DE1795270C3 - 1-hydroxy-2-pyridone - Google Patents

Description

The invention relates to l-hydroxy-2-pyrionc of the general formula I.

R ¹
I. -R * .1
J O R ¹ I. OH

(D

R ^{1 is} an alkyl radical with 1 to 11 carbon atoms, a cycloalkyl radical with 5 to 6 carbon atoms, which is optionally bonded to the pyridone ring via a methylene or ethylene group, a benzyl radical which is optionally substituted by a halogen atom or a «-furyl radical, R ² and R ^{4 is} either a hydrogen atom or a low molecular weight alkyl group and R ^{3 is} a low molecular weight alkyl group, where R ² and R ^{1 can} also jointly denote a trimethylene group.

The invention also relates to a process for the preparation of the compounds of the general Formula I, which is characterized in that an unsaturated Λ-keto ester of the more general. Formula 11 or IH

Ri R3 R ₄
R ₁ -CO-CH-C = C-COOR ₅ (11)

, R3 R ₄

R ₁ -CO-C = C-CH-COOR ₅

.15

40

in which R ₁ to R _{4 have} the above meaning and R _{5 represents} a low molecular weight alkyl group or a mixture of the two isomeric esters reacts with hydroxylamine under acidic or alkaline conditions.

5. Pharmaceutical preparations consisting of a 1-hydroxy-2-pyridone defined in claim 1 and the usual auxiliaries or carriers.

55

60 in which R 1 to R _{4 have the above meaning and R 1 is} a low molecular weight alkyl group, or a mixture of the two isomeric esters is reacted with hydroxylamine under acidic or alkaline conditions.

Instead of free hydroxylamine or its salts, derivatives of hydroxylamine such as Hydroxylamine sulfonic acids or oximes of lower aliphatic aldehydes or ketones are used.

The process can be varied within wide limits. So can the implementation of the unsaturated Ketoesters to the l-hydroxy-2-pyridones can be carried out in several stages, with the as an intermediate resulting oxime ester is isolated; but it can also be used directly in a one-pot process to be completed.

You can, for example, in a buffered system by the action of salts of hydroxylamine on the ketoester to produce the oximes in question and then in more acidic or cause the ring closure in an alkaline medium.

It is also possible in the unbuffered system, optionally with the addition of mineral acids, of the ketoc star with salts of hydroxylamine to get directly to the l-hydroxy-2-pyridones.

Another procedure is that the oxime formation and ring closure by Heating the reaction partners in the presence of low molecular weight fatty acids such as formic acid or acetic acid, causes the alcohol component of the keto ester as a volatile ester of the present Carboxylic acid abdeslillicrl.

The reaction temperature is not critical in any of the processes described, but it is recommended the specific procedural conditions. z. B. the necessary removal of volatile components, adapt. Win the examples tend to be the manufacture of the l-hydroxy-2-pyridone according to the Process according to the invention can be carried out at 0 as well as at 140.degree.

The reaction can be carried out in the presence or absence of solvents. Suitable

Examples of solvents are water, lower alcohols and glycols. GlykoÜither, Glycerin, lower Carboxylic acids. Dimethylformamide. Dimethylacetamide, N-methylpyrroüdon, acetonitrile or dimethyl sulfoxide.

The Λ-ketoesters used as starting materials can be particularly advantageous by condensation of carboxylic acid chlorides with / .V-dialkyl acrylic acid esters win in the presence of Friedel-Crafts catalysts.

Compounds according to the invention Processes can be produced are, for. B.

l-hydroxy-4,6-dimethyl-2-pyridone (Example 1),
1-Hydroxy-3,4,6-trimethyl-2-pyridone
(Example 5 b),

