AU624088B2 - Substituted azacyclohexyl derivatives - Google Patents

Description

a,.

OPI DATE 23/05/89 wE AOJP DATE 29/06/89 AP I D 253'45 88

PCT

PCT NUMBER PCT/CH88/00198 (21) Internationales Patenzeasiche in 4 C/H8/09 (7)GmismrVrrtr:CB-EG G aet teilung, Klybeckstrasse 141, CH-4002 Basel (CH).

(22) Internationales Anmeldedatum: 21. Oktober 1988 (21.10.88) (81) Bestimmungsstaaten: AU, DK, Fl, HU, JP, KR, NO, us.

(31) Prioritatsaktenzeichen: 8725118 2500/88-3 Veroffentlicht (32) Prioritaitsdaten: 27. Oktober 1987 (27.10.87) A'it internationalern Recherchenbericht.

Juni 1988 (30.06.88) (33) PrioritAtslander:

GB

CH

(71) Anmelder (fuir alle Bestimmungsstaaten ausser US): CI- BA-GEIGY AG [GH/CH]; Klybeckstrasse 141, CH- 4002 Basel (CH).

(72) Erfinder;und ErfinderlAnmelder (nurfir US) KUMP, Wilhelm EAT! CH]; Friedrich-Oser-Strasse 10, CI--4 105 Biel-lBenken MENEAR, Keith, Allan [GB/GB]; 27 Stoneybrook, Hills Farm Lane, Horsham, West Sussex (GB).

(54) Title: SUBSTITUTED AZACYCLOHEXYL DERIVATIVES (54) Bezeichnung: SUBSTITUIERTE AZACYC LOH EXYL-D ERIVATE £Hi

YH

3

H

3

H

3 00 CH3 H 1 3 C ?R1

CH

3

H

3

H

(57) Abstract The invention, concerns the manufacture of substituted azacyclohexyl derivatives of rifamycins having the formula and their salts, where R, stands for hydrogen or trialkylacetyl, R 2 stands for hydrogen or acetyl, and R 3 stands for alkyl, which possess useful pharmacological properties.

(57) Zusamnmenfassung Die Erfindung betrifft die Herstellung Von substituierten Azacyclohexyl-Derivaten von Rifamycinen der Formel (I) und ihre Salze, worin R, Wasserstoff oder Trialkylacetyl bedeutet, R 2 Wasserstoff oder Acetylbedeutet und R 3 Alkyl bedeutet, weiche wertvolle pharmakologische Eigenschaften besitzen.

St t VERIFIED TRANSLATION OF -1- 4-17107/-/16742/MA 1916

PCT

Substituted azacyclohexyl derivatives The present invention relates to novel substituted azacyclohexyl derivatives of rifamycins of formula Ra H 3

H

3

H

3

H

3 CO AH AH 6 i

SCH

3 S RICH

(I)

H

3

C

H

-R

and salts thereof in which R 1 is hydrogen or trialkylacetyl, R 2 is hydrogen or acetyl and R 3 is alkyl, to their preparation and use and to pharmaceutical preparations and the manufacture thereof.

The numbering of the ring system corresponds to that used, for example, in US Patent No. 4 005 077.

The compounds of formula I contain a number of chirality centres, and accordingly the present invention also includes the corresponding optical isomers, for example diastereoisomers.

The compounds of formula I may be in the form of salts, especially pharmaceutically acceptable salts. As the

I

able to form acid addition salts. Such salts are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as Cl-C 4 alkanecarboxylic acids that are unsubstituted or substituted, for example, by halogen, for example acetic acid; unsaturated or saturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid; hydroxycarboxylic acids, for example glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, for example aspartic acid or glutamic acid; or with organic sulfonic acids, such as unsubstituted or, for example, halogen-substituted,

C

1

-C

4 alkane- or aryl-sulfonic acids, for example methanesulfonic acid, bromobenzenesulfonic acid or toluenesulfonic acid._ Corresponding acid addition salts can also be formed with the additionally present basic centre. Further, the compounds of the invention containing an acid phenolic hydroxyl group can form salts with bases, for example alkali metal salts, such as sodium or potassium salts. In addition, corresponding internal salts can be formed.

