DE2418777A1 - SIOMYCINS A HALF-BEST, THEIR SALT, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

¹¹ Half esters of siomycin A, their salts, process for their preparation and medicinal products "

Priority: April 18, 1973, Japan, No. 43 900/1973

The invention relates to half esters of siomycin A, their salts, processes for their preparation and medicaments.

Siomycin is an antibiotic that is produced by growing the microorgan ■ nism Streptomyces sioyaensis is produced. This strain was isolated 1 <? 59 from a soil sample taken from Shioya, Kobe, Japan, and American Type Culture Collection deposited under the number ATCC 13989. Siomycin in particular shows a broad spectrum of antibacterial activity against gram-positive bacteria and mycobacteria; See U.S. Patent 3,082,153. Streptomyces sioyaensis forms two more antibiotics, so that up now siomycin A, B and C have been isolated from cultures of this strain; See J. Antibiotics, 22 '(1969), pages 364 to 368. Siomycin A was characterized by -certain properties-

409844/1005

but its chemical structure has not yet been clarified.

Siomycin A shows disadvantages with regard to its solubility. It is soluble in dioxane, but slightly soluble in methanol, ethanol and chloroform and butanol. Due to its insolubility in water, its use for pharmaceutical preparations is necessary limited. Because of its excellent antibacterial effect - for example, its minimal inhibitory concentration is against gram-positive bacteria 0.1-0.78 y / ml - is an improvement its solubility in various solvents, especially in water, is very desirable.

The object of the invention is therefore to 'derivatives of siomycin A with to create an improved solubility in various solvents, in particular iri.Water, compared to siomycin A. This object is achieved by the invention.

The invention thus relates to half-esters of siomycin A. with aliphatic dicarboxylic acids having 2 to 15 carbon atoms, cycloalkanedicarboxylic acids or monocyclic aryldicarboxylic acids and the ammonium, alkali metal or alkaline earth metal salts of these half esters.

The invention also relates to a process for the preparation of the half-esters of siomycin A and their salts, which is characterized is that in a known manner Siomycin A in an inert solvent with a dicarboxylic acid or its reactive derivative converts and, if necessary, the received-_j

4098A4 / 1005

ne compound ^ by reacting with an inorganic base in a salt transferred.

Specific examples of aliphatic dicarboxylic acids with 2 to 15 carbon atoms are:

Ethane, propane, 2-methylpropane, 2-ethylpropane, 2-butylpropane, Butane, 2-methylbutane, 2,3-dimethylbutane, 2-ethylbutane, 3-propylbutane, cis-2-butene, trans-2-butene, cis-2-methyl ~ 2-butene, 2-ethyl-2-butene, 2-ethyl-3-methyl-2-butene, 2-butyne, Pentane, 2-methylpentane, 3-methylpentane, 2-methyl-3-ethylpentane, 2-ethyl-3-propylpentane, 2-pentene, 2-methyl-2-pentene, 2-methyl-3-pentene, 2-ethyl-2-pentene, 2-butyl-3-pentene, 2-pentyne, hexane, 2-methylhexane, 2-ethylhexane, 2-pentylhexane, 2,4-dimethylhexane, 2-methyl-5-methylhexane, 2-hexene, 3-methyl-2-hexadiene, 2,4-hexadiene, 2-methyl-2,4-hexadiene, 3-ethyl-2,4-hexadiene, 3-hexyne, heptane, 2-methylheptane, 3-methylheptane, 4-propylheptane, 2,3-dimethylheptane, 2-heptene ~, 5-methyl-2-heptene, 2,4-heptadiene, octane, 2-methyloctane, 2,3-dimethyloctane, 2,3,4-trimethyloctane, 2-methyl-3-athyloctane, 2-octene, 2,4-octadiene, 2,4,6-octatriene, nonane, 2-methylnonane, 2,5-dimethylnonane, decane, 3-methyldecane, undecane, 5-methylundecane, dodecane, tridecane, tetradecane and pentadecane dicarboxylic acid, Cycloalkanedicarboxylic acids, such as cyclopropane, Cyclobutane-1,2-, 4-methylcyclobutane-1,2-, cyclopentane-1,2-4-ethylcyclopentane-1,2-, Cyclohexane-1,2-, 3-methylcyclohexane-1,2-, 4-methylcyclohexane-1,3- and cycloheptane-1,2-dicarboxylic acid, .and monocyclic ^ aryldicarboxylic acids, such as 1,2-benzene, 3-methyl-1,2-benzene, 3-ethyl-4-methyl-1,2-benzene, 4-propyl-1,2-benzene, 1,3-benzene, 2-methyl-1,3-benzene, 4,5-dimethyl-1,3-benzene, _j

40984471005

4-methyl-5-ethyl-1,3-benzene, 1,4-benzene, 2-methyl-1 _f 4-benzene and 2-methyl-5-propyl-1,4-benzenedicarboxylic acid.

Although the dicarboxylic acids mentioned are in free form for production the half-ester of siomycin A can be used, their reactive derivatives are preferably used, such as the acid anhydrides, acid halides, amides, esters, ketones, azides, in particular acid anhydrides, and other corresponding compounds, These reactive derivatives of dicarboxylic acids can be prepared in a manner known per se from the corresponding dicarboxylic acids. The compounds of the invention are obtained by reacting at least 1 mole of the dicarboxylic acid per mole of siomycin A.

The reaction can be carried out in a period of about 30 minutes to 10 hours in a temperature range from 0 to 150 ^° C. and, if appropriate, in the presence of a catalyst customary for ester formation. If, for example, the dicarboxylic acid is used in free form, the reaction is preferably carried out in the presence of an acidic catalyst such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid or boron trifluoride. If acid anhydrides and acid halides are used instead of the free dicarboxylic acids, the reaction is preferably carried out in the presence of a basic catalyst in the form of an inorganic or organic base. Examples of inorganic bases are ammonium hydroxide, alkali metal hydroxides such as lithium, potassium and sodium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide. Examples of organic bases are lower alkylamines and hetero- _j

40984W1005

cyclic amines such as ethylamine, butylamine, pyridine and picoline.

