DE3314479A1 - PLEUROMUTILIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS PHARMACEUTICALS - Google Patents

Description

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New pleuromutilin derivatives, processes for their preparation and their uses

The invention relates to new pleuromutilin derivatives of the formula

ι V ²

O.CO.CH ₀ .SC-CH R_

I ² ι \ / ³

I Ch ₃ ^ n _x

where R, for ethyl or vinyl and R "for a lower alkoxy, the amino, a lower alkylamino optionally substituted by amino, lower alkylamino, lower dialkylamino or hydroxy, a lower one Dialkylamino group or a five- or six-membered saturated one Heterocycle which contains one or two nitrogen atoms as heteroatoms and which is optionally replaced by a lower alkyl group may be substituted, and R, and R. are identical or different and represent hydrogen or a lower alkyl group, and their acid addition salts and quaternary salts, and processes for their preparation "and their uses.

According to the invention, the compounds of the formula I are obtained by man

a) for the preparation of compounds of the formula

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CH.

O.CO.CH ₀ .SC

OH

CH

NH. R.

Yes

wherein R 1, R 1 and R, have the above meaning, a compound of the formula

O.CO.CH ₀ .R _c
O CH, j ^λ -

II

wherein R, has the above meaning and R ₁ - is chlorine, bromine or an -O.SCL.R ^ group, where R is alkyl or aryl, with a compound of the formula

HS-C- CH

CH ₃

CO.

NH. R.

III

_ _{ο β} »ο ß * α» ίι Λ &

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in which R "and R" have the above meaning, reacts or
b) for the preparation of compounds of the formula

ο.co. cn _n . sc-CH

ι 2 ι

O CH ₀ ι CH Λ S-- - ^ O CH, X ! - ^ 1
/ CH, \ CH ₃ OH

³ \ r ^R 4

wherein R ,, R "and R, have the above meaning and R, for a lower one Alkyl group, compounds of the formula Ia are alkylated by known methods and the compounds obtained are converted into their acid addition salts as desired or quaternary salts.

Process variant a) can be carried out, for example, by a compound of the formula IH is dissolved in a solution of sodium in an anhydrous lower alcohol, for example in "ethanol or methanol." this solution is now the solution of a compound of formula II in one Solvent inert under the reaction conditions, e.g. in an aliphatic ketone such as ethyl methyl ketone or acetone, is added. the The reaction proceeds preferably at room temperature to the boiling point of the reaction mixture, in particular at 25 to 55 ° C, and lasts for example between 2 and 12 hours.

Process variant b) can be used for the alkylation of amino groups known methods, such as those used by CA. Bühler and D.E. Pearson in Survey of Organic Chemistry, Wiley Interscien-

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ce are described. Depending on the amount of alkylating agent used one obtains mono- or dialkylated end products or mixtures. Preferably monoalkylated end products are obtained when using equivalent ones Amounts of alkylating agent dialkylated by reaction with an excess of the alkylating reagent. From the reaction mixture can after methods known per se, the end product can be isolated and, if necessary, purified.

The compounds of the formula I can be converted into their acid addition salts and vice versa. The corresponding quaternary salts can be obtained from the compounds of the formula I by methods known per se.

The compounds of the formula I, their pharmacologically acceptable acid addition salts and quaternary salts have interesting ones with low toxicity biological, in particular antimicrobial properties and can hence it can be used as a remedy. They develop an inhibitory effect against bacteria, as demonstrated by in vitro studies with the serial dilution test using various strains of bacteria, e.g. B. from Staph. aureus, staph. epidermidis, strept. pyogenes, strept. aronson. Strept. pneumoniae, Strept. faecalis, Aerococcus viridans, Haemophilus spp. and Neisseria gonorrh., from a concentration of about 0.06 to 50 μg / ml, and in vivo by experiments on mice. In particular has also been shown to have an inhibitory effect against mycoplasma, e.g. B. against mycoplasma hominis, Mycoplasma pneumoniae and Ureaplasma urealyticum, and chlamydia, e.g. B. found against Chlamydia trachomatis, which is from a Concentration of about 0.02 to 5 μg / ml showed. Therefore, the invention Compounds used as antibacterial antibiotics.