1-Hydroxy-4-methyl-6-ethyl-2-pyridone
(Example 7),

l-Hydroxy-lo-dimethyl-S-ethyl ^ -pvridone
(M.p. 142 C),

1-hydroxy-4-ethyl-5,6-dimethyl-2-pyridone
(Example 6c),

l-HydroxyO-ethyl ^ -methyl-o-isobutyl-2-pyridone (M.p. 101 C),

1-Hydroxy ^ -methyl-o-cyclohexyl ^ -pyridone
(Example 6a),

l-hydroxy ^ -methyl-o-cyclohexylmethyl-

2-pyridone (Example 60,
l-Hydroxy-4-methyl-6 - (/ i-cyclohexylethyl) -

2-pyridone (example 6g),
l-hydroxy ^^ - dimethyl-ö-cyclopemyl-

2-pyridone (melting point 132 C),
1-Hydroxy ^ -methyl-o-isopropyl ^ -pyridone

(Example 8),
1-Hydroxy-3,6-dibutyl-4-methyl-2-pyridone

(oil; characteristic 1R bands for hydroxy

pyridone),
1-Hydroxy-4-methyl-6-heptyl-2-pyridone

(Example 6b),
1-Hydroxy-4-methyl-6-undecyl-2-pyridone

(M.p. 63 C),
1-Hydroxy-3,4-dimethyl-6-benzyl-2-pyridone

(M.p. 129C),
l-Hydroxy-4-methyl-6- (4-chlorobenzyl) -

2-pyridone (Example 6e),
1-Hydroxy-4,5-trimethylene-6-methyl-2-pyridone

(Example 6d),
1-Hydroxy-4-methyl-6 - (<i-furyl) -2-pyridone

(Example 13),
l-hydroxy-3,4-dimethyl-6- (4-nuorbenzyl) -

2-pyridone (m.p. 133 C).

The compounds that can be prepared according to the invention have good antimycotic properties. They can be in free form and also in the form of their salts, in particular those with physiologically harmless alkaline compounds can be used.

The compounds according to the invention are not only effective against common skin fungi (Trichophyton- and Microsporum species) and against Candida albicans, but also against palhogenic germs, such as. B. Cryptococcus neoformans, Blastomyces dcrmatilidis, Nocardiaasteroides, Dermatophilus congolense, also Aspergillus fumigatus and other molds such as B. Mucor miehei, Absidia corymbifera, Aspergillus Niger.

The superiority of the compounds according to the invention over the prior art shows from the following test report:

The compounds according to the invention are in all germs that are responsible for skin and Mucosal mycoses come into question, highly effective (in vitro). These germs are in the following Divided into groups:

a) Dermatophytes ("skin fungi" in the narrower sense with the genera Trichophyton, Microsporum, Epidermophyton),

b) yeasts, essentially of the genus Candida (main species: Candida albicans "Ca."),

c) Molds (Aspergillus fumigatus "A. f." etc.) (less important).

The effectiveness of the compounds according to the invention, is broader than those of any compounds commonly used as antifungal agents. from these are listed:

A. griseofulvin (antibiotic),

B. Nystatin (antibiotic),

C. amphotericin (antibiotic),

D. 2-Ni * phthyl-N-methyl-N- (3-tolyi) -thiocarbamate.

E. 1 - (p-chlorobenzyl) -2-methyl-benzimidazole hydrochloride,

F. 5,5'-dichloro-2,2'-dihydroxy-diphenylmethane
+ Salicylic acid,

G. Decamethylene bis (4-amino-undecylenate)

+ Cetylpyridinium chloride -I- l- (2,4-dihydroxyphenyl) n-hexane,
H. 4-chlorosalicylic acid butylamide + salicylic acid.

Effective

IA) IB)

Dermale yeasts
phylen

(Cl
Molds

A.
B.
C.
D.

F.
G.

broad effect only through several complementary compounds

Invention + + +

proper connections

* means well effective.
I + I mean very weakly effective.
(I + Il means indicated effective.
(- I means practically ineffective.
means inverse.

For comparison, the same direction of action was used as a compound. ie with effectiveness against all 3 groups taking IL. the listed connection.

CH ₁ -

CH, ■ HCI

The efficiency with three important germs was compared to several l-hydroxy-2-pyridones to F .. tested, to the experimental method (cf. "Arzneimittelforschung". Vol. 23. [1973], pp. 670 bis 672).

In the table below:

MIC = minimum inhibitory concentration.

T. m. = Trichophyton mentagrophytes.

Approx. = Candida albicans.

A. f. = Aspergillus fumigatus.

The in vivo efficacy was based on the experimental Guinea pig skin mycosis tested (pathogen: Microsporum canis).

»3

R,

i
OH

connection

R,

In vitro
MIC in

Tm.

ml

Approx.

Λ. Γ.