Examples of inert solvents which can be used according to the invention are chloroform, trichloroethane, dioxane, dimethylformamide, dimethyl sulfoxide, Pyridine or a mixture of these solvents in which the starting materials are soluble.

The siomycin A used according to the method can be obtained by cultivating a strain of Streptomyces sioyaensis in a period of 72 to 120 hours at temperatures of about 25 to 32 ° C under aerobic conditions in an aqueous nutrient medium and then Isolation of the antibiotic formed from the fermentation broth according to US Pat. No. 3,082,153 and J. Antibiotics, Vol. 22 (1969), pp 364 to 368 can be obtained. It can also contain a crude product containing siomycin A as a starting material for the inventive. proper procedures serve.

The half esters of siomycin A with dicarboxylic acids are made of carbon, Oxygen, hydrogen, nitrogen and sulfur atoms are built up and have a structure in which one or more esterified by about 5 hydroxyl groups of siomycin A with one of two carboxyl groups of a dicarboxylic acid is. Accordingly, these esters are hereinafter referred to as

Di-

esters I, II and III of siomycin A designated with a / carboxylic acid. ".

It can be assumed that the half-esters I, II and III of Siomycin A in the number and position of the ^ Siomycin-A group-bound ester groups distinguish, where J

409844/1005

the number of ester groups in half-ester I is higher than in half-esters II and III.

The proportions in which the half esters I, II and III of siomycin A are formed depends on the reaction conditions away. If the reaction is carried out at an elevated temperature for a longer period of time and using a more than 1 molar Amount of the dicarboxylic acid carried out, the half-esters I can be used as Main product can be obtained. The initial conditions are preferably in accordance with the reactant present Acid derivative chosen in order to obtain the desired half ester as the main product, since the proportions obtained the half-esters I, II and III depend on the type of acid derivatives used, even with the same reaction conditions.

The half-esters of siomycin A can be isolated and purified in good yields by customary methods. The so obtained Half esters can easily be converted into the corresponding * in a manner known per se by reacting with the theoretical amount of a base. Salts, such as lithium, sodium, potassium, calcium or ammonium salts, are transferred.

The half esters of Siomycin A and their salts are very stable * powdery compounds. They are valuable medicinal substances, there they have better solubility and an increased antibacterial effect in the body than siomycin A itself. You keep their antibacterial effect over a long period of time, while their toxicity is very low.

409844/1005

The half esters of Siomycin A and their salts with inorganic bases are available in various for pharmaceutical processing Easily soluble in solvents. They are very easily soluble in dilute alkaline solutions, as the half-esters at least contain a free carboxyl group. Their sodium salts are also very light in water and dilute alkaline solutions soluble, while siomycin A is used in lorn / OS ^ agents is almost insoluble.

Table I shows the solubilities of several according to the invention Compounds prepared compared to the solubility of ■ siomycin A in various solvents. It will the solubilities of siomycin Λ and its half-esters in 0.1 percent aqueous sodium hydrogen carboruit solution are given. For the sodium salts of the half ester of Siomycin A, distilled water was used as the solvent.

409844/1005

Table I.

link

Solubility in percent

Siomycin A

HaTbester I of siosycin A with butanedicarboxylic acid

Sodium salt of the half ester -I of siomycin A with butanedicarboxylic acid

Half ester II of siomyein A with butanedicarboxylic acid

Sodium salt of half-year II of the " Siomycins A with butane licarboxylic acid

Half ester I of the Sionr ^ cins A with Pentanedicarboxylic acid

Sodium salt of the half ester I of siomycin A with pentanedicarboxylic acid

Half ester II of Sioi- ^ cins A with Pentanedicarboxylic acid

Sodium salt of the half ester II of siomycin A with pentanediearboxylic acid

Half ester I of siomycin A with hexanedicarboxylic acid

Sodium salt of the half ester I des Siomycins A with hexanedicarboxylic acid

Half ester II of siomycin A with hexanedicarboxylic acid

Sodium salt of half ester II of siomycin A with hexanedicarboxylic acid

Half ester III of siomycin A with hexanedicarboxylic acid

Sodium salt of the semi-ester III of siomycin A with hexanedicarboxylic acid

Half ester I of siomycin A with heptanedicarboxylic acid

Sodium salt of half ester I of siomycin A with heptanedicarboxylic acid 0.00015 2.0

20.0 1.0 3.0

2.5 10.0 1.0 3.0 1.0 5.0 0.5 3.0 0.5 3.0

1.0 5.0

409844/1005

Half ester II of siomycin A with _Q ^

Heptanedicartonic acid *

Sodium salt of the half ester II des, ₀

Siomycins A with heptanedicarboxylic acid *

Half ester III of siomycin A with _Q ^

Heptanedicarboxylic acid '

• Sodium salt of the half ester III des * q

Siomycins A with heptanedicarboxylic acid '

Half ester I of siomycin A with ^ q

cis-butenedicarboxylic acid *

Sodium salt of the half ester I of the 4 0

Siomycins A with cis-butenedicarboxylic acid '

Half ester II of siomycin A with ^ ₀

cis-butenedicarboxylic acid '

Sodium salt of the half ester II des. _Q

Siomycins A with cis-butenedicarboxylic acid '

Half ester I of Siomycin A with ₀ , -

cis-2-methylbutenedicarboxylic acid '

Sodium salt of the half ester I des

Siomycins A with cis-2-methylbutenedicarbon-4.0

acid

Half ester II of siomycin A with cis- ₀ , -2-methylbutenedicarboxylic acid *

Sodium salt of the half ester II des

Siomycins A with cis -2-methylbutene-dicarbon-2.5

acid

Half ester III of siomycin A with ^ ₀

cis-2-methylbutenedicarboxylic acid '

Sodium salt of the half ester III des

Siomycins A with cis-2-methylbutene dicarbon-5.0

Half ester I of siomycin A with _o , -

Cyclohexane-1,2-dicarboxylic acid '*

Sodium salt of the half ester of I Siomycins A. _n with cyclohexane-1,2-dicarboxylic acid »

Half ester II of Siomycin A "with. _O , .. Cyclohexane-1,2-dicarboxylic acid» ^

Sodium salt of the half ester II of Siomycin A "with cyclohexane-1,2-dicarboxylic acid ^z *

409844/1005

From Table I that the Halbester of Siomycins A and its sodium salts ₉ Iprozentiger aqueous sodium bicarbonate as are much better soluble in both O in distilled water, is seen as Siomycin A.

