KR950013565B1 - Synergistin and their salts, their preparation and pharmaceutical compositions thereof - Google Patents

Abstract

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Description

Cenerzistin and a pharmaceutical composition comprising the same.

The present invention relates to cinerzistin derivatives, their preparation and pharmaceutical compositions comprising them.

European patent application EP 133,097 describes cinerzistine derivatives substituted at the 5δ position which have the advantage of solubility.

Pricynamycin and virinimamycin are known compounds: J-Pruid Homemealine, Bull, Soc, Chim Fr 2,585-911 (1968).

The present invention provides novel cinerzistin derivatives of the following formula (I) and their salts.

Wherein Y is hydrogen or multimethylamino and R is 3- or 4-quibuclidinyl. The compounds of formula (I) are in isomeric form and these isomers and mixtures thereof are within the scope of the present invention.

According to a feature of the invention, compounds of formula (I), wherein Y and R are as defined above, are prepared by reacting a thiol of formula (II) with a compound of formula (III).

R-SH

Wherein R is as defined above.

Wherein R is as defined above.

The reaction is generally reaction mixtures with −78 ° C. in a chlorinated solvent (eg chloroform) or an alcohol (eg methanol), an organic solvent such as cairn (eg acetone), or a mixture of such solvents. At a temperature between reflux, preferably at about 20 ° C.

It should be noted that when the symbol R is 3-quinuclidinyl, the thiol of the formula of the (R) or (S) configuration induces the cinerzistin derivative of the formula (I) of the corresponding configuration.

Thiols of formula (II) wherein R is 3-quinuclidinyl can be obtained from thiol esters of formula (IV) by any known method in which thiols are obtained from thiol esters without affecting other parts of the molecule.

R-S-COR '

Wherein R is as defined and R 'is alkyl having 1 to 4 carbon atoms, preferably methyl. The reaction may be carried out in particular by the decomposition of alcohols in monocalic media, for example in alcohols such as methanol, in the presence of sodium hydride or sodium methylate at temperatures up to the reflux temperature of the reaction medium.

Thiol esters of formula (IV) are represented by R.P. Similar to the methods described in Volante, Tet Let, 22 (33), 3119 (1981), starting with an alcohol of formula (V) and a thiocarboxylic acid of formula (IV), triphenylphosphine and dialkyl Azodicarboxylates can be prepared by treatment with a mixture, for example diisopropyl azodicarboxylate.

ROH (V)

R'-CO-SH (IV)

In the above formulas R and R 'are as defined above and the reaction is carried out under similar, reference to those described above.

Alcohols of formula (V) of the (R) or (S) type induce thiol esters of the general formula (IV) in the (S) or (R) configuration, respectively.

Formula (Y) of type (R) or (S) may be prepared according to the method described in Acta, Pham, Suec, 16,281 (1979) of B. RINGDAHL et al.

Thiols of formula (II) wherein R is a 4-quinuclidinyl radical, are described in A. Grob. Obtainable by the method described in Helv, Chim Acta, 57,2339 (1974).

When the product of formula (I) takes the form of a mixture of isomers, it is possible to separate the latter by any known method that does not adversely affect the spray, for example by high performance liquid chromatography.

The product of formula (I) can be purified by customary known methods such as crystallization, chromatography or continuous extraction in acidic and basic media. As is known in the art, since cinerzistin is sensitive to alkaline media, the term "basic media" as used herein refers to an alkaline media at that point sufficient to release the parent material from the acid addition salt. That is, it means a medium whose pH does not exceed 7.5-8.

The product of formula (I) can be converted to acid addition salts by the action of acids in chlorinated solvents or organic solvents such as alcohols, ketones, esters. The salt precipitates after concentrating the solution as appropriate. This can be filtered or separated. Acid addition salts can also be obtained as aqueous solutions by adding an aqueous solution of the relevant acid to the product of formula (I).

Synepzirt obtained by fermentation is Gram-positive bacteria (e.g., staphylococcus. Streptococcus, Pheumococcus or Enterococcus and Gram-negative bacteria (e.g. For example, there is a great demand in the pharmacological work for the treatment of certain conditions caused by Haemophilus, Gonococcus or Meningococcus, but such cinerzistin is used in aqueous media. It has the disadvantage of insolubility and therefore they can only be administered orally generally in the form of gelatin capsules, dragees, or tablets As a result of this insolubility, it is impossible to use known cinerzistin when the patient cannot swallow it. This is especially the case in pediatrics and inpopulation, while the active range of cinerzistin is in many cases, for example coma sepsis. It is a very important drug in some cases.

The novel products according to the invention preserve the general range of activity of cinerzistin, with the significant advantage that they are soluble in water at therapeutically useful dosages with their salts. They are particularly active against Staphylococcus aureus Smith at concentrations of 1-125 μg / ml in vitro and at doses of 5-50 mg / kg in vivo injected subcutaneously in rats.

In addition, they are particularly valuable in terms of their low toxicity. They LD ₅₀ is generally greater than 150 mg / kg in subcutaneously injected mice.

The product according to the invention additionally exhibits a synergistic phenomenon when used in combination with a soluble derivative of pristinamycin II _B of formula (VII) or pristinamycin II _A.

Wherein R ₁ is

1) i) the alkyl moieties each containing 1 to 5 carbon atoms, together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, 1-azinyl, monopolyno, thiomorpholino and 1 One or two alkylamino or dialkylamino radicals which can optionally form a saturated heterocyclic system selected from piperazinyl (optionally substituted by alkyl having 1-5 carbons); Or alternatively ii) substituted with 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl, 2- or 3-azetidinyl or 2-, 3- or 4-azinyl radicals Alkylthio radicals containing 1-5 carbon atoms.

2) a radical of formula (VIII)

Het-S- (VIII)

Wherein Het is a 3-pyrrolidinyl, 3- or 4- piperidyl, 3-azetidinyl or 3- or 4-azinyl radical optionally substituted by alkyl of 1-5 carbon atoms;

3) the alkyl moieties comprise 1-5 carbon atoms and, together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azinyl, morpholino, thiomorpholi Dialkylaminoralicals capable of optionally forming a saturated heterocyclo system selected from a furnace and 1-piperazinyl (optionally substituted by alkyl having 1-5 carbons); or

4) a radical of the following general formula (IX),

R ₂ -S- (O) n (IX)

Wherein R ₂ is i) 4- to 7-each nitrogen-containing heterocyclic optionally containing one or more other heteroatoms selected from sulfur, oxygen and nitrogen in the sulfoxide or sulfone state and optionally substituted by alkyl Radicals; Or ii) N-alkyl-N-cycloalkylamino, alkylamino, dialkylamino or dialkyl carbamoyloxy (alkyl moieties of the last two radicals comprising phenyl, cycloalkylamino and 3-6 ring atoms, Together with their attached nitrogen atoms, they may optionally form 4- to 7-angled saturated or unsaturated heterocyclic crabs, optionally containing other heteroatoms selected from sulfur, oxygen and nitrogen in the sulfoxide or sulfone state and optionally substituted by alkyl. One or more 4- to 7-each nitrogen optionally substituted by one or two radicals selected from: or optionally comprising one or two other heteroatoms selected from sulfur, oxygen and nitrogen in the sulfoxide or sulfone state -Containing heterocyclic radicals (this heterocyclic radical is optionally substituted by alkyl and said heterocyclic radical is carbon Alkyl attached to the chain containing them), provided that at least one of the substituents contained in the alkyl chain is a nitrogen-containing substituent capable of forming a salt; (S) -methyl-2-pyrrolidinyl) methyl radical; n is 1 or 2 and at least one of the substituents contained in the above alkyl chain is a nitrogen-containing substituent capable of forming a salt or is a ((S) -1-methyl-2-pyrrolidinyl) methyl radical: n is 1 or 2, and the alkyl radicals mentioned above are straight or branched and each includes 1 to 10 carbon atoms unless otherwise specified.

Pristinamycin II _B derivatives of formula (VII) may exist in isomeric form. This isomeric form and mixtures thereof may advantageously be combined with the products of formula (I).

