DD253616A5 - PROCESS FOR PREPARING NEW PLEUNROMUTILINE DERIVATIVES - Google Patents

Abstract

The invention relates to derivatives of 14-O - & (1-amino-2-methylpropan-2-yl) thioacetyl! Mutilin and -19,20-dihydromutilin, in particular N-acyl-14-O - & (1-amino-2 -methylpropan-2-yl) thioacetyl! mutilin or -19,20-dihydromutilin, in particular new pleuromutilin derivatives of the formula I, wherein R 1 is ethyl or vinyl and R 2 is an aminoalkyl group whose alkyl moiety may be substituted by hydroxy or a five-membered one Heterocycle, and their acid addition and quaternary salts, as well as processes for their preparation and their use. Formula I

Description

Field of application of the invention

The invention relates to a process for the preparation of derivatives of 14-0 - [(1-amino-2-methylpropan-2-yl) thioacetyl] -mutiline and -19,20-dihydromutilin, in particular N-acyl-MO-KI-amino ^ -methylpropane ^ -yl-thioacetyl-jmutiline or-19,20-dihydromutilin.

The compounds according to the invention have interesting biological and chemotherapeutic properties.

In particular, they show an inhibitory effect against bacteria and antiparasitic activity.

They are used as medicines in veterinary medicine, for example for the control of bacteria and in particular for the treatment of microorganism infections and for growth promotion in domestic and farm animals.

Characteristic of the known technical solutions

There is no information available on which compounds have hitherto been used to control microorganisms and anaerobes.

There is also no information available about processes for the preparation of pleuromutilin derivatives.

Object of the invention

The aim of the invention is to provide novel compounds which can be used for controlling microorganisms and anaerobes in veterinary medicine.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, new pleuromutilin derivatives of the formula

0.GO.GH ₂ .SG

0 GH

, HH. GO.

manufactured,

wherein R _{1 is} ethyl or vinyl and R _{2 is} an aminoalkyl group whose alkyl moiety may be substituted by hydroxyl, or a five-membered saturated heterocycle, and their acid addition and quaternary salts.

According to the invention, the compounds of the formula I are obtained by reacting a compound of the formula _f

O.CO.CH ₂ .SGCH ₂ .

- O CH,

OH

wherein Ri has the above meaning acylated, in particular with an active ester of a compound of formula

HOOC-R ₂ , III

wherein R _{2 has} the same meaning as R ₂ , but wherein the amino groups contained in R ₂ are protected by a protective group, and then cleaved the protecting group and the compounds obtained, if desired, converted into their acid addition salts or quaternary salts.

The process according to the invention can be carried out, for example, by reacting a compound of the formula II and a compound of the formula III in a solvent which is inert under the reaction conditions, e.g. in a di (lower) alkylcarboxamide such as dimethylformamide, dissolved or suspended and the reaction allowed to proceed at room temperature or elevated temperature, preferably at room temperature. The subsequent cleavage of the protective groups can be carried out by methods known per se, for example by reductive deprotection with Pd / activated carbon and hydrogen or by treatment with trifluoroacetic acid. From the reaction mixture, the end product can be isolated according to methods known per se and optionally purified.

The compounds of the formula I can be converted into their acid addition salts and vice versa. From the compounds of the formula I, the corresponding quaternary salts can be obtained by methods known per se. The compounds of formula I may have at least one asymmetric carbon atom and therefore exist in the form of diastereoisomeric isomers and mixtures thereof which may be separated by known methods. The use of optically active starting materials leads to the corresponding end products. The invention relates to both the isomers as well as their mixtures.

