BE639292A - - Google Patents

Description

       

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  ,, YM, Muàddf de mr4garation The present invention relates to / Compounds of the tetraoyoline series comprising an oxygen bridge connecting the 4 and 6 positions of the rings in the rings A and C and also having a 4-hydroxy rump or a Group
 EMI1.2
 4-dimdthylaLmino Some of the novel 4-hydroxy t4traayc'loxyd08 and 4-diM <! Thylaninotdtï'aayolcxyde <of the present invention can be represented by the following general formula
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 in which neither rophaente a hydrogen atom or dehum locbne and n2 is a hydroxy or dimethylamino group, The halono atoms are z by way of exception chlorine,
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 bromine and iodine.
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  The nomenclature of the new compounds of the present invention is contained on the hypothetical compound bathed in all the name of "tetracycloxide" which would have the
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 following formula!
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 da The system / numbering of "tetracyoloxide"
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 is the same as for tetracyclines and the oxygen atom
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 heterooyo11 that is not numbered. The full chemical name of "tetxaoyoloxide" according to the nomenclature of Chvmi, aai Abtracte is ,,, + a, â.5ns 1.

   Xa, 1, laa * d6aahydra b $ td, db8ta paxy, .Oa x, alpha * txhydraxrw ,, llr 1 * trnxa S <* naphtao & neo & rboxamid94 When El is a hydroebne atom, and ftg is a hydroxy group in the General formula disclosed above. In 00 cases, the compound represented is 4-hydroxy. tetraoyoloxpde whose entire chemical name according to the nomenclature of Chemical Abstraots is 1, u, + a,, ga, 6, i, i, lla, ,,, adahylra * I b $ ta, âb3 * dpaxy, l, pha, 0,1, alpha- ttrrhydraxy1,, 1,, 12 tr, oxa nephtnanawaarbaxeml.de. A common name for 4-hydroxytdtraeycloxide is 4-dcdimethyl-am1no.4.oxo.6.dÓmethyltdtraoyol1ne.4,6hÓm1oetal.

   When p1 is a hydrogen atom and Rg a dimethylamino orpe

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 in the General formula set out above, in this case the
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 compound represented is 4-dimethylaminotetraoyoloxide whose full chemical name according to the nomenclature of Ch .. mical Abstracto is 1 ,. :. at. .5. .lx.lh, 18,12 ddcahydro4alpha-dimthylamind.4bta, ôb8tapoxyj, 10,12g alpha-trihydroxy.lpll ,, 12-trioxo-2-naphtacene-carboxamide,
The novel compounds of the present invention are well-defined crystalline substances having characteristic ultra-violet absorption spectra indicating the presence of a blocked BCD ohromophore. We can
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 Conveniently recrystallize the 4-hydroxytdtracycloo xides from a mixture of methylcellosolve-0.1N hydrochloric acid and they are quite stable in acidic methanol.

   Although they are extremely insoluble in water,
 EMI3.3
 4-dimethylaminotetraoycloxides can be hydrolyzed by forming the corresponding 4-hydroxytétracyeloxydoa. The conditions for hydrolysis cannot be strictly defined but, in general, hydrolysis is faster when the aqueous medium is more acidic. Hydrolysis is also favored in water-soil systems- in /
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 Before acids laequeat the dilution solvent (eg, dimethylformamide, dimethyleultoxide, methyl cellosolve) increase the solubility of 4 dlmethylamina # tetraoyoloxides.

   4-hydroxytetracyoloxides and -d1. MÓthYlam1notÓtraoyoloxides both degrade rapidly at alkaline pH values.
 EMI3.5
 In accordance with the prdeonto invention, there is provided a process for preparing compounds of the tetracycline series having an oxygen bridge connecting the 4 and 6 positions of rings A and C, said process being characterized

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 in that the corresponding G-ddmethyl.4.d1m4thylwm1no.6-hydroxy-tetracycline is oxidized and, if desired, the 4-dlmethylamino group is replaced by a hydroxyl group during or after the oxidation,
For example,

   the new compounds of the present invention can easily be prepared with
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 good yields when treating 6-demethyltetracy * * lino or a 7-halos <$ no-6-demethyltetraoyollne with an oxidant absent. Suitable oxidizing agents are, for example, oxygen, a halogen eletroph11o 'of which a suitable source (alkali metal chlorate and hydrochloric acid), merouric acetate or equivalent mercury salts, cupric acetate or equivalent copper salts;

  , alkali metal periodates, potassium permanganate, alkali metal peroxides and ferric salts. The oxidation can conveniently be carried out in a suitable solvent such as, for example, alaoial acetic acid, methanol, dimethyl .
 EMI4.3
 formamid, methylcolloso.ve and the like at temperatures between 10 (f and> 50 ° C for a time ranging from as short as 5 minutes to 8 hours or more. The production of 4-dim6thylaminotetracyolOndOJS is promoted under these conditions. anhydrous, but the presence of a significant amount of water does not exclude the possibility of iso-
 EMI4.4
 ler some of the 4-dimethylaminotetracycloxides.

   When the oxidation is produced under aqueous conditions, in this case the 4-hydroxytetraoycloxides are obtained. The oxidation of 6-demethylttracycline with mercuric acetate is characteristic of the different conditions which lead to the 4-hydroy-yt6traoyoloxy of a part and 4-dimethyl.

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 tetraoycloxide on the other hand. When the 6-d4mdthyltdtraoya cline is oxidized by mercuric acetate in the systems
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 various solvents set out in Table 1 below # the product obtained in each case depends on the water content of the solvent system as it is also indicated
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 in table 1 o1.do8Boua.



  TA3L !! TO I.
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<tb>



  Basai <SEP> n * <SEP> System <SEP> of <SEP> solvents <SEP> Product <SEP> obtained
<tb>
 
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 D1m6thylfarmam1de Predominantly anhydrous 4.1mdthlam1not6tra. 2 D1mdth11formarn1do cyoloxide Of a predominant manlftreet plus 5 water 4-dimethylaminotdtracyclo. Dimdthylformamide 1161an.; t of 4-dimdthylarainoplus 15% water tdtracycloxide and 4-hydrpxytetraoyoloxide P1mthylrormam1de 4.hyGroxytdtraoyoloxyd .. t
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<tb> plus <SEP> 50% <SEP> water <SEP> only
<tb>
 Although the solvent system in Test # 3 did not
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 is not strongly acidic, it is likely that the 4-di.rathyl-amnotetraayoloxide in the product mixture could eventually convert to 4-hydroxytdtracycloxide.