In the 4) part of formula (VII): when -R ₂ is a heterocyclic radical, this radical is for example 3-azetidinyl, 3-pyrrolidinyl, 3- or 4-piperidinyl or 3- Or 4-azinyl; When —R ₂ is an alkyl radical containing a heterocyclic substituent, the heterocyclic radical may be, for example, one of the aforementioned radicals or 2-azetidinyl, 2-pyrrolidinyl, 2-piperidyl, 2- Azepinyl, piperazinyl, 4-alkylpyrerazinyl, quinolyl, isoquinolyl or imidazolyl; When —R ₂ comprises alkyl dialkylamino or dialkylcarbamoyloxy radicals in which the alkyl moieties together with the nitrogen atom to which they are attached form a heterocyclic radical, for example, 1-azeti Diyl, 1-pyrrolidinyl, piperidino, 1-azinyl, morpholino, thiomorpholino, 1-piperazinyl, 4-alkyl-1-piperazinyl, N in sulfoxide or sulfone form -Alkyl-1-homopiperazinyl or 1-amidazolyl.

The product of formula (VII), wherein R ₁ is as defined in part 1), 2), 3) above, is the subject of European patent application (USP 4590004) published as No. 135,410 and by the method described in this patent application It can be prepared from mycin II _A.

The product of formula (VII), wherein R ₁ is defined in section 4) above, can be prepared by oxidizing the salt of a pristinemycin II _B derivative of formula (X), a protected derivative thereof:

Wherein R ₂ is as defined above provided that when R ₂ comprises a sulfur-containing heterocyclic system, sulfur may be in the sulfide, sulfoxide or sulfone state.

The reaction is generally carried out in an aqueous medium or in a solvent, preferably in a chlorinated solvent (eg methylene chloride 1,2-dichloroethane or chloroform) or an alcohol (eg methanol or 3-butanol) or a mixture of these solvents. In the field, optionally prepared by an oxidant. The reaction is optionally carried out under nitrogen. Suitable oxidizing agents for obtaining the product of formula (VII) with n = 1 include percarboxylic acid or persulfonic acid (e.g., peracetic acid, pertritouroacetic acid, performic acid, perbenzoic acid, m-chloroperbenzoic acid, Mention may be made of organic or inorganic peracids (eg, periodic acid or persulfate), such as p-nitroguavenic acid, permaleic acid, mono and phthalic acid, percalactic acid or p-toluene and sulfonic acid.

When it is necessary to obtain the product of formula (VII) with n = 2, the reaction is advantageously performed with certain pertrifluoro by acting hydrogen peroxide and selenium dioxide on the salt of the compound of formula (X) or peracid with those mentioned above. In acetic acid or m-chloroperbenzoic acid.

When using the pristinamycin II _B derivatives of formula (X) in salt form, salts formed with organic or inorganic acids, preferably with trifluoroacetic acid, tarparic acid, acetic acid, benzoic acid or hydrochloric acid, are used.

When the compounds of formula (X) are used in the form of salts or protected derivatives, they are advantageously carried out at temperatures between -40 and 50 ° C.

When it is necessary to obtain the product of formula (VII) with n = 1, the pristinemycin II _B derivative of formula (X) is dissolved in the presence of an alkali metal bicarbonate (eg sodium bicarbonate) at a temperature between -60 and 40 ° C. It is beneficial to use

When R ₂ comprises an alkylamino or cycloalkylamino substituent, it is possible to use protected derivatives of the product of formula (X), the latter of which any introduction and removal of which do not affect other parts of the molecule. It can be protected with an amine-protecting group. Advantageously, a prefluoroacetyl group is used. It can be removed after the reaction by treatment with an alkali metal bicarbonate (eg sodium bicarbonate or potassium) in an aqueous solution.

The product of formula (X) can be prepared analogously to the process described in the European patent application published as 135,410 by acting a thiol of formula (XI) on pristinemycin II _A.

R ₂ -3H (XI)

Wherein R ₂ is as defined above.

The product of formula (VII), wherein n is 2, can also be prepared by oxidizing the product of formula (VII), wherein n is 1. The reaction is carried out under conditions similar to those described above for obtaining the product of formula (VII) with n equal to 2 starting with a pristinemycin II _B derivative of general formula (X).

The products of general formula (XI) can be prepared analogously or accordingly to the methods described in the following examples and in particular according to the methods described below:

C.C. Urqusrt et al., Org, Syntth., 21, 36 (1941); A. I. Vogel J, Chem. Soc., 1822 (1948); J.II. Chapman and L.N. Owen, J. Chem. Soc., 579 (1950); H.R. Snyder et al., J. Am. Chem. Joc., 69, 2672 (1947); D.D. Reynolds et al., J. Org. Chem., 26, 5125 (1961); J. W. Raeffele et al., Proc. Sci. Toilet Goode Assoc., 32, 52 (1959); H, Barror et al., J. Org. Chem., 27, 641 (1962); And J.H. Biel et al., J. Amer. Chem. Soc., 77, 2250 (1955)

If appropriate, isomers of the product of formula (VII) may be separated by chromatography or by high performance liquid chromatography.

Other cinerzistin derivatives in the present invention, when they are combined at a ratio between 10-90% and 90-10%, in vivo 10-200 mg of a subcutaneously injected rat with a dose of 0.1-10 μg / cc in vitro. There is a synergistic effect on the antimicrobial action of Pristinamycin II _A against Staphylococcus aureus Smith at a dose of / kg.

For therapeutic applications, the new products according to the invention can be used as they are, i.e. in the basic state, but when used in aqueous solutions, this represents an important advantage of the products according to the invention and their pharmaceutically acceptable salts. Ie, a salt that is non-toxic at the dosage employed, preferably as a pharmaceutically acceptable salt per se or, if appropriate, as a base (solubility of the base is at least equal to the dosage at which the solution obtained is therapeutically active. It is particularly advantageous to use in combination with a soluble derivative of pristinemycin II _B of formula (VII) or pristinemycin II _A which dissolves.

Pharmaceutically acceptable salts include addition salts of inorganic acids such as hydrochloride, bromate, sulfate, nitrate, phosphate, or acetates, propionates, succinates, maleates, fumarates, methanesulfonates, P-toluenesulfonates, ises Mention may be made of addition salts of organic acids such as thionates, citrates, adipic salts, lactobionic acid salts or substitution derivatives of these compounds.

The following examples illustrate how to practice the invention. The NMR spectra of the products shown in these and reference examples show the general properties common to all products of formula (I) or formula (VII) and the specific properties characteristic of each of the products according to their substituents. Indicates.

In the following examples, specific properties are mentioned which are merely attributed to various radicals. All of them are represented by J.O. ANTEUNIS et al. [Eur, J, Biochin. 58, 259 (1975).

In the product of general formula (VII), all protons are designed according to the numbers shown in the following formula (XIII).

Unless otherwise noted, spectra were recorded at 250 MHz in deuterium chloroform; Chemical shifts are expressed in ppm relative to the tetramethylsilane signal. The abbreviations used below are as follows: s = single, d = double, t = triple, m = multiple, c = composite, dd = double duplex, dt = double duplex, ddd = double duplex, dddd = Double Dual Double Dual.

It should be noted that different isomers can be classified arbitrarily according to chemical shifts observed by NMR.

; 〈5(d, H₂₇) 이성체 A₂또는 〉5(d, H₂₇) 이성체 A₁; 거의 5.50(넓은 d, H₁₃) ; 거의 6.6(8에서

; ≥8(s, H₂₀).Isomers A ₁ and isomers A ₂ of the product of formula (XIII) _wherein R ₁ is R ₂ S (O) _n -radical (n = 1) are referred to as isomers exhibiting the following properties: almost 1.7 (s, 33 In -CH ₃ ); At almost 3.8 (s, 17

; <5 (d, H ₂₇ ) isomer A ₂ or> 5 (d, H ₂₇ ) isomer A ₁ ; Nearly 5.50 (wide d, H ₁₃ ); Almost 6.6 (at 8

; ≧ 8 (s, H ₂₀ ).

; 거의 4.8(m, H₁₃) ; 〈 5(d, H₂₇) 이성체 B₂또는 〉5(d, H₂₇) 이성체 B₁; 거의 5.70(한정 AB, H₁₁및 H₁₀) ; 거의 7.7(8에서

; 거의 7.8(s, H₂₀).Isomers B ₁ and isomer B ₂ of the product of general formula (XIII), wherein R ₁ is R ₂ S (O) _n 0 radicals (n = 1), are referred to as isomers exhibiting the following properties: almost 1.5 (s, 33 In -CH ₃ ); At almost 3.7 (s, 17

; Almost 4.8 (m, H ₁₃ ); <5 (d, H ₂₇ ) isomer B ₂ or> 5 (d, H ₂₇ ) isomer B ₁ ; Almost 5.70 (limited AB, H ₁₁ and H ₁₀ ); Almost 7.7 (from 8

; Almost 7.8 (s, H ₂₀ ).

