JPH03170053A - Method of predicting biological activity of antibiotics and novel beta lactam antibacterial agent derived by the same - Google Patents

Abstract

PURPOSE: To quantitatively predict the conformity by minimizing the species energy of molecule as the function of two surface angle of the molecule while holding the length and angle of the bond constant, and uniformly mapping subspace. CONSTITUTION: The species energy of molecule is minimized as the function of two surface angle of the molecule while holding the length and angle of the bond constant. Before the minimizing, the subset of the parameter for forming a base for specific subset of complete parameter space is considered. For ϕ two surface angle and ψ two surface angle of backbone of the molecule of the subset, 0, ±90, 180 degrees are formed, and for the first two surface angle of side chain, -60, 180 degrees are formed, and ωtwo surface angle and the other two surface angle are all maintained 180 degrees. The unspecified number of the points of the subspace of the parameter corresponds to the species energy of the relative molecule. Then, the subspace is mapped to the uniform random distribution, and hence several points are discovered near the protrusions of the minimum amount of the energy.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel antibacterial agents and methods for predicting their biological activity relative to penicillin. More specifically, this application describes the candidate compounds,
A molecular modeling method for determining suitability and reactivity for bacterial cell wall receptors, that is, a method for predicting the structural form that will exhibit activity, is described.

It has been known since the 1910q-era that β-lactam antibiotics, such as penicillins and cephalosborins, exert their efficacy by interfering with the bacterial cell wall itself. This interference may also be caused by penicillin-binding protein J
It has been discovered that PBPs occur by covalent bonding with serine residues in the active site of one or more enzymes of a group called (PBPs). These enzymes help complete bacterial cell wall integration by cross-linking peptide glucan chains, and these enzymes are essential for cells. All known PBPs are -Ser-X-
It has the sequence X-Lys-, and the simplest reaction kinetic description of the reaction between PBP and β-lactam antibiotics is as shown in the following formula l, where A is a generalized structure. Since PBP is regenerated by the deacylation process,
Useful antibacterial activity includes k3/k≧l O O O M-
'see-' and k4≦1x10-' sec-
It is thought that there is a need to have a

Step I Step 2 The question, then, is what, if any, is the causal relationship between antibacterial activity and the "lock-and-key" interaction between PBP and antibiotics. be. The present invention determines the causal relationship between antimicrobial activity and the lock-and-key interaction between PBPs and selected antibiotics, thereby determining whether any selection is proportional to penicillin compatibility and reactivity. A means by which the ``compatibility (Wang Cheng 1) J and ``reactivity (Step 2)'' of the candidate structure can be predicted with a certain degree of quantitative accuracy in comparison to the compatibility and reactivity of penicillin. There are some that aim to provide.

Another object of the present invention is to create novel non-beta-lactam compounds with antimicrobial activity by this model.

One aspect of the present invention provides molecular seed energy (strain
A method for determining the molecular structure of a large molecule that minimizes energy or molecular parameters, the method comprising selecting one of a large number of most probable random structures to identify starting parameters for a minimization method. characterized in that a point energy is first calculated, and a predetermined number of said random structures with a minimum energy are selected for said minimization method. Accordingly, in another aspect of the invention, a method is provided for determining the suitability and reactivity of any selected candidate antimicrobial compound, the method comprising: (a) a serine-lysine active site serine contained in a penicillin-binding protein; simulating the reaction of said compound with a model of said penicillin binding protein by determining the relative ease of forming a four-centered relationship between the OH of and a reactive site of said compound; and (b) determining the activation energy for the four-center reaction of the chemically active functional group of said compound with methanol relative to the activation energy of the corresponding reaction of methanol with N-methylazetidinone. There is a method that provides a method consisting of the following. Another aspect of the invention is a non-β-lactam-containing compound, wherein the compound is capable of forming a transition structure with four centers, the transition structure including a model of a penicillin-binding protein in response to the compound. The compound contains serine OH groups contained in
The object of the present invention is to provide a compound having an activation energy for reaction with methanol that is not much larger than 1/mol. Still another aspect 8 of the present invention is a compound represented by the following general formula (I): (wherein, X is a group selected from S, 0, CH2, N}I, NR? and Se, and Y is a group selected from (IH.NH2, NIICOR9 and SH, R,, R2. R3, R4, RS, R6 and R7 each mean a hydrogen atom, an alkyl group or an aryl group, R9 is a β-lactam group) (meaning the active side chain) as well as pharmaceutically acceptable salts thereof.

The active side chains of β-lactams are those side chains known to be active in β-lactam antibiotics. The permissible substituents in the beta-lactam antibiotics used in this invention include any of the wide range of permissible substituents described in the literature for penicillin and cephalosborin compounds. Such substituents include, for example, the formula ? XQ (wherein, X means an oxygen atom or a yellow atom, and Q is C, ■ an alkyl group (for example, methyl or ethyl)
, C2■ alkenyl group (for example, vinyl or brobenyl) or an aryl C1-4 alkyl group (for example, a phenyl C,-4 alkyl group such as a benzyl group).

Such substituents may also include, for example, those of the formula carbonyl) and substituted and unsubstituted aliphatic (by way of example meaning a group selected from alkyl, preferably C.-C6 alkyl (for example methyl, ethyl, inglovir or n-probyl)).

Specific examples of the substituted vinyl group represented by the above formula include 2
-carboxyvinyl, 2-methoxycarbonylvinyl,
Mention may be made of 2-ethoxycarbonylvinyl and 2-cyanovinyl.

Permissible substituents for other β-lactams also include those of the formula -CI{2Y, where Y is a hydrogen atom or a nucleophile atom or group, such as a nucleophile residue or a derivative of a nucleophile residue. and unsubstituted or substituted methyl groups represented by the following. That is, Y is, for example, a nucleophilic nitrogen atom, a carbon atom,
It can be derived from a wide range of nucleophiles characterized by having sulfur or oxygen atoms. Such nucleophiles are widely described in the patent and technical literature relating to β-lactam chemistry, including, for example:
U.S. Patent No. 4,385,177 (Patentee Foxton et al., Patent date: May 24, 1983), Column 4, No. 42
Examples include the compounds described from line 8MA to line 24, and the descriptions referred to from column 34, line 51 to line 36i, line 17. Yet another aspect of the invention is represented by the following general formula, (wherein X is so.c++., NH.NR. and S
There is a group selected from e, Y is O}I. N.H. , NHCOR, and SH; , R2, R3, R. , R1, R6, R
, and R6 each represent a hydrogen atom, an alkyl group, or an aryl group; R9 represents an active side chain of a β-lactam) and pharmaceutically acceptable salts thereof.

Yet another embodiment of the present invention is a compound represented by the following general formula (II1): [wherein, ? -Y is S-S, CHte}12. S-CH2,
Cf+2-S,S-NR■ NRa-S, (:lIJ-
0,O-CI+2.0-NRa. NRa-0, Se-S
e, Cll*-Ctlt, Se-CH*, Z is a group remaining from OH, Nll*, NHCORs and 3B, Rl, R2, R3, R4. Rs. Ra and R6
each represents a hydrogen atom, an alkyl group or an aryl group, R7 represents an alkyl group or an aryl group, and R represents an active side chain of a β-lactam] and pharmaceutically acceptable salts thereof. There are things to do.

Yet another aspect of the present invention is a compound represented by the following general formula (rv): R5 [wherein X is a group selected from S, 0, Cl2, N}I, NR6 and Se, ? is N. is a group selected from CI1 and CR7, where Z is OH. Nll■, SN or NIICORt (Y
or N), Z means RIG (when Y or CH or CR,), Rl, R2, R3. R4, R1, R. and R
, respectively mean a hydrogen atom, an alkyl group or an aryl group, R9 means an active side chain of a β-lactam, R,. provides R++-CH-Rll (wherein R. means an alkyl group or an aryl group, and Rl! means OH, N}11.NHCOR9 or SH)] and pharmaceutically acceptable salts thereof. It is something to do.

Furthermore, another aspect of the present invention is a compound represented by the following general formula (V): [wherein X is a group selected from S, 0, CH2, NH, NIIS and Se, and Y is NR6-Z and Rl. R2. RI R4, R. J and R6 each mean a hydrogen atom, an alkyl group or an aryl group, Z is 0}1, 311, NH2 or N}ICOl'l
, R9 refers to the active side chain of a β-lactam] as well as pharmaceutically acceptable salts thereof.

There it is. The trick is, R, is a hydrogen atom, and l is N.
IICOR9 (wherein R means a lower alkyl group, especially a pencil group).

The term "alkyl group" as used in the present invention refers to an alkyl group containing up to 20 carbon atoms, preferably an alkyl group of the order prime number or from 1 to 6, where the alkyl group is optionally substituted with functional groups such as free, etherified or esterified hydroxy or mercapto groups, such as lower alkyl or lower alkylthio; optionally substituted lower alkoxycarbonyloxy or lower alkanoyloxy; halogen; oxo; nitro; optionally substituted amino, such as lower alkylamino, lower alkylamino, lower alkylamino, oxo lower alkylene amino or Lower alkylamino, as well as acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halogeno-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted carhamoylamino , uretocarbonylamino or guanisinocarbonylamino; furthermore, in case q, alkali metal salts,
It may also be present in the form of a salt, such as an acyl or acyl form such as lower alkanoyl or penzoyl.

