JPS61140598A - Chemical compound, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application] The present invention relates to new chemical compounds, their preparation and their uses, and in particular to a "class of erythromycin derivatives. These compounds have antibacterial properties. They have antibacterial properties, especially against Durham-positive bacteria, but also against some Durham-negative bacteria, and therefore they have antibacterial properties against a wide range of bacteria.
Not for use in the treatment of bacterial infections in humans and animals caused by

[Conventional technology]

Erythromycin is disclosed in U.S. Patent No. 2,653,899 [
Bunch, R.L., et al.: Firstly not described in Erai@IJIII. The structure of erythromycin is shown below.

In the formula, Bh represents hydrogen or hydroxy, and Bh represents hydrogen or methyl gold.

The basic structure of erythromycin is (1) a 14-membered lactone ring called an erythronolide ring, with all digits i not shown in the above formula.

(11) a first sugar ring known as a desosamine ring indicating a number of single prime digits; (ili) a second sugar ring known as a fradinose ring indicating a number of double prime digits. Shougong Sunaru.

The erythronolide ring exists in two forms.

Erythro Nori l'A (R” = OH) Erythro Nori)
'B(Ra=ti) 4 The main naturally occurring erythromycins are as follows.

Erythromycin B a H, hA
OH0M5 B HC)I.

COH) ID HI-1 Of these, erythromycin A is especially the most important.

Erythromycin, and especially erythromycin A, is an antibiotic that is widely used clinically in the treatment of infections caused by Durham positive and some Durham #1 bacteria. The main drawback of erythromycins is their poor acid stability resulting in poor and variable oral absorption.

Various attempts have been made to modify erythromycin to produce derivatives with improved acid stability without loss of antimicrobial activity.

(98)-9-Dihydroerythromycin A (having a 9-hydroxy group in place of the 9-keto group) has a description but has less antimicrobial activity [P.F.
, F. Wiley) et al., J. Am. Chem. Soc., 1955.

77.3676-3677: M e Buie e Cigal (M
, V. 8igal 'I et al., 11956, 78, 3.
88-395: and Tea Grabsky (T, GIa
h-ski) et al.
ki Chem) J1976.50.12F! 11゜Erythromycylamine and erythromycin oxime (9
-keto groups are substituted on amino or oxime groups) and various N-substituted derivatives of erythromycylamine have also been described [UK Patent No. 1.100.5].
No. 04 (Prinos 7 Armory (Pliv8)
Pharmaceutical 'I): E, H, Massay et al. [
Tetrahedron Letters
Letters) J 197 (1, #a 2.

157-160: and G H Tames CG, H
, Timrr+s) et al. “Ibid. J 1971, /h
2.

195-198) and various erythromycin oxime ethers have also been described [US Pat. No. 3,869].
, 445 and U.S. Pat. +163.014 (both R, l-1a11.as et al. Niazet Laboratories): U.S. Patent No. 4,349
゜No. 545 [Nis-Guin P Ambrielles (S,
(?ouir+ d” Ambrrerpβ): Rouselle Ukraf]: and [Antimicrobial Agents and Chemotherapy (?ouir+ d” Ambrrerpβ):
ial agents and Chemotherapy
y) J 1 974, 6, 479)゜9-
Aldehyde erythromysylamine condensation products with N, 6- or 9-, 11-0 cyclic substituents have already been disclosed [U.S. Pat. No. 4,048,306 (R. Meyer (R.

Maier”) I:): Boehringer-Ingelheim)].

]4F-deoxy-11-〇-methylthiomethyl4'-
Oxo-erythromycin B and (1) 41-deoxy-9,11-g-(optionally substituted) methylene-
4g-Ogysoerythromycin B6. -9-hemiacetal and the corresponding 4'-monohydroxy, 2',
F mono-diacetyl-41-ehi, and 41-mi-acetyl-4'-trimethane derivative, and (I+>4'-deoxy-49-oxo~,4'-Q-acetyl-41-ehy, and h41 - shrimp - its conversion to erythromycin B: and 41-formyl-11-11 once methylthiome-1,000-erythromycin B, 9.11-g-methylene-erythromycin B6,9-hemiaceter A/;
11-0-methyl-e+7-samycin B and 11-9
Its conversion to n-butylene erythromycin B: and also 47-zooxy-4F-oxoerythromycin A is described in U.S. Pat. Fl No. 42,069, No. 3. R
Fl No. 4.903 and No. 3. Fl No. 84,904 [All P. H. Jones CP, H, Jones
s) et al. Nearbot Laboratories].

41-deoxy-4'-amino-erythromycin de''h, *!-deoxy-4'-aminoe 11thromycin A6,9-hemiketal and 41-deoxy-4F-
Oxo-erythromycin 86.9-hemiketal and the corresponding 11-0-acetyl and H]].

12-cyclic carzenate 6fj conductor and also 41-deoxy-41-aminoe 11-thromycin B and 41-
Deoxy-41-Ogisoe 11thromycin A4'-
9-oxime or 4'-〇-acetyloxime is disclosed in US Pat. No. 4,150.220 [F.C.
F,C,5riavolino): 1,9-dihydroerythromycin (Dll, 12-cyclic carbonate) is also described in T. Grabsky (T.

flabski) et al.: “Roc
znikiChem) J 1976, 50, 12
81 and 9-dihydro-11,12
-o-isopropylidene-11thromycin A and the corresponding 41-shrimp compounds are disclosed in U.S. Pat. No. 4,382,08
No. 6 (F-C, 8cia
It is described in vol. 7 Eiser].

6-9-methyl, 6.11-di-methyl-(1)-
0-methyl- and]1-identical ethyl-erythromycin A, and also 6-0-methyl-6゜41-di-9-methyl-1 and 6,11.4'-) ethyl-erythromycin BH European Patent No. 0n41355A1, No. 0n41355A1 (No. 1080818A1 and No. 0nROR19)
No. A1 (all Taisho Pharmaceutical) VC description ζ.

[Problem that the invention seeks to solve]

The erythromycin derivatives according to the invention have improved acid stability a' compared to erythromycin A while retaining good antibacterial activity at-.

[Means for solving problems]

The present invention provides antimicrobially active 9°11 methylene derivatives of 9-dihydroerythromycin even if the methylated groups are substituted.

