according to Range 76. 81, A is -CR2CR2-1-CR2CR2CHz-
1-CHCH2, item 76, 77, 78, 79 or 80
Compounds listed. 82, a compound having the formula [wherein R2 is hydrogen, anionically charged or normally
is an easily removable carboxyl protecting group for
When R2 is hydrogen or a protecting group, a reverse ion also exists.
]; or a pharmaceutically usable salt thereof. 83. Claims in which R” is p-nitrobenzyl
A compound according to item 82. 84, Claim 8 in which R” is anionically charged
2 compounds. 85, a compound having the formula [wherein R8 is hydrogen, RI is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
]; Phenyl; R alkyl, R alkenyl and
Hyalalkynyl (however, the aryl part is phenyl)
aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (with the exception of the above heterocyclic group)
Heteroatoms in a minute are 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
(the alkyl moiety has 1 to 6 carbon atoms)
selected from the group consisting of:
Minutes are C1-C6 alkyl (optionally amine, halo, hydrogen).
By droxy or carboxyl? ! # has been replaced
) No mouth -〇R3 1 -CNIζ3R4 -N R3R4 1f -NI(CNR"R4 R3δNR4- CO2R3 ;0 〇10δR3 S R3 ♀ -S R' RiCN -N. 108O3R3 -OS o, R3 -NR35O2R' -NR3 (i'=NR" 3 -NR3C02R4 NO2
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to O carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety];
Nyl; Ralkyl, Ralkenyl and Hialua
Luquinyl (however, the aryl part is phenyl, fatty
group moieties have 1 to 6 carbon atoms); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (however, the above heterocyclic moiety)
Heteroatoms are more powerful than 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
the lukyl moiety has 1 to 6 carbon atoms)
selected, or R3 and R4 are at least one
a 5- or 6-membered nitrogen-containing heterocyclic ring together with the nitrogen to which it is linked.
may be formed: R9 must not be hydrogen.
is as defined for R3; or the formula
In the middle, R1 and R8 together represent C- to CtO alkylidene or
is substituted by hydroxy C2~C! . Al
Kylidene is represented by bf; A is cyclobenzene, cyclohexane.
xylene or C2-C6 alkylene (optional 1 or
Substituted by more CI~C@ alkyl groups
]; R2 is hydrogen, anionically charged or a common capacitor.
It is an easily removable carboxyl protecting group (with the exception that R2
When is hydrogen or a protecting group, the opposite ion also exists)
;Y is hydrogen, C1-C6 alkyl, hydroxy s-8
C1-c6 alkyl, carboxyl, carbamoyl,
Rolo, bromo, iodo, fluoro or phenyl];
Alternatively, the compound according to claim 85, wherein R1 and R8 together represent a compound n87, which can be used as a medicine. 88. The compound according to claim 85, wherein R1 is 0)I H3CH-. 89R1? 1 H3CH-, the patent claim in which the supply pair arrangement is 5R, 68, 8R
A compound according to Range 85. 90, A is -CH, CH, -1CHZ CR2CHz-
1-CHCH2-185, 86, 87, 88 or 89 item
Compounds described. 91, a compound having the formula [wherein R8 is hydrogen, R1 is hydrogen;
Substituted and unsubstituted: alkyl, alkenyl and alkynyl
(having 1 to 10 carbon atoms); dichlorofurkyl and
Cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
having 1 to 6 carbon atoms in the carbon atoms and alkyl moieties
); Phenyl; Ralkyl, Ralkenyl and H
Aralkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms); hetero
Aryl, heteroaralkyl, heterocyclyl and
Heterocyclylalkyl (but the heterowalking part above)
Raw heteroatoms are from 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
the alkyl moiety has 1 to 6 carbon atoms)
selected from; where the substitution positions relating to the above residues are selected from;
C, -wC, alkyl (M meaning is amino, halo, hydro
10 R3 010δNR3R- -NR3R' -80, NR3R4 R3 NR'- -CO2R" = 0 0CR3 -S R"-8R' ? 18R" CN -N3 108OsR" 10SOR3 -NR" 802 R'-NR"9=NR4 3 -NR3C0,R' NO2 independently selected from the group; to
with respect to which the groups R3 and R4 are hydrogen; alkyl, alkenyl;
and alkynyl (having 1 to 10 carbon atoms);
Chloalkyl, cycloalkylalkyl and alkylsilyl
Chloalkyl (3 to 6 carbon atoms in the cycloalkyl ring and
and 1 to 6 carbon atoms in the alkyl moiety);
R; Ralkyl, Ralkenyl and Hyalal
. quinyl (however, the aryl part is phenyl, and the fat
having 1 to 6 carbon atoms); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (however, the above heterocyclic moiety)
A heteroatom consists of 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of
or R3 and R4 are at least 1
a 5- or 6-membered nitrogen-containing heterocyclic ring with nitrogen atoms linked to
]; R9 must not be hydrogen.