Furthermore, optionally functionally modified carboxy groups, such as carboxyl present in salt form, esterified carboxyl groups, such as lower alkoxycarbonyl, optionally substituted carbamoyl groups, such as N-lower alkylcarhamoyl or N,N-cy lower alkylcarhamoyl, as well as optionally substituted uretocarbonyl or quanicinocarbonyl groups: nitrile group: optionally functionally modified Good sulfo groups, such as sulfamoyl or sulfo, which may be present in salt form:
or a phosphono group optionally substituted with 0-mono- or 0.0-disubstituted, for example by optionally substituted lower alkyl, phenyl or phenyl-lower alkyl. Further examples include substituents which may be unsubstituted or monosubstituted so as to form a salt such as an alkali metal salt.

The term "aryl group" as used in the present invention means a carbocyclic or heterocyclic aryl group. Examples of dicyclic aryl groups include, for example, phenyl or naphthyl groups, which optionally contain up to three halogen atoms, C,-6 alkyl groups, C,-6 alkoxy groups, halo((: +-6) Alkyl group, hydroxy group, amine group, carboxy group C, -6 alkoxycarbonyl group, C1-6 alkoxycarbonyl=(C+-S) alkyl group, nitro group, sulfonamito group, CI- 6 alkylcarbonyl group, amito (CON++2) group or C,
-6 means an alkylamino group.

The term "heterocyclic" means that the ring consists of up to 4 beta atoms selected from oxygen, nitrogen and sulfur atoms, optionally up to 3 halogen atoms, C1-6
Alkyl group + C I- 6 alkoxy group, halo (C +
-s) Alkyl group, hydroxyl group, amino group, carboxy group. CI-6 alkoxycarbonyl group, C1-6
Alkoxycarbonyl-(C+1.)alkyl group, aryl group, oxo group, nitro group, sulfonamito group, C
, -6 alkylcarbonyl group, amide group or C1-6
It means a single or fused ring which may be substituted with an alkylamino group.

Suitable C1-6 alkyl groups include straight-chain or branched groups, such as methyl, ethyl, n-probyl, isobrobyl, n-phthyl, sec-butyl, isophthyl, E-tutyl, and the like. It will be done.

Possible structures for peptides (e.g., enzymes), penicillins, and cephalosborins are available from the Quantum Chemistry Program Exchange (QuantuIIChe) at the University of Indiana, Bloomington, Indiana, USA.
Mistry Program Exchange -
Computer program M obtained from QCPE)
Listened using MP2 (85). This program {yo,
Calculate the species energy of a molecule in terms of the contribution to the species energy of the molecule associated with bond stretching, bond angle bending, bond deformation, and electrostatic and van der Waal interactions of nonbonded atoms It is something. To perform this calculation, you must enter the Cartesian coordinate values of all atoms and define a list of bonded and attached atoms. If the type of atoms present in the molecule of interest is known, then the seed energy can be calculated using the Newton-Raphson
son) technique can be applied to an unconstrained, multivariate, nonlinear function that includes all of the individual contributions mentioned above. This function is called a force field. In order to proceed with the minimization in a reliable manner, it is important that the geometry entered at the beginning of the calculation be reasonably accurate and close to the bottom of the energy well.

For each of the different molecules examined by the computer program MMP2 (85), it is first necessary to determine parameters relating to the type of atoms present inside this molecule. These parameters include, among others, standard bond lengths and bond angles and stretching and bending force constants. The length and angle of the bond can be obtained from the accumulation of vibrational data, and the others can be calculated by the molecular orbital (MO) method. A general method for parameter expansion is described in the paper "Molecular 0 Mechanics (Molecular
Mechanics). )I! l!
The parameters for peptides (e.g. enzymes), penicillins and cephalosborins to define the force field required for P2 were previously unknown, but these parameters were initially determined and compared to known Experimental crystal structures are tested for their ability to reproduce and the known effects of solvents on the morphology (three-dimensional structure) of different structural types are investigated. These parameters are PEPCON (Appendix 1)
(About Bebutide) ． PENCON (Appendix 2
) (for penicillin). CEPARAM
(Appendix 3) (for cephalosporins). The second requirement necessary to use the computer program MMP2 (85) is the definition of an initial set of Cartesian coordinate values. For small molecules such as penicillins and cephalosborins, experimental crystal structure coordinates can be used. Then, by minimization with appropriate parameters, it is possible to obtain a calculated structure that reproduces the experimental structure. This structure progresses to other forms, and a series of dihedral movements around each of the dihedral angles of the molecule results in a spherical minimum of the dihedral angle.

This is an option available in the computer program MMP2 (85), which works well. However, such techniques are impractical for the analysis of peptides due to the very large number of dihedral angles that must be investigated for any such molecule containing two or more amino acid residues. Not. I want to. Computer program ECEPP (E+*pirical Conf) available from QCPE
OrationalEnergy Program
for Peptides) has been changed to random
2000 numbers containing the most probable backbone and dihedral angle permutations using a number generator.
It is possible to calculate the one-point energy of 00 initial structures. The 50 structures with the minimum energy identified in this way are read out and quadratic minimization method (quadratic minimization) is performed.
procedure) and then using the Newton-Raphson method @P: MM for face reduction.
P2 (85) - Changed to matte. The purpose of this initial search is to identify suitable starting parameters. This approach has been extensively tested, works well, and has been applied for the treatment of PBP as described below.

By actually applying these techniques, nine penicillins of the initial series (la-1i) were investigated. Of these nine penicillins, 1a-1d are highly active antibiotics (ampicillin, penicillin G, penicillin V) that are widely used as medicines, and le-1f is a significantly less active antibiotic. Yes, 1g-
1i was biologically inert. The morphological analysis of these compounds shows that the antibacterial activity is specifically related to the three-dimensional structure in which the carboxy group as well as the side MN-H protrude from the convex surface, i.e. the receptor, i.e. P
It can be seen that this is related to the interaction between BP and the lock and key that bond hydrogen.

1C: R- PlICH2CO- 1d: RII PhOCH2CO- A morphological analysis was then performed on cephalosborins 2a-2c. Each of these compounds has a phenoxyacetyl side chain, penicillin V (
ld). The ▲3 monoisomer 2a is biologically active but readily equilibrates with the biologically inactive ▲2 monoisomer 2b. The reason for the lack of 4-2b activity has not been established so far, but
It has been suggested that the EP▲2 monoisomer 2c shows better compatibility with PBP receptors and has antibacterial activity. However, such compounds are also inert. Therefore, the reason for this lack of activity is also unknown.

It has been found that cephalosborin compounds 2a-2c, like penicillin compounds 1a-1d, preferentially adopt a form in which the side buttons N-H occupy the convex surface of the molecule. As in the case of penicillin, the interaction of the lock and key with the receptor is therefore primarily due to the carboxyl group and the %N on this side.
It is naturally assumed that it is involved in a linear bond with -H.

CO2- C○2- The active site serine D-alanylcarboxybebutitase transbebutidase of the Streptomyces strain R61 was crystallized by the introduction of a β-lactam compound, and its crystal structure has not been partially analyzed. There is. The pFI dependence of the same enzyme was also investigated. These two tests showed that the carboxyl group of penicillin is closely associated with the protonated terminal amino group of the lysine residue of X-X-Lys. Its crystal structure confirms that in the complex, the β-lactam ring of penicillin is present in close proximity to the active site serine. The pH-dependent test excludes the involvement of histicine in the chemical method, unlike the behavior of chymotrivcin and related serine proteases. This result suggests that seson O-H is involved in a chemical reaction with the substrate. From these observations, the amino acids surrounding the unique serine residue,
That is, in this case, Val-Gly-Ser-Va
by l-Thr-Lys. It is shown that a valid model of the active site of PBP is obtained. Therefore, Veptite Ac-Va I-G ly-Ser-Va l-Th
r-Lys-NH-elfs was subjected to an ECEPP search of 200,000 initial structures, followed by )4MP2 (
85) The program selected 50 low-energy structures identified by this search. One low energy structure with adjacent lysine and serine side chains has been found. The structure is characterized by a set of sihetral angles summarized in Table 1 below, and the structure is shown in FIG.

The structure shown in FIG. 1 has several aspects of interest. Its convex surface is mainly hydrophobic, and its concave surface contains serine and lysine side buttons and is naturally woody. The concave surface also contains the aZ l' oxygen of the N-terminal acetyl group. These three sites are shown in FIG. 1 as S (serine), L (lysine), and A (acetyl group). It seems clear that a lock and key relationship exists between the concave surface of FIG. 1 and the previously defined convex surfaces of penicillins and cephalosborins.

For such a relationship, it is necessary to bring the carboxy group of the antibiotic into contact with the terminal amino group of lysine, and it is also necessary to bring the side chain N-H of the antibiotic into contact with its acetyl oxygen. be.

The receptor is N Hy −. ．． -Ox C and N-H. ．． ．． ．． Supermolecular (supramolecular) structures that are linked to the substrate via O=C hydrogen bonds are therefore desirable. To obtain the structure and energy of such a supermolecule using the program MMP2 (85)?
Is it necessary to devise a manual paste to output the starting set of cult coordinates?

Computer blocks are written based on the following approaches to problems: A is a receptor molecule containing N, IK atoms, and B is a substrate molecule containing an N2 atom bonded to A. The geometry of A and B is known as Cartesian coordinates, or internal coordinate values, and assumes that transformations between the two forms of coordinate system are possible. Therefore, the departure is (3N+-
6) and (3N.-6) using predetermined internal coordinate values. In order to describe the geometric configuration of a supermolecule containing (N10N!) atoms, 3(N*10N2) − 6 internal coordinate values, that is, 6 new internal coordinate values, are specified,
Needs to be minimized. These typically consist of one bond length, two bond angles and three cyhetral angles, and these may be referred to as "intra-molecular" internal coordinate values. To use the computer program shown in the source code listing or appendix 4, one of the desired hydrogen bond interactions is selected and its distance is 1.7-2.5 angstroms, i.e. Set to typical intramolecular hydrogen bond distances. Then, the initial value given to the remaining five variables is minimized and the second hydrogen bond distance is used as a brochure: the resulting supermolecule geometry is now expressed in Cartesian coordinates. If displayed, the second hydrogen bond distance or 1
．． 7-2.5 angstroms, lllM
It is considered suitable for minimization by P2(85).