Salts which are unsuitable for pharmaceutical purposes are also included, since these salts can be used, for example, for the isolation and purification of compounds of the invention or the pharmaceutically acceptable salts thereof.

Trialkylacetyl is especially tri-C 1

-C

7 alkylacetyl, preferably tri-C 1

-C

4 alkylacetyl, in which alkyl is in each case as defined hereinafter. Pivaloyl is most preferred.

Alkyl is especially Cl-C 7 alkyl and is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, and further comprises corresponding pentyl, hexyl and heptyl radicals. Ci-C 4 alkyl, especially methyl, is preferred.

111:1: i 3 Derivatives that are derived, for example, from rifamycin SV, are known to have pronounced antibiotic properties and can be used, for example, for the treatment of tuberculosis. The finding, verified by experiments, that the compounds of formula I and the pharmaceutically acceptable salts thereof do not exhibit any corresponding antibiotic activity in the conventional pharmacological test models for assessment, is therefore all the more surprising.

Surprisingly, however, they do have a significant lipidlowering activity, which can be demonstrated in animal tests, preferably carried out on mammals, for example rats.

Thus, the lowering of very low density, low density and high density lipoproteins (VLDL, LDL and HDL) in serum can be demonstrated in two test procedures in male rats with genetic hypercholesterolaemia (procedure A) and in normolipaemic rats of both sexes (procedure B).

Albino rats having a body weight of 180-240 g and with free access to standard rat feed and drinking water are used.

The rats are Sprague Dawley progeny of the COBS strain.

The test compound is administered orally to groups of 8 to rats, daily for 5 consecutive days, in a 3 corn starch solution. Two hours after the last administration the animals are sacrificed by being bled by cardiac puncture under anaesthesia with carbon dioxide. For a period of 16 hours before being sacrificed the animals receive no more food. The total cholesterol, lipoprotein and triglyceride blood plasma levels are determined separately for each test animal. In order to determine the lipoproteins the VLDL and LDL fractions are precipitated from 1 ml of ethylenediaminetetraacetic acid anticoagulated plasma by the addition of 200 units of heparin and manganese chloride to a final concentration of 46 mmol/litre and centrifuged off.

SM4.

l: e i 4 4 -4- The supernatant solution is combined with the remaining plasma and analysed enzymatically for their content of cholesterol and triglycerides using test systems supplied, I for example, by Sigma Chemical Co. (St. Louis, MO, USA).

The test for antibiotic activity is carried out, for example, on the one hand in vitro by determining the minimum inhibitory concentration (MIC) in the conventional plate test. The microorganisms used for this purpose are especially Mycobacterium tuberculosis TB H 37 Rv and Staphylococcus aureus. When using compounds having a lipidlowering indication, an antibiotic activity is considered a disadvantage, as it can lead to the formation of strains of microorganisms that are resistant to antibiotics, especially in the case of long-term administration.

In the above-described test methods, the compounds of the invention, when administered repeatedly in the dosage range of from about 1 to about 10 mg/kg per day, exhibit a significant hypolipidaemic activity. Thus, for example, it can be shown that, depending on the test procedure, the minimum effective dose of the compounds of the invention when administered in a single dose is from about 1 to about 3 mg/kg, and that a 75 lowering of the LDL fraction can be achieved by repeated administration of 10 mg/kg daily.

Surprisingly, the compounds prepared in accordance with the invention have virtually no antibiotic activity; the MIC for various pathogenic strains of Staphylococcus aureus, for example, is higher than 130 Lg/ml. Such values are about 1000 times higher than concentrations normally required for a corresponding effect.

Especially on account of their LDL-lowering activity, the compounds of this invention can be used, for example, as hypolipidaemic agents for the treatment of hyperlipidaemiae, mainly of types IIa and IIb, and arteriosclerosis, Ii ,A4/.