In particular, the present invention is applicable to -I9' Award (1) [In the formula, R and R2 may be the same or different; represents a 5-spanked 6-membered heterocyclyl group (containing oxygen or sulfur atoms as heteroatoms), or R1 and R taken together represent an unsubstituted or substituted divalent hydrocarbon group (% alkylene group); Represents an unsubstituted or substituted alkyleneoxyalkylene or alkylenethioalkylene group: 3 represents hydrogen or hydroxy: R4 represents hydrogen, fluorine or hydroxy: R5 and R may be the same or different. Moyo〈contains hydrogen or methyl: one of R7 and R is hydrogen, hydroxy, alkoxy, alkanoyloxy, amino, substituted amino or of the formula R,9-
80 □- and the rest of R7 and R8 represent hydrogen, or R and R8 taken together represent an oxo group, oxime group, or
- represents a substituted oxime group: and R9 represents an organic group] or an acceptable ester or acid addition salt thereof.

The term "hydrocarbon" used in the Kokou Specifications 18ffli
I contains up to 10 carbon atoms, preferably up to 10 carbon atoms, and preferably up to 6 carbon atoms. A preferred hydrocarbon group is (C4,6)argyl.

(C,2,6"1 Flukenyl% (C2,6)alkynyl, (C6,7)cycloalkyl, aryl, (C,...
”)cycloalkyl(C4-6)alkyl,
C1,6) alkyl, (C1-6) alkyl (C6,7
) cycloargyl and H(C,~6)alkylaryl.

Examples of suitable optional substituents for the above-mentioned hydrocarbon groups are heterocyclyl, amino, (01-6)alkanoylamino, (
Mono-, di- or tri)-(01-6) alkylamino, hydroxy, (C1-6) alkoxy, (C4-6) alkoxy (C1-6) alkoxy, aryloxy, mercapto h(01-6) alkylthio, heterocyclyl Salts and esters thereof, (C1,)alkanoyloxy, arylcarzenyloxy, thio, ester, sulfamoyl, carbamoyl, substituted carbamoyl, amidino, guanidino, nitro, chlorine, bromine, fluorine, calzegyloxy, and the like; Contains all heterosifylcarbonyloxy, acyl and acyloxy groups.

Any alkyl group or moiety herein may be straight-chain or partially branched, unsubstituted or substituted (and may contain, for example, up to 12 carbon atoms, preferably up to 6 carbon atoms, especially Alkyl group or moiety is unsubstituted or substituted methyl, ethyl, n-propyl, isozolobyl%1
1-Ityl, sec-butyl, inbutyl or tertiary-butyl groups may also be used. Examples of suitable optional #L groups of any such argyl groups or moieties include the above-mentioned substituents on hydrocarbon groups and hydrocarbon groups other than the above-mentioned alkyls, such as (C2,6
) including all alkenyl and aryl groups.

As used herein, the term "aryl" includes phenyl and 7-methyl, which are unsubstituted or halogen, (C1,6)alkyl, phenyl, (C)alkoxy, halo( C1,6) alkyl, H1-6Proxy, amino, nitro, calzexy, (C1,6)
Alkoxycarzenyl, CC1,6)alkoxycarzenyl (C)alkyl, other than (C1,)alkyl S-6 nyloxy and (C4,6)alkylcarbonyl groups and other above-mentioned hydrocarbon groups and preferably up to 5, preferably up to 3 substituents selected from the above-mentioned hydrocarbon groups other than aryl.

The compound according to the present invention of the general formula (11) is a 9,11-acetal and 9.11-ketal derivative of 9-dihydroerythromycin.This compound has two isomeric forms at the 9-position, namely (98) -isomer and (9R)-isomer. (9S)-isomer is preferred.

The hydrocarbon group represented by R or R2 will preferably be an unsubstituted or substituted alkyl or aryl group. Advantageously, the alkyl group will be a lower argyl group, such as a (C1-6) alkyl group. Advantageously the aryl group will be a phenyl group.

The heterocyclyl group represented by R or R2 is preferably furyl, chenyl, dihydrofuryl, tetrahydrofuryl, dihydrochenyl, tetrahydrochenyl, hyranyl, dihydrobiranyl, tetrahydropyranyl, thiapyranyl, dihydrothiapyranyl or tetrahydrofuryl. Probably a thiapyranyl group.

Preferably, at least one of R1 and R2 represents hydrogen.

R1 and R2 together preferably represent an alkylene group, even if the oxygen or sulfur atom is interrupted at a position other than the nitrogen end, and therefore together with the carbon atom to which they are attached, R and R2 is a heterocyclyl group (e.g. tetrahydrofuryl, tetrahydrochenyl, tetrahydropyranyl or tetrahydrothiapyranyl group) or a calzecyclic group (e.g. cyclohexyl group) bonded via a carbon atom not adjacent to the heteroatom. ) is shown.

In a preferred compound of general formula (1), one of R and R2 is hydrogen, and R and the other are hydrogen, unsubstituted or substituted alkyl (especially lower alkyl), or unsubstituted or substituted aryl (especially 7enyl) or unsubstituted or substituted heterocyclyl (especially furyl).

Preferred substituent layers for hydrocarbon or heterocyclyl groups R1 and/or R2 and preferred φ&(l substitution a) for divalent groups R, -4-R
Examples include in particular alkoxy, alkogylalkoxy, aryloxy, hydroxy, amino, substituted amino (such as monoalkylamino and dialkylamino), calzoxy, esters (eg alkoxycarzenyl), acyloxy ( [Acyl] means organic carzenyl) (e.g. alkanoyloxy), carbamoyl (H2N-C(=0)-) and substituted carbamoyl (
Examples include N-alkylcarnomoyl and N,N-dialkylcarnomoyl) groups. The optional alkyl moiety of such a substituent may itself be substituted with -L, for example on one of the above-mentioned substituents (and any alkyl moiety advantageously contains up to 6 aa, preferably up to 4 carbon atoms). An example of a substituent in which an alkyl moiety is itself substituted is an alkoxyalcogyl substituent.

In the compound of general formula (1) R6 preferably represents a hydroxyl group as in the erythronolide A ring, ie in other words the compound of general formula (1) is preferably a derivative of erythromycin A. However, the parent compound may be erythromycin B or other naturally occurring derivatives of erythromycin in which R5 represents a hydrogen atom.