The compounds of the formula I are also effective against obligate anaerobes an inhibitory effect, as demonstrated by in vitro studies in the serial dilution test and show in vivo on the mouse. This was done in vitro using different strains, e.g. of Bacteroides fragilis,

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Bacteroides thetaiotaomic, Bacteroides vulgatus, Sphaerophorus varius, Sphaerophorus freundii, Clostridium perfringens, Bacteroides melaninogenicus and Sphaerophorus necrophorus, an inhibitory effect from about 0.008 to 50 μg / ml was found. In the in vivo tests one obtains satisfactory Final results when administered at a dose of approximately 10 to 300 mg / kg Body weight p.o. or s.c. The compounds of formula I can therefore used to combat infections caused by obligate anaerobes.

For the application, the dose to be administered depends on the one used Compound and the type of administration so / ie the type of treatment. Satisfactory results are obtained when administered to larger mammals a daily dose of about 10 to 300 mg / kg body weight. This amount can optionally be in correspondingly smaller doses from two to be given four times a day or in sustained release form. For larger mammals the daily dose is about 1 to 3 g. The compounds of the formula I can be used in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts, the salts being of the order of magnitude have the same effectiveness as the corresponding free bases. Suitable acid addition salts are the hydrochlorides, hydrogen fumarates, Fumarates and naphthalene-1,5-sulfonates.

The compounds of the formula I can be administered orally or parenterally will. As indifferent auxiliaries or additives for the production of corresponding Galenic forms of administration can be sweeteners, flavors, colors, preservatives, fillers or carriers, for example Diluents, such as calcium carbonate, sodium carbonate, lactose, polyvinylpyrrolidone, Mannitol or talc, granulating and disintegrating agents, such as Use starch or alginic acid, binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Orally administrable preparations can contain customary suspending agents, for example methyl cellulose, tragacanth or sodium alginate. as Examples of suitable wetting agents are lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan monooleate. As a preservative, two

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for example use ethyl o-hydroxybenzoate. For the production of capsules calcium carbonate, calcium phosphate or kaolin, for example, can be used as diluents.

The compounds of formula I can be used in a similar manner as for this Using known standard compounds, e.g. such as erythromycin, can be used.

A suitable daily dose for a particular compound of formula I will depend on a number of factors, for example their relative activity. This is z. B. for 14-O- [l-Amino-l-CZ-hydroxyethane-l-ylaminocarbonyl) -2-methylpropan-2-yl] thioacetylmutUin hydrochloride was determined in a septicemic model infection of the mouse and is about 40 mg / kg body weight (ED, _-n for oral administration) compared to 68 mg / kg body weight for erythromycin. The compounds according to the invention can therefore be used in a dose that is similar to or lower than the dose generally used for erythromycin (ζ. Β 4x500 mg).

The compounds of the formula I and the corresponding starting materials contain asymmetric carbon atoms and can therefore exist in the form of diastereoisomeric forms and mixtures thereof. Such mixtures can be separated by known methods. The invention includes both isomers and mixtures thereof. Connections of D-shape are preferred.

The starting compounds of the formulas II and III are known or analogous available by known methods. The starting materials of the formula III can be obtained, for example, in accordance with the reaction scheme below will.

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CH

CH.

. COOH

N — CH0-

CH ₃ CH ₃

CH.

1 !

CO.Ε

h "c

'3 ^CH 3

CH ₃

CH.

^^ N-CHO

CH ₃ CH ₃

F ³

CH- 1

■■ 3 y ι

CH ₃

\ NO,

—CO.R,

- CHO

-> IHb

-> · Ilia Ro = H)

(R = lower alkyl)

Lower alkyl (or alkoxy) preferably has 1 to 4 carbon atoms and for R, and R. in particular denote methyl. Examples of R “as Heterocycle are pyrrolidine, irnidazolidine, pyrazolidine, and piperidine, preferably Piperazine, unsubstituted or by lower alkyl, in particular substituted by methyl.