9U-.' 1

*'T

1 I for example when hyperlipoproteinaemia is a risk factor.

Accordingly, the compounds of formula I and the pharmaceutically acceptable salts thereof can be used, for example, as pharmaceutical agents, for example as hypolipidaemic agents for the treatment of hyperlipidaemiae, mainly of types IIa and IIb, and of arteriosclerosis when I hyperlipoproteinaemia is a risk factor. The invention further relates to the use of the compounds of the invention for the preparation of medicaments, especially hypolipidaemic agents and antiarteriosclerosis agents, and for therapeutic and prophylactic treatment. The commercial manufacture of the active substances also falls within the scope of this invention.

The invention relates especially to compounds of formula I and salts thereof in which R 1 is pivaloyl and R 3 is methyl.

The invention relates especially to the novel compounds described in the Examples and to the preparation thereof.

The invention further relates to processes for the preparation of the compounds of the invention. The preparation of compounds of formula I and salts thereof is carried out in a manner known pr se and comprises, for example, reacting a compound of the formula R H3 YH 3

YH

3 Rz 2 0\

H

3 CO 6H 6H 1 CH3 i 9Ri H3C *mod \N_1 X H (I I a or a salt thereof with a compound of formula

L

i i l r, i I i

'I

6- Z-CHZ-.* R3 .H3 (IIb) wherein Z is reactive esterified hydroxy, or b) for the preparation of compounds of formula I and salts thereof in which R 1 is trialkylmethylcarbonyl and R 2 is acetyl, heating a compound of formula R H3 CH3 H3 c A H AEH t

J

H3CO\

CH

3 0 I i ii -CH9-* -R3 (II), or c) heating or irradiating a compound of formula

(IV)

and, if desired, converting a compound of formula I obtainable by the process or in another manner, or a salt thereof, into a different compound of the invention or a ~NT 0 s- ^v i I:: i l i 7 salt thereof, or converting a free compound of formula I obtainable by the process into a salt and/or a salt obtainable by the process into the free compound of formula I or into a different salt.

Salts of the starting materials of formulae IIa, III and IV that contain an acid phenolic hydroxy group are corresponding salts with bases of the kind indicated hereinbefore, whereas corresponding starting compounds with basic centres can also form corresponding acid addition salts similar to the acid addition salts of formula I.

Reactive esterified hydroxy is especially hydroxy esterified with a strong inorganic acid or organic sulfonic acid, and is, for example, halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, CI-C 7 alkanesulfonyloxy that is unsubstituted or substituted, for example, by halogen, for example methanesulfonyloxy or trifluoromethanesulfonyloxy, C 5

-C

7 cycloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or benzenesulfonyloxy that is unsubstituted or substituted, for example, by Cl-C 7 alkyl or halogen, for example p-bromobenzenesulfonyloxy or p-toluenesulfonyloxy.

The reactions described hereinbefore and hereinafter in the variants are carried out in a manner known per se, for example in the absence or, normally, in the presence, of a suitable solvent or diluent or a mixture thereof, the process being carried out, as required, with cooling, at room temperature or with heating, for example in a temperature range of approximately from -80° to the boiling temperature of the reaction medium, preferably from about to about +180°C and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

4T- -i S-8- The working up of the reaction product from the reaction mixture obtainable in accordance with the process is effected in a manner known per se, for example by dilution with water and/or, if desired, by neutralisation or slight acidification (to about pH 3) with an aqueous acid, such as an inorganic or organic acid, for example a mineral acid or, advantageously, citric acid, and the addition of a water-immiscible solvent, such as a chlorinated hydrocarbon, for example chloroform or methylene chloride, the reaction product passing into the organic phase from which it can be obtained in purified form in conventional manner, for example by drying, concentrating the solvent by evaporation, and crystallisation and/or chromatography of the residue, or by other customary methods of purification.