The 8-position of erythromycin is preferred because it likely has only a methyl substituent like naturally occurring erythromycin, and R5 represents a hydrogen atom. 8-HyP-roxy and 8-fluoro derivatives have been described [[J. Antibiotics].
) J XXVI, 575-581 (1973'l and
XXVl, 1439-145(1(19F!3)1 and R4 will represent a hydroxyl group or a fluorine atom.

The 10R5 heir in the 6th position of the general award +11 is a hydroxyl group, which is a naturally occurring sulerythromycin VC, but it may also be a methoxy group. Erythromycin's 6-0-methyl S conductor a European patent No. 1 (1
No. 41355A1 [Y, Watanabe
abe '+ et al.: Taisho Seijuku] -Ffi.

One 0R6 group at the 31-position of the fradinose ring may be a hydroxy group or a methoxy group. Preferably, R6h-1-lithromycin A and L in BVC represent a methyl group.

The 41-position of the fradinose group would preferably have a hydroxyl group, similar to that in erythromycin A and B (R'=) (R,8=Of-1). Fraginose ring 4
Various modifications at the f-position have already been mentioned and these modifications will not be introduced into the compounds according to the invention.

(i) 4'-Deo*C 4'-O*7tf1m body CR,7+R8=0=) is disclosed in U.S. Patent No. 3. R42, (1
No. 69, No. 3, RR4, '403 and No. i, 1
5 n, 22 (described in No. 1 (all mentioned above)
OH:R8-) () and 4v-deoxy-41-alkanoyloxy-4F-epi-bound alE form (R'=alkanoyloxy, Toku KC Town COO-: 1'L8=H) are described in the above-mentioned US Patent No. 3. 8 g Described in No. 4.903: ((1) 14'-0-argyl derivatives (R, 'straight R8 = alkoxy, especially methoxy: R7 and R8 and = H) are described in the above-mentioned Yorotsunozo patent. No. 011801'1l
RA1: llψ 47-dioxy-41-amino derivatives (R' or R8 = = Niamino is a substituted amino: R'# and IIL8 and =H) are described in the aforementioned U.S. Pat. No. 4,150.220. Not listed in the No.: M 4'-deoxy'/-4'-o*'/A derivative [R7+R,8=oxime (=N-01-T) or substituted oxime, especially acetyl oxime (=N- 0-CO-C
)l, )”1 Kemata the aforementioned U.S. Patent IE 4,150.2
Described in No. 20: (V.47-o-sulfonyl derivative (R,7=H,
R,8=几'-8o2-o-) is described in U.S. Patent No. 3.
836.5) No. 9, No. 3,869,445 and No. a, n 63,014 [all R Haras (R,
H Kasumi 11as) and Niazet Laboratories]: and (1 order 4f-deoxyconductor (R,'= R8= H
) is Japanese Patent No. 58-049396 (Toyo Jozo) vr
I have not mentioned it.

In the 4f-deogycy 4'-(ill-substituted amino) derivative, the substituted amino groups R7 and R8 will preferably be groups of formula 1, where R1 represents a hydrocarbon group.

4F,, -o-sulfonyl derivative (R7 or R18 represents a sulfonyl derivative group of formula 1)
is preferably an unsubstituted or substituted hydrocarbon or azahydrocarbon group, a 11% alkyl, an alkenyl, an unsubstituted or substituted group (especially phenyl, nitrophenyl, halophenyl or alkylphenyl), unsubstituted or ha-substituted aralkyl (particularly benzyl, nitrobenzyl, halopencyl or haalkylbenzyl), device 11? Ht! Conversion of 1-ruoxyargyl C
From %r7
It will be a D-substituted ethyl [special f R, -CH2-CH,, - (R in the hole is defined below)] group.

4'-substituent R-CI-12-CI-12-8o, -
0-group R0 is full amino, substituted amino, carbamoyl, substituted carbamoyl, sulfamoyl, substituted full 7
Amoyl, substituted urei P1 substituted thioureido, alkoxy, alkylthio, substituted 11-aloxy, optionally substituted arylthio, optionally substituted benzyloxy, substituted 4-functional benzylthio, substituted fluor7onyl, substituted sulfinyl, substituted alkyl, substituted alkanoyl, substituted cyano and the aforementioned U.S. Pat. No. 3,869.445 and $4.06.
No. 3,014 contains more details [including other groups described].

Preferably, RFi hydrocarbon group, especially IF (C1-), shows a methyl group in % of argyl group.

The present invention is -B,? (Including #1-acceptable esters of compounds of formula (1), especially 1-1 esters that are hydrolyzed in vivo.Such esters include any of the esters of compounds of general formula (1).
The ester is formed by the τ- and P-roxy groups of the densamine beak, although normally the ester is formed by the τ- and P-roxy groups of the densamine beak, all of which are described in U.S. Pat.
Booth (R, W, Booth et al.), No. 2,993,833 [V, CJtpphpns: Eli Lilly], No. 3.836.5) No. 9, No. 3. R4
2, (I B No. 9, I B No. 3.869,445, I B 3. FI No. 84,903, I B No. 3. R 84,904 and I B No. 4,15 n, 22 (described in 'I will give a 2'-9-amyl derivative of the type ζi.

Suitable pharmaceutically acceptable in vivo hydrolyzable esters include those that readily degrade in the human body leaving behind the original compound or salt thereof. For example, pharmaceutically acceptable
Rufat I! Group 71F carboxylic acids include those derived from alkanes, alkenoic acids, cycloalkanoic acids and alkaniic acids, in particular those derived from alkanes, alkenoic acids, cycloalkanoic acids and alkanioic acids, in which the alkyl or alkenyl moiety advantageously has up to 6 carbon atoms. Examples of specific esters are acetate, propionate, butyrad, Aku I
+rate and ethyl succinate.

The present invention also includes acid addition salts of the -19'r(+) compound, particularly pharmaceutically acceptable acid addition salts. Such acid addition salts are especially formed at the 3'-dimethylamino group of the densamine ring.
Good morning.

Various acid addition salts of ηthromycin are disclosed in U.S. Patent No. 2.
No. 761,859 [C.I. Ho7hin, Jr.]
CC, L)loffi+ne, J')Niazette Lazeratories] and U.S. Patent IE2.l'152,429
No. [J, T, 5hpple
Suitable acid addition salts of the compounds of the present invention include pharmaceutically acceptable inorganic acid addition salts such as sulfates, nitrates, phosphates, and phosphates. ,
Hydrochlorides and hydrobromides and pharmaceutically acceptable organic acid addition salts such as acetates, tartrates, malates, citrates, succinates, benzoates, ascorbates, methane-sulfonates , α-keto-gel tarrate, α-glycerophosphate and glucose-1-phosphate Kanakuramu. A suitable silicate addition salt is lauryl sulfate a salt.