Preferably R _{1 is}
R ₂ =

Vinyl or ethyl amino, alkylamino or alkoxy hydrogen or alkyl (methyl)

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Combinations of these groups are particularly interesting. A special Group of compounds of the formula I is those in which R "represents a lower Alkoxy, the amino, a lower alkylamino optionally substituted by hydroxy, amino or lower dialkylamino, a lower one Dialkylamino, the piperazino or a lower 4-alkylpiperazino group and R., R, and R. have the above meanings.

In a further preferred group of compounds of the formula I R_ means a lower alkoxy, the amino, one by amino or Hydroxy-substituted lower alkylamino or a lower dialkylamino group, and R., R, and R. have the above meanings.

Particularly preferred are compounds of the formula I in which R "represents the Amino, a lower alkylamino or a lower alkoxy group and R ,, R, and R. have the above meanings.

Two particularly preferred compounds are 14-O - [(1-amino-1-methylaminocarbonyl-2-methylpropan-2-yl) thioacetylldihydromutilin and

M-O ^ Xl-Amino-1-methylaminocarbonyl ^ -methylpropan-Z-ylHhioacetyllmutilin and their hydrochlorides.

In the following examples, which explain the invention in more detail, their Should not restrict the scope in any way, all temperatures are : 0 values in degrees Celsius.

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Example 1; 14-Q-iIl-amino-] - (2-hydroxyethan-1-ylaminocarbonyl) -2-methylpropan-2-yPthioace!: Yl} -nutiline hydrochloride (method a);

2 g of 3-methyl-3-mercapto-2-aminobutyric acid (2-hydroxyethyl) amide, 4.63 g Pleuromutilin-22-O-tosylate and 3.73 g of tetrabutylammonium hydrogen sulfate , 5 are in a heterogeneous mixture of 45 ml IN NaOH and 100 ml Dichloromethane added. After a reaction time of 3 hours, the dichloromethane phase is separated off and worked up. For further travel. The crude product is purified on silica gel (mobile phase: chloroform / methanol = 8/1) chromatographed. An amorphous substance is obtained.

Example 2j D-14-Q - [(] - Amino-1-carbomethoxy-2-methylpropane-2-

yl) thioacetyl] mutilin hydrochloride (method a):

4 g of D-penicillamine methyl ester hydrochloride are in a solution of 0.92 g of sodium was taken up in 70 ml of methanol and kept at 25 ° for 1 hour for complete formation of the thiolate salt. This solution 10.6 g of pleuromutilin-22-O-tosylate, dissolved in 100 ml of methyl ethyl ketone, are added to. After a reaction time of 24 hours (25 °) it is worked up as usual and over silica gel (mobile solvent: toluene / ethyl acetate = l / l) chromatographed. Mp: 133 °

Analogously to that described in Examples 1 and 2, the following can also be used Compounds of formula I are obtained (Bp. 3 to 20):

Bp: ^R l ^R 2 ^R 3 ^R 4 amorphous 3 C ₂ H ₅ -NKCH ₂ CH ₂ OH H H Il
_ Il _
_ Il 4th
5
6th -CH = CH ₀
Il
II -NH ₂
-NHCH ₃ III III - "- (L) 7th _ II _ -0.CH ₃ H H II _ 8th _ II _ -0.CH ₂ CH ₂ CH ₂ CH ₃ H H 11th 9 C ₂ H ₅ -NHC ₇ H ₅ ' CH ₃ H

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Bp: ^R l ^R 2 ^R 3 ^R 4 _ Il _ 10 C ₂ H ₅ -NH ₂ CH ₃ H _ Il _ 11th C ₂ H ₅ -NKC ₂ H ₅ H H _ Il _ 12th CH = CH ₂ -NKCH ₃ CH ₃ H _ Il _ 13th CH = CH ₂ -NKCH ₂ CH ₂ .N H H _ "_ 14th C ₂ H ₅ -N ^ ^3
S CH H H Il _ 15th C ₂ H ₅ -NH.CH ₃ H H _ Il _ 16 CH = CH ₂ - <_> ™ 3 H H _ Il _ 17th C ₂ H ₅ _ Il _ H H _ Il 18th C ₂ H ₅ -ν ya H H _ Il _ 19th CH = CH ₂ -OCH ₃ CH ₃ H Il 20th
ι ^C 2 ^H 5 -NH ₂ H H