The compounds of formula I and their pharmacologically acceptable acid addition and quaternary salts have low biological toxicity interesting biological, especially chemotherapeutic properties and can therefore be used as a remedy. They exert an inhibitory effect against bacteria as determined by in vitro studies with the serial dilution test using different bacterial strains, e.g. Staph. aureus, staph. epidermidis, Strept. pyogenes, Strept. pneumoniae, E. coli, Klebsieila pneumoniae, Haemophilus spp., Leptospira spp., Erysipelothrix rhusiopathiae and obligate anaerobes, e.g. B. Bacteroides fragilis, was detected from a concentration of about 0.008 to 25 / xg / ml. In particular, an inhibitory activity against mycoplasmas and chlamydia was found, which showed from a concentration of about 0.008 to 0.5 μg / ml. "The chemotherapeutic activity of the compounds was by experiments in mice, using different bacterial strains, and in chickens, under This inhibitory effect was observed from a concentration of about 12 to 50 mg / kg of body weight.Therefore, the compounds according to the invention can be used as antibacterial antibiotics.Also, the abovementioned compounds exhibit antiparasitic activity, in particular against coccidia, as well as a growth promotion activity. To test the effectiveness against coccidia, the test was carried out in vivo on chicken. The effects can be confirmed in these animal experiments in doses of 20-150 mg / kg diet, depending on the duration of application. The growth-promoting properties were determined in chicken and pork in the dosing range of 10-50 mg / kg feed. The compounds of the formula I therefore appear suitable for the chemotherapeutic treatment of coccidioses in poultry and as "growth promoters" in the abovementioned species The compounds of the formula I can be administered orally, locally or parenterally In the preparation of the corresponding administration forms, the compounds of the If appropriate, they are administered as water-soluble, physiologically tolerable salts, alone or in suitable dosage forms, together with inorganic or organic, pharmacologically indifferent excipients, for example as constituents of capsules, tablets, granules, gelatin-coated powders, injection preparations and instillation preparations, which contain a 50 to 500 mg per capsule.) Moreover, the compounds according to the invention form excellent additives to feed mixtures (as a premix) or drinking water and thinning fluids for artificial insemination and egg-feeding techniques. For the application, the dose administered depends on the compound used and the mode of administration and the type of treatment. Satisfactory results are generally obtained as antibacterial and antianaerobic agents when the compounds are used at a daily dose of about 10 to 300 mg / kg of body weight. In larger mammals, satisfactory results are obtained when administering a daily dose of about 1 to 3 g. This amount may optionally be given in correspondingly smaller doses two to four times daily or in sustained release form. 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 having, on the order of magnitude, the same activity as the corresponding free bases. Suitable acid addition salts are the hydrochlorides, hydrogen fumarates, fumarates and naphthalene-1,5-sulfonates. As indifferent auxiliaries or additives for the preparation of appropriate galenic administration form can sweeteners, flavors, dyes, preservatives, fillers or carriers, for example diluents such as calcium carbonate, lactose, polyvinylpyrrolidone, Ma η η it or talc, granulating and disintegrating agents, such as Starch or alginic acid, binders, such as

Starch, gelatin or acacia and lubricants such as magnesium stearate, stearic acid or talcum. Orally administrable preparations may contain conventional suspending agents, for example methylcellulose, tragacanth or sodium alginate.

Suitable wetting agents are, for example, lecithin, polyoxyethylene stearate or polyoxyethylene sorbitan monooleate. As a preservative, for example, ethyl-o-hydroxybenzoate can be used. For the preparation of capsules can be used as a diluent, for example, calcium carbonate, calcium phosphate or kaolin.

The compounds of formula I can be used in a similar manner to the standard compound tiamulin known for this use.

The starting compounds of the formula II are novel and can be obtained by reacting a compound of the formula

O. CO. CH -, - .R

wherein Ri has the above meaning and R _{5 is} chlorine, bromine or an -O.SO2.R6 group, wherein R _{6 is} alkyl or aryl, with the compound of formula

CH, 3

HS.C.CH-.NH.

I ^{2 2} ν

implements. This reaction can be carried out, for example, by dissolving in a solution of sodium in an anhydrous lower alcohol, e.g. B. in ethanol or methanol, a compound of formula V dissolves. To this solution is added the solution of a compound of formula IV in a solvent inert under the reaction conditions, e.g. in an aliphatic ketone such as ethyl methyl ketone or acetone. The reaction preferably proceeds at room temperature to the boiling point of the reaction mixture, in particular at 25 to 55 ° C, and duration, for example, between 7 and 15 hours.

The starting materials of the formulas III, IV and V are known or can be prepared analogously to known methods or as described in the examples. The compounds of formula V are for example as described in F.J. Carroll, J.D. White and M.E. Wall, J. Org.

Chem. 28/1240 (1963).

The alkyl groups appearing as substituents are preferably lower alkyl groups, in particular having 1 to 4 carbon atoms. If R _{2 is} a heterocycle, it may contain one or two heteroatoms, one heteroatom being nitrogen and the optionally present second heteroatom being sulfur.

As protective groups for the amino function in the starting compounds of the formula IM, those which are generally known as amino protective groups can be used, for example -CO.O.CH ₂ C ₆ H ₅ , -CO.OC (CH ₃ I ₃ or COO CH ₂ .CCI ₃ .

Preferred meanings of the substituents are as follows:

R ₁ = a) ethyl

b) vinyl, with vinyl being particularly preferred R ₂ = a) aminoalkyl

b) aminohydroxyalkyl

c) as a) and b), wherein the alkyl part has 1 to 6, preferably 1 to 4 carbon atoms.

d) 5-membered saturated heterocycle

e) 5-membered saturated heterocycle containing a nitrogen atom and optionally a sulfur atom. Combinations of these groups are particularly preferred.

