JPS63208596A - Effect enhancer of novel antibacterial agent and 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 novel antibacterial agents that interfere with bacterial cell wall synthesis by inhibiting the enzyme D-AQa-D-A (la myrigase). DHP) and thus enhance the antibiotic action of carbapenem antibiotics.

The selective toxicity of many antimicrobial agents is due to the fact that their targets are structures present only in susceptible bacteria. One of these structures is the peptidoglycan rebarrier polymer, which plays a vital role in protecting bacteria from lysis. A number of agents, such as beta-lactams, bacitracin and flavomycin, interfere with the assembly of this polymer by blocking the enzymatic reactions involved in the final stages of assembly.

Peptidoglycan biosynthesis is a precursor substance UDP-MurNAc-AQa-D that is biosynthesized by a multienzyme pathway that ends with the addition of D-alanine-D-alanine to the UDP-MurNAc-tripeptide. -G Q
u-Lys-D-A11a-D-alanine. The formation of D-alanyl-D-alanine is catalyzed by D-alanyl-D-alanine ligase (synthetase). It is known that inhibition of D-alanyl-D-alanyl ligase terminates peptidoglycan biosynthesis resulting in bacterial cell lysis in vivo. Such inhibitors can be used as antibacterial agents.6 For example, D-cycloserine, a pseudo-D-alanine, is a reversible inhibitor of ligase at both donor and acceptor sites and is the most potent ligase inhibitor so far described. It is an effective antibacterial agent. (F, C.

Neuhaus et al., Biochemistry, Vol. 3, 471-4.
81 pages (1964)).

It is also known that a dipeptide analogue of D-alanyl-D-alanine is an inhibitor of gauze. (F,C
, Neuhaus et al., Biochemistry Vol. 8, 5119.
~5124 pages (1965) and F. C. Neuhaus.

Hammens, Pharmac, Ther, Vol. 14, pp. 265-319 (1981)).

Renal dehydropeptidase (E, C, 3°4.13.
11) is a mammalian enzyme that metabolizes carbapenem antibiotics such as chenamycin and imipenem. Inhibition of this enzyme increases the urinary recovery and reduces nephrotoxicity of these antibiotics. EPO Publication No. 0091594 from Sunlough Ocean describes aminocarboxylic acid derivatives with dipeptidase inhibitory activity. This problem and the development of cilastatin as a renal dehydropeptidase inhibitor for use in combination with imipenem also F.

Discussed in M. Kaban et al., J. Antimicrobial Chemotherapy Vol. 12, Supplement, pp. 1-35 (1983).

U.S. Pat. No. 4,374,131 to Petrillo (assigned to E.R., Squipp & Sons, Inc.) discloses that amino and substituted aminophosphinyl agents are useful hypertensive agents due to their angiotensin converting enzyme (ACE) inhibiting action. -Alkanoyl compounds are disclosed.

E, D, Torset, etc. (Merck & Company)
Proc, Natl, Acad, Sci, U
SA Vol. 79, pp. 2176-2180 (April 1982) discloses phosphorus-containing inhibitors of angiotensin converting enzyme.

Against this background, the search for new and more effective antibacterial agents that are gauze inhibitors continues.

It has been discovered that compounds of Structures I and 3, shown below, are inhibitors of D-7 ranyl-D-alanine ligase and are useful in the treatment of bacterial infections. These compounds can be administered alone or in combination with other antibiotics such as D-cycloserine or β-lactam antibiotics. These compounds also inhibit renal dehydropeptidase E, C, (3,4,13°11) and are useful in enhancing the in vivo effects of penem and carbapenem antibiotics such as imipenem.

The present invention provides phosphinodipeptides represented by formulas (1) and (2) and their stereoisomers and racemic compounds: 0R.

■ [In the formula, R1 is H, CH,; R1 and R3 are (a) hydrogen; (b) c-C12 straight chain or branched alkyl; (C) at-C1, straight chain or branched chain Monoalkenyl: (d) C, ~C2°aralkyl (the alkyl chain is straight or branched C8-C1); (e) heterocyclic alkyl (the alkyl chain is straight or branched C8-C1); , the heterocycle is a 5- to 6-membered ring (a fully aromatic ring containing 1 to 3 O, N or S heteroatoms optionally fused with a benzene ring), and the acid groups of R2 and R6 above is halo, hydroxy, carboxy, 01-C4 alkoxycarbonyl, 07-C16 arylalkoxycarbonyl, C1-C7 cycloalkyl, 02-C, alkoxy, C, -C, aryloxy, amino, mono- or di-C1-C , alkylamino, thio, C1-C4 alkylthio, C6-C1t arylthio, C1-C, aralkylthio or radical -8-(CH,), -CH(NH,C0OH(n=1-
2) (However, when substituted with one of the thio groups defined above, R3 or R
6 is at least C2 alkyl), the aryl or aromatic heterocyclyl ring can be further substituted with C1-C4 straight or branched alkyl, trihalomethyl, nitro, halo, cyano or sulfonamide; R3 and R4 is hydrogen, C1-C4 alkyl.

C6-C18 aryl or C7-C1, aralkyl. ] Also a pharmaceutically acceptable carrier and formula! The present invention provides a pharmaceutical composition useful for the treatment of antibacterial infections, comprising a pharmaceutically effective amount of an antibacterial compound or mixture thereof represented by: R8 and R5 are as defined above; R3 and R4 are independently selected from hydrogen, lower alkyl, aryl lower alkyl; the carbon atom attached to R1 (bonded to phosphorus) is D(S) or Located in DL (SR) configuration, R
The carbon atom attached to 2 is in the D(R), DL(R8) configuration, and if R5 is present, the double bond is in the E or Z
It's in the layout. ].

Preferred embodiments of structures I and (2) for antibacterial action are RL is methyl, R3 and R1 are small radicals such as methyl, ethyl, bromomethyl, chloromethyl, etc.
The carbon attached to R1 includes those in the O(S) configuration.

Formula in combination with a pharmaceutically effective amount of a carbapenem or penem antibiotic! The present invention provides a pharmaceutical composition useful for the treatment of antibacterial infections, comprising a pharmaceutically effective amount of a DHP-inhibiting compound or a mixture thereof represented by: R4 or ■, where R8 is H, CH , R2 and R1 are as defined above: R□ and R4 are independently selected from hydrogen, lower alkyl, aryl lower alkyl; and in addition, the carbon attached to R□ (bonded to the phosphorus) is in the L (R) or DL (SR) configuration, and the carbon attached to R2 is in the D (R), L (S) or D
in the L(R8) configuration; if R8 is present, the double bond is in the E or 2 configuration. ].

Structure for DHP inhibitory action! A preferable embodiment of and (■) is that R4 is methyl, R2 and R2 are n-heptyl,
Long chain alkyl groups such as n-hexyl (halo, hydroxy, carboxy, 01-C4 alkoxycarbonyl,
C1-C16 arylalkoxycarbonyl, 03-C
7 cycloalkyl, C1-C4 alkoxy.

06-C13 aryloxy, amino, mono- or di-C1-C, alkylamino, thio, 01-C4 alkylthio, C, ~C1, arylthio, 07-co aralkylthio or radical) Lt-5-(CH,), -C
H(NH,)COOH (n=1-2), provided that R8 or R8 is at least C2 alkyl when substituted with one of the thio groups defined above. , and the aryl or aromatic heterocycle further contains C
2-C4 straight or branched alkyl, trihalomethyl,
(can be substituted with nitro, halo, cyano or sulfonamide), and the chain carbon attached to R1 (α to phosphorus) is preferably in the L(R) configuration.

When R5 is present, it is in two configurations.

The novel compounds of structural formulas I and II above represent new and useful antibacterial agents and dehydropeptidase inhibitors.

Alkyl and alkenyl groups for R2 and R5 represented by any of the variables include, unless otherwise specified, straight or branched alkyl and monoalkenyl groups and linear hydrocarbon radicals of 1 to 12 carbon atoms, such as methyl. , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, SaC-butyl, t-butyl, n-pentyl, isopentyl, n-hebutyl, n
-nonyl, 4,4-dimethylpentyl or vinyl, allyl, 1-butenyl, 2-butenyl, 5-hexenyl, and the like. Ethyl and chloromethyl are preferred enemies for antibacterial action. n-butyl, n-pentyl for DHP inhibition.

N-hebutyl or 1-butenyl are preferred opponents.

Aralkyl groups represented by the above variables have from 1 to 8 carbon atoms in the alkyl portion, specifically mentioned "aryl" represents phanyl, naphthyl or biphenyl; representative examples are benzyl, phenethyl, 4-phenyl- n
-butyl, δ-phenyl-n-octyl, and the like.

Aromatic heterocycle or paheteroaryl" substituents are synonymous and the groups listed above contain 1 to 3 O, N or S heteroatoms, preferably one 0 or S and/or 1 to 3 represents a 5- or 6-membered aromatic ring containing N heteroatoms, specifically pyridyl, chenyl, furyl,
Imidazolyl and thiazolyl and all bicyclic groups derived therefrom, any of the above heterocyclic groups can be fused to a benzene ring, such as indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzofuryl and benzothenyl.

The substituents mentioned on the alkyl and alkenyl chains can furthermore be present on the aromatic rings of the aralkyl, heterocycloalkyl and heteroaryl groups. Substitution sites include all available sites, and substitutions can include one or more of the same or different groups.

Substituents are halo (meaning fluoro, chloro, bromo or iodo); hydroxy; carboxyEC1-C4 straight-chain or branched alkoxycarboxy, such as methoxycarbonyl and/or ethoxycarbonyl; C7-C1
, arylalkoxycarbonyl, such as benzyloxycarbonyl, n-butyloxycarbonyl; C3-C
, cycloalkyl, such as cyclopentyl and cyclohexyl; C1-C4 alkoxy, such as t-butoxy and ethoxy; C6-C1□aryloxy, such as biphenyloxy, benzyloxy; amino; mono- or di-C2-C, dialkylamino, such as methyl Amino, isopropylamino.

n-butylamino, isohexylamino, N.

N-diethylamino, methylethylamino, methyl-
t-butylamino, di-n-octylamino; thio; C
1-C4 alkylthio, e.g. methylthio, ethylthio; c6-c1□arylthio, e.g. phenylthio; C
7-C1° aralkylthio, e.g. benzylthio, naphthylmethylthio; radical -3-CH, -CH(NH,
)COOH and -8-(CHz)*-CH(NH,)
COOH (both preferably in the L configuration):
When a thio substituent is present, R, /R, is at least C
, which must be an alkyl group; if an aryl or heteroaryl group is present in the substituent, the ring carbon may further be a straight-chain or branched 01-C4 alkyl group, such as methyl,
Ethyl, isopropyl, t-butyl; trihalomethyl (
"Halo" has the same meaning as above), for example trichloromethyl, trifluoromethyl; nitro, cyano or sulfonamide.

Preferred compounds are those in which R1 is methyl; R2 and R2 are: 01-C1° straight or branched chain alkyl; C7-C14
Aralkyl (both groups are halo, amino, mono- or di-C-C4 straight or branched alkylamino, carboxyl, 02-C4 alkoxycarbonyl, hydroxy,
01~C, alkoxy, C, -C, cycloalkyl, 0
6-C1° aryloxy, thio, C1-C9 straight or branched chain alkylthio, C6-C1° arylthio, C
7-C14 aralkylthio, -5-(CH,), -CH
(NH2)CO□H (n=1-2), provided that when substituted with one of the thio groups defined above, R2 or R6 is at least C2 alkyl. , the aryl group ring carbon can be further substituted with straight-chain or branched C1-C4 alkyl; R1 and R4 are hydrogen, C□-C4 straight or branched alkyl, such as methyl, ethyl, C7-C4 , aralkyl such as benzyl are preferred enemies.

