CA1089457A

CA1089457A - 5-nor-bicyclomycin-5-one derivatives

Info

Publication number: CA1089457A
Application number: CA278,748A
Authority: CA
Inventors: Beat Muller; Wilhelm Kump; Oskar Wacker
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1976-05-21
Filing date: 1977-05-19
Publication date: 1980-11-11
Also published as: ES458932A1; DE2722164A1; FR2351981A1; DK221377A; FR2351981B1; ATA361277A; AU2532077A; AU510339B2; SE7705884L; ZA773018B; AT350720B; BE854841A; US4322419A; GB1545021A; JPS52142092A; NL7705595A

Abstract

Abstract of the Disclosure Derivatives of 5-norbicyclomycin of the formula

Description

~U~ t7 ~ 2 --The present invention relates to bicyclic compounds having the basic skeleton of the 2-oxa-7,9-diazabicyclo[4,2,2]decane of the formula 6 5 : :
7 N ~ ~ 4 8 ~ ~ 3 .1 2 and, in particular, derivatives of the 5-norbicycl~ycin of the formula d ~- R
OR N/

C`O CH2 H--C--ORa (I) CH3--C--ORb wherein each of Ra, Rb, Rc and Rd individually represents ~ ?~
hydrogen atom or oxa-(lower alkyl), oxa-~lower cycloalkyl), lower alkanoyl, benzoyl, lower alkoxycarbonyl, or any two of the symbols Ra, Rb and Rc together represent carbonyl, lower alkylidene, or lower cycloalkylidene, R represents hydrogen or -~
lower alkyl or lower alkyl which is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino, di-(lower alkyl)-amino, ~ :
carboxy or lower alkoxycarbonyl, or represents phenyl or phenvl- ~:
(lower alkyl), or phenyl or phenyl-(lower alkyl) whose ring is ,Ç~
.
., , . ~

~ . . . ~ ~ . . . .. . .

a~lS~

substituted by halogen, nitro, lower alkyl or lower alkoxy, or represents acyl derived from a lower alkanesulfonic acld, benzenesulfonic acid or from benzenesulfonic acid whose phenyl ring is substituted as indicated hereinabove, or an~inocar-bonyl which is unsubstituted or N-substituted by lower alkyl r or represents lower alkoxycarbonyl or acyl derived from a carboxylic acid derived from any of the above-defined unsub-stituted or substituted lower alkyl, phenyl or phenyl-~lower alkyl) radicals or from a pyridyl or pyridinio-(lower alkyl) radical, and X represents a bivalent group of the formula -O- or -NH-, and of pharmaceutically acceptable salts of such a compound, provided it contains a salt-forming group, and also to a process for the manufacture of said compounds and to preparations which contain them and to the use of the latter, as well as to therapeutic methods of combating in-fectious diseases which comprise the use of these compounds and preparations.

In the above c~mpounds of the formula I, the group ~X-R is ~y~- or a _ -oriented with respect to the rest of the molecule, ~or exa~ple in relation to the 6-hydroxyl group. Unless other-wise specifically stated, a process product can be both a mixture of both isomeric forms and an individual isomer.

An example for a phenyl lower alkylgroup isthe trityl group, examples for a2-oxaalkylor 2-oxacycloalkyl group are in particular ~0~ 7 a l-butoxyethyl or 2-tetrahydropyranyl group.

Unless stated to the contrary, the term "lower" used through-out this specification to qualify organic groups and radicals means that these contain not more than 7, preferably not more than 4, carbon atoms.

In an alkylidene radical two free valencies originate from a single carbon atom.

Examples of lower alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl.
Examples of Lower alkylidene radicals are methylene, iso-propylidene or lsobutylidene.

In a cycloalkylidene radical two free valencies originate from a single carbon atom. ;

Examples of lower cycloalkyl radicals are cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as bicyclo[2,2,2]octyl, 2-bicyclo~2,2,1]heptyl, and also 1-, 2-or 3-methylcyclopentyl, 4-tert.-butylcyclohexyl, 4~4-di-methylcyclohexyl, 2,4,6-trimethylcyclohexyl and 2,4,4,6-tetra- ;~`
methylcyclohexyl. Examples of cycloalkylidene groups are cyclopentylidene and cyclohexylidene radicals.

~ 5~7 Examples for phenyl-lower alkyl radicals are benzyl, 1- or 2-phenylethyl- 1-, 2- or 3-phenylpropyl, diphenylmethyl (viz.
benzhydryl) and trityl.

Examples for lower alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.-butoxy. Examples for oxa-(lower alkoxy) groups ORa, ORb, ORC and ORd are lower alkoxy groups which are substituted especially in the l-position, as in the butoxyethoxy moiety, or in the 2-pos~tion, as in the 2-methoxy-ethoxy moiety. Examples for oxa-(lower cycloalkoxy) groups are 2-tetrahydrofuranyloxy and 2-~etrahydropyranyloxy.

Examples for an optionally halogenated lower alkanesulphonyl group are methanesulphonyl and trifluoromethanesulphonyl.
Examples for a substituted benzenesulphonyl group are p-toluenesulphonyl (i.e. tosyl), p-chlorobenzenesulphonyl, p-bromobenzenesulphonyl and 2,4-din:itrobenzenesulphonyl.

Examples for a lower alkoxycarbonyl group which i5 unsub-stituted or substituted in particular by lower alkyl, lower alkoxy, nitro and/or halogen, are methoxycarbonyl, ethoxy-carbonyl, tert.-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-iodoethoxycarbonyl. Acyl radicals of the following acids are particularly preferred: propionic, butyric, iso-butyric, valeric, isovaleric, capronic, trimethylacetic and diethylacetic acid, and, most preferably, acetic acid, but also corresponding halogenated lower alkanecarboxylic acids, '` ~`'' ` ' . - . ~ .. .
~ - . - . - .