Isomers A of the product of formula (XIII), _wherein R ₁ is not R ₂ S (O) _n- , isomers A ₁ and A ₂ of the product of formula (XIII), _wherein R ₁ is R ₂ O (O) _n -radical. Same as above, but only. In 27, H is referred to as an isomer showing an NMR characteristic characterized by almost 4.7 (d, j≤ (Hz).

Isomers B of the product of formula (XIII) _wherein R ₁ is not R ₂ S (O) _n are the same as those described above for isomers B ₁ and B ₂ of the product of formula (XIII), with H almost Isomers showing NMR properties characterized by 4.6 (d, j ≧ 2.5 Hz).

In the following examples, flash chromatography is a purification technique, the properties of which are W.C. STILL, M KAHN and A.MITRA [J. Org. Chem., 43,2923 (1978)], using silica of particle size 40-53 um at moderate pressure (50 kPa).

In the following examples, unless otherwise stated, all products can be dissolved in water with hydrochloride at a concentration of at least 2% by weight.

Example 1

3-mercaptoquinuclidine (2.8 g) was added to a solution of 5δ-methylenepristinemycin II _A (4.4 g) in a mixture of methanol (40 cc) and chloroform (20 cc). Stir for 44 hours at temperature. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is suspended in ethyl ether (100 cc) and then filtered off. The solids thus obtained are washed with ethyl ether (3 × 10 cc), purified by flash chromatography [eluent: methylene chloride / methanol (90:10 by volume)] and 100 cc of fractions are collected. After combining the oils from 11 to 35, the dry state is also concentrated under reduced pressure (2.7 kPa) at 30 ° C. The residue is stirred by stirring in ethyl ether (120 cc). The obtained solid was separated by filtration and purified again by flash chromatography [eluent: methylene chloride / methanol (volume 85: 15)] and 100-cc of oil was collected. The oils from 3 to 7 were combined and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. After stirring the residue in ethyl ether (50 cc), the solid thus obtained is filtered off, washed with ethyl ethyr (3 x 5 cc) and dried under reduced pressure (27 Pa) at 20 ° C. This gave a melting point of 200 ° C. and obtained 58-[(3-quinuclidinyl) thiomethyl] pristinemycin I _A (1.7 g) in the form of a pale yellow solid.

[NMR spectrum]

4 mixtures of isomers

2.88 and 2.89 (2s, 4-N (CH ₃ ) ₂ ), 3.21 and 3.22 (2s, 4-CH ₃ ), 6.51 and 6.53 (2d, 2-NH-), 6.57 and 6.58 (2d, 4ε), 7.82 And 7.85 (m, H ₆ of two dominant isomers), 7.95 (m, H ₆ of two thirteen isomers) 8.78 and 8.81 (2d, six -NH- of two dominant isomers), 8.98 and 9.0 (2d, 6 -NH-) 5% strength of the two thirteen isomers of 5δ-[(3-quinuclindinyl) thiomethyl] pristinamycin I _A were obtained as follows:

Product ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 100mg

0.1 hydrochloric acid ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.98cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ enough 2cc

3-mercapto quinuclidin can be prepared as follows: Sodium methylate (0.5 g) is added to a solution of 3- (acetylthio) quinuclidin (14.5 g) in methanol (15 cc). The reaction mixture is heated at reflux for 1 h. Sodium methylate (0.5 g) is added again and the mixture is heated at reflux for 2 hours. The reaction mixture is concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). Distilled water (40 cc) is added to the obtained residue, followed by acetic acid (approximately 1 cc) to obtain a pH of about 8. The mixture obtained is extracted with methylene chloride (3 x 20 cc). The combined organic phases are dried over sodium sulphate and filtered and then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The resulting yellow oil is distilled under reduced pressure (920 Pa): The distillate fraction is collected at about 94 ° C. Thus, 3-mercapto quinuclidin (2.8 g) was obtained.

3- (acetylthio) quinuclidine can be obtained in the following way: A solution made by dissolving triphenylphosphine (42 g) in tetrahydrofuran (300 cc) is kept at 5 ° C. under a nitrogen atmosphere, and Diisopropyl azodicarboxyl tape (31.6 cc) was added dropwise over 30 minutes. The resulting suspension is stirred by stirring at 5 ° C. for 30 minutes. A solution made by dissolving 3-hydroxyquinuclidine (10.2 g) and thiol acetic acid (11.4 cc) in tetrahydrofuran (600 cc) is added to this suspension over 30 minutes, and kept at 5 ° C. Stir the reaction mixture for 20 hours at a temperature of about 20 ℃. It is then concentrated to dryness under these reduced pressure (2.7 kPa) at 40 ° C. The oil obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The resulting oil is dissolved in ethyl ether (400 cc) and then washed with hydrochloric acid (3 × 200 cc). The combined aqueous pjases were washed with ethyl ether (100 cc) and then neutralized to pH 7 by addition of sodium bicarbonate. Then, the pH of the obtained solution is adjusted to 9 or more by adding several 10N sodium hydroxide aqueous solution. The mixture is extracted with methylene chloride (3 x 160 cc). The combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. This gave 3- (acetylthio) quinuclidin (14.7 g) in the form of a yellow oil [Rf = 0.33: eluent: methylene chloride / methanol (volume 90: 10)]

Example 2

Two purifications by flash chromatography, starting with 5δ-methylenepristinamycin I _A (6.15 g) and (3S) -3-mercaptoquinuclidine (1.1 g), were carried out in a manner similar to that described in Example 1. 50-cc of oil [primary flash chromatography: eluent: methylene chloride / methanol (90:10 by volume), 12 to 36 parts of the concentrate to dryness: secondary flash chromatography: eluent : Methylene chloride / methanol (90:10 by volume, concentrated from 3 to 20 in a dry state), collected and collected as pale yellow powder 5δ-{[(3S) -3-quinuclidinyl] thiomethyl}. Obtain pristinamycin I _A (2.6 g). This product can be obtained in crystalline state by the following method:

5δ-{[(3S) -3-quinuclininyl] thiomethyl} pristinemycin I _A (2.6 g) is dissolved in methanol (20 cc). Obtain a yellow solution. Filtration and drying under reduced pressure (27 Pa) at 30 ° C., followed by scraping, showed crystalline precipitation. The melting point is about 200 ° C. and 5δ-{[(3S) -3-quinuclidinyl] thiomethyl} pristinamycin I _A (1.2 g) in the form of white crystals (crystal product in combination with methanol) is obtained.

NMR Spectrum: 1 Isomer (Isomer Tracking for 5δ Carbon)

0.62 (dd, J = 15 and 6, 1H, 5β2)

4.98 (dd, J = 14 and 7.5, 1H, 5ε ₁ ), 5.30 (m, 2H, 5 and 4α), 7.90 (dd, 1H, H ₆ )

5δ-{[(3S) -3-quinuclidinyl] thiomethyl} pristinamycin I _A can also be crystallized in the following manner:

5δ-{[(3S) -3-quinuclidinyl] thiomethyl} pristinamycin I _A (2.6 g) is dissolved in acetone (87 cc) that is refluxed beforehand. The obtained solution is filtered, and the insoluble substance is rinsed with acetone (10 cc). After 3 hours at 20 ° C., the obtained crystals were filtered and dried. The obtained product (14.8 g) was recrystallized from acetone (75 cc) under the same conditions, filtered, and then dried under reduced pressure (90 Pa) at 20 ° C., whereby white crystals (12.2 g) having a melting point of approximately 185-190 ° C. were obtained. .

(3S) -3-mercaptoquinuclidin can be obtained in the following manner.

=-118°, C=1.1, 메타놀)A solution made by dissolving (3S) -3- (acetylthio) quinuclidine (29 g) in methanol (30 cc) is kept at approximately 25 ° C, and 10 N aqueous sodium hydroxide solution (30 cc) is slowly added to the solution. The reaction mixture is stirred by stirring at a temperature of about 20 ° C. for 2 hours. The pH of the reaction mixture is then adjusted to a value of about 9 by adding acetic acid (approximately 10 cc). The resulting mixture is extracted with methylene chloride (3 x 100 cc). The combined organic phases are dried over sodium sulphate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue obtained is purified by distillation under reduced pressure (970 Pa), whereby (3S) -3-mercaptoquinuclidin (12 g) is obtained in the form of white crystals which melt at 46 ° C. and distill at 95 ° C. under 970 Pa. (

= -118 °, C = 1.1, methanol

(3S) -3- (acetylthio) quinuclidine can be obtained in a manner similar to that described in Example 1, including triphenylphosphine (104.8 g), diisopropyl azodicarboxylate (80.8 g) and Start with (3R) -3-hydroxyquinuclidin (25.7 g). This affords (3S) -3- (acetylthio) quinuclidin (30 g) in the form of a yellow oil. [Rf = 0.2: Eluent: methylene chloride / methanol (volume 90:10)] R.P. According to Brante, Tet. Lat., 22 (33), 3119 (1981), three carbons of (R) atomic arrangement are converted to carbons of (S) atomic arrangement during the reaction.