Preferred compounds of structure I for antibacterial activity are those in which the stereochemical configuration of the carbon attached to R (attached to phosphorus) is D(s), DL
(SR), and each chain carbon attached to R2 is D(R)
, DL(R5). R□ and R
It is particularly preferred when the stereochemical configuration of the carbon attached to 2 is D (S) and D (R), respectively.

Compounds suitable for antimicrobial action include those in which the carbon atom attached to R8 has a D stereochemical configuration and the double bond has a Z or E configuration.

Structure suitable for use as a DHP inhibitor! Or, in the compound of Includes compounds which are preferably in the Z configuration.

The compounds of formulas I and II can be used in the form of salts derived from inorganic or organic acids and bases. Such acid addition salts include the following acetates, adipates, alginates,
Aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, digluconate, dodecylate.

ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2
- Hydroxyethane sulfonate, lactate, maleate.

Methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, bamoate, pectate, persulfate, 3-phenylpropionate, picrate, propionate.

Includes succinate, tartrate, thiocyanate, tosylate and undecanoate.

Base salts include alkali metal salts such as aluminum salts, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine; Includes salts with amino acids such as arginine and lysine. This gives water- or oil-soluble or dispersible products.

A further aspect of the present invention is the formulation as an antibacterial agent administered separately or in combination with other antibacterial agents such as D-cycloserine, fosfomycin, pentididone, cefoxitin, cefftazidine, chenamycin, imibenem, ampicillin, etc. and ■ Uses of the compound.

Pharmaceutical compositions useful in the treatment of antibacterial infections include a pharmaceutically acceptable carrier and an antibacterial compound of formula ■ or ■, or a mixture thereof, wherein the compound contains carbon atoms attached to R1 and R2 in the D configuration, and R5 is present. If the double bond is E or 2
Preferably, it includes a pharmaceutically effective amount of (in the configuration).

Preferred specific antimicrobial compounds useful in the compositions include 1-(aminoethyl)-(2-carboxy-n-propyl)phosphinic acid, 1-(aminoethyl)-(2-carbomethoxy-n
-propyl)phosphinic acid, 1-(aminoethyl)-(
2-carboxy-〇-butyl)phosphinic acid.

1-(aminoethyl)-(2-carboxy-5-phenyl-n-pentyl)phosphinic acid.

1-(aminoethyl)-(2-carboxy-n-nonyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-5-(4-pyridyl)-n-pentyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-5-(4-pyridyl)-n-pentyl)phosphinic acid, ethyl)-(2-carboxy-3
-chloro-〇-zolopyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-3-bromo-n-propyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-n-hexyl)phosphine acid, 1-(aminoethyl)-(2-carboxy-2-n-octenyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-2-propenyl)phosphinic acid.

Includes 1-(aminoethyl)-(2-carboxy-4-phenyl-2-butenyl)phosphinic acid and 1-(aminoethyl)-(2-carboxy-5-phenyl-2-pentenyl)phosphinic acid.

Further pharmaceutical compositions include D-cycloserine, fosfomycin, pentididone, and cefoxitin.

Ceftazidine, Chenamycin, Imipenem.

An effective amount of a second antimicrobial compound selected from ampicillin and the like can be included in combination.

Also provided is a method of treating a bacterial infection in a mammalian host, comprising administering to the host a therapeutically effective amount of the composition described above.

Pharmaceutical compositions useful in the treatment of bacterial infections include compounds of Formula I or ■ (where the carbon attached to R1 is in the L(R) configuration and the carbon attached to R3 is in the L(R) configuration) in combination with a pharmaceutically effective amount of a carbapenem or penem antibiotic. carbons are in the D(R) or L(S) configuration, and when R5 is present, the double bond is preferably in the 2-configuration).

In particular, preferred HP inhibitory compounds useful in the compositions include 1-
(aminoethyl)-(2-carboxy-n-propyl)
Phosphinic acid, 1-(aminoethyl)-(2-carbomethoxy-n-propyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-n-butyl)phosphinic acid, 1-(aminoethyl)-( 2-Carboxy-5-phenyl-n-pentyl-n-probyl)phosphinic acid, 1
-(aminoethyl)-(2-carboxy-n-nonyl)
Phosphinic acid, 1-(aminoethyl)-(2-carboxy-5-(4-pyridyl)-n-pentyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-3
-chloro-n-propyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-3-bromo-n-propyl)phosphinic acid, 1-(aminoethyl)-(2-
Carboxy-n-hexyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-2-n-octenyl)
Phosphinic acid, 1-(aminoethyl)-(2-carboxy-2-propenyl)phosphinic acid, 1-(aminoethyl)-(2-carboxy-4-phenyl-2-butenylpropyl)phosphinic acid and 1-(aminoethyl)-(2-carboxy-4-phenyl-2-butenylpropyl)phosphinic acid ethyl)−
(2-carboxy-5-phenyl-2-pentenyl)phosphinic acid.

Also provided is a method of treating a bacterial infection in a mammalian host, comprising administering to the host a therapeutically effective amount of the composition described above.

The ligase enzyme inhibitory effect of compounds of formula I was determined using D-cycloserine as a control and standard ligase inhibitor.
C. Neuhaus operation (Biochemistry Vol. 3 47)
1-480 (1964), which is hereby incorporated by reference), was evaluated in vitro with some modifications. The operation is as follows.

D-alanyl-D-alanine ligase Streptococcus faecalis (ATCC8043)
Neuhaus (J, Biol, Chew.

237, p. 778, 1962). Cell-free extracts were prepared by sonication followed by centrifugation at 27*OOOX g for 30 min.
Proteins were precipitated with 55% ammonium sulfate. The sediment was dissolved in 0.05M Tris-CQ buffer (pH 7.0
), dialyzed against 0.0025M glutathione, and stored in liquid nitrogen. No loss of activity was observed after 1 year.

The assay mixture was 0.05M Tris-CQ buffer (pH 7,
9), 0.01M KCQ, 0.008MMgCQ*-
o, o O5M ATP-0-005M(14C-1
)-D-alanine and enzyme (specific activity = 0.38 unit/
■Protein) Contained 5 μa. Verified capacity is 0.1m
It was Q.

The inhibitors were pre-incubated with the enzyme, MgCQ, KCQ and buffer for 40 minutes at room temperature before ATP and substrate were added.The samples were then incubated at 37°C for 30 minutes.

20μQ of each sample was deposited on high-resolution pre-grooved silica.
The reaction was stopped by applying it to the pre-absorbent layer of the gel TLC plate. Plate with ethanol:ammonium hydroxide:H
It was developed for 2-3 hours in lO (11:1:8), and the radioactive range was confirmed and integrated using a Peltor trilinear analyzer. The I'C50 was determined for the active compound (70
% inhibition).

Representative test data with compounds of the invention using the procedure described above is shown below.

D A Q a -A Q a' Gauze DL
HH535 DL Methyl H165 D Methyl H124 DL Methyl Methyl 60DL
Ethyl H50 D Ethyl H45 DL Phenylpropyl H20 DL n-Hebutyl H12,5 D n-Heptyl H4 D H210DL n-
Pentyl, (E, Z isomer) 700DL Benzyl, (E isomer) 210 ■ Formula! and In Vitro Antibacterial Testing of Hymetics of H. F., R., Atherton et al., Anti-Microbial Agents and Chemotherapy Vol. 15,
The antibacterial data shown below was obtained using the synthetic agar medium described on page 677 (1979).

The compounds of the invention also inhibit dehydropeptidase action (renal dipeptidase, EC 3,4,13°11) and thus enhance the antibiotic action of carbapenem antibiotics. Renal dehydropeptidase action was determined by M, Berbman and H.
, Schleich Z., Physiol, Chew, Vol. 205, p. 65 (1932). Also, B. J., Campbell et al., Bio-chi.
m, B 1ophys, Acta, Volume 118, 3
71 (1966), incorporated herein by reference.

An in vitro screen was performed to demonstrate the ability of compounds of Formula I to inhibit the action of renal dipeptidase enzymes. This measured the ability of compounds to inhibit the hydrolysis of glycyldehydrophenylalanine (GDP) by solubilized preparations of dipeptidase isolated from pig kidneys.

The operation is as follows. 50mM “MOPS” (3-(
5 μg of lyophilized enzyme and the test compound at a final concentration of 0.1 mM are added to the 1/0 system, -PH7,1 containing N-morpholino)propanesulfonic acid) buffer. After incubation at 37°C for 5 minutes, GDP is added to a final concentration of Oo5mM. Continue to incubate at 37℃ for 10 minutes to complete GDP hydrolysis.
Measure the optical density over time at 75 nm. Enzyme inhibition is measured relative to a standard procedure without inhibitor;
Expressed as inhibitor binding constant Ki. This is the enzyme 50
is the inhibitor concentration that yields % inhibition.

The table below summarizes some representative data using compounds of the invention.

Dehydropeptidase action DL methyl 10L
Methyl 10D Methyl 140DL n-butyl,
4L phenylpropyl 2
7D Phenylpropyl 1000DL
4-pyridylpropyl 12D
H-230 L H27 DL n-pentyl mixture 5.80L
Phenethyl Z 16DL
The in vivo efficacy of DHP inhibitors that increase the metabolic stability of phenethyl E7 carbapenem antibiotics was determined by measuring the urinary recovery of such antibiotics in the presence and absence of coadministered dehydropeptidase inhibitors. It can be proven. Specifically, F, M, Kaban et al., J, Antimicrobial Chemotherapy, Volume 12, Supplement, 1-3
5 (1983), and the observation of this potentiation can be made by measuring the doses required to treat infections in animals with dehydropeptidase-sensitive antibiotics alone or in combination with dehydropeptidase inhibitors. is also possible.

For administration, the compositions of the present invention may also contain other conventional pharmaceutically acceptable ingredients as necessary or desired. Such a component generally refers to a carrier or excipient.

Conventional techniques can be utilized to prepare such compositions in suitable dosage forms. Any dosage form will contain a pharmaceutically effective amount of a compound of the invention.

The compositions of the invention can be administered parenterally, which is suitable when used in combination with carbapenem antibiotics such as imibenem. They may also be administered orally, and the compounds of the invention can be used to treat localized antibacterial infections. These compounds may therefore be prepared in a number of suitable dosage forms such as tablets, capsules, suspensions, solutions, etc. for oral administration, and solutions, suspensions, etc. for parenteral administration.

Emulsions, liquids for intravenous administration, ointments for topical administration,
It can be present as a transdermal patch or the like.

Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may include sweetening agents to provide a pharmaceutically elegant and palatable formulation. , colorants, and preservatives. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients can also be manufactured by known methods. The excipients used include (1) inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; (2)
Granulating agents and disintegrants such as corn starch or alginic acid; (3) binders such as starch, gelatin or gum acacia; (4) lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and produce a sustained action over a long period of time. Specifically, retardants such as glyceryl monostearate or glyceryl distearate can be used.

Also, U.S. Patent Nos. 4,256,108 and 4,160
, 452 and 4,265,874 can be coated to produce therapeutic penetrant tablets for controlled release.

Optionally, oral administration may be in the form of hard gelatin capsules, in which the active ingredient is mixed with inert excipients, such as calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules, in which the active ingredient is mixed with water or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions usually contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients.