According to the invention! - Examples of compounds include:

+119.11-Ω-ethylidene-9-dihi P mouth z+I
xomyshiyA[-19'Equation (1)[oi-tl-R=
CI(5゜R-1(, R=OH0R=R=H, R6=C
l-1,, I'L H.

R8=OH1: (il) 9.11 -methylene-9-dihy-Ploerythromycin A [R'42= in general formula (1)]1.
Same as R, 5 to R8 compound (+)]: (Song 9, 1l-Q-isopropylidene-9-dihyP loerythromycin AC-W formula (1) R at r , kefhi compound (+)):・IV)9
．． 11-0-Propylidene-9-dihydroploe II Thromycin A (general formula (1) [R1=C2H5, R=
H, R, '~R8 Same as compound (1)]: (V19,
11-〇-benzylidene-9-dihi f.

loerythromycin A C-F formula + in Ilr +(,
= phenyl, I'L = I-1, R3-R8 compound (1
): rvi'19. z-θ-n-butylden-9--) and rloerythromycin AC general formula m[b where R1=C,H,,R-)1, R4 is the same as compound (1)]: (Vllo9--) .11-9-isobutylidene-9
-DihyP loerythromycin A [1 (j=(C)-1,)2C1-1-, R2=)1 in the general formula ill.
Same as compound (1)]: and (yllj g , 11-o-771/7 II
Lite:y-9-)hydroerythromycin (Al [
In general shell m, R1=frill, R2=)1. R'
〜R8 (same as compound (1))]: a Fi-0-methyl derivative corresponding to the zara, a corresponding derivative in which the 8-position and/or the 4g-position are modified as described above: and also such f Pharmaceutically unacceptable esters and acid addition salts of compounds.

Erythromycin derivatives having hydroxy substituents at the 9- and 1]-positions (any reactive groups other than the 9- and 11-hydroxy groups are retained) according to the uninvented invention.

React the substituent on the thromycin structure with the aldehyde P or ketone or its reactive derivative, if necessary, and then react the substituents on the thromycin structure, if necessary, with (h) remove any securing groups; and (cl
The preparation may be carried out by forming one or more pharmaceutically acceptable esters or acid addition salts.

More specifically, the compound of general formula (1) or a pharmaceutically acceptable ester or acid addition salt thereof has the formula -W [wherein R,
R, R, R, R and R8 are as defined for general formula (1), and any reactive group (other than 9-hydroxy group and 11-hydroxy group) in compound r of general formula (II)
A compound of general formula (...) (in which R and R2 are as defined for general formula (1)) or a reactive derivative of this compound and gold: (II) General formula (lv) X-C-Y[N) R,2 (wherein R and R are as defined for the general f(ilK: React with a compound with a different structure (easily substituted and exhibiting a truncated group): and then remove any protecting groups, if present: and optional K (a) groups R5, R7 and (b) converting any one or more of R into other such groups; and/or (b) forming a pharmaceutically acceptable ester or acid addition salt.

The compound of general formula (1F) (in which R3 and R8 each represent hydroxy, R4, R5 and R each represent hydrogen, and R represents methyl) is 9-dihydroerythromycin, which is well known. may be prepared by a method such as reduction of erythromycin A with sodium zerohydride or sodium trimethoxy zerohydride IJp.
This may be done as described in the above-mentioned document.

The compound of general formula (■) in which each of a5, R4, R5 represents hydrogen, R represents methyl and R represents hydroxy is 9-dihydroerythromycin B, which can be used, for example, by similar well-known compounds. It may be prepared by reduction of cierythromycin B by the method of

Other compounds of general formula (II) may also be prepared from erythromycin A or B or the corresponding 9-)hydrochlorinated conductor by methods known per se. For example, the 6-, 8- or 41-positions are substituted other than in naturally occurring erythromycin A or B (i.e. R5 is methyl or R is hydroxy or fluorine or R7 is other than hydrogen and / or R8 is other than hydroxy) may be formulated as VcM as described in the respective references cited above.

Generally #! of the compound of general formula (It)! Depending on the structure, the reduction of the 9-oxo group of erythromycin A or B to a 9-hydroxy group may occur before or after modification of other positions on the erythromycin molecule.

Before carrying out the reaction of a compound of general formula (If) with a compound of general formula (厘) or a reactive derivative thereof or with a compound of general formula (m), any reactive group of the compound of general formula (II) is May be protected.

In particular, the 3'-Cumethylamino group may be protected by an N-protecting group, N-protection can be achieved by well-known methods such as Fi-H-Flynn et al.
[J-amer-Oh
em-Sac, J 1955, 77.3104-3
106).

Examples of suitable N-protecting groups are benzyloxycarzenyl and substituted penzyloxycarzenyl (e.g. evap-methylbenzyloxycarzenyl, p-nitrobenzyloxycarzenyl, p-'lomobenzyloxycardenyl, p -phenylazopenzyloxycarzenyl, and p-<p'
-methoxyphenylazone-penzyloxycarzenyl) The preferred N-protecting group is penzyloxycarzenyl. ) would be advantageous to protect. Especially at the 2'- and 4"-positions, especially at the 2'- and 4"-positions.
It is convenient to use the same radicals which are commonly used to protect the 7-mino moiety, especially the benzyloxycarzenyl group, to protect the ζ-droxy group present in the '-hydroxy group.

Any reactive substituents present on radicals R7 or R8 must preferably also be protected in a conventional manner.

The present invention also provides compounds of general formula (V), which are useful as intermediates in the preparation of compounds of general formula ('I).

[In the formula, 113 represents H or OR; R represents H or OH3; R represents H or OHs; 81% and R18(7)-Ti H, OH, O2, N22
．． NH2゜N)IZ, II-converted NH2, substituted NHz
, ani-))/yloxy or R9-EIO-0-(
In the formula, R9 represents an organic group; a 17 and R18 are H, or R17 and R18 together represent oxo; R19 represents ■ or 2; and 2 represents a protective group. represents an N-protecting group, preferably a substituted benzyloxycarzenyl group or especially a benzyloxycarzenyl group].