In \ no

"/ o-Hem-

niunii

H CH, - H

31.25 125 125 48.1

(be
knows) CH, C ₂ H ₅ H CH, - C ₂ H ₅ - H 1.95 3.9 7.8 75. ( \
CH-
/ C ₄ H ₁ , CH CH, - Ί CH, CH ₃ CH ₃
I. -propylene- CH, - H 7.8 62.5 31.25 81.9 CH, - fti C ^ C ^ VX Γ ~ Ί-Ι Γ * \ Λ
C Π ^ l " K ^ Γ12 ^ - * ~ 1 ^ - ti ι CH, - CH, - H 3.9 7.8 15.6 81.9 3 CH, - CH, C ₄ H, - H 1.95 1.95 7.8 86.3 4th CH ₃ - C ₁₁ H ₂ , - H CH, - C ₄ H ₁ , 1.95 0.98 1.95 81.9 5 CH, - <ThV- H H 1.95 1.95 3.9 89.4 6th C ₇ H ₁₅ CH, - 7th H H 1.95 1.95 1.95 85.6 CH, - 8th H CH, - H 1.95 1.95 1.95 91.9 9 H H 3.9 1.95 3.9 100 H H 1.95 0.98 88.0 0 11th

—CH ₂ -

1.95

1.95

1.95 88.0

13 Cl- <> - CH, - H

E [l- (p-chlorobenzyl) -2-methylbenzimidazole]

In summary, the above test results show that the in vitro effect of E. in (a) skin fungi is lower than that of the normal fungus Pyridone; with (b) yeast and (c) mold it is much worse.

The in vivo effect of the commercial product Ii. is (with equimolar application) less than that of all pyridones according to the invention.

The pyridones of the invention are effective to a significant degree also against bacteria and trichomonads (both are important hot haul or mucous membrane infections).

CH, - H

1.95 1.95 1.95 91.2 3.9 62.5 62.5 7.5 -7.8 Toxicology:

The LD ₅ ,, of the pyridones according to the invention is generally over 1 g / kg animal (perorally).

For 4-methyl-6-cyclohexyl-1-hydroxy-2-pyridone it is z. B. at 3 g for mouse, rat and rabbit.

In the case of local applications, no direct relationship (chemotherapeutic index) can be established between LD ₅₁ , 6s and ToxiziUil. But it can be said that at z. B. 20 local treatment of a very large area of the body (skin) of z. B. 2000 qcm can be applied to humans at all

Ready-to-use amount (1% preparations) still do, experience shows, in the range of 20 · 2000 · 0.02 (ιτιΓ · 0.01 (ie 1% in solution) = 4.0g person of 50 kg weight, WV = * _{) g kg. = 0.08 g kg.

ie, the relation LD ₅₀ kg animal orally applied. The amount on humans is 750: 1 for a single application (local) and 37.5: 1 for 20 applications (local). When the same compound is applied locally to animals, 0.1% solutions of the pyridones according to the invention (5 to 10 times use) are already present effective, while this dose can be tolerated for months without any reactions, as experiments on guinea pigs have shown.

Example I.

740 g of hydroxylamine hydrochloride. 750 g sodium formate and 1495 g of the by condensation of Acctylhlorid with,;, i-Dimethylacrylsäuremethylcster obtained mixture of 5-oxo-3-methyl-hxen- (2) -säurc- (l) -methylester and 5-oxo-3-methyl-hexen (3) acid- (1) -methylcsier are mixed with 1500 ml of formic acid heated to 110 to 130 C, with the formed Amcisensäurcmelhylestcr distilled off over a column. Then the formic acid becomes the largest Partial distillation, ice is added to the residue, and the precipitated 1-hydroxy-4,6-dimethyl-2-pyridone is filtered off with suction and washed with cold water. The yield of the compound melting at 135.degree is 571 g. Another 59 g can be made from the mother liquor to win. The structural proof follows from the elemental analysis (calculated: C 60.5. H 6.5. N 10.0 ",,: found: C 60.8. H 6.8. N 10.0%) and the cleavage for literaturbckanmen 4,6-dimethyl-2-pyridone by boiling with Raney-Niekel in ethanol.