- . . , - - : , .:: . -4S'~
-- 6 ~

such as chloroacetic acid, bromoacetic acid or ~-bromoiso-valeric acid, phenylacetic or phenylpropionic acld.

The compounds of the formula I, provided they contain salt- :
forming groups, can be in the form of salts, preferably physiologically tolerable salts. If a comp~und of the formula I contains an acid group, such as carboxyl, salts can be formed with bases, vi~. primarily metal or ammonium salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines. Suit~
able amines for the salt formation are in particular acyclic, ~
carbocyclic and carbocyclic-acyclic primary, secondary and, -most preferably, tertiary mono-, di- or polyamines, and hetero~
cyclic bases, such as~lower alkylamines, for example triethyl- :`
aminè, hydroxy-lower alkylamines, for ~xample 2-hydroxyethyl~
amine, di-(2~hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine~s or tri-(2-hydroxyethyl)-amine, basi.c aliphatic esters of car- .
boxylic acids, for example 2- (diethy~amino) -ethyl 4-aminoben- :
æoate, lower alkylenamines, for ex~mple l-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine 3 or benæyl-amines, for example N,N'-dibenzylethylenediamine, and base~ ; :
of the pyridine type, for example pyridine, collidine or quino- ;;~.. ~.
line. Compounds of the fonmula I, which contain a basic group in the substituents,~can form addition salts, in particular acid addition salts, for example with inorganic acids, such as :~
hydrochloric acid, sulphuric acid or phosphoric acid, or wi~h ,`''' ~''''~ ' -~

~U8~
:

suitable organic carboxylic or sulphonic acids, for example trifluoroacetic acid. Compounds of the formula I whichcontain both an acid and a basic group ~s substituents,can alsobe in the form of an inner salt, i.e. in zwitterion form. Addition salts also comprise quaternary salts which are formed, for example, by addition of a hydrocarbon halide to a tertiary amino group or th~ aromatic nitrogen atom of an aromatic hetero-cyclic ring. Examples are the methanesulphona~e, ~he bromide or the chloride o a tri-lower alkylammonio compound~ such as a trimethylammonio or pyridinio compound.

The novel compounds of the present invention exhibit useful pharmacological, especially antibiotic, for example anti-bacterial, properties, and/or can be used as intermediates for obtaining sush compou~ds.
,~
Particularly preferred compounds are those of the formula ; ~ R
OH NJ

~H ~ CH2 ' (IA) O~
H- C~ OH

~ : .` .';, ~ g~S7 wherein RA represents hydrogen or lower alkyl or lower alkyl which is substituted by hydroxy, lower alkoxy, lower alkanoyl-oxy, amino, di-(lower alkyl)-amino, carboxy or lower alkoxy-carbonyl, or represents phenyl or phenyl-(lower alkyl), or phenyl or phenyl-(lower alkyl) whose ring is substituted by halogen, nitro, lower alkyl or lower alkoxy, or represents acyl derived from a lower alkanesulfonic acid, benzenesul-sulfonic acid or from benzenasulfonic acid whose phenyl ring :
is substituted as indicated hereinabove, or aminocarbonyl :~
which is unsubstituted or substituted by lower alkyl, or represents lower alkoxycarbonyl or acyl derived from a car-boxylic acid derived from any of the above-defined unsub-stituted or c;ubstituted lower alkyl, phenyl or phenyl-(lower alkyl) radicals or from a pyridyl or pyridinio-(lower alkyl) radical, and X represents a group of the formula -O- or -NH-, or a pharmaceutically acceptable salt of such a compound, provided it contains a salt-forming group.

Examples for amino-lower alkyl radicals are 2-aminoethyl, 2-dimethylaminoethyl, 3-aminopropyl or 4-aminobutyl. Examples for hydroxy-lower alkyl radicals are hydroxymethyl, 2-hydroxy- .~ `
ethyl and 2-hydroxypropyl. Examples for lower alkanoyloxy--lower alkyl radicals are acetoxymethyl, 2-formyloxyethyl and

2-acetoxyethyl, and examples for lower alkoxy-lower alkyl ` :~
radicals are methoxymethyl, ethoxymethyl, 2-methoxyethyl and ~;
2-ethoxyethyl. ; -~.. ,~.. ~, ;

9~

g Carboxyl groups can be in the free form, as salts or as lower alkyl esters, in particular methyl and ethyl esters.

The novel compounds reveal useful pharmacological properties, as is shown both in the in vitro test and in animaltests.Thus the in vitro test results show them to have antibiotic, in particular antibac~erial, properties, for ex~mple against Enterobacteria (in concentrations of 0.025 to 0.5 mg/ml). In animal tests too, or against Proteus sp. (in concentrations of 0.1 to 0.5 mg/ml), for example on mice in doses of 16 to 100 mg/kg (subcutaneous administration) the novel com- ;
pounds show antibacterial properties against Escherichiacoli and Klebsiella, and, in doses of 20 to 700 mg/kg (subcuta~
neous administration), against Proteus sp. To be singled out for special mention is 5-methoxyimino-S-norbicyclomycin, i.e.
the compound of the formula IA, wherein -X-RA represents the methoxy group, for which an effective dose ED50 of 16 to ~`
20 mg/kg was found against Enterobacteria, for example Escherichia coli and Proteus sp., when administered subcuta-neously to mice. Bicyclomycin, to the contrary, is not suffi-ciently effective against Proteus. The novel compounds can therefore be used for example in the form of antibiotic preparations for the treatment of infectious diseases, or as preservatives, or as additives to animal feeds. In addition, ~
they can be used for the preparation of other compounds with ~-such an antibiotic action.