In method (+) of the process according to the invention, the compound of general formula (Tr) which may contain a protecting group is an aldehyde P of general formula (II) (R and/or R''=H) or a ketone (R1
, R2 is not ■] or a reactive derivative thereof. Suitable reactive derivatives of aldehydes or ketones of general formula (1) are, for example, acetals of general formula GV) ) containing enol ethers. r(We-(Ill in R1 and R2
is as defined for general formula (T), and each of R and R may be the same or different and is a hydrocarbon group, preferably a (01-6) hydrocarbon group, preferably an alkyl group, especially a methyl or ethyl group. and R is an optionally substituted monovalent hydrocarbon radical f'lK with loss of a hydrogen atom on the carbon atom with free valence; corresponding optionally substituted 2fi! fi indicates a hydrocarbon group.

The reaction according to method (i)K is preferably carried out in the presence of an acid catalyst. Preferred acid catalysts include pyridinium, such as pyridinium tosylate and pyridinium chloride. Other suitable acid catalysts are, for example, zinc chloride, steel sulfate, trifluoroborate ethylate and organic sulfonic acids (e.g. p-)luenesulfonic acid [optional K, e.g. ) with].

Advantageously, the reaction is also carried out in the presence of drying agents such as anhydrous calcium sulfate, magnesium sulfate, sodium sulfate, cupric sulfate or molecular sieves.

The reaction according to method (+) will suitably be carried out in an inert solvent. Suitable solvents are, for example, ether solvents such as tetrahydrofuran, .quaxane, ethoxyethane and 1.
2-dimethoxyethane), hydrogenated solvents (e.g. chloroform and methylene chloride) and aromatic solvents (e.g. toluene).

The reaction according to method (1) will suitably be carried out at a cooled to slightly elevated temperature, preferably at room temperature. For example, the reaction temperature is -30℃~
+30°C, preferably 0°C to +30°C, especially +10°C to +2
It will be carried out at a temperature within the range of 5°C.

In method (11) of the method according to the present invention, a compound of general formula (1) which may contain a protecting group is reacted with a compound of general formula (1). In general formula (5), each of X and Y is mutually exclusive. may be the same, but preferably, ( may be different from each other, as shown in the leaving group).

Examples of suitable leaving groups X and Y are halogen atoms (e.g. chlorine, bromine and iodine), alkylsulfonyloxy groups (e.g. methanesulfonyloxy) and arylsulfonyloxy groups (e.g. p-)lue/sulfonyloxy).
- Contains ir.

Preferably each of X and Y represents a halogen atom, in particular a different halogen atom. More preferably, X represents bromine or bromine, and Y represents bromine or iodine. A general formula in which X represents halogen and Y represents iodine (compounds with a ring are preferred for @).

The reaction according to method (1i) is preferably carried out under strong base conditions. Examples of suitable strong groups are hydrogenated) IJum,
potassium hydride, lithium amide, sodium amide P,
Includes potassium amide, potassium 1-butoxide, butyllithium and lithium diisopropylamide.

The reaction according to method (11) will suitably be carried out in an inert solvent. Suitable solvents are, for example, polar aprotic solvents (eg N,N-dimethylformamide, N.

diN-dimethylacetamide P, cumethylsulfoxide, hexamethylphosphoric triamide and N-methylpyrrolidinone and mixtures of these solvents of 2s or more) and x
'tt or higher polar aprotic solvents and one or more ether solvents (e.g., tetrahydrofuran, dioxane, :x toxyethane and 1,2-dimethoxyethane).

The reaction according to process (l+) will suitably be carried out at cooled to ambient temperature, preferably at sub-cooled temperature. For example, the reaction temperature is -30°C to +
30°C preferably 1°C to +20°C t15Ko°C to +1
It will be carried out at a temperature within the range of 5°C.

Any group R9R7 after completion of the reaction according to method (+) or (11) above and preferably before removal of any protecting group
and R may be converted into any other such group within the above definition by well known methods, such as those disclosed in the above-mentioned literature. For example, a compound in which R8 represents hydrogen and R represents hydrogen is converted into a compound in which R and R8 together represent oxo, and optionally thereafter R represents hydrogen or acetoxy, and R represents (by a method similar to that described in the aforementioned US Pat. No. 3,884,903).

After completion of the reaction according to methods (1) or (11) above and after any conversion of any groups R5, R7 and R, any protecting groups may be removed by conventional methods. Preference is given to using hydrogenation methods.

The hydrogenation is preferably carried out using a transition metal catalyst such as palladium, such as palladium on carbon (charcoal).

Radium on sulfuric acid, radium on calcium carbonate or radium black]. A preferred catalyst is radium on carbon (sometimes called palladium on charcoal): for example 5%, 10%, 20% or 30% palladium on carbon. Low, medium or high pressure hydrogen is used for this reaction. A pressure of, for example, 1 to 6 atmospheres (absolute) may be used, a pressure of 1 atmosphere (absolute) may be conveniently used.The reaction is preferably carried out at non-extreme temperatures, such as θ°C to 30°C, preferably 12°C to 2
It will be carried out at a temperature within the range of 5°C. It is generally convenient to carry out the reaction at ambient temperature. The reaction is preferably 4.5-5.
0, which may be maintained using a suitable buffer such as H4,8 acetate buffer. Suitable solvents for carrying out the hydrogenation include ethanol-pv, n-pronol, isopronominol, tetrahydrofuran, dioxane, ethyl acetate, mixtures of two or more of these solvents or such solvents or mixtures in the presence of water. . A preferred solvent is ethanol.

It is convenient to perform a reductive methylation to preserve the dimethylamino group in the 3'-position, which will advantageously be carried out simultaneously with the reductive removal of the protecting group as in the method of Purine et al., supra.

Compounds of general formula (I) can be prepared at any convenient stage of the manufacturing process, for example before or after the removal of any protecting groups and/or the group R,
Before or after any conversion of R and R to other such groups,
It may be converted into its pharmaceutically acceptable salt or ester by conventional methods.

Isolation and purification of compounds according to the invention will be carried out using conventionally used methods and will include chromatographic steps. Preferably the product is isolated in crystalline form.