Example 2

19.8 g of 5 - () xo-3-methyl-hcxcn- (3) -s; iurc- (l) -isobulyl- : ster with a solution of 9 g of hydroxylamine sulfate and 3 ml conc. Sulfuric acid in 30 ml of water heated to 100 ° C. for 2 hours. After cooling down the pH is adjusted to 4 with sodium carbonate. 5.15 g of 1-hydroxy-4,6-dimethyl-2-pyridone crystallize out. A further 1.7 g of the same product can be obtained by extracting the solution with Meihylcnchlorid be obtained.

Example 3

To dissolve 40 g of hydroxylamine hydroehlorul and 26 g of sodium carbonate in 150 ml of water are 78 c of the ester mixture used in Example 1 and 50 ml of methanol are added and the mixture is stirred at room temperature for 5 hours. Then will extracted with methyl chloride, washed the organic phase with water and distilled. It will 76.5 g of the mixture of isomeric oxime esters with a boiling point of 90 to 110 C'0.1 Torr were obtained.

Calculated ... C 56.2. H 7.7. N 8.2, OCH ₃ 18.1%:

found ... C 56.2. H 7.8. N 9.3. OCH, 17.7%.

17.1 g of the distillate are heated with 15 ml of glacial acetic acid at a bath temperature of 140 ° C. for 1 hour and the methyl acetate formed is distilled off. The residue is poured onto ice. Crystallize in the process 5.3 ρ l-hydroxy-4,6-dimethyl-2-pyridone.

Example 4

15.6 g of the ester mixture used in Example 1, 8 g of hydroxylamine hydrochloride and 9.4 g of sodium acetate are in a mixture of 15 ml Methanol and 15 ml of water were stirred at OC for 24 hours. Then a solution of 6 g of sodium hydroxide in 12 ml of water is made at the same temperature added, stirred for 1 hour, acidified to a pH of 4 and the methanol was distilled off in vacuo. 3.5 g of 1-hydroxy-4,6-dimethyl-2-pyridone crystallize out from the residue.

Example 5

is a) 15.6 g of the Hstcrgcmisches used in Example 1 are shaken with a solution of 8 g of hydroxylamine hydrochloride in 25 ml of water at 25 C, after about 4 hours a homogeneous solution is formed. After 48 hours, sodium carbonate is used a pH of 4 is set and the precipitated 1-hydroxy-4,6-dimethyl-2-pyridone is filtered off with suction. the Yield is 4.6 g.

b) Under the same reaction conditions, the 5-oxo-2,3-dimethyl-hexen (2) acid (1) ethyl ester is obtained the l-hydroxy-3,4,6-trimethyl-2-pyridone with a melting point of 130 C.

Calculated ... C 62.7. H 7.2. N 9.2%;
found .... C 62.7. H 7.1. N 9.3%.

B c i s ρ i e 1 6

a) 11.2 g of that obtained by condensation of Hcxahydrobcnzoylchlorid with ^., i-Dimethylacrylsäurc-Methyller obtained mixture of 5-oxo-3-methyl-5-cyclohexyl-pentene- (2) -c- (l) -methylester and 5-oxo-3-methyl-5-cyclohexyl-pentene (3) acid (1)) methyl ester are with a solution of 4.6 g of sodium acetate and 4 g of hydroxylamine hydrochloride in shaken a mixture of 8 ml of water and 15 ml of methanol at 25 C for 20 hours. Then will a solution of 4 g of sodium hydroxide in 8 ml of water was added with cooling, for a further 1 hour at room temperature shaken, extracted with benzene and the aqueous phase acidified to pH 6. 3.5 g of 1-hydroxyethyl-o-cyclohexyl-2-pyridone are obtained with a melting point of 144 C.

Calculated ... C 69.5. H 8,?. N 6.8%;
found ... C 69.2. H 8.3. N 6.8%.

Under the same conditions, one obtains

b) from the 5-oxo-3-methyl-dodecen (2) acid i [l) methyl ester the 1-hydroxy-4-methyl-6-n-heptyl-2-pyridone with a melting point of 48 C.

Calculated ... C 69.9. H 9.5. N 6.3%;
found .... C 70.0. H 9.5. N 6.2%.

c) from the 5-oxo-3-ethyl-4-methyl-hexen (3) acid ( H-methylester l-hydroxy ^ -ethyl-S ^ -dimethyl-2-pyridone with a melting point of 138 C.