The half-esters of siomycin A and their salts have an antibacterial effect on a wide variety of microorganisms on. Table II below shows the antibacterial activity of the half-esters of siomycin A and its sodium salts Comparison to that of Siomycin A indicated.

409844/1005

Table II

Microorganism
link Minimum inhibitory concentration, v / ml B. C D 0.39 • 0.1 Siomycin A A. 0.78 0.39 6.25 Ξ; P, 1.56 Half ester II of Siomycina A with
Butanedicarboxylic acid 0.39 , 12.5 6.25 6.25 0.1 3.13 Sodium salt of the half ester II des
Siomycins A with butanedicarboxylic acid 6.25 25th 6.25 1.56 1.56 0.39 Sodium salt of the half ester II des
Siomycins A with pentanedicarboxylic acid 6.25 6.25 1.56. 0.78 1.56 0.20 Sodium salt of the half ester II des
Siomycins A with hexanedicarboxylic acid 1.56 1.56 3.13 0.39 0.78 Sodium salt of half-ester II des
Siomycins A with heptanedicarboxylic acid '0.78 6.25 3.13 0.78 0.10 Sodium salt of the half ester III des
Siomycins A with heptanedicarboxylic acid 3.13 1.56 1.56 1.56 0.2 0.2 Sodium salt of the half ester II des
Siomycins A with octanedicarboxylic acid 0.78 1.56 3.13 0.78 ' 0.1 0.05 Sodium salt of the half ester III des
Siomycins A with octanedicarboxylic acid 1.56 0.78 1.56 • 0.1 0.39 <0.025

of
with Tabel,, Microorganisms JI - FOJ B. > 50 Inhibition concentration, C > 50 D. - 12 - E. 25th F. of
with 12, 3.13 // ml 12.5 1 of
with Halbesters I des
Dodecanedicarboxylic acid "setting 12, 3.13 3.13 0.73 O , SS link of
with Kalbesters II des
cis-butenedicarboxylic acid, Minimal • 6, 5 3.13 3.13 0.39 O , 78 Sodium salt
Siomycins A of
with Halbesters, II des
cis-methylbutenedicarboxylic acid A. 12 » 5 12.5 1.56 0.39; 1 , 78 Sodium salt
Siomycins A Kalbesters III des
cis-methylbutenedicarboxylic acid > 50 25th 6.25, 0.78:
I. Sodium salt
Siomycins A Halbesters Il des
Cyelohexane-1,2-dicarboxylic acid 6.25 5 Sodium salt
Siomycins A 1.56 Sodium salt
Siomycins A 1.56 6.25

A B C D E F

Bacillus subtilis PCI Bacillus anthracis Staphylococcus aureus FDA 209 PJC-1 Staphylococcus aureus 80257 Diplococcus pneumoniae type I Streptococcus pyogenes C-203

From Table II it can be seen that the compounds of the invention and their sodium salts are very effective against gram-positive bacteria.

In Table III the therapeutic effect of the sodium salts of the half esters of siomycin A compared to siomycin A is shown infected mice summarized:

Table III

link ED ₅₀ , rag / kg B. Siomycin A " A. 75.2 Sodium salt of the half ester II des
Siomycins A with butanedicarboxylic acid 23.2 Sodium salt of the half ester II of the "
Siomycins A with pentanedicarboxylic acid 16.5 3.5 Sodium salt of the half ester II des
Siomycins A with hexanedicarboxylic acid 4.4 2.1 Sodium salt of the half ester III des
Siomycins A with heptanedicarboxylic acid 2.5 3.1 2.5

A: Diplococcus pneumoniae type I B: Streptococcus pyogenes C-203

Groups of 10 mice each weighing 19 to 21 g are standardized by intraperitoneal injection with a Diplocoocus pneumoniae or Streptococcus pyogenes C-203 inoculum infected. Immediately or after 4 and 8 hours after infection, the test animals are administered the sodium salts of the half-esters of siomycin A subcutaneously and they are administered Survival observed up to 7 days after infection.

409844/1005

From Table III it can be seen that the sodium salts of the half esters of siomycin A are therapeutically much more effective are called Siomycin A..

The acute toxicity of the compounds of the invention has been increased Mice weighing 19 to 21 g were examined. In Table IV, the LD ^ Q value for groups of 5 mice each is at indicated intraperitoneal application.

Table IV ';

link LD ₁ -Q for mice,
! mg / kg ] 250-500 Half ester II of siomycin A with [-? 50-500
Pentanedicarboxylic acid. j 250-500 Half ester II of siomycin A with
Hexanedicarboxylic acid Half ester III of siomyein A with
Heptanedicarboxylic acid

From Table IV it can be seen that the compounds of the invention have low toxicity.

The connections of the. Invention can as usual in the form of Injection preparations, liquids, suspensions, emulsions, ointments or tablets in combination with appropriate carriers, Stabilizers, emulsifiers, preservatives and / or wetting agents orally, subcutaneously or intravenously in doses of 0.1 to 100 mg / kg body weight can be administered to humans and pets.

409844/1005

The examples illustrate the invention.