Variant a): Z is preferably halogen, such as chlorine, bromine or iodine, as well as sulfonyloxy, such as methanesulfonyloxy or E-toluenesulfonyloxy.

The reaction is conducted in a manner known per se, advantageously in the presence of a base.

Suitable bases are preferably non-nucleophilic tertiary amines, for example tri-lower alkylamines, basic heterocycles and carbocyclic amines, such as ethyl diisopropylamine, triethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non- (DBN), as well as 1,8-diazabicyclo[5.4.0]undec-7-ene

(DBU).

Variant b): The treatment of compounds of formula III is carried out with heating, for example in a temperature range of approximately from 50' to 180°C, especially approximately from 100° to 170°C.

9 The starting material of formula III can be prepared, for example, by reacting rifamycin S or 3-halo-rifamycin S, especially 3-bromo-rifamycin S, with an aming af formula HI N-CH- R3 S. (IIIa).

&3 The reaction is carried out especially with an excess of the amine of formula IIIa, for example in a temperature range of from about 0" to about 100'C, a mixture of the quinone and hydroquinone form being formed. This mixture can be converted into the corresponding hydroquinone (derivative of rifamycin SV) by reduction, for example by catalytic hydrogenation (R 1 By treatment with corresponding acylating agents, for example with an acid anhydride, such as pivaloyl chloride, in the presence of a base, such as pyridine, compounds of formula III in which

R

1 is trialkylacetyl can be obtained.

Variant c): The reaction is carried out especially in an organic solvent, for example an alcohol, such as methanol, ethanol or isopropanol, a ketone, such as acetone or methyl ethyl ketone, a chlorinated hydrocarbon, such as chloroform or trichloroethane, an ether, such as diethyl ether, a base, such as pyridine or triethylamine, or a nitrile, such as acetonitrile. Preferred solvents are isopropanol and pyridine.

If the temperature is too low, the reaction proceeds very slowly, whereas at too high a temperature substantial amounts of unwanted by-product are formed. A suitable temperature range is from about 50 to about 90°C, preferably about T. 0 9 10 Irradiation is carried out in a manner known per se, for example using conventional sources of irradiation, such as microwave irradiation.

The resulting product can be purified and isolated, for example by chromatography and/or recrystallisation from a suitable solvent, such as petroleum ether.

The starting material of formula IV can be prepared in a manner known per se, for example by treating a compound of formula

SH

3 YH3 YH 3

H

3

CO

CH

3

I"

?H

CH

3 H3C\ II II YH3 SoN-CH 2

*-R

3 h, (IVa) with an acylating reagent that introduces the trialkylacetyl group in positions 8 and 14.

The trialkylacetyl group can be introduced in a manner known per se with a suitable acylating agent, using at least two equivalents of the latter. It is possible to use, for example, a corresponding carboxylic acid, if necessary in the presence of a suitable condensing agent, such as dicyclohexylcarbodiimide, but preferably a reactive derivative of such an acid, such as an anhydride, especially a mixed anhydride, for example one with an inorganic acid, such as a hydrohalic acid, especially hydrochloric acid or hydrobromic acid (that is to say, a corresponding acid halide, for example an acid chloride), or with an ,f r° 1^W'R 'I -^vus -I 1i organic acid, such as (trifluoro-)acetic acid or a suitable monoester of carbonic acid, or alternatively a symmetric anhydride, or an inner anhydride, that is to say the corresponding ketene. The carboxylic acid derivative employed as acylating agent is preferably used in the presence of a basic agent. A suitable basic agent is especially a non-acylatable organic base, such as a heteroaromatic base, for example pyridine, collidine or quinoline, a tertiary amine, for example triethylamine, Nethylpiperidine, N-methylmorpholine or 1,4-dimethylpiperazine, or 1,5-diazabicyclo[5.4.0]undec-5-ene.