~ '~'' '' :' ~............................................................ ~;. ':`

L5 ~

The compounds of the formula I are obtained by reacting a 5-norbicyclomycin-S-one compound of the formula II

oRd O
/~ ' .~
~H ~ CH2 ,;
(~1 --0 / ( II) H--C--OR
CH3--C--oRb :,`.
wherein Ra, Rb, Rc and Rd are as defined in formula (I), with a co~pound of the formula . R-X-NH2 (III) .
wherein R and X are as already defined, or with a salt thereof, and, if desired, in a resultant compound~ removing or intro~
ducing one or more hydroxyl protectîve groups Ra, Rb, RCand/or Rd or converting them intoother hydroxylprotective gxoups,and,if ~ ~
desired, within the definition of the final products,converting ~ -a resul~ant compound into another compound, and/or,ifdesired, ~ :
converting a resultant compound with a salt forming group into the free compound or into another salt, and/or, if desired, ;~
s~parating individual isomers from a Fesultant isomer mixture. ~
':' `

:-. :- . -. :.. . -: : .. - . . : -, .. , . . ~ ~

Preferably, 5-norbicyclomycin-5-one, which has free hydroxyl groups, is used as s~arting material of the formula II.

Starting materials of the formula III are hydroxylamine and 0-substituted hydroxylamines of the formula R-O-NH2 (IIIa) wherein R is as defined above, and the corresponding acid addition salts. Starting materials of the formula III are also hydrazine or hydrazine hydrate and, in particular mono-substituted hydrazines, including semicarbazide, and the corresponding salts.
.~'.

They are characterised by the formula R
~-NH2 (IIIb) H

wherein R is as already defined herein. Salts of compounds of the formula III are primarily acid additions salts, in par-ticular with mineral acids, such as hydrohalic acids, for example hydrochloric or hydrobromic acid, or sulphuric acid.

: ` .

The above reaction is carried out in a manner known per se, `~
and, when using acid addition salts of compounds oftheormula ; III, in the presence o a basic reagent. Suitable bases are inorganic bases, such as carbonates or hydrogen carbonates of alkali metals or alkaline earth metals, for exa~ple sodium :~:
~. .,, ; ~ ~

`

hydrogen carbonate, or organic bases, for example tertiary organic bases, such as correspondin~ heterocyclic bases, for example pyridine or quinoline, or tertiary aliphatic, cyclo- :
aliphatic or aromatic amines, for example tri-loweralkylamine such as triethylamine, and also alkali metal or alkalineearth metal salts of organic carboxylic acids, such as lower alkane-carboxylic acids, for example acetic acid,such as sodium acetate. ~

The reaction is preferably carried out in the presence of a ~ ~.
suitable solvent or diluent, such as an alcohol, for example .
a lower alkanol, such as methanol or ethanol, an ether, such as a cyclic ether, for example tetrahydrofurane or dioxane, .
or an ether of a glycol, such as a lower alkyl etherof aglycol or polyglycol, for example ethylene glycol dimethyl ether or . .
diethylene glycol dimethyl ether, or a halogenatedhydrocarbon, such as a chlorinated alkane, for example methylene chloride, :
and water, or a solvent or diluent mixture) with cooling or ~.
preferably with heating, for exampl~3 at temperatures of 20 .
to 100C, and, if appropriate, in a closed reaction vessel ~-~
and/or in an inert gas atmosphere, for example in a nitrogen or argon atmosphere. ~ :
:'`~` ' In the process of the present invention and also in any addi-tional steps which it may be necessary to carry out, free ~unctional groups which are present in the starting materials .

~ ~4~ 5 or in the c~mpounds obtained in accordance with the process and which do not participate in the reaction, for example free amino groups in the group R, can, if necessary, be temporarily protected by acylation, tritylation or silylation, and, in particular, free hydroxyl groups in the bicyclomycin skeleton can be protected for example by etherification or esterifi-cation in a manner known per se, and, when the reaction is complete, set free, if desired, individually or together.
Thus, for example, hydroxyl groups which are protected as tetrahydropyranyl ether, for example in the 1'-, 3'- and/or 6-position, can be set free by conventional acid catalysed hydrolysis.

Resultant compounds of the formula I can be converted in a manner known per se into other compounds of the formula I.

For example, in a compound of the formula I, in which R in the grouping -NH-R represents hydrogen, and each of Ra, Rb and Rc is preferably different fr~m hydrogen~ the amino group can be substituted by methods which are known per se, in par~icular acylated, in a manner known per se, by treatment with acids, such as carboxylic acids, or reactive derivatives thereof, such as anhydrides, halides, for example chlorides, :~
and ketenes.

, ,. !; ~.

1~ ~ 9 ~ 5 7 It is also possible, for example in a compound ofthe formula I, wherein R in the grouping -O-R represents hydrogen, to substi-tute, preferably to alkylate, the free hydroxyl groupby methods which are known per se. In particular, a corresponding oxime with a free hydroxyl group can be treated in a mannerknown per se with a diaæoalkane, preferably diazomethane, preferably avoiding a large excess of the reactant and inappropriately long reaction tlmes.

Salts of compounds of the formula I càn be prepared in a manner ;~
known per se. Thus salts of compounds of the formula I with an acid grouping can be formed for example by treatment with metal~;
compounds, such as hydroxides, carbonates and hydrocarbonates of alkali metals or alkaline earth metals, andalsowith alkali ~`
metal salts of suitable carboxylic acids,for examplethe sodium salt of -ethylcaproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts ~
of compounds of the formula I with basic groups are obtained ~ ;
in similar manner, for example by treatment with an acid or a suitable anion exchanger. Inner salts of compounds o the formula I which contain a salt-forming amino group and a free carboxyl group, can be formed for example by neutralising salts, such as acid addition sal~s, to the isoelectric point, or example with weak bases, or by treatment with liquid ion exchangers.

