JPS58131952A - Manufacture of novel amino acid derivative - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel amino acid conductor and a pharmaceutical composition containing the compound, as well as a method for producing the same. Nu-CB-Co-mu1 - [wherein Mu1 is hydroxy, C1-4 alkoxy, C1-, cycloalkoxytc, '-4 aralkoxy, phenyl ring canitro, C1-, alkoxy or)% substituted with rogen or phenoxy, which may have the general formula -(Nu-
CH-Co), -Y (wherein is hydrogen, alkyl, aralkyl, and hydroxy-substituted aralkyl or heteroaralkyl; Y is hydroxy, C1-4 alkoxy or C2-, aralkoxy; r is 1-1
Bl is a halogen or a group of the formula -80,OR, -080,011.

-〇PO(OH), or -8-8R” (R” is C1
~4 alkyl, aralkyl or aryol) or formula (
is the residue obtained by removing the group Bl from the compound of 1); the wing is hydrogen or C3-4 alkyl: R1 is hydrogen, C1-4 alkoxycarbonyl, C1-, aralkoxycarbonyl, Halogen in phenyl ring.

is phenoxycarbonyl, C1-4 alkanoyl, or benzoyl which may have an alkoxy or nitro substituent; V is hydrogen, C1-4 alkyl, carboxy, C1-4
Alkoxycarbonyl, phenoxycarbonyl.

or a carboxamide; n is 1, 2, 3. or 4; m is 1.2. Or 3: t is 1. ! , or 3].

Salts and optically active isomers of the above compounds are also included within the scope of the present invention.

Some of the novel compounds of this invention have useful pharmaceutical properties, and others can be used as intermediates in the preparation of compounds with useful physiologically relevant drug properties.

Among the novel compounds of the present invention, particularly advantageous with regard to biological activity are gamma-L compounds of the following general formula (xxiv):
- Glutamyl taurine.

H,N-CH-C0OH CH.

Co-NH-CB, -CH, -80 OH
ospherica1-Genetical-Mudap
tational-+5yste! It has a wide range of therapeutic and preventive effects against pathological changes directly or indirectly related to damage to IT1).

To explain the AGA8 obsession, we will enumerate the most important tissues and organs that make up this system.

(a) Biological interfaces (skin and other skin-like structures) that form the boundary between living organisms and the atmosphere that serves as their habitat.

cornea and conjunctiva 2 oral and pharyngeal cavities, respiratory tract and lungs); (b
) Skeletal system and body limbs (tubular and cancellous bone joints, synovial membranes, skeletal musculature); (c) organs involved in the regulation of terrestrial ionic balance (transepithelial transport system, catgut and kidney); (d) ocular teeth (with tooth bases and anchored by the roots) necessary for the breakdown of solid food; terrestrial auditory, olfactory and sound-forming organs;

The compounds prepared according to the invention exert biologically favorable therapeutic effects on the organs of the above-mentioned systems as well as their tissues.

In addition, the compounds of the present invention also exhibit the following effects on the MuG-8 system: radiation protection, wound healing promotion, and activation of Mensenchyma v.
Protection against increased risk of infection and contamination of the mucous membranes and skin (lysozyme production of moist mucous membranes, development of the hairy epithelium of the respiratory tract, etc.), increased protection against viral and bacterial infections of the skin.

In response to the significantly increased stress effects of terrestrial life (e.g. meteorological and drastic diurnal changes, increased risk of damage), this compound is effective in reducing peripheral tissue damage induced by glucocorticosteroids, e.g., connective tissue. There is a tendency to stabilize the adaptation syndrome by simultaneously preventing damage to the presubstrate, etc.

Development of immunodynamic equilibrium (increased recognition of self and non-self cells) 0 The compounds of the present invention may enhance the effects of vitamin A metabolism, partly directly and partly through the production of more polar vitamin A metabolites. It exerts its activity through inhibition. This activity is
25-hydroxycholecalciferol-1- in renal tubules
α-hydroxyler-W (2S-h7oxy-c
holecalciferol-1-α-hydr
oxylase) enzymes similar to those caused by parathyroid hormones. The above facts explain the wide and diverse biochemical, pharmacological and therapeutic activities of the compounds of the present invention.