Figures 2 to 5 show that the receiver motel is penicillin ■, ▲
Three-dimensional diagrams showing the results of binding to 3-cephalosvorin V, ▲2-cephalosvorin V, and 4-ep▲2-cephalosvorin V, respectively, are shown. In each case, serine O-H is β
- It can be seen that it is located on the convex surface of the lactam compound. This 4-center interaction is shown in detail in penicillin II shown in FIG.

From the Teccult coordinates of C-0-H and (0)N-C of the optimized complex, standard substrate (in this case, penicillin
), the root mean square deviation of the interaction looking at four different centers is
(rms) and can be expressed in angstroms. When this is done for the series of penicillin compounds 1a-1i, all active penicillins have an rmS of less than 0.2 Å and all inactive penicillins have an rmS of less than 0.4
It can be seen that the rlls are larger than angstroms. For the series shown in Figures 2 to 5, the rms
The deviations are 0.000 and 0.00, respectively. +49, b,338 and 0.148 angstroms.

This indicates that the ``compatibility'' of biologically active ▲3-cephalosborin and biologically inactive 4-EB ▲2-cephalosvorin with respect to penicillin receptors is the same. It has been suggested. Biologically inactive ▲2-cephalosborin has poor suitability.

The biological activity of a drug depends not only on its ability to adapt to its receptor, i.e., step 1 of formula 1 above, but also on its ability to carry out a chemical reaction on its receptor, i.e., step 2 of formula 1 above. . The chemical reaction shown in Figure 2-6 is C7-0 (Ser)'
(see A) as well as a four-center method consistent with N--H (Scr) bond formation. This is an unprecedented chemical mechanism.

Hydrolysis and alcoholysis of β-lactam compounds have received much attention both experimentally and theoretically.
In water larger than H8, the rate-determining step is addition to the carbonyl group, forming a tetrahedral intermediate, but p116
In the lower region, there is a rate-determining proton transfer from the convex side of the molecule to the β-lactam nitrogen. In the biologically relevant pn region 6-8, hydrolysis is extremely slow and the possible existence of a molecular (four-center) mechanism in this region remains to be determined. Similarly, all of the aforementioned theoretical studies of β-lactam hydrolysis emphasize anionic addition to the carbonyl group of the β-lactam.

The early type of molecular orbital (MO) calculations represented an accepted and well-established procedure for investigating the mechanisms of chemical reactions. Such calculations were made by GALISSIAN Inc., Bitzhak, Pennsylvania, USA.
Computer blockrum GAUSSI obtained from
It can be implemented using sets based on low level (STO-3G) and (3-21G) using AN 82 and GAUSSIAN 85. Semi-empirical type molecular orbital calculations can be performed on the basis of relatively large molecular systems, and the molecular orbital calculations are valid once they have been determined for earlier calculations on the same system. Semi-empirical method AMI, MN
DO and MI NDO/3 are in the computer program AMPAC available from QCPE and can be obtained from there.

Table 2 shows initial data for the reaction of N-methylazeticinone with water and with methanol via the exo-oriented N- and O-protonated structures (▲E≠ , kcal/mol). For hydrolysis reactions, O-protonated structures require lower STO-3G levels (STO-3G
//STO-3G) and 1.75 kcal/mol. More suitable 3-21G level (3-
21G//3-21G), one point calculation is N-
Increase the selection of protonated transition structures to 5.66
Make it kcal/mo+. Similar results can be seen in the methanolysis of N-methylazetidinone. These results show that the four-center interactions seen in Figures 2-6 reflect not only a pure chemical method but also an energetically favorable chemical method. The N- and O-protonated methanol decomposition transition structures are shown in Figures 7 and 8, respectively. Table 2 also summarizes the semi-empirical results for the hydrolysis of N-methylazetidinone as well as methanololysis, which correctly reproduces the preferential selection of the N-protonated transition structure by MINDO/3. It's obvious to do so. I want to. MINDO/3 was used to determine the activation energy for the reaction of a number of bicyclic azetidinones with methanol. These are summarized in Table 3 below.

Table 2 Relative ▲E≠(kcal/mol) a) Relative energy for hydrolysis and methanol decomposition of N-methylazetidinone via N- and O-protonated transition structures a) a) is displayed. In each row of Table 3 below, the response of a different structural type is compared to that of the penam ring system, the parent backbone of penicillin, and the data is explained below for each row.

Spoon 11 Exo (EX
O) Calculation ▲▲E≠(kcal/mol, MINDO/3)-2 versus N-methylazetidinone for methanol degradation of β-lactam compounds via the formation
．． 80 -4.15 -4.11 -0.25 0.46 -2.80 -386 -2.35 (1) The relative reactivity is in the following order: carbapenam>penem>oxapenam>penem. Oxapenicillins and penems having penicillin C3 and C6 substituents are known to have antibacterial activity. Although the carhapenam ring system is known, carhapenicillin has not yet been produced. (2) In comparing the penum and cephem ring systems,
Its relative reactivity is Penham〉▲3-Cephem〉▲2-
The order is cephem, acetoxymethyl-▲3-cephem. Among those with a common acylamino side chain, penicillins have higher potency than acetoxymethyl-3-cephalosboris, the latter generally having higher potency than 3-methyl-3-cephems. It has a high strength, and ▲2-cephem is inactive.

(3) Introduction of C3α monocarboxy group enhances its reactivity. The carboxyl group greatly reduces the reactivity of evimerization (C3β) and thus promotes methanol decomposition via hydrogen bonding. (4) The introduction of the C2 substituent reduces the reactivity of the C3α monocarboxy group if it is not present.

(5>6 The β-acylamino substituent has little effect on its reactivity. As a result, the chemical reactivity of penicillin is slightly different from that of its parent penum.

Figures 9 to 11 show the exo (ex) of penicillin, respectively.
o) Shows a three-dimensional view of the N- and O-protonated transition structures for methanol decomposition and O-flotonated endo methanol decomposition of Penam. The energy of such an ent orientation transition structure is approximately 1 kcal/mol higher than the O-protonated exo structure, and 5-6 kcal/+wol higher than the N-protonated exo structure.

Table 4 summarizes the ``compatibility'' and ``reactivity'' of the different ring systems of penicillin V and the cephalosborin compounds 2a-2C, showing ▲▲E for the reaction of carboxylated substrates with methanol Indicated by ≠.

The product rms x▲▲E≠ represents a combination of compatibility and reactivity, and is intended to correctly order the different classes of antibiotics in order of their biological activity. Based on this amount, cephalosborin compound 2b is inactive due to its poor compatibility with the receptor, and cephalosborin compound 2C is inactive due to its decreased reactivity.

The differences between cephalosborin compounds 2b and 20 are compared to the differences shown in Table 3, row 3. The difference is based on the fact that when the carboxy group is present on the convex side of the molecule, the chemical reaction is facilitated by hydrogen bonding of the attacking alcohol with the carboxy group. Thus, cephalosborin compound 2c has regained the compatibility lost in cephalosborin compound 2b, or at the same time has decreased reactivity. From these considerations, it has been shown that by binding a substituent that serves as a hydrogen bond donor onto the convex surface of cephalosborin compound 2c, it restores its chemical reactivity while retaining acceptable compatibility with its receptor. It is shown that there is. Possible sites for attachment of the required substituents include S. C4 and C7 (see numbers in Table 4). F, C
H: +O and C 11 20 8 or 04 and C
Although the required attachment to 7 does not enhance the reactivity of cephalosborin compound 2C, its alpha-oriented sulfoxide form (3) exhibits better reactivity than penicillin. The malon Mu conductor (4), which combines the favorable properties of cephalosborin compounds 2b and 20, exhibits somewhat reduced reactivity compared to penicillin (▲
▲E≠ -3.51kcal/IIlo1) However,
The product rIls x ▲▲E≠ is intermediate between the active and inactive compounds shown in Table 4 below. Compounds (3) and (4) are therefore novel β-lactams containing structural forms of potential biological interest. Table 4 C-0-H of serine and N of azetidinone ring in the complex of β-lactam compound and penicillin receptor
- Difference in the root mean square (rp garden) of the Cartesian coordinates of the C-0 atom for penicillin ■ (Angstroms); activation energy for the reaction of azetidinone with methanol (kcal/ Ill
o l) ; product rams▲▲E≠ C) MINDO/3 calculation of the right equation It is also possible to design completely new structural forms compatible with the combination of suitability and reactivity developed in the present invention. be. Based on the dihedral angle of penicillin ■, when the carboxyl group is oriented, the dihedral angle at the "reaction site" becomes -15 (1 to -160°, and N
When a hydrogen bond donor such as -H or O-H is oriented, the dihedral angle at its "reactive site" is -150 to -1
The reaction site must be one that reacts with methanol via a 4-centered transition structure, and its E is about 3-4 kcal/mol smaller than that of the reaction with azetidinone. A systematic calculation of the activation energy shows that the ikuno group (-C-
N-) is identified as a functional group with the required reactivity, and when this group is introduced into a cyclic structure with a dihedral angle of the required strength, it becomes a candidate for antibacterial activity via the penicillin-cephalosporin mechanism. Structure 5 was identified as the structure. The results are shown in Figure 12. The W raw yolk polypeptide contains 46 amino acid residues, 327 heavy atoms, and 636 atoms, including hydrogen atoms. This published crystal structure contains 1.5 angstroms of diffraction data. The Cartesian coordinate values of the heavy (non-hydrogen) atoms in this crystal structure are. used as input to MMP2 (85), hydrogen is added using options available in MMP2 (85), and Newtonian
Ranson minimization was performed using PEPCON.