-- . - , Salts can be converted in the cust:omary manner in~o the free compounds, metal and ammonium salts for example by treatment with suitable acids, and acid addition salts or example by treatment with a suitable base.

Resultant mixtures of stereoisomers can be separated into the individual isomers by methods which are known per se, for example by fractional crystallisation, adsorption chromato-graphy ~column or thin-layer chromatography), or other appropriate methods of separation.

The process also comprises those embodiments of the invention in which compounds obtained as intermediates are used as ~; `
starting materials and the remaining process steps are carried out therewith or in which the process is interrupted at any stage, or starting materials can be used in the form of deri-vatives or formed du_ing the reaction.

Preferably, the starting materials and reaction conditions are so chosen that the compounds referred to at the outset as~eing especially preferred are obtained.

The starting materials of the formula II used in accordance `
with the invention are novel They can be prepared forexamplc by oxidative elimination of the methylene group in a compound of the bicyclomycin type of the formula :.
'.

-- 16 - :

oRd ' ~' 2 ::~

~ ~H2 . ~
(~ /H2 ~ .. '' O (IV) H- C- ORa CH3- C - oRb wherein Ra9 Rb, Rc and Rd are as previously defined herein, and, if desired, in a resultant compound, introducing or-re-moving one or more hydroxyl protective groups Ra, Rb, Rc and/or .Rd or converting them into other hydroxyl protective groups. ::

The oxidative elimination of the methylene group can be accom~
plished in a manner known per se, for example byoxidatiDn with potassium permanganate or by hydroxylation, for example with osmi~m tetroxide, and subsequent glycol cleavage, or exampl with periodic acid or lead(IV) salts, the hydroxyl groups of the starting material being preferably protected and optionally ~ :
subsequently removed. Advan~ageously, the methylene group is removed by ozonisation, because, among other reasons, unpro~
tected hydroxyl groups are not affected.

. ;

"~

~0~3'~57 The ozonisation can be carried out in a manner known per se, for example by introducing a flow of oxygen which contains ozone into a solution of a bicyclomycin co~pound in a solvent which is inert to ozone until the theoretical amount of ozone has been consumed, and b~ decomposing the resultant ozonide thermally or by hydrolysis, reduction or oxida~ion. Suitable solvents ~or ozonisation are polyhalogenated, in particular chlorinated, lower alkanes, such as dichloromethane, chlorofo and dichloromethane, and in particular lower alkanols, such as me~hanol and ethanol, lower alkanecarboxylic acids,such as acetic acid, butyric acid, and preferably propionic acid, and the esters thereof with lower alkanols, such as ethyl acetate, as well as mixtures of such solvents. Preferred media are solvents and solvent mixtures which remain liquid even at low temperatures, for example below -20C and preferably also below -50C, and which still retain a good dissolving power for the -starting materials to be oæonised. ~he ozonisation is carried out at decreased temperature, for example between +10 and -80C, preferably between -18 and -70C. Normally the reac- ~ `~
tion is carried out with a small excess of ozone, which can be easily detected by the residual blue colouration of the reaction mixture. The decomposition of the resultantozonide is effected in the present process preferably by adding dimethyl sulphide, after which the reaction mixture isbrought ~`
to room temperature. The presence of water, for example of ;~

.~ ~' ., . .~ ~ _ __ _ _ _ _ . _ . .. .. _. __ _. _ _ _ .. ,. _ ,_ .

- ~o~

moisture or ~ater of crystallisation, does not affect these reactions.

~ree bicyclomycin of the formula IV, wherein Ra, ~b,RC and Rd represen~ hydrogen atoms, is.preferably used as starting material for the removal of the methylene group byozonolysis.
However, it is also possible to use corresponding derivatives, ;
fox example 1',3',6-tri-tetrahydropyranyl ether, with equal success.

The pharmacologically useful compounds of the present invention :;
can be used, for example, for the manufacture of pharmaceutlcal preparations which contain an effective amount of the active ;
substance together or in admixture with inorganic or organic ~:
solid or liquid pharmacologically useful carriers, which are suitable preferably for enteral or parenteral administration.

~ ~, Tablets or gelatin capsules are therefore used which contain the active substance together with diluents, for example lactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/or glycin, and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium :~
stearate, and/or polyethylene glycol. Tablets also contain binding agents, ~or example magnesium aluminium silicate, starches, such as maize, wheat, rice or arrow root starch, ~:

~' ~

-` 10~

gelatin , tragacanth 9 methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorption agents, colourants, flavouring matters and sweeteners. It is also possible to use the novel pharma-cologically active compounds in the form of preparationswhich can be administered by injection, for example, by intravenous injection, or of infusion solutions. Such solutions are pre-ferably isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations that contain the active substance alone or together with a carrier, for example mannitol.

The pharmaceutical preparations, can be sterilised and/or contain adjuvants, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubility promoters,salts for regulating the osmotic pressure and/or buffers~Thepharma ceutical prepara~ions which, if desired, can contain further pharmacologically useful substances, are manufactured in known manner, for example using conventional mixing, granulating, `;
confectioning, dissolving or lyophilising methods, and they contain from 0.1% to 'oo%, especially from l~ to 50%t and ~-~
lyophilisates up to loo~ of the active substance. In partic- ;
ular, pharmaceutical preparations are prepared as dosage units. ~;`
~' 1~ ''l57' - ~o -Throughout the description and in the Examples, for the sake of clarity the nomenclature of the corresponding compounds is derived from bicyclomycin [systematic name: 6-hydroxy-5-methylene-(1',2',3'-trihydroxy-2'-methylpropyl)-2-oxa-7,9-diazabicyclo[4,2,2]decane-8,10-dione] or from 5-norbicyclom-ycin-5-one [systematic name: 6-hydroxy-1-(1',2',3'-trihydroxy-2'-methylpropyl)-2-oxa-7,9-diazabicyclo[4,2,2]decane-5,8,10-trione] as basic substance.