Example ϊ

10, Og Siomycin Ä Tssmäea dissolved in 60 ml pyridine and mixed with 6.0 g butanedicarboissaixreaxili3fdrld. The mixture is heated in an oil bath for 1 hour to a temperature of 93 Ms 95 ° C. while stirring, then O ml of distilled water and 100 ml of C3alorofona are added and the mixture is shaken vigorously. The ChloroformscbJLcht -uira. separated and evaporated under reduced pressure. The residue is taken up in benzene and separated from the insoluble matter, which is dissolved in a mixture of chloroform and methanol (8% 2%). After combining the solutions, the mixture obtained is chromatographed on a column loaded with silica gel (particle size 0.05 to 0.2 mm, manufacturer Merck), which elutes with a mixture of chloroform and methanol, the concentration of methanol in The fractions containing the half-ester of SioBiycin A with butanedicarboxylic acid are combined and concentrated. The concentrated solution is poured onto a silica gel plate GF (manufacturer Finaa Merck) and mixed with a mixture of chloroform and methanol

(8: 2) chromatographed as eluent. The den Half ester I of siomycin A with butanedicarboxylic acid containing Part of the silica gel is extracted with a mixture of chloroform and methanol and the extract obtained is concentrated. the concentrated solution is mixed with ethyl acetate in order to precipitate the half-ester. Yield 60 percent:

409844/1005

The half ester II of siomycin A with butanedicarboxylic acid is isolated in a corresponding manner from the fractions of the chromatogram containing this ester. Yield 15 percent.

Half ester I of siomycin A with butanedicarboxylic acid: yellowish powder. F. 265 Ms 280 ⁰ C (dec.).

The compound shows no defined decomposition point. Around 200 ° C it turns yellow and, with increasing decomposition, brown. R „- ¥ ert in the thin layer chromatogram on Kieselgal GF (manufacturer Merck): R- = 0, mobile phase chloroform / methanol (8: 2). Neutralization equivalent 500.

Solubility: readily soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution; almost insoluble in diethyl ether, chloroform and water. Specific optical rotation: Γ &] ψ - 63.2 + 2.0 ° (c = 0.525, in methanol).

IR absorption spectrum in paraffin oil (NuJoI) ₇ maxima at the following wave numbers (cm ~ ¹ ): 3345, 1735, 1663 (broad); see figure

UV absorption spectrum in methanol:

Maximum: Λ _max ( ^nm ) ^{= 2} 55; locjf = 4.75 (shoulder); see figure

Elemental analysis (%);

anhydrous compound: C, 50.42; H 5.10; N 14.57; S 7.93, hydrate of compound: C 45.77; H 5.45; N 12.21; S 7.62;

H ₂ O 10.68. ^

409844/1005

Half ester II of siomycin A with butanedicarboxylic acid; Colorless or pale yellow powder.

Melting point: the compound does not show a defined decomposition point. At 200 ^° C. it changes color to yellow, then increasingly brown, then dark brown. ■

R "value in the thin-layer chromatogram on silica gel GF (manufacturer Merck): R ~ = 0.3; Mobile phase chloroform / methanol (8: 2 percent by volume).

Neutralization equivalent: 780.

Solubility: readily soluble in a mixture of chloroform and • methanol and in an aqueous solution of sodium hydrogen carbonate. Almost insoluble in diethyl ether, chloroform and water. .

Specific optical rotation: / q / jj - 144.0 ± 3.7 ° (c = 0.507, in

Methanol).

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3360, 1732, 1660 (wide); see FIG. 3.

UV absorption spectrum in methanol:
Maxima: ^, _rnax (nm) lo

245 '4.76 (shoulder)

290 4.40 (shoulder)

310 4.13 (shoulder) see Figure 2. ·

409 8 44/1006

Elemental analysis (%):

anhydrous compound: C -48.52; H 5.04; Έ 14.76; S 8.02; Hydrate of the compound: C, 45.69; H 5.35; M 13.32; S 7.89;

H ₂ O 8.80.

Example 2

0.8 g of the half ester II obtained according to Example 1 des Siomycins A with butanedicarboxylic acid are in 70.8 g of a 0, Iprozeritigen aqueous sodium hydrogen cartoonate solution dissolved. The solution is filtered to remove minor impurities; after freeze-drying, the powdery one is obtained Sodium salt of the starting compound. 95 percent yield.

Example 3 According to Example 1, but using pentanedicarboxylic acid

anhydride, the half-esters I and II of -Siomycin A are with

Half-

■ al Ii 'ι

Pentanedicarboxylic acid produced. Yield of the ester I 50 percent, of the half-ester II 20 percent.

Half ester I of siomycin A with pentanedicarboxylic acid yellowish powder. Melting point: The compound does not show a defined melting or decomposition point. It changes color by 200 ° from yellow to brown.

in the thin layer chromatogram according to Example 1: R _f = 0

Solubility: readily soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Nearly

insoluble in diethyl ether, chloroform and water. ,

409844/1005

Specific optical rotation: / ö / ^ ² ' ⁵ -68.7 + 2.2 ° (c = 0.504,

in methanol).

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3340, 1725, 1658 (broad); see FIG. 4.

UV absorption spectrum in methanol: maxima: λ _{Μ & χ} (™ 0

245 4.78 (shoulder)

285 4.49 (shoulder)

see figure 5.

Elemental analysis
anhydrous compound: C 49.61; H 5.14; N 14.37; S 8.53; Hydrate of the compound: C, 46.35; H 5.70; N 11.51; S 7.75;

H ₂ O 10.45.

Half ester II of siomycin A with pentanedicarboxylic acid: pale yellow powder. Melting point: The compound does not show a defined melting or decomposition point. At 200 ^° C. it changes color to yellow, then brown.

R ^ value in the thin-layer chromatogram according to Example 1: R "= 0 * 49".

Solubility: readily soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform and water. Specific optical rotation: / α / ²² » ⁵ - 84.0 £ 4.1 ° (c = 0.306, in methanol). _,

409844 / 1G05

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cnf ¹ ): 3340, 1730, 1655 (broad); see figure 6.

UV absorption spectrum in methanol: maxima: At " _qv ( ^nm ) l o g

245 4.71 (shoulder)

285 4.51 (shoulder)

310 4.20 (shoulder)

see figure 5.