Example 21: 14-0 - [(l-Dimethylamino-l-carbomethoxy-2-methyIpropan-2- yl) thi0a cetyllmuttlin hydrochloride (method b):

A solution of 1.04 g of 14-0 - [(i-Amino-1-carbomethoxy-2-methylpropan-2-yl) thioacetyl] mutilin hydrochloride, G, 29 g of potassium carbonate and 0.53 g of dimethyl sulfate in 15 ml of dimethylformamide is heated to 100 ° for 10 minutes warmed up. After working up and chromatography over silica gel (mobile solvent: hexane / ethyl acetate = 3/2), the Title compound.

Analogously, as described in Example 21, the following compounds can also be used of formula I can be obtained:

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Bps ^R l ^R 2 ^R 3 ^R 4 amorphous 22nd CH = CH -OCH ₃ CH, H _ Il _ 23 C ₂ H ₃ -NKCH ₃ CH ₃ H _ " 24 C ₂ H ₅ -NH-C ₂ H ₅ CH ₃ CH ₃ _ Il _ 25th C ₂ H ₅ -NH ₂ CH ₃ CH ₃ _ Il 26th C ₂ H ₅ -NH ₂ CH ₃ H _ Il _ 27 CH = CH -NKCH ₃ CH ₃ H

Example 28; D-14-O-i (l-Amino-1-methylaminocarbonyl ^ -methylpropane ^ - yI) thiocetyl] mutiUn hydrochloride

A solution of 13.54 g of D-penicillamine acetone adduct (F. Asinger, K. Gluzek, monthly magazine f. Chemie 114, 47-63 [1983]) in 300 ml of dioxane and 24 ml of pyridine are added to 62.5 ml of phosgene in toluene while cooling with ice. The reaction mixture is kept at 25 ° for 1.5 hours and then 62.5 ml of an 8.03 molar methylamine solution in ethanol are added. After a reaction time of one hour, the precipitate is filtered off and washed with dichloromethane. One receives after Evaporation of the filtrate in vacuo, the protected methylamide, which is recrystallized from diisopropyl ether.

= 136.8 ° (CHCl ₃ , c = 2 g / 100 ml)
= 295.8 ° (CHCl ₃ , c = 2 g / 100 ml)

The protective group is removed and the reaction with the pleuromutilin tosylate is carried out analogously to Examples 1 and 2 described.

= + 44 ° (CHCL, C = 11.4 mg / ml)

^Ca] 436 ^{= 114} °

> ^c = ⁿ » ⁴ mg / ml)

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" NMR SPECTRA
Example: spectrum:

7.66 (m, 1H, NH-CO); 5.78 (d, IH, H _14, H _{HM H13} = 9 Hz); 3.75 (m, 2H, CH ₂ -OH); 3.48 (m, 2H, -CH ₉ -NH-); 3.35 (s, 1H, -N-CH-CO); 2.31, 2.19 (s, s, 2 χ CH ₃ , (CHj) ₁₆ , (CH ₃ J ₁₈ ); 0.9

(d, 3H, (CHj) ₁₇ , J = 7.2Hz); 0.72 (d, 3H, (CHj) ₁₅ , J = 6.3 Hz).

5.78 (d, IH, H ₁ ,, J ₁ , -. ,, -_ = 8.1 Hz); 3.72 (s, 3H, COOCHJ;

JL4 rl JL «+, in.? j

3.25 (s, 2H, S-CH ₂ -CO); 3.44 (s, 1H, N-CH-CO); 3.35 (m, IH, H ₁₁ ).

7.68 (m, 1H, NH); 5.62 (d, IH, H ₁₄₁ J ^ _{4 H13} = 8.1 Hz); 3.74 (m, 2H, CH ₂ OH); 3.45 (m, 2H, -CH ₂ NH-); 3.38 (s, 1H, H ₂ N-CH-CO); 1.42, 1.45 (s, s, 2 χ CH ₃ , -SC (CHj) ₂ -); 3.26 (s, 2H, S-CH ₂ -CO).