The following Examples will serve to illustrate the invention. ;~

Preparation of the startin~ materials ~;-A) A flow of ozone-enriched oxygen is introduced at -70Cat a speed of approx. 20 litres/hr into a solution of 8 g of bi-cyclomycin monohydrate in 350 ml of methanol. After about 45 minutes, when a permanent blue colouration ensues,2.2 ml of dimethyl sulphide are added and the reaction mixture isbrought gradually to 0C. The crystallised product is collected with suction and the mother liquor is concentrated to about a third of its volume and allowed to stand in order to obtain the second crop of crystals of the same quality. The resultant 5-nor-bicyclomycin-5~one has a melting point of 160-162C, which rises to 171-175C after c~ystallisation from ethyl acetate-methanol.

.

~' ~

1~394S~7 B) A solution of 11.5 g of bicyclomycin-6,1',3'-t~i-tetrahydro-pyranyl ether in 200 ml of methanol is ozonised as described in A) and treated with dimethyl sulphide. After it has warmed to room temperature, the reaction mixture is concentrated and the residue dissolved in a very small amount of ether. The solution is added dropwise into petroleum ether and the white amorphous precipitate is collected with suction and dried in a high vacuum. The resultant 5-nor-bicyclomycin-5-one-6,1',3'-tri-tetrahydropyranyl ether melts unsharp between 65 to 75C.
C) 3 g of bicyclomycin-3'-benzoate in methanolic solution are ozonised under the conditions of A). The excessozone isdestroyed with dimethy:L sulphide and the solution is concentrated in a waterjetvacuum. The residue is precipitated from methanol with ethyl acetate and yields amorphous 5-nor-bicyclomycin-5-one-3 benzoate with a melting point o~ 125-130C.
'''-, ' ~,' ~ '' . 1~7 ;';

: . . - .- - - ~ . .. : , . ~ .

~ 7 Example 1 A mixture of 2.43 g of 5-nor-bicyclomycin-5-one in 160 ml of ethanol and 0.75 ml of pyridine is treated with 0.56 g of hydroxylamine hydrochloride and heated, with stirring, to 60C
until, after approx. 1 hour, thin-layer chromatography reveals that no more starting material is present.The reactionmixture is concentrated and chromatographed over 100 g of silica gel.
The product is eluted with a 1:1 mixture (v/v) of chloroform and methanol and crystallised from methanol. Additional crys-tallisation ~rom methanol/ethyl acetate affords 5-hydroxy~
imino-5-nor-bicyclomycin, which melts at 185-1~7C(with de-composition); []D= ~ 19 ~ 1 tc 0.95; water).
,`, Example 2 Following the procedure described in Example 1, a mixture of 18.24 g o 5-norbicyclomycin-5-one, 5.02 g of 0-methylhydroxyl-amine hydrochloride, 5 ml of pyridine and 1250 ml of ethanol is stirred for 30 minutes at 60C and worked up. The crude pro~
duct is obtained by chromatography over 300 g of silicagel and ~lution with a 4:1 mixture (v/v) of chloroform/methanol. Re- ~-crystallisation from methanol/ethyl acetate gives 5-methoxy--imino-5-nor-bicyclomycin with a melting point of 165-168C.

., ......

~ .-. . . . .. . . . . .

J~

Example 3 _ Following the procedure described in Example 1, a mixture of 1.824 g of 5-norbicyclomycin-5-one, 0.957gofO-benzylhydroxyl-amine hydrochloride, 0.5 ml of pyridine and 120 ml of ethanol is stirred for 1 hour at 60C and worked up. The crude product ~. :
is obtained by chr~matography over 100 g of silica gel and elution with a 4:1 mixture (v/v~ of chloroform/methanol.Recrys-.tallisation frvm ethyl acetategives S-benzyl-oxyimino-5-nor-bicyclomycin with a melting point of 108-110C; [~]D =
+ 18 + 1 (c- 1.1; dioxane), :. -,'`,. ~

Example 4 ',`: '',:
Following the procedure described in Example 1, a mixture of ~.
0.608 g of 5-nor-bicyclomycin-5-one, 0.283 g of 0-methoxy-carbonylmethylhydroxylamine hydrochloride, 0.65 ml of pyridine ~:.
and 40 ml of ethanol is s~irred for 1 hour at 50C and.pH 7-8 and further worked up. The crude productis obtainedby chromato-graphy over 30 g of si.lica gel and elu~ion with a 4:1 mixture :
(v/v) of chloroform/methanol. Recrystallisation from ethyl acetate gives 5-methoxycar~onylmethoxyimino-5-nor-bicyclomycin with a melting point of 150-151C.

,. .
, ~ :

1V~ S7 Example 5 A suspension of 2.43 g of 5-nor-bicyclomycin-5-one and 1.16 g of phenylhydrazine hydrochloride in 0.675 ml of pyridine and 160 ml of ethanol is stixred at room temperature until a clear solution formsand thin-layerchromatography revealsthatno more starting material is present. l~e solution is concentrated in-a water jet vacuum and the residue is recrystallised from , . . . . ... .. . . .. .. . .. .. ... . . . . .. . . .
methanol to give 5-nor-bicyclomycin-5-one phenylhydrazone, which melts at 160C (with decomposition); ~JD = ~ 76 + 1 '`
(c - 0.97; dioxane); ~ max' 282 and 302 ~ ( = 16300 and 13300 respec~ively). ~`