must be defined for R3; or
is R1 and R11d in the formula, together with C2-CtO alkyl
C2-CI substituted by dene or hydroxy
O alkylidene fi = Table b-f S Att cyclopene
Tylene, cyclohexylene or C2-C6 alkylene (
optionally substituted with one or more alkyl groups
); R1 is hydrogen, anionically charged or easily
is a removable carboxyl protecting group (provided that R2 is water)
When it is an element or a protective group, a reverse ion also exists)];
Or a combination of 93, R1 and R8 that can be used as a medicine.
92. A compound according to claim 91, which represents: 94. The compound according to claim 91, wherein R1 is H H3CH7 . 95, R'? 1 H3CH- and the absolute configuration is 5R16S, 8R.
Compound 0 described in Range 91 96, A is -C12CHm -1CHHz CH2CHz
-1-CHCH, -1 Item 91.92.93.94 or the compound described in Item 95. 97, Compounds having the formula [wherein R- is hydrogen, anionically charged or
is an easily removable carboxyl protecting group (fC
When R2 is hydrogen or a protecting group, a reverse ion also exists.
); or a salt thereof that can be used as a medicine. Claim 98R2 is p-nitrobenzyl
Compound described in No. 97m. Claim 97, wherein 99R2 is anionically charged.
Compounds described. 100, a compound having the formula [wherein R8 is hydrogen, R1 is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
]; phenyl, aralkyl, aralkenyl and
Hyalalkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
and heterocyclylalkyl (with the exception that the above heterocyclic part
Heteroatoms in minutes include 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of:
The rukyl moiety has 1 to 6 carbon atoms)
selected from; in which the substituents related to the above residues are
, %C, alkyl (optionally amino, halo, hydroxy)
(convex R・SR3 CN N3 -0803R3 -OS o2R3 -NR3S o2R4 -NR3C=NR't3-NR3CO2R'-NO. Yo! independently selected from the group consisting of:
Regarding moieties, the groups R33 and R4 are hydrogen; alkyl, alkyl;
Kenyl and alkynyl (having 1 to 10 carbon atoms)
;cycloalkyl, cycloalkylalkyl and alkyl
cycloalkyl (3 to 6 carbon atoms in the cycloalkyl term)
having 1 to 6 carbon atoms in the child and alkyl moiety];
phenyl; ar-alkyl, ar-alkenyl and hyar
Alkynyl (however, the aryl part is phenyl, and the fatty acid
aliphatic moieties have 1 to 2 carbon atoms); and hetero
Aryl, heteroaralkyl, heterocyclyl Ez
heterocyclylalkyl (but the above heterothyroid
Hetero Jf atoms in minutes are 1 to 4 Wp elements, nitrogen or sulfur
Select from the group atoms, which are adjoint to the hetero
from the alkyl moiety (having 1 to 6 carbon atoms)
ii R3 and R4 are selected independently or ii R3 and R4 are
Contains 5- to 6-membered nitrogen with at least one linked nitrogen.
May form anomalous terms; R9 must not be hydrogen.
Except that it is not, it is better to be defined for R3.
; or R1 and R8 together are '4-CIO alkyly
02-CI substituted by dene or hydroxy
O represents alkylidene; A is cyclopentylene,
lohexylene or C2-c6 alkylene (optionally mono- or
is substituted with more C1-C4 alkyl groups
); R2 is hydrogen, anionically charged or a common capacitor.