(4) Effects of vitamin A properties (a) Pharmacological and biochemical effects Effect of promoting the incorporation of labeled sulfate into rat cartilage, and into the crystalline lens, liver and lung tissues of chicken embryos; rat cartilage Effect of promoting the incorporation of labeled phosphorus into the body; Effect of promoting acid content of chondroitin sulfate: Effect of favoring wound healing (against the decrease in wound healing induced by administering cortisone to rats and dogs) (Also effective): Increases mast cell granulation reduction; Vitamin A enrichment in cases of experimental vitamin deficiency or excess in rats and chickens;
Effects on reducing stress ulcers in rats and increasing lysozyme production: Trace elements (silicon).

Effects that affect the alternation of copper, zinc, manganese, fluorine):
Action to promote epithelial formation; action to increase the activity of alkaline phosphate enzyme; action exerted on cyst formation induced by local action of vitamin A: very flat course of the dose-response curve and high dosage Effect of activating the Golgi apparatus: Promoting the production of goblet cells: Effect of increasing serum vitamin A concentration.

(b) Use in clinical treatment: Keratoconjunctivitis sicca (5yn
obroncbitis): pancreatic fibrosis;
Periodontal disease: increased predisposition of the skin and mucous membranes to viral and mfI infections; cortisone antagonism; surgical wounds and lesions of the mucous membranes: colonic erosions; pruritus; taste and olfactory disorders.

(a) Ilkl theory and biochemical effects Transient hypoglycemic effect: Effect to reduce phosphate urine and increase serum phosphate level: Radiation hypnosis effect: Target reaching in maze test in inactive animals Action to promote: Action to reduce experimental fluorosis and cadmium poisoning: Action to reduce experimental Egyptian bean toxicity; Action to increase renal cyclic adenosine-phosphate excretion; Action to reduce hepatic tyrosine aminotransferase Action to increase enzyme activity.

(b) Use in clinical treatment Less severe irradiation injury; Vitiligo; Asthenia: Mental uplifting effect; Effects on degenerative aging and improving memory function: Keloid predisposition; Ankylosis formation in spondylosis; Disease; sclerotic fundus (5 sclerotic fundus)
: Starchoid disease; patchy scleroderma; fibrous mammopathy.

The duration of treatment with the compounds of the invention varies within wide limits. When given an oral dose of chemically pure active substance of 5 µf three times a day, some patients were no longer symptomatic (e.g., sicca rhinolaryngopharyngitis) after 2 weeks; Treatment for some diseases may require 1 to 2 months (e.g., periodontitis, Shiso-Gren syndrome), while other diseases may require 3 to 6 months (e.g., ankylosis). formation of spondylosis).

The compounds of the invention can be converted into cosmetic or pharmaceutical compositions for use in human and veterinary treatment.

The composition may contain as active ingredient only the compound of the invention (and may also contain other biologically active substances).
Preferably, the dosage is 50 to 500 nanograms per day, taken three times a day.

One tablet consists of a biologically inert carrier (e.g. lactose, starch) and the usual auxiliary substances (e.g. granulating agents and lubricants such as polyvinylpyrrolidone, gelatin, Merck, magnesium stearate, ultrafine silica, etc.) 2 to 20 μt, preferably about 10 μt, of the active ingredient of the present invention in admixture with
Contains. Considering this very low dosage, in order to homogeneously disperse this active substance in the tablet, the active ingredient in solution form is mixed with the tablet mass before granulation and a homogeneous mixture is created using a kneader. Preferably, it is prepared. Because the required effective dosage is so low, the active ingredients of the invention can be produced at acceptable cost in large laboratory-scale equipment, even when producing trillions of tablets. The active ingredient is stable, so the tablets can be stored for long periods of time. The active ingredient content in the case of devo tablets or 5 pansulated capsules is 10 to 30 μV.