(3R) -3-hydroxyquinuclidin is prepared according to the methods described by B. Ringdal, B. Risulf and R. Daalbom, Acta Pharms, ues, 16, 281 (1979).

Example 3

Performed in a similar manner to that described in Example 1, starting with 5δ-methylenepristinamycin I _A (6.15 g) and (3R) -3-mercaptoquinuclidine (1 g) and purified by flash chromatography. Then, 40-cc of oil [eluent: methylene chloride / methanol (volume 85: 15)] was collected and the oil of 20 to 30 was concentrated to dryness, and 5δ-{(3R) -3-quinuclidinyl. ] Thiomethyl} pristymycin I _A (2 g) was obtained in the form of a powder having a melting point of approximately 200 ° C.

NMR Spectrum

4.95 (dd, 1H, 5ε ₁ ), 5.28 (c, 2H, 5α and 4α), 7.87 (c, 1H × 0.85, one of H ₆ of the primary isomer), 7.93 (c, 1H × 0.15, secondary 1 of H ₆ of the isomer)

5δ-{(3R) -3-quinuclidinyl] thiomethyl} pristinamycin I may be recrystallized in the following manner: 5δ-{[(3R) -3-quinuclidinyl] thiomethyl} protinomycin Dissolve I _A (14.15 g) in methanol (75 cc). Distilled water (4cc) was added to this solution, and it left to make crystal | crystallization at 4 degreeC. The obtained crystals are filtered and rinsed with a methanol / water (by volume 95: 5) mixture (4 × 10 cc). Drying under reduced pressure (90 Pa) at 42 ° C yields white crystals having a melting point of 190 ° C.

=+121°, C=1.1, 메탄올)(3R) -3-mercaptoquinuclidin can be obtained in a manner similar to that described in Example 2, wherein (3R) -3- (acetylthio) quinuclidin (32.5 g) and 10N aqueous sodium hydroxide solution (35 cc) (3R) -3-mercaptoquinuclidin (11.5 g) is obtained in the form of white crystals which melt at 45 ° C. and distill at 90 ° C. under 830 Pa. (

= + 121 °, C = 1.1, methanol)

(3R) -3- (acetylthio) quinuclidin can be obtained in a similar manner as described in Example 1, including triphenylphosphine (104.3 g), diisopropyl isoticarboxylate (80.8 g) and ( 3 g) -3-hydroxyquinuclidin (25.7 g). This gave (3R) -3- (acetylthio) quinuclidine (33.8 g) in the form of a light brown oil. [Rf = 0.4; Eluent: methylene chloride / methanol (volume 80: 20)]

(3R) -3-hydroxyquinuclidin is described by B. Ringdal et al., Acta Pharm. Succ. 16, 281 (1979).

Example 4

It is carried out in a similar manner as described in Example 1, starting with 5δ-methylenepristinamycin I _A (3.5 g) and 4-mercaptoquinolidine (0.6 g) and concentrating to dryness to obtain a solid in ethyl ether. Stir in the mix. After filtration, a beige solid (3.6 g) was isolated, purified by flash chromatography and a 50-cc fraction [eluent: methylene chloride / methinol (volume 85: 15)] was collected. After concentrating the oils from 1) to 35 in a dry state, washing with ethyl ether, filtration, and drying the final solid under reduced pressure (2.7 kPa) at 20 ° C., the melting point was about 200 ° C. and grayish white. Obtain 5δ-[(4-quinucynyl-thiomethyl] pricynamycinI _A (1.2 g) in powder form.

NMR spectrum (two isomers on 5δ carbon in ratio of approximately 85:15): 0.62 (dd, J = 15 and 5.5, 1H,

4-mercaptoquinuclidin is described in A.GROB, Helv. Chim. It may be obtained according to the method described by Acta 57, 2339 (1974).

Example 5

The procedure is similar to that described in Example 1. Start with 5δ-methylenevirginiamycin S (1.2 g) and (3R) -3-mercaptoquinuclidin (0.21 g) dissolved in methanol (20 cc). After purification by flash chromatography, a 10-cc fraction (eluent: methylene chloride / methanol (volume 95: 5 by volume) up to fraction 35), and methylene chloride / methanol (volume 80: 20) by volume] was then collected. The oils from 47 to 55 were concentrated to dryness and dried under reduced pressure (2.7 kPa) at 30 ° C. to give 5δ-{[(3R) -3-quinuclidinyl] thiomethyl} -viriniamycin S (0.6 g). It has a melting point of about 185 ° C and is obtained in the form of a slightly grayish white powder.

Example 6

The procedure is similar to that described in Example 1, but starts with 5δ-methylenevirginiamycin S (1.1 g) and (3S) -3-mercaptoquinuclidine (0.19 g) dissolved in methanol (20 cc). After purification by flash chromatography, a 10-cc fraction [eluent: methylene chloride / methanol (90:10 by volume)] was collected, and the fractions 19 to 32 were concentrated to dryness and decompressed at 30 ° C ( Drying under 2.7 kPa) yields 5δ-{[(3S) -3-quinuclidinyl] thiomethylvirginiamycin S (0.5 g) in the form of a pale yellow powder with a melting point of about 190 ° C.

Example 7

The experiment was carried out in a similar manner to the method shown in Example 2, except that (3S) -3-mercaptoquinuclidin (1.62 g) was stirred as a starting material and at -20 ° C for 20 hours, and the beige meringue The same product (11.4 g) was obtained after concentration at 30 ° C. under reduced pressure (2.7 kPa) in a dry state, which was stirred in diethyl ether (100 cc), filtered, and then filtered in the same solvent (3 × 20 cc). Rinse with. This product was recrystallized in acetone as shown in Example 2 to give a small number of isomers, quantified by HPLC, with a white crystalline form with a melting point of about 198-200 ° C., characteristically similar to that of the product obtained in Example 2. 5%-{[(3S) -3-quinuclininyl] thiomethyl} pristinemycin I _A (6.5 g) containing 3% can be obtained.

Example 8

(3S) -3-mercaptoquinuclidin (0.18 g) dissolved in acetone (5 cc) at -20 ° C was added to a solution containing 5δ-methylenepristinamycin I _A (1 g) in acetone (20 ° C). Add over time. After stirring for 18 hours at −20 ° C., the reaction mixture was filtered and the fixture was rinsed with acetone (3 × 2 cc). After drying in air, 5δ-{[(3S)-was obtained as a white crystalline form with a melting point of about 190 ° C., containing 3% of a small number of 5δ-isomers quantified by HPLC and having properties similar to those obtained in Example 2. 3-quinuclidinyl] thiomethyl} pristinamycin I _A (6.5 g) is obtained.

Example 9

(3S) -3-mercaptoquinuclidin (0.16 g) dissolved in acetone (5 cc) at −78 ° C. was added to a solution containing 5δ-methylenepristinamycin I _A (1.22 g) in acetone (15 cc) And, the obtained solution is stirred by stirring under nitrogen at -78 ℃ for 24 hours. The reaction mixture was then concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa) to afford 1.4 g of a cream-white solid having characteristics similar to the product obtained in Example 2 with a few isomers 5% quantified by HPLC. Get

Reference Example 1

Trifluoroacetic acid (0.4 cc) was added to 26 [(2-diisopropylaminoethyl) thio] pristinamycin II _B (isomer A) (3.59 g) dissolved in dichloromethane (40 cc) under nitrogen atmosphere at 0 ° C. Then, it is added to 85% pure meta-croperperchloro perbenzoic acid (1.06 g) at a temperature maintained at 0 ° C. After stirring for 20 hours at 25 ° C., the reaction mixture is treated with saturated aqueous sodium bicarbonate solution. Tilt the organic acid gently and wash the aqueous phase with methylene chloride (3 x 100 cc). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. to give a yellow solid (4.2 g). This is purified by flash chromatography [eluent: chloroform / methanol (by 90:10 volumes)] to obtain a 20-cc portion. Combine parts 22 to 28 and concentrate to dryness under reduced pressure (2.7 kPa) at 30 ° C. to obtain a pale yellow solid which is stirred in ethyl ether (10 cc) and mixed. The obtained solid is separated by filtration to give 26-[(2-diisopropylaminoethyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (0.62 g) in the form of a yellow powder with a melting point of about 155 ° C.