(1) Suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxyb, lobil methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic.

(2) (a) Natural phosphatides such as lecithin; (b) condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; (c) condensation products of ethylene oxide and long-chain aliphatic alcohols, such as hebutade ethylene oxycetanol, (d) condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or (e) condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols. Condensation products such as dispersants or lubricants such as polyoxyethylene sorbitan monooleate.

The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. May include.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol, and sweetening agents and flavoring agents may be added to provide a vague oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules are suitable for preparing aqueous suspensions and present the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Such dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. In addition, excipients 1 such as the sweetening, flavoring and coloring agents mentioned above may also be present.

The pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers include (1) natural gums such as gum arabic and gum tragacanth;
) Natural phosphatides such as soy and lecithin, (3
) esters or partial esters derived from fatty acids and hexitol anhydride, tateevasorbitan monooleate; (4) condensation products of said partial esters with ethylene oxide 1, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs are sweeteners.

For example, glycerol, propylene glycol.

Can be prescribed with sorbitol or sucrose. Such formulations may also contain a detoxifying agent, a preservative, and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable excipients and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides and fatty acids such as oleic acid in the preparation of injectables.

For topical use, creams, ointments, jellies, solutions or suspensions containing the composition of the present invention are used.

Therapeutic doses for humans can vary as needed. Generally, the oral dose of the antimicrobial compounds of this invention when given orally will range from 250 to 4 grams per patient administered three to four times per day. Intravenous or intramuscular doses are 100 to 1 g administered 3 to 4 times daily.0.0.
It is administered in combination with antibiotics in amounts of 1 to 10 μ/kg/day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Specifically, formulations intended for oral administration may contain 100 to 2000 μ of active agent combined with any convenient amount of carrier material, which may vary from about 5 to 95% of the total composition. .

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration.

However, the specific dosage level for any particular patient will depend on the activity of the particular compound used, age, body weight, general condition, gender, diet, time of administration, route of administration, excretion rate, drug combinations, and treatment. It will be understood that this will depend on a variety of factors, including the severity of the particular disease.

The compound of formula (■) has the following reaction scheme (R* -R* -R1
(as defined above unless otherwise specified).

As will be apparent to those skilled in the art and illustrated in the Examples below, reactive groups not included in the reaction, such as amino, carboxy, mercapto, etc., are protected by standard methods in peptide chemistry prior to the coupling reaction and then deprotected. can be protected to obtain the desired product. Cbz represents carbobenzyloxy.

Cbzaminoalkylphosphonic acid (Cbzamino
alkylphosphonous acids) (
1) is P, A.

Bartlett et al., (J, A*aer, Chew,
Soc.

106, pp. 4282-4283 (1984)) and E., Baylis et al. (J. Cha Peng.

Soc, Perkin Trans, Volume 1, 2845-285.
3 (1984)) and the method of Baylis (supra).
Both methods are cited here. Compounds derived from both optically active and racemic substances are claimed in this invention.

The protected aminoalkyl phosphonite (1) is esterified with either diazomethane or triethyl orthoformate to give the methyl or ethyl ester (2) and deprotonated with either sodium methoxide or ethoxide in the corresponding alcohol. , with an appropriately substituted acrylate to obtain the protected form (4) of formula 1. Acrylate is Tetrahedron Volume 36, 1036~
1070 (1980), which is incorporated by reference.

On the other hand, compound 4 can be prepared by converting the protected aminoalkylphosphonic acid (1) to J with an appropriately substituted 3-heropropionate or acrylate in the presence of a trialkylsilyl chloride such as trimethylsilyl chloride and a tertiary amine such as triethylamine. (Tetrahedron Lett, Vol. 25, pp. 4737-40, 47
41-44 (1984), to which reference is made.

Phosphinic acid 3 can be esterified with diazomethane to obtain compound 4.

Compound 4 is converted to formula 1 by two standard routes.

The carbobenzyloxy group can be removed by hydrogenation in an alcohol such as ethanol with a catalyst such as Pd/C or by cleavage with HBr in acetic acid followed by treatment with propylene oxide followed by concentrated hydrochloric acid. The ester hydrolyzes therein to yield a compound of formula I (R,=H). The carboxy ester (R1=alkyl) can be separated by desalting the ester hydrobromide salt 6. The phosphine ester (R9=alkyl) can be separated by selective hydrolysis of the carboxyester 5.

This alternative route involves the conjugate addition of a phosphonoester to trimethyl-2-phosphonoacrylate under the conditions previously described.6 The anion is then captured with an aldehyde, producing the dehydro compound as a mixture of E and Z isomers. do. This same intermediate was substituted with a protected aminoalkyl phosphonoacid by a substituted 2-bromomethyl acrylate in J. Tottachili et al., Tetrahedron Lett, Vol. 25, 47.
37-40, pp. 4741-44 (1984), who cites this literature, the olefins can then be selectively catalyzed using homogeneous catalysis. Complexes with organophosphine ligands (COD), such as RhCQ, in methanol, which can be reduced, can be used to obtain compounds and can be further prepared by the operations already described.

An asymmetric organophosphine ligand such as (-)2.3-〇-isopropylidene-2゜3-dihydroxy-1,4-bis(diphenylphosphino)butane, ((-)DIOP) is Alternatively, it can be used to produce the R stereoisomer in high enantiomeric excess.

Diastereomers suitable for antimicrobial action correspond to the absolute stereochemistry of D-AQa-D-ARa at the R and R2 carbons, generally D(S), D(R
) or S, R-diastereomer, R
6 is E or 2.

Corresponds to an L-amino acid (R stereochemistry) at the carbon with a diastereomeric jt R structure suitable for dehydropeptidase inhibition. The stereochemistry at R2 can correspond to either a D or L-amino acid for good activity (R or S). R6 of dehydro analogs
The stereochemistry at can be either E or Z, preferably Z.

If both antibacterial and dehydropeptidase actions are desired, it is preferred that the carbon atom bearing R is in the DL form.

Suitable diastereomers are isolated by chromatographic treatment or resolution of the intermediate or its final product or salt thereof.

Racemic compounds can be separated by standard methods including the use of optically active amines and acids as resolving agents.6 The following examples illustrate the invention:
It should not be construed as limiting the scope of the invention.

Production of phosphonic acid methyl ester CbzNHPI( 0CH.

E., Baylis et al. [J. Chew, Soc.

Perkin Trans., pp. 2845-2853 (1984)]. Volume ■, 165-1
67 (1943)] with diazomethane in an ether solution. The compound was purified by standard chromatography on silica gel.

TLC (silica, 9:1. ethyl acetate:acetonitrile) R+ = 0.51 NMR (CDCI2., TMS) 61.2 and 1.5
(2d, 3H): 2.2 and 10.1 (d, L
H): 3.6 (d, 3H); 3.9 (m, L
H); 5.0 (s, 2H); 6.0-6.6 (overlapping doublet, LH): 7.2 (s, 5H).

0.36 g of 1-benzyloxycarbonylaminoethylphosphonite methyl ester in 3 mQ of methanol at 0°C
(0,0014 mol) of sodium methoxide in methanol (2N solution 0.77 mA)
After dropping over 0 min, methyl acrylate 0.12
The reaction mixture to which 6 m12 (0,0014 mol) was added was stirred at 0 °C for 30 minutes, and then at room temperature for 4 hours, then IN
Diluted with HCQ.

The mixture was extracted twice with ethyl acetate. The organics were dried over sodium sulfate, filtered over magnesium sulfate and evaporated in vacuo. The product mixture was purified by chromatography (silica gel, 9:1 ethyl acetate:acetonitrile) to give methyl-1-benzyloxycarbonylaminoethyl-[
2-Carbomethoxy-1-ethyl]phosphinate 0.
34 g was obtained.

TLC (silica, 9:1. ethyl acetate:acetonitrile) R+ = 0.47 NMR (CDCQ, ) δ1.4 (m, 3H); 2.
00-2.2 (m, 2H); 2.5-2.7° (m
y 2H); 3.7 (s, 3H); 3.7-3.
9 (m, 3H): 4.1 (quintet, IH); 5.1
(s, 2H); 5.2 (d, l/2H): 5.55
(d, 1/2H); 7.4 (s, 5H).

C1s Hat N Os P -1/2 Hz O
Elemental analysis calculation value for N, 3.97: C, 51,13; H, 6
, 25 measured value N, 3.64; C, 50,78;
H,6,46 Mass Spectrum - M''343 Next, 300 μ of the above intermediate was dissolved in 30% H in acetic acid (5 mA).
Stirred in a solution of Br for 12 hours.

The reaction mixture was evaporated in vacuo, poured into H105mffi and washed twice with diethyl ethyl. The aqueous layer was evaporated in vacuo, dissolved in concentrated hydrochloric acid 51a, stirred at 50°C for 3 days and then evaporated in vacuo. The hydrochloride salt was dissolved in 1 m Q of methanol and diluted with 20 m m of propylene oxide. The precipitated solid was filtered and washed with ether to give the title compound as a hygroscopic glass.

TLC (silica, 1:1:1:1.n-butanol:
H, O: acetic acid: ethyl acetate) Rf = 0.28 NMR (D, O) 5 1.35-1.5 (2 duplicates d,
3H); 1.85-2.0 (m, 2H): 2.55
-2.85 (ABQ, 2H): 3.25-3.35
(ms LH) - Elemental analysis calculated values for C, Hl, N04P, 1/2H, O N, ? , 19; C, 30, 84: H, 6
,68 measurement value N, 6.79: C, 30,87:
H,6,70 mass spectrum (FAB) M+1,182
Methyl 1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-propyl]phosphinate was produced by the same method used in Example 2 using methyl methacrylate.

NMR (CDCQ,) 61.2-1.4 (m.

6H); 1.7-1.9 (m, LH)3 2.2-2
．． 4 (m, LH); 2.8-2.95 (m.

LH); 3.7 (s, 3H); 3.65-3.8 (m
, 3H); 4.0-4.2 (m, LH); 5.1
5 (s, 2H); 5.4-5.55 (m.

LH) Near, 35 (s, 5H).

Elemental analysis calculation values for C,,H,4NO,P N,
3.92; C, 53,78: H, 6,72 measurement value
N, 3.87; C, 53,81; H, 6,47 This compound was then deprotected by the procedure used in Example 2 to give 1-aminoethyl-(2-carboxy-1-propyl)phosphinic acid. was generated.

TLC (silica, 1:1:1:1.n-butanol:water, acetic acid, ethyl acetate) Rf = 0.4NMR (D, O) δ
1.25 (d, 3H); 1.35-1.45 (2 duplicates d, 3H); 1.7-1.9 (m, LH);
2.1-2.25 (m.

LH); 2.75-2.9 (m, LH): 3.3-
3.45 (m, LH).

Elemental analysis calculation value for C, H,, No4P, 3/4H, O N, 6.71: C, 34, 54: H, 6
,76 measurement value N, 6.61: C, 34,84;
H,6,69 Methyl Carboxyester Esters with carboxylic acid functionality were produced for all examples and were prepared by adding amino-substituted alkyl-
(2-carboxy-substituted alkyl)phosphinic acid was then saturated with HCO gas or treated with a few drops of sulfuric acid, then stirred for 24 hours and the reactants were evaporated in vacuo. The amine salt is then desalted with propylene oxide as in Example 2 to yield the carboxy ester of the previous example.