   Capable after 2 hours at room temperature, a considerable amount of 4-dinethylaninotetraoyoloxide is still present. After the oxidation is complete, the product can be obtained by standard procedures. In the back case
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 4-din.ethylamînotetraLoyo, oxidized # the most suitable / way of proceeding is to simply dilute the reaction mixture

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 with a non-solvent, for example water at neutral pH, which results in the precipitation of the product. In the case of 4-hydroxytetracycloxides, the product can also be precipitated by diluting the reaction mixture with a non-solvent, for example water at a somewhat acidic pH.

   The 4-hydroxytetracycloxides can then be purified by recrystallization from a mixture of methylcello-solve-0.1N hydrochloric acid.



   The present invention is described in greater detail, in the following specific examples which are however in no way intended to limit the scope and spirit of the invention.



    EXAMPLE 1, 4-Hydroxytetracycloxide -
In a solution of 800 cm3 of methanol and 170 cm3 of concentrated hydrochloric acid, 86 g of 6-demethyltetracycline are dissolved. Then a solution of 8.6 g of sodium chlorate in 40 en.3 of water is added over a period of 10 minutes. At the start of the addition the temperature of the reaction mixture is 19.5 ° C, while at the end of the addition the temperature rose to 25.5 ° C. 5 minutes after the end of the addition. , the temperature of the reaction mixture rose to 32 ° C., a heavy precipitate beginning to form.

   The reaction mixture is then stirred at room temperature for 10 minutes and then at the temperature of the bath for one hour. The reaction mixture is then diluted with 200 cc of water, the precipitate is filtered off and washed several times with water.



  The yield of vacuum-dried product is 50 g.



  The 4-hydroxytetracycloxide is recrystallized as follows!

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 It is dissolved for 1 s in 20 μl of methylellooolve and stirred with 200 mg of Daroo for 20 minutes. The Daroo is removed by filtration and the crystalline, lisé white product is precipitated by the addition of 4 volumes of 0.1 N hydrochloric acid.



   EXAMPLE 2.
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  4.hYdroxytJtroyoloxYdO.



  We dissolve in 30 have? 4, 6. (! úrnethyltJtracycl1ne) acetic acid and to this solution is added 15 g of N-ohloro8ucc.n1 mlde for a duration of 5 minutes * The resulting solution is stirred at room temperature for> 0 minutes and then poured back in 300 em3 of water, the precipitate which forms is removed by filtration and dried * in an oven under vacuum.
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 4-hydroxytdtraoycloxydo in the same manner as in Example 1, EXAMPLE 3.
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  4.hydroxyttraevaloxydo.



  In z30 cm> do d1m4th) 'ltormam1do. 10 of 6.dúm.thylttraoycl1ne is dissolved and the resulting solution is exposed to air at room temperature for 10 days. The solution is effected by evaporation of the solvent under reduced pressure followed by d3xaye, to the residue of aduhè. in 250 o J of 0.1 N hydrochloric acid, and the insoluble substance is collected by filtration, this crude product is purified.
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 by 4 <-hydroxyt4traoyoloxydCt by r.or1stal11aat1on as in Example 1.

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  EXAMPLE 4. FfychloTO-hydroxytetraeyeloxide rrssrs # 6-ddrjdthyl-7-ehlorotetracycline (46,, 5-) dan is dissolved. Glacial acetic acid (300m3), Concentrated HCl (85m3) is added to this solution and the resulting solution is then cooled to just above freezing temperature with an ice bath. Drop & drop is added to this stirred cooled solution over a period of 10 minutes a solution of sodium chlorate
 EMI8.2
 (4 ,,) in 20 cm? At the end of this addition period, the clave bath is removed and the reaction mixture is stirred for an additional 10 minutes * and then poured into 3 liters of water.

   The precipitated reaction mixture is added at room temperature for two hours, then placed in a refrigerated chamber (4 C) overnight. The product is collected and dried. Yield 33.3g. A sample of analytical purity is obtained as follows: 8 the crude substance is dissolved (44s)
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 in 250 cm 3 of di, methyloxmrlda and treated with Darco 0-60 (10; d. The solution is filtered and diluted with one liter of water to obtain a precipitate having the nature of a sum. collect the gum and we retreat again
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 with the Darco a-Go in the d1m6thrltormarn1de.

   A slow addition of two volumes of water gives a crystallized product. By repeating this procedure on the isolated crystals, a sample (23g) is obtained which, on analysis, appears correctly as a product with one mole of crystallization.
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 tion of d1methyltormarn1do.

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  EXAMPLE 5.



  4-dtfnethyltdtracyeline (50c) is dissolved in dlrnethylformamido (400, cn3). To this solution is added acetato morourlquo (36.9 days). The mixture is stirred overnight at room temperature and then filtered. The filtrate is cooled to ice bath temperature and then combined with three volumes of cold water. The precipitate is collected by filtration, washed well with cold water and dried.

     Roundly 42.8g,
Similar results are obtained using the corresponding amounts of either cupric acetate or
 EMI9.2
 In addition, by simply bubbling oxyr "bne (air) through a solution in dlmethylformamide of 6.d6md. thyltdtraoyollne, the product is obtained. in the latter case, it is necessary to resort to a prolonged reaction time.
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  ËXSP.LE ,,, 6.



  -chloro-4-diM <Shylainino, .raei By replacing the 6-d <îm <îthylt <5tr * cyclin employed in Example 5 by an OUQnt1td dquiraol4culalrt of 1-chloro-6-âô'm ± thyU ± tracyollno and by following practically the same operating mode as that described in the example,. 7-chloro-4-dinôthylwninottraoyoloxydô is obtained.



