JPS5953264B2 - Method for producing novel α-aminooxycarboxylic acid hydrazide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel substituted α-aminooxycarboxylic acid hydrazide derivatives.

The novel compounds produced by the present invention are compounds of the following formula (I) and acid addition salts thereof.

X2N-O-CH-Co-NH-NHZ(I) (in the formula,
X represents a cyclopentylidene group or a methylene group having at least one substituent selected from alkyl having 1 to 5 carbon atoms, phenyl, halophenyl, hydroxyphenyl, nitrophenyl, aminophenyl, furyl and nitrofuryl; R represents hydrogen, a benzyl group or an alkyl group having 1 to 5 carbon atoms optionally having a methylthio substituent; Z represents an acyl group derived from pyridinecarboxylic acid.

) The new compound produced by the present invention is basic;
Acid addition salts are formed and therefore processes for preparing acid addition salts of compounds of formula () are also encompassed within the scope of this invention.

The new compounds of formula (1) have valuable pharmaceutical properties and can be used primarily as antituberculous agents.

GB 1323170 describes certain anti-tuberculous active α-aminooxycarboxylic acid hydrazides having free or acyl substituted amino groups.

The reaction between α-aminooxycarboxylic acids and carbonyl compounds has long been used for analytical purposes (J.Bl.
Ol. Chem. 539 (1936)).

Certain Schiff bases produced in such reactions have plant growth regulating activity (J. Am. Chem-SOc.
718 (1947)), and some contain vitamin K.
(see British Patent No. 621,934). J. Med. Chem. l, 824 (1964)
describes certain aldoximes and ketoximes of α-aminooxyacetic acid and ethyl α-aminooxyacetate.

Schiff bases formed from certain α-aminooxycarboxylic acids have been studied at ActaChemica Scandinavica9l in connection with the study of semisynthetic penicillin derivatives.
It was judged in 9th 317 (1965). However, these documents do not mention anything about the biological effects of these oximes and Schiff bases. H
elveticaChimicaActa'46p76
6 (1963), as a result of investigating the bacteriostatic activity of certain aminooxycarboxylic acid derivatives, particularly derivatives of Schiff bases, it was found that the bacteriostatic activity exerted on various microorganisms is due to the presence of free aminooxy groups. It is described as something.

PrOgressinMedicinalChemis
Try2i Dou 1348 (1967) includes various nitrofurfurylidene conductor systems. effects are mentioned, but no mention is made of their antituberculous effects.

When X is a monosubstituted methylene group in formula (I),
The substituents are alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or pentyl groups, phenyl groups or furfuryl or nitrofurfuryl groups optionally with halogen, hydroxy, nitro or amino substituents. could be.

When X is a di-substituted methylene group, it has two of these substituents. R is hydrogen or an alkyl group of 1 to 5 carbon atoms such as benzyl group or ethyl, propyl, butyl or pentyl group optionally with a methylthio substituent.

Since the compound of formula (1) in which R is a group other than hydrogen contains an asymmetric carbon atom, it can be produced in the form of a pure optically active isomer or a racemate depending on the starting material. Racemates can be resolved in a manner known per se, for example by forming a pair of diastereomeric monosalts. As mentioned above, z is an acyl group derived from pyridinecarboxylic acid, such as an isonicotinoyl group.

According to the invention, the compound of formula (1) is a compound of formula (I[):(
In the formula, X and R have the above-mentioned meanings, and w is hydrogen, an alkyl group having 1 to 5 carbon atoms, or a phenyl group having one or more halogen or nitro substituents). The formula (): H2N-NHZ (111) (in the formula,
z is an acyl group derived from pyridine carboxylic acid) and then, if desired,
They are prepared by converting the resulting base into its acid addition salt using conventional methods, or by converting the resulting salt into its free base or another salt using conventional methods.