Compounds according to the invention, ie compounds of general formula H and their JI! Pharmaceutically acceptable salts and esters have antibacterial properties and are useful in the treatment of bacterial infections in animals, especially humans, including mammals, especially humans, and livestock, including farm animals. The compound is, for example, Bacillus subtilis (Bac
illus 8ubtilis), Corynebacter-i
um xerosig&), Sartina ° Lutea (5a
rcinalutea) r Staphylococcus aureus (5t-aphylococcus Saureus)
), Streptococcus faecalis (5trep
tococcus Faecalis), Streptococcus pyogenes (5treptOCOCCu!
” p3'-ogenes), Streptococcus 7
・Agalactia (5treptococcus aga)
lactia), Streptococcus pneumonia (5treptococcus pneumonia)
).

Haemophilus sp.
It may be used to treat infections caused by a wide range of Durham-positive and Durham-negative bacteria, including Neisseria spl, Chlamydia sp, and Legionella sp.

The compounds according to the invention are preferably provided in substantially pure form, eg at least 50% pure, advantageously at least 75% pure. Impure or less pure forms of the compounds according to the invention may be used, for example, for the preparation of purer forms of the same or related compounds (e.g. the corresponding salts, esters or free acids) suitable for pharmaceutical use. It will be used. The purity of any compound used as an intermediate is not as critical as that of the compound used as the final product;
Such intermediate compounds are nevertheless advantageously provided in substantially pure form. It is generally advantageous to provide the compounds according to the invention in crystalline form, preferably aqueous or solvated crystalline form.

The invention provides pharmaceutical compositions comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient.

The present invention also provides a method of treating bacterial infections in animals, particularly humans and domestic animals, and mammals, comprising administering a compound or composition according to the invention to a patient in need thereof.

The compounds and compositions according to the invention may be formulated to be administered in any convenient manner used in human or veterinary medicine, as well as other antibiotics.

The compounds and formulations according to the invention may be formulated for administration by any route, such as oral, topical or parenteral. The compositions may be made in the form of tablets, capsules, powders, granules, troches, creams, syrups or solutions, such as solutions or suspensions, which may be suitable for oral use or in sterile form for parenteral administration by injection or perfusion. will be prescribed.

Tablets and capsules for oral administration are presented in unit dosage form and contain, for example, binders such as syrup, gum arabic, gelatin, nlubitol, tragacanth or polyvinylpyrrolidone; excipients such as lactose, sucrose, corn starch, Calcium phosphate, sorbitol or glycine; tablet lubricants such as magnesium stearate, Merck, Po.

Conventional excipients may also be included, including: tyrene glycol or silica; disintegrants such as potato starch; and pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

The tablets may be coated according to methods well known in the pharmaceutical practice of fluorocarbons.

Oral solutions may be presented, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as a dry product for reconstitution with water or other suitable vehicle before use. Such solutions include, for example, suspensions such as sorbitol.

Methyl cellulose, crucose syrup, seratin,
HyP-oxyethylcellulose, calxoxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous media (which may contain edible oils); e.g. glycerin), propylene glycol or ethyl alcohol:
Preservatives such as methyl or propyl p-hyP-roxy tetrazoate or sorbic acid; and, if desired, conventional additives including conventional flavoring and coloring agents may be included.

A compound or composition according to the invention will preferably be administered to a patient in an antimicrobially effective manner.

The composition according to the invention is preferably administered at 0.0000000000000 depending on the method of administration.
It will contain 1% or more by weight, preferably 10 to 60 weight percent of a compound according to the invention (based on the total weight of the composition).

The compounds according to the invention will suitably be administered to patients at a daily dose of 1.5 to 5 or 9/9 body weight.

100-3000 for adults (approximately 70 to 4 weight)
■ For example, about 15001 v of a compound according to the invention will be administered daily. Preferably, the dose for the deceased is 5 to 20 ml per day. However, higher or lower doses may be used in accordance with normal clinical practice.

When the composition according to the invention is provided in the form of a unit dose, the unit dose will suitably contain from 25 to 1 OOO12, preferably from 50 to 500, of the compound according to the invention.

No toxicological side effects are exhibited when the compounds according to the invention are administered within the above-mentioned dosage ranges.

〔Example〕

The following examples illustrate the preparation of compounds according to the invention.

Example 1 (98)-9,11-0--! 'Tylidene-9-dihydroerythromycin A (a) (9E? Fu9, 11-0-ethylidene-
9-dihydro-2'-0,H-dipenzyloxycarzenylude-N-methylerythromycin A(9and)-
9-dihydro-2'-0,N-dibenzyloxycarginyl-des-N-methylerythromycin A C700
(2), pyridinium tosylate (70rn9) and aceto7A/dehyde (3,5WLl) were dissolved in t-dry tetrahypfuran (5,5m). Anhydrous calcium sulfate (
1,0,) was added and the mixture was stirred for 67°.

The mixture was diluted with ethyl acetate (501 rll) and filtered. Rinse solution F with water (2 x 30 d) and dry (
Na2E104). The solvent was removed and the resulting residue was chromatographed on silica gel using ethyl acetate-hexane as eluent. The title compound was obtained as a colorless gum (500 ml). [α]6°= −
65,0° (3,1% weight f!#/volume t.

CHOl, medium).

(b) (98)-9,11-0-ethylidene-9-
The compound from dihydroerythromycin A l(a) (350 μ) was mixed with ethanol (15
yxl) and acetate buffer (H4,8; 1.2m
1) and hydrogen (1) dissolved in the solution t-30 min.
Atmospheric pressure) Shake with T10% palladium/charcoal (100W9). 37% formaldehyde solution (1.5WL
l) Q added and hydrogenation f: continued for 1.5 hours. catalyst 1
It was removed by filtration and washed with ethanol and water.

Ethanol was removed from the filtrate under reduced pressure and the residue was diluted to approximately 30ml with water. The solution was made basic (~pHlt) using potassium carbonate and ethyl acetate (2X3
01d). Wash the combined extracts with water for 20 minutes.
m/) and dried (1i32 days under O4). Removal of the solvent gave the title compound as a colorless foam (270~).
σ]ru0 = -31,2° (1,0% weight/volume.

aHal, medium), vmax (OT1015) 3570.
3440 and 1725m-'; mass spectrometry y', 7
s 1.4931 (a3.H71No1゜M
, 761.4929).

Example 2 (9B)-9,11-0-methylene-9-dihydroerythromycin (a) (98)-9,11-0-methylene-9-dihydro-2'-0,N-dibenzyloxycalse Nirude-N-methylerythromycin A (98)-9-dihydro-2'-0,11-dipenzyloxycarzenilude-N-methylerythromycin A (800 ■) anhydrous potassium carbonate powder (500wI9), 15-crown-5-c-te/l/ (1.

