JPS60120896A - 14-substituted carbamoyl-14-de(hydroxymethyl)- mycaminosyl tylonolide derivative and its production - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is H or OH; R1 is (substituted) hydrocarbon group, heterocyclic group or heterocyclic-lower alkyl; R2 is H or lower alkyl or R1 and R2 may together with adjacent N form heterocyclic group] and its salt. EXAMPLE:14-Butyloxycarbamoyl-14-de(hydroxymethyl)-O-mycaminosyl tylonolide. USE:Antibacterial agent for Gram-positive bacteria having strong antibacterial activity compared with known tylosin. It is useful also as a remedy for infectious diseases of animals and as a feed additive. It can be administered by injection as well as by oral administration. PREPARATION:The compound of formula II [R3 is H or -OR4 (R4 is OH-protecting group); R5 and R6 are lower alkyl or together form lower alkylene] is amidated with the amine of formula III, and is subjected to the removal of the OH-protecting group and of the acetal group.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 14-1 superior carbamoyl-14-f
'(Hydroxymethyl)-mycaminosyltylonolide derivatives and their production method. More specifically, the present invention relates to a compound of the formula (where R is a hydrogen atom or a hydroxyl group, RI is a hydrocarbon residue which may have a substituent, and a complex formula: i1: a heterocyclic group). -lower alkyl group, R2 hydrogen atom or lower alkyl group (2, R8 and R2ri may form a complex with adjacent nitrogen atoms), or a salt thereof.

The present invention also provides a method for formula (wherein R3 is a hydrogen atom or -OR group, R4 is a hydroxyl protecting group, R5 and R6 each represent a lower alkyl group, or - together represent a lower alkylene group) A compound represented by the formula (wherein R1 and R2 have the same meanings as above) is amidated with an amine [1], followed by elimination of the Hodo group in a bowl of water (H%9) and deacetalization. A method for producing a compound represented by formula [1] or a salt thereof with this as a percentage is also reported.

The above-mentioned ingredients are pharmaceutically acceptable.

Such suitable salt and 1. This includes salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and salts with pIkr acids such as vinegar, propionic acid, citric acid, succinic acid, malic acid, aspartic acid, and glutamic acid. Ru. The non-persistent period of the pond is also included.

The above-mentioned new compound [l] has stronger antibacterial activity against butterfly and duram-positive bacteria (-) than the known tylosin, and has clinically excellent curative effects not only as an oral agent but also as an injection (2). It is expected to be very useful as an antibacterial agent.Also #
*It is also useful as a medium infection treatment agent, a feed additive to prevent bad fruit, or to promote growth.

The present invention [In terms of the naming of such compounds, when the compound represented by the formula, that is, R is a hydroxyl group, O-mycaminosyl
tylonol ide [Tetrahedron L
etter8゜4737-4740 (1970)]
, when R is a hydrogen atom, 4'-deoxy-〇-
Mycaminosyl chloride CJ, AntibM%mm
, 34 (10), l 374-1376 (198
1):].

Starting material (6)ld used in the present invention, formula (wherein R
3.O is obtained by oxidizing 10HO of the compound represented by (R6 and R6 have the same meanings as above) to -000)1.

The intermediate [5] has the compound [2] at its 2nd and 4th positions.
The hydroxyl group at position '' or the hydroxyl group at position 7 is secured with an appropriate binding group, and the aldehyde ? 4tM protection by i-acetalization [
-CH, OH of the compound represented by the formula (where fL3, R, , R, and R6 have the same meanings as above) is replaced by -C
It is obtained by changing I(OKβ).

In the above method, the aldehyde base is first protected from the acetalized VC, and then the water IfI is
4 points for keeping the ship together.

Upper ml of water, 12-protecting groups and 1- are lower alkanoyl groups such as acetyl, propionyl, and butyryl, chloroacetyl, diolacetyl, trichloroacetyl,
Examples include /S-logenated acetyl groups such as trifluoroacetyl, but an acetyl group is sometimes preferred. The above-mentioned introduction of acetyl disease is carried out by reacting the above-mentioned compound [2] with acetic anhydride in an inert organic solvent such as dichloromethane, chloroform, or acetone. The reaction proceeds optically at room temperature. The reaction progress was performed using thin layer chromatography (TLC) such as silica gel, 11%
Since tracking is carried out by fast liquid chromatography (t(PLO), etc., the reaction can be completed as appropriate while watching for the disappearance of the compound [2].The formula obtained from the reaction solution (in the formula, R8 and To collect the compound *J represented by R4 (having the same meaning as above), process the reaction solution with water, pi (under alkalinity of 8 to 9.5, and add a non-hydrophilic organic solvent such as chloroform, dichloroethane, This is done by extraction with methyl isobutyl ketone, ethyl acetate, butyl acetate, etc. If more refined! For example, by column chromatography using benzene-acetone-based solvents, chloroform-methanol-based solvents, etc..
No. 7-5000, Japanese Unexamined Patent Publication No. 58-140 (1-96, t# Application No. 57-78895, % axis No. 1987)
-78897 specification, buttocks, etc.