In the compound of formula (), the substituent R' is hydrogen, methyl,
It represents ethyl, propyl, butyl or pentyl or substituted phenyl, such as p-nitrophenyl, trichlorophenyl, trifluorophenyl, pentachlorophenyl or pentafluorophenyl groups.

Although all the compounds produced by the present invention are new,
Some of the starting materials are known, and new starting materials can be prepared by known methods, for example as described in Pankali Patent No. 160,181 or as shown in the examples below.

In a preferred embodiment of the process of the invention, activated esters of the formula (), preferably pentachlorophenyl esters, i.e. compounds in which R' is an ester-forming group, preferably a pentachlorophenyl group, or R' of the formula (Uf) are used. N,N'-dicyclohexylcarbodiimide, an acid in which is hydrogen, is reacted with a substituted hydrazide, preferably isonicotinic acid hydrazide, at room temperature in the presence of an organic solvent, preferably dimethylformamide.

The reaction mixture is allowed to stand for 1 to 72 hours, preferably 16 hours, then by-products (e.g. pentachlorophenol or N,N/-disitalohexyl urea) are removed by filtration or extraction and the mixture is evaporated to remove the product if necessary. The product is purified by extraction or crystallization. The compounds produced according to the present invention have excellent antituberculous activity, and compounds having an isonicotinoyl substituent on the hydrazine group are particularly effective.

In addition to their remarkable antituberculous activity, compounds having a 5-nitrofurfurylidene group have the advantage of being effective against resistant microorganisms of the genus Mycobacterium.

To the best of the inventor's knowledge, the compounds prepared according to the present invention are the first 5-nitrofurfurylide 7 compounds with antituberculous activity.
It is a derivative. In vitro tests of the new compounds according to the invention were carried out on a nutrient medium containing albumin 2.5 (Fb).

Add 0.0 of a fresh bacterial culture to the medium containing the test compound.
1 Takumi was inoculated and cultured at 37°C for 3 weeks. The inhibitory concentration was then measured. The bacteria used in the test were Mycobacterium tuberculosis H3, Rv (M.t.H3,
Rv), Mycobacterium tuberculosis (M.t.) resistant to isonicotinoyl hydrazide (INH),
Mycobacterium tuberculosis (M.t.) and Mycobacterium Kansasii (M.t.) resistant to streptomycin (Strp.). The test results obtained are shown in Table 1.

The compounds produced according to the invention can be prepared in the form of pharmaceuticals for oral and/or parenteral administration, such as tablets, coated tablets, injectable preparations,
It can be used for treatment in the form of suppositories.

The daily dosage of active compound for the treatment of mammals is about 2 to
801! If/Kfl preferably 10-50111/Q
The amount can be added in portions or in a slow-release manner. Product purity was determined by thin layer chromatography.

The Rf values shown in the examples are based on n-hexane as the eluent,
Measured on silica gel 0G'' (Stahl) using a 1:1:8 mixture of glacial acetic acid and chloroform. The melting point of the compound was determined using a Dr. TOttOli type apparatus. In some cases 1.R.
,N. M. R. and confirmed by mass spectrometry. The specific optical density of the optically active substance was measured using an Obton (0pt0n) spectrophotometer. Next, the present invention will be further explained by examples.

Example 1 N-(N″-5-nitrofurfurylidene)-D-α-aminooxybutyryl-N′-isonicotinoylhydrazine D-α-aminooxybutyric acid hydrochloride 3.10 g (0.
020 mol) was dissolved in 7.0 d of water and 1.649 (0.020 mol) of sodium acetate was added to this solution.