4.7,10,13-pentaoxacyclopentadecane) (2 drops) and chloroiodomethane (1 ml). The mixture was stirred and cooled on ice while sodium hydride (50% dispersion in oil; 100 μl) was added in one portion. Mixture "II: Stirred for 30 minutes and cooled on ice, then the cooling bath was removed and stirred. The mixture was diluted with ethyl acetate (toomg) and diluted with dilute-11a2SOs.
(30MI) and water (3m40m/). The solution was dried*(Na2804) and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate-hexane as eluent.

The title compound was obtained as a colorless f~ crystal (520~). Melting point 118-119°C (ether hexane). [α
) i' = -74,3° (1,35% weight t/volume,
0HO13). (Actual value: 0, 63.6%;
H, 7,9%; N, 135%6” 55H7
0 as 9NO17, 63.5%; H, 7,95%
; N, 1.4%).

The compound from Droethromycin A (2a) was converted to the title compound using a method similar to that described in Example 1(b).

The title compound was obtained as colorless crystals. Melting point 140~
142°C (methylene chloride/hexane).

[α) j5 = -63,3° (work, 0chi weight/appearance,
cuC13).

Mass spectrometry, M, 747, 4761 (C58H6
M as 9N015, 747°4752).

Example 3 (98)-9,11-0-isopropylidene-9゛-cyhydroerythromycin<9B)-9-dihydroerythromycin A (500
~) and 2-methoxypronozone (0,7ynl)
f Drying: x Dissolved in tanol-free chloroform (lQd).

Pyridinium chloride (1201R9) was added and the mixture was stirred for 16 hours. The solution was washed with potassium carbonate solution and dried (Na2804). The solvent was removed and the residue was dissolved in 7 setsone (1(1/)) and water (10(1)/
) dissolved in a mixture of Bring up to H3.5 using solution i 1 MHCjl f and leave for 2 hours. The solution was made alkaline using potassium carbonate and extracted with ethyl acetate. The solution was dried (Na2so4) and the solvent removed to give a colorless gum (420 Da). 3:2 methanol/phosphate buffer (0,0
Chromatography on silanized silica gel using 67M, H7) was performed. The title compound was obtained as a colorless foam (320 Da). [α): 5 = -30,4° (1,0 weight/volume, in 0HOA'3). vmax (0HO
I3) 3530.3400 and 1725cy+, mass spectrometry 9M.

775.5)06(M as C4oH73NO43,
77s, 5082).

Example 4 (9B)-9,11-0-propylidene-9-dihydroerythromycin A (a)(98)-9,11-0-propylidene-9-dihydro-2'-0,M-dibenzyloxycal -Nil-
Des-N-methylerythromycin A (9s)-9-dihyp,-2'-0,N-dibenzyloxycarzenyldes-N-methylerythromycin A (500) and pyridinium tosylate (70~) were added to 1, 2-dimethoxyethane (5d) and propionaldehy r<5rn
t).

Add anhydrous calcium sulfate (1,0,) Q and mix 1
Stirred for 1:10 days. The mixture was diluted with ethyl acetate (50d)
Diluted with K. and filtered. Wash the filtrate with water 2x30
m/) and dried (Na2804). The solvent was removed and the resulting gum was chromatographed to give the title compound as a colorless gum (105)f9).

[αzo2=-62.5°(t, o % weight/volume t
+ in CHO13).

(b) (98)-9, t l -0-propyridien-
The product from 9-SchihiP loerythromycin A 4(a) was converted to the title compound using a method similar to that described in Example 1(b).

The title compound was obtained as colorless crystals. Melting point 127~
129°C (methylene chloride, hexadiene).

[α) 20 = -36,0° (1,0% weight/appearance,
during CHOA'3).

vmax (CHOJ3) 3530, 3440 and 1725m.

Example 5 (98)-9,11-0-n-butylidene-9-dihydroerythromycin A Using a method similar to that described in Example 4 but replacing zolopyrenaldehyde P with n-butyraldehyde. use,
The title compound was obtained as colorless crystals. [α3 people 0=
-38,6° (1,0% weight/volume.

0HC15].

Example 6 (9B)-9,11-0-iso-butylidene-9-dihydroerythromycin A Using a method similar to that described in Example 4 but using isobutyraldehyde P instead of propionaldehyde, the 9 title was prepared. The compound was obtained as colorless crystals. [α)20=
-3s, s° (1,0% weight/volume, in CHO115)
.

Example 7 (98)-9,l 1-0-Benzylidene-9-dihydroerythromycin A (98')-9-dihydroerythromycin A (370rn9)t''pyridinium p-toluenesulfone-) in benzaldehyde (ego) (125~) and anhydrous sulfuric acid (I) (a o omq). The mixture was stirred at room temperature for 7 days. The mixture was diluted with ethyl acetate (50
-] and powdered potassium carbonate (1,0
). The mixture was filtered and the solution was washed twice with water. The solution was dried (Na2so4) and the solvent was evaporated under reduced pressure to give a blue oil.

Oil TL-3: 2 methanol/phosphate buffer CO, 06
7M.

, H7,0)? Chromatography on silanized silica gel gave the title compound as colorless crystals (50~). R1O, 16°νmax (0HO13)35
20°3450 and 1725cm.

Example 8 (9L)-9,l 1-0-Furfuriritin-9-dihydroerythromycin A
9El)-9-dihydroerythromycin A (370~
) and pyridinium p-1 luenesulfonate (130
m9) was treated with anhydrous copper sulfate (■) (3001n9) and the mixture was stirred at room temperature in the dark for 10 days. The mixture was diluted with ethyl acetate (5QmJ) and washed with potassium carbonate solution (30#L/) and water (3X20d). The solution was dried (Na2S04) and the solvent was evaporated under reduced pressure to give a brown oil. Chromatography of the oil on silanized silica gel with kumquats in l:l to 3:2 methanol/phosphate buffer (0,067!, H7,0) yielded the title compound as a pale yellow foam (45η). ]6°=
−45.8° (1.0% w/v, in aHol15).

M”, 813.4898. (M as C42H71N014, 813°4878).