Elemental analysis (%) i

anhydrous compound: C 51.59; H 5.18; N 15.03; S 9.30; Hydrate of the compound: C, 49.06; H 5.04; N 12.85; S 8.48; 2 ° 7, i3.

Example 4 5 g of siomycin A are dissolved in 30 ml of pyridine and mixed with 3.0 g of hexanedicarboxylic anhydride offset. The mixture is 1 hour in

and stirred / oil bath heated to 93 to 95 ° C. / then 100 ml of distilled water are added. The resulting mixture is extracted first with 80 ml, then with 20 ml of chloroform. The chloroform extracts are combined and evaporated under reduced pressure receives 10.3 g of a residue which is dissolved in 100 ml of chloroform. After adding 150 ml of distilled water to the chloroform solution, the resulting mixture is shaken and filtered. The residue is dissolved in a mixture of chloroform and methanol (8: 2) and the solution obtained

under reduced pressure to 1.50 g of the half ester I des

Siomycins A with hexanedicarboxylic acid in the form of a pale yellow _j

409844/1005

Evaporated powder.

The chloroform layer of the filtrate is reduced under reduced pressure Evaporated pressure. 6.1 g of a residue are obtained which, in a mixture of chloroform and methanol (8: 2) is resolved. The solution obtained is chromatographed on a plate with silica gel GF and, after work-up, results in accordance with Example 1 the half-ester I of siomycin A with hexanedicarboxylic acid. Yield 54.6 percent.

The fractions of the thin-layer chromatogram in which the half-esters II and III of the siomycin A containing hexanedicarboxylic acid are combined and placed on a plate with silica gel GF chromatographed. After further work-up according to Example 1, ester II is obtained with 20 percent, ester III with 10 percent yield.

Half ester I of siomycin A with hexanedicarboxylic acid: pale yellowish powder. Melting point: The compound does not show a defined melting or decomposition point. At 200 ^° C. it changes color to yellow, then brown.

Rp value in the thin layer chromatogram according to Example 1: FL> = 0.10.

Solubility: Well soluble in a mixture of chloroform and. Methanol and in aqueous sodium hydrogen carbonate solution. B'ast insoluble in diethyl ether, chloroform, methanol and water. Specific optical rotation: / o / Jp - 61.5 £ 3.3 ° (c = 0.3i4, in a mixture of equal parts of chloroform and methanol). _

409844/1005

IR absorption spectrum in paraffin oil (Nujol), maxima at, the following wave numbers (cm ~ ¹ ): 3350, 1726, 1660 (broad); see Figure 7..

UV absorption spectrum in methanol:

Maxima 'λ Max (nm) 1 79 t 245 4, 44 (Shoulder) 290 4, (Shoulder) "please refer Figure 8

Elemental analysis (%):

anhydrous compound: C, 51.42; H 5.36 / N 13.32; S 8.26; Hydrate of the compound: C, 49.25; H 5.39; N 12.29; S 7.81;

H ₂ O 5.44.

Half ester II of siomycin A with hexanedicarboxylic acid: Colorless crystalline powder. Melting point: The compound does not show a defined melting or decomposition point. Around 200 C it turns yellow, then brown. R ~ value in the thin-layer chromatogram according to example 1: R ^ = 0.56.

Solubility: readily soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Nearly insoluble in diethyl ether, chloroform, methanol and water. Specific optical rotation: / a / jp '- 118.4 + _ 5.3 ° (c = 0.304, in a mixture of equal parts of chloroform and methanol).

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm "" ¹ ): 3340, 1731, 1653 (broad); see figure 9.

_J 409844/1005

UV absorption spectrum in methanol: maxima: λ-max ^ ¹¹¹¹¹ ^ 1ος | £

245 4.83 (shoulder)

285 4.52 (shoulder)

310 4.20 (shoulder)

see figure 8.

Elemental analysis
anhydrous compound: C, 51.18; H 5.24; N 14.73; S 8.86; Hydrate of compound; C 48.74; H 5.56; N 13.57; S 8.65;

H ₂ O 3.83.

Half ester III of siomycin A with hexanedicarboxylic acid; 'Pale yellow powder. Melting point: the compound has no defined melting point or decomposition point. At 200 ⁰ C it turns yellow, then brown, ■

R ~ value in the thin layer chromatogram according to Example 1: R _f = 0.48.

Solubility: readily soluble in a mixture of chloroform and methanol and in% aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water. · · Specific optical rotation: / q / jp ' ⁵ -140.2 + _ 6.0 ° (c = 0.301, in a mixture of equal parts by volume of chloroform and methanol.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cnf ¹ ): 3360, 1728, 1653 (broad); see Figure 10. '

409844/1005

UV absorption spectrum in methanol: maxima: ^ _max (nm) locj

245 4.83 (shoulder)

285 4.53 (shoulder)

310 4.25 (shoulder)

see figure 8.

Elemental analysis (%):

• anhydrous compound: C 51.89; H 5.77; N 14.56; S 8.97; Hydrate of the compound: C, 49.37; H 5.53; N 13.78; S 8.46;

H ₂ O 5.44.

Example 5

38 mg of the half ester II obtained according to Example 4 are dissolved in 3.36 g of 0.1 percent aqueous sodium hydrogen carbonate solution with stirring dissolved at room temperature. The mixture is left to stand for 3 hours and then to remove insolubles Impurities filtered. The resulting filtrate, pH 6.2, is freeze-dried and gives the sodium salt of the starting compound as a colorless powder. 98 percent yield.

Sodium salt of half ester II of siomycin A with ilexanedicarboxylic acid:

White dust. Melting point: around 200 ^° C. the compound turns yellow, then brown.

R ^ value in the thin layer chromatogram according to Example 1: R _f = 0.56.

_J 409844/1005

Solubility: Soluble in a mixture of chloroform and methanol as well as in methanol and water. Almost insoluble in diethyl ether and chloroform. Specific optical rotation: ⁵ - 70.2 + 8.2 ° (c = 0.134, in water).