    The new compositions of the present! invention
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 are useful, for example, in the synthesis of 4-di "(al! <yl 1nr6r1eur) ..amlno-6.d & mdthyl titraoyc Un .. until pr4itntt 'not synthetically obtained, ..

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  The present invention also relates to
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 new ddim4thylamina4..amino zubatitud-6. demúthyltôtraoyo11nes and a process for preparing the so-called new compounds. The news 4.J1mdthylam1no.



  4-am1no aubat.t a6-dmcthylttrayalina of the present invention can be represented by the following general formula
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 wherein R represents a hydrogen or halogen atom, R1 is a hydrogen atom or a lower alkyl radical having two or more carbon atoms and R2 is a lower alkyl or hydroxy lower alkyl radical. The lower alkyl groups targeted by the present invention are those which contain a number of carbon atoms of up to about 6 carbon atoms.

   Suitable lower alkyl hydroxy groups may be, for example, beta-hydroxy-ethyl, gamma-hydroxy-propyl, beta-hydroxypropyl and the like. The halogen atoms are, for example, chlorine, bromine and chlorine atoms. iodine. A preferred embodiment of the present invention can be represented by the general formula above, wherein R is hydrogen or halocene and R 1 and R 2 each represent an interior alkyl group,. provided that R1 and R2 cannot together represent methyl radicals.

   The novel compounds of the present invention are well-defined crystalline substances having characteristic ultraviolet absorption spectra.



  They can be suitably purified either by crystallization from a suitable solvent or by partaco column chromatography.



   The novel compounds of the present invention can be easily prepared from 4-hydroxy. Suitable substituted tetracycloxides having the following general formula:

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 wherein R is hydrogen or halogen, For example, a suitable substituted 4-hydroxy-tetracycloxide can be aminated under reduction with a primary interior alkyl amine or with a lower alkanol amine
 EMI12.2
 thus obtaining 4-dedimethylamino-4-mono- (1nté laughing) -anino-6-dCmdthyltdtraoyoline or 4-dedimethyl. amino-4-mono- (hydroxy alkyl analyzer) -6-ddmvthyltetra oyolino corresponding.

   Said reductive amination process can be accomplished in a solvent for the starting compound in the presence of the necessary primary amine.
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 and a catalyst based on metal and gaseous hydrosone at pressures between atmospheric pressure and pressures above atmospheric pressure.



  Usually, the amination is carried out properly.
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 reducing at hydrocede pressures of between about 1 and about 4 atmospheres. Temperature does not appear to be critical in reductive amination.



    Temperatures between 0 C and 50 C, ot in general room temperature are preferred because they generally give the best results. The metal-based catalyst is preferably of the noble metal-based type, advantageously employed on a support such as finely divided alumina, active charcoal, etc. in which form they are commonly accessible,

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 In a bad way we can do)! ' amination
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 reducing Cane are sticky taxa than lower alkanols, la (limdthyltornamides mth;

  7.aalicsolva, t <! Trahydrofurano otcodo La 4 * àdddimcthylanino * 4 * mono (allcyl Lower) mano6cmcthylttrayalino or the 4 * rlédim <2thylamino <-4 <monochy: roxa.ky, infCrio, r) aminobdtrcyoi, inc. obtained can then be treated with a lower alkanal, thus obtaining new compounds according to
 EMI13.2
 wherein R1 and R2 both represent lower alkyl groups or wherein R1 is lower alkyl and R2 is lower hydroxyalkyl.



  This reductive alkylation process can be accomplished by any chemical or catalytic reduction using procedures well known to those skilled in the art. The catalytic reduction, which is particularly suitable for the reductive alkylation of the starting compounds mentioned above can be accomplished in a solvent for the starting compound in the presence of a carbonyl compound.
 EMI13.3
 and a metal-based catalyst and heros:; bner'c: as: GUx all. pressure between the atmospheric pressure and the pressures auper1eurea & the pressure at8OÍph6r1quo.



  Ordinarily, the reductive alkylation is carried out

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 suitably i dosages of hydrogen range from about 1 to about 4 atmospheres. Although temperatures to some extent higher than 41evdoo facilitate the catalytic nation hyerocde, temperatures within the range are used.
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 between 0 and 5000 and in # 5n <5ral the ambient temperature because it generally gives the best results. The metal-based catalyst may be of the base metal type such as nickel chromite or copper chromite or it may be of the noble metal type such as finely divided platinum, palladium or rhodium.

   We employ
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 advantageously catalysts based on noble metals on a support such as finely divided alumina, activated charcoal, infusoiros, etc., in what form they are, commonly available. The hydro-
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 cJnat10n until the quantity of 11o hydrogen gas has been absorbed and at this time the hydrogenation is stopped. Solvents chosen for catalytic reduction
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 must not be able to react with the starting materials, the products or the hydrogen under the conditions of the reaction.

   A variety of solvents can be used
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 this errvb t, a reduced laboratory experiment set aS. nlmu .. '\ 1 allows the selection of a suitable solvent for any particular starting compound.
 EMI14.7
 can carry out the catalytic reduced alkylation in solvents such as water, for example, ethanol, tthAnol, lower alkoxy alkanol, for example. example 2 * mdthoxy- $ thanol, 2-dthoxycthanol, lo tdtrahydrofuran, dioxane, la: lm4thylrormam1de, etc ...

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   A variety of chemical reducing agents can be used in the reductive alkylation process.



   Said agents include reducing agents using sodium borohydride or with metals active in mineral acids, for example zinc, tin or iron in hydrochloric acid, reducing agents with pairs of metals such as the copper-zinc pair, the tin-mercury pair, the aluminum almacam or the magnesium amalgam and the reducing agents with formic acid.



  Of these, reducing agents with zinc and hydrochloric acid and reducing agents with formic acid are preferred. When using aqueous systems in the reductive chemical alkylations mentioned above, it is in some cases desirable to use an organic solvent miscible with water, particularly when the starting compound has limited solubility in the mixture. The water-miscible solvent does not alter the course of the reduction but simply provides more efficient reduction. For example a shortened reaction time by providing more intimate contact of the reactants.