It is a carboxyl protecting group that is easily removed and re-extended (however, R2
When is hydrogen or a protecting group, the opposite ion is also present)
;Y is hydrogen, C, -C6 alkyl, hydroxy, -8-
C, ~C6 alkyl, carboxyl, carno (moyl,
Chloro, bromo, iodo, fluoro or haphenyl]
or CHa CH-, which can be used as a medicine.
Compounds listed. 102. The compound of claim 100, wherein R1 and R8 are together. 105l71? 101. The compound of claim 100, which is 1 H3CH . 104. A patent claim in which R" is ?H Cn3CH and the absolute configuration is 5R16S, 8R
A compound according to Range 100. 105, A is -CH2CH2-, -CH1CH2C
H2-1-C) ICHt-1100, 101, 102,
A compound according to item 106 or 104. 106, a compound having the formula [wherein R11 is hydrogen, R1 is water]
elemental; substituted and unsubstituted; alkyl, alkenyl and alkyl
Nyl (having 1 to 10 carbon atoms); cycloalkyl
and cycloalkyl (3 to 6 carbons in the cycloalkyl ring)
having 1 to 6 carbon atoms in the atoms and alkyl moieties);
Phenyl; Ralkyl, Ralkenyl and Hir
Rualkynyl (aryl moiety is phenyl, aliphatic
moiety has 1 to 6 carbon atoms); heteroaryl;
heteroaralkyl, heterocyclyl and heterocyclyl
lylalkyl (with the exception of a heterogen in the above heterocyclic moiety)
from the group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms
The alkyl moiety selected and associated with the heterocyclic moiety is
having 1 to 6 carbon atoms)
; Substituents related to the above residues in the formula C1-C6 alkyl (optionally amino, halo, hydroxy);
) -○R3 -(!'NR3R4 1 -CNR3R4 NR3R4 -S o2NR3R4 1 -NHCNR3R4 R3SaNR4- -C02R3 =0 1 0CR3 S R3 1 S R9 - R9 CN N5 =080313 - OS 02R3 -NR3SO2R'-NR3C=NR' Table 3 - N l13C02R' No2 In the formula, with respect to the above-mentioned substituents, the groups R3 and R4 are hydrogen;
Alkyl, alkenyl and alkynyl (1 to 1o carbons)
atom); cycloalkyl, cycloalkylalk
Kyl and alkylcycloalkyl (in cycloalkyl section)
3 to 6 carbon atoms and 1 to O carbon atoms in the alkyl moiety
]; Phenyl: R-argyl, R-arke
nyl and aralkynyl (however, the aryl part is
and the aliphatic moiety has 1 to 6 carbon atoms]
; ordinary heteroaryl, heteroaralkyl, heteroaryl
Rosyclyl and heterocyclylalkyl (but the above
Heteropressor in the heterothyroid part contains 1 to 4 oxygen, nitrogen or
is selected from the group consisting of Bihuang atoms, and the heterocyclic moiety
The alkyl moiety associated with has 1 to 2 carbon atoms.
], or R3 and R4 are selected from
Contains 5- or 6-membered nitrogen with both nitrogens linked together
may form a heterocyclic ring; R9 must not be hydrogen
except as defined for R3;
Alternatively, in the formula, R1 and R8 together represent C2-CIO alkyl
C2-C substituted by lydene or hydroxy
tO represents alkylidene; Ail cyclopentylene;
Cyclohexylene or C2-C6 alkylene (optionally
substituted by one or more C8-C4 alkyl groups
); R2 is hydrogen, anionically charged or
is an easily removable carboxyl protecting group (but
When R2 is hydrogen or a protecting group, a reverse ion may also be present.
]; or a compound as a medicine. 10a The compound of claim 1061, wherein R1 and R8 collectively represent. 109, R1? 106. The compound according to claim 106, which is 1 CH, CH-. 110, Claims in which R' is 0H C1(3C)l- and the absolute configuration is 5R16S, 8R
A compound of paragraph 106. 11t A is -CII2 CR2-, C112CH2
CH2-1-CHCHz-1H3 The compound described in item 106, 107, 108, 109 or 110
Compound. 112, a compound having the formula [wherein R2i-j, hydrogen, anionic charge]
or a commonly used easily removable carboxyl protecting group.