The above acetalization is carried out by a known acetalization method. For example, in the presence of an acid such as trifluoroacetic acid, trichloroacetic acid, or p-toluenesulfonic acid, a lower compound such as methanol or ethanol is used. It is carried out by reacting lower glycols such as alcohol, ethylene glycol, propylene glycol, etc. In order to separate and purify the obtained acetal [4] from the reaction solution, the above-mentioned method of separating and purifying the compound [3] and It can be carried out in the same manner. An example of the production of the above acetal [4] 1. is described in JP-A-57-28100, #Gan-Sho 57-78897 Mei Mal Sai, etc. .

The oxidation reaction of -CH201-■ to -CHO of °γ acetal 4] is a reaction product between (CH3)25 and N-chlorosuccinimide in an inert organic solvent such as dichloromethane, benzene, or toluene +>z = rc acetal [4]
Total reaction or reaction of 2SO with p-) toluenesulfonyl chloride, p-) toluenesulfonyl chloride, p-) toluenesulfone Ca S hydrate or methanesulfonic anhydride in an organic solvent such as hexamethylphosphoramide (CI 3) Either react with acetal [4] or react with acetal [4]
] and (C1(3) 2SO and if of trifluoroacetic acid
FN, N'-dicyclohexylcarbodiimide (1)
CC) is reacted and the combined sulfoxonium salt is treated with an alkali such as triethylamine and ammonia.

The obtained intermediate [5] can be separated and purified from the reaction solution in the same manner as the method for separating and producing f# from the above-mentioned compound [3].

Intermediate W [5] -Cf (0 to -co o ti
To obtain the starting material [6] for vc oxidation, an alkali chlorite, e.g. Na0
It is performed by C/2 pharynx. Reaction uTLC above.

) (Because it is tracked by PLC etc., there is no intermediate material 'if
The reaction may be completed after waiting for the disappearance of [5].

In order to obtain the starting material [6] from the above reaction solution, the reaction solution is adjusted to pH 5 to 7 with an alkaline aqueous solution, such as aqueous ammonia, and extracted with a non-hydrophilic organic solvent, such as chloroform.
This is carried out by distilling off the solvent 7.

Next, the carboxyl group amidation of the product [Sakir6] is carried out by a known amidation method. A particularly preferred amidation method includes a mixed acid anhydride method. For example, the starting material [6] is added to the third
(7) (where R1 and R2 have the same meanings as above) by reacting a chloroformic acid ester such as ethyl chloroformate with a chloroformic acid ester such as ethyl chloroformate, All you have to do is react.

Examples of the amine [7] include known primary M amines. For example, alkylamines, alkenylamines,
Cycloalkylamines, arylamines, aralkylamines: 4 digits. These carbohydrate bulk residues are suitable for 1a
For example, lower alkoxy groups, lower alkoxy carbonyl groups, etc.
It's okay. Also included are amines having a heterocyclic group and lower alkyl amines having a heterocyclic group. Also included are secondary amines having an N-lower alkyl group in the above-mentioned -class amines. Also included are 3- to 8-membered cyclic amines which may have a different 11i'i atom, such as a chamber atom, an oxygen atom or a ken-huang atom, in the ring.

The above amidation reaction proceeded sufficiently at room temperature, and TLC, HP
Since it can be traced by LC etc., the reaction products, i.e., R+, R2, R3, R4, R5 and R
The reaction may be appropriately terminated after the maximum amount of the compound represented by (6 has the same meaning as above) is produced.

To produce compound [8] from the reaction oil, use the same method as for producing compound [3] above.
, - can be done.

Next, a protecting group for the hydroxyl group of compound [8], especially acetyl-4
The 2-elimination is carried out by heat treatment in a lower alcohol which may be mixed with water. Examples of lower alcohols include methanol and ethanol, but methanol is particularly preferred.
, t (as traced by PLO etc., compound [8]
Wait until it disappears and then terminate the reaction as appropriate.

Deacetalization is carried out by hydrolysis with aqueous water. This deacetalization may be performed before the step of removing the hydroxyl protecting group.