A particularly preferred compound is 14-0- [1- (2-amino-3-methylbutyrylamino) -2-methylpropan-2-ylthioacetyljmutiline as the free base or as the hydrochloride, especially in the D form.

embodiment

The invention will be explained in more detail with reference to some examples.

In the following examples, which explain the invention in more detail but are not intended to limit its scope in any way, all temperatures are given in degrees Celsius.

Example 1: M-O-ti-ta-amino-S-methylbutyricamino-methylpropan-a-yl-thioacetyn-IS (O-dihydromutilin.hydrochloric):

A solution of 1.85 g of Z-valine-4-nitrophenyl ester and 2.35 g of lA-O-KI-amino-methylpropan-o-thioacetylHS ^ O-dihydromutiline in 30 ml of dimethylformamide is kept at 25 ° for 7 hours. The reaction mixture is then poured into water and extracted by shaking repeatedly with ethyl acetate. After backwashing the organic phase with 0.1 N hydrochloric acid and then with NaCl-saturated water to give the protected title compound, which is used without further purification for deprotection.

A solution of 3.1 g of this Z-protected compound in 150 ml of ethanol is mixed with 60 mg of Pd / activated carbon (palladium on charcoal, 10%) and stirred under hydrogen atmosphere for 1 hour. The title compound is obtained in virtually quantitative yield.

The process can also be carried out with BOC-valine-4-nitrophenyl ester, the deprotection being carried out as follows:

3 mmol of the BOC-protected compound are dissolved at -10 ° in 25 ml trifluoroacetic acid and kept at this temperature for 10 minutes. Subsequently, the reaction mixture is brought to 25 °, allowed to react for a further 2 hours and poured in the sequence to 100 ml of 10% NaHCCV solution. After repeated extraction with ethyl acetate and back washing of the organic phase, the crude product is obtained, which is chromatographed on silica gel (eluent: CHCl3 / CH3OH = 7 / I).

Analogously as described in Example 1, the following compounds of formula 1 can also be obtained:

bp: ^R l ^R 2 · 2 -CH = CH ₂ -CH ₂ -NH ₂ 3 - "_ -CH-CH ₀ (D) I NH ₂ 4 _ .. _ -CH.CH-.CH.CH ₀ NH ₂ 'CH ₃ 5 -C ₂ H ₅ -CH.CH, (D) I " NH ₂ 6 -CH = CH ₂ -CH.CH ₃ (L) NH ₂ 7 - ^η - _L ~ j. ^(L) H - δ - »- jj (L) H 9 -CH ₂ CH ₂ -NH ₂ 10 -CH = CH ₂ -CH-7 CH-CH- II ³ NH ₂ CH ₃ (L) 11 yy _(D) H 12 - CH - CH - CH ₀ NH ₂ CH ₃ (D) 13 - * - -CH- CH ₂ OH - NH ₂ (L)

- / - έθύ ΟΙΟ

NMR spectra (CDCl ₃ )

Example: Spectrum:

5.62 (d, IH, H _14, J _H14H13 = 7.5 Hz); 7.72 (t, IH, NHCO), -

3.42 (d, IH, N-CH-CO, 3 = 6.25 Hz); 3.32 (d, IH, H ₁₁ ,

⁰ HIlHlO ⁼ 6'25 ^{Hz); AB} - ^S y ^{stem: (v} a = ³ · ^{17 'V} B ^{= 3} · ^27' J _AB = 15 Hz, S-CH ₂ -CO).

7.68 (t, IH, NH); 5.73 (d, IH, H _14, J = _H14H13 8.75 Hz); 3.75 (s, 2H, CO-CH ₂ -NH ₂ ); 3.38 (d, IH, H ₁₁ , J _HI1H10 = 6.25 Hz); 3.28 (m, 2H, = C-CH ₂ -NH); 1.25, 1.26 (s, s, 6H, according to CH-J.

7.78 (t, IH, NH); 5.74 (d, IH, H _14, J = _H14H13 8.75 Hz); 4:03 (q, IH, -CH-CH _3, J = 7.5 Hz); 3.37 (d, IH, Η _χ1 , J _H11H10 = 6.25 Hz); 1.25 (s, 2xCH ₃ , according to CH ₃ ); 3.3 (m, 2H ₁ = C-CH ₂ -NH).