Injectable preparations containing the active ingredient of the invention in powder ampoules, optionally mixed with a biologically inert bath diluent, contain 5 to 10 μt of active ingredient per ampoule. It is preferable that Parenteral application is preferably by intramuscular, subcutaneous or intravenous injection. The active ingredient according to the invention in the prescribed formulation does not irritate tissues or vessel walls and can also be applied in the form of 5 drops.

Herbal medicines such as cocoa butter or synthetic waxes (eg Imhausen mass) can be used for this purpose.

GFR) using 2 to 20 μt1 (approximately 1
It can be prepared with an active ingredient content of 0 μt.

Common hydrophilic or hydrophobic ointment bases (e.g. cholesterol, paraffin, glycerin, lanolin, linseed oil)
The dermatological or cosmetic ointment prepared by the above method may have an active ingredient content of 1 to 1.0 μf/f.

Aerosol formulations contain the active ingredient at a concentration of 0.1 to 1.0 μf/
It is preferable to contain F at a concentration. The active ingredient content of sublingual tablets is approximately 10 μt per tablet, and the disintegration time is 0.5 to 1 hour.

Polymers of high molecular weight with a sustained effect can also be prepared, for example in the form of suspensions with an active ingredient content of 1 to 5 μl/f. Molecular weight organic bases (e.g., protamine,
(histones) can be used to prepare injectable preparations with such a sustained effect.

The composition contains active ingredient in an amount of IO to 20βV per ampoule.

Dermatological and cosmetic powders have an active ingredient content of 0.1
to 1 μt/f (contains a conventional carrier (eg, talc)).

Eye drops applied for ophthalmology and ointments miscible or immiscible with tears contain active ingredients in amounts ranging from 0.1 to 1.0μ.
f/F.

The most preferable dose for pediatric use is 1 kg body weight.
The ratio is 0.3 μt of active ingredient per F.

All germicidal compositions are preferably prepared by sterile filtration.

Combinations of the above formulations containing the compounds of the invention increase, intensify or improve the intended prophylactic, therapeutic or cosmetic effect. The following supplementary ingredients should mainly be used.

Vitamin A, vitamin C.

Vitamin E, vitamins, sputum trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radium-like and immunosuppressive products, psychotropic drugs (especially tranquilizers and thymolebotics).

thymoleptics), organosilicon compounds,
Gerontological preparations, oral antidiabetic agents, anti-inflammatory agents, antihistamines, etc.

The appropriate amount of each component in the combination formulation is generally about the same as the usual therapeutic amount when used alone.

The compounds of the invention can also be used as additives in therapeutic and nutritional premixes. When used in such compositions, the compounds increase weight gain and also reduce vitamin A requirements and/or improve vitamin A absorption and metabolism.

This compound improves the absorption of trace elements and also increases their blood levels. When used as a feed additive, it can be administered to animals in a daily oral dose of 100 to 300 nanograms per body weight, preferably about 200 nanograms per day of body weight. This is generally at a concentration of 1 to 2 μt/lkf feed (i.e. 1
to 2 capes/ton or 0.001 to 0.002
ppm).

Considering the extremely low concentrations required, the compounds of the invention can also be incorporated into microcapsules containing vitamin premixes or other useful feed additives.
It can also be administered as an additive to drinking water or licking salts. The compounds of the invention can also be used in veterinary medicine in the same form as they are applied in human treatment (epithelialization, wound healing, bone fractures, etc.).

The common structural feature of the compounds of general formula (11) is α-t
an it-substituted dicarpodicarboxylic acid moiety, whose ω-carboxyl group is amide to a primary or secondary amino group containing a strong acidic group in the ω position in addition to other substituents in the alkyl side chain. It means that they are connected through a bond.

The compound of general formula (amount) or its salt or optically active isomer can be produced according to the present invention by the following method.

General formula (-) R’-NH-CH-COA” drunkenness (C12).