The acylation is normally carried out in the presence of a solvent or diluent, using also an excess of the acylating agent or of the base, for example pyridine, together with an acylating agent. Other solvents which, for example, can also be used in admixture with a base, are, for example, non-acylatable organic solvents, such as hydrocarbons, for example pentane, hexane or cyclohexane, halogenated hydrocarbons, for example methylene chloride or chloroform, ethers, for example diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran or dioxane, acid esters, such as ethyl acetate, and acid amides, for example acetamide or dimethylformamide.

The reaction is normally carried out at room temperature or at slightly elevated temperature, for example up to about and, if necessary, in an inert gas atmosphere. The acylation conditions, especially the amount of acylating agent used, the reaction medium, the temperature and the reaction time, should be so chosen that both acyl groups are introduced, the procedure used preferably being as described in detail in the Examples. Th course of the reaction may advantageously be monitored by means of customary analytical methods, especially by thin-layer chromatography.

.T 12 The starting material of formula IVa is known or can be prepared in a manner known per se, in which connection reference is made especially to the PCT Application published under the number WO 87/02361.

The invention further relates to the novel compounds obtainable by the above-described process variants.

A compound of formula I obtainable in accordance with the invention or in another manner, or a salt thereof, can be converted in a manner known per se into a different compound of formula I.

Compounds of formula I in which R 1 is hydrogen can be acylated in a manner known per se, for example by reaction with the appropriate carboxylic acid or a reactive derivative thereof. Such reactive derivatives are, for example, anhydrides, including mixed anhydrides, such as an acid halide, for example an acid chloride, or anhydrides with a formic acid ester, activated carboxylic acid esters, such as cyanomethyl ester, (4-)nitrophenyl ester, and polyhalophenyl esters, for example pentachlorophenyl ester. The reaction with the carboxylic acid or a salt thereof is carried out with removal of water, for example azeotropic removal of the water of reaction, or by treatment with a suitable condensing agent, for example N,N'-dicyclohexylcarbodiimide. The reaction with a reactive acid derivative is advantageously carried out in the presence of a base.

Similarly, the acetyl radical R 2 can be introduced into compounds of formula I in which R 2 is hydrogen by treatment with a suitable acetylating agent.

The acetyl radical R 2 and the acyl radical R 1 can be replaced by hydrogen by treatment with strong bases, such as alkali metal hydroxides. The acyl radical R 1 can also BNT S- 13 13 be removed selectively in the presence of the acetyl radical R 2 for example by treatment with a fluoride, such as an alkali metal fluoride, for example sodium or caesium fluoride, or with an ammonium fluoride, for example tetrabutylammonium fluoride.

Salts of compounds of formula can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula are obtained by treatment with an acid or with a suitable ion exchange reagent.

Salts can be converted in customary manner into the free compounds; acid addition salts, for example, by treatment with a suitable basic agent.

Depending on the procedure and on the reaction conditions, the compounds of the invention having salt-forming, especially basic, properties, can be obtained in free form or, preferably, in the form of salts.

Owing to the close relationship between the novel compound in free form and in the form of its salts, hereinbefore and hereinafter references to the free compound or its salts shall also, where appropriate with regard to context, include the corresponding salts or the free compound respectively.

The novel compounds, including their salts of salt-forming compounds, can also be obtained in the form of hydrates or include other solvents used for crystallisation.

Depending on the choice of starting materials and procedures, the novel compounds may be in the form of one of the possible isomers or in the form of mixtures thereof, for example depending on the number of asymmetric carbon atoms they may be in the form of pure optical isomers, such as antipodes, or in the form of mixtures of isomers, for S |j

L

cc: C a '-II' p- r I (57) Zusammenfassung Die Erfindung betrifft die Herstellung von substituierten Azacyclohexyl-Derivaten von Rifamycinen der Formel (I) und ihre Salze, worin R Wasserstoff oder Trialkylacetyl bedeutet, R 2 Wasserstoff oder Acetyl bedeutet und R 3 Alkyl beund.: ih' deutet, welche wertvolle pharmakologische Eigenschaften besitzen.

i i 14 example racemates, mixtures of diastereoisomers or mixtures of racemates.

