FI88714C - Pleuromutilin derivatives promoting growth - Google Patents

Description

1 F F 71 4

GROWTH-ENHANCING PLEUROMUTIL LINE DERIVATIVES - PLEUROMU ACCOUNTING BEFRÄMJANDE TILLVÄXT

The invention relates to compounds of formula I for enhancing the growth of animals, CH3 o.co.ch2.s.c.ch2.nh.co.r2 ch3 '„CH, A.

10 0 <3 X.

Λ / vch, A

(Tl3 I

15 tH3 'OH

wherein R 1 is ethyl or vinyl and R 2 is lower aminoalkyl which is unsubstituted or substituted in its alkyl moiety by hydroxy, or a heterocyclic saturated ring which may contain one or two heteroatoms, one of which is nitrogen and the other the possible heteroatom is sulfur, as well as its acid addition or quaternary salts.

Pleuromutil derivatives are already known from Finnish patent publication 25 FI-58635 and application publication FI-831367. Known pleuromutilin derivatives differ from the compounds of formula I in the group attached to the sulfur atom.

The compounds can be prepared by acylation of 14-O-30 [(1-amino-2-methylpropan-2-yl) thioacetyl] mutilin or -19,20-dihydromutilin, and in particular by reacting a compound of formula II 2 ·> 8 714 CH 3 O.CO. CH? .SCCH, .NH_ CH 3 5? To react with a reactive ester of formula III.

hoocr2 · III

Wherein R 2 'has the same meaning as R 2 above, except that the amino group therein is protected, by removing any protection of the amino group; and recovering the obtained compound in free form, in the form of an acid addition salt or a quaternary salt.

The compounds of the invention may be prepared by dissolving or suspending a compound of formula II and a compound of formula III under reaction conditions in an inert solvent, e.g. di (lower) alkyl carboxylic acid amide such as dimethylformamide, and allowing the reaction to proceed at room temperature or elevated temperature, preferably room temperature. Deprotection can be carried out according to conventional methods, e.g. by reducing the deprotection with Pd / activated carbon and hydrogen or by treatment with trichloroacetic acid. The final products can be isolated from the reaction mixture and, if necessary, purified by conventional methods.

The compounds of the formula I can be converted into their acid addition salts and vice versa in a known manner. The corresponding quaternary salts can be obtained from the compounds of the formula I in a known manner.

3,88714

The compounds of formula I have at least one asymmetric carbon atom and can thus exist as diastereometric isomers and mixtures thereof which can be separated in a known manner. The use of Optises-5 ti active starting materials leads to similar end products. The invention relates to both isomers and mixtures thereof, and the latter means the latter unless otherwise indicated. Compounds in substantially the "D" form are of particular interest, except when R 2 is aminohydroxylalkyl.

The compound of formula I has interesting growth promoting activity. Growth-promoting properties were observed in chickens and piglets in the dose range of 10-50 mg / kg based on feed weight -15 na. The compounds of formula I are thus found to be useful as growth promoters.

To promote the growth of domestic animals, the dosage will, of course, vary with the size and age of the animal and the effect desired. Preferred doses in drinking water are 0.0125-0.05 w / v, in particular 0.0125-0.025, and in feed 20-400 g / t, in particular 20-200 g / t. It is especially advantageous to administer the active compound to chickens in drinking water and to piglets in feed.

The compounds can be used in the form of the free base or in the form of a physiologically acceptable acid addition salt and quaternary salts. Such salt forms have the same order of activity as the free base forms.

Examples of suitable acid addition salts are hydrogen fumarate, fumarate, naphthalene-1,5-sulfonate and especially the hydrochloride.

The compounds may be administered orally, topically or parenterally and in admixture with conventional acceptable diluents and carriers and, optionally, other excipients, and may be presented as tablets, 4 H 8 7 1 4 capsules or injectables.

The compounds also form excellent additives for mixing with feed (as a premix) or drinking water, as well as with diluents for artificial insemination and 5 egg implantation.

To promote the growth of domestic animals, the animal is administered an effective amount of a compound of formula I or a physiologically acceptable acid addition salt or quaternary salt thereof.