Calculated ... C 64.7, H 7.8. N 8.4%;
found .... C 64.9, H 7.8. N 8.6%,

d) from the 2-acetyl-cyclopentene-1-acetic acid methyl ester the l-hydroxy ^ .S-trimethylene-ö-methyl-2-pyridone of melting point 178 ° C

Calculated ... C 65.4. H 6.7. N 8.5%;
found .... C 65.3. H 6.9. N 8.4%.

c) from the 5 - () xo-3-methyl-6- (4-chlorophenyl) -hcxcn- (2) -acid- (l 1-methyl ester of 1-hydroxy-4-methyl-6- (4-chlorobenzoyl) -2-pyridone with a melting point of 141 C.

Calculated ... C 62.5. 114.9. N 5.6. Cl 14.2 "",:
found .... C 62.3. Il 5.0. N 5.9, Cl 14.4%.

f) from 5 - () xo-3-methyl-6-cyclnhexyl-hexen (2) -acid- (1) -methyl-1-hydroxy-methyl-o-cyclohexylmethyl-2-pyridone, melting point 131 C. Calculated ... C 70.5. H p.7. N 6.3%:
found .... C 70.2, HS, 7th. N 6.5%.

g) and from the 5 - () xo-3-methyl-7-cyclohexyl-hepten- (2) -säurc- (1) -methylcster l-hydroxy-4-methyl-6 - (/; - cyclohexylethyl) -2-pyridone with a melting point of 90 C.

Calculated ... C 71.4. H 9.0. N 6.0%:
found .... C 71.6. H X.7, N 5.8%.

Example 7

8.5 g of 5-oxo-3-methyl-hcpten- (2)-acid- (1) -methylester are shaken with a solution of 3.85 g of hydroxylamine hydrochloride and 4.5 g of sodium acetate in 12 ml of water for 15 hours at room temperature A solution of 4 g of sodium hydroxide in 8 ml of water is then added, after standing at room temperature for half an hour the mixture is cooled to 0 C, the sodium salt of l-hydroxy-2-pyridone which has precipitated is filtered off with suction, dissolved in water and precipitated by acidification pH value of 5 eliminates the free l-hydroxy-4-methyl-6-ethyl-2-pyridone. The yield is 2.9 g, the compound melts at 110 ^° C.

Calculated ... C 62.7. H 7.2. N 9.2%:
found .... C 62.7. H 7.2, N 9.4%.

Example 8

ZueincrlösvOn9.85 g of hydroxylamine hydrochloride and 8 g of tertiary sodium phosphate in 30 ml of water, 20 ml of methanol and 20 g of the mixture of 5-oxo-3,6-dimethyl-hepten obtained by condensation of isobutyl chloride with methyl dimethylacrylate - (2) Acid- (l) -methylstcr and 5-oxo-3,6-dimethyl-hepten- (3) -acid- (l-nicthylstcr added and shaken for 15 hours at room temperature. 14 g of sodium hydroxide are then added , dissolved in 30 ml of water, added, after one hour of shaking at room temperature, acidified to pH 5 and the 1-hydroxy-4-methyl-6-isopropyl-2-pyridone shaken out with methylene chloride, giving 5.6 g of the compound melting at 110 ° C.

Calculated . found ..

C 64.6. H 7.9, N 8.4%; C 64.6, H 8.0, N 8.2%.

Example 9

To a boiling solution of 139 g of hydroxylamine hydrochloride in a mixture of 500 ml of water and 50 ml of conc. Hydrochloric acid, the solution of 260 g of the ester mixture used in Example 1 in 220 ml of methylene chloride is added dropwise within 30 minutes, the methylene chloride being distilled off. It is still heated for an additional hour at 100 ⁰ C, then with sodium hydroxide solution to a pH value of 4, cooled to 0 ⁰ C, the precipitate filtered off with suction and washed with cold water until salt-free. 110 g of 1-hydroxy-4,6-dimethyl-2-pyridone are obtained.