The calculated structure shows that the rIls deviation from the experimental structure is 0.29 angstroms for the hackbone heavy atom and 0 for all heavy atoms.
．． It becomes 310 angstroms.

Using the Cartesian coordinate values of the crystal structure of penicillin V, the PENCON parameter is 0 for all atoms.
The experiment of Example 1 was repeated except that the rms deviation was 1 angstrom.

The Cartesian coordinates of the crystal structure of ▲2-cephalosborin with phenoxyacetyl side chain are entered, and the energy key is entered along with the CEPARAM parameter.
was minimized using lMP2 (85). The obtained rI
The Ils deviation was 0.35 angstroms.

Bebutide Gly-Trp-IAet-Asp-Phe
-NH2 is input into ECEPP and the 2 of this molecule
An initial search of 00,000 initial forms was conducted. The structure of the 50 minimum energy keys identified in this way was
minimized by ECEPP using nimizationprocedure)? , then MMP2 (85
) was selected using PEPCON parameters. One structure is particularly preferred, the cyhetral angle of this structure being Trp-Met-Asp-Phe-Nll of the above compound.
It was identical to that of gastrin tetrapeptide containing .

Peptide Ac-Va I-Gly-Ser-Va I-
Thr-Lys-NHCH3 was processed as in Example 4 above and 50 final structures were investigated. One of the structural defects had lysine and serine side chains on the same side of the molecule. The structure is shown in Figure 1 and its dihedral angles are summarized in Table 1. The receptor model of Example 5 was coupled to Benisison V using the computer program of Appendix 5. The final lowest energy complex of several forms of penicillin is shown in FIG.

Compounds thus identified can then be identified according to standard chemical procedures known to those skilled in the art.

The present invention will be explained in detail with reference to the following specific examples of the compounds produced.

Example 7: 3-carboxyl-5-hydroxymethyl-
6.6-dimethyl-▲'-1.4-thiazine In the following formula ■, X - s; Y = OH; R
+=R2 error Cll yu; R:+ = R4 wealth R5- R
．． -H. The D- and L-configurations at position 03 were created.

Step 1 Methyl isopropyl ketone (15 a+1, 140
mmol) and potassium chloride (1.1 g. 14.8 a
ueol) was added to the solution in water (9.6 ml). The mixture was stirred, heated to 60°C, and irradiated with a 350 watt tank lamp attached to the side of the flask. Then bromine (11.9 g, 74
．． 4 ■ol) was added dropwise. When the first few drops of color disappeared, I changed the heating bath to a cold water bath and changed the 350 watt bulb to a 60 watt bulb. The addition of bromine was carried out at an internal temperature of 4
At a rate sufficient to maintain temperatures between 0 and 45 degrees Celsius! I ruled. When the addition was complete (25 minutes), the resulting reaction mixture was allowed to stand for 2 hours, and the organic phase was then separated, washed with water magnesium monoxide, and dried over anhydrous calcium chloride. 7 g of compound Al was obtained by fractional distillation.
bp82-86/145Lorr; NMR (CDCl
i) 2. :15(31{,s), 1.77(6
H, s) A1 Step 2 Promeketone A I (4.65 g, 28 amount 101
) was dissolved in glacial acetic acid (40 μl) and freshly recrystallized lead tetraacetate (12.5 g, 28.2 gaol) was added. The mixture was heated at 100° C. for 2 hours without stirring and then cooled to room temperature. Ethylene glycol (2 ml) was then added to destroy unreacted lead tetraacetate. The resulting reaction mixture was diluted with ether (100 ml).
The mixture was diluted with water, washed successively with 10% sodium carbonate, water and then saturated sodium chloride, dried and evaporated. The obtained residue was distilled and bP57-60℃/1
The 20 Lorr fraction was further chromatographed (silica gel, 5%) (10% -> 15% j--te)
Bromoketoacetate B
I got 1. NMR CCDCI3: 5.15 (
2H, s). 2.13 (IL s), 1.87
(68, s) Step 3 Triethylamine (l40l) was dissolved in methylene chloride (31l)
ml) was added. The solution was cooled to -20°C and gaseous hydrogen sulfide was introduced for 10 minutes. Then promoketoacetate in methylene chloride (1.0 ml)
B l (200 mg) was added dropwise over 10 minutes with stirring. The resulting yellow solution was diluted with methylene chloride (3
0 ml) and pack into a box. Successive washing with 2N hydrochloric acid, water, and saturated sodium chloride gave mercaptoketoacetate C1. NMR ((:DC)3) 5.16
(2H, s), 2.18 (3L s), 1.5
7 (6H, s), 1.55 (LH, s) Step 4 Triphenylphosphine (258 IIlg, 0.01g) in dry tetrahydrofuran (1.0n+I).
98 i + mol) at -78°C under nitrogen atmosphere,
Add dimethyl acetylene cyclocarboxylate (without stirring).
A solution of 144 mg, 0.99 mmol) dissolved in tetrahydrofuran (1.0 ml) was added dropwise.

The resulting white slurry was kept at -78°C for 10 minutes and then mixed with Boc-L (or D-) monoserine (184
Ilg. 0.90 mol) in tetrahydrofuran (
1.0 ml) was added dropwise. -7 temperature
8° CC was maintained for 20 minutes, and the resulting reaction mixture was then warmed to room temperature and held at that temperature for 2 hours. After removing the solvent, the residue was purified by chromatography on silica gel. The obtained purified product was
% -> 221 -> $30 -> 351 Beta-lactone compound D1 was obtained by elution with ethyl acetate-hexane. NMR (CD(:h) 5.2
9 (IIL br). 4.92 (IH, br
), 4.34 (211, br). 1.07 (
9H, s). Step 5 The above compound C I (79.9 mg, 0.45 m
mol) of degassed dry dimethylformamide (1.
Lithium cyisobrobylamide (0.8 ma+ol) was dissolved in tetrahydrofuran (1
．． 5 ml) was added dropwise. The addition was carried out at -60°C under nitrogen and the resulting reaction mixture was
Warm at 25°C for 50 minutes, cool again to -55°C, and add the above compound D l (56.4 mg, [110
Question 01) Degassed dry dimethylformamide (0.
5 ml) was added dropwise. After the addition was complete, the mixture was warmed to -20''C, stirred for 25 minutes, then diluted with ethyl acetate (:10 ml) and washed with 0.5N hydrochloric acid (2 ml). The resulting aqueous layer was extracted with ethyl acetate (2x 10 ml),
The obtained organic extracts were combined and added to water (2 x 5 ml),
The mixture was then washed with saturated sodium chloride (5 ml), dried and evaporated. The resulting oily residue was subjected to preparative layer chromatography using an IOX20cI1 plate coated with silica gel to convert methylene chloride-ethyl acetate-acetic acid (1.7:0.3:
0.05) as eluent to obtain compound E.
1 (77 tag. 70.3$) was obtained. N M
R (CDCl3) 5.43 (LH, br),
5.20 (IN, d, 18 Hz), 5.04
(Ill, d, 18 }12), 4.45 (I
}I, br). 2.97 (it{, br),
2.78, 2.74 (IHdd, 4,5, 9.0
Hz), 2.17 (3H.s). 1.48
(3H, s) 1.47 (3H, S), 1.44
(9L s) Step 6 The obtained acid E 1 (77 mg) was mixed with methylene chloride (1
and treated with an ethereal solution of cyazomethane at 0°C. After removing the solvent, the residue was used as an eluent and hexane-ethyl acetate}-(1.4:
0.6) on a 5xlOcm silica gel plate to obtain ester F 1 (48.2 mg).

NMR (CDCh) 5J2 (IH, br
d), 5.15 (LH, d, 11 Hz), 5.
07 (IH. d, 11 }1z), 4.48
(IH, br, q), 3.76 C3H, s),
2.91 (IH, q, 4.12Hz), 2.
74 (ill, q. 5.5. 12Hz), 1
．． 47 (6H, d), l. ．． 44 (9tl, s
) Step 7 The obtained ester Fl (746 o+g) was placed in tetrahydrofuran (IIIf) and the concentration was adjusted to 0.25M at room temperature.
Treated with lithium oxide (0.4 ml). 25
After a minute, an additional 0.4III lithium oxide was added.
The mixture was stirred for 35 minutes, then boxed with ethyl acetate (10 a+1) and then added with 0.5N hydrochloric acid (2 x
Washed with S ml). The resulting aqueous layer was extracted with ethyl acetate (2 X 5 ml) and the resulting organic extracts were combined and washed with water (I X S ml) and then with saturated sodium chloride (l X 5+*l). After that, it was dried and evaporated. The resulting residue was dissolved in minimal methylene chloride, treated with an ethereal solution of diazomethane, concentrated and the resulting residue was purified on a 10×20 cm silica gel plate. Hexane-ethyl acetate (1.4
: 0.6), the compound G l (14.
4 g) was obtained. NMR((;DC+3) 5.2
2 (IH, br), 4.58 (211, d)
, 4.48 (IH, br). 3.75 (3}1
, s), 3.06 (IH, br). 2.92
(III, br), 2.74 (IH, dd,
5, Ill{z). 1.46 (9H, s), 1.44 (611, S) Step 8 Obtained compound G 1 (5 mg, 0.015 m
mol) of freshly dried pyridine (0.2 +il)
Silver nitrate (3.4 mg, 0
．． 02 +uiol), then t-butyldiphenylchlorosilane (6.3 mg, 0.02311100
was added. The resulting solution was stirred at room temperature under nitrogen for 15 minutes. After removing the solvent, the raw material is pre-variated.
When purified by layer chromatography, compound H
1 (S.Smg) was obtained. NMR (CDCI.) 7.69 (4H, m),
7.41 (6H, ai), 5.07 3.72 1.43 1.10 (IH, br), 4.70 (2H, s
), (3}1, s), 2.70 (IH,
dd).