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3380, 1728, 1655 (see FIG. 11).

UV absorption spectrum in methanol: Maxima: A _max (mn)

245 '4.80 (shoulder) 285 * ■' '4.49 (shoulder) 310 4.15 (shoulder)

see Figure 12.

Elemental analysis' (%):

Hydrate of the compound: C 47.34, H 5.44; N, 12.96; S 7.99;

Na 2.48; H ₂ O 7.77.

Example

0.6 g Heptandicarbonsäureanhydrid are added to a solution of 10.0 g Siomycin A in 6 ml of pyridine, and the resulting mixture is heated for 1 hour at 100 ⁰ C in an oil bath. After adding 10 ml of distilled water and 20 ml of chloroform, the mixture is shaken. The chloroform layer is separated and evaporated under reduced pressure. 1.6 g of a residue are obtained, which is dissolved in 50 ml of chloroform. After adding distilled water, the mixture is shaken, the chloroform layer separated, washed with water and evaporated under reduced pressure. A solution of the obtained J

409844/1005

The residue becomes a column and a thin layer chromatogram subject. After further work-up according to Example 1, the half-esters I are obtained (yield 60 percent), II (yield 20 percent) and III (yield 15 percent) of siomycin A with heptanedicarboxylic acid.

Half ester I of siomycin A with heptanedicarboxylic acid *. Pale yellow powder. Melting point: The compound does not show a defined melting or decomposition point. At 200 ^° C. it changes color to yellow, then brown. -

R ~ -value in the thin layer or more oma t ο grams according to example 1: R _f = 0.10.

Solubility: Soluble in a mixture of chloroform and methanol as well as in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water. Specific optical rotation: / a / jp ' ⁵ -73.2 + _ 3.5 ° (c = 0.325, in a mixture of equal parts by volume of chloroform and methanol). .,

IR absorption spectrum in paraffin oil (Nujol), maxima for the following the wave numbers (cm "): 33 ^ 0, 1728, 1657 (wide); see Figure 13.

UV absorption spectrum in methanol: maxima: R _max (nm) log £

250 4.76 (shoulder)

290 4.45 (shoulder)

see Figure 14. j

409844/1005

Elemental analysis (%) i

water-free compound: C, 52.41; H 5.62; N 13.41; S 8.26; Hydrate of the compound: C, 50.21; H 5.60; N 12.54; S 7.91;

H ₂ O 3.56.

Half ester II of siomycin A with heptanedicarboxylic acid Z pale yellow powder. Melting point: The compound does not show a defined melting or decomposition point. At 200 ^° C. it changes color to yellow, then brown.

R _f value in the thin-layer chromatogram according to Example 1: FU - 0.47.

Solubility: Soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water. Specific optical rotation: / ö / jp ' ⁵ - 128.6 + _ 5.5 ° (c = 0.308, in a device made of equal parts by volume of chloroform and methanol).

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3363, 1730, 1656 (broad); see FIG. 15.

UV absorption spectrum in methanol:
Maxima: ^ _max (nm) log β

245 4.78 (shoulder)

290 4.43 (shoulder)

310 4.14 (shoulder)

see Figure 14.

L _l

409844/1005

Elemental analysis
anhydrous compound: C, 53.21; H 5.72; N 14.07; S 8.73; Hydrate of the compound: G 50.68; H.5.63; N 13.48; S 8.36;

H ₂ O 4.94.

Half ester III of siomycin A with heptanedicarboxylic acid: Almost colorless crystalline powder, melting point :. The connection does not show a defined melting or decomposition point. At 200 ° C it turns yellow, then brown.

R ^ value in the thin layer chromatogram according to Example 1: R _f = 0.56.

Solubility; Easily soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water, specific optical rotation / ά / jp ' ⁵ - 119.3 + 5.0 ° (c = 0.322, in a mixture of equal parts by volume of chloroform and methanol.

IR absorption spectrum in paraffin oil (Nu ^ ol), maxima at the following wave numbers (cm "" ¹ ): 3330 to 3380, 1731, 1663 (broad); see Figure 16..

UV absorption spectrum in methanol: Maxima :? Tmax ^(nm)

250 4.78 (shoulder)

290 4.47 (shoulder)

310 4.19 (shoulder)

see Figure 14.

409844/1005

Elemental analysis (%) '.

anhydrous compound: C 52.00; H 5.34; N 14.33; S 8.73; Hydrate of the compound: C, 48.74; H 5.49; N 13.36; S 8.38; '

H ₂ O 6.40.

Example -7

1.80 ml octanedicarboxylic acid anhydride are added to a solution of 300 mg Siomycin A in 1.8 ml of pyridine, and the resulting mixture is stirred for 1 hour at 100 ⁰ C in an oil bath. After adding 5 ml of distilled water and 10 ml of chloroform, the mixture is shaken. The chloroform layer is separated and evaporated under reduced pressure. 483 mg of a residue are obtained which, according to Example 1, is subjected to a column chromatogram and a thin-layer chromatogram. The half-esters I (yield 30 percent), II (yield 20 percent) and III (yield 15 percent) of siomycin A with octanedicarboxylic acid are obtained.

Half ester I of siomycin A with octanedicarboxylic acid:

Powder. R ^ value in the thin layer chromatogram according to Example 1:

R _f = 0.10 to 0.30.

Solubility: Soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Insoluble in diethyl ether, chloroform, methanol and water.

IR absorption spectrum in ParaffincSl (Nujol), maxima at the following Wavenumbers (cm "): 1730, 1670.

J 409844/1005

Half ester II of siomycin A with octanedicarboxylic acid:

Powder. R ~ value in the thin-layer chromatogram according to Example 1:

Rf = 0.53.

Solubility: Soluble in a mixture of chloroform and methanol and in an aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 1730, 1660 .. ...

Half ester III of siomycin A with octanedicarboxylic acid: powder. R ~ value in the thin layer chromatogram according to Example 1: R _f = 0.49.

Solubility: Soluble in a mixture of chloroform and methanol and in an aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 1730, 1660 to 1670.