Example 10

s 260 g of the Esiergcmix used in Example 1; are dissolved in 250 ml of chlorobenzene and 115 t powdered hydroxylamine hydrochloride heated to 100 ° C. for 4 hours with stirring. After that, au Cooled to room temperature and the failed hy-

ίο hydrochloride of l-hydroxy-4,6-dimethyl-2-pyridone ir suctioned off with a yield of 101g. By dissolving in water and adjusting a pH value of 4 läßi the free l-hydroxy-4,6-dimethyl-2-pyridone can be obtained therefrom. Example 11

In 39 g of Estergemi used in Example 1 ULTRASONIC 18.3 g acetone oxime dissolved, 5 ml of 1N-salt acid is added and in an oil bath at 150 ^c C heated · when a column to be released methanol and acetone abdcstilliert, for a further 2 hours Heated to 150 C and then distilled in vacuo.

From the fraction passing over at 120 to 150 C / 7 Torr, 13.4 g of 1-hydroxy-4,6-dimethyl-2-pyridone crystallize on cooling from the melting point

135 C off.

Example 12

8 g of hydroxylamine hydrochloride are dissolved in 100 ml of methanol, 10 g of anhydrous sodium acetate

-, o and 22.4 g of a mixture of 5-oxo-3-methyl-5-cyclohexyl-pentene- (2) -acid- (1) -methy! esler and 5-oxo-3 - methyl - 5 - cyclohexylpentene - (3) - acid - (2) - methyl ester added and stirred at 0 C for 20 hours. A solution of 10 g of sodium hydroxide is then added

added in 15 ml of water and stirred at 0 C for a further 10 hours. In the vacuum, the methanol is now largely distilled off, the residue with 100 ml Wassci taken up, extracted with methylene chloride, acidified to a pH of 2, again with methylene chloride

Shaken out chloride, this acidic extract concentrated in vacuo and concentrated with 50 ml. Hydrochloric acid added. It the hydrochloride of 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone crystallizes from, the sucked off, with conc. Washed hydrochloric acid and rubbed with

_4S 100 ml of water is converted into the free l-hydroxy-4-methyl-6-cyclohexyl-2-pyridone.

Example 13

52 g of the mixture of 5-oxo-3-methyl-5 - («- furyl) pentene (2) acid (1) methyl ester and 5, obtained by condensation of pyrogenic acid chloride with (V-dimethylacrylic acid-methylestci) -Oxo-3- methyl-5 - (<i-furyl) -pentene- (3) -ic acid- (1 methyl ester who with 20 g of hydroxylamine hydrochloride, 20 g of Na-

trium formate and 75 ml of formic acid heated to ^{80 r C for 6 hours.} The formic acid is then distilled off in vacuo, the residue is mixed with water and extracted three times with 25 ml of methylene chloride each time. The combined organic phases are with 25 ml

Washed with water and then shaken with a solution of 5 g of sodium carbonate in 30 ml of water and cooled to ^{0 ° C.} 3.2 g of the sodium salt crystallize out, from which the free l-hydroxy-4-methyl-6- (a-furyl) - is obtained by dissolving in water and acidifying

2-pyridone with a melting point of 146 "C can be obtained.

Calculated ... C 62.8. H 4.8. N 7.3%; found .... C 63.0, H 4.7, N 7.4%.

Claims (4)

Patent claims: 1. l-Hydroxy-2-pyridones of the general formula IR ³ (D R ¹ OH in which R ^{1 is} an alkyl radical with 1 to 11 carbon atoms, a cycloalkyl radical with 5 to 6 carbon atoms, which is optionally bonded to the pyridone ring via a methylene or ethylene group, a benzyl radical which is optionally substituted by a halogen atom or a «-furyl radical, R ² and R ^{4 is} either a hydrogen atom or a low molecular weight alkyl radical and R ^{3 is} a low molecular weight alkyl radical, where R ² and R ^{3 can} also jointly represent a trimethylene group. 2. 1-Hydroxy ^ -methyl-o-cyclohexyl ^ -pyridone. 3. 1-Hydroxy-4-methyl-6- (4-chlorobenzyl) -2-pyridone. 4. Process for the preparation of 1-hydroxy-2-pyridones according to claim 1, characterized in that an unsaturated -i-ketoester of the general formula 11 R2 j R4 R ₁ -CO-CH-C = C-COOR ₅ (11) or III R, R, R, R ₁ -CO-C- = C-CH-COOR ₅ (Hl)