-1-Propyl phosphinic acid H A solution of 100 μl of 1-aminoethyl-(2-carboxy-1-propyl)phosphinic acid in methanol (5 mQ) was cooled to 0°C and After stirring the sealed reaction mixture at room temperature for 12 hours, the methanol was removed in vacuo to yield the title compound as the hydrochloride salt, which was desalted by the procedure of Example 2 using propylene oxide to yield the title compound. (80■).

NMR (D, O) 51.2 (d, 3H); 1.3 (
d, 1.5H); 1.5 (d, 1.5H); 1°8-3.0 (m, 3H); 3.3-3.7 (m.

IH); 3.6 (s, 3H).

Mass spectrum (M”+ 1) 210-n-butyl]
Methyl-1-benzyloxycarbonylaminoethyl-[2-&carbomethoxy 1-n-butyl]phosphinate was produced by the method described above in Example 2, except that methyl phosphinate-2-ethyl acrylate was used.

NMR (CDCΩ3) 60.8 (duplicate, 3H); 1.5
(2d, 3H); 1.4-3.2 (m, 5H);
3.7 (s, 3H); 3.7 (d, 3H); 3.
8-4.3 (m, IH): 5.1 (s, 2H); 5.
8 (d, 7.5H); 6.3 (d, 5H) near, 3 (s, 5H).

The above compound was deprotected by the method described above to produce 1-aminoethyl-[2-carboxy-1-n-butyl]phosphinic acid as a hygroscopic glass.

TLC (silica, 1:l:l:1.n-butynol, water, acetic acid, ethyl acetate) Rf = 0.37 NMR (D, O)
δ0.9 (t, 3H): 1.3-1.5 (2,3
H); 1.55-1.8 (me3H): 1.95-
2.1 (m, H); 1.6-1.75 (m, LM)
: 3.2-3.3 (m, LH).

C, Hl, No4P, 2H, (],: Elemental analysis calculation value for N, 6.16: C, 37,00; H, 7,
04 measurement value N, 5.95; C, 36,92; H
,7,42-Mass Spectrum M+H210 Methyl 1-benzyl-oxycarbonylaminoethyl-[2-carbomethoxy-1-n using methyl-2-propyl acrylate by the method described in Example 2
-pentyl]phosphinate was prepared.

TLC (silica, 9:1. ethyl acetate:acetonitrile) Rf = 0.45 NMR (CD (dll) 60.9 (tt 3
H); 1.25, 1.5 (2d, 3H): 1.4-
3.0 (m, 7H); '3.65 (duplicate s, 3H
): 3.7 (d, 3H); 1.6-4.4 (m, LH
); 5.0 (s, 2H); 5.8 (d, 5H
); 6.4 (d, , 5H); 7.3 (s,
5H) C engineering. Elemental analysis calculation values for H2, NO, P, 1/42H, O N, 3.59; c, 55.45; H,
7,18 Measured value N, 3.66; C, 55,42;
H,7,10 Mass Spectrum M''385 The above intermediate was deprotected to produce 1-aminoethyl-[2-carboxy-1-n-pentyl]phosphinic acid by the method described earlier.

TLC (silica, 1:1:1:1.n-butanol:
H, O: acetic acid: ethyl acetate) Rf = 0.4 NMR (D, O) δ 1.85 (t, 3H); 1
．． 2-1.5 (m, 7H); 1.5-1.9 (m.

4H): 1.9-2.1 (m, LH): 2.
6-2.8 (m, IH); 3.2-3.35
(m, IH) Mass spectrum M-H222 Calculated elemental analysis values for C, Hl, No4P, IH, O N, 5.80: C, 39,83; H, 7,46
Measured value N, 5.96: C, 39,48; H, 7
, 5l-n-hexyl]phosphinic acid Methyl 1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-1-n
-hexyl]phosphinic acid was produced.

TLC (silica, 9:1. ethyl acetate:acetonitrile) Rf=0.54 NMR (CDCΩ□) 60.9 (tt 3H); 1.
1-3.2 (m, 12H); 3.6 (s, 3H); 3
．． 6 (d, 3H); 3.7-4.3 (m, IH): 5
．． 0 (s, 2H); 5.5 (d, 5H); 5.9
(d, 5H); 7.3 (s, 5H).

Mass spectrum M''399 This intermediate was converted to 1-aminoethyl-[2-carboxy-1-n-hexyl]phosphinic acid by the method described earlier.

NMR (D, O) 61.85 (t, 3H): 1.15
-1.50 (m, 7H); 1.55-1.8 (m.

3H); 1.95-2.1 (m, IH): 2.6
-2.8 (m, IH): 3.15-3.3 (m.

IH).

C.H. No4P, 1/4 H, Ok one pair elemental analysis calculation value N, 5.79; C, 44, F2: H, 8
,28 measured value N, 5.75; C, 44,40;
H,8,08 Mass Spectrum M"238 -Methyl-1-n-pentyl]phosphine Methyl-1-benzyloxycarbonylaminoethyl-[ 2-carbomethoxy-4-n-pentyl]phosphinate was produced.

NMR (D, O) δ 1.9 (overlap d, 6H): 1.5
-3.2 (m, 9H); 4.6 (d, 3H): 3.8
-4.3 (m, LH): 5.1 (s, 2H);5.
5 (d,, 5H): 5.9 (d,, 5H) near, 2
(s, 5H).

C,,H,. Elemental analysis calculation value for NO, P, 1/4H, 0 N, 3.46: C, 56,51; H, 7
,44 measured value N, 3.56: C,56,34:
H,7,47 Mass Spectrum M''400 This intermediate was converted to 1-aminoethyl-[2-carboxy-4methyl-1-n-pentyl]phosphinic acid by the method described in Example 2.

NMR (CDCQ, ) 61.95 (duplicate d, 6H);
1.3-1.65 (m, 6H); 1.75 (overlap t
, LH); 1.9-2.1 (m, LH); 2.7
-2.9 (m, IH); 3.15-3.35 (m,
IH).

C.H. Elemental analysis calculation value for No, P, L H, 0 N, 5.49: C, 42, 35: H, 7,
84 measurement value N, 5.55: C, 42, 79: H
,8,03 Mass spectrum M-236
Methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-5-cyclohexyl-1-n-pentyl]phosphinate was produced using 1-propyl coacrylate.

NMR (CDCQ, ) 60.8-3.1 (m, 23H)
; 3.6 (st 3H): 3.6 (d, 3H)
; 3.6-4.2 (m, LH); 5.0 (s, 2H
); 5.2(d, 0.5H): 5.5(d, 0.5H
); 7.2 (s, 5H).

Elemental analysis calculation values for C□H,, NO, P N, 3. Go; C, 61, 66: H, 8
, 19 measured value N, 3.19: C, 61, 32;
H,8,08 Mass Spectrum M''468 This compound was converted to 1-aminoethyl-[2-carboxy-5-cyclohexyl-1-n-pentyl]phosphinic acid by the method of Example 2.

TLC (silica, 1:l:1:1.n-butanol:H
, O: acetic acid: ethyl acetate) R+ = 0.66 NMR (D, 0) 60.8-3.2 (m, 23H); 3
．． 7-4.2 (m, IH) Mass spectrum M"H304 Lostanejung-1 Methyl-1-benzyloxycarbonylaminoethyl-
[2-Carbomethoxy-1-nonyl]phosphinate was prepared by the method described in Example 2 in 60% yield.

NMR (CDCII, 300MHz): δ0.9 (m
, 3H); 1.2-1.4 (m, 13H); 1.
6 (m, 2H); 1.8 (m, LH); 2.2 (
m, IH); 2.8 (my IH); 3.7 (
m16H); 4.1 (m, LH); 5.0-
5.3(rn, 3H); 7-4(br
Calculated elemental analysis values for s@5H)-C,, H3@NO,P N, 3.17; C, 59,85;
H, 8, 22 measurement value N, 3.06; C, 59, 9
4: H,8,03 mass spectrum (cation FAB)
: M''H442 (100%) Analytical TLC: R+ = 0.69 (ethyl acetate/acetonitrile/methanol, 9:1:0.5) The title compound was prepared by the procedure described in Example 2.

NMR (DIO-300MHz): δ 0.8(t
t 3H); 1.3-1.5 (m, 13H); 1
．． 5-1.8 (m, 3H): 2.6 (m, LH);
2.7 (m, LH); 3.2 (m, 1H)Ct
Elemental analysis calculation value for s Hz -N O4P L pair N, s, ot; C, 51,60; H, 9,38
Measured value N, 5.03; C, 50,94; H, 9
,02 mass spectrum (cation FAB): M”H
280 (100%) Analytical TLC: R+=0.67 (ethyl acetate/1-
butanol/acetic acid/water, 1:1:1:1) 1 to 19 1 phenyl-1-n-propyl]phosphine amount using methyl-2-benzyl acrylate according to the method used in Example 2. -benzyloxycarbonylaminoethyl-[2-carbomethoxy-3-phenyl-1-n-propyl]phosphinate was produced.

TLC (silica, 9:1. ethyl acetate:acetonitrile) Rf=0.61 NMR (cocQa) 61.1-1.5 (2d.

3H): 1.7-3.1 (m, 5H); 3.4-
3.6 (m, 6H); 3.7-4.3 (m, IH
): 5.0 (s, 2H): 5.6 (d,, 5H)
: 6.1 (d,,5H); 7.0 (b 8
, 5H); 7.2 (s, 5H).

Elemental analysis calculation value for C,, Hl, NO,, 1/4 H, O N, 3.20: C, 60, 34: H, 6
,44 measured value N, 2.78; C, 60,17;
H,6,54 Mass Spectrum M''433 This compound was converted to 1-aminoethyl-[2-carboxy-3-phenyl-1-n-propyl]phosphinic acid by the method of Example 2.

TLC (silica, l:1:1:1.n-butanol:H
, O: acetic acid: ethyl acetate) Rf = 0.42 NMR (D, 0) 61.25-1.45 (m, 3H)
; 1.7-1.9 (m, IH); 2.0-2.15 (
m, LH): 2.8-3.1 (m, 3H); 3.
1-3.3 (m, LH): 7.2-7.45 (2 duplicates, 10H).

Elemental analysis calculation values for C1,H,,N04P,LH,O N, 4.84; C,49,82: H,6,2
2 measurement value N, 4.61: C, 49, 45: H,
6,32 Mass Spectrum pJi-1270 Methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-4-
Phenyl-1-n-butyl]phosphinate was produced.

TLC (silica, 9:1. ethyl acetate: acetonitrile) Rf = 0.57 NMRC CDCL) δ1.2 (d, 1.5H); 1.
5 (d, 1.5H): 1.6-3.1 (m, 7H)
: 3.6 (s, 3H); 3.6 (d, 3H): 3
．． 7-4.3 (m, IH): 5.0 (s, 2H); 5
．． 4 (d,,5H); 5.9 (d,,5H)
;7.1 (s, 5H); 7.3 (s, 5H).

Mass spectrum: M+1 448 This compound was purified by the method of Example 2 to obtain 1-aminoethyl-[2
-carboxy-4-phenyl-1-n-butyl]phosphinic acid.

TLC (silica, l:1:1:1.n-butanol:
H,O: acetic acid:ethyl acetate) R+=0.3O NMR (D, ○) 61.35-1.5 (duplicate d.

8H): 1.85-2.05(m, 3H): 2.1
-2.3 (m, IH); 3.3-3.45 (m.

8H); 7.2-7.45 (m, 10H).