Combine parts 35 to 45 and concentrate to dryness at reduced pressure (2.7 kPa) at 30 ° C. to give a pale yellow solid. Stir this in ethyl ether (15 cc). The obtained solid was separated by filtration to give 26-[(2-diisopropylaminoethyl) sulfinyl] pristinamycin II _B (80% isomer A ₁ , 20% or less in the form of pale yellow powder with a melting point of about 145 ° C). Isomer A ₂ ) is obtained.

26-[(2-diisopropylamino ethyl) thio] pristinamycin II _B can be prepared by the following method:

2-diisopropylaminoethanethiol (16 g) dissolved in dichloromethane (30 cc) was dissolved in prestinamycin II _A in a mixture of dichloromethane (260 cc) and methanol (520 cc) under nitrogen atmosphere at -30 ° C. 52 g). The solution is stirred by stirring at -20 ° C for 20 hours, and then concentrated under reduced pressure (2.7kPa) at 30 ° C. The solid obtained is stirred with ethyl ether (2 x 1000 cc), decomposed by filtration and crystallized in acetonitrile (100 cc). The crystals were separated by filtration and dried at 40 ° C. under reduced pressure (90 Pa). This gives 26-[(2-diisopropylaminoethyl) thio] pristinemycin II _B (Isomer A) (33.6 g) in white crystalline form at a melting point of about 122 ° C.

2-diisopropylaminoethanediol is DD. D. REYNOLDS. D.L. FLELDS and D.L. JCHNSON, J. ORG CHEM, 26, 5125 (1961)].

Reference Example 2

Sodium bicarbonate (1.22 g) is added to 26-[(2-diisopropylaminoethyl) thio] pristinamycin II _B (isomer A) (10 g) dissolved in chloroform (330 cc). The mixture is cooled to −50 ° C. and 98% pure meta-chloroperbenzoic acid (2.98 g) dissolved in chloroform (100 cc) is added dropwise. The mixture is stirred for 2 hours and 15 minutes at -50 ° C and then treated with saturated aqueous sodium bicarbonate solution. After stirring for 15 minutes at 25 ° C., the mixture is decanted and then the aqueous phase is washed with dichloromethane (3 × 200 cc). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at −30 ° C. to give a white meringue-like product (10.62 g). The product is dissolved in ethyl acetate (400cc) and treated with 0.1N aqueous hydrochloric acid solution (140cc). After the pH of the aqueous solution is adjusted to 4.2 by the addition of PH4.2 buffer (400cc). Tilt the aqueous phase and wash the organic phase with PH4.2 buffer (400 cc). The combined aqueous phases are washed with methyl acetate (2 x 150 cc). After tilting, the aqueous phase is adjusted to PH7-8 by the addition of sodium bicarbonate and washed with dichloromethane (3 x 300 cc). The organic phases are combined and washed with PH7.5 buffer (3 × 200 cc). The aqueous phase is washed with dichloromethane (50 cc) and then the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. to give a pale yellow solid (8.04 g). This was stirred with ethyl ether (100 cc), mixed by filtration and dried at 40 ° C. (90 Pa). This gives 26-[(2-diisopropylaminoethyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (7.5 g) in the form of a yellow powder at melting point, about 158 ° C., which is obtained by reference to NMR properties. Similar to the feature of Example I.

Reference Example 3

Experiments were carried out using 26-[(2-diethylaminopropyl) thio] pristymycin II ... (6.3 g), trifluoro acetate (0.72 cc) and meta-chloroper benzoic acid (1.91 g) as starting materials. Except for the use, experiments in a similar manner to the method shown in the Reference Examples. After purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)], a 60-cc portion was obtained, and portions 7 to 9 were concentrated to dryness under reduced pressure (2,7 kPa) at 30 ° C. 26-[(2-diethylaminopropyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (0.99 g) is obtained in the form of a yellow powder with a melting point of about 150 ° C.

After concentrating the dry portions 23 to 35 under reduced pressure (2,7 kPa) at 30 ° C., 26-[(2-diethylaminopropyl) sulfinyl] pristina in the form of a beige-yellow powder having a melting point of about 160-170 ° C. Obtain Mycin II _B (Isomer A ₁ ) (0.64 g).

26-[(2-diethylaminopropyl) thio] pristinamycin II _B can be prepared by the following method:

The experiment is conducted in a similar manner to the method shown in Example I of EP-135 410, except that pristinemycin II _A (3.15 g) and 2-diethylaminopropanethiol (1.8 g) are used as starting materials. . After purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)], a 20-cc portion was obtained, and portions 3 to 5 were concentrated to dryness under reduced pressure (2,7 kPa) at 30 ° C. 26-[(2-diethylaminopropyl) thio] pristymycin II _B (1.4%) is obtained in the form of a yellow powder with a melting point of about 160 ° C.

2-diethylaminopropanethiol can be prepared in the following manner:

A 10 N aqueous sodium hydroxide solution (25 cc) is added to a solution of 1- (S-isothioureido) -2-diethylaminopropane dihydrochloride (29.5 g) dissolved in distilled water (150 cc). The mixture is brought to 100 ° C. for 1 hour, cooled to 20 ° C., adjusted to pH 9 by addition of 12N aqueous hydrochloric acid solution (8 cc), and extracted with ethyl ether (3 × 100 cc). The ether phases are combined, dried over potassium carbonate, filtered and concentrated to 30 ° C. under reduced pressure (2.7 kPa). The mixture was clarified by distillation but yielded 2-diethylamino-1-propane 1ol (5.8 g) (melting point (2.7 kPa) 78 ° C.) in the form of a colorless liquid.

1- (S-isothioureido) -2-diethylaminopropane dihydrochloride can be prepared by the following method.

Thiourea (16.7 g) is added to a solution of 1-chloro-2-diethylaminopropane hydrochloride (41 g) dissolved in dimethyl formamide (200 cc). The mixture is allowed to reach 100 ° C. for 30 minutes and then cooled to 20 ° C. The white precipitate formed is collected by filtration and washed with dimethylformamide (3 × 20 cc) followed by ethyl ether (3 × 20 cc). Obtained 1- (S-isoisoureido) -2-diethylaminopropane dihydrochloride (29.6 g) as a white crystalline form having a melting point of 247-249 ° C.

1-Chloro-2-diethylaminopropane hydrochloride can be obtained by the following method:

2-Diethylaminopropanol hydrochloride (45.2 g) is added to thionyl chloride (100 cc) for 15 minutes and then the mixture is heated to 80 ° C. After stirring for 2 hours, the excess thionyl chloride is distilled off, and the residue is taken up with ethyl ether (200 cc). 1-chloro-2-diethylaminopropane hydrochloride is crystallized. After filtration, white crystals (48.2 g) at a melting point of 112 ° C. are obtained.

2-diethylaminopropanol hydrochloride can be obtained by the following method:

At 20 ° C., a solution of ethyl 2-diethylaminopropionate (66 g) dissolved in ethyl ether (330 cc) is slowly added to a suspension of ethyl hydride aluminum lithium hydride (10.6 g) (maintained under nitrogen). . The reaction is held for 5 hours at a temperature of 35 ° C. and the temperature is then lowered to 0 ° C. At 0 ° C., water (12.4 cc), aqueous sodium hydroxide solution (9.1 cc) and then water (41.3 cc) are added dropwise and the mixture is stirred for 30 minutes. Filter on sintered glass and wash with ethyl ether. The ether phase is dried over potassium carbonate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. A yellow liquid (43.8 g) was obtained, which was then dissolved in acetone (200 cc) and subsequently subjected to 4.5 N solution (78 cc) in which hydrogen chloride gas was dissolved in ethyl ether. 2-diethylaminopropynol hydrochloride is crystallized. After filtration, white crystals (45.2 g) having a melting point of 97-100 ° C. are obtained.

Ethyl 2-diethyl aminopropionate can be obtained according to BRAUN company, Beilstein, 61, 1425 (1928).