Example 6 A clear solution of 0.446 g of semicarbazide hydrochloride in 80 ml of ethanol is treated at 90C (bath temperature) with 0.33 ml o~ pyridine and then with 1.21gof5-nor-bicyclomycin- `
5-one, and the reaction mixture is allowed to stand for 1 hour at this bath temperature. The product, which begins to preci-pitate in crystalline form while heating, crystallisesout com~
pletely on cooling and is then collected with suction and washed with a small amount of ethanol. The resultant 5-nor-bicyclomycin-S-one semicarbazone melts with dec~mposition at 195C; ~a]D = + 48 + 1 (c = 0.93; water) ~,.. `~.. `'i?.~ ';

~ 9 Example 7 A mixture of 5.7 g of 5-nor-bicyclomycin-5-one-3'-benzoate and 0.855 g of 0-methylhydroxylamine hydrochloride in 0.85 ml of pyridine and 150 ml of ethanol is stirred at 60C until, after

3 1/2 hours, thin-layer chromatography reveals that no more -starting material is present. The solution is concentrated and the residue is chromatographed over 100 g of silica gel.Elution ~`
with a 4:1 mixture (v/v) of chloroform/methanolgives 5-methoxy- -imino-5-nor-bicyclomycin-3'-benzoate, which is purified by precipitation from a solution of ethylacetate/ether. After it has been dried in a high vacuum, the product melts at 104-110C.
Example 8 A mixture of 4 g of 5-nor-bicyclomycin-5-one-6,1',3'-tri-tetrahydropyranyl ether and 0.60 g of 0-methylhydroxylamine hydrochloride in 0.576 ml of pyridine and 100 ml of ethanol is stirred at 60C until, after 2 1/2 hours, thin-layer chro-matography shows that no more starting materialis present. The solution is concentrated and the residue, which consists of crude 5-methoxyimino-5-nor-bicyclomycin-6,1',3'-tri-tetrahydro-pyranyl ether, is dissolved in 30 ml of methanol. Then 20 ml ;
of 50% (v/v) aqueous acetic acid are added and the mixture is stirred for 30 minutes at room temperature and concentrated in a water jet vacuum. The residue îs chromatographed over 100 g of silica gel and elution with a 4:1 mixture (v/v) of chloro-.~i ~ ~ .

fJ~7 form/methanol yields a crude product which, after recrystalli-sation from methanol/ethyl acetate, melts at 165-168C and is identical with the 5-methoxyimino-5-nor-bicyclomycin of Example 2.
Example 9 A solution of 1.824 g of 5-nor-bicyclomycin-5-one in 120 ml of ethanol is treated under reflux with 1.125 g of pyridinio-acetohydrazide chloride (Girard reagent P). The clear solution is heated for a further 30 minutes and then allowed to cool, ~`
After the solution has stood for about 2 hours at room tempera-ture, the product begins to crystallise~Recry~tallisation from methanol/ethyl acetate gives the pyridinioacetylhydrazone chloride of 5-nor-bicyclomycin with a melting point of 182-185C.

Example 10 Following the procedure described in Example 1~ a mixture of 1.82 g of 5-nor-bicyclomycin-5-one, 1.31 g of 0-carboxymethyl-hydroxylamine hemihydrochloride, 2 ml of pyridine and 120 ml of ethanol is stirred for 90 minutes at 60C and concentrated.
The crystallised product is purified by chr~matograp7ny over ;`~
silica gel and elution with a 4:1 mixture (v/v) of chloroform/
methanol. Recrystallisation from methanol gives 5-carboxy-methoxyimino-S-nor-bicyclomycin with a melting point of 160-163C; []D ~ + 28 ~ 10 (c = 0.896; water).
. ;
.:

~'~

t~

Example 11 :~' Following the procedure described in Example 13 a mixture of 1.82 g of 5-nor-bicyclomycin-5-one, 0.720 g of 0-(2-hydroxy~
ethyl)-hydroxylamine hydrochloride, 120 ml of ethanol and 0.72 ml of pyridine is stirred for 2 1/4 hours and concen-~rated. The product is purified by chromatography over silica gel and elution with a 4:1 mixture (v/v)ofchloroform/methanol.
Precipitation from methanol/ethyl acetate yields amorphous 5-(2-hydroxyethoxyimino)-5-nor-bicyclomycin with a melting polnt of 88-94C; ~]D = + 19 + 1 (c~0.644; dioxane).

Example 12 Following the procedure described in Example 1, a mixture of 1.82 g of 5-nor-bicyclomycin-5~one~ 1.15 g of 0-(2-dimethyl- ;
aminoethyl)-hydroxylamine hydrochloride, 120 ml of ethanol and 2.5 ml of pyridine is stirred ~or 2 1/4 hours at 50C. On cooling, the product separates out in crystalline form. Recrys~
tallisation from ethanol gives 5-(2-dimethylamino-ethoxyimino~
5-nor-bicyclomycin hydrochloride with a melting point of 210C
(with decomposition); [~]D = + 12 + 1 (c = 1.160; water).
~`;

~'~

', ~ ' s~

Example 13 A mixture of 1.82 g of 5-nor-bicyclomycin-5-one, 0 921 g of dime~hylamino-acetohydrazide (Girard reagent D), 120 ml of ethanol and 1 mlof pyridine is heated,with stirring,to reflux.
After 20 minutes a crystalline product begins to precipitate.
After cooling, the crystals are collected with suctionand re-crystallised rom methanol/ethyl acetate to give5-nor-blcyclo-mycin-5-one-dimethylaminoacetylhydrazon with a mel'ing point of 188C (with decomposition); [a]D = + 31 + 1 (c =l.OO;
water).