C13H! . Elemental analysis calculation value for NO, P, 1/4H20 N, 4.83: C, 53,88; H, 6
, 90 measured value N, 4.62: C, 53,78;
H,7,19 Mass Spectrum M''-1284 Methyl-1-benzyloxycarbonylaminoethyl-[2-
Carbomethoxy-5-phenyl-1-n-pentyl]phosphinate was prepared.

TLC (silica, 9:l, ethyl acetate:acetonitrile) R+ = 0.44 NMR (CDC11,) δ1.2 (d, 1.5H)
;1.5 (d, 1.5H); 1.5-3.2 (
m, 9H): 3.6 (d, 3H); 3.7
(s, 3H); 3.7-4.2 (m, IH); 5.
0 (s, 2H); 5.5 (d, 5H);
5.9 (d, 5H); 7.1 (s, 5H
); 7.3 (s, 5H).

This compound was prepared using the method of Example 2 to prepare 1-aminoethyl-[2
-carboxy-5-phenyl-1-n-pentylcophosphinic acid.

TLC (silica, 1:1:l:1.n-butanol:
H, O: acetic acid: ethyl acetate) R+ = 0.32 NMR (D, O) δ1.3-1.4 (2 duplicates d.

3H); 1.4-1.7 (m, 5H); 1.85-
2.0 (m, IH); 2.1-2.3 (m, IH)
;2.45-2.6 (m, IH); 2.6-2.8
(m, IH); 3.45-3.55 (m, IH);
7.1-7.3 (m, 10H).

Mass spectrum: (M+1) 266 C14H,, No, P, elemental analysis calculation value for 1.5 H2O N, 4.413: C, 51,53; H,
7,66 measurement value N, 4.04; C, 51,35
: H,7,41-1-n-propyl]phosphinic acid using methyl-2-t-butoxycarbonylmethyl acrylate by the method used in Example 2.
1-Benzyloxycarbonylaminoethyl-[2-carbomethoxy-3-butoxycarbonyl-1-propyl]phosphinate was prepared.

TLC (silica, 9:1. ethyl acetate:acetonitrile) R+ = 0.58 NMRCCDCQ, ) 61.2 (d, 1.5) I): 1
．． 5 ('d, 1.5H); 1.4 (st
9H); 1.8-3.2 (m, 5) ();
1.625 (s.

3H); 1.64 (d, 3H): 1.8-
3.3 (m, LH): 5.05 (s, 2H):
5.3(d,,5H): 5.7(d,
, 5H); 7,2(s, 5H).

Elemental analysis calculation values for c, H,, No, p, 1/4H, O N, 3.03; C, 54,60; H, 6
,98 measured value N, 3.15; C, 54,65;
H,6,94 Mass Spectrum M''457 This compound was converted to 1-aminoethyl-[2,3-carboxy-1-n-propyl]phosphinic acid by the method of Example 2.

NMR (D, O) δ 1.3 (d, 1.5H): 1.
55 (d, 1.5H); 1.8-2.4 (m.

2H): 2.6-2.8 (m, 2H); 2.9-
3.7 (m, 3H) Mass spectrum: CM" -1) 238 11-L East 1-7 2 辷 e t 王 j s 辷 ny λ y" - 9htvytt 1 - n -pentyl] Phosphine Example Dimethyl-2-(3-
trimethyl-1-penzyloxy (carboxy-1-propyl) acrylate
Ru[2,5-dicarboxy-1-n-pentyl]phosphinate was prepared.

TLC (silica, 9:1. ethyl acetate:acetonitrile) Rv = 0.48 NMR (CDCQ, ) 61.2-3.1 (m, 12
H); 3.55 (s, 3H): 3.6 (d, 3H
); 3.7-4.2 (m, IH): 5.0 (s, 2M
); 5.3 (d, 5H): 5.75 (d, 5H
) Near, 2 (s, 5H).

Mass spectrum = M''443 This compound was converted to 1-aminoethyl-[2,5-dicarboxy-1-n-propyl]phosphinic acid by the method of Example 2.

NMR (D, O) 61, 1-2, 8 (m, 1
2H): 3.1-3.6 (m, LH) Mass spectrum: (M"+1) 268゜ヱMethyl-2-[4-t
-butyldimethylsilyloxy-1-n-butyl coacrylate to prepare methyl-1-penzyloxylponylaminoethyl-[2-carboxy-6-t-butyldimethylsilyloxy-1-n-butyl]phosphonate. Manufactured.

TLC (silica, 9:1. ethyl acetate: acetonitrile) R+ = 0.59 NMR (CDCQ, ) 60.0 (s, 6H); 0
．． 9 (s, 9H); 1.1-3.2 (me 12H
); 1.4-1.7 (m, 9H): 1.7-4
．． 3 (m, IH); 5.0 (s, 2H); 5.4 (
d,,5H): 5.8(d,6H); 7.2(s,
5H) - Mass vector: 529 in M This compound was converted to 1-aminoethyl-[2-carboxy-6-hydroxy-1-n-hexyl]phosphinic acid by the method of Example 2.

NMR (D!O) 61.15-3.2 (m, 12H)
; 3.25-3.65 (m, 3H) mass spectrum:
(M1+1) 264° Loss 11-L Broiled 1-aminoethyl-[2-carboxy-4-1-naphthyl)-1-n-butyl]methyl phosphinate-1-benzyloxycarbonylaminoethyl-
[2-Carbomethoxy-4-(1-naphthyl)-1-n
-butyl]phosphinate was prepared by the method described in Example 2 in 65% yield.

NMR (CD Cj2 a -300MHz)
"61.4 (q, 3H); 1.9-2.2 (m, 3H
); 2.3 (ms LH): 3.0 (m, 3H)
; 3.7 (m.

6H): 4.1 (m, IH); 5.1 (m, 3H)
;7.2-8.0 (m, 12H).

Elemental analysis calculation value for C,, Hz, No, P, 172H, O N, 2.76: C, 63,96; H,
6,51 measurement value N, 2.42; C, 63,85:
H,6,33 mass spectrum (EI): M14
97 (10%) analytical TLCR+ = 0.58 (ethyl acetate/acetonitrile/methanol 9:1:0.5) The title compound was prepared by the procedure described in Example 2.

NMR (D, 0.300MHz): δ1.4(q.

3H); 1.8 (m, IH); 2.1 (m, 3
H); 2.8 (m, LH); 3.1 (m, 3H):
7.4-8.1 (m, 7) 1) Elemental analysis calculated value for C12Hzs N 04 P -3/ 2 Hz O N, 3,86; C, 56,30: H, 6,
90 measurement value N, 3.66; C, 56,23; H,
6,71 mass spectrum (anion pAB): M-
H334 (25%) Analytical TLC: R+ = 0.67 (Ethyl acetate/1-butanol/acetic acid/water 1:1:1:1) Ao'1 -13 = -Zi' and 1 Methyl-1- Penzyloxycarbonylaminoethyl
[2-carbomethoxy-4-(2-naphthyl)-1-n
-butyl]phosphinate was prepared by the method described in Example 2 in 75% yield.

NMR (CD CQ 3-300 MHz)
: δ1.4(m, 3H): 1.8-2.1(m, 3H
); 2,3 (m, IH); 2.7 (m, 2H);
2.9 (m.

LH); 3.6-3.7 (m, 6H); 4.
1 (m, LH); 5.1-5.3 (m, 3H);
7.3-7.8 (m, 12H).

Elemental analysis calculation value for C,, H, No, P, 1/2H20 N, 2.76; C, 63,96; H, 6
, 51 measured value N, 2.40: C, 63, 79:
H,6,43 mass spectrum (EI): M” 497
(12%) Analytical TLC: R+ = 0.67 (ethyl acetate/acetonitrile/methanol 9:1:0.5) The title compound was prepared by the procedure described in Example 2.

NMR (D, 0.300MHz): δl, 3(q*3H
); 1.8 (m, 1B); 2.1 (m, 3H)
;2.8 (m, 3H); 3.2 (m, LH);
7.4-7, 9 (m, 7H) Mass spectrum (cation FAB): M+8336
(199%) Analytical TLC: Rf = 0.65 (ethyl acetate/1-butanol/acetic acid/water 1:1:1:1) 4-methyl-1-benzyloxycarbonylaminoethyl-
[2-Carbomethoxy-5-(4-pyridyl)-1-n
-pentyl]phosphinate was prepared by the method described in Example 2 in 84% yield.

NMR (CD CQ 3.300 MHz)
: δ1.35 (q, 3H): 1.80 (m, IH
): 2.25 (m, LH); 2.55 (m, L
H); 2.6 (m, 5H): 2.80 (m,
LH): 3.6 (d, 3H); 3.7 (s, 3
H); 4.1 (m.

LH); 5.1 (d, 12Hz, 5H); 5.1
(s, 2H): 5.7 (d, 12Hz, 5H) near, 1 (d, 6Hz, 2H); 7.35 (brs
.

5H); 8.5 (d, 6Hz, 2H).

C! Elemental analysis calculation values for 3H3□N, O, Pbn N
, 6.06; C, 59,73: H, 6,76 measurement value N, 5,99; C, 59,08: H, 6,7
3 mass spectrum (cation FAB): M”H46
3 (100%) Analytical TLC: Rf=0.30 (ethyl acetate/acetonitrile/methanol 9:1:0.5) The title compound was prepared from the above compound by the method described above.

NMR (D, 0.300MHz): δ1-3(qt3H
); 1.7 (m, 5H): 2.1 (m, LH)
;2.8 (m, IH); 3.0 (m, 2H)3
3.2 (rn, IH); 7-9 (d
p 8 Hz @ 2 H) ;8,6 (d
, 8Hz, 2H).

Mass spectrum (cation FAB): M+H3O1
(100%) Analytical TLC: R+=0.15 (ethyl acetate/1-
Butanol/acetic acid/water 1:1:1:1)-
Example 2 except that 1-propyl phosphine 1-(L)-benzyloxycarbonylaminoethylphosphonite methyl ester is used.
Methyl-1-benzyloxycarbonyl-1-7minoethyl[2-carbomethoxy-1-propyl]phosphinate was produced by a similar method used in .

TLC: (Silica, 9:1. Ethyl acetate:acetonitrile) Rf=0.54 NMR (CDCQ3): δ1.2-1.5 (m.

6H); 1.7-1.9 (m, LH); 2.
2-2.4 (m, LH); 2.8-3.0 (m, IH
): 3.7 (s, 3H); 3.6-3.8 (d, 3
H); 4.0-4.2 (m, LH); 5.1 (s,
2H); 5.2-5.4 (m, LH); 7.3 (s
, 5H).

Elemental analysis calculation values for C1cH,, NOGP, 1/2H, O N, 3.82; C, 52,45; H, 6
, 60 measured value N, 3.98; C, 52,76;
H,6,55 mass spectrum: FAB (M+H)=
358 This compound was deprotected by the procedure used in Example 2 to give 1-L-aminoethyl-(2-carboxy-1
-propyl)phosphinic acid was produced.

TLC: (Silica, 1:1:1:1.n-butanol, water, acetic acid, ethyl acetate) R+ = 0.52 NMR (D, O): δ1.25 (t, 3H); 1.3
-1.5 (duplication d v 3 H); 1-7-1,
9 (m-IH); 2.1-2.3 (m, IH
); -2,75-2,9 (m, I H); 3.3-3
．． 5 (m, IH).

C* Calculated elemental analysis value for Hi4NO4P, IHzO N, 6.57: C, 33,81;
H, 6, 62 measurement value N, 6.51: C, 33,
63: H,6,39 Mass spectrum: FAB (M
+H)=196-1-Propyl-phosphine 1-(D)-Benzyloxycarbonylaminoethylphosphonate Methyl-1-benzyloxycarbonyl-D was prepared by the same method used in Example 2, but using methyl methacrylate. -7minoethyl[2-carbomethoxy-1-propyl]phosphinate was produced.