7.76 (t, IH, NH); 5.76 (d, IH, H _14, J = _H14H13 8.75 Hz);

CH-I ²

3.43 (dd, IH, CO-CH-NH ₂ , J = 3.75 Hz, 3 '= 8.75 Hz); 3.25

(d, 2H, CH-CH ₂ -NH ₂ ); AB system: (V _A = 3.17, Vg = 3.25, J _A8 = 15 Hz, -S-CH ₂ CO).

5.64 (d, IH, H ₁₄ , J _H14 j ₁₃ = 8.1 Hz) -, 3.56 (q, IH, CH ₃ -CH, J = 7.5 Hz); 3:44 (d, IH, H _n, J = _H11H10 6.25 Hz); AB system: (V _A = 3.17, V g = 3.25, J _AB = 15 Hz, S-CH ₂ -CO); ABX system: (V _A = 3.33, V _β = 3.25, ν _χ = 7.75, J _Aβ = 13.4 Hz, ³ AX ⁼ " ³ BX ^{= 7} ' ^{5 Hz} ' C-CH ₂ -NH).

7.74 (t, IH, NH); 5.75 (d, IH, H _14, J = _H14H13 8.75 Hz); 3.56 (q, IH, CO-CH-NH, J = 7.5 Hz); 3.36 (d, IH, H ₁₁ ,

³ HIlHlO ⁼ 6'25 ^{Hz); AB} - ^S y ^{stem: <v} a = ³ · ^{17 'V} B ^{= 3} x ^24'

CH ₃ J _AB = 15 Hz, S-CH ₂ -CO); 1.4 (d, 3H, CO-CH-NH ₂ , J =

7.5 Hz).

7.72 (t, IH, NH); 5.77 (d, IH, H _14, J = _H14H13 8.75 Hz); AB system: (V _A = 4.29, V _β = 4.13, J _AB = 10 Hz, S-CH ₂ -NH); 3.36 (m, IH, H ₁₁ ).

8.07 (m, IH, NH); 5.76 (d, IH, H _14, J _H14J13 = 8.75 Hz);

f 2

3.84 (dd, IH, CO-CH-NH, J = 5 Hz, J ¹ = 8.75 Hz); 3.38 (d,

IH, H ₁₁ , J _h11h1 q = 6.25 Hz); AB system: (V _A = 3.17, V _β = 3.25, J _AB = 15 Hz, S-CH ₂ -CO); 3.25 (m, 2H ₅ = C-CH ₂ -NH).

5.62 (d, IH, H _14, J _H14H13 = 7.5 Hz); 3.24 (d, IH, H _n , ^J H11H1O ^{= 6} ' ^25Hz) 5 ABX system: (V _A = 3.34, V _β = 3.26, V _x = 7.38, J _{AB =} 13.5Hz, J _AX = J _5x = 7.5 Hz, NH-CH ₂ -C ^); 3.83 (t, 2H, NH ₂ -CH ₂ , J = 5 Hz); 2.38 (t, 2H, CH ₂ CO, J = 5 Hz).

7.68 (m, IH, NH); 5.74 (d, IH, H _14, J = _H14H13 8.75 Hz); 3.2 • (s, 2H, S-CH ₂ -CO); 3.38 (m, IH, H ₁₁ ); 3.25 (d, IH, CH-CH _3,

J = 3.75 Hz).

8.05 (t, IH, NH, NH-CH ₂ -CS); 5.73 (d, IH, H ₁₄ ,

CH ₂

^J H14H13 ⁼ 8'75 ^{Hz); 4} * ⁴⁸

6.25); 1.25, 1.22 (s, s, according to CHJ); AB system: (V _A = 3.18,

V ₈ = 3.24, J _AB = 15 Hz, S-CH ₂ -CO).

7.8 (m, IH, NH); 5.75 (d, IH, H _14, J = _H14H13 8.75 Hz); 3:38

(d, IH, H _11, = ⁶ JHIlHlO ^{'25 Hz); 3} x ^{24 (d} ' ^1H ' ^CH - ^NH 2 ^{); 3} · ² (s, 2H, S-CH ₂ -CO); 3.31 (m, 2H, CH ₂ -NHCO).

7.9 (m, IH, NH); 5.75 (d, IH, H _14, J = _H14H13 8.75 Hz); AB system: (V _A = 3.18, V _β = 3.28, 3 _AQ = 15 Hz, S-CH ₂ -CO); 3.36 (m, IH, H ₁₁ ); 3.91 (dd, IH, -CHH'-OH, J ₁ = 10 Hz, J ₂ = 5 Hz); 3.71 (dd, IH, -CHH'-OH, J ₁ = 10 Hz, J ₂ = 6.25 Hz); 3.5 (dd, IH, NH ₂ -CH-CH ₂ , J ₁ = 6.25 Hz, J ₂ = 5Hz).