(However, when R2 is hydrogen, a reverse ion also exists.
); 11A rL" is p-nitrobenzyl
Claim 112 Compound 114, R2 is anionically charged
A compound according to item 112. 115, Compounds bearing the formula [wherein R8 is hydrogen, R1 is hydrogen]
;Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to B in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
]; phenyl) ar alkyl, ar alkenyl and
Hyalalkynyl (the aryl part is phenyl,
aliphatic moiety having 1 to 6 carbon atoms); heteroaryl
heteroalkyl, heteroalkyl, heterocyclyl and hihete
Rosyclylalkyl (however, the above heterocyclic moiety
a group consisting of 1 to 4 oxygen, nitrogen or sulfur atoms
an alkyl selected from and associated with the heterocyclic moiety;
selected from the group consisting of 1 to 6 carbon atoms.
selected; in which the substituents relating to the above residues are c',
-yc6 alkyl (optionally amine, halo, hydroxy
or substituted by carboxyl) -〇R3 〇1〇convex NR3R' monocrystalline R3R4 -NR"R4 -8o2NR3R' -N) ((!'NR3R4 1 R3CNR4- -Co2RB =0 - OCR3 -8lζ3 SR9 ? SR9 1 independently selected from the group consisting of CN -N3 -OS os R3 -OS o, R3 -NR35O2R'-NR''C=NR43-NR3C02R'NO2;
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety);
Nyl; Ralkyl, Ralkenyl and Hialua
ruquinyl (however, the aryl part is phenyl, and the fat
group moieties have 1 to 6 carbon atoms); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (however, the above heterocyclic moiety)
A heteroatom consists of 1 to 4 oxygen, nitrogen or sulfur atoms.
an alkyl group selected from the group consisting of
the ru moiety has 1 to 6 carbon atoms)
, or at least one of R3 and R4 is connected.
May form 5 or 6 negative nitrogen-containing allochthonous cells with 9 chords.
; R9 must not be hydrogen;
or R1 and R8 are defined as υ; or R1 and R8 are
, together with C2-CIO alkylidene and hydroxy
represents a C2-CIO alkylidene substituted with
; A is cyclobenzene, cyclohexylene or 1dCz
~C6 alkylene (optionally one or more C1-C
(substituted by 4 alkyl groups); R2 is
Hydrogen, anionically charged or commonly used easily removable carboxylic acid
xyl protecting group (provided that R2 is hydrogen or a protective group)
(when the opposite ion is present); Y is hydrogen, C, -
C, alkyl, hydroxy, -5-C1-C6 alkyl
, carboxyl, carbamoyl, chloro, bromo, io
or used as a medicine.
Usable power that salt. ? 1 or CN3C)l-
Compounds listed. 117, the compound according to claim 115, wherein R1 and R' together represent
a R1? 1 CH, CH-. 119, R1? 1 H3CH- and the absolute configuration is 5R16S, 8R.
A compound according to Range 115. 120A is -CH2CH2-1-CN2 CN2 CN
2-1-CHCH, -1SN3 115.116.117.118 or 119
Compound. 121, a compound having the formula [wherein R8 is hydrogen, Hl is hydrogen]
Substituted and unsubstituted: alkyl, alkenyl and alkini
(having 1 to 10 carbon atoms); cycloalkyl and
and cycloalkylalkyl (3 to 6 in the cycloalkyl ring)
carbon atoms and 1 to 6 carbon atoms in the alkyl moiety
phenyl, aralkyl, aralkenyl and
Hyalalkynyl (however, the aryl part is phenyl)
and the aliphatic moiety has 1 to 6 carbon atoms);
loaryl, heteroaralkyl, heterocyclyl and
Hiheterocyclylalkyl (with the exception of the above heterocyclic group)
Concentrating heteroatoms include 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group consisting of
the alkyl moiety having 1 to 6 carbon atoms);
Substitution classification with respect to the residues in note 1, C, -C6 alkyl (optionally amino, halo, hydroxy)
substituted by cy or carboxyl)-o e
N R3R4 1 -CNR3R4 -NR3R'-8O2NR3R' -NllCNrt3R4 R3g N R3R' -CO,Ie8 =〇-3R" 〇LR9 SR9 CN N3 -0803R3 -OS o, R3 -NR35O,R'-NR3C=NR' 3 -NR3C02R' N02 where the above substituents are
, the groups R3 and R4 are hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 10 carbon atoms);
Cycloalkyl, cycloalkylalkyl and hyalkyl
Cycloalkyl (3 to 6 carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety);
Nyl; Ralkyl, Ralkenyl and Hialua
ruquinyl (however, the aryl part is phenyl, and the fat
group moieties have 1 to 6 carbon atoms]; and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (but in the above heterocyclic moiety)
A heteroatom consists of 1 to 4 oxygen, nitrogen or sulfur atoms.