A solution of 2.849 (0.020 mol) of 5-nitrofurfurol in 10.071 Lt of methanol was added dropwise to this mixture at room temperature while stirring. The reaction mixture was left at room temperature for 16 hours, then 23.0 d of water was added. The precipitated product was separated, dried, and recrystallized from ethyl acetate to obtain D-α.
2.129 (88%) of -N-(5-nitrofurfurylidene)-aminooxybutyric acid was obtained. Melting point: 117-118
°C (after recrystallization from ethyl acetate), Rf = 0.77, [α
] Chi=+34″ (c=1,1 in ethanol). Elemental analysis: Calculated value (C, HlOO6N2): C, 44.7% H, 4.1% N, ll.6% Actual value: C, 44 .8% H, 4.O% N, 1.6% D-
α-N-(5-nitrofurfurylidene)-aminooxybutyric acid 1.09 (0.00412 mol), isonicotinic acid hydrazide 0.559 (0.004 mol), N,merized cyclohexyl carbodiimide 0.859 (0. 0
0412 mol) and anhydrous dimethylformamide 10.0
The mt mixture was stirred at room temperature for 16 hours.

The precipitated N,N'-dicyclohexyl urea was separated from P and P
The liquid was evaporated to dryness under reduced pressure. The residue is 1Nf1Lrit1
The solution was extracted with 3×5 d of ethyl acetate. The aqueous phase was neutralized with solid sodium bicarbonate to pH=7, the precipitate was separated from P, washed with water, and recrystallized from a mixture of ethanol 509b and water to yield the title compound 0.96f1 (
69 (Fb) was obtained. Melting point: 164-1660C, Rf
=0.15, [α]M=+1324 (c=1, in ethanol). Elemental analysis: Calculated values (Cl5H, 1O6N,): C, 49.2% H, 4.3% N, 2O. O% actual value: C, 49.3% H, 4.4 (!) N, l9.9 (
Fb Example 2N-(N″-5-nitrofurfurylidene)-Dα-aminooxy-r-methyl-mercabutobutyryl-N′-isonicotinoylhydrazine Example 2 Preparation of the title compound using appropriate starting materials It was manufactured in the same manner as 1.

Yield 70%: Melting point 130-135°C (after recrystallization from ethyl acetate): Rf = 0.17: [α] M = +89 (c =
1 in ethanol). Elemental analysis: Calculated value (Cl6H,,O5N,S): C, 47.2% H, 4.2 (FbN, l7.2% Actual value: C, 47.2% H, 4.3% N, l7 D-α-N-(5-nitrofurfurylidene)-aminooxy-r-methylmercaptobutyric acid as starting material is prepared analogously to Example 1 to ensure better handling suitability of this compound. It was converted into its synchhexylammonium salt for the purpose.

The salts obtained are liberated into the acid form by methods known per se before use. Melting point of product: 158-159°C. Elemental analysis: Calculated values (C22H3, O, N, S): C, 56.3 (FbH, 7.5% N, 9.O (Fb actual values: C, 56.3% H, 7.4% N) ,9.l(F
b Example 3N-(N'5-5-nitrofurfurylidene)-D-α-aminooxy-β-phenylpropionyl-N'-isonicotinoyl-Razine hydrochloride D-α
-Aminooxy-β-phenylpropionate hydrochloride 2
．． 179 (0.010 mol) and 5-nitrofurfurol 1.429 (0.010 mol) were reacted in the same manner as in the first half of Example 1 to obtain D-α-N-(5-nitrofurfurylidene)- Aminooxy-β-phenylpropionic acid 2.75f1 (919b) was obtained.

Melting point: 156-158°C: Rf = 0.52: [α] Wisdom =
-86 (c=0.6, in ethanol). Elemental analysis: Cl4Hl2O6N2: C, 55.
2% H, 4. O% N, 9.2% Actual value: C, 55.
2% H, 4. 1% N,9. l%D-α-N-(5-
Nitrofurfurylidene) aminooxy-β-phenylpropionic acid 1.0f1 (0.0046 mol), pentachlorophenol 1.229 (0.0046 mol) and N,N'-dicyclohexylcarbodiimide 0.95f
i. (0.0046 mol) was dissolved in 10.0 d of dioxane at room temperature with stirring.