Example 14 Following the procedure described in Example 1, a mixture of 1.82 g of 5-nor-bicyclomycin-5-one, 1.11 g of tosylhydrazide tp-toluenesulphonic acid hydrazide) and 100 ml of ethanol is heated for 4 hours to 50C and thereafter concentrated. The `~
product is purified by chromatography over silica gel and elution with a 4:1 mixture (v/v) of chloroform/methanol. Re-crystallisation from methanol gives 5-nor-bicyclomycin-5-one tosylhydrazone with a melting point of 185-186C ~with decom-position); []D = ~ 33 + 1 (c = 1.001; water).

. :

. . " , ~. . " .. . . . .....

~0~

Example 15 Following the procedure described in Example 1, a mixture of 1.82 g of 5-nor-bicyclomycin-5-one, 1.1 g of isonicotino-hydrazide (4-pyridine carbohydrazide) and 60 ml of ethanol is heated for 4 hours to 50C and thereafter concentrated. The product is purified by chromatography over silica gel and ~;
elution with a 2:1 mixture (v/v) of chloro~orm/methanol,affor-ding the 4-pyridinecarbohydrazone of 5-nor-bicyclomycin-5-one with a melting point of 161-165C twith decomposition, []D ~ + 19 + 1 (c = 0.889; water).

Example 16 :`
A solution of 2.73 g of 5-nor-bicyclomycin-5-one and 1.04 g of ~.
ethyl carbazate ~H2N.NH.CO.OC2H5) in 60 ml of dioxane is treated with 0.15 ml of acetic acid and stirred for 7 hours ~ -at 60C. The reaction mixture is concentrated in vacuo and the residue is chromatographed over silica gel and elution is effected with a 4:1 mixture (v/v) of chloroform/methanol~ ~
giving the amorphous ethoxycarbohydrazoneof5-nor-bicyclomycin- ~-5-one with a melting point of 140-143 ; ~]D ~ + 34 + 1 (c - 1.017; water).

, .
~ " , .
.

~ " , ~ ~ ~. } ~

' ' '',',; ' ~v~s~

Example 17 A mixture of 2 ml of isobutyl chloroformate and 20 ml oftetra-hydrofurane is added dropwise in the course of 20 minutes to a ~igorously stirred solution of 2 g of 5-methoxyi~ino-5-nor-bicyclomycin in 30 ml of pyridine which has been cooled to -15C. The mixture is subsequently stirred for 1/2 hour at -10C and then the precipitated pyridine hydrochloride is re-moved by ~iltration. The residual solution is concentrated in a high vacuum. Chromatography of the residue over silica gel with chloroform/methanol 19:1 as eluant yields two components:
the more rapidly eluted 5-methoxyimino-5-nor-bicyclomycin 1',3'-carbonate and the more slowly eluted amorphous 3l-0-iso-butyloxycarbonyl-5-methoxyimino-5-nor-bicyrl~mycin;
[]D = + 39 -~ 1(c - 0.725; dimethyl sulphoxide).

`~ ` . ' .,

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of a 2-oxa-7,9-diazabicyclo[4,2,2]decane derivative of the formula (I) wherein each of Ra, Rb, Rc and Rd individually represents hydrogen atom or oxa-(lower alkyl), oxa-(lower cycloalkyl), lower alkanoyl, benzoyl, lower alkoxycarbonyl, or any two of the symbols Ra, Rb and Rc together represent carbonyl, lower alkylidene, or lower cycloalkylidene, R represents hydrogen, lower alkyl, a lower alkyl which is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino, di-(lower alkyl)-amino, carboxy or lower alkoxycarbonyl, or represents phenyl or phenyl-(lower alkyl), or a phenyl or a phenyl-(lower alkyl) whose ring is substituted by halo-gen, nitro, lower alkyl or lower alkoxy, or represents an acyl derived from a lower alkanesulfonic acid, benzenesul-fonic acid, a benzenesulfonic acid whose phenyl ring is substituted as indicated hereinabove, or an acyl derived from a carbonic acid amide or (lower alkyl)-monoester or from a carboxylic acid derived from any of the above-defined unsubstituted or substituted lower alkyl, phenyl or phenyl-(lower alkyl) radicals or from a pyridyl or pyri-dinio-(lower alkyl) radical, and X represents a bivalent group of the formula -O- or -NH-, and of pharmaceutically acceptable salts of such a compound, provided it contains a salt-forming group, which process com-prises reacting a compound of the formula (II) wherein Ra, Rb, Rc and Rd are as defined in formula (I) above, with a compound of the formula R - X - NH2 (III) in which R and X are as defined in formula (I) above, or with a salt thereof, and, if a compound is required in which any of the symbols Ra, Rb, Rc and Rd represents hydrogen, subjec-ting to hydrolysis a resulting compound in which one or more of the symbols Ra, Rb, Rc and Rd represent a hydroxyl protec-tive group as defined hereinabove, and/or, if required, con-verting a resultant compound containing a salt-forming group into a pharmaceutically acceptable salt or a resultant salt into the free compound or into another pharmaceutically acceptable salt, and/or, if required, separating one indivi-dual isomer from a resulting isomer mixture.

2. A process according to claim 1, wherein start-ing materials are selected so as to produce a compound of the formula I, wherein X represents the group -O- and the other symbols are as defined in claim 1.

3. A process according to claim 1, wherein start-ing materials are selected so as to produce a compound of the formula I, wherein Rb represents hydrogen, each of Ra, Rc and Rd represents 2-tetrahydropyranyl, and the other symbols are as defined in claim 1.

4. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula I, wherein Ra, Rb and Rd each represents hydrogen, Rc represents hydrogen atom, lower alkanoyl, benzoyl or lower alkoxycarbonyl, and the other symbols are as defined in claim 1.

5. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula (IA) wherein RA represents a hydrogen atom, a lower alkyl, a lower alkyl which is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino, di-(lower alkyl)-amino, carboxy or lower alkoxycarbonyl, or represents phenyl or phenyl-(lower alkyl), or a phenyl or a phenyl-(lower alkyl) whose ring is substituted by halo-gen, nitro, lower alkyl or lower alkoxy, or represents an acyl derived from a lower alkanesulfonic acid, benzenesul-fonic acid, a benzenesulfonic acid whose phenyl ring is substituted as indicated hereinabove, or an acyl derived from a carbonic acid amide or (lower alkyl)-monoester or from a carboxylic acid derived from any of the above-de-fined unsubstituted or substituted lower alkyl, phenyl or phenyl-(lower alkyl) radicals or from a pyridyl or pyridi-nio-(lower alkyl) radical, and X represents a group of the formula -O- or -NH-, or a pharmaceutically acceptable salt of such a compound, provided it contains a salt-forming group.

6. A process according to claim 5, wherein starting materials are selected so as to produce a compound of the formula (IA) wherein X represents the group -O- and RA
represents lower alkyl, phenyl-(lower alkyl), hydroxy-(lower alkyl), lower alkanoyloxy-(lower alkyl), di-(lower alkyl)-amino-(lower alkyl), carboxy-(lower alkyl) or hy-drogen.

7. A process according to claim 5, wherein starting materials are selected so as to produce a compound of the formula IA, wherein X represents the group -NH- and RA re-presents hydrogen, lower alkyl, phenyl, a phenyl which is substituted by halogen, nitro, lower alkyl or lower alkoxy, or represents an acyl derived from a carbonic-acid amide or (lower alkyl)-monoester, from benzenesulfonic acid, from a benzenesulfonic acid substituted by halogen, nitro or lower alkyl, from a pyridinecarboxylic acid, from lower alkanoic acid or a lower alkanoic acid substituted with phenyl, di(lower alkyl)-amino or a pyridyl.

8. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula I wherein =N-X-R represents hydroxyimino, lower alkoxyimino, phenyl-(lower alkoxy)-imino- or lower alkoxy-carbonylmethoxyimino.

9. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula I wherein =N-X-R represents phenylhydrazo, semi-carbazo or pyridinio-(lower alkanoyl)-hydrazo.

10. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula I wherein =N-X-R represents carboxy-(lower alkoxy)imino, hydroxy-(lower alkoxy)imino or di-(lower alkyl)amino-(lower alkoxy)imino.

11. A process according to claim 1, wherein starting materials are selected so as to produce a compound of the formula I wherein =N-X-R represents di(lower alkyl)amino-acetylhydrazo, lower alkoxycarbonylhydrazo, isonicotinoyl-hydrazo or tosylhydrazo.

12. A process according to claim 1, wherein starting materials are selected so as to produce a compound, which is selected from a group consisting of the following com-pounds: 5-benzyloxyimino-5-nor-bicyclomycin; 5-carboxy-methoxyimino-5-nor-bicyclomycin; 5-methoxyimino-5-nor-bicyclomycin-6,1',3'-tri-tetrahydropyranyl ether; 5-nor-bicyclomycin-5-one phenylhydrazone, 5-nor-bicyclomycin-5-one semicarbazone, and 5-nor-bicyclomycin-5-one pyri-dinioacetylhydrazone chloride.

13. A process according to claim 1, wherein 5-nor-bicyclomycin-5-one is reacted with hydroxylamine to pro-duce 5-hydroxyimino-5-nor-bicyclomycin.

14. A process according to claim 1, wherein 5-nor-bicyclomycin-5-one is reacted with O-methylhydroxylamine to produce 5-methoxyimino-5-nor-bicyclomycin.

15. A process according to claim 1, wherein 5-nor-bicyclomycin-5-one is reacted with O-methoxycarbonylmethyl-hydroxylamine to produce 5-methoxycarbonylmethoxyimino-5-nor-bicyclomycin.

16. A process according to claim 1, wherein 5-nor-bicyclomycin-5-one 3'-benzoate is reacted with O-methyl-hydroxylamine to produce 5-methoxyimino-5-nor-bicyclomycin 3'-benzoate.

17. An 2-oxa-7,9-diazabicyclo[4,2,2]decane deri-vative of the formula wherein each of Ra, Rb, Rc and Rd individually represents hydrogen atom or oxa-(lower alkyl), oxa-(lower cycloalkyl), lower alkanoyl, benzoyl, lower alkoxycarbonyl, or any two of the symbols Ra, Rb and Rc together represent carbonyl, lower alkylidene, or lower cycloalkylidene, R represents hydrogen, lower alkyl, a lower alkyl which is substituted by hydroxy, lower alkoxy, lower alkanoyloxy, amino, di-(lower alkyl)-amino, carboxy or lower alkoxycarbonyl, or represents phenyl or phenyl-(lower alkyl), or a phenyl or a phenyl-(lower alkyl) whose ring is substituted by halogen, nitro, lower alkyl or lower alkoxy, or represents an acyl derived from a lower alkanesulfonic acid, benzene-sulfonic acid, a benzenesulfonic acid whose phenyl ring is substituted as indicated hereinabove, or an acyl derived from a carbonic acid amide or (lower alkyl)-monoester or from a carboxylic acid derived from any o? the above-de-fined unsubstituted or substituted lower alkyl, phenyl or phenyl-(lower alkyl) radicals or from a pyridyl-or pyridi-nio-(lower alkyl) radical, and X represents a bivalent group of the formula -O- or -NH-, or a pharmaceutically acceptable salt thereof, provided that the compound contains a salt-forming group, whenever prepared by the process of claim 1 or by any obvious chemical equivalent thereof.

18. 5-Hydroxyimino-5-nor-bicyclomycin, whenever prepared by the process of claim 13 or by any obvious chemical equivalent thereof.

19. 5-Methoxyimino-5-nor-bicyclomycin, whenever prepared by the process of claim 14, or by any obvious chemical equivalent thereof.