CO-A'' [wherein R1, M1 and n each have the same meanings as above, A'') t, hydroxy, p-nitrophenoxy.

pentachlorophenoxy, or C2-4 alkoxycarbonyloxy] A compound of the general formula (-) [wherein R, R'', m and t are each as defined above; B2 is hydrogen or a compound of the formula - 80, OH, -080 voice, -o
po(oti)2 or -5-s-n'(R' is group B
: is the group of the compound of the formula (-) (residue obtained by removing the compound force)], if necessary, converting the compound thus obtained into its salt or liberating it from its salt, and/or the above compound is produced in an optically active form by using an optically active reagent or by optically resolving the obtained racemic product. According to the method of the present invention, the compound of general formula (1) has an acid amide bond. Manufactured by forming.

In this case, a suitable α-aminodicarboxylic acid derivative having a protecting group or another substituent on the α-amino group and optionally also on the carboxyl group is added via its ω-carboxyl group to, for example, 2-aminoethanesulfonic acid. , 3-aminopropanesulfonic acid, 2-phosphoethanolamine, 3-phosphopropaturamine or cystic acid. A wide range of protecting groups can be applied in this reaction.

The most preferred method of attachment is the activated ester method.

For the generation and selective removal of conservative radicals, as well as conjugation methods, see E, 5chr3dor and x, Li1bke,
"The peptides" vol. 1. Peptide synthesis method, Academic Press (1965
) is described in detail.

It can also be achieved, for example, by acylating the amino group of cystamine or a substituted cystamine derivative with an α-aminodicarboxylic acid derivative. Several coupling methods can be used to carry out the acylation, such as the "active ester" or mixed anhydride method. The product of this coupling reaction can be reacted with hydrogen peroxide or a peracid. O to produce suitable compounds of general formula (1) via oxidative elimination of disulfide bonds The present invention will be explained in more detail by the following examples.

However, the present invention is not limited to these.

Example 1 40.85f (0.11 mol) of carbobenzyloxy-L-glutamic acid α-benzyl ester (Lieb
ig's Ann, 655, 200/1962) in 500-mL acetonitrile. The solution was cooled to -15°C, excluding moisture in the air, and heated to 15.4 m (0.
, 11 mol) of triethylamine are added to the stirred solution followed by 15.411/(0.11 mol) of isobutyl chloroformate. This mixture was heated to -15℃ for 4 hours.
Stir for 0 minutes, then add 28g (0.2 mol) of triethylamine, 11.26F (0.05 mol) of cysteamine @ dihydrochloride and finally 250st of acetonitrile. The mixture is stirred vigorously at -15° C. for 2 hours and then at room temperature for 4 hours.

The reaction mixture is evaporated in vacuo at 30°C. The residue is mixed with 200 °C of ice-cold water under cooling and stirring, and the resulting mixture is evaporated in vacuo at 35°C. Add 250sIt of water to the residue and 5
00- ethyl acetate is added and the mixture is placed in a separatory funnel. The ethyl acetate phase was sequentially treated with 250 - water, 2 x 250
- 5% aqueous sodium carbonate solution, 2 x 250ml of 1N hydrochloric acid and 250ml of water. (The aqueous-alkaline washing solution is acidified with hydrochloric acid and extracted with ether.
unreacted carbobenzyloxy-glutamic acid α
- The benzyl ester is recovered. ) The ethyl acetate solution is dried over anhydrous sulfuric acid (IJ) and evaporated to dryness under vacuum at 30°C. A thick oily residue was obtained, which crystallized on standing. The residue was triturated with 250 m of anhydrous ether, the crystalline material was separated, and the ca.
The crude product of O-42f was mixed with 100-ethyl acetate and 170-
Recrystallize from wt ether. 29.3 ffJN,
N'-bis(N-carbobenzyloxy-gamma-C
α-benzyl)-L-glutamine]-cysteamine is obtained. m, p, 91-92°C.

Analysis C44■. N401682 (MW=859
．． OS) Calculated value: C61, S2 Chi, II 5.8
9*, Ns, 5ziB 7.461 Actual value: C60,8S%, H5,91chi, N6.
61%.

8 7.7211 Example 2 5.42 f (11 mmol) of carbobenzyloxy-
L-glutamic acid (α-benzyl)-r-p −=
) o 7 = c = Jl/ Ester (Chem,
1ler, Is.