   A large number of said solvents are available for this purpose and include among others dimethylformamide, dimethoxyethane, methanol, ethanol, dioxane, tetrahydrofuran and the like,. compounds
The preparation of the present invention comprises the alkyl. direct bonding of a compound of formula I, in which
R1 and R2 represents a hydrogen atom with a lower alkyl halide, a lower alkyl sulfonate or an interior alkyl sulfate.

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   The novel compost of the present invention can be isolated by various procedures well known in the art. For example, insoluble substances such as salts or spent catalysts can be removed by filtration, followed by removal of the solvent under reduced pressure. The residue can then be treated with aqueous acid followed by removal of insolubles by filtration. The resulting acidic solution can be extracted with a suitable solvent such as butanol. Concentration of the butanol extract provides the desired product which can then be purified either by crystallization or by partition column chromatography.



   Los 4-hydroxytetracycloxides having the following general formula:
 EMI16.1
 in which represents a hydrogen or halogen atom, which constitute the starting substances for obtaining the new compounds of the present invention can be easily prepared in good yields by treating 6-demethyltetracycline or a 7-halo-6- demethyltetracycline with a suitable oxidizing agent such as sodium chlorate in the presence of hydrochloric acid or with an N-halosuccinimide.

   The reaction is conveniently carried out in a suitable solvent such as, for example, Glacial acetic acid, methanol, dimethylformamide and the like, at temperatures between -10 C and 35 C for as short as a few minutes.

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 up to an hour or more. When the reaction is complete, the product can be obtained by standard procedures. For example, it is quite convenient to simply dilute the reaction mixture with a non-solvent eg water, which results in precipitation of the product.

   The crude product can then be purified for by recrystallization from a mixture of methyl-.
 EMI17.1
 cellosolve-hydrochloric acid 4 "l.t,
The novel compounds of the present invention are endowed with biological activity and possess
 EMI17.2
 antibaoteric, broad spectrum, for example, the antibacterial spectrum of .dd,

  mthy.amino4 mthyiCthylemina 6-demethyltetracyoline and 4-dedimethylamlno-4 mdthyl (bta hydroxy dthyaj zun.no 6 crdthyltdtraayoline was determined in a standard manner by the technique of
 EMI17.3
 aar band dilution. The antibaotdr.an spectrum of a compound represents the amount needed to inhibit the growth of various typical bacteria and is commonly used in the testing of new antibiotics. The
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 minimum inhibitory concentrations? XiM608 in '"' 3S per cm3 of these two compounds vis-à-vis various test organisms are shown in Table 11ci-
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 below.

   For comparison purposes, the ant1baot6r1.n spectrum of 6-demethyltetracycline hydrochloride against the same organisms is incorrectly shown in the table,

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 EMI18.1
 'T.'Al1t :: .. U.u
 EMI18.2
 (I) -d 3c'lmvîthylajnino-Hm <3thyXcHhylamlno- <3-dtfmdthyl- tetracycl1ne (2) 4-dúd1múthylamlno-4-môthy1 (bOta-hydrOxYúthyl) amino-6-dtfmdthyl- tetracycline ) (2) ruz) Ncobactcr1um ranac 1 15 2 Mycobactcrium smcLat10 15 4
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<tb> ATCC <SEP> 607 <SEP> 2
<tb>
 
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 Staphylocaoaur aurcus 209 P + 15
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<tb> Baoillus <SEP> subtilis <SEP> ATCC <SEP> 6933 <SEP> 1 <SEP> 15 <SEP> 1
<tb>
 
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 Streptoc o c c u s pyocnos 2 2 Skre2tococcus i,

   -mima n 11 125. 250 125 3tanhyloooccus albus ne 69 125> 250> 250 Stycptococcus b6tan '' 80 126> 250 250 Dacillua cerous ni * 5 1 2 1 Pseudomonas. aoruinosa 62 250 | > 1 Eschcr1ch1a coll ATCC 9637 8 62 15 Salmon-el, la L: .l1tnart. ', M 8 62 15 p.! TctocoCCU8 accal8 ATCC 8043 4 15 4 Klobsie 11a 2ncumo ATCC 10031 z + 4 4 Prcteus ru3. ACCO 9484 8 15 15

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 The new compost of our own invention already possesses an unusual activity v1e - '. Y18 des m1croocan18mo8 cram.ndat1t. such as O-lqb2rtOi.1 19U and Salmonella typhosa. It has been determined that when administered in a single dose by tubing per vision '
 EMI19.2
 oral 16 m3 / kj body weight ooatrt oher1oh1a colt infeotions in mice, 4.dddimethylamino.



  ! -mdthylprapylruninaC-dCm3thyltdtraayalira, is two times more active than tc3tracyolinet, + .. dddimdthy3, amina4 d1éthylam1no-G-dlmûthyltútraoyo11no is three times more active than tdtracyoline, d.mamylthy3, and + .. d1ethylam1no-G-dlmûthyltútraoyo11no is three times more active than tdtracyoline, d.mamylthyltin and + .. -6-ddmdthYlt.tracycline is twice as active as 6-dSmLthyi, tStraoya7.ino, This aspeot of the invention is described in greater detail in conjunction with the particular examples
 EMI19.3
 following which are in no way intended to limit the scope and spirit of the invention.



  EXAMPLE, 4 * d idlmthylamino * -ûth; faftmlno * i-dwwdthylt <troyoilinie '' We dissolve 4-hydroxytJtraoyoloxydo (y0 a) in Io tetrahydrorurano (150 cni3) and add aqueous Ilethylo amine h 70 (60 em3), The solution is combined with 750 mg of 10% palladium on charcoal as a catalyst and immediately placed in a 500 cm3 flask.
 EMI19.4
 subject to hydrogenation at ', 5 k; by orna. The r4ctuctri amination is practically complete in 20 minutes. We eliminate the
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 catalyst by filtration and the filtrate is taken up in a1Q1t under reduced pressure, The crude product is collected with
 EMI19.6
 Ether and dried. It is then formed into a suspension in m4lthanol (40 om3) and concentrated HCl is added, obtaining a solution having an apparent pH of one.