Example. 8th

0.18 g Dodecandicarbonsäureanhydrid are added to a solution of Ο "3 g Siomycin A in 1.8 ml of pyridine ^ and the resulting mixture is stirred for 1 hour at 97 ⁰ C in an oil bath. A small amount of cold distilled water and 10 ml of chloroform are added and the mixture is shaken. The obtained chloroform layer

409844/1005

■ is evaporated under reduced pressure. 0.34 g is obtained an oily residue, from which one after a column and

according to example 1 L,

a thin layer chromatogram / tLie half esters / (yield 20 percent) and II (yield 30 percent) of siomycin A with dodecane

dicarboxylic acid.

Half ester I of siomycin A with dodecanedicarboxylic acid:

-Powder. Melting point: The compound turns at about 200 ⁰ C

brown and decomposes over 250 ⁰ C..

R_p value in the thin layer chromatogram according to Example 1: Rj. = 0 to 0.35.

Solubility: Well soluble in a mixture of chloroform and Methanol and -in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform, methanol and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following number of lines (cm "" ¹ ): 1730, 1660 to 1670.

Half ester II of siomycin A with dodecanedicarboxylic acid powder. Melting point: The compound discolor at about 200 ° C • brown and decomposes over 250 ⁰ C.

R _f value in the thin layer chromatogram according to Example 1: R _f = 0.58.

Solubility: Soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. ,

/ 100H

Almost insoluble. In diethyl ether, chloroform, methanol and water.

IR absorption spectrum in paraffin oil (HuJoI), maxima at the following ¥ ell numbers (cm ~ ¹ ): 1735, 1660 to 1670,

Example 0.7 g of CIS-Butendlcarbonsäiiireanhydrld are to a solution of 10.0 g of siomycin A are added to 6 ml of pyrldine and the resulting product

Mix is according to Example 1 in the half esters / (yield 40 percent) and II (yield 10 percent) of the siomycin A with cis-butenediocarboxylic acid convicted.

Half ester I of siomycin A with cis-butenedicarboxylic acid: powder. R ^ value in the thin-layer chromatogram according to Example 1: R _f = 0.

Solubility: Easily soluble in a mixture of chloroform and Methanol and in aqueous sodium hydrogen carbonate solution. Nearly Insoluble in diethyl ether, chloroform and water.

IR absorption spectrum in paraffin oil (liujol), maxima at the following ¥ ell numbers (cm ~ ¹ ): 3400, 1725, 1645.

Half ester II of siomycin A with cis-butenedicarboxylic acid: powder. R ^ -liert im thin-layer chromatography "according to Example 1: R _f = 0.24.

409844 / 100S

Solubility: Soluble in a mixture of chloroform and methanol and in aqueous sodium hydrogen carbonate solution. Nearly insoluble in diethyl ether, chloroform and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3400, 1730, 1640 to 1665.

Example 10

0.78 g of cis-2-methylbutenedicarboxylic anhydride become one Solution of 10.0 g of siomycin A in 6 ml of pyridine and the resulting mixture according to Example 1 in the half-ester I (yield 40 percent) and II (yield 15 percent) of the siomycin A with cis-2-methylbutenedicarboxylic acid.

Half ester I of siomycin A with cis-2-methylbutenedicarboxylic acid: powder. R ^ .- value in the thin layer chromatogram according to Example 1: Rj> ⁼ 0.

Solubility: readily soluble in a mixture of chloroform and methanol, as well as in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at following no. the wave numbers (cm " ¹ ): 1730, i'660. to 1670.

Half ester II of siomycin A with cis-2-methylbutenedicarboxylic acid: powder. Melting point: The compound discolor at about 200 ⁰ C brown and decomposes over 2.60 ⁰ C.

409844/1005

Rp value in the thin layer chromatogram according to Example 1: R _f = 0.37.

Solubility: Soluble in a mixture of chloroform and methanol as well as in aqueous sodium hydrogen carbonate solution. Almost insoluble in diethyl ether, chloroform and water. IR absorption spectrum in paraffin oil (Nujal), maxima at the following wave numbers (cm ~ ¹ ): 1730, 1650 to 1670.

Example 11. *

180 mg of cyclohexane-1,2-dicarboxylic acid anhydride become a solution of 300 mg of siomycin A in 1.8 ml of pyridine and the resulting mixture according to Example 1 in the half-ester I (yield 40 percent) and II (yield 40 percent) of the siomycin A with cyclohexane-1,2-dicarboxylic acid.

Half ester I of siomycin A with cyclohexane-1,2-dicarboxylic acid: powder. R ^ value in the thin layer chromatogram according to Example 1: R _f = 0.20 to 0.44.

Solubility: Soluble in a mixture of chloroform and methanol as well as in aqueous sodium hydrogen carbonate solution. Nearly insoluble in diethyl ether, chloroform and water.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 3400, 1735, 1650 to 1670.

Half ester II of siomycin A with cyclohexane-1,2-dicarboxylic acid: Powder. R ^ value in the thin-layer chromatogram according to Example 1:

409844/1005

R, = 0.52.

Solubility: Soluble in a mixture of chloroform and methanol as well as in aqueous matrix hydrogen carbonate solution. Nearly insoluble in diet ether, chloroform and water.

IR absorption spectrum in paraffin oil (Nu ^ oI), maxima at the following wave numbers (cm ~ ¹ ): 3360 to 3400, 1730, 1650 to 1670.

Example 12

0.3 g of 1,2-benzenedicarboxylic anhydride become a solution of 0.5 g of Siomycin A in 3 ml of pyridine and the obtained "Geraisch is converted into Haibester I according to Example 1 (yield 45 percent), II (yield 15 percent) and III (yield 15 percent) of the siomycin A with 1,2-benzene dicarboxylic acid.