This reaction mixture was left at room temperature for 16 hours, and the precipitated N,
N'-dicyclohexylurea was separated and the bottom liquid was evaporated to dryness under reduced pressure. The residue was recrystallized from an 8:2 mixture of ethanol and water to give D-α-N-(5-nitrofurfurylidene)-aminooxy-β-phenyl-propionic acid pentachlorophenyl ester 2.129 (83%). Melting point: 164-165℃: Rf = 0.77: [α seat = +
134~(c=1 in ethanol). Elemental analysis: Calculated value (C2OH, lO, N2Cl,): C, 43.5
O! ) H, 2. O% Ce, 32. O% actual value: C,
43.6% H, 2. 1% Cl, 3l. 9%D-α-
N-(5-nitrofurfurylidene)-aminooxy-β
-Phenyl-propionate pentachlorophenyl ester 1.0f1 (0.0018 mol) and isonicotinic acid hydrazide 0.25f! (0.0018 mol) was dissolved in 10.0 TILI of anhydrous dimethylformamide and the solution was stirred at room temperature for 6 hours.

The reaction mixture was then evaporated to dryness under reduced pressure. The residue was dissolved in 101 LI of ethyl acetate and washed with 3.times.5 ml of 1M sodium bicarbonate solution and then 2.times.5 ml of water. The organic phase was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was treated with 207 nl of 0.5N ethereal hydrochloric acid, and the precipitated salt was separated, dissolved in hot ethanol and, after cooling, precipitated from the solution with diethyl ether. Thus, N-(N'5-5-nitrofurfurylidecy)-D-α-
Aminooxy-β-phenylpropionyl lumer isonicotinoyl hydrazi heptahydrochloride 0.64g (81%)
I got it.

Melting point: 75-76°C; Rf = 0.08: [α] = +86
: (c=1, in ethanol). Elemental analysis: Calculated values (C,.

H, 8N, CO:C, 52.3% H, 3.9% Ce
, 7.7% Actual value: C, 52.2 (FbH, 4.O%
Cl, 7.7% The following compounds were prepared from the appropriate starting materials in a similar manner to Examples 1-3.

Example 4 N-(N″-m-nitrobenzal)-aminooxyacetyl-N′-isonicotinoylhydrazine Melting point: 1
58-160°C (after recrystallization from ethanol) Elemental analysis: Calculated values (COH,,O,N,): C, 52.59bH, 3.8% N, 2O. 4% real 21
・゛ ゛C, 52.5! FbH,3,9(!)N,2
O. 5% Example 5N-(N2-1-methyl-p-aminobenzal)-aminooxyacetyl-N'-isonicotinoylhydrazine Melting point: 175-177°C (after recrystallization from ethanol)
C elemental analysis: Calculated value (ClIHl?0,N
．． ): ゛CoCt5&F%H, 5.29hN, 2l. 4% actual shelf value; ゛7C, 58. ▼%H:12%N,2
l. 2%; Example 6 N-(N″-p-hydroxybenzal)-aminooxyacetyl-N′-isonicotinoylhydrazine Melting point: 203-204°C (reconsolidated from ethanol FM) Elemental analysis: Calculated value (ClHiO, Sl): C, 57.4% H, 4J, 1fbN, 17.89i
Actual value: C, 57.5% H, 4.6% N, l7.8
% Example 7 N-(N″-0-chlorobenzal)-aminooxyacetyl-N′-isonicotinoylhydrazine Melting point: 147-149°C (after recrystallization from ethanol) Elemental analysis: Calculated value (Cl6H,3O,N4Cl ): C, 54.1% H, 3.9% C2, 1O.7% Actual value: C, 54.0% H, 4.0% Ce, ・10.7
% Example 8 N-(N'5-cyclopentylidene)-aminooxyacetyl-N'-isonicotinoylhydrazine Melting point: 160-161°C (after recrystallization from water) Elemental analysis: Calculated value (C,, Hl6O , N4): C, 56.5% H, 5.8% N, 2O. 3% actual value: C, 56.5% H, 5.8% N, 2O. 1% Example 9 N-(N'5-furfurylidene)-aminooxyacetyl-N'-isonicotinoyl-hydrazine Melting point:
123-125°C (after recrystallization from water) Elemental analysis: Calculated value (C,,H,,O4N4): C, 54. 1% H, 4.2% N, 19.4% Actual value: C, 54.2% H, 4.3lfbN, 19.4% Example 10 N-(N″-1-methyl-benzal)-aminooxy Acetyl-W-Isonicotinoidj Solehydrazine Melting point: 160-162°C (after recrystallization from ethanol) Elemental analysis: Calculated value (C,,H,.