   We shake

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 EMI20.1
 the ac1d1t140 solution for OD minute and during this time a by-product crystallizes. The by-product is removed by filtration. The triethylamino is added to the filtrate, obtaining a solution having an apparent pH of 7.0. Two glass beads are added and the mixture is shaken.
 EMI20.2
 the solution for two hours. The crystallized 4 * dedimcthyl am9na-thylam.no-6drrthylttraaya.na which forms is filtered off and washed successively with chloroform and ether. Yield; 1.15g.
 EMI20.3
 r: Xë: 1tPLZ -dd.m4th laminob.rntY leth 2arino -dcmth 7, t3trao a7.ina a. Zúthlat1on.

   We suspend the 4-dddimdthyl, amino-4 - <! Thyl-amino-6''d <SmJthylt <! Traoyolin (2.0r .. :) in methanol (150 cm3) and add a sufficient quantity of 12 N HCl to obtain a clear solution with
 EMI20.4
 apparent fold value which is not less than 4.5.

   Aqueous formaldi.hydo is added to 37 (>, 2 ora2) jet the solution is combined with the catalyst, PQ11t .. on carbon (600mu) in a flask holding the pressure of 500 cm>, The transfer is carried out above in a flask filled with nitrogen to reduce the risk of inflammation. The flask is placed in a low pressure hydrogenation do Paar apparatus, after having replaced the atmosphere in the
 EMI20.5
 flask using the hydrocnc, shake at 3.15-3.5 k; by pressure om2 for 17 hours at a temperature of about 50 C. The catalyst is removed by filtration and concentrated
 EMI20.6
 In the filtrate at sicoitc or at reduced pressure. The reaidu is collected with dldthor and it is abaha in a vacuum oven.

   Chromatography on paper shows that the crude product does not contain any residual starting material.
 EMI20.7
 that he presents the oonf1Grat1on 4.pl.

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 b, Convo1 ".e1on d2, ¯toue a can" naturÔ !!: in 04.



  The crude 4..mrthyi.dthylaminc derivative, pr6c1, is dissolved in propyH'neulycol (90om3) and to this solution is added a solution of calcium chloride dihydrate (205) in water (2.0 em3). We r & lc the ré oultanto 8.9 solution with de ethanolomino ot one proceeded to the plugs under a layer of nitrogen and one placed in an oven (56 C) for a period of one week, At the end of the week, one add the solution drop by drop or stir,
 EMI21.2
 in water (450crn,). The pro1p1t is returned to colitis. The citoau Ce Cdlite a <3ohu in methanol is suspended and the product, which is in the form of an al of calcium, in solution, lowering the pH to 1 with 12 N HOl.

   Colitis is filtered off and washed with sufficient methanol to remove any staining in the colitis.
 EMI21.3
 We take the filtrate zut s1cc1tJ we pressure puduite ot the residue is divided between butanol (150cm3) and water (150 cm3) h fold 0.8, The phase is extracted ttuC! 'W33 Car times 8uppllmcntair08 with butanol (100 om3 and 50 cm3) and the combined butanol extracts are treated with Darco, filtered and taken up with dryness under reduced pressure.

 <Desc / Clms Page number 22>

 
 EMI22.1
 



  00 Z2ritc; tt on ,, We dissolve the residue aJoh4 (3. i? 5u}? Ftft3 10 mthQr.Ql (12 em5) null contains a joutto of I 1211, We dilute the solution with water (12 cm3) and filtered for clarification. The pH of the filtrate is raised to 5.0 h with trlJthylamine. Dilution of the solution with water (12 cm3) initiates the formation of crystals, the pH is then raised to 2 and the solution is diluted. The mixture is added to a tlaco bath for an hour and a half, the precipitate is collected and washed with cold muthanol. Yield 1660 ml.
 EMI22.2
 A second harvest is obtained by adjusting the pH
 EMI22.3
 of the filtrate at 4.0 with the triethylamine and stirring in the cold for one hour. Roundly 200 mjo! PÏ, Q ².in.4.mt! N.G.d.1pb9r9ÓtraoYc.



  Methylamine hydrochloride (844C) (0.1% methylcollooolvc (20 03) is dissolved and 10 N NaOH, an apparent pH of 10, is added. The salt which is formed by the filtrate is removed from both the solution. containing the aminet, 7hloro..hYGroxttraoycloxo is added, followed immediately by the addition for 1.1urQ of 2 minutes of sodium borohydride (93) The solution is stirred for 30 minutes, then taken up again in high pressure. reduced pressure The solid wut is taken up in water (100 cm 3 and the pH is adjusted to 0.8 with HCl.



  The insoluble substances are removed by filtration and the filtrate is cytrzlt with bUtrmol '. Removal of the butanol under reduced pressure affords the crude 4 -d <SdimJthylM! Ino "4'-ntothyl * ^ 3, n.cârthy * 1'oh, crtraca ,, ra.
 EMI22.4
 of this substance can be effected by crystallization processes or by chromatocraphic means,

 <Desc / Clms Page number 23>

 EXAMPLE 10.
 EMI23.1
 dd1mthlam1no.lt.m6thYldthYlam1no.6-dJthllt6traoyol1n.



  4-dôd1aethylarn1no-4 is suspended. me "thylamino 6 di2m3thylté" tracyolin (1.0) in m4thyl. cellosolve (20 cm3). Then 2N aulxtric acid is added to an apparent pH of 4.0. The result is a complete solution. Add 1 # aodthaldehyde (3 oz) and 10% palladium darbon cio bols (300 m 3) to the solution and the mixture is hydrocene under a pressure of 3.5 kj / cm 2 for 17 hours. the catalyst by filtration and the
 EMI23.2
 filtrate, e1oo1tÓ under reduced pressure.

   We reoueillo the product using ether. The main product is
 EMI23.3
 ment by the two possible emeros in position 4 of the -cicSdimcfthy, amino umûthy3, thylsmino-ddcm6thyltdtracyax9, re, The isolation of pure components can astro accomplished by chro matoaraphie of partaae, EXAMPLE il u-d4dimth .araino + .. n- ro-d4dimth. larlno..ct: mth xtûtrao c.ine ..