Half ester I of siomycin A with 1,2-benzenedicarboxylic acid: powder. R ^ value in thin-layer chromatography according to Example 1: R _f = 0 to 0.1.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 1730 (shoulder), 1720 (shoulder), 1670.

ilalbester II of siomycin A with 1,2-benzene dicarboxylic acid powder. R _f - ¥ ert in the thin layer chromatogram according to Example 1: R _f = 0.21.

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (approx " ¹ ): 1730, 1720, 1670.

Half ester III of siomycin A with 1,2-benzene dicarboxylic acid:
Powder. R ~ value in the thin-layer chromatogram according to Example 1:

^R f ⁼ ° » ^Zt0

IR absorption spectrum in paraffin oil (Nujol), maxima at the following wave numbers (cm " ¹ ): 1730, 1640 to 1670.

L J

4098 ^ / 1005

Claims (16)

Patent claims 1. / Half ester of siomycin A with aliphatic dicarboxylic acids with 2 to 15 carbon atoms, cycloalkanedicarboxylic acids or raonocyclic aryldicarboxylic acids and the ammonium, alkali metal or alkaline earth metal salts of these half esters. 2. Compounds according to claim 1, characterized in that the alkali metal salt is a lithium, sodium or potassium salt. 3. compounds "according to claim 1, characterized in that .the alkaline earth metal salt is a calcium salt. 4. Compounds according to claim 1, characterized in that the aliphatic ^ dicarboxylic acid ethane, propane, 2-methylpropane, 2-ethylpropane, 2-butylpropane, butane, 2-methylbutane, - 2,3-dimethylbutane, 2-ethylbutane, 3-propylbutane, cis-2-butene, trans-2-butene-, cis-2-methyl-2-butene ~, 2-ethyl-2-butene, 2-ethyl-3-methyl-2-butene, 2-butyne, pentane, 2-methylpentane, 3-methylpentane, 2-methyl-3-ethylpentane, 2-ethyl »3-propylpentane, 2-pentene, 2-methyl-2-pentene, 2-methyl-3-pentene, 2-ethyl ~ 2-pentene, 2-butyl-3-pentene, 2-pentyne, hexane, 2-methylhexane, 2-ethylhexane, 2-s-pentylhexane, 2,4-dimethylhexane, 2-methyl-5-methylhexane, 2-hexene ~, 3-methyl-2-hexene, 2,4-hexadiene, 2-methyl-2,4-he: radien-, 3-ethyl-2 , 4-hexadiene, 3-fiexin, heptane, 2-methylheptane, 3-methy! Heptane, 4-propylheptane, 2,3-Diraethy! Heptan-, 2-Hepten «, 5-Methyl-2-hepten-, 2,4-heptadiene, octar; -, 2-methyloctane, 2,3-dimethyloctane, _j 98 ^ 4/1005 2,3,4-trimethyloctane, 2-methyl-3-ethyloctane, 2-octene, 2,4-octadiene, 2,4,6-octatriene, nonane, 2-methylnonane, 2,5-dimethylnonane, decane, 3-methyldecane, undecane, 5-methylundecane, Is dodecanoic, tridecanoic, tetradecanoic or pentadecane dicarboxylic acid. 5. Compounds according to claim 1, characterized in that the cycloalkanedicarboxylic acid is cyclopropane, cyclobutane-1,2, 4-methylcyclobutane-1,2-, cyclopentane-1,2-, 4-ethylcyclopentane-1,2-, Cyclohexane-1,2-, 3-methylcyclohexane-1,2-, 4-methylcyclohexane-1,3- or cycloheptane-1,2-dicarboxylic acid. 6. Compounds according to claim 1, characterized in that. the monocyclic aryldicarboxylic acid 1,2-benzene, 3-methyl-1,2-benzene, 3-ethyl-4-methyl-1,2-benzene, 4-propyl-1,2-benzene, 1,3-benzene, 2-methyl-1,3-benzene, 4,5-dimethyl-1,3-benzene, 4-methyl-5-ethyl ~ 1,3-benzene-, 1,4-benzene-, 2-methyl-i, 4-benzene-, or 2-methyl-5-propyl-1,4-benzenedicarboxylic acid. 7. Process for the preparation of the half-esters of Siomycin A. and their salts according to Claim 1, characterized in that siomycin A is used in a manner known per se in an inert solvent with a dicarboxylic acid or its reactive derivative, and optionally the compounds obtained converted into a salt with an inorganic base. 8. The method according to claim 7, characterized in that an acid according to claim 4 is used as the dicarboxylic acid. 409844/1005 9. The method according to claim 7, characterized in that an acid according to claim 5 is used as the dicarboxylic acid. 10. The method according to .Anspruch 7, characterized in that an acid according to claim 6 is used as the dicarboxylic acid. 11. The method according to claim 7, characterized in that one an acid anhydride, acid halide, amide, ester, ketone or azide is used as the reactive derivative. 12. The method according to claim 7, characterized in that one as an inert solvent, chloroform, trichloroethane, dioxane, dimethj ^ lformamide, dimethyl sulfoxide, pyridine or a mixture this solvent is used. 13. The method according to claim 7, characterized in that the catalyst used is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boron trifluoride, ammonium hydroxide, Potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, ethylamine, butylamine, pyridine or picoline are used. 14 .. Process for the production of alkali metal, alkaline earth. metal and ammonium salts of half-esters of siomycin A, thereby gekennzeiclinet that one half ester of Siomycin A with the theoretical amount of an alkali metal, alkaline earth metal or ammonium base converts. 4098-4 / 1005 15. The method according to claim 14, characterized in that the base sodium hydrogen carbonate, potassium hydrogen carbonate, Calcium hydroxide, lithium hydroxide or alijmanium hydroxide turns. 16. The method according to claim 7 »characterized in that nan the aliphatic dicarboxylic acid, cycloalkaneclicarboxylic acid, monocyclic acid Aryldicarboxylic acid or the reactive derivatives of these acids in an amount of at least 1 mole per mole of siomycin A is used. .17. Medicament "consisting of a compound according to claim .1 and common carriers and / or diluents and / or auxiliary materials. _J 40 9 8 hki 100 F.