TLC: (Silica, 9:1. Ethyl acetate:acetonitrile) Rf=0.54 XL 300 NMR: δ1.15-1.45 (
m.

6H); 1.7-1.9 (m, IH); 2
．． 2-2.4 (m, IH); 2.8-3.0 (m, I
H): 3.7 (s, 3H); 3.55-3.8 (m,
3H): 4.0-4.2 (m, IH); 4.95
-5.1 (m, LH); 5.1 (s, 2H); 7.
4 (st5H).

C1,H,,NO,P,1/2H,04,: Elemental analysis calculation value for N, 3.82: C,52,46: H,6
, 60 measurement value N, 4.04: C, 52,02;
H,6,50 mass spectrum: FAB (m+H)=
358 This compound was deprotected by the procedure used in Example 2 to give 1-D-aminoethyl-(2-carboxy-1
-propyl)phosphinic acid was produced.

TLC: (Silica, 1:1:1:1.n-butanol, water, acetic acid, ethyl acetate) R+ = 0.64 NMR(D20): δ1.2(d, 3H); 1
．． 3-1.4 (overlap 2d, 3H); 1.65-1.8
(m.

LH); 2.05-2.2 (m, IH): 2.
7-2.9 (m, LH); 3.25-3.4 (m, L
H).

C, H14NO, P, 1/4H, OL: Elemental analysis calculation values for N, ? , 01; C, 36, 10; H, 7
,07 measurement value N, 6.70; C, 36,05;
H,6,99 mass spectrum: FAB (m+H)=
196゜(2m+H)=391 [Left] 1'' L 1-L-aminoethyl-(2-carboxy-1-n-butyl phosphine 1-(L)-benzyloxyaminoethylphosphonite methyl ester and methyl- Methyl-1-benzyloxycarbonyl-di-aminoethyl-[2-carbomethoxy-1-n-butyl]phosphinate was produced by a method similar to that used in Example 2, except that 2-ethacrylate was used.

TLC: (Silica, 9:1. Ethyl acetate:acetonitrile) Rf=0.54 XL 300 NMR (CDCQ, ): 50.8
-1.0 (m, 3H); 1.2-1.45 (m, 3H)
:1.5-1.7 (m, 2H); 1.15-1.
9(m, IH): 2.15-2.35(m, IH)
;3.65-3.85 (me IH); 3.7 (
s.

3, H); 3.6-3.8 (m, 3H); 4.0-
4.2 (m, IH): 5.1 (s, 2H); 5
．． 3-5.5 (m, IH); 7.35
(s, 5H).

Elemental analysis calculation values for C1, H, NO, P, 1/2 H, O N, 3.68; C, 53,68: H, 6
, 89 fixed value N, 4.00: C, 53,80;
H,6,70 mass spectrum: FAB (m+H)=
372 This compound was deprotected by the procedure used in Example 2 to give 1-L-aminoethyl-(2-carboxy-1
-n-butyl)phosphinic acid was produced.

TLC: (Silica, 1:1:1:1.n-butanol, water, acetic acid, ethyl acetate) R+ = 0.57 NMR (D, O): 50.85 (t, 3H); 1.3
-1.45 (2d, 3H); 1.55-1.7 (m
.

2H); 1.75-1.8 (m, IH); 2.0
5-2.2 (m, LH); 2.6-2.75 (m, I
H); 3.3-3.4 (m, IH).

Cxta,, N 04 P -1/ 2 H,04
Elemental analysis calculation value for C N, 5.71; C, 34,29; H, 6
,58 measured value N, 5.74; C, 34,36;
H,6,51 mass spectrum: FAB (m+H)”
210-1-n-Butyl phosphine Methyl-1-benzyloxy was prepared by the method described above in Example 2 except using 1-(D)-benzyloxyaminoethylphosphonite methyl ester and methyl-2-ethyl sulfate. Carbonyl-D-aminoethyl-[2-carbomethoxy-1-n-butyl]phosphinate was produced.

TLC: (Silica, 9:1. Ethyl acetate:acetonitrile) R+ = 0.58 NMR (CDCQ, ): δ 0.7-1.1 (m.

3H); 1.1-2.4 (m, 7H); 3.7(
s, 3H); 3.6-3.8 (d, 3H)? 3.9
-4.3 (m, LH); 5.1 (s, 2H); 5
．． 9(d, 1/2H): 6.4(d, 1/2H):
7.2 (brs, 5H).

C,,H,,NO,P,1/2H,OL, Pair elemental analysis calculation value N, 3.68; C, 53,68: H, 6
, 89 measured value N, 3.81; C, 53, 63:
H,6,51 mass spectrum: FAB (m+H)=
372 This compound was deprotected by the procedure used in Example 2 to give 1-D-aminoethyl-(2-carboxy-1
-n-butyl)phosphinic acid was produced.

TLC: (Silica, l:1:1:1.n-butanol, water, acetic acid, ethyl acetate) R+ = 0.46 XL 300 NMR (DzO): δ 0.85 (duplicate tv 3H) = x. 3-1.4 (duplication d, 3H);
2.55-2.7 (m, 2H); 2.75-2.9 (
m, IH): 2.05-2.2 (m, IH); 2.
6-2.85 (m, LH); 3.3-3.4 (m, I
H).

C, HL, No4P, 11/2 Elemental analysis calculation value for H2O N, 6.04; C, 36,29; H, 6
,96 measured value N, 6.07; C, 36,40;
H,7,27 mass spectrum: FAB (m+H)
=210(2m+H) =419 -1-nonyl]phosphinic acid co(L)01 (The title compound was converted to methyl 2-
Produced from n-hebutylpropenonyyl-. Spectral data of the obtained compound NMR 300 MHz DO: δ 3.2 (m, LH) 1.6 (br s
, 2H) 2.7 (m, IH) 1.4 (q
, 3H) 2.0 (m, LH) 1.2 (br
s, l0H) 1.7 (m, LH) 0.8 (
t, 3H) - quantity spectrum (ion FAB 278 (MH, 100%) Bean JLU - Near C1□H,, Calculated value for No4P Measured value C: 51.60 51.53H:
9.38 9.07N: 5,0
1 4.78-1-Nonyl]phosphine This compound was converted to methyl 2-phosphine by the general procedure of Example 20.
Produced from n-hebutylpropenoate. Spectral data of the obtained compound NMR 300 MHz D O: δ 3.2 (m, IH) 1.6 (br s,
2H) 2, 7 (m, IH) 1.4
(q, 3H)2.0 (m, IH) 1
．． 2 (br s, l0H)1.7 (m, LH
) 0.8 (t, 3H) quantity spectrum ion FAB 27B (MH, 100%) 5-! -2r Calculated value for No4P Measured value C: 51.60 50.97H:
9.38 9.04N: 5,01
5.02 Propenyl phosphinic acid Triethylamine (2,87
+ w 20 mmol), trimethylsilyl chloride (2,
60mA.

20 mmol) and methyl 2-bromomethyl acrylate (1.66 g, 9.3 mmol) were added. After stirring at room temperature for 20 hours, the reaction mixture was dissolved in H,0,2N H
The CQ was then washed with a saturated NaCQ solution and dried over anhydrous magnesium sulfate. The resulting mixture of filtration and evaporation was purified by silica gel chromatography (eluting with chloroform then 10% methanol-chloroform) to give 2.50 g (79% yield) of product.

NMRCCDCQ, δ) 1.4 (m, 3H).

2.9 (m, 2H), 3.75 (s, 3H), 4.2 (
m, LH), 5.10 (s, 2H), 5.60 (d.

LH), 5.85 (m, LH), 6.30 (m.

LH), 7.30 (s, 5H).

in methanol (20 m m ) and H,O (amjl) [
1-(benzyloxycarbonylamino)-ethyl]
(2-methoxycarbonyl-2-propenyl)phosphinic acid 341. of 1N NaOH (2.2 mm, 2
．． 2 mmol) was added and the mixture was refluxed for 3 hours.

After evaporating the methanol, the aqueous layer was washed twice with chloroform and then acidified with 2N H'ca.

The aqueous solution was extracted four times with chloroform, and the combined organic layers were dried over anhydrous magnesium sulfate.

After filtration and evaporation, 330 μm of [1-(benzyloxycarbonylamino)ethyl](2-carboxy-2-propenyl)phosphinic acid (yield: 100%) was obtained. A solution of the phosphinic acid (163 mg, 0.5 mmol) obtained above and sodium iodide (300 mg, 2 mmol) in acetonitrile (3 mfl) was then added to trimethylsilyl chloride (0.25 mΩ).

The mixture was stirred at room temperature for 6 hours. H,O was added and the mixture was washed 8 times with chloroform and adjusted to pH 4 by adding saturated sodium carbonate solution. After evaporation to dryness, ethyl acetate (10 mQ) was added and the precipitate was filtered. It was dissolved in methanol (10 mQ) and the insoluble material was filtered off. The methanol was evaporated and the residue was purified by reverse phase column chromatography (eluting with C-18,H,0) (
60 μm of 1-aminoethyl)(2-carboxy-2-propenyl)phosphinic acid (yield 62%) was obtained.

TLC (Silica, Pig/-/L/: Acetic acid: HtO=4
: 1 : 2) R+=0.15N M R(CD3
0 D) l-4(m, 3H)-2-8(m, 2H
), 5.4 (m, LH), 5.9 (m.

IH) 3-bromopropyl phosphine H [1-(benzyloxycarbonylamino)ethyl](2-hydroxy-2-
A mixture of propenyl)phosphinic acid (330 µ, 1 mmol) was stirred at room temperature for 4.5 hours. Ether (20m
After addition of A), the precipitate was filtered, washed thoroughly with Tau chill and then dissolved in methanol 2IIQ.

20 mQ of propylene oxide was added to obtain a colorless powder, which was filtered and washed with ether to obtain 145 μl of (1-aminoethyl)(2-carboxy-3-promopropyl)phosphinic acid (53% yield). generated.

TLC (silica, butanol:acetic acid:H,O=4:
1:2) R+=0.2O NMR (CD, OD, 300MH,) 1.4 (m.

3H), 2.1 (m, 2H), 3.3 (m, IH)
= 3.7 (m, LH) Robenyl phosphinate distilled at 0°C methanol 2.5 mQm finate ester in water (synthesized by the procedure shown in Example 1) 1.05
A solution of 3 g (4,097 mmol) of 2, ON methanolic sodium methoxide (4,50 mmol, 1
．． 1 equivalent) and 2.25 mQ for 10 minutes. When the base addition was complete, the mixture was stirred for a further 5 minutes at 0°C, then 0.96 mQ of trimethyl-2-phosphonoacrylate (full strength) in 1 mA of distilled methanol (
1.20g.

6.2 mmol, 1.5 eq.) solution was added dropwise over 5 minutes. After 1 hour at 0°C, 0.9011 ft of 37% aqueous formaldehyde (formalin) was added dropwise over 5 minutes (0.90 mQ = 0.36 g = 12 mmol = 3 equivalents), the mixture was warmed to room temperature and Stir for hours.