The starting materials of formula II are novel and can be prepared by reacting a compound of formula IV o.co.ch2tr5

15 I

| VS ~ CH3 IV

20 / '• H3 ™ 3 wherein R1 is as defined above and R5 is chlorine, bromine, or O.SOa.R6, where R1 is alkyl or aryl, to react with a compound of formula V CH3

HS.C.CH-.NH, V

This reaction can be carried out, for example, by dissolving a compound of formula V in a sodium solution in an anhydrous lower alcohol, e.g. ethanol 35 or methanol. To this solution is then added a solution of a compound of formula IV in an inert solvent under reaction conditions, e.g. an aliphatic ketone, such as ethyl ethyl ketone or acetone. The reaction is preferably carried out at room temperature - at the boiling point of the reaction mixture, in particular 25-50 ° C.

The starting materials of the formula III, IV and V are either known or can be prepared analogously to known methods, e.g. the compounds of the formula V, as described: F. J. Carroll, J.D. White and M. E. Wall, J. Org. Chem. 28/1240 (1963).

Alkyl groups present as substituents are preferably lower alkyl groups, especially those having 1 to 4 carbon atoms. When R2 represents a heterocyclic ring, this may contain one or two heteroatoms, one heteroatom being nitrogen and optionally the other heteroatom in the ring being sulfur.

As the amino-protecting groups of the starting materials of the formula III, amino-protecting groups can be generally used, e.g. -CO.O.CH2.C6H5, -CO.O.C (CH3) 3 (BOC) or -co.o.ch2cci3.

A particularly suitable single compound is 14-O- [1- (2-amino-3-methylbutyrylamino) -2-methylpropan-2-ylthioacetyl] mutilin as the free base or the hydrochloride, especially in the (D) form.

In the following examples, which illustrate the invention but do not limit its scope in any way, the temperatures are given in degrees Celsius.

Example 1: 14-O- [1 - ((D) -2-amino-3-methyl-butyrylamino) -2-methyl-propan-2-yl-thioacetyl] -19,20-dihydromutilin. Hydrochloride 30 1.85 g of N-benzyloxycarbonylvaline 4-nitrophenyl ester and 2.35 g of a solution of 14-O [(1-amino-2-methylpropan-2-yl) thioacetyl] -19,20-dihydromutilin in 30 ml of dimethylformamide maintained at 25 ° for 7 h. The reaction mixture is poured into water and shaken repeatedly with ethyl acetate. After washing with 0.1 N hydrochloric acid and then with saturated NaCl solution, the protected final product is obtained, which can be deprotected without further purification.

3.1 g of this Z-protected compound in 150 ml of ethanol are mixed with 60 mg of Pd / activated carbon (palladium on carbon, 10%) and stirred under a hydrogen atmosphere for 1 h. The title product is practically obtained as a quantitative catch. The process can also be carried out with the 4-nitrophenyl ester of BOC-valine, the deprotection being carried out as follows. 3 mmol of the BOC-protected compound are dissolved in 25 ml of trifluoroacetic acid at -10 ° C and kept at this temperature for 10 min. The reaction mixture is then brought to 25 [deg.] C., allowed to react for a further 2 h and then poured into 100 ml of 10% NaHCO3 solution. After repeated extraction with ethyl acetate and washing of the organic phase, the crude product is obtained, which is purified by chromatography on silica gel (eluent CHCl3 / CH3OH = 7/1).

The following compounds of formula I can be prepared analogously to Example I.

I; 7 Q8 714

Example R ^ Rj 2 -CH = CH2 -CH2.NH2 5 3 - "- -CH.CH3 (D) nh2 4 - * - -CH.CH_.CH.CH-, I 2 I 3 NH2 ch3 10 5 -C2H5 - CH.CH3 (D) NH2 6 -CH = CH2 -CH.CH3 (L) nh2

15 7 - - - __S

I I (L) -

B

20 8 j {(L,

B

9 -C2H5 -CH2CH2.NH2 25 10 -CH = CH_ -CH - CH-CH, 2 I I 3 NH2 CH3 (L) 11 - - - ___ i t (D) -

30 H

12 --- - CH - CH - CH3

NH-CH 2 (DJ

35 13 - "- - CH - CH2OH

NH_ (L)

__I

Δ * 8714 NMR spectrum (CDCl 3)

Example Spectrum 5 l 5.62 (d, 1H, H14, JH14H13 = 7.5 Hz); 7.72 (t, 1 H, NHCO); 3.42 (d, 1H, N-CH-CO, J = 6.25 Hz); 3.32 (d, 1H, Hn, JH11H10 = 6.25 Hz ^ * AB "system (va = -1 2 * 17» vb = ^ .27, JAB = 15 Hz »s-CH2'CO) · 10 2 7.68 ( t, 1H, NH), 5.73 (d, 1H, H14, JH14H13 = 8.75 Hz), 3.75 (a, 2H, CO-CH2-NH2), 3.38 (d, 1H, Hn, · 3Η11Η10 = 6.25 Hz) 3.28 (m, 2H, = C-CH 2 -NH), 1.25, 1.26 (s, a, 6H, gem. CH 2).