selected from the group of
(having 1 to 6 carbon atoms)
or at least one of R3 and R4 is connected.
forms a 5- or 6-membered nitrogen-containing heterocyclic ring with the gold element
good; or R9 must not be hydrogen;
is defined for R3; or R1
and R8 are collectively C, ~ CIOC6 alkylidene
C2-CIO alkylidene substituted by xy
represents -J-;AH cyclopentylene, cyclohexylene
or C2-C6 alkylene (optionally one or more
) is substituted by a C1-C4 alkyl group of
R2 is hydrogen, anionically charged or easily removable.
(provided that R2 is hydrogen or
When it is a protecting group, the opposite ion is also present); or
Compounds that can be used as medicines. 125. The compound according to claim 121, wherein R' and R8 together represent. 124, R1? 121. The compound of claim 121, which is 1C)13CH-. 125, a patent claim in which R" is ?1 H3CH-, absolute, opposite configuration is 5R16S, 8R
A compound according to item 121. 126, A is -CH2CH2-1-C & CH2C
Ht-1-CHCH, -1R3 The compound described in item 121, 122, 123, 124 or 125
Compound. 127, a compound having the formula [wherein R2 is hydrogen, an ionically charged or normally
Easily removable carboxyl retaining group (only
When R2 is hydrogen or a protecting group, a reverse ion also exists.
); or the location where it can be used as a medicine. 12B, Claim in which R2 is p-nitrobenzyl
Compounds according to the range No. 127. 129. Claims in which R2 is an anionic load
A compound according to item 127. 130, a compound of the formula [wherein R8 is hydrogen, R1 is hydrogen; substituted
and unsubstituted, substituted: alkyl, alkenyl and alkynyl (
having 1 to 10 carbon atoms); cycloalkyl and cycloalkyl;
Chloalkylalkyl (3 to 6 carbons in the cycloalkyl ring)
having 1 to 6 carbon atoms in the elementary atoms and alkyl moieties)
; Phenyl; R alkyl, R alkenyl l'ph
alkynyl (just 1-, the aryl part is phenyl)
aliphatic moiety it has 1 to 6 carbon atoms);
Teroaryl, heteroaralkyl, heterocyclyl
and heterocyclylalkyl (but the above heterocyclic
Partially raw heteroatoms are 1 to 4 oxygen, nitrogen or sulfur atoms
selected from the group consisting of:
The alkyl moiety has 1 to 6 carbon atoms.
selected from the group; in the formula - substitutions for the above residues;
C1-C6 alkyl (optionally amino, halo, hydrogen)
substituted by droxy or carboxyl)1
0 OR3 -MustNR3R4 -NR3R4 502N R3R' -NHI! l'NR3R'; the above substitutions in the formula
Regarding the groups R3 and R4, hydrogen; alkyl, alke
nyl and alkynyl (having 1 to 1 o carbon atoms);
Cycloalkyl, cycloalkylalkyl and alkyl
Cycloalkyl (5y6 carbon atoms in the cycloalkyl ring)
and having 1 to 6 carbon atoms in the alkyl moiety];
nyl; ar-alkyl, ar-alkenyl and ar-a
Ruquinyl (however, the alkyl part is phenyl, and the fatty
having carbon atoms in the group part number 1 to B); and heteroa
Ryl, heteroaralkyl, heterocyclyl and hehe
Terocyclylalkyl (but in the above heterocyclic moiety)
Heteroatoms are υ such as 1 to 4 oxygen, nitrogen or amber atoms.