Resulting mixtures of racemates can be separated in known manner into the pure isomers or racemates on the basis of the physico-chemical differences between the components, for example by fractional crystallisation.

Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific immobilised enzymes, via the formation of inclusion compounds, for example using chiral Crown ethers, only one enantiomer being complexed, or by conversion into diastereoisomeric salts, for example by reaction of a basic end product racemate with an optically active acid, such as a carboxylic acid, for example tartaric or malic acid, or a sulfonic acid, for example camphorsulfonic acid, and separation of the resulting mixture of diastereoisomers, for example on the basis of their different solubilities, into the diastereoisomers from which the desired enantiomers can be freed by the action of suitable agents. It is advantageous to isolate the more active enantiomer.

The invention also relates to those embodiments of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the form of a derivative or salt and/or its racemates or antipodes or, especially, is formed under the reaction conditions.

In the process of this invention it is preferred to use those starting materials that lead to the compounds A4/

ITTO

I,'2 .1, 15

I

referred to at the outset as being especially valuable.

The invention further relates to novel starting materials that have been specially developed for the preparation of the compounds of the invention, especially novel compounds of formula III, their use, and processes for their preparation, the variables R 1

R

2 and R 3 having the meanings given for the respective preferred groups of compounds of formula I.

The present invention also relates to the use of compounds of formula I and salts thereof alone or together with adjuncts, as well as in conjunction with other active substances, as agents for the therapeutic treatment, that is the curative as well as preventive treatment, of diseases or pathological conditions that are indicated or caused, for example, by an increased content of chlolesterol and/or triglycerides in blood, especially in blood serum. The active ingredients of the invention are administered to the warm-blooded animals requiring treatment, primarily humans, in therapeutically effective amounts, preferably in the form of pharmaceutical compositions together with conventional pharmaceutical carriers and/or adjuncts. Depending on the species, body weight, age and individual condition, for example daily doses of about 1 to about 100, preferably of about 3 to about mg/kg of body weight, which doses may be exceeded in acute cases, are administered to warm-blooded animals. The invention also relates by analogy to the corresponding method of medical treatment.

The invention further relates to pharmaceutical preparations that contain the compounds of the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for the preparation thereof.

The pharmaceutical preparations of the invention, which H 16 contain the compound of the invention or pharmaceutically acceptable salts thereof, are for enteral, such as oral or also rectal, and parenteral administration to warm-blooded animals, and contain the pharmacological active ingredient on its own or together with a pharmaceutically acceptable carrier.

The novel pharmaceutical preparations contain, for example, from about 10 to about 80 preferably from about 20 to about 60 of the active ingredient. Pharmaceutical preparations of the invention for enteral or parenteral administration are, for example, those in dosage unit forms, such as dragies, tablets, capsules or suppositories, as well as ampoules. These pharmaceutical preparations are prepared in a manner known per se, for example by conventional mixing, granulating, confectioning, dissolving or lyophilising methods. For example, pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, and/or polyvinylpyrrolidone, if desired disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are especially flow agents, flowregulating agents and lubricants, for example silicic acid, i. r |Ii 1 8 17 talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions that optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, to produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.

Colouring substances or pigments may be added to the tablets or dragee coatings, for example for the purposes of identification or to indicate different doses of active ingredient.

Other orally administrable pharmaceutical preparations are dry-fill capsules made of gelatin, and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of a granulate, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers.

In soft capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers to be added.

Suitable rectally administrable pharmaceutical preparations are, for example, suppositories that consist of a comnbina- tion of the active ingredient with a suppository base material. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules that u 18 contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

There are suitable for parenteral administration especially aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, are used, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, where appropriate, also stabilisers.

The dosage of the active ingredient depends on the species of warm-blooded animal, the age and individual condition, as well as on the mode of application. Normally, an approximate daily dose of about 150 mg to about 1500 mg, advantageously in several equal partial doses, is proposed in the case of oral administration to a warm-blooded animal weighing about 75 kg.