1 5 3 7.78 (t, 1H, NH); 5.74 (d, 1H, H 2, JH 14 H 13 = 8.75 Hz); 4.03 (q, 1H, -CH-CH 3, J = 7.5 Hz); 3.37 (d, 1H, Hn, J H 11 H 10 = 6.25 Hz); 1.25 (s, 2xCH 2, gem. CH 3); 3.3 (m, 2H, = C-CH2-NH).

Δ 4 7.76 (t, 1H, NH); 5.76 (d, 1H, H 14, JH 14 H 13 = 8.75 Hz); CH 2 3.43 (dd, 1H, CO-CH-NH 2, J = 3.75 Hz, J '= 8.75 Hz); 3.25 (d, 2H, CH-CH 2 -NH 2); AB-System: (VA = 3.17, VQ = 3.25, 25 JAQ = 15 Hz, -S-CH 2 CO).

5.64 (d, 1H, H14, JH14J13 = 8.1 Hz); 3.56 (q, 1H, CH 3 -CH, J = 7.5 Hz); 3.44 (d, 1H, Hu, JH11H10 = 6.25 Hz); AB-Sya-tem: (VA = 3.17, Vg = 3.25, JAQ = 15 Hz, S-CH2-CO); ABX-3Q System: (VA = 3.33, Vg = 3.25, νχ = 7.75, JAQ = 13.4 Hz, JAX = JBX = 7.5 Hz * C'CH2-NH) · 2 7.74 (t, 1H, NH) ; 5.75 (d, 1H, Ηχ4, JH14H13 = 8.75 Hz); CH- \ 3 35 3.56 (q, 1H, CO-CH-NH, J = 7.5 Hz); 3.36 (d, 1H, .Hn, 9 Q 8 71 4 JH11H10 * 6.25 Hz); AB-Sy3tem: <VA = 3 · 17 »VB = 3'24 '? * 3 JAB = 15 Hz, S-CH2-CQ); 1.4 (d, 3H, CO-CH-NH 2, J = 7.5 Hz).

Δ 7.72 (t, 1H, NH); 5.77 (d, 1H, H 2, J H 14 H 13 = 0.75 Hz); A8

System: (V- = 4.29, VR = 4.13, J. R = 10 Hz, S-CH - NH); 3. * (m,! Η? Ηη).

10a 0-07 (m, 1H, NH); 5.76 (d, 1H, Jμι JH14J13 = 0.75 Hz); 3.04 (dd, 1H, CO-CH-NH, J = 5 Hz, J = 8.75 Hz); 3.38 (d, 1H, H 2 H, J 1 Hihiq = 6.25 Hz); A8-System: (VA = 3.17, VQ = 3.25, JAB = 15 Hz, S-CH2-CO); 3.25 (m, 2H, SC-CH 2 -NH).

159 5.62 (d, 1H, H14, JH14H13 = 7.5 Hz); 3.24 (d, 1H, Hu,

Jhuhiq at 6f25 Hz); ABX-Systemi (VA at 3.34, Vg at 3.26, Vx at 7.38, JAB at 13.5 Hz, JAX at JBX at 7.5 Hz, NH-CH2-C S); 3.83 (t, 2H, NH 2 -CH 2, J and 5 Hz); 2.30 (t, 20 2H, CH 2 CO, J at 5 Hz).

7.68 (m, 1 H, NH); 5.74 (d, 1H, Ηχ4, JH14H13 = 8.75 Hz); 3.2 (a, 2H, S-CH 2 -CO); 3.38 (m, 1 H, Hu); 3.25 (d, 1H, CH-CH 3, J and 3.75 Hz).

25 11 8.05 (t, 1H, NH, NH-CH 2 -C 5 ·); 5.73 (d, 1H, Ηχ4, 1¾ JH14H13 * 8.75 Hz) j 4 · 48 (dd »1H» NH-CH.CG, J a 8.75, J * = .. 3Q 6.25); 1.25, 1.22 (a, a, mixed CH 2); AB System: (V ^ = 3.18,

Vg = 3.24, JAB = 15 Hz, S-CH2-CO).