4 5.76 (d, IH, H _14, J = 8.1 Hz _{HI4 H13);} 7.1 (b, IH, NH); 3.35 (s,

IH, NH-CH-CO); 3:35 (m, IH, H _11); 3.25 (s, 2H, S-CH ₂ -CO).

7.25 (m, 1H, NH); 5.78 (d, IH, H _14, J = 8.1 Hz _{H14 R13);} 3.35

(s, IH, N-CH-CO); 2.85 (d, 3H, N-CH _3, J = '4.5 Hz); jl.5 (s, 6H, 2 χ CH ₃ , -SC (CH ₃ ) ₂ -).

6 '5.76 (d, IH, Η _1Λ , J _{H13H1 / i} = 8.1 Hz); 3.3 (s, 1H, N-CH-CO);

3.4-3.5 (m, 5H, -N-CH _2, H _n, S-CH ₂ -CO); 2.84 (t, 2H, -N-CH ₂ -, J = 6.3 Hz); 7.52 (m, IH, NH).

5.78 (d, IH, H _14, J = 8.1 Hz _{H14 H);} 3.72 (s, 3H, COOCH ₃ ); 3.46 (s, IH, N-CH-CO); ' 3.25 (s, 2H, S-CH ₂ -CO); 3.36 (d, IH,

^H ll ' ^J Hll, H10 ^{= 6 3 Hz)}

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5.8 (d, IH, H _14, J = 8.1 Hz _{H14 H13);} 4.15 (t, 2H, _U-CH2, J =

6.3 Hz); 3:35 (m, IH, H _11); 3.28 (s, 2H, S-CH ₂ -CO); 3.45 (s, 1H, N-CH-CO).

5:52 (d, IH, H _14, J _H14H13 = 9 Hz); AB system: IT ^ = 3.29,

Vj ₃ = 3.42, S-CH ₂ -CO, J _AB = 15 Hz); 3:45 (m, IH, H _11); 3.14

(m, 2H, N-CH ₂ CH ₃ ); 2.82 (s, 1H, CO-CH-NHCH ₃ ); 2.2 (s, 3H, N-CHJ.

10.26 7.15 (m, 1H, NH); 5.62 (d, IH, H _14, J _H14H13 = 9 Hz); 3.42 (m,

IH, H ₁₁ ); 2.85 (s, 1H, CO-CH-NHCH ₃ ); 2.40, 2.42 (s, s, 3H, NHCH ₃ ); 1.43, 1.48 (s, s, 6H, SC (CH ₃ ) J.

7.25 (b, 1H, NH); 5.63 (d, IH, H _14, J _H14H13 = 9 Hz); 3.32 (s,

IH, CO-CH-NH ₂ ); 3.24 (AB system, 2H, S-CH ₂ -CO, J _Aβ = 16 Hz).

12.27.70 (m, 1H, NH); 5.74 (d, IH, H _14, J _H14H13 = 9 Hz); 3.38,

3.40 (s, s, 1H, CO-CH-NHCH ₃ ); 2.83, 2.86 (s, s, 3H, CO-NHCH ₃ ); 2.32, 2.44 (s, s, 3H, -NHCH ₃ ).

7.45 (b, IH, NH); 5.77 (d, IH, H _14, J _H14H13 = 9 Hz); 3.31 (s, 1H, CO-CH-NH ₂ ); 3.3 (m, 2H, CO-NH-CH _2); 2.55 (q, 4H, N- (CH ₂ -CH ₃ ), J = 8 Hz); 1.44 (s, 6H, SC (CHJ ₂ -); 1.02 (t, 6H, N- (CH ₂ -CH ₃ ) J.

5.61 (d, IH, H _14, J = 9Hz _H14H13); 3.86, 3.88 (s, s, 1H, CO-CH-NH ₂ ); 3:43 (d, IH, H _11, J _HnH10 = 7 Hz); 3.24, 3.26 (s, s, S-CH ₂ -CO); 2.98, 3.15 (s, s, 2x3H, N- (CH ₃ ) J; 1.38 (s, 6H, SC (CHJ ₂ -).