20 mΩ of ethyl acetate and 5 mQ of INHCQ were added to the reactants.
was added and cooled to 0°C. The organic layer was removed, and the aqueous layer was re-extracted with 5 mA of ethyl acetate. The combined organic extracts were washed twice with brine SmQ each, and then filtered through an anhydrous sodium sulfate/anhydrous magnesium sulfate stopper. The solution was filtered, all volatiles removed under vacuum to produce a pale yellow part, and purified by medium pressure liquid chromatography on silica gel, eluting with 9/1 ethyl acetate/acetonitrile.

Purification by this method yielded 1.181 g (3,3
3 mmol, 81%) was produced as a viscous oil.

NMR300MHz CDCQ: δ7.3-7.4
(m, LH) 4.2 (m, LH) 6.4 (d
, LH) 3.75 (m, 6H) 5.8 (d, I
H) 3.0 (q, 2H) 5.2 (s, 2H)
1.4 (q, 3H) 5.1 (br s, IH
) Quantity spectrum (EI M”355 (0.5%) Calculated value for Genjihii Nitachi Nisho C 5HzNOsP Measured value C:
54.08 53.01H: 6
．． 24 6.19N: 3.94
3.73TLC: (Ethyl acetate/n-butanol/acetic acid/water, 1:1:1:
1) R+ = 0.85-chloro-n-propyl phosphine H Methyl(tobenzyloxycarbonylaminoethyl)-(2-carbomethoxy-2-propenyl)phosphinate obtained in Example 27 (101 mg, 0.296 mmol) was suspended in 4 mQ of concentrated hydrochloric acid and heated at 50° for 2 weeks.

The reaction mixture was diluted with 15 mQ of distilled water, and 5 mQ of ethyl acetate was added.
Washed three times with Q. The aqueous layer was evaporated to dryness and the residue was dissolved in 5 mA of distilled water and lyophilized to produce a pale yellow solid. The solid was dissolved in 1 mA of dry methanol and treated with excess propylene oxide. The precipitate was filtered off and dried under vacuum to give the title compound 52 (0.23 mmol, 75%
) was produced as a white powder.

NMR200MHz D ○: δ 3.9 (m, 2H) 2.0 (m, IH) 3.
3 (m, 2H) 1.5 (q, 3H)2
．． 2 (m, IH), quantity spectrum (NI-FAB) M-H228 (100%) Acid Z and Z Z-isomer Oxycarbonylaminoethylphosphonite methyl ester (1,054 g, 4.1 mmol), 2-trimethylphosphonoacrylate (1,2 g, 6.18 mmol) and phenylpropionaldehyde (1,6
3 g, 12.2 mmol). Chromatographic separation (silica, 9:1.ethyl acid:acetonitrile)
to produce the Z isomer of the title compound (0,929 g) and the E isomer of the title compound (0,654 g) as oils.

TLC (silica, 9:1:0.5. ethyl acetate: acetonitrile: methanol) Rf = 0.67 (both isomers) NMR (300 MHz, CDCQ: Z isomer
E isomer 7.2-7.4 (m, 10H) 7.2-7.4 (
m, l0H) 7.0 (m, LH) 6.2 (m
, LH) 5.5 (d,, 5H) 5.4 (d,
, 5H) 5.1 (m, 2.5H) 1.4 (m
, 2.5H) 4.1 (m, LH) 4.1 (m
, LH) 3.7 (m, 6H) 3.7 (m, 6
H) 2.6-3.0 (m, 6H) 2.7-3.0 (
m, 6H) 1.3 (m, 3H) 1.3 (m
, 3H) Spectrum EI E isomer: 459 (M+, 1%) Z isomer: 459 (M+, 1%) Methyl-1-benzyloxycarbonylaminoethyl (
Example 3 Each of the E and Z isomers of 2-carbomethoxy-5-phenyloct-2-enyl)phosphinate
Treatment with concentrated hydrochloric acid as described in Section 3 produced the hydrochloride salt of the title compound (66% yield for the E isomer, 79% yield for the Z isomer) as a white powder.

TLC (silica, 1:1:1:1. ethyl acetate: n
-butanol:acetic acid:water) RfZ isomer = 0.59 E isomer = 0.57 NMR (20-OMHz D O: Z isomer E isomer 7.2-7.4 (m, 5H) 7.2 -7.4 (m,
5H) 6.8 (m, IH) 6.0 (m
, LH) 3.3 (m, 7H) 3.1-3
．． 3 (m, 7H) 1.3 (q, 3H) 1.
3 (q, 3H) quantity spectrum EI E isomer: 296 (MH, 100%) Z isomer:
296 (M-H, 100%) 1-t by the method described in Example 27.
-butoxycarbonylaminoethyl phosphonic acid methyl ester (0,616 g, 2. furomillimoles) (Example 36), 2-trimethylphosphonoacrylate (1,0
8g.

5.54 mmol) and hexanal (0.55 g,
5.5 mmol). The product was purified by chromatography (silica, 5% methanol in ethyl acetate) to give the title compound (Q, 805 g) as a mixture of E/Z isomers.

TLC (silica, 9:1:0.5. ethyl acetate: acetonitrile: methanol) Rf = 0.4 ONMR (300
MHz, CDCQ ) near, 0 (m, 5H, Z isomer)
2.5 (m, I H) 6.2 (m, 5H, E isomer) 2.3 (m, I H) 5.0 (m, L
H) 1.9 (m, LH) 4.1 (m, LH
) 1.5 (s, 9H) 3.7 (m, 6H)
1.3 (m, 8H) 3.0 (m, 2H)
0.9 (t, 3H) amount spectrum FAB: 392 (M+H, 38%) Calculated value for Cz-HI3NOs P-1/2 Hz O Measured value C: 53.99 53.23H :
8.80 8.3ON: 3.50
3.51 The title compound was converted into methyl-1-t-butoxycarbonylaminoethyl-(2-carbomethoxy-1-oct-2-ethyl)phosphinate (0,17
6 g, 0.45 mmol) according to Example 33 by stirring in concentrated hydrochloric acid. The title compound (0.105 g) was obtained as a hydrochloride salt as a hygroscopic white powder.

TLC (silica, 1:l:1:1 ethyl acetate:n
-butanol:acetic acid:water) R+=0.57NMR300
MHz, CD 00 near, 0 (m, 5H, Z isomer) 2.4 (m, IH) 6.2 (m, 5H, E isomer) 2.2 (m, 2H) 3.3 (m, IH)
1.2-1.5 (m, 8 H) 2-8 (
me 2 H) 0.8 (br s
-3H) quantity spectrum (NI FAB: 262 (MH, 100%) QC)l.

1-(D) in 2.5 ml of distilled methanol at 0 °C
--Benzyloxycarbonylaminoethylphosphonic acid methyl ester 1.0405 g (4,0
2.5 mmol) solution. ON methanolic sodium methoxide (4.4 mmol, 1.1 eq.) 2.2 m
I processed my emotions for 10 minutes with fi. When the base addition was complete, the mixture was stirred for a further 5 minutes at 0°C, then 0.94 m of trimethyl-2-phosphonoacrylate (full strength) in 1 mf of distilled methanol! (1,18g, 6
．． 1 mmol, 1.5 eq.) solution was added dropwise over 5 minutes. After 1 hour at 0°C, 0.93 mfl 37% aqueous formaldehyde (formalin) was added dropwise over 5 minutes (0.93 mA = 0.37 g = 12 mmol =
3 eq.), the mixture was warmed to room temperature and stirred at room temperature for 3 hours.

The reaction was cooled to Oo by adding 20 waQ of ethyl acetate and 5 mQ of IN HCQ. The organic layer was removed, and the aqueous layer was re-extracted with 5 mQ of ethyl acetate. The combined organic extracts were washed twice with brine, SmQ, and then filtered through an anhydrous sodium sulfate/anhydrous magnesium sulfate stopper. The solution was filtered and all volatiles were removed under vacuum to produce a pale yellow part, which was purified by medium pressure liquid chromatography on silica eluting with 5% methanol/ethyl acetate. Purified in this way, 1.091 g of the pure title compound (
3.07 mmol, 75%) was purified as a viscous oil.

NMR300MHz CD OD near, 3-7.4
(m, 5H) 4.2 (m, LH) 6.4 (d
, IH) 3.75 (m, 6H) 5.8 (d,
LH) 3.0 (dd, 2H) 5.2 (s, 2
H) 1.4 (dd, 3H) 5.1 (brs,
LH) Quantity Spectrum EI): 355 (,5%) 1H 15th Emperor Ct* Calculated value for Has N O-P -172HI O Measured value C: 52.75 53.01H:
6,36 6.19N: 3,85
3.73Rf (ethyl acetate/n-butanol/acetic acid/water, 1:1:1:1): 0.85 sd Methyl in 10 m Q of THF (dried at room temperature under nitrogen)
1-D-benzyloxycarbonylaminoethyl)-(
A solution of 2-carbomethoxy-2-propenyl)phosphinate (2.26 g, 6.34 mmol) was treated with 0.94 g of anhydrous lithium iodide (7.0 mmol, 1.1 eq.). The mixture was stirred at room temperature for 72 h and tf
fic (ethyl acetate/n-butanol/acetic acid/water, 1
: 1 : 1 : 1) showed complete disappearance of starting material and appearance of product at RfO, 70.

All volatiles were removed under vacuum and the residue was redissolved in 30 mQ of 5% aqueous sodium bicarbonate and linearized with ethyl acetate (10
The aqueous layer was cooled to 0 °C and made acidic (pH 1) by gradual addition of 6N HCQ. The acidified mixture was extracted with ethyl acetate (6 times with 10 mQ each) and combined. The organic extract was washed once with brine and filtered through an anhydrous sodium sulfate/anhydrous magnesium sulfate plug. Filtration and removal of solvent in vacuo yielded the title compound (1,779 g, 5.2
2 mmol, 82%) as a pale yellow solid.

NMR300MHz CD OD: δ7.3-
7.4 (m, 6H) 4.0 (m, LH) 6
．． 3 (d, LH) 3.7 (m, 3H) 5
．． 8 (d, LH) 3.0 (d, 2H) 5
．． 1 (brs, 2H) 1.3 (dd, 3
H) Quantity spectrum FAB: 342 (100%), M+H near 1 minute C1, H,. No, P, 1/2H, (]: Calculated value Measured value C: 51.43 51.09H:
6.03 5.67N: 4.00
4.02R1=ethyl acetate/n-butanol/acetic acid/water, 1:l:1:1):0.70 HOH dry methanol 3+aQ and benzene 0.5mff
A solution of 0.172 g (0,504 mmol) of 1-D-benzyloxycarbonylaminoethyl)-(2-carbomethoxy-2-propenyl)phosphinic acid in
．． 5 cyclooctadiene-rhodium(I) chloride dimer 2
5■ and (-)2.3-'O-isopropylidene-2
．． 40 ps in the presence of 70 μ of 3-dihydroxy-1,4-(diphenylphosphino)butane ((-)DIOP)
Hydrogenated at i. Hydrogen addition was completed after 3 hours. The mixture was diluted with 10 mQ of ether, cooled to 0°C, and filtered to remove the product. The crude product was recrystallized three times from aqueous acetic acid to give the title compound.

NMR300MHz CD OD: δ7.3-7
．． 5 (m, 6H) 2.2 (m, LH) 5.1
(dd, IH) 1.8 (m, LH) 4.0
(m, IH) 1.3 (dd, 3H) 3.7 (
s, 3H) 1.2 (d, 3H) 2.9 (m,
IH) Quantity spectrum (NI FAB): 342 (40%), M-H Tennin Tachioka C,,H,. Calculated values for NO, P Measured value C: 52.48 52.49H: 6
,46 6.16N: 4.08
4.25 Flame x Skin: +30.1' (CH,O
H,C=0.3)(1-D-benzyloxycarbonylaminoethyl)-(2-carbomethoxy-2-D-methyl-1-ethyl)phosphinic acid to give the title compound by the procedure described in Example 2. Conversion was achieved with a yield of 60%.