12 7.8 (m, 1 H, NH); 5.75 (d, 1H, Ηχ4, JH14H13 = 8.75 Hz); 3.38 (d, 1H, Hu, JH11H10 s 6'25 Hz); 3 * 24 (d ‘1H’ ch’nh2); 3.2 35 (a, 2H, S-CH 2 -CO); 3.31 (m, 2H, CH 2 -NHCO).

ίο ¢ -8 7 t 4

Example Spectrum 13 7.9 (m, 1H, NH); 5.75 (d, 1H, Hu, JHUH13 = 8.75 Hz); AB-System: (VA = 3.18, Vg = 3.28, JA0 = 15 Hz, 5 S-CH2-CO); 3.36 (m, 1 H, Hn); 3.91 (dd, 1H, -CHH'-OH, s 10 Hz, J2 = 5 Hz); 3.71 (dd, 1H, -CHH'-OH, = 10 Hz, J2 = 6.25 Hz); 3.5 (dd, 1H, δ ,, - CH-CH- ,, = 6.25 Hz, J2 = 5 Hz).

The 14-O-[(1-amino-2-methylpropan-2-yl) thioacetyl] -19,20-dihydromutilin required as a starting material can be prepared as follows.

4.6 g of sodium are dissolved in 500 ml of ethanol (abs.), 14.1 g of 3-amino-2-methyl-2-propyl-15-l-mercaptan (FI Carroll, JD White, ME Wall, J. Org. Chem. 28, 1240 (1963)) and stirred for 1 h at 25 ° C. The reaction mixture is then stirred with 53.2 g of 19,20-dihydro-pleuromutilin-22-O-tosylate in 300 ml of ethyl methyl ketone and kept at 25 ° C for 20 h. The product is poured into ice water and repeatedly extracted with ethyl acetate. After washing the organic phase with NaCl-saturated water, the crude product is obtained, which is purified by chromatography on silica gel (eluent: CHCl3 / CH3OH = 7/1).

NMR (COCl 3): 5.8 (d, 1H, H 2 O, λ max δ 14 = 13 = 9 Hz); 3.38 (d, 1H, Hu, JH11H10 = 6.1 Hz) and 3.17 (s »2H» S-CH2-CO); 2.65 (α, 2H, N-CH2-CS ·); 1.7 (b, 2H, NH 2); 1.28 (s, 6H, 2 x CH 2).

i

Claims (6)

R 1 is ethyl or vinyl and R 2 is a lower aminoalkyl which is unsubstituted or substituted in its alkyl moiety by hydroxy, or a heterocyclic saturated Spring which may contain one or two heteroatoms. , One of which is nitrogen and the other possible heteroatom is sulfur, in free form or in the form of an acid addition salt or a quaternary pea salt. 1. A compound of formula I for use as a growth-promoting substance for animals, fh3 o.co.ch2.s.c.ch2.nh.co.r2 ™ 300/3. 10 rr rCH3 i 2. A compound according to claim 1, characterized in that Rx is vinyl and R2 is (D) - 1-amino-2-methylpropyl. 3. A compound feed for promoting the growth of animals, characterized in that the compound feed contains a compound of formula 30 O.CO.CH2.S.C.CH2J / H.CO.R2 ch3 o C5A. rVVCH3] * I: 35 AA A \ _ / CHa 4 i ο '' 14 '^ -! Wherein Rx is ethyl or vinyl and R2 is a lower aminoalkyl which is unsubstituted or substituted in its alkyl moiety by a hydroxy, or a heterocyclic saturated 5-ring which may contain one or two heteroatoms, one of which is nitrogen and the other possible hetero atom are sulfur, in free form or in the form of an acid addition salt or a quaternary site. Feed mix according to claim 3, characterized in that Rx is vinyl and R2 is (D) - 10-amino-2-methylpropyl. Feed mixture according to claim 3 or 4, characterized in that the amount of compound of formula I in the feed mixture is 10 - 400 mg / kg, advantageously 20 - 200 mg / kg of feed. Use of the compound of claim 1 or 2 as growth promoting agent for animals in drinking water 0.0125 - 0.05, advantageously 0.0125 - 0.025 wt / volume. in