Reference Example 4

The experiment starts with 26-[(2-diethylaminopropyl) thio] pristinemycin II _B (Isomer A) (4 g), 98% pure meta-pichloroperbenzoic acid (1.3 g) and solid sodium bicarbonate (1 g) The experiment was conducted in a similar manner to that shown in Reference Example 2, except that the substance was used. Purified by flash chromatography [eluent: chloroform / methanol (93: 7 vol.)] And concentrated to dryness in parts 21 to 48 under reduced pressure (2.7 kPa) at 30 ° C., then 25-cc portions were collected To give 26-[(2-diethylaminopropyl) sulfinyl] pristinamycin II _B (isomer A ₂ ) (2.69 g) in the form of a yellow powder having properties similar to those of the product obtained in Reference Example 3 do.

The experiment was carried out in a similar manner to that shown in Reference Example 1, except that it was carried with prastinamycin II _A (15 g) and 2-diethylaminopropanethiol (4.62 g). Ethylaminopropyl) thio] pristinemycin II _B (isomer A) can be obtained. Purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)] and concentrations of 27 to 52 in a dry state under reduced pressure (2.1 kPa) at 30 ° C. yielded a 40-cc portion. Yield a yellow solid (12 g). It is stirred in ethyl ether (60 cc), filtered and dried. The melting point yields 26-[(2-diethylaminopropyl) thio] pristinemycin II _B (Isomer A) (8.2 g) in the form of a pale yellow powder at about 122 ° C.

Reference Example 5

The procedure consists of 26-[(1-diethylamino-2-propyl) thio] pristinemycin II _B (isomer A) (4.58 g), 98% pure metachloroperbenzoic acid (1.29 g) and solid sodium bicarbonate (1.14 g). ) Is similar to the procedure shown in Reference Example 2, except for starting material). After purification by flash chromatography [eluent: chloroform / methanol (97: 3 vol)], concentrated portions 59 to 77 and 79 to 97 were dried under reduced pressure (2.7 kPa) at 30 ° C., respectively. A compound is obtained: from 97 in part 79, pale yellow solid 26-[(1-diethylamino-2-propyl) sulphate] pristinamycin II _B (first isomer) (1.47 g) at melting point 132 ° C.

And 26-[(1-diethylamino-2-propyl) sulphate] pristinamycin II _B (second isomer) (1,07 g) as a pale yellow solid at melting point 128 ° C.

The experiment was carried out in a similar manner to that shown in Example 1, except that prastinamycin II _A (13 g) and 1-diethylamino-2-propanethiol (4 g) were used as starting materials, and 26-[(1 -Diethylamino-2-propyl) thio] pristinamycin II _B (isomer A) can be obtained. Flash chromatography eluent: purified by chloroform / methanol (190: 10 vol) and concentrated to dryness from 40 to 55 under reduced pressure (2.7 kPa) at 30 ° C., then 50-cc fractions were collected To give a pale yellow solid (8 g). This is crystallized in acetonitrile (30 cc). After filtration and drying, 26- (1-diethylamino-2-propyl) thio-pristymycin II _B (isomer A) (5.91 g) is obtained as a white crystalline form with a melting point of 136 ° C.

1-dimethylamino-2-propanethiol is described in R. T. WRACG, J, Chem. Obtained according to the method shown by Soc. (C), 2028 (1969).

Reference Example 6

The procedure consists of 26 [[(2R) -2-dimethylaminobutyl) thio] pristinemycin II _B (isomer A) (1.7 g), sodium bicarbonate (0.50 g) and 98% pure meta-chloroperbenzoic acid (0.45 g). ) Is similar to the method shown in Reference Example 2, except for using as a starting material. Purified by flash chromatography [eluent: ethyl acetate / methanol (85: 15 vol.)] And concentrated to dryness from part 35 to 58 under reduced pressure (2.7 kPa) at 30 ° C. to yield a white solid (1.1 g). ). This is stirred in ethyl ether (30 cc). After filtration and drying, 26-[[(2R) -2-dimethylaminobutyl] sulfinyl] pristinamycin II _B (isomer A ₂ ) (0.95 g) is obtained in the form of a white solid at a melting point of about 126 ° C.

Experiments were performed in a manner similar to that shown in Reference Example I, except that pristinemycin II _A (8 g) and (2R) -2-dimethylaminobutanethiol (2.3 g) were used as starting materials. 2R) -2-dimethylaminobutyl] thio] pristymycin II _B (isomer A) can be obtained. Purified by flash chromatography [eluent: dichloromethane / methanol (90: 20 vol.)] And concentrated under reduced pressure (2.7 kPa) at 30 ° C. in portions 36 to 55 in a dry state, then pale at a melting point of about 120 ° C. To give 26-[[(2R) -2-dimethylaminobutyl] thio] pristymycin II _B (isomer A ₂ ) (3 g) in the form of a yellow solid.

After separation by filtration, 0.9 g of this product was crystallized in acetonitrile (5 cc) to give 26-[[(2R) -2-dimethylaminobutyl] thio] pristinemycin II _B ( Isomer A ₂ ) (0.2 g) is derived.

The experiments did not include triphenylphosphine (52.4 g), diisopropene azodicarboxylate (40 cc), (R) -2-dimethylaminobutanol (12R) and thioacetic acid (15.2 cc) as starting materials. And (R) -2-dimethylaminobutanethiol can be obtained in a similar manner to the method shown in Reference Example 7 below (in this case, the intermediate thioester is directly hydrolyzed during promatography on silica gel. Decomposes)

After purification by flash chromatography (eluent: dichloromethane / methanol (85: 15 vol: 2000 cc) after dichloroethane (1000 cc), then dichloromethane / methanol (80: 20 cc: 4000 cc)), A 100-cc portion is obtained and concentrated to dryness in portions 42 to 60 under reduced pressure to give a yellow oil (14 g) which is purified by distillation to give a colorless liquid [melting point (4 kPa) 70-75 ° C.]. (R) -2-dimethylaminobutanethiol (2.4 g) is obtained.

M. WENCHOEFER group, J, Heterocycl. (R) -2-dimethylamino-1-butanol can be obtained in a manner similar to that shown by Chem., 7 (6), 1407 (1970).

Reference Example 7

Experiments consisted of 2-[[(2S) -2-dimethylamino-3-phenylprefill] thio] pristinemycin II _B (Isomer A) (2.67 g), sodium bicarbonate (0.7 g) and 98% pure meta-chlorofe Experiments in a similar manner to that shown in Reference Example 2, except starting with benzoic acid (0.7 g). Experiment in a similar manner to that shown in Flash 2. After purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)], 20-cc portions were collected and concentrated to dryness in portions 19 to 23 under reduced pressure (2.7 kPa) at 30 ° C. To give a pale yellow solid (1.3 g). This was stirred in ethyl ether (50cc), separated by filtration, and separated into 26-[[(2S) -2-dimethylamino-3-phenylpropyl] sulfinyl] pristinamycin II in the form of a pale yellow solid at a melting point of about 150 ° C. Obtain _B (isomer A ₂ ) (1.17 g).

A 1% strength aqueous solution of 26-[[(2R) -2-dimethylamino-3-phenylpropyl] sulfinyl] pristinamycin II _B (isomer A ₂ ) is obtained by the following compound:

Product ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 30mg

0.1N hydrochloric acid ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.45cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ qs 30cc

The experiment was similar to the method shown in Example 1 for the preparation of starting materials, except starting with pristinemycin IIA (7.13 g) and (S) -2-dimethylamino-3-pinylpropanethiol (2.65 g). Experimental methods can be used to produce 26-[[(2S) -2-dimethylamino-3-phenylpropyl] thio] pristinemycin II _B (isomer A). After purification with flash chromatography (eluant: ethyl acetate / methanol (80: 20 vol)), collect 60-cc portions and dry portions 33 to 43 under reduced pressure (2.7 Pa) at 30 ° C. Concentrate to give a pale yellow solid (4.6 g). Stir in ethyl ether (50 cc), filter and dry under reduced pressure (90 Pa) at 45 ° C. This gives 26-[[(2S) -2-dimethylamino-3-phenylpropyl] thio] pristinamycin II _B (Isomer A) (3.6 g) in the form of a pale yellow powder with a melting point of about 110 ° C.