O, N, ): C, 6l. 5% H,5. 1% N, 18
．． O% actual value: C, 6l. 4% H, 5.3% N, l
8.2 Example 11 N-(N″-cyclopentylidene)-D-α-aminooxy-β-phenylpropionyl-N′-isonicotinoylhydrazine Melting point: 191-194°C (recrystallized from aqueous ethanol) after), [α]R=71 (C=1, in ethanol).

Elemental analysis: Calculated values (C2OH2, O3N4): C, 65.6% H, 6. 1% N, 15.3% Actual value: C, 65.5CfbH, 6, 2% N, 15.3% Example 12 N-(N7'-m-nitrobenzal)-D-α-aminooxy-β -Phenyl-propionyl-N'-isonicotinoyl-hydrazine hydrochloride Melting point: 76-78 c
, [α]M=+72 acid (c=1, in ethanol).

Elemental analysis: Calculated value (C22H, OO, N, ce): C, 56.3% H, 4.3% C2, 7.59) Actual value: C, 56.39l) H, 4.4% Cl ,7.4%
Example 13 N-(N″-5-nitrofurfurylidene)-aminooxyacetyl-N′-isonicotinoylhydrazine Melting point: 168-170°C (after recrystallization from water) <Elemental analysis:
Calculated value (Cl3HllO, N,): C, 46.9% H
, 3.39bN, 2l. O% actual value: C, 46.8% H, 3.3% N, 2l. O9b Example 14 N-(N'5-isopropylidene)-aminooxyacetyl-N'-isonicotinoylhydrazine Melting point: 13
5-136°C 0 Elemental analysis: Calculated value (C, lH, 4O, N4): C, 52.8% H, 5.6 (FbN, 22.4% Actual value: C, 52.7% H, 5 .7% N, 22.4% This compound was dissolved in a 36% solution of hydrogen bromide in glacial acetic acid.
0W11 and the salt formed was precipitated by adding 10.0d of anhydrous diethyl ether to obtain its hydrobromide salt.
,639 (96%).

Melting point: 152°C, Rf=0.07.

Elemental analysis: Calculated values (Cl, Hl, O3N4Br): C, 39.9Ol) H, 4.5% Br, 24.89
b Actual values: C, 39.8% H, 4.6% Br, 24.9%.

Claims (1)

[Claims] 1 General formula (II): ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, X and R have the meanings below: R' is hydrogen, carbon number 1- 5 alkyl groups or a phenyl group having one or more halogen or nitro substituents) with the formula (III): H_2N-NHZ(III) (wherein Z is from pyridinecarboxylic acid) the hydrazine derivative (which is the acyl group to be derived) and then, if desired, the resulting base is converted into its acid addition salt by conventional methods or the resulting salt is converted into its free base or another salt by conventional methods. Formula (I): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (wherein, Represents a methylene group having at least one substituent selected from hydroxyphenyl, nitrophenyl, aminophenyl, furyl and nitrofuryl; R is hydrogen, a benzyl group, or a carbon number of 1 to 5, optionally having a methylthio substituent represents an alkyl group; Z represents an acyl group derived from pyridinecarboxylic acid) or an acid addition salt thereof.