selected from the group consisting of:
The rukyl moiety has from 1 to
selected, or R3 and R4 are at least one
a 5- or 6-membered nitrogen-containing heterocyclic ring together with the nitrogen to which
may form; R9 must not be hydrogen
as defined for R3; or
R1 and R8 together represent C2-CIO alkylidene or
C2-CIO alkyl substituted by hydroxy
Represents lidene; R5 is substituted and unsubstituted: alkyl,
alkenyl and alkynyl (having 1 to 10 carbon atoms)
]; cycloalkyl and cycloalkylalkyl
3 to 6 carbon atoms in the chloroalkyl ring and in the alkyl moiety
having 1 to 6 carbon atoms); Phenyl; Ralkyl
ar, aralkenyl and aralkynyl (however, aralkenyl and aralkynyl
The reel part is phenyl, and the aliphatic part is 1 to 6 charcoal.
(containing an elementary atom); heteroaryl, heteroaralal
Kyl, heterocyclyl and heterocyclylalkyl (upper
The heteroatom shown in the above is 1 to 4 oxygen, nitrogen,
or a sulfur atom, and the heterocyclic
The alkyl moiety attached to the moiety contains 1 to 6 carbon atoms.
selected from the group consisting of
The groups include C1-C6 alkyl (optionally amine, fluoro,
to chloro, carboxyl, hydroxy or carbamoyl
Fluoro, chloro or habromo; -0R3; -0CO2R3; -0COR3; -CONR3R';-08O2R3;8R3;18O3R3;-CO,R'';-CN; phenyl (optionally 1 to 3 fluoro, chloro, bromo,
C1-C6 alkyl, -〇R3, -NR3R', -S
substituted by o3R3 or -CONR3R4
) (The above R5fifr repression medium R conidia R4 and R9 are
or R5 is selected independently from
Divalent phenylene or C1-c4 alkyl which forms a monovalent group
May represent cyclobenzene; A may represent cyclobenzene,
lohexylene or C2-c6 alkylene (optionally mono- or
is replaced by more C1 to C4]
R2 is hydrogen, anionically charged or easily removable.
(provided that R2 is hydrogen or
When it is a anchor group, there is also an inverse ion;
contains at least one nitrogen and is linked to A through a ring nitrogen
, thereby forming a quaternary ammonium group or
Non-[9 mono-, py- or polycyclic non-aromatic heterocyclic residues
]; or a method for producing its salt that can be used as a medicine.
(1) an intermediate of the formula (wherein R1 and R8 are as defined above) in an inert organic solvent;
and R21 is a commonly used easily removable carboxy group.
diphenyl chlorophosphate in the presence of a base.
to form an intermediate of the formula (wherein R1, R8 and R'' are defined above).
(2) Intermediate ■ in an inert organic solvent and in the presence of a base
mercapta of the expression % expression % (where the expression middle person is as defined above)
a reagent and an ash, and an intermediate of formula (where R1, IN, A and R31 are defined above).
(3) In an inert organic solvent and in the presence of a base, intermediate ■ was obtained.
Contrary to methanesulfonyl chloride or its blind acylated equivalent.
Correspondingly, intermediates of the formula (wherein R1, R8 and R21 are defined above)
(4) Intermediate ■ in an inert organic solvent was used as an iodide ion source.
React to replace methanesulfonyloxy group with iodo group
and intermediates of formula (wherein R1, R8, A and R2' are defined above)
and (5) forming the intermediate in the presence of silver ions in an inert organic solvent.
■ undergoes nucleophilic substitution with an amine of the formula, where the amine is as defined above.
The iodo group of intermediate ①1 is substituted with a group, and the formula (in the formula, XeIrJJ:A-nrJ)
, A%R', and R3/ are as defined above.
), and in the case of r9rW, carboxyl
Removal of the syl protecting group R11 resulted in the corresponding unblocked
Compounds of formula I can be used as pharmaceuticals to obtain their salts.
A method characterized by a step of