(S) -2-dimethylamino-3-phenylpropanethiol can be prepared in the following manner:

Sodium methylate (0.2 g) was added to (S) -2-dimethylamino-3-phenylpropanethiol acetate (preparation: 20 g) dissolved in methanol (50 cc) under a nitrogen atmosphere, for 2 hours. To reflux to heat the mixture. The mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. to obtain a purified liquid by distillation. Colorless liquid melting point (4 Pa) at 95 ° C. yields (S) -2-dimethylamino-3-phenylpropanethiol (2.4 g), which is used as in the following reaction.

(S) -2-dimethylamino-3-phenylpropanethiol acetate can prepare the following method:

After adding triphenylphosphine (41.97 g) and tetrahydrofuran (310 cc) at 0 ° C. under nitrogen atmosphere, diisopropyl azodicarboxylate (31.5 cc) was added dropwise and stirred at 0 ° C. for 30 minutes. Leave the mixture. To a white suspension was obtained dropwise a mixture of (S) -2-dimethyl amino-3-phenylpropanol (15 g) and thioacetic acid (11.44 cc) in tetrahydrofuran (1600c). After stirring for 1 hour at 0 ° C. and for 1 hour 30 minutes at 25 ° C., the mixture is concentrated to dryness at 30 ° C. under reduced pressure (2.7 kPa). The oil obtained was treated with methanol (190 cc) and the white solid was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is then stirred with isopropyl ether (200 cc) and further filtered to remove the white replacement precipitate. The filtrate was concentrated to give a yellow oil (45 g) which was purified by flash chromatography (eluant: dichloromethane / methanol (90:10 volume)) and 100-cc portions were collected. After concentration from 37 to 55 in a dry state under reduced pressure (2.7 kPa) at 30 ° C., (S) -2-dimethylamino-3-phenylpropanethiol acetate (10.4) in an orange-yellow oil form (containing triphenylphosphine oxide) g) is obtained.

(S) -2-dimethylamino-3-phenylpropanethiol is obtained from T, HAYASHI group, J. Org. It may be prepared by a method similar to that shown by Chem., 48, 2195 (1983).

[Reference Examples 8 to 26]

The experiment was conducted in a similar manner to that shown in Reference Example 2, to prepare the following product.

Reference Example 27

The experiment was carried out using 26-[[(S) -1-methyl-2-pyrrolidinyl] methylthio] prestinamycin II _B (isomer A) (7.8 g), trifluoroacetic acid (0.91 cc) and meta-chloroper The experiment was conducted in a similar manner to that shown in Reference Example 1, except that benzoic acid (2.4 g) was used as the starting material. Purification by flash chromatography [eluent: chloroform / methanol (by 90:10 volumes)], followed by concentration of parts 26 to 36 under reduced pressure (2.7 kPa) at 30 ° C. in dry state, with a light melting point of about 140 ° C. Obtained 26-[[(S) -1-methyl-2-pyrrolidinyl] ₃₃ methylsulfinyl] prestinamycin II _B (isomer A ₂ ) (2.3 g) as a yellow powder.

26-[(1-methyl-2-pyrrolidinyl] methylthio] prestinamycin II _B can be prepared by the following method:

Experiments were carried out in the examples of European patent application EP 135,410, except that pristinemycin II _A (10.5 g) and [(S) -1-methyl-2-pyrrolidinyl] methanethiol (3.14 g) were used as starting materials. Experiment in a similar manner to that shown in 1. Purified by flash chromatography [eluent: chloroform / methanol (by 90:10 volumes)] and concentrated to dryness in parts 20 to 35 under reduced pressure (2.7 kPa) at 30 ° C., yellow at a melting point of about 120 ° C. A isomer (7.8 g) is obtained as a powder.

4N aqueous sodium hydroxide solution (100 cc) was added to crude S-[(S) -1-methyl-2-pyrrolidinylmethyl] isothiouronium dihydrochloride (25 g) dissolved in distilled water (100 cc), Stir the mixture for 2 hours at 90 ° C. under a nitrogen atmosphere. The reaction mixture is cooled to 0 ° C., treated with 12N aqueous hydrochloric acid solution (25 cc) and extracted with methylene chloride (2 × 200 cc). The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure at 30 ×. This gives [(S) -1-methyl-2-pyrrolidinyl] methanethiol (5.9 g) in the form of a pale yellow oil which is used in the next step reaction without further purification.

Rf = 0.15: silica gel chromatography: eluent: chloroform / methanol (by 90:10 volume)

Thiourea (10.7 g) was added to [(S) -1-methyl-2-pyrrolidinyl] chloromethane hydrochloride (11.9 g) dissolved in ethanol (50 cc) and the mixture was stirred at reflux for 48 hours. Mix The mixture is concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). The residue is taken up with hot ethanol (100 cc) and then filtered over activated vegetable charcoal. The filtrate was concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C., followed by S-[(S) -1-methyl-2-pyrrolidinylmethyl] isothiouronium dihydrochloride and excess thiourea Obtained pale yellow oil (25 g).

Rf = 0.1: silica gel chromatograph: eluting agent: chloroform / methanol (by 90:10 volume)

[(S) -1-Methyl-2-pyrrolidinyl] chloromethane hydrochloride can be prepared according to the method shown by T, HAYASH I group J, Org, Chem, 48, 2195 (1983).

Reference Example 28

Experiments started with 26-[(1-methyl-4-pyrrolidyl] thio] prestinamycin II _B (2.6 g), trifluoroacetic acid (0.3 cc) and meta-chloroperbenzoic acid (0.8 g) Except that, the experiment was conducted in a similar manner to that shown in Reference Example 1. After purification by flash chromatography [eluent: chloroform / methanol (90:10 by volume)], 40-cc portions were collected and Concentrate from 20 to 35 in dry state under reduced pressure (2.7 kPa) at 30 ° C. to 26-[(1-methyl-4-piperidyl) sulfinyl] prestinamycin II _B into a yellow powder with a melting point of about 170 ° C. (Isomer A ₂ ) (0.33 g) is obtained.

26-[(1-methyl-4-piperidyl) thio] prestinamycin II _B can be obtained by the following method:

The experiment was carried out in Europe, except that triethylamine (0.6 g) was added to the reaction mixture and at the same time starting with pristinemycin II _A (3.15 g) and 1-methyl-4-piperidinethiol (1.6 g). The experiment is conducted in a similar manner to that shown in Example 1 of patent application EP 135,410. Purified by flash chromatography [eluent: methylene chloride / methanol (92: 8 volumes)] and concentrated to dryness in parts 4 to 20 under reduced pressure (2.7 kPa) at 30 ° C., at a melting point of about 180 ° C. Yield 26-[(1-methyl-4-piperidyl] thio] prestinamycin II _B (0.9 g) as a yellow powder.

1-Methyl-4-piperidinethiol can be prepared by the method shown by H, BARRER and R.E.YLE, J.Org, Chem., 27, 641 (1962).

Reference Example 29

Trifluoroacetic acid (0.92 cc) is added to 26-[(2-diethylaminoethyl) thio] prestinamycin II _B (7.8 g) dissolved in methanol (60 cc) under nitrogen atmosphere. After 15 minutes at 0 ° C., the temperature rises to 15 ° C. and then selenium phosphate (1.37 g) is added. When all selenium dioxide is dissolved, 30% strength aqueous hydrogen peroxide solution (7 cc) is slowly added at a temperature below 25 ° C. After stirring for 1 hour at 25 ° C., the reaction mixture was cooled to 10 ° C., treated with saturated aqueous sodium bicarbonate (50 cc) and extracted with methylene chloride (4 × 5 cc). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The yellow solid obtained is purified by flash chromatography [eluent: chloroform / methanol (by 90:10 volumes)] and 40-cc portions are collected. After concentration of parts 31 to 38 to dryness under reduced pressure (2.7 kPa) at 30 ° C., a yellow solid is obtained. This was purified by flash chromatography [eluent: ethyl acetate / methanol (80: 20 by volume)] and 40-cc portions were collected. After concentration of the fractions 27 to 33 dry under reduced pressure, a white solid is obtained. It was stirred in ethyl ether (50 cc), separated by filtration, and dried under reduced pressure (90 Pa) at 30 ° C. This gives 26- (2-diethylaminoethyl) sulfonyl pristinamycin II _B (Isomer A) (0.5 g) in the form of a white solid at a melting point of about 150 ° C.