(9H, s), 1.28 (3H, s), (9H, s
) 4.41 2.55 1.26 (1■, (IH, (3H, br) + dd), SL Step 9 The silylated ester (5 mg) was mixed with formic acid (
5 ml). After 33 minutes, the resulting reaction mixture was frozen and the solvent was removed by lyophilization, yielding Enercon Form II. NMR (+1:DCIff) 7.69 (4}1,
m), 7.40 (6H, thought), 5.90 (IH,
s), 4.65 (IH, br), 3.79
(3L s), 3.76 (IH, br),
3.17 (ltl, dd, 10.15
Hz). 3.00(II{, dd, 3,
Is}lz), 1.49 (3H, s),
1. :11 (3H,s), 1.08 (gH,s) Step 1O The obtained thiacin If was treated with lithium hydroxide to remove the ester protecting group in the same manner as described in Step 7 above. ．． Furthermore, when the silylated protecting groups are partially removed, the resulting reaction mixture contains 3-carboxy-5-
Hydroxymethyl-6,6-dimethyl-▲'-1.4-
Contains thiazine.

Example 8 - In the combined formula TI of 3-carboxy-5-(2-hydroxypropyl)-6,6-dimethyl-▲'-1,4-thiazine, X-s; y-on; R,
= R2-Cll,; R, - R. Company Rs =
Rs: R7-CH: + Both the D- and L-configurations at C3 were produced, but the R- and S-1 epimers at C8 were not separated: the D-isomer is active.

Step 1 Ethyl 2-methylcyclobrobancarboxylate (5 mg,
A solution of 38.9 miol) dissolved in dry ether (5 ml), stirred under nitrogen, was mixed with magnesium powder (1.935 g, 0.080 g-atom).
and methyl bromide (12.43 g, 87.6 mmol) in dry solution (42 ml). This addition took 30 minutes and stirring was continued for 2.75 hours at room temperature and then for 2 hours under reflux. The resulting reaction mixture was cooled in a water bath and saturated ammonium chloride (10ml) was added with stirring. Of the separated phases, the aqueous phase was diluted with ether (2 x 20 m
l) and extracted. The organic phases obtained were combined, dried and evaporated. The resulting residue was distilled at 131-136°C to obtain tertiary alcohol A2 (4.24 g, 95%) represented by the following formula.

Step 2 The alcohol A 2 (4.24 mg) cooled in a water bath
, 37 ml 1o 1 ) was added ice-cooled 48% hydrobromic acid (15 ml). Mix this mixture in a water bath for 3
It was shaken vigorously for 0 minutes and separated into two layers. The aqueous layer was extracted with hexane (2 x 20 ml), and the resulting organic phase was mixed with saturated aqueous acid salt (2 x 10 it) and water (2 x 20 ml).
x 10 ml), saturated sodium sulfate (2 x 1
0 ml), dried over anhydrous sodium sulfate, and then distilled. By distillation, bromide B2 is reduced to 3.
72 g (60%) were obtained. Boiling point 46-54℃/10
torr day r Step 3 Obtained bromide B 2 (3.72 IIlg, 21
Potassium acetate (3.1 mg, 31.6 + imol) was added to a solution of 1.0 mmol) in aqueous acetic acid (20 ml). The mixture was heated under reflux for 12 hours, cooled and then poured into water (30 Ill). Extraction with ether (3 x io.ml) and subsequent washing of the organic phase with saturated sodium carbonate, water, then saturated sodium chloride, drying and distillation at room temperature yielded the acetate C2. 2.82g<85%).

N M R ((:DCI:+) 5.10 (IH,
brt), 4.88 (III, q, 61{z)
, 2. :10 (It{, m), 2.19 (
IH, m), 2.02 (3N, s), 1.71
(3H, br s), 1.52 (3H, br
s), 8.00 (3H, d, 6Hz) Step 4 Obtained acetate C 2 (120 mg, 2.0
1.5 mmol) was dissolved in methanol (2 ml) and potassium hydroxide was dissolved in methanol (1.38 ml).
A 5M solution was added dropwise to treat. The resulting reaction mixture was
After standing for an hour, the mixture was neutralized with 1.5M methanolic hydrogen chloride and the solvent was removed. The resulting residue is dissolved in methylene chloride, and this solution is washed successively with water and saturated sodium chloride, dried, and then distilled to obtain alcohol D.
2 (208+ig, 99%) was obtained. Step 5A The alcohol D 2 (312 tag, 2.7
:l mlol) to dimethylformamide (2 ow
t-tutyldimethylchlorosilane (5:15 rag, :l.55 mm
ol) was added. This mixture was stirred for 2 hours and then filtered. The insoluble material was titrated with ether (20 ml) and the resulting organic material was washed successively with saturated sodium bicarbonate, water, saturated sodium chloride, dried and distilled to yield the silylated rheta compound E 2 A ( 620 mg,
100%) was obtained.

Step 5B The alcohol D 2 (25 mg, 0.22
wIIol) in dimethylformamide (0.2 ml)
This solution was successively dissolved in pyridine (27L I,
0. :13 ol), t-butyldiphenylchlorosilane (90 pLL O.35not), then silver nitrate (
56 B, 0.33 mol). After stirring this mixture at room temperature for 4 hours, the resulting product was milled in the same manner as described in step 5A above to obtain compound E2B.

Step 6A Obtained olefin E 2 A (6241 g, 2
．． 731 ol) with acetone (: lml) and 18-
Crown-6 (100 tag, 0.27 Il
lol) and acetic acid (0.16 ml) was added, followed by potassium permanganate (6031 g).
A solution of t 3.82 old ol) dissolved in water (7.5 ml) was added dropwise. The mixture was stirred for 1 hour and then diluted with methylene chloride (50 ml). The resulting organic phase was washed successively with 20% sodium bisulfite, water, 0.5N hydrochloric acid, saturated sodium bicarbonate, water, and then saturated sodium chloride, then dried and distilled. The resulting residue was subjected to flash chromatography using silica gel (7 g). 4-) Ruth, Kel body F 2 A (479
The obtained olefin (77.5 mg, 0.22
mmol) was oxidized with potassium permanganate in the same manner as in Step 6A to obtain the ketol compound F2D.

NMR (CDCI*) 7.72 (41L m)
, 7.43 (6H, II1), 4.43 (IH
, q, 611y. ), :l. 81 (IH, s
), 2.81 (18, dd, 5. 16}17
．． ). 2.58 (III, dd, 7. 16H
z), 1.31 (38, s), 1.29 (3
11, s), 1.10 (:tH, d, 5Hz
), 1. D4 (9+1, s) Step 7A The obtained ketol body F 2 A (478 mg,
18: To a solution obtained by dissolving iHo I) in methylene chloride (5 ml), triethylamine (0
．． 76 ml, 4.0 mmol) and methanesulfur chloride (0.24 ml, 1 tnol) were added; the reaction solution was stirred at room temperature for 5 hours, and methylene chloride (80 ml) was added. ) and diluted with water.
Washed successively with 5N hydrochloric acid, saturated sodium bicarbonate, water, then saturated sodium chloride. The obtained product was subjected to flash chromatography on silica gel (3 g) and showed 7% -> 8% ->! H −> Elution with 10% ethyl acetate/hexane yields compound m G
2A (432 mg, 70%) was obtained. Step 7B The obtained ketol body F 2 B (277 mg,
0.72■01) in the same manner as in step 7A (by processing, the mesylate form 0 2 B C233 mg)
I got it.

N M R (CD(:I:+) 7.41 (4H,
m), 7.4]. (6H, m), 4.44 (
ltl, dd). :I. 08 (3H, s),
2. ! Is (IH, dd, 6.18Hz),
2.27 (IH, dd, 7.18Hz), 1
．． 63 (:IH, s), 1.61 (3H, s
), 1.15 (3}1, d, 6Hz), 1.
fl6(98, S) Ph Step 8A Methylene chloride (5 ml) was saturated with hydrogen sulfide at -20°C and triethylamine (0.14 ml, I
mioi) and the mesylate (2:l:l mg
, 0.5 ol) were added continuously. This solution -
The mixture was stirred at 20°C for 10 minutes, then at -20°C to >0°C for 45 minutes, diluted with methylene chloride (30 ml), and washed successively with 0.5N hydrochloric acid, water, and saturated sodium chloride. , dried and distilled, b. After drying at 1 torr, mercabutane (170 mg, 85%) was obtained.

NMR (fl:D(:Iz) 4.37 (IH, m
), 2.98 (IH, dd, 5,118?.)
, 2.63 (18, dd, 4. 11Hz)
, 1.98 (IH, s) 1.49 (38,
s). 1.48 (311, s), 1.17
(3L d,5}1z), 0.84 (9H,
s), 0.05 (38, s), 0.01
(:lH,S) Step 8B The obtained mesylate compound 02B was converted to the mercabutane compound H2B in the same manner as in the step 8A.