NMR300MHz DO: δ3.25
(m, LH) 1.68 (m, IH) 2.8
1 (d, LH) 1.38 (dd, 3H)
2.10 (d, IH) 1.27 (d, 3
H) Mass spectrum NIFAB: 194 (55%), M-HR ethyl acid/n-butanol acid/water, 1: 1: 1: 1): 0.35-phenyl-2
-Z-Butenyl Phosphine Emperor OCH.

A, Methyl 1-penzyloxycarboni The title compound was converted into 1-benzyloxycarbonylaminoethylphosphonic acid methyl ester (1,154 g, 4.49 mmol), 2-trimethylphosphonoacrylate (1,31 g
.

6.7 mmol) and phenylacetaldehyde (1
, 08 g, 8.9 mmol) by the procedure described in Example 29.

The crude product was purified by chromatography (silica, 9:1 ethyl acetate:acetonitrile) to yield 0.41 g of the title compound.

NMR300MHz CD CQ: 67.0-7.
4 (m, IIH) 3.7 (m, 6H) 5.5
(d,, 5H) 3.6 (m, 2H) 5.1 (m
, 2.5H) 3.1 (m, 2H) 4.1 (m
, IH) 1.4 (q, 3H) quantity spectrum (FA
B; 446 (M1H, 100%) Calculated value for original U [C,, Hl, NO, P, 1/2H, 0
Measured value C: 60.79 60.03H:
6.43 6.11N: 3.08
3.141-benzyloxycarbonylaminoethyl-(2-carbomethoxy-(4-phenyl-
27z-butenyl)phosphinic acid methyl ester (0,
1 g, 0.23 mmol) was stirred in concentrated hydrochloric acid (5 mg) for 1 week. After concentration in vacuo, the hydrochloride salt of the title compound (0,051 g) was obtained as a white powder.

TLC (silica, 1:1:1:1 ethyl acetate:n-
Butanol:acetic acid:water) Rf=0.43HMR200M
Hz D O: δ 7.0-7.8 (m, 6H) 3.0 (m,
2H) 3.7 (m, 2H) 1.5 (q,
3H) 3.4 (m, IH) IL Mupe L Gokami (FAB): 282 (M-H, 55%)
The title compound was prepared in 63% yield following the procedure described in Example 1 with the only difference being the use of di-t-butyl dicarbonate in place of benzyl chloroformate to protect the amino group. The title compound was purified by chromatography (silica, 9:1 ethyl acetate:acetonitrile).

TLC (silica, 10:1 ethyl acetate:ethanol)
Rf=0.7Q NMR (300MHz, CDCQ,) 1.3 (m.

3H): 1.4 (s, 9H); 3.8 (d, 3H
); 4.0 (m, LH); 4.8 (br ct, IH
); 6.1 (s, 0.5H); 7.9 (s, 0.
5H) Procedural amendment February 5, 1988

Claims (1)

[Claims] 1. Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II [In the formula, R_1 is H, CH_3; R_2 or R_5 is (a) hydrogen (b) C_2 to C_1_2 straight chain or branched chain alkyl; (c) C_2 to C_1_2 straight chain or branched chain monoalkenyl; (d) C_7 to C_2_0 aralkyl (alkyl chain is straight chain or branched chain C_1 to C_9 (e) heterocyclic alkyl (the alkyl chain is a straight or branched chain C_1 to C_8, the heterocycle is a 5- to 6-membered ring optionally containing 1 to 3 O fused to a benzene ring; fully aromatic containing N or S heteroatoms; the groups R_2 and R_5 above are halo, hydroxy, carboxy, C_1-C_4 alkoxycarbonyl, C_7
~C_1_6 arylalkoxycarbonyl, C_3~
C_7 cycloalkyl, C_1 to C_4 alkoxy, C
_6~C_1_2 Aryloxy, amino, mono- or di-C_1~C_8 Alkylamino, thio, C_2~C_
4 alkylthio, C_6-C_1_2 arylthio, C
_7~C_1_6 aralkylthio or radical-S
-(CH_2)_n-CH(NH_2)COOH(n=
1 to 2) (provided that when substituted with one of the thio groups defined above, R_2 or R_5 is at least C_2 alkyl), an aryl or aromatic heterocyclyl ring can be further substituted with C_1-C_4 straight-chain or branched alkyl, trihalomethyl, nitro, cyano or sulfonamido, halo; R_3 and R_4 are hydrogen, C_1-C_4 alkyl,
C_6-C_1_2 aryl or C_7-C_1_6
It's Aralquil. ] Compounds represented by these and their stereoisomers and racemic compounds. 2, R_1 is methyl, R_2 or R_5 is C_1-C_1_0 straight-chain or branched alkyl, C_7-C_1_4 aralkyl (both groups are halo, amino, mono- or di-C_1-C_4 straight-chain or branched alkyl) Amino, carboxyl, C_1~
C_4 alkoxycarbonyl, hydroxy, C_1-C
_4 alkoxy, C_5-C_6 cycloalkyl, C_
5~C_1_0 aryloxy, thio, C_1~C_4
Straight-chain or branched alkylthio, C_6-C_1_0 arylthio, C_7-C_1_4 aralkylthio, -S
-(CH_2)_n-CH(NH_2)CO_2H(n
=1-2) (However, when substituted with one of the thio groups defined above, R_2 or R_
5 is at least C_2 alkyl), the aryl group can be further substituted with straight-chain or branched C_1-C_4 alkyl), R_3 and R_4 are hydrogen, C_1-C_4 straight-chain or branched alkyl, For example, methyl, ethyl, C_7~C_
A compound according to claim 1, wherein the 1_4 aralkyl is benzyl. 3. The compound according to claim 1, wherein the stereochemical configuration of the carbon attached to R_1 and the carbon attached to R_2 is D(S), DL (SR), or D(R), DL(RS), respectively. . 4. The compound according to claim 1, wherein the stereochemical configurations of carbon atoms attached to R_1 and R_2 are D(S) and D(R), respectively. 5. The compound according to claim 1, wherein the stereochemical configurations of carbons attached to R_1 and R_2 are L(R), D(R), L(S), and DL(RS), respectively. 6. The compound according to claim 1, wherein the stereochemical configuration of the carbon atom attached to R_1 is D(S), and the configuration of the double bond is Z or E. 7. The compound according to claim 1, wherein the stereochemical configuration of the carbon atom attached to R_1 is L(R), and the configuration of the double bond is Z. 8, 1-(aminoethyl)-(2-carboxypropyl)phosphinic acid 1-(aminoethyl)-(2-carbomethoxypropyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-n-butyl)phosphine Acid 1-(aminoethyl)-(2-carboxy-5-phenyl-n-pentyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-n-nonyl)phosphinic acid 1-(aminoethyl)-(2 -carboxy-5-(4-
pyridyl)-n-pentyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-3-chloro-n-propyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-3-bromo-n-propyl) ) 1-(aminoethyl)-(2-carboxy-n-hexyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-2-n-octenyl)phosphinic acid 1-(aminoethyl)-(2 -carboxy-2-propenyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-4-phenyl-2-butenyl)phosphinic acid 1-(aminoethyl)-(2-carboxy-5-phenyl-2-pentenyl) ) A compound according to claim 2 selected from phosphinic acids. 9. A pharmaceutical composition useful for the treatment of antibacterial infections comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an antibacterial compound represented by formula I or II or a mixture thereof: ▲Mathical formula, chemical formula, table, etc. There are ▼ I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II [In the formula, R_1 is H, CH_3; R_2 and R_5 are (a) hydrogen; (b) C_1 to C_1_2 straight or branched chain alkyl; ( c) C_2-C_1_2 straight-chain or branched monoalkenyl; (d) C_7-C_2_0 aralkyl (the alkyl chain is straight-chain or branched C_1-C_8); (e) heterocyclylalkyl (the alkyl chain is straight-chain or branched chain C_1 to C_8, and the heterocyclyl ring is fully aromatic containing 1 to 3 O, N or S heteroatoms optionally fused to a benzene ring in a 5- to 6-membered ring); The groups R_2 and R_5 are halo, hydroxy, carboxy, C_1-C_4 alkoxycarbonyl, C_7
~C_1_6 arylalkoxycarbonyl, C_3-
C_7 cycloalkyl, C_1 to C_4 alkoxy,
C_6~C_1_2 Aryloxy, amino, mono- or di-C_1~C_8 Alkylamino, thio, C_1~C_
4 alkylthio, C_6-C_1_2 arylthio, C
_7~C_1_6 aralkylthio or radical -S-
(CH_2)_n-CH(NH_2)COOH, (n=
1 to 2) (provided that when substituted with one of the thio groups defined above, R_2 or R_5 is at least C_2 alkyl), an aryl or aromatic heterocyclyl ring can be further substituted with C_1-C_4 straight-chain or branched alkyl, trihalomethyl, nitro, halo, cyano or sulfonamide; R_3 and R_4 are hydrogen, C_1-C_4 alkyl,
C_6-C_1_2 aryl or C_7-C_1_6
The carbon atom attached to R_1 or R_2, which is an aralkyl, is in the D(S) or DL(RS) configuration, and when R_5 is present, the double bond is in the E or Z configuration. ]. 10. A pharmaceutical composition useful for the treatment of antibacterial infections comprising a pharmaceutically effective amount of a DHP inhibitory compound represented by formula I or II or a mixture thereof in combination with a pharmaceutically effective amount of a carbapenem or penem antibiotic: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ I ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II [In the formula, R_1 is H, CH_3; R_2 and R_5 are (a) hydrogen; (b) C_1 to C_1_2 straight chain or Branched alkyl; (c) C_2-C_1_2 straight-chain or branched monoalkenyl; (d) C_7-C_2_0 aralkyl (the alkyl chain is straight or branched C_1-C_8); (e) heterocyclylalkyl ( The alkyl chain is straight or branched C_1 to C_8, and the heterocyclyl ring is a fully aromatic ring containing 1 to 3 O, N or S heteroatoms optionally fused to a benzene ring with 5 to 6 members. The above groups R_2 and R_5 are halo, hydroxy, carboxy, C_1-C_4 alkoxycarbonyl, C_7
~C_1_6 arylalkoxycarbonyl, C_3~
C_7 cycloalkyl, C_1 to C_4 alkoxy, C
_5~C_1_8 Aryloxy, amino, mono- or di-C_1~_8 Alkylamino, thio, C_1~C_4
Alkylthio, C_6-C_1_2 arylthio, C_
7~C_1_6 aralkylthio or radical -S-(
CH_2)_n-CH(NH_2)COOH(n=1~
2) (provided that when substituted with one of the thio groups defined above, R_2 or R_5 is at least C_2 alkyl), the aryl or aromatic heterocyclyl ring is further substituted with C_1-C_4 can be substituted with straight-chain or branched alkyl, trihalomethyl, nitro, halo, cyano or sulfonamide; R_3 and R_4 are hydrogen, C_1-C_4 alkyl,
C_6-C_1_2 aryl or C_7-C_1_6
It's Aralquil. Furthermore, the carbon attached to R_1 is in the L(R) or DL(SR) configuration, and the carbon attached to R_2 is in the D(R), L(S) or D
in the L(RS) configuration, and if R_5 is present, the double bond is in the E or Z configuration. ].