204/1963) was dissolved in 50% pyridine. This solution was cooled to 0°C, and a solution of 1.25F (10 mmol) taurine dissolved in 20% water was dissolved under vigorous stirring for 30 minutes. Add dropwise. Its i 3.08d(22
mmol) of triethylamine is added dropwise to the mixture;
Stop cooling and stirring. The mixture is left at room temperature for 72 hours and then evaporated in vacuo.

Dissolve the residual 50-mL in water and add 1N hydrochloric acid to the solution until the yellow coloration disappears. p-2) washing the solution with 10×50 ether to remove lophenol;
Evaporate the aqueous phase in vacuo. 69t of carbobenzyloxy-γ-(α-benzyl)-L-glutamyltaurine triethylammonium salt is obtained.

Example 3 0.47F (1 mmol) of carbobenzyloxy-α
-L-glutamyl-(γ-p-nitrophenyl ester)-glycine methyl ester is dissolved in 6-pyridine. This solution was cooled in a water bath, and then mixed with a solution of 0.125 F (1 mmol) of taurine in 2.
28 mg (2 mm! J moles) of triethylamine are added. Each reactant should be added in small portions to always obtain a clear solution. The reaction mixture was left at room temperature for 3 days,
It is then evaporated in vacuum. The oily residue was triturated with ether and petroleum ether and dried over sulfuric acid under vacuum. Carbobenzyloxy-α-L-glutamic acid (α-benzyl)- is obtained. Example 4 1.083 F (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl)- r-p
-nitrophenyl ester in 6-hyricine-water 2:l
Dissolve in the mixture and add 278q (2 mmol) of homotaurine and 0.59d (4,2 mmol) of triethylamine to this solution.
Leave for an hour and then evaporate in vacuo. The oily residue is dissolved in water, neutralized with hydrochloric acid and subjected to ether extraction in a continuous extractor for 8 hours to remove p-nitrophenol. Evaporation of the aqueous phase in vacuo yields 1.68f of carbobenzyloxy-γ-(α-benzyl)-L-glutamyl-homotaurine.

Example 5 1.083 F (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl)-r-p-
Nitrophenyl ester 278-(2 mmol) of N
- react with methyltaurine in the manner described in Example 4. 1
．． 59F carbobenzyloxy-γ-(α-benzyl)-L-glutamyl-N-methyltaurine is obtained.

Example 6 2.87F (6.6 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl>-r-p-nitrophenyl ester) was dissolved in 20 m/m of pyridine to give 1
．． A solution of 25f (6 mmol) of L-cystic acid hydrate in a mixture of 17m water and 17m pyridine is added. To this mixture was added 2.6 sg (18°6 mmol) of triethylamine, and the reaction mixture was brought to room temperature at 72°C.
Leave it for a while.

This solution is evaporated in vacuo at 30°C. The residue was dissolved in 20 m/m of water and the solution was acidified with concentrated hydrochloric acid, followed by 15×1
Wash with 0- ether. The aqueous phase is evaporated in vacuo at 35°C. Carbobenzyloxy-r-(α-pencyl)-
L-/rutamyl-L-cystic acid is obtained.

Example 7 1.083 f (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl)-rp
- Dissolve the nitrophenyl ester in a 2=1 mixture of water and add 282 q (2 mmol) of colamine phosphate (U.S. FF 14'? 2,730) to this solution.
．． 542) and 0.87 Wd (6.2 mmol) of triethylamine. The mixture is left at room temperature for 72 hours and then evaporated in vacuo. The residue is treated as described in Example 4. 1.25F carbobenzyloxy-r
-(α-benzyl)-L-glutamyl-colamine phosphate is obtained.

Example 8 526q (1.1 mmol) of carbobenzyloxy-
L-aspartic acid (α-benzyl)-β-p-2) o 7 enik esthetics/I/ (Chem, B
Er.