NMR (CDCIz) 7.71 (4H, m),
7.40 (6H, m), 3.00 (IH(
dd, 6. 1+iHz), 2.75 (
Ill, dd, 7, 161-1z). 1
．． 93 (IH, s). 1.46 (3}1, s
). 1.45 (:lH,s), 1.1:l (3
H, d, . 6Hz). 1.05 (9H, s)P
h ■ Step 9 Under nitrogen, the obtained mercaptan H2A (100
B, 0.36 gaol) was dissolved in degassed dimethylformamide (1.0 ml). This solution-
After cooling to 55° C., n-butyllithium (0.8 all of a 1.6 M hexane solution) and diisoprobylamine (0.36 IIll, 0.259 g, 2.5
Tetrahydrofuran (0.8 ml) degassed lithium cyisopropyl amide prepared from
) in a solution of 0.45a+1. The resulting reaction solution was stirred at -45°C for 30 minutes, and the previously obtained beta-lactone DI (D- or L monolith) (
5[i. 8 mg, 0. A solution of 1 mmol) in degassed dimethylformamide (0.8 ml) was added. This mixture was stirred at -30°C for 20 minutes, diluted with methylene chloride (10Ill), and then
．． Washed with 5N hydrochloric acid. The resulting aqueous layer of methylene chloride (
The organic extracts obtained were combined and washed with water. Then, it was saturated with sodium chloride, dried, and distilled. After drying the resulting residue under high vacuum, flash chromatography (silica gel, 4
Purification by g, 0% 8z ethyl acetate methylene chloride (1! acetic acid) gave the coupled product I2D or 12L.

1 2 D (83%; [alo ◆2.33 (
c.O. 1, ') O *) Ltm)) N M R (CDCIs) (L isomer)
4.48 (01, br). 4.32 (IH,
fll), 2.83, 2.71 (28
, II1), 2.71.2.62 (2H, +*
), 1.44 (9H, s), 1.43
(6}1, s), 1.16(3H, d
, 6}1z), 0.85 (9H, s)
, 0.05 (3H, s). 0.00 (:
The NMR spectrum revealed a 1:1 mixture of epimers in the 2-hydroxybrobyl side chain.

1 2 L (83%; [(XID +2.:13
(c O.1, ')loloform)) NMR (CDCI3) (one isomer) 5.2
8 (IH, br, t), 4.48 (II-
1, br), 4.32 (IH, m),
2.86, 2.79 (2tl, m), 2.70
, 2.61 (2H. m), 1.43 (9
tl, s), 1.42 (5H, s),
1.16 (3H, d, BHz), 0.8
3 (9Ls), 0,04 (31{, s
), 0.00 (3H, s) NMR spectrum revealed a 1:l mixture of epimers in the 2-hydroxypropyl side chain. Step 10A Compound 1 2 D (22.7 tsg, 0.0
Formic acid (0.3 ml) was added to 49 m+*ol). The solution was shaken at room temperature for 20 minutes, then the solvent was removed by lyophilization. The resulting residue was dissolved in ether (
The ether phase was extracted with water (1 ml) and the resulting aqueous phases were combined and neutralized with sodium bicarbonate. and then lyophilized to give compound 2 (511 g, 40%) with the D form at C3 as a mixture of epimers in the 2-human xyprovir side chain.

NMR (D20) 4.2:l (IH, m).
3.80 (Ill. m), 310 (Ill. q)
, 2.70 - 2.85 (3H, [0), 1.
40 (6H, s), 1.15 (311, d) Step 10B The method of Step 10A was repeated with the obtained compound QI 2L to obtain Compound 2, which has an L-configuration at C3.

Example 9 Hyoassay of Compound 2-D The antibacterial activity of the compound obtained in this example was measured using plates inoculated with either Sartina lutea or Escherichia coli. In the former case, penicillin G was used as the standard; in the latter case, cephalexin was used as the standard. As a result, this compound was found to be 800 times less active than penicillin G and 10 times less active than cephalexin; the L monoisomer of compound 2 was found to be inactive in both assays. It turns out that there is.

Example 10 During the synthesis of 2-thia-4-carboxy-6=(2-hydroxypropyl)-7,7-dimethyl-▲'-i,s-thiazepine, X-Y-S-S. Z-
OH;R+ = R2-R7-Cfh;R
Although both the D- and L-configurations in 3-R4-Rs-RsC4 were prepared, the R- and S monoisomers at C9 were not resolved; the L monoisomer is active (Figure 13). Formula I L-cysteine hydrochloride tm (4.1 mg, 0.02 [
i lIlmol) in 90% methanol-water (OJ5
ml), and in this solution, the mercabutan compound (Example 2, Step 8A) (7.1 rag. 0.02
A solution obtained by dissolving 5 mmol) in methanol (0.:15 ml) was added, followed by addition of iodine (5.5 mmol) in methanol (0.:15 ml).
01 g, 0.026 mmol) and triethylamine (7.0 g, 0.026 mmol) were added. After the resulting reaction mixture was left at room temperature for 30 minutes, the solvent was removed under reduced pressure. The residue was partitioned between pH 7 phosphate buffer (containing 1 drop of sodium D thiosulfate) and methylene chloride. The obtained Mizui was extracted with ethyl acetate (1 x 5 all) and then freeze-dried. This residue was titrated with methanol, the methanol extract was combined with the methylene chloride and ethyl acedate extracts, and the mixture was evaporated. The obtained raw material was diluted with methylene chloride-methanol-water (1.8:0) as an eluent.
．． 2: 0.15), 10x 15 cra
Purification using Alkuna plate gave Lercisulfite compound A4-L (8.9B, 802) represented by the following formula.

NMR (D20) 4.19 (IH, m),
3.92 (IH, dd, :l.711z),
:l. 18 (IH, biased), 3. G4 (1}1,
m), 2.92 (IH, I1), 2.76 (i
ll, m), 1.43 (5}1, s), 1.1
2 (38, d, 7}1z) This compound is a mixture of Ebimer in the 2-hydroxybrobyl side chain. H This experiment was repeated using D-cysteine instead of L-cysteine, yielding compound A4-D shown below.

The resulting acids A4-D and A4-L were dissolved in water containing *sodium carbonate and tested for antibacterial activity in a plate assay using Sartina lutea.

An inhibition zone was observed for the L monoisomer and not for the D monoisomer. The inhibition is attributed to the formation of the ring structure 3L, whose interaction with the penicillin receptor model is shown in FIG.

Example 11: 3-carboxy-5 one year old ximino-1,4
-Synthesis of Thiazine In formula IV, X-s; R. -R2-
o;R, -R. -R. −H;
N; Z-OHD- and L monoisomers are described.

h Ethyl bromoacetate (0.99 g, 5.95 mmol) was added to a solution of D-cysteine (605.8 B, 5 gaol) dissolved in methanol (10 ml).
l), then triethylamine (1,4 I. 1.
02 g, 10 mmol) were added continuously. After stirring this solution at room temperature for 20 minutes, ether (20
ml) was added. The collected biomass was collected by filtration, washed with ether, and dried. SOOmg of this material was suspended in dimethylformamide (5 ml) and added with p-toluenesulfonic acid (458B, 2.41 mao
l) was added. Cyphenylcyazomethane was added dropwise to the resulting solution until the color of the diazo compound disappeared, and the reaction solution was stirred overnight. Next, this solution was diluted with ether (20 ml) and then diluted with water (2κ10
+*I). The aqueous phase was made alkaline with saturated sodium carbonate and treated with ethyl acetate (3 x 10 ml
) was extracted. The resulting organic extracts were combined, washed with water, then saturated sodium chloride, dried, and evaporated. 370 mg of this residue (0.99 msoJ) was added to
- After dissolving in dioxane (8 ml), 2-pyridone (47 lIg, 0.49 gaol) was added and the solution was heated at 102°C under nitrogen for 7 hours. Furthermore, 2-bilitone C23. S Teng g, 0.25a
mol) was added and heating continued for 4 hours.
At this time, the solvent was removed under reduced pressure and the residue was purified on 15 g of silica gel, 8% ethyl acetate.
When eluted with hexane, thiazinoneben 7: HF'
J Lester A5-D (252 mg, 78$)
was gotten. NMR (CDCI+) 7.14 (toll, m)
, 6.95 (IH, s), s), 6.
48 (IH, s), 4.46 (I}l
, m), :l. :l:I (2H,s), 3.2
1 (1N, dd, 4, 1511zL 2.!18
(]}I. dd, 9. 15 Hz) Step 2 Thiacinone A 5-D (252 @g, 0
．． 77 msual) and dry tetrahydrofuran (5 mSual).
Tetrahedron Lett from phosphorous bentasulphide and diphenyl ether by dissolving under nitrogen
ers 3815 (198:l) (344 mg, 0.46 gaol) was added. The solution was stirred for 35 minutes and concentrated, and the residue was purified on silica gel (8 g). When this was eluted with 15% ethyl acetate/hexane, the thioamide compound B5
-D (214 IIlg, 81%) was obtained.

NMR (CDCL) 8.59 (LH, s)
, 7.15 (IOH, a+), 5.98 (li
t, s), 4. :19 (LH, m), 3.7
9 (2H, s). :l. 32 (It{, dd,
4, 15tlz). 3.02 (IH, dd,
8, ISIIz) Step 3 Obtained thioamito compound B5-D (80 mg,
0.231 ol) was dissolved in dry tetrahydrofuran (92 ml) under nitrogen while stirring in a water bath and treated with sodium hydride C80%. 8.4 mg, 0.28
■ol) was added. After stirring in a water bath for 5 minutes, the reaction solution was mixed with methylyotite]OJLI (0.48 1
IILlol). When the reaction was complete in 25 minutes, it was diluted with ether, extracted successively with water, saturated sodium bicarbonate, saturated sodium chloride, dried,
Distillation gave a crude product, which was purified on silica gel.