To extract the target product [1'3] from the reaction solution, use an alkaline aqueous solution, such as aqueous ammonia, to adjust the pI (adjust to 9 to IO to 11).
, non-koji, extracted with an aqueous organic solvent, such as chloroform,
1. It is carried out by distilling off the solvent.

If further binding is required, it may be carried out by known methods for separating and purifying macrolide antibiotic proboscis, such as chromatography using adsorbents such as silica gel, viscous alumina, and adsorption resins. I can do it.

Next, the minimum inhibition degree of microbial growth (IV I C') of the target compound [1] of the present invention was measured, and the results are shown in Table 1. The symbols in the table have the following t and taste.

A; 14-butylcarbamoyl-14-f (hydroxymethyl)-〇-mycaminosyl ylonolide (R1;
Butyl, R, = H, R = Ot (object compound [l]
) B; 14-benzylcarbamoyl-14-te(hydroxymethyl-〇-mica-kinosyltylonolide (R1;
benzyl, R, =) (, R = OH, the target compound [l
]) C: 14-(N-methyl-benzylcarbamoyl)-t
4-de<hydroxymethyl)-〇-mycaminosyl cylonolide (R3=benzyl, R2=methyl, R=OH
Target compound [l])*: Macrolide-resistant group A bacteria (erythromycin, oleandomycin, 16-membered macrolide antibiotic-resistant isolates) A manufacturing example of the invention will be specifically explained. Note that the R/values in Reference Examples and Examples are as specified in [1. Unless otherwise specified, measurements were made by TLC using the following carrier and developing solvent.

Carrier: Merck'MDC-F'ertigplat
ten kieslgel 60F25. , Art
5715 developing solvent; a; benzene-acetone (a: l) b; benzene-
Acetone (5: l) c; Chloroform-methanol-trowel aqueous ammonia (10
0:10:1) d; Chloroform-methanol (3:1) Reference example l? , 4'-di-O-acetyl-0-mycaminosyl chylonolide dimethyl acetal z, 4'-di-0-acetyl-0-mycaminosyl chylonolide 4.23.
9 was dissolved in 27 ml of methanol, and trifluoroacetic acid B mt was added thereto under water cooling, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 7-thiammonium aqueous solution and extracted with chloroform. Wash the chloroform layer with water [5, Whatman l P
After passing through SF paper, it was dried under reduced pressure to form a foamy solid of 7,4/
3.96 g of -di-0-acetyl-0-mycaminosylsilonolide dimethyl acetal was obtained.

TLC: R/a = 0.35, R/b = 0
．． 15 Reference Example 2 2/, 4/-di-O-acetyl-23-dedihydro-0-mycaminosylsilonolide Dimethyl acetal Dry dichloromethane 40ml 1 KN-chlorosuccinimide 1.37.9 was dissolved 2, and dimethyl sulfide 1 was dissolved in this under water cooling. A white precipitate formed when .03 ml was quickly added. The reaction mixture was cooled to -25° C. under a stream of argon gas, and a solution of 4'-di-0-acetyl-0-mycaminosyl silonolide dimethyl acetal 5.0.9 in dry dichloromethane (lod) was added for 10 min. After removing moisture, the mixture was stirred at -25°C for 2 hours. Triethylamine Q was added to this reaction solution, 24ml! Methylene chloride solution containing 2
ml and stirred for 5 minutes. The resulting reaction solution was returned to room temperature [2. After adding 50 ml of water, the mixture was separated. The dichloromethane layer was passed through Whatman IP STP paper and then reduced to IE. Silica gel (Merck #
Column chromatography was performed on a column of too II (Art 7734), eluting with 7 tons of charged benzene (12:1 l). R/a = 0.
Fractions around 53 were collected and concentrated to give 2.6 g of the title compound 1 (8,, 3H, 12-CH,)
% 2.06(s,, 6H.

0COCH,X 2), 2.35 (s,, 61(,
-N(CH3) 2 ), 3.22 (s,, 3 H
, OCH,), 3.29(s,, 3H.

QCHa ), 4.39 (d, -I H, H1')
, 4.50(d, d,, 1 t-t, t(-20>
, 4.77 (t,, L H, H-4'), 4.91
(d, d,, l H, l(-2'), 5.25 (d
,t.