97.1789/1964) in 5-pyridine. The solution is cooled to 0° C. and a solution of 125q (1 mmol) of taurine in 2 ml of water is added in portions followed by 0.28 m/(2 mmol) of triethylamine. The reaction mixture is left at room temperature for 48 hours and then evaporated in vacuo. The residue is dissolved in water and IN hydrochloric acid is added dropwise to this solution until the yellow coloration disappears. Solution 10X to remove p-nitrophenol
Wash with 5-5 ether and evaporate the aqueous phase in vacuo. 47
84 carbobenzyloxy-β-(α-benzyl)-
L-aspartyltaurine is obtained.

Example 9 526wII (1.1 mmol) of carbobenzyloxy-L-aspartic acid (α-benzyl)-β-p-
When the nitrophenyl ester is reacted with 139q (1 mmol) of homotaurine with K as in "l [IIJs," carbobenzyloxy-β-(α-benzyl)-L-
Aspartyl homotaurine is obtained.

Example 1O Carbobenzyloxy-L-aspartic acid (α-benzyl)-β-p-nitrophenyl ester in Example 7
React with colamine phosphate as follows. Carbobenzyloxy-β-(α-benzyloxy)-L-
Asbarthylcolamine phosphate is obtained.

Example 11 =3.711 (10 mmol) of carbobenzyloxy-L-glutamic acid α-benzyl ester are dissolved in 60-methyl acetonitrile. The solution is cooled to -IS DEG C. and 1.4 m (10 mmol) of isobutyl formate and 1.4 sd (10 mmol) of triethylamine are added dropwise with stirring. The mixture was stirred at −15° C. for 30 min, then 2.05 f (l Q mi I) mol) of bromoethylamine hydrobromide, 1.4 sd (10 mmol) of triethylamine and 40- of acetonitrile were added to Cool to ℃ and add. This mixture was heated to -15℃ for 2 hours.
time.

It is then stirred at room temperature for 4 hours. The mixture was then strained,
The r liquid is evaporated in vacuo at 35°C to obtain a residue.

Preferred embodiments of the method of the present invention after forging will be summarized.

1. Compound of general formula (■), preferably N-carbobenzyloxy-amino-dicarboxylic acid-α-pencyl-ω
- a p-nitrophenyl ester is reacted with cystamine in the presence of aqueous pyridine, or a compound of formula (1), preferably N-carbobenzyloxy-aminodicarboxylic acid-α-benzyl ester, is reacted in the form of a mixed anhydride. How to react with cystamine.

2. Compound of general formula (1), preferably N-carbobenzyloxy-amino-dicarboxylic acid-α-benzyl-ω
A method of reacting a -p-nitrophenyl ester with a compound of formula (1111), preferably taurine, N-methyl-taurine, homotaurine, chloramine phosphate or cystic acid, in the presence of aqueous pyridine.

3. A method in which a phantom compound, preferably N-carbobenzyloxy-amino-dicarboxylic acid-α-benzyl ester, is reacted with a loalkylamine hydrohalide in a mixed anhydride state.

Continuation of page 1 141102 7162-4H143/
14 7162-4H16110071
44-4H C07F 9109 7311-4H
Priority claim @March 26, 1975 ■Hungary (H
U)■CI-1558 0 Inventor: Aálvard Furry Hungarian State 1074 Budapest Cienzieri Utsza 23 @ Inventor Felen Sievestię Hungarian State 1103 Budapest Giergieli Utsza 72 @ Inventor Göran Herr State of Cher-Hungary 1094 Budapest Márton Utsza 35/A @ Inventor Eržiebet PendifiHungary 1122 Budapest Székács Utsza 17 Procedural Amendment January 1980 1O Director of the Patent Office Kazuo Wakasugi 1, Case Display of patent application filed on December 10, 1982 (2) Showa era
Year Application No. 2 Title of invention Process for producing new amino acid derivatives 3 Person making the amendment Patent applicant related to the case 4 Attorney 5 Date of amendment order Voluntary 6 Number of inventions increased by amendment None 8 Amendments The Scope of Claims column in Toshi I41 of the Attachment to Contents is amended as follows.

"1. General formula (:) %formula% [During the ceremony.