Elution with 10% ethyl acetate/hexane yielded the monomethylimine C5-D (59.1 I1g,
75%)

NMR (CDCI:+) 7. :15 (ID
H, m), 6.95 (ill, s), 4.
53 (l}I, m), :I. 27 (1B
, dd, S, 181Iz), 3.18(I
H, dd, 5. 18}1z), 2.99 (
IH, dd, 3, 1:lHz), 2.81 (
it-1, dd, 4, 1:lIlz),
2. :17(:It{,s) Step 4 The obtained thiomethylidine compound C5-D(5
9+mg, 0.165 mol) was dissolved in tetrahydrofuran (0.5 ml), and this solution was dissolved under nitrogen to dissolve hydroxynoleamine hydrochloride (68.8 tsg) in tetrahydrofuran (0.5 ml).
,Q,9! ] auaol) and 1.65 M methanolic sodium methylene (OJ ml, 0.5 Hol) were dissolved in methanol (0.7 ml) and added to the resulting solution. After the reaction was completed in 10 minutes, the reaction solution was diluted with methylene chloride (10 ml), washed successively with saturated sodium bicarbonate, water, and then saturated sodium chloride, dried, and distilled. This raw material was chromatographed using silica gel (1.5 g) to give 1.
Elution with 2% ethyl acetate-methylene chloride yielded the oximinoester D5-D (52.7
tag, 942) was obtained. NMR (CD
CI:l) 7.34 (IIH, Cabinet),
6.93 (LH, s), 5.97 (III,
s), 4.28 (IH. m), 3.30 (
18, d, 13Hz), 3.21 (18, dd
, 3. 1:lHz), 3.16 (1}1, d
, 1:lllz), 3.08 (Ift, dd,
7, 1:tHz) The obtained ester (47B) was dissolved in formic acid (1 ml). After 5 hours at room temperature, the resulting reaction mixture was frozen and the solvent was removed by lyophilization. The resulting residue was partitioned between ether and water, the ether layer was once extracted with water, and the resulting aqueous extracts were combined and freeze-dried again to obtain compound 4-D. NMR (DJ) 4.15 (IH, m). 3.
50 (IL d, 1411z) 3.34 (IH,
d, 14Hz), 3.15 (IHldd, 6.
15Hz). 3.02 (1}1, dd, 6.
15Hz) The L-enantiomer of compound 4 is prepared using L-cysteine as a starting material instead of D-cysteine.
It can be obtained by the method described above.

Example 12: Synthesis of 3D-carboxy-5-phenylacetylhydrazilu▲4-thiazine thiomethylimine C5-D (llmg, 0.
031 mmol) and phenylacetic acid hydrazide (9
．． 21g, 0.01i2mmol) in methylene chloride (
The resulting solution was stirred overnight under nitrogen. This reaction solution was subjected to preparative layer chromatography using silica gel to obtain the adduct P.
C14 mg, 9H) was obtained. NMR (CDCI3) 7.34 (IH, m),
6.89 (IH, s), 6.55 (IL br
s), 4.24 (IH, br s), 3.7B
(2}1,s)1,155 (ltl,br,s)
, 3.33 (lit, d, 1SIIz), 3.17 (IH, d, ISHz), 3.05 (
211,br) adduct P (101lg, 0.022
mmol) was treated with formic acid (0.411). The resulting solution was left at room temperature for 5 hours, and the solvent was removed by lyophilization. The resulting residue was mixed with ether (0.211) and water (0.
．． The ether layer was partitioned between water (0.2 l) and the ether layer was partitioned between water (0.2 l).
2 ml) and extracted once. The aqueous phases are then combined and lyophilized to give 5kQ (:I mg. 47
%) was obtained. NMR (DJ, NaHCO:+) 8
．． 33 (IH, s), 7.28 (5H, m),
3.98 (IH, m). 3.55 (2H,
s), 3. :15 (IH, d, 17.5Hz).
3.12 (IH, d, 17.5Hz), 3.
11 (Ill, br d, 15 Hz), 2.8
:l (IH, br d, 15Hz), Cll+, S) This l, isomer QL, compound C5 l. was produced in the same manner using as the starting Th substance.

h啼▼W Il1 − + + −−+ψ=−0 yen 1 1 + I PI 1 − 11 [F] N dimension Toma dimension N ~

1 ~l+1 irritation▼call111l+I1+1PIPlF+-++-1-1μ-F'
l l+l Pl-? J Nψφφ171−ψ
φ[F] φψψmisakikFlψ
[F]000φψ−ADDEn O. P ^ (Tomo 2) Zero KY Ri ■ ? 1+ fi-1+ :: ■=83=expansion:: M l”
l +:::÷3:::: PI FI M L! !
： ：； ：： e ：： ：；：：5：：１N″5″
``11-000===-111-1111 1--11--,,,111~~N~l+lFl l+l l+I
M PI FI F'l M t/'I Ll'l L
l'l +J'l Ll'l LIT Ll'l Ll
'l-φ111-ψψφ11+3.36 5.10 2.2O n7.90 0.60 4.70 +7. no 31.111 10JQ 97.60 211.00 +26. ln 11A. Ql1 94.60

[Brief explanation of the drawing]

FIG. 1 shows the structure of a penicillin receptor model, in which the binding to penicillin and cephalosborin is between C-0-H of serine and (0)C-N of penicillin or cephalosborin. It is equally connected to the four-centered interaction between FIG. 2 shows a stereoscopic view of penicillin V bound to the bebutide of FIG. FIG. 3 shows a stereoscopic view of ▲3-cephalosvorin bound to bebutyto in FIG. FIG. 4 shows a stereoscopic view of ▲2-cephalosvorin bound to the peptide of FIG. Figure 5 shows 4-Ebi▲2 spun to the peptide in Figure 1.
- shows a stereoscopic view of cephalosborin. FIG. 6 shows an enlarged view of the four-center interaction between the C-0-H of serine and the β-lactam ring shown in the $2 diagram. Figure 7 shows the ex of N-methylazeticinone in methanol.
Figure 2 shows the N-protonated transition structure (initial calculation) for attack on the o-plane. ffi8[2I is a diagram showing the ○-protonated transition structure (initial calculation) for the attack of methanol on the exO plane of N-methylaceticinone. Figure 9 shows MINDO/3 for reacting methanol to penicillin via the N-protonated route.
This is a three-dimensional diagram of the transition structure calculated using . Figure 10 shows the MINDO/
This is a three-dimensional diagram of the transition structure calculated using 3. FIG. 11 is a three-dimensional diagram showing the transition structure for the reaction of methanol to penam via endo attack. FIG. 12 shows a stereoscopic view of the complex of 5 to the peptide of FIG. FIG. 13 shows a three-dimensional diagram showing the interaction of the cyclic structure with a model of the penicillin receptor. 1! Lit engraving (no change in content) CH3CO - NH -Va l- G ly -
Sor-Va I-Thr-Lys-NHCH
3FIGURE 2 PENVS FIGURE CEPHIAS FIGLIRE CEPH25 FIGURE CEPH37 FIGURE6 FIGURE 8 FIGURE PENGNT FIGURE PENGOT FIGURE ENDOPEN F IGURE DRUG4S FigL 1re

Claims (1)