1)(, r(-15), 5.82 (d,, l i(
, l(-13), 6.37(d,, 11(, H-10
), 7.29(d,,l)I IH-tt), 9.
69 (d,, l f(, CHO, J = 2.7
) Mass (CI, isobutane); 726 (Ml
(”, #Ii always small), 694 (M)l”-32
), 676.664.662 (694-32), 25
8.216.156, 29 Reference Example 3 2/ , 4/-Dini-O-acetyl-14-carboxy-14-de<hydroxymethyl)-0-mycaminosyl silonolide Dimethyl acetal 2/ , , i/-G 0-Acetyl-23-dedihydro-0-mycaminosyl silonolide 2.6 g of dimethyl acetal was dissolved in acetone 36F11, and 17.9 m of a 0.3 M sulfamino acid aqueous solution and 0.3 M of sulfamino acid aqueous solution were dissolved therein.
19.3 mJ of 2M sodium chlorite water bath solution was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was adjusted to pH 5-6 with aqueous ammonia solution and diluted with 200 ml of aaa form.
IC11 was extracted. The extract was dried over anhydrous magnesium chloride and dried under reduced pressure to obtain 2.5 g of the title compound.

TLC; R/a=0, Rfd=0.66”+3f
(), 2.06, 2.07 (each 1.3 H, 0
COC) (II containing 2.38 (s,, 6 H, N (
CH3)2), 3.22 (8-.

3 H,0Cf(3),3.29(a,,3t(,0
CH3), 4.40(d,,I H,)I-1'),
4.51 (br, t,, I H.

H-20), 4.79 (t,, l H, H-4'), 4
．． 93 (d.

-1, 7.27 (d,, I H, H-11) Mass
(CI, isobutane') ;666 (M)(-Co2
-32), 634 (666-32), 258.2 1
6.1 56.29 Example 1 14-Butylcarbamoyl-t4-te<hydroquinemethyl)-0-mycaminosylsilonolide i, 4'-di0-acetyl-23-dedihydro-0 −
Mycaminosylsilonide 200tn9ft was dissolved in 2ml of dry dichloromethane, 95ttl of triethylamine was added thereto, and 49μl of ethyl chloride was added while cooling to 0°C, followed by stirring at 0°C for 30 minutes. Then, after adding 0.27 ml of butylamine to this reaction solution,
Stirred at room temperature for 1 hour. Add 20ml of chloroform to the reaction solution/
was added, and the mixture was washed with dilute hydrochloric acid, water, and dilute ammonia water in that order. The chloroform layer was passed through a Whatman IPSF and then concentrated under reduced pressure. Residue silica gel (manufactured by Merck & Co., Ltd., A
Fractions eluted with charge 15 and benzene-acetone (6:l to 4:l) were collected and concentrated under reduced pressure. The residue was deacetylated by bathing in 5 ml of methanol and heating at 55° C. overnight. All methanol was distilled off under reduced pressure 1, and the remaining apricot was treated with acetonitrile-water-trifluoro+6" acid (3a2: 0-1v/v) 5
ml and stirred at room temperature for 1 hour to deacetalize. Pour the reaction solution into 10ml of water and dilute with dilute ammonia water.
H9 and extracted twice with chloroform 2Qrnl. After drying the chloroform layer over anhydrous magnesium sulfate, the desired product 761112 was obtained by drying under reduced pressure.

Mass (CI, isobutane); 667 (MH”
), 649.192.174.133 t,, 3 H, -NH(Cf(,) 3CH8), 1
．． 83(s,, 3H.

12-CH5), 2.50 (s, , 6H, -N
(CH3) , ), 4.25(d,,1 f(,H-1
'), 5.29 (d, t,, l H.

H-15), 5.71 (t,, L H, NH),
5.95 (d,.

it(, I(-13), 6.32 (d,, l i(,
H-10), 7.30 (d,, I H, H-11), 9
．． 69 (s,, I H.

CHO) Example 2 14-benzylcarbamoyl-14-de(hydroxymethyl-〇-mycaminosylsilonolide) In Example 1, 0.3 ml of pendylamine was used instead of 0.27 ml of butylamine. The object of the dance was obtained. Collection: 1t85.6 Noda Mass (CI, isobutane); 701 (Ml-1+)
, 683.493.475.192.174.133P
MR(CD(J,,100MH2)δ; 1.80
(s,.

ρpm 3f(,l2-CH,), 2.51(s,, 6k
l, -N(CHl), I), 4.24(d,, L
l(, L(-1'), 4.44(d,, 21(.

-CHlN1(-) , 5.29 (d, t,, l
H, H-15), 5.95 (d,, l H, H-1
3), 6.00 (br, t,, tH.

NH), 6.30 (d,,l H, H-10), 7.
1-7.4 (6H, H-11, phenyl proton)
,9.68(s,,IH,CHO) Example 3 14-(N-methyl-benzylcarpamol)-14-
De(hydroxymethyl)-0-mycaminosylsilonolide In Example 1, v instead of 0.27 ml of butylamine
Using 0.35 ml of CN-methyl-benzylamine, the title product was obtained. Sorption 6o, 5 drops Mass
(CI! Isobutane); 715 (MH+),
697.507.192.190,1746)I,
-N(C)(3)2'), 2.85.3.01 (11..3 H each.