  The 4-hydroxyttraoycloxide (3.0) is dissolved in tutrahyarouran (150 cn3 and the n-propyl amine (4.5 cm3) is added. The solution is combined with 10% palladium on carbon (750 mg). ) and we immediately place in a
 EMI23.4
 500 cm3 flask and subjected to hydrocdnation under a pressure of 3.5 kcVom2. The reductive assay is practically complete in 20 minutes, the catalyst is filtered off and the filtrate is taken up to 100% under reduced pressure.

   The crude product is recovered with ethor and dried. It is then suspended in methanol (40 cm3) and concentrated here is added, obtaining a solution having an apparent pH of 1. acidified solution

 <Desc / Clms Page number 24>

 for 30 minutes and the crystallized by-product is removed
 EMI24.1
 which is formed by filtration. The triethylaraine is added to the filtrate, obtaining a solution having an apparent pH of 7.0.

   Two glass beads are added to the solution and shaken at -9 C for 18 hours.
 EMI24.2
 4-dedim <Sthylar! Ino-4-n-propylan! Ino-6-dmethyltëtraoycline crystallized which is formed by filtration and washed successively with chlorofome and ether,
 EMI24.3
 EXElPLIS .12, .cidimth Iamino4-mcth 1n-ro laminoA6d6meth ltdtrae oline 4-dodimethylamino-4-n-prcpylamino- ..dméthyittracyeline (1, C7û) and formaldehyde at 37, s on! 3) are combined with (50om), the pH of the solution being adjusted to> # 3.4.5 with hydrochloric acid, to this solution "palladium at -10.1 on carbon (300 m3) is added and the mixture is subjected to mixing at hydrogenation under pressure
 EMI24.4
 3.5k # / om2 for 24 hours.

   The catalyst is removed by filtration and the filtrate is taken up to dryness under reduced pressure. The residue is collected with ether and dried. The crude product consists largely of
 EMI24.5
 a m61ana; c dcs two possible dimples in 4 of .dcdimthylamina-4..msthyln-propy? Amino-fi-demcthyltdtra-cycJ.1no. pure "natural" ltdplmure can be done by partition chromatography.

 <Desc / Clms Page number 25>

 
 EMI25.1
 



  Xn!? LS, * kddl, r6 hd, ri, taw # -n ut J.rinor6.dath itûtrac ol n We dissolve 4-hydroxytdtracycloxyd9 (3.0 ,,) in earlyt-ahydro t \ 1rano (150 om3 ) and we co, 1 ', ..;' Q the Solution with 10/3 palladium on carbon (750 mJ) oanis a flask t'a ',' 500 t; t.1'e We add xi i ? uyalrl3J'1C (5! 7ol3) and the hydrogenation is started under a pressure of 3 # 5 k3lom as quickly as possible. After 20 minutes, the reaction is stopped and the catalyst is removed by filtration. odconcantro the filtrate A siccitw under reduced pressure.



  We perform six These ruactions. The combined crude products are dissolved in methanol (200 µl) and the pH 1.0 is rh 1.0 with concentrated HCl. The solution is left cold for 30 minutes ot the yellowing yellow product is removed.
 EMI25.2
 tallized by filtration. The filtrate is adjusted to pH 2 with triethylamine and then shaken with gentle glass beads at -8 ° C. for 18 hours. The crystallized product is collected and washed successively with cold methanol, chloroform and ether. Round 3.9 g.



    EXAMPLE..,. 14.
 EMI25.3
 



  ..ridimeth Iamino4- 2-h drox tth 1 amino- ..sr h tetracycline -
4-hydroxytetracycloxide (4.0g) is dissolved and
 EMI25.4
 y in methanol (150 cm3), / without delay, 2-aminotSthanol (7.0 om3) is added. to vigorously stirred solution. The resulting clear solution is transferred to a
 EMI25.5
 quickly in a 500 em flask filled with nitrogen which contains 1.2% of 10.1% palladium on carbon. The flask is placed on a Paar hydrogenation apparatus. We

 <Desc / Clms Page number 26>

 carry out the reduction for 20 minutes press us
 EMI26.1
 of 3'5 .ram8 The catalyst is removed by filtration t n téx: rvr: tal # f, .4tr: ia under reduced pressure, forming a viscous oil. Methanol (12 or.

    to this oil and the resulting solution in aectone (270 cm3) is added drop & drop with vigorous stirring. We collect the? The resulting precipitate by at3on, the <5thor was washed and dried, Yield: 4.1g.



     The crude substance is dissolved in a mixture
 EMI26.2
 of water (60 em3) and methanol (20 cc). The solution is made strongly acidic by rapid addition of HCl
 EMI26.3
 concentrated (3 cm3). The M4lano is aite for one hour at the temperature of the - ,,, lace bath and then it is filtered. At
 EMI26.4
 filtrate, triethylamine (about 4cm3) is added all at once, obtaining a clear alkaline solution.
 EMI26.5
 The pH is then adjusted by lento addition of 6N HCl to about 6.5 and at this time crystal formation occurs. The mixture is aite at the temperature of an ice bath laying 30 minutes.

   The product is collected by filtration, washed with 25% methanol and dried in a vacuum oven. Yield: 910 mg.



     EXAMPLE 15.
 EMI26.6
 



  -dédimÓthYl1n-4- (3-hYdroxyproPY1nO-6-demethYl- tjgaeycl1nc - We dissolve 4-hydroxy *%, dtracycloxide (4.0) in m4thanol (150 em3) and, without delay, we add 3-aminopropanol ( 8.6 cm 3) to the vigorously stirred solution The resulting clear solution is rapidly transferred to a flask filled with nitrogen which contains 1.2 g.

 <Desc / Clms Page number 27>

 10% palladium on carbon. We place the flaoon on
 EMI27.1
 anar, low pressure hydrogenation apparatus. The reduction is carried out for 20 minutes under a pressure of 35 kg / cm 2. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to obtain
 EMI27.2
 a viscous oil.

   Methanol (15 cm 2) is added to this oil and the resulting solution stirred dropwise.
 EMI27.3
 drop in acetone (% 00 ots?) with vigorous stirring. The resulting precipitate is collected by filtration. washed with dther and dried, Yield 4: 1a.