15 7.3 (b, IH, NH); 5.64 (d, IH, H ₁₄ , ^ _Η14Η13 = 9 Hz); 3.38 (s,

IH, CO-CH-NH ₂ ); 3:45 (d, IH, H _11, J _H11H1Q = 7 Hz); 2.82, 2.88 (s, s, 2x3H, N- (CHJJ; AB system: V = 3.2, Vj ₃ = 3.4,

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J _AB = 16 Hz, S-CH ₂ -CO); 1.45, 1.49 (s, s, 2x3H, SC (CH ₃ ) ₂ -).

5.75 (d, IH, H _14, J _H14H13 = 9 Hz); 3.84, 3.88 (s, s, IH,

CO-CH-NH ₂ ); 3.7 (m, 4H, N- (CH ^ ₂ -); 3.38 (m, IH, H ₁₁ ); AB system: Y ^ = 3.2], Yj ₃ = 3.29, S-CH ₂ -CO, J _Aß = 16 Hz);

2:32 (s, 3H, N-CH _3).

5.61 (d, IH, H _14, J _H14H13 = 9 Hz); 3.84, 3.86 (s, s, IH, COCH-NH ₂ ); 3.7 (m, 4H, _N-CH2); 2.4 (m, 4H, _N-CH2); 2.31 (s, 3H, _N-CH3); 1:36 (s, 6H, SC (CH _{3) 2} -); 3.41 (d, IH, H ₁₁ , ³ HIlHlO ^{= 7 Hz)}

5.61 (d, IH, H _14, J = _H14H13 8.75 Hz); 3.85, 3.87 (s, s, 1H, CO-CH-NH ₂ ); 3.6 (m, 4H,> N-CH _2); 2.9 (m, 4H,> N-CH _2); 3:42 (d, IH, H _11, J _H11H10 = 6.25 Hz); 2.4 (m, IH, H _1Q ).

19.22 5.75 (d, IH, H _14, J = 8.1 Hz _{HM H13);} 3.76 (s, 3H, COOCH ₃ );

3.15 (s, 1H, N-CH-CO); 3.32 (s, 2H, S-CH ₂ -CO); 2.38 (s, 3H,

N-CH ₃ ).

7.2 (m, IH, NH); 5.66 (d, IH, H _14, J _H14H13 = 8.1 Hz); 3.42 (d,

IH, H ₁₁ , J _HnH10 = 6.3Hz); 3.4 (s, 1H, NH-CH-CO);

AB system: ν ~ _Α = 3.22, Y] ₃ = 3.34, J _Aβ = 15.3 Hz); 1.42, 1.48 (8, s, 2x3H, SC (CH ₃ ) ₂ ); 1.4, 0.96 (s, s, 2x3H,

5.77 (d, IH, H _14, J = 8.1 Hz _{Ηχ3 H14);} 3.72 (s, 3H, COOCH ₃ );

3.39 (s, 2H, S-CH ₂ -CO); 3.28 (s, 1H, N-CH-CO); 2.42 (s, 6H, -N (CHj) ₃ ); 1.4, 1.2 (s, s, 2 χ CH ₃ , (CHj) ₁₆ , (CHj) ₁₈ ).

24 6.38 (m, 1H, NH); 5.62 (d, IH, H _{14), H14H13} J = 9 Hz);

AB system: V ^ = 3.40, Vg ¹ = 3.47, S-CH ₂ -CO, J _AB = 15 Hz); 3.34 (m, 2H, N-CH ₀ -CHJ; 2.94 (s, 1H, CO-CH-N (OL) J;

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2.45 (s, 6H, N (CH ₃ ) ₂ ).

25 5.62 (d, IH, H ₁₄ , J _H14H13 = 9 Hz), AB system: V ^ = 3.39,

V ^ = 3.46, S-CH ₂ -CO, J _AB = 15 Hz); 2.48 (s, 6H, N

28 5.76 (d, IH, H _14, J = _H14H13 8.5 Hz); 3.32 (s, 1H, H ₂ N-CH-CO-);

2,825 (d, 3H, NCH ₃ , J = 5 Hz); AB system of the CO-CH ₂ -S-

Grouping (position of the 4 lines: 3.29, 3.23, 3.2, 3.14).