The required as starting materials I ^ O-td-amino ^ -methylpropan ^ -dithioacetyl-IS ^ O-dihydromutilin can be obtained as follows:

4.6 g of sodium are dissolved in 500 ml of ethanol (absolute), with 14.1 g of 3-amino-2-methyl-2-propyl mercaptan (FI Carroll, JD White and ME Wall, J. Org. Chem. 28, 1240 1963]) and stirred for 1 hour at 25 °. The reaction mixture is then mixed with a solution of 53.2 g of 19,20-dihydropleuromutilin-22-O-tosylate in 300 ml of ethyl methyl ketone and kept at 25 ° for 15 hours .. It is poured into ice water and extracted repeatedly with ethyl acetate. After washing back the organic phase with NaCl-saturated water to give a crude product which is chromatographed over silica gel (eluent: CHCl3 / CH3OH = 11 1).

NMR (CDCl ₃ ): 5.8 (d, 1H, H ₁₄ , Jmims = 9Hz); 3.38 (d, 1 H, H _11, J _H iihio = 6.3 Hz); 3.17 (s, 2H, S-CH ₂ -CO); 2.65 (s, 2H, N-CH ₂ -C =); 1.7 {b, 2H, NH ₂ ); 1.28 (s, 6H, 2xCH ₃ ).

Claims (3)

Invention claim: 1. A process for the preparation of an N-acyl-MO-tO-amino-methyl-propane-o-thioacetynmutiline
and 19,20-dihydromutilin derivatives of the formula CH " , SGCH ₂ .HB.GO. wherein R _{1 is} ethyl or vinyl and R _{2 is} an aminoalkyl group, their alkyl part by hydroxy
may be substituted or denote a five-membered saturated heterocycle, and their
Acid addition and quaternary salts, characterized in that a compound of the formula CH O ₀ GO.CH ₀ . SCCH ₀ . wherein R _{1 is} ethyl or vinyl, acylated, in particular with an active ester of the compound of formula HOOC-R ₂ , III wherein R _{2 has} the same meaning as R ₂ , but wherein the amino groups contained in R ₂ are protected by a protective group and then splits off the protecting group and the
obtained compounds in free form or in the form of their acid addition salts or quaternary salts. 2. The method according to item 1, characterized in that a compound of formula I is prepared, wherein a) R _{1 is} vinyl and R _{2 is} a five-membered saturated heterocycle or an unsubstituted one
Aminoalkyl group, and which, if it contains an asymmetric carbon atom, is present in the D-form or b) R _{1 is} vinyl and R _{2 is} aminohydroxalkyl. 3. Process according to item 1, characterized in that a compound of the formula I is prepared, selected from 14-0- [1 - ((D) -2-amino-3-methylbutyrylamino) -2-methylpropan-2-ylthioacetyl] -19.20-dihydromutilin, MO-fi-i-aminoacetylamino-1-methylpropan-1-ylthioacetyl] mutilin, 14-0- [1 - ((D) -2-aminopropionylamino) -2-methylpropan-2-yl-thioacetyl] -mutiline, 14-0- [1- (2-Amino-4-methylvalerylamino) -2-methylpropan-2-yl-thioacetyl] mutilin, 14-aminopropionylamino) -2-methylpropan-2-yl-thioacetyl] -19,20-dihydromutilin , 14-0- [ Aminopropionyl-amino-methyl-propane-y-thioacety-mutilin, 14-0- [1 - ((L) -thiazolidin-4-ylcarbonylamino) -2-methyl-propan-2-yl-thioacetyl] -mutiline, MO-ti-dD-pyrrolidine-1-yl-carbonyl-amino-1-methyl-propane-1-yl-thioacety-D-mutilin, 14-0- [1- (3-aminopropionyl-amino-1-methyl-propane-1-yl-thioacetyl] -ISH-O-dihydromutilin, 14 -0- [1 - ((L) -2-amino-3-methylbutyrylamino) -2-methylpropan-2-yl-thioacetyl] mutilin, 14-0- [1 - ((D) -pyrrolidin-2-ylcarbonylamino) 2-methylpropan-2-yl-thioacetyl] mutilin and 14-0- [1 - ((L) -2-amino-3-hydroxypropioniiamino) -2-methylpropan-2-yl-thio-acetyl] mutilin in the form of free bases, acid addition salts or quaternary salts.
4. The method according to item 1, characterized in that 14-0- [1 - ((D) -2 _r amino-3-methylbutyrylamino) -2-methylpropan-2-y! -Thioacetyl] mutilin in the form of the free base, acid addition salts or quaternary salts.