     The crude substance is dissolved in mdthanol
 EMI27.4
 (D5cm3) and add 1G. concentrated Until an apparent pH of 1.0 is reached. The mdlanac was stirred at ice bath temperature for half an hour and the yellow by-product which formed was filtered off. The pH of the filtrate was raised to an apparent value of 5.2 by addition of tridthylamine. the mixture is stirred at the temperature of the ice bath for one hour and the crystals which form are collected by filtration and washed successively with chloroform ot thor. Yield:

   1.0g,
 EMI27.5
 r; XEr1? I.f. 16 # Cl4dittttii ltrJin aw ,. p., Z7 Cli ox th 1 rz4th ..... 1no: ,, ...



  (6mÓ..tr.illt.,. RMcHnc # a, xh, xß3on * We dissolve the 4..d <.td1mdth) '1'1.'1À.fl <J "t- (2 hyr; xoaty .. 'thy2.amina cir4thy.tc:traayv.ina (3t0j) in methanol (150 cm containing here concentrated (3 drops) and formaldehyde the J.'1UOUX to' '' '. (6 in?). the solution with 1.2 g of 10% palladium on carbon in a 500 cm3 flask The mlango is placed on

 <Desc / Clms Page number 28>

 
 EMI28.1
 a Paar hydrogenation apparatus. and the thy4eroo nat1on is carried out at a pressure of 3 # 5 kZ / om2 and 55 "C for 17 highs * The catalyaour is removed by filtration and the filtrate is concentrated at low pressure under reduced pressure.
 EMI28.2
 collect the rJ $ 1u using ethor and we * echo it, b.

   ± g "nverdon de, outo l, .9. NtQ.n" DàLur-e, 112 "in C4-
The conversion is carried out essentially of the
 EMI28.3
 ! a3taa manner for that described for 4.ddd1m'thylo .. wwi; hy2, îthy2ttra4no-6-dtfffléthyitiStraoyolino. o..1r1cat1pn ... We dissolve the gross subsistence 110
 EMI28.4
 QUO-L-1-1-td eup4r1our¯ (l, Oz) in methanol (5 om3 '. The solution is diluted with water ((5 cm3), the pH being maintained in the region of 1.0 by addition of HCl The solution is treated with Darco (200 m3) and then filtered. The pH is raised.
 EMI28.5
 0 filtrate with 30% triothylamine in methanol. The solution is diluted with water (5 OM3) and the pH is raised again to 3.5, thereby starting crystallization. The pH is maintained at 3 5 during the crystallization process.

   The mdlanze is moderately acitated at ice bath temperature for one hour, the crystals are collected, washed with a small amount of methanol.
 EMI28.6
 cold diluted and dried. Yield: 400 mZ.



  EXAMPLE 17, t Clia, ttltïi .flmirt0u..Ci, citi3tiam.tâQ 1V t ol I1 a # Ethylatlon - 4dimdthyl is dissolved. ninocthv..m3no-Eïcidmthyitaracyali.ne (2.0j) in a ut-iioxane mtjAanse (200 em3) and aa4taidhyda (10 on! 3) <.



  ?.: nbinc! the solution with the catalyst (10% Pd / C, 800 nm) in a 500 cm3 flask and the hydroso-

 <Desc / Clms Page number 29>

 
 EMI29.1
 Nation under a pressure of 3 * 5 Igt * / cm2 at 50-60 "0 at 17 huurqa. The catalyst is filtered 11 min. and the filtrate is concentrated to 81 ° C under reduced pressure.



  We put the rs1 <lU in auspunsion Cana un mulano do Skcl1ysolv B (100 em5) and d'Jther (> O em3), it is rtoucillo by filtratinn ut on obeho, b. Conversion .1 (; any: 1 "nayurol1"
 EMI29.2
 in 01,
 EMI29.3
 The inversion is carried out exactly rto the way 1UU glue described, for the 'J ..;': dlm ..: thylamino- '1- l "\ thylth'laMlno..i $ -m. Th'l t': trav "ol1no.
 EMI29.4
 Whereon, - The high quality crude substance (3) is dissolved in methanol (15 c:, tj). We dilute the
 EMI29.5
 solution avoo (14 water (15 cn3), tan ('15 that the pH is maintained at 1.0 by addition. o I! C1, the solution is treated with Caro.) (500 ttj) and filtered, We add the tr1th11lU11nu Itnttmunt to the filtrate for lovcp IQ pu 5 # 5, Uns, 'ilution our> pl' notary with dt water (15 oisj) 'causes the or1stall1sati, :: n.

   During the crystallization process, the pH (. (, T r.tnu> .5 during the crystallization process. The temperature of the Cc. Bath is added to the temperature for two hours. The product is collected by rltrat.1J. '1, we 1 <. I & vw with a low {' "\, umtit6 \ 10 nJthanol 'iluJ cold tfc ein the dryer, Ken' emont 1.51+ ;.

 <Desc / Clms Page number 30>

 
 EMI30.1
 



  :;: t; 1f? LE 1 !!] :) thlnM) jt \ "" lmJ l..i thYl..M1n,) .. 9 "', tl' mJth was t t'a, o yc3J .. ! ls.



  We dissolve the 11 ..: 16dlrnthylam1no.4.Jthylamlno .. $ ..



  \ lmJth'lttl'acycl1nc 2 JlO) in 40 cnt3 of mthyl- ccilosolvo and we treat with ora? vlodide do methylo the temperature anhiantc for 24 hours or with 7 om3 I sulfate and. tnuthylc at ambient tc'3praturj pcn ,,. ant 21. hours. Lu nrow'uit is identical with that produced. 'In Example 4.