The required new raw materials can be obtained as follows will:

A) 3-methyl-3-mercapto-2-aminobutyric acid (2-hydroxyethyl) amide (for example 1,3):

a) 2,2,5,5-Tetramethyl-3-formyl-4- (4-nitrophenyloxycarbonyI) thiazolidine .
21.7 g of N-formyi-protected acetone adduct of penicillamine, 14.6 g of 4-nitrophenol and 22.7 g of NjN'-dicyclohexylcarbodiimide are dissolved in 260 ml of ethyl acetate and kept at 25 ° for 24 hours. After working up and chromatography on silica gel (mobile solvent: hexane / ethyl acetate = 2/1), a colorless oil is obtained which crystallizes through.

NMR (CDCl ₃ ): 8.35 (s, 1H, N-CHO); 8.2 (d, 2H, arom. H, J = 8 Hz); 7.25 (d, 2H, arom. H, J = 8Hz); 4.92 (s, 1H, N-CH-CO); 1.92 (s, 6H, 2 χ CH ₃ ); 1.6, 1.75 (s, s, 2 χ CH ₃ ).

b) ^^, S ^ -Tetramethyl ^ -formyl ^ -hydroxyäthylam'inocarbonylthiazolidine
A solution of 1.3 g of 2,2,5,5-tetramethyl-3-formyl-4- (4-nitrophenyloxycarbonyothiazolidine and 0.48 ml of ethanolamine in 50 ml of benzene is kept at 25 ° for 20 hours The benzene solution is evaporated and the residue is taken up in ethyl acetate. To remove the remaining 4-nitrophenol, it is repeatedly shaken out with water and then evaporated to dryness. After chromatography on silica gel (mobile phase:

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Chloroform / methanol = 7/1) the title compound is obtained in the form of a colorless oil.

NMR (CDCl ₃ ): 1.46, 1.6, 1.92, 1.97 (s, s, s, s, 4 χ 3H, CH ₃ ); 5.66 (s, 1H, N-CH-CO) J 3.45 (m, 2H ₅ -CH ₂ -N-); 3.7 (m, 3H, CH ₂ -O-, OH); 8.35 Cs, IH, HC = O); 7.17 (t, IH, -NH-CO, J = 5.4 Hz).

c) 3-methyl-3-mercapto-2-am'inobutyric acid (2-hydroxyethyl) amide 2.6 g of 2,2,5,5-tetramethyl-3-formyl-4-hydΓOxyäthylaminocaΓbonylthiazolidin are taken up in 150 ml of methanolic HCl and 18 Held at 25 ° for hours. After the solvent has been removed, it is taken up again in 100 ml of 0.1 N HCl and the reaction mixture is heated to 100 ° for 15 minutes. After working up, the title compound is obtained in free form.

NMR (D ₂ O): 3.98 (s, 1H, N-CH-CO); 3.2-3.7 (m, 4H,

1.47, 1.52 (s, s, 2 χ CH ₃ ).

Analogously as described, the following new starting products can also be used will be obtained:

B) 3-methyl-3-mercapto-2-aminobutyric acid amide (for example 4): NMR (D ₂ O): 4.0 (s, 1H, H ₂ N-CH-CO); 1.52, 1.58 (s, s, 2 χ CH ₃ ).

C) 3-methyl-3-mercapto-2-aminobutyric acid methylamide (for example 5.15): O NMR (D ₂ O): 3.84 (s, 1H, H ₂ N-CH-CO); 2.73 (s. 3H, _N-CH3); 1.38, 1.43 (s, s,

2 χ CH ₃ ).

D) 3-methyl-3-mercapto-2-aminobutyric acid (2-aminoethyl) amide (for example 6):

NMR (D ₂ O): 3.95 (s, 1H, H ₂ N-CH-CO); 3.1-3.7 (m, 4H, -NH.C 1.43, 1.49 (s, s, 2 χ CH ₃ ).