The following Examples illustrate the above-described invention, but in no way limit the scope thereof.

Example 1: 30 g of 1,8-di-O-pivaloyl-3-[4-(2,4,6-trimethylbenzyl)piperazin-l-yl]-rifamycin SV are dissolved, with the application of heat, in 1000 ml of 2-methoxyethanol and the solution is refluxed for 5 hours under nitrogen. The solvent is then concentrated by evaporation under vacuum and the residue is crystallised twice from methanol, yielding 8-O-pivaloyl-l-deoxy-15-deoxo-l,15-oxyi* i d~_ 19 3 4 2 ,4,6-trimethylbenzyl)piperazin-l-ylJ-rifamycin of formula I in which R 1 is pivaloyl, R 2 is acetyl and R 3 is methyl. Melting point 160-165°C.

C

56

H

73

N

3 0 1 2 M 979, found 979; 1 H-NMR (360 MHz, CDC1 3 TMS): 1.49 9H, pivaloyl at 0-8).

H3\ H o

H

3 CO 6H 6H CH 3 SR CH3 H3C S I H3C\ RI pivaloyl CH3 3 0 H3C The starting material can be prepared as follows: A mixture of 5 g of 3-[4-(2,4,6-trimethylbenzyl)piperazinl-yl]-rifamycin SV, 50 ml of dry pyridine and 4.5 ml of pivaloyl chloride is kept at 50°C for 30 minutes. The solvent is then evaporated under vacuum. The oily residue is dissolved in ethyl acetate and the solution is washed with 2N hydrochloric acid, with a buffer solution of pH 7, and with a solution of sodium chloride. The whole is dried over sodium sulfate and concentrated by evaporation and the yellow residue is crystallised from ether/hexane, yielding 1,8-di-O-pivaloyl-3-[4-(2,4,6-trimethylbenzyl)piperazin-lyl]-rifamycin SV with a melting point of 203-204°C.

C

61

H

83

N

3 0 16 mol. wt.: 1081 (found, MS) Example 2: Solid tetrabutylammonium fluoride trihydrate is added in portions at room temperature, while stirring, to a solution of 10.7 g of the target product of Example 1 in 200 ml of tetrahydrofuran unti 'the initial red colour of the solution has changed to yellow. After the addition of water and acidification with citric acid, the reaction product is taken up in ethyl acetate. The ethyl acetate A4O 20 extract is washed with water and a solution of sodium chloride, dried over sodium sulfate and concentrated by evaporation under vacuum. The residue is crystallised from ether yielding l-deoxy-15-deoxo-l,15-oxy-3-[4-(2,4,6trimetlylbenzyl)piperazin-l-yl]-rifamycin of formula I in which R 1 is hydrogen, R 2 is acetyl and R 3 is methyl, in long lemon-yellow prisms which are recrystallised from methanol/water. Melting point: 175°C

C

51

H

65

N

3 0 11 mol. wt.: 895 (found, MS,FD). UV spectrum in 0.01N alcoholic HC1, maxima in nm/E: 241/37240; 298/23000; 330 (shoulder); 437/9920.

H3C-C

H

3

H

3 CO H H H3c 6.

H

3

C

C H S-H CH3/

H

3

H

3

C

Example 3: A solution of the reaction product of Example 2 is allowed to stand at room temperature for 21 hours in dioxane/lN sodium hydroxide solution After dilution with water and acidification with citric acid, the reaction product is taken up in ethyl acetate and crystallised from ethyl acetate/ether, yielding 25-deacetyl-3-[4-(2,4,6trimethylbenzyl)piperazin-l-yl]-l-deoxy-15-deoxo-l,15-oxyrifamycin of formula I in which R 1 is hydrogen, R 2 is hydrogen and R 3 is methyl, in the form of yellow crystals having a melting point of 190-195