-coyC! ! J), 4.25 (br,, d,,
I H, H-10, 4, 47, 4, 59 (tani br, s,
, 2 H, -CH2N CHm), □1 5.5 (m,, l f(, f(-15), 5.9
2 (br,,d,.

11(,1(-13), 6.29.6.35 (each br
,d,, I H#1(-10), 7.0~7.4 (
6H, H-11, phenyl proton), 9.70
(s,, L H, CHO) Example 4 14-Diethylcarbamoyl-14-de(hydroxymethyl)-0-mycaminosyl chloronolide In Example 1, 0.28 ml of diethylamine was used instead of 0.27 ml of butylamine. The title object was obtained using Collection j#53In9 Mass (CL isobutane);667 (Mf(
+), 649.476.192.190.174.15
6, 32 IR (KBr); l 640 t:tn -” (
-C0NH-)4.25 (d,, l H, H-1'
), 5.47 (d, t,, IH.

H-15), 5.91 (d,, I H, H-13)
, 6.35 (d,, I H, i(-10), 7.3
3 (d,, I H, d -11), 9.70 (s,
, L H, CHO) Example 5 14-dimethylcarbamoyl-14-deChydroxymethyl)-0-mycaminosyl chloronolide In Example 1vC, 223 Wu? of dimethylamine hydrochloride was substituted for 0.27 ml of butylamine. The title object was obtained using a solution of 0.38 d of triethylamine and 4 ml of dichloromethane. Collection j#49~Mass
(CI, Inbuta y); 639 (MH+),
621.192.190.174,! 32(s,, 3
H, l2-CH,), 2.51 (s,, 6 H.

1(-15), 5.94 (d,, L H, H-13
), 6.36 (d,, I H, H-10), 7.3
2(d,, L H, f(-11), 9.70(s,,
l H, Cf (0) Patent applicant Toyo Jozo Co., Ltd. Representative Tetsuo Suta Procedural amendment (voluntary) / Indication of the case Showa 5G Patent Application No. 2.2g25 Otsu No. 28 Title of the invention / ≠ - Substituted carbamoyl / ψ-de(hy-1-roxymethyl)-mycaminosyl silonolide derivative and its manufacturing method 3 Relationship with the case of the person making the amendment Patent applicant t Date of the amendment order Voluntary Specification to be amended Page 12 Correct "Presence F" in line 1g to "in the presence". Correct "alkali" from the bottom line of page 72 to the first line of page 73 to read "base."

On page 1q, line 2 of the same page r　Kiesl　J “Kiesel J. Correct.

Same page 27, line 6 "/2://" Correct it to "/22/".

Same page 27 line 72 1”-CONH-J “Corrected to -CON-J.

Claims (1)

[Scope of Claims] (In the formula, R is a hydrogen atom or a hydroxyl group, R1 is a hydrocarbon residue which may have a 1a substituent, a phosphorus cyclic group or a phosphorus group-lower alkyl group, (R2 represents a hydrogen atom or a lower alkyl group, and R1 and R2 may form a monomer with adjacent nitrogen atoms) or a salt thereof. CI (3 (in the formula, R3 is a hydrogen atom or -OR group, R1 is a hydroxyl group, 4 groups, R5 and R6 each represent a lower alkyl group, or - together represent a lower alkylene group); The compound represented by formula (1) (wherein 1 has a substituent group, is also a substituted hydrocarbon residue, a phosphor group or a heterocyclic group, or a lower alkyl group, R
2 represents a hydrogen atom or a lower alkyl group, and R6 and R2 together with the adjacent nitrogen atom are amidated with an amine represented by *f shadow formation, and then the hydroxyl group is A formula characterized by elimination and deacetalization (in the formula, R represents a hydroxyl group or a hydroxyl group,
R. and R2 has the same meaning as above) or a method for producing a salt thereof. 3), the hydroxyl group is lower alkanoyl J & also Id
Claim 2 1r which is a halogenated acetyl group
! Manufacturing method described. 4) The production method according to claim 3, wherein the lower alkanoyl group is an acetyl group. 5) The method for producing al according to claim 2, wherein the amidation is carried out by a mixed acid anhydride method. 6) Heat treatment in a lower alcohol even if it contains water to eliminate the protective group of the hydroxyl group 1. The manufacturing method according to claim 2, which is carried out by 7) The production method according to claim 2, wherein the deacetalization is carried out by hydrolysis with acidic water.