    

Claims (1)

CLAIMS EMI31.1 1 * Compounds of the t'tra07011n series having an oxygen bridge connecting the 4 and 6 positions of rings A and 0 and also having a 4-hydroxy group or a 4-diraethyl-amino group. 2.- Compound of formula EMI31.2 in which R1 is a hydrogen atom or a halogen atom EMI31.3 Ob R2 has a hydroxy or methylamine group. 3t '* 4-hydroxytetracycioxide, 4 ***' -oh7.oro..J..hydroxytetracycioxide. 3, bee 7-bromot4-hydroxytetracycloxide. 6, 7-1odo-hydroxyt'trao101oxide. 7t ** 4-dtm6thylamino t'trao1cloxide. 61 "7''chlox'o-4'-dim4thylâminot <t! '' Aeyclo <y <ï <tt 9 <'* 7bromoIdi ethylaminotbtacy0lbxyrle. .ü. 7-iodo-4-dimethylaminotetracycloxydte 11.- compound of formula EMI31.4 <Desc / Clms Page number 32> EMI32.1 in which R is a hydrogen or halogen atom, bzz R3 this a hydrogen atom or lower alkyl radical and EMI32.2 R eet a lower alkyl or hydroxy lower alkyl radical, EMI32.3 damn condition that R3 and R. cannot be simultaneously the EMI32.4 methyl radical. EMI32.5 12.- 4-dedimethylamino-If.-methylamino..6-d6l14thyl-tetracycline. 40 13.- 4-Dedi! Aethylamino-4-methylamino'-6-de !!! <thyl-7 " EMI32.6 chlorotetracycline. EMI32.7 14 '"4-dedimethylamino-4-ethylamino-6-demethyltetra EMI32.8 cycline. EMI32.9 15.- tfd6dimethylmino lpéthy.aminob-ddmethyl? bromot4traoycline. 16. "tda, methylamino. N propylamino6 demethyl EMI32.10 tetracycline * EMI32.11 17. l dedanthylemino tnbutylamino6 demthtit9 EMI32.12 cycline. EMI32.13 19.- 4-Dedimethylamin-4- (b8ta-hydrox1'th, 1) -amino-6 dembthy.tbtraaycline. 190 "4 - dddimethylamino-4 (&& = a-h 'roxypePel), - amifibom 19 .'- Wédlraet hylamino-4- (gamma-hydroxypr opyi) -amihe-6.dmethyltetraoyaline. 20. 4 dedimethylamino t methy, ethy.eua3nowldmth " EMI32.14 tetracycline, EMI32.15 21. "4-Dedimethylamino-4-methylethylamino-6-demethyl-7-iodottracyo11ne. 22. "4-d'dimethylamino-4-mthyl-n-propylamino-6- d'methylt6traoycline. 23. 4-dediMethylamino-4-di <thyla! Aino-6-demethyl " EMI32.16 tetracycline. EMI32.17 24.- td6d, methylaminotfméthyJ. (Beta-hydroxydttl amino-6-demethyltetraoycline. <Desc / Clms Page number 33> 25.- Proceeds to prepare compounds of the series EMI33.1 t'tracyol1n, "having an oxygen bridge connecting the 4 and 6 positions of rings A and 0, characterized in and that the b.dem6thy¯-dimâthylaminoôhydrayttraayoin correorondan. top is oxidized and if desired, Io group 4 is replaced -dimsthylamino with a hydroxyl group during or after oxidation. 26 * - Process according to claim 23, characterized in that a solution of a compound of format t is treated EMI33.2 EMI33.3 in which R is a hydrogen atom or dhl4gn dana EMI33.4 a system of anhydrous solvents with an oxidizing aClnt 'a ttmplftturii included. between about -10 C and rowing 31 * 0, to form a compost of formula EMI33.5 EMI33.6 wherein R is a hydrogen or halogen atom. 27or A process according to claim 25. cM '<tat <! * i <4 en and that we treat * a solution of a component # 6 of fcr <Ml <" <Desc / Clms Page number 34> OH N (CH3) 2 EMI34.1 t t OH " OH 00 OH 0 in which R is a hydrogen or halogen atom, in an aqueous solvent system, with an oxidizing agent at a temperature of between about -10 ° 0 and about 35 C to form a compound of the formula EMI34.2 EMI34.3 where R is a dfh1droc'n, or halos "'atom. 28.) OC'd 'according to any one $ owe r ".nd1aat1onl 25 to 27, characterized in that the oxidizing agent is oxygen, EMI34.4 an electrophilic halogen, mercuric acetate, copper acetate, alkali metal periodates, potassium permanganate, alkali metal peroxides or a ferric acid. 29.- Process for preparing 4-dedimethylamino-4, - amine substitul-6-desnethyltetracyclinee of formula EMI34.5 EMI34.6 where R 1 is a hydrogen or halosn atom., R 1 is a cI'h1cb'o atom, ent or a lower alkyl group, having two atoms. of carbon or more and R4 is a group EMI34.7 lower alkyl or hydroxy interior alkyl oaract41-i. ' in and <Desc / Clms Page number 35> that the corresponding tetracycline * of formula I in which R or R represents a hydrogen atom is subjected to an alkylation. * 30.- The method of claim 29, characterized in that it is alkylated with the aid of a lower alkanal or a compound capable of forming the alkanal under the reaction conditions, in a reducing medium, at a temperature between 0 C and about 70 C . 31. A process according to claim 29, characterized in that the alkylation is carried out with a lower alkyl halide or a lower alkyl sulfonate or a lower alkyl sulfate. 32.- Process for the preparation of a compound of formula EMI35.1 in which R is a hydrogen or halogen atom and R is a lower alkyl or lower hydroxyalkyl radical, said process being characterized in that a compound of formula is subjected to reductive amination EMI35.2 wherein R1 is defined as a coma * specified above with an interior alkyl amine or an interior hydroxy alkyl mine at a temperature of between about 0 C and 70 C. <Desc / Clms Page number 36> 33.- Procedure for preparing compounds of the tetracycline series comprising an oxygen bridge connecting the 4 and 6 positions of rings A and C and also having a EMI36.1 4-hydroxy group or a 4¯dlmethylanino group, in substances as described above. 3 ..- Composed of the series of titracyclines having an oxygen bridge connecting the positions. 4 and 6 of rings A and C and also having a 4-hydroxy group or a 4'-dimethylamin-no group when prepared by the process, in substance, as described above. EMI36.2 35 '"Process for preparing d.dim6thylam: 1.no-4-aaino isubatitud-6-demethylteracyclines, in substance, as described above. 36.- 4ad'aéthyam.za.am, na aubstitue-6 <-deMe-thyltetracyclines, when prepared by the process according to any one of claims 29 to 31 and 35 *