Reference Example 30

The procedure consists of 26-[(2-diisopropylaminoethyl) thio] pristinamycin II _B (Isomer A) (6.86 g), trifluoroacetic acid (0.77 cc), selenium oxide (1.15 g) and 30% strength. It is similar to the procedure shown in Reference Example 29, except that the aqueous hydrogen peroxide solution (6.33 cc) is used as the starting material. After purification with flash chromatography [eluent: ethyl acetate / methanol (80:20 by volume)], 40-cc portions were collected, and the parts 28 to 31 were dried under reduced pressure (2.7 kPa) at 30 ° C. Concentrate to give a yellow solid (0.7 g). This is again purified by flash chromatography [eluent: ethyl acetate / methanol (85: 15 volumes)] and 30-cc portions are collected. After concentration of portions 26 to 33 to dryness under reduced pressure, a yellow solid is obtained which is stirred in ethyl ether (30 cc) and mixed. Isolation by filtration and drying under reduced pressure (90 Pa) at 30 ° C. 26-[(2-diisopropylaminoethyl) sulfonyl] pristinamycin II _B (isomer A) (0.6 g) is obtained in the form of a pale yellow solid at a melting point of about 140 ° C.

The present invention also provides (1) one or more diluents or auxiliaries that are compatible with the product and are pharmaceutically acceptable; Or (2) a pharmaceutical composition consisting of the product of formula (I) in free base form in combination with any one of the pristinemycin II _A or preferably the soluble derivatives of the general formula (VII) pristinemycin II _B.

The pharmaceutical composition according to the present invention can be used parenterally, orally, rectally or topically and may comprise other physiologically active ingredients if desired.

Sterile compositions for parenteral administration are preferably aqueous or non-aqueous solutions, or suspensions or emulsions. It is possible to use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, or other suitable organic solvents as solvents or excipients, in addition such compositions may be additives, in particular wetting agents. , Osmotic modifiers, emulsifiers, dispersants, and stabilizers. Sterilization can be carried out in several ways, for example aseptic filtration, by incorporating a sterilizing agent in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which, in use, can be dissolved in sterile medium for injection.

Compositions for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, comprise an excipient such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

As solid compositions for oral administration, tablets, pills, powders or granules can be used. In such compositions, the active product according to the present invention (if appropriate combined with another pharmaceutically compatible product) is mixed with one or more additives or inert diluents such as sucrose, lactose or starch. The composition may also include other materials than diluents, for example lubricants such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs can be used including inert diluents such as water or liquid paraffin. The composition may also contain other substances besides diluents, for example wetting agents, sweetening agents or flavoring agents.

Compositions for topical administration can be, for example, creams, ointments, lotions, eye drops, drops or aerosols.

In the treatment of humans, the products according to the invention are particularly useful for the treatment by infection of bacterial causes, the dosage depends on the desired effect and duration of treatment. For adults, the dosage is generally from 2000 to 4000 mg per day, parenterally, especially intravenously or by slow perfusion.

In general, the practitioner will determine the dosage that is deemed most suitable according to age, weight and all other factors that are specific to the patient being treated.

The following examples illustrate the composition according to the invention.

Example A

Injectable solutions for perfusion containing 5 g / l of active product and having the following composition are prepared according to the general technique:

5δ-[(3S) -3-quinuclidinyl] thiomethyl

Pristymycin I _A ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 5 5

0.1N aqueous hydrochloric acid solution ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 49cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ enough 1000cc

Example B

Injectable solutions for perfusion containing 1 g / l of active product and having the following composition are prepared according to the general technique:

5δ-[(3S) -3-quinuclidinyl] thiomethyl

Pristymycin I _A ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.4g

26-[(2-diethylaminopropyl) sulfonyl]-

Pristinamycin II _B , Isomer A ‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.6g

0.1N aqueous hydrochloric acid solution ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 12.6cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ enough 1000cc

Example C

Injectable solutions for perfusion containing 1 g / l of active product and having the following composition are prepared according to the general technique:

5δ-[(3S) -3-quinuclidinyl] thiomethyl

Pristymycin I _A ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.4g

26-[(2-diethylaminopropyl) sulfonyl]-

Pristinamycin II _B , Isomer A ‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.6g

0.1N aqueous hydrochloric acid solution ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 12.3cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ enough 1000cc

Example D

Injectable solutions for perfusion containing 1 g / l of active product and having the following composition are prepared according to the general technique:

5δ-[(3S) -3-quinuclidinyl] thiomethyl

Pristymycin I _A ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.4g

26-[(2-diethylaminopropyl) sulfonyl]-

Pristinamycin II _B , Isomer A ‥‥‥‥‥‥‥‥‥‥‥‥‥ 0.6g

0.1N aqueous hydrochloric acid solution ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 12.7cc

Distilled water ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ enough 1000cc

Claims (7)

Cenerzistin and its pharmaceutically acceptable salts in the form of isomers or mixtures thereof.

Wherein Y is hydrogen or dimethyl amino and R is 3- or 4-quinuclidinyl. The cinerzistin of claim 1, which is 5δ-[(3S) -3-quinuclidinyl] thiomethyl pristinamycin I _A and a pharmaceutically acceptable salt thereof. The cinerzistin of claim 1, which is 5δ-[(3R) -3-quinuclidinyl] thiomethyl pristinamycin I _A and a pharmaceutically acceptable salt thereof. The cinerzistin of claim 1, which is 5δ-[(3R) -3-quinuclidinyl] thiomethylviriniamycin S and a pharmaceutically acceptable salt thereof. The cinerzistin of claim 1, which is 5δ-[(3R) -3-quinuclidinyl] thiomethylviriniamycin S and a pharmaceutically acceptable salt thereof. A pharmaceutical composition having a therapeutic effect on infection of a bacterial cause comprising one or more cinerzistins as claimed in claim 1 in combination with one or more common diluents or adjuvants. Therapeutic effect against infection of a bacterial cause comprising one or more cinerzistins as claimed in claim 1 in combination with a soluble derivative of pristinamycin II _B of the following formula or a known pristine mycin of pristinemycin II _A form Pharmaceutical compositions having.

Wherein R ₁ is 1) i) 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-a together with the nitrogen atom to which the alkyl moieties each contain 1-5 carbon atoms and to which they are attached One or two alkylaminos capable of forming a saturated heterocyclic system selected from zefinyl, morpholino, thiomorpholino and 1-piperazinyl (substituted or unsubstituted by alkyl of 1-5 carbon atoms) Dialkylamino radicals; Or ii) carbon number substituted with 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidyl, 2- or 3- amizethidinyl or 2-, 3- or 4-azinyl radicals Alkylthio radicals comprising -5; 2) Radicals of Formula Het-S- wherein Het is 3-pyrrolidinyl, 3- or 4-piperidyl, 3-azetidinyl or 3- or unsubstituted or substituted by alkyl having 1-5 carbon atoms; 4-azinyl radical; 3) alkyl moieties, together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, 1-azetidinyl, 1-azinyl, morpholino, thiomorpholino and 1-piperazinyl ( A dialkylamino radical capable of forming a saturated heterocyclic system selected from substituted or unsubstituted by alkyl of 1 to 5 carbon atoms, or

Radicals in which R ₂ may contain one or more other heteroatoms selected from sulfur, oxygen and nitrogen in the sulfoside or sulfone state and are substituted or unsubstituted by alkyl to 4- to 7-each nitrogen-containing heterocycle. Is a click radical; N-alkyl-N-cycloalkylamino, alkylamino, dialkylamino or dialkylcarbamoyloxy containing phenyl, cycloalkylamino and 3-6 ring atoms (the last two alkyl moieties are the nitrogen to which they are attached Together with the atoms, it may comprise other heteroatoms selected from sulfoxide or sulfone sulfur, oxygen and nitrogen and may form 4- to 7-angled saturated or unsaturated hetercyclic systems substituted or unsubstituted by alkyl. One or more 4- to 7-each which may be substituted by one or two radicals selected from, or may include one or two other heteroatoms selected from sulfur, oxygen and nitrogen in the sulfoxide or sulfone state Nitrogen-containing heterocyclic radicals, which heterocyclic radicals are unsubstituted or substituted by alkyl and the hetercyclic radicals are Alkyl chain containing 2-4 carbon atoms substituted with a chain containing them, provided that at least one of the substituents contained in the alkyl chain is a nitrogen-containing substituent capable of forming a salt [(S ) -1-methyl-2-pyrrolidinyl] methyl radical; n is 1 or 2 and the alkyl radicals mentioned above are straight or branched and each includes 1 to 10 carbon atoms unless otherwise specified. (The pristinamycin can be used in the form of isomers or mixtures thereof and in the form of acid addition salts.)