Example 9 (9E+)-9, Ih-0-euteridene-9-dihydroerythromycin A (9s)-c+-J hydroerythromycin AC1,0,) and pyridinium p in acetaldehyde (5d)
-) Luenesulfonate (360■) was added to anhydrous copper sulfate (U)
)(t,o,)K and the mixture was stirred at room temperature for 10 days. The mixture was diluted with ethyl acetate (5(1/)) and washed with potassium carbonate solution (30 m) and water (3 x 30 m).The solution was dried (Na2SO4) and the solvent was removed under reduced pressure to give a blue color. A foam of 1=1 to 3:2 methanol/phosphate buffer (0,067M) was obtained.

, H7.0) to give the title compound as colorless crystals (500 cm), melting point 143-145°C (dichloromethane/hexane). (%lQ value 20, 61.2; H ,
9,4; N, 1.75° C39H71NO43 as C161,45; B, 9.4; N,
1.85%). Other properties are the same as the sample from Example 1(b).

Example 1O (9El-9,11-0-inzolobylidene-9-dihydroerythromycin A (7) in dry ethanol-free chloroform (10d)
9S)-9-) Hydroerythromycin A (500Tn
9) was treated with 2,2-dimethoxypronogne (2 mA!) and pyridinium hydride (120114 iJ). The mixture was stirred for 14 days at room temperature. The mixture was diluted with diluted loform (50ml) and potassium carbonate solution (3ml) was diluted with potassium carbonate solution (3ml).
It was washed with 0 ml of water (30 ml). The solution was dried (Na25Oa) and the solvent was removed under reduced pressure to yield a colorless foam. The foam was chromatographed on silanized silica gel using L21-3:2 methanol/phosphate buffer (0,067!!!, H7,0) to produce a colorless foam (90%).
(2)] The title compound was obtained. The product had the same properties as described for the sample from Example 3.

Agent Patent Attorney Masaaki Aki Sawa Other name

Claims (15)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 and R^2 may be the same or different, hydrogen, unsubstituted or substituted carbon represents a hydrogen group or an unsubstituted or substituted 5- or 6-membered heterocyclyl group containing an oxygen or sulfur atom as a heteroatom, or R^1 and R^2 together represent an unsubstituted or substituted divalent Represents a hydrocarbon group or an unsubstituted or substituted alkyleneoxyalkylene or alkylenethioalkylene group; R^3 represents hydrogen or hydroxy; R^4 represents hydrogen, fluorine or hydroxy; R^5 and R^6 each of which may be the same or different and represent hydrogen or methyl; one of R^7 and R^8 is hydrogen, hydroxy, alkoxy, alkanoyloxy, amino, substituted amino or of formula R
^9-SO_2-O- and the rest of R^7 and R^8 represent hydrogen, or R^7 and R^8 together represent an oxo group, an oxime group or a substituted oxime group: and R ^9 represents an organic group) or a pharmaceutically acceptable ester or acid addition salt thereof. (2) In general formula (I), each of R^1 and R^2 may be the same or different and is a hydrogen atom, an alkyl group, an aryl group, or a 5- or 6-membered group containing an oxygen or sulfur atom as a hetero atom. The compound according to claim 1, which represents a heterocyclyl group and each of these groups may be unsubstituted or substituted. (3) The compound according to claim (1) or (2), wherein in the general formula (I), at least one of R^1 and R^2 represents a hydrogen atom. (4) In general formula (I), one of R^1 and R^2 represents a hydrogen atom, and the other one of R^1 and R^2 represents an unsubstituted or substituted alkyl or aryl group. A compound according to claim (1). (5) In general formula (I), R^3 represents a hydroxy group, R^4 represents a hydrogen atom, and R^6 represents a methyl group. Compounds described in one section. (6) Claim No. 1 in which the compound is 9,11-¥0¥-ethylidene-9-dihydroerythromycin A
) Compounds described in section 2. (7) Claim No. (1) in which the compound is 9,11-¥0¥-methylene-9-dihydroerythromycin A
Compounds described in Section. (8) The compound is 9,11-￥0￥-isopropylidene-
The compound according to claim (1), which is 9-dihydroerythromycin A. (9) The compound is 9,11-￥0￥-propylidene-9-
Claim No. 1, which is dihydroerythromycin A (
Compound described in section 1). (10) The compound is 9,11-￥0￥-benzylidene-9
-dihydroerythromycin A. The compound according to claim (1), which is dihydroerythromycin A. (11) The compound is 9,11-￥0￥-n-butylidene-
The compound according to claim (1), which is 9-dihydroerythromycin A. (12) The compound is 9,11-￥0￥-isobutylidene-
The compound according to claim (1), which is 9-dihydroerythromycin A. (13) The compound is 9,11-￥0￥-furfurylidene-
The compound according to claim (1), which is 9-dihydroerythromycin A. (14) A pharmaceutical composition comprising a compound according to any one of claims (1) to (13) together with a pharmaceutically acceptable carrier or pharmaceutical additive. (15) General formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^3, R^4, R^5, R^6, R^7 and R
^8 is as defined in claim (1), even if any reactive groups (other than 9-hydroxy and 11-hydroxy groups) are protected in the compound of general formula (II). Good] and (i) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^1 and R^2 are as defined in claim (1)) ) or a reactive derivative of such a compound: or (ii) General formula (IV) ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (wherein R^1 and R^2 are the claims as defined in paragraph (1) and each of X and Y may be the same or different and represent a readily substitutable group) and then any protection, if present, group and optionally converting (a) any one or more of the groups R^5, R^7 and R^8 to other such groups; and/or (b) a pharmaceutically acceptable ester or A method for producing a compound of general formula (I) as defined in claim (1), or a pharmaceutically acceptable ester or acid addition salt thereof, which comprises forming an acid addition salt. ■General formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V) [In the formula, R^1^3 represents H or OH; R^1^4 represents H, F or OH; R^ 1^5 represents H or CH_3; R^1^6 represents H or CH_3; one of R^1^7 and R^1^8 represents H, OH, OZ, N
Z_2, NH_2, NHZ, substituted NH_2, substituted NHZ
, represents alkanoyloxy or R^9-SO_2-O- (in the formula, R^9 represents an organic group), and the rest of R^1^7 and R^1^8 represent H, or R^1^ 7 and R^1
^8 together represent oxo; R^1^9 represents H or Z; and Z represents a protecting group, especially an N-protecting group, preferably a substituted benzyloxycarbonyl group or especially a benzyloxycarbonyl group ] compound.