* η on

331U79

-21- 900-9321 / WA

E) 3-methyl-3-mercapto-2-aminobutyric acid (n) butyl ester (for Example 8);

NMR (D ₂ O): 4.13 (s, 1H, H ₂ N-CH-CO); 4.25 (t, 2H, -COOXH ₂ -); 1.5, 1.56 (s, s, 2 χ CHA

F) 3-methyl-3-mercapto-2-aminobutyric acid (2-diethyiaminoethyl) amide (for example 13):

NMR (CDCl _1. ): 4.0 (s, 1H, NH-CH-CO); 3.7 (m, 2H, CONH-CH _9); 3.3 (m, 2H, CH ₂ -N- (CH ₂ -CH ₃ ) ₂ ); 1.52, 1.48 (s, s, 2xCH ₃ , S-CiCH ^); 1.32 (t, 2x3H, N- (CH ₂ CH ₃ ) ₂ , J = 7.2 Hz).

G) 3-methyl-3-mercapto-2-aminobutyric acid dimethylamide (for example 14);

ο NMR (D ₂ O): 4.4 (s, 1H, NH-CH-CO); 3.12, 3.95 (s, s, 2x3H, N- (CH ₃ ).,); 1.44,

1.35 (s, s, 2x3H, S-

H) 3-methyl-3-mercapto-2-amino-l- (4-methylpiperazinyl) butyric acid (for Example 16, 17):

NMR (D ₂ O): 3.65 (m, 4H, N- (CHg) ₂ ); 2.4 (m, 4H, N- (CH ^ ₂ ) J.2.32 <s, 3H, N-CH ₃ ); 1.35, 1.44 (s, s, 2x3H, SC (CH ₃ ) ₂ ).

I) 3-methyl-3-mercapto-2-amino-l-piperazinylbutteΓSä * UΓe (for example 18):

NMR (D ₂ O): 3.8 (m, 4H, N- (CHg) ₂ ); 3.3 (m, 4H, N- (CH ^ ₂ ); 1.46, 1.44 (s, s, 2x3H, SC (CH ₃ ) ₂ ).,. ·

Claims (2)

90D-9321 / WA SANDOZ-PATENT-GMBH 7850 Lörrach patent claims; 1. New pleuromutilin derivatives of the formula CH _{3 /}
C. O.CO.CH ₀ .SC-CH
^l 1 \ O CH where R, for "ethyl or vinyl and R" for a lower alkoxy, the amino, a lower alkylamino optionally substituted by amino, lower alkylamino, lower dialkylamino or hydroxy, a lower one Dialkylamino group or a five- or six-membered, saturated heterocycle containing one or two nitrogen atoms as heteroatoms and which may optionally be substituted by a lower alkyl group, and R, and R are the same or different 900-9321 / WA and represent hydrogen or a lower alkyl group, and their acid addition salts and quaternary salts. 2. Process for the preparation of new pleuromutilin derivatives of the formula CO.R O CH O.CO.CH ₀ .SC-CH where R, for ethyl or vinyl and R_ for a lower alkoxy, the amino, a lower alkylamino optionally substituted by amino, lower alkylamino, lower dialkylamino or hydroxy, a lower one Dialkylamino group or a five- or six-membered, saturated Herocycle containing one or two nitrogen atoms as heteroatoms and which may be substituted by a lower alkyl group can, stand and R, and R. are identical or different and are hydrogen or a lower alkyl group, and their acid addition salts and quaternary salts, characterized in that a) for the preparation of compounds of the formula O.CO.CH ₂ .SC CH CH ₃ NlH. R. Yes i> · ο α ο « , * λ η οί -3- 900-9321 / V / A wherein R., R "and R" have the above meaning, a compound of the formula O CH. I I I O.CO.CH ₂ .R ₅ .CH. II CH. OH wherein R- has the above meaning and R _{5 represents} chlorine, bromine or a -O.SCL.R ^ group, where R, alkyl or aryl, with a compound of the formula HS-C-CH CO. NH. R. Ill wherein R_ and R, have the above meaning, converts or b) for the preparation of compounds of the formula O CH ₃ r ¹ T ^ O.CO.CH ₂ .SC-CH
'CH ^ N. ^Λ 1 CH. Ib CH. OH 331U79 - 4 - 900-9321 / WA where R ,, R ~ and R. have the above meaning and R ^ is a lower one Alkyl group, compounds of the formula Ia are alkylated by known methods and, if desired, the compounds obtained in their acid addition salts or quaternary salts.