[Scope of Claims] (1) A method for determining the molecular structure of a polypeptide, which method determines the seed energy of the molecule by keeping the bond length and bond angle constant, and determining the dihedral angle (dihedral angle) of the molecule. ), before that minimization consider a subset of parameters that forms the basis for a certain subset of the complete parameter space, and where said subset is the φ2 of the backbone of the molecule. It consists of 0, ±90, 180 degrees for the face angle and ψ dihedral angle, −60 and 180 degrees for the first dihedral angle of the side chain, and the ω dihedral angle and the other two dihedral angles. All of the face angles are maintained at 180 degrees, each of the unspecified number of points in this parametric subspace corresponds to the species energy of the associated molecule, and then the subspace is expanded to a sufficiently rich,
By subjecting it to a discontinuous, randomly distributed, uniform mapping, there is a probability of arbitrary size that some points (r) are seen in the vicinity of the convexity of the minimum amount of local energy. a set of points (r) and then using this set of points (r) for initializing a minimization method. (2) The method of claim (1), where a reasonable number for said randomly selected discrete subset is a polypeptide containing up to 10 amino acid residues. has 200,000 pieces and points (
The set of r) becomes 50 pieces. (3) The active site of penicillin binding protein (PBP) has the sequence Ac-Val-Gly- as shown in the table below.
A method for identifying a compound having antibacterial activity, characterized in that the compound is modeled as a peptide containing Ser-Val-Thr-Lys-NHCH_3 and identified by calculating the ability of a candidate molecule to bind to the peptide. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4) In the method described in claim (3), the ability of the candidate molecule to bind to the peptide is determined by the carboxy group of the substrate as well as the N-H (or O- H) and its interaction between the terminal amino group of each lysine residue and the acetyl oxygen of the receptor peptide. (5) The method according to claim (4), wherein the intrinsic reactivity of the compound toward the peptide is higher than the intrinsic reactivity of the compound toward methanol as compared to the reactivity of the penam ring system of penicillin. To predict by determining. (6) The product of the rms difference for C-O-H of serine and the rms difference for the appropriate functional group of the candidate compound versus penicillin V via a complex with four centers. and determining the intrinsic reactivity of said functional group that reacts with methanol relative to the reactivity of the penem ring system of penicillin. (7) In the method described in claim (5), the functional group has the following formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (8) In the method described in claim (5), the functional group has the following formula. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (9) (a) Serine contained in penicillin-binding protein
By determining the relative ease of forming a four-centered relationship between the serine OH of the lysine active site and the reactive site of the compound, simulate the reaction and (b) determine the activity for the four-center reaction of the chemically active functional group of said compound with methanol, relative to the activation energy of the corresponding reaction of methanol with N-methylazetidinone. A method for determining the suitability and reactivity of any selected candidate antimicrobial substance towards PBPs, characterized in that the energy is determined. (10) Non-β-lactam-containing compounds can form a four-centered transition structure that includes a serine OH group contained in a model of a penicillin-binding protein that reacts with the compound. and said compound has an activation energy for reaction with methanol that is no more than 3 kcal/mol greater than the activation energy exhibited by N-methylazetidinone. . (11) having a structure in which the dihedral angle with the reaction site is 150 to 160 degrees, and the hydrogen bond donor is oriented so that the dihedral angle with the reaction site is -150 to -160 degrees;
and the reaction site reacts with methanol via a transition structure having four centers, and its activation energy ▲E≠ is not higher than the activation energy for reaction with azetidinone by 3-4 kcal/mol or more. An antibacterial agent characterized by: (12) The antibacterial agent according to claim (11),
The hydrogen bond donor is N-H or O-H. (13) In the antibacterial agent according to claim (12),
The structure is characterized in that it has an imino group (-C=N-) as a functional group having the required reactivity. (14) An antibacterial agent characterized by having the following core. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (15) An antibacterial agent characterized by having the following core. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (16) An antibacterial agent characterized by having the following core. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (17) In the antibacterial agent described in claim (11),
The core is characterized in that it has an imino group (-C=N-) as a functional group that imparts the required reactivity. (18) (a) Compound represented by the following general formula (I):
▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, X is a group selected from S, O, CH_2, NH, NR_7 and Se, and Y is selected from OH, NH_2, NHCOR_9 and SH R_1, R_2, R_3, R_4, R_5, R_6 and R_7 each mean a hydrogen atom, an alkyl group or an aryl group, R_9 means an active side chain of a β-lactam) and its pharmaceutically acceptable (b) Compounds represented by the following general formula (II): ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (wherein, Y is a group selected from OH, NH_2, NHCOR_9 and SH, R_1, R_2, R_3, R_4, R_5, R_6, R
_7 and R_8 each mean a hydrogen atom, an alkyl group or an aryl group, and R_9 means an active side chain of β-lactam) and a pharmaceutically acceptable salt thereof; (c) in the following general formula (III) Compound shown: ▲ Formula,
There are chemical formulas, tables, etc. ▼ (III) [In the formula, X-Y is S
-S, CH_2CH_2, S-CH_2, CH_2-S
, S-NR_8, NR_8-S, CH_2H-O, O-
CH_2, O-NR_8, NR_8-O, Se-Se,
A group selected from CH_2-CH_2 and Se-CH_2, Z is a group selected from OH, NH_2, NHCOR_9 and SH, R_1, R_2, R_3, R_4, R_5, R_6 and R_8 are a hydrogen atom and an alkyl group, respectively. or an aryl group, R_7 means an alkyl group or an aryl group, R_9 means an active side chain of β-lactam, and a pharmaceutically acceptable salt thereof; (d) General formula (IV) below Compounds represented by: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) [In the formula, X is a group selected from S, O, CH_2, NH, NR_6 and Se, and Y is N, CH and CR_7 Z means OH, NH_2, SH or NHCOR_9 (when Y is N), Z means R_1_0 (when Y is CH or CR_7)
R_1, R_2, R_3, R_4, R_5, R_6 and R_7 each mean a hydrogen atom, an alkyl group or an aryl group, R_9 means an active side chain of β-lactam, R_1_0 is ▲ mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R_1_1 means an alkyl group or an aryl group, and R_1_2 is OH, NH_2, NHCOR_9 or S
H)] and pharmaceutically acceptable salts thereof; and (e) a compound represented by the following general formula (V): ▲ Numerical formula, chemical formula, table, etc. ▼ (V) In the formula, X is S , O, CH_2, NH, NR_5 and S
is a group selected from e, Y is NR_6-Z, R_1, R_2, R_3, R_4, R_5 and R_6
each represents a hydrogen atom, an alkyl group or an aryl group; Z represents OH, SH, NH_2 or NHCOR_7; R_9 represents the active side chain of a β-lactam); and pharmaceutically acceptable salts thereof; antibacterial compounds. (19) The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is a group selected from S, O, CH_2, NH, NR_7 and Se, and Y is A group selected from OH, NH_2, NHCOR_9 and SH, R_1, R_2, R_3, R_4, R_5, R_6 and R_7 each mean a hydrogen atom, an alkyl group or an aryl group, and R_9 is an active side chain of a β-lactam. The novel antibacterial compound according to claim 18, characterized in that it consists of a compound represented by: or a pharmaceutically acceptable salt thereof. (20) Claim No. (19) characterized in that X is S.
) Compounds described in section 2. (21) R_1, R_2, R_3, R_4, R_5, R
21. The compound according to claim 20, wherein _6 and R_7 are each a hydrogen atom or a lower alkyl group. (22) The compound according to item (21), wherein the lower alkyl group is a methyl group. (23) General formula (II) below: ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, X is a group selected from S, O, CH_2, NH, NR_8 and Se, and Y is A group selected from OH, NH_2, NHCOR_9 and SH, R_1, R_2, R_3, R_4, R_5, R_6, R
_7 and R_8 each mean a hydrogen atom, an alkyl group, or an aryl group, and R_9 means an active side chain of a β-lactam) and a pharmaceutically acceptable salt thereof. Characteristic claim No. (18)
Novel antibacterial compounds described in Section. (24) Claim No. (23) characterized in that X is S.
) Compounds described in section 2. (25) R_1, R_2, R_3, R_4, R_5, R
Claim No. (24), wherein _6, R_7 and R_8 are each a hydrogen atom or a lower alkyl group.
Compounds described in Section. (26) The compound according to item (25), wherein the lower alkyl group is a methyl group. (27) General formula (III) below: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, X-Y is S-S, CH_2CH_2, S-CH
_2, CH_2-S, S-NR_6, NR_8-S, C
H_2H-O, O-CH_2, O-NR_8, NR_8
-O, Se-Se, CH_2-CH_2 and Se-C
A group selected from H_2, Z is a group selected from OH, NH_2, NHCOR_9 and SH, and R_1, R_2, R_3, R_4, R_5, R_6 and R_8 each represent a hydrogen atom, an alkyl group or an aryl group. , R_7 means an alkyl group or an aryl group, R_9 means an active side chain of a β-lactam, and claim 18 consists of a compound represented by and a pharmaceutically acceptable salt thereof. ) Novel antibacterial compounds described in section 2. (28) The compound according to claim (27), wherein -X-Y is -S-S-. (29) R_1, R_2, R_3, R_4, R_5, R
29. The compound according to claim 28, wherein _6 and R_8 are each a hydrogen atom or a lower alkyl group, and R_7 is a lower alkyl group. (30) The compound according to item (29), wherein the lower alkyl group is a methyl group. (31) The following general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) [In the formula, X is a group selected from S, O, CH_2, NH, NR_6 and Se, and Y is A group selected from N, CH and CR_7, Z means OH, NH_2, SH or NHCOR_9 (when Y is N), Z is R_1_0 (when Y is CH or CR_7)
R_1, R_2, R_3, R_4, R_5, R_6 and R_7 each mean a hydrogen atom, an alkyl group or an aryl group, R_9 means an active side chain of β-lactam, R_1_0 is ▲ mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R_1_1 means an alkyl group or an aryl group, and R_1_2 is OH, NH_2, NHCOR_9 or S
19. The novel antibacterial compound according to claim 18, characterized in that it consists of a compound represented by the following formula: and a pharmaceutically acceptable salt thereof. (32) Claim No. (31) characterized in that X is S.
) Compounds described in section 2. (33) R_1, R_2, R_3, R_4, R_5, R
33. The compound according to claim 32, wherein _6 and R_7 are each a hydrogen atom or a lower alkyl group. (34) The compound according to item (33), wherein the lower alkyl group is a methyl group. (35) The compound according to any one of claims (31) to (34), wherein Z is OH and Y is N. (36) The following general formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, X is a group selected from S, O, CH_2, NH, NR_5 and Se, and Y is NR_6-Z, R_1, R_2, R_3, R_4, R_5 and R_6
each means a hydrogen atom, an alkyl group or an aryl group, Z means OH, SH, NH_2 or NHCOR_7, R_9 means the active side chain of a β-lactam) and its pharmaceutically acceptable 19. The novel antibacterial compound according to claim 18, characterized in that it consists of a salt of: (37) The compound according to claim (36), wherein Z is NHCOR_7 (in the formula, R_7 means a phenyl group or a lower alkyl group). (38) The compound according to claim (37), wherein R_7 is a benzyl group. (39) R_1, R_
2. The compound according to claim 36, (37) or (38), wherein R_3, R_4, R_5 and R_6 are each a hydrogen atom or a lower alkyl group. (40) The compound according to claim (36), (37) or (38), wherein R_1, R_2, R_3, R_4, R_5 and R_6 are each a hydrogen atom. (41) X is S, R_1, R_2, R_3, R_
4 and R_6 and Z are NHCObenzyl groups, the compound according to claim 36. (42) The compound according to claim (18), wherein the compound is 3-carboxyl-5-hydroxymethyl-6,6-dimethyl-▲^4-1,4-thiazine. (43) The compound is 3-carboxyl-5-(2-hydroxypropyl)-6,6-dimethyl-▲^4-1,4-
The compound according to claim (18), which is a thiazine. (44) The compound is 2-thia-4-carboxyl-6-(
2-hydroxypropyl)-7,7-dimethyl-▲^5
The compound according to claim (18), which is -1,5-thiazepine. (45) The compound is 3-carboxyl-5-oximino-
Claim No. (1) characterized in that it is 1,4-thiazine.
Compound of item 8). (46) The compound according to item (18), wherein the compound is 3D-carboxy-5-phenylacetylhydrazyl-▲^4-thiazine.