Group 1 is hydroxy, C1-4 alkoxy, C3-6 cycloalkoxy, C7-self aralkoxy, phenoxy whose phenyl ring may be substituted with nitro, C1-4 alkoxymody or halogen, or the general formula -(NH -CH
-Co), -Y (where V is hydrogen, alkyl, aralkyl, hydroxy-substituted aralkyl or heteroaralkyl, IY is hydroxy, C1-4 alkoxy or C1-4 aralkoxy, and '' is an integer from 1 to 10) is a group of ) and B! is a halogen or a group of the formula -80!OH, 080tOH1
-OPO(OH)t also L/ < Bar8-8Ra (n
” 4;Jc.

alkyl, aralkyl or aryl) or formula (1)
is the residue obtained by removing group B1 from the compound; 8 is hydrogen or C1-4 alkyl.

B"kl, hydrogen, C3-4 alkoxycarbonyl.

C7-9 aralkoxycarbonyl, phenoxycarbonyl which may have a halogen, alkoxy or nitro substituent on the phenyl ring, C1-4 alkanoyl or benzoyl, and V is water 111a + C1-4 alkyl, carboxy.

CI~, alkoxycarbonyl, phenoxycarbonyl, or carboxamide, and n is 1.2, 3. Or 4.

m is 1.2. or 5, and the number t is 1, 2, . or 3], or a salt thereof, or an optically active isomer thereof.

General formula (il) B''-Nl(-CH-COA''(CHriaCo-A'' nitrophenoxy,
pentachlorophenoxy, or C2-4 alkoxycarbonyloxy]. or formula -80,OH, -080,O
H.

-0PO(OH)s or -8-8-R' (number 8 is a residue obtained by removing group B3 from the compound of formula +iiD)].

The compound thus obtained may be converted into or liberated from its salt, and/or said compound may be converted into optically active form by the use of an optically active mineral strip or by optical resolution of the racemic product obtained. Manufactured in A method consisting of things. ”■0 In the detailed description of the invention column, “hydrogen” on page 18, line 1 of the specification is corrected to “halogen.”

Claims (1)

[Claims] 1. General formula (R' -NH-OH-Co-m1 [wherein A1 is hydroxy, C1-4 alkoxy, C3-, cycloalkoxy, C7-, aralkoxy, phenyl ring] cannitro, C1-4 alkoxy or halogen-substituted phenoxy, or general formula -(NU-CH
-Co), -Y (wherein R5 is hydrogen, aS alkyl, aralkyl, hydroxy-substituted aralkyl or heteroaralkyl; Y is hydroxy, C1-4
alkoxy or C7-9 aralkoxy; r is 1-
B1 is a group of halogen or the formula -〇〇20H, -080,OH
. -0PO(OR)2 or -8-8R3(R” is C1
~4 alkyl, aralkyl or aryl) or formula (
is the residue obtained by removing the group B1 from the compound of ll; R is hydrogen or C1-4 alkyl; R1 is water
+Ct~4 alkoxycarbonyl, C7~. aralkoxycarbonyl, phenyl ring dihalogen, phenoxycarbonyl which may have an alkoxy or nitro substituent, C1-4 alkanoyl, or benzoyl; R2 is hydrogen, C1-4 alkyl, carboxy, C1-4
4 alkoxycarbonyl, phenoxycarbonyl, or carboxamide; n is 1, 2, 3. or 4; m is 1, 2 . or 3; t is % l, 2. or 3] A method for producing a compound, a salt thereof, or an optically active isomer thereof, which has the general formula (-) R'-NH-CB -COA'' (CB,). , AI and n are as defined above, and A2 is hydroxy, p-di)lophenoxy, pentachlorophenoxy, or C2-4 alkoxycarbonyloxy. In the formula C, 11.R'', m and t are each as defined above; hippo, hydrogen or the formula -so, oTl, -080,'? I
, -0PO(011)! Or -B-B-m'
(No. 4 is a residue obtained by removing the group from the compound of formula (III))] and, if necessary, converting the compound thus obtained into its salt or converting it from its salt. A method comprising liberating and/or producing said compound in optically active form by the use of an optically active reagent or by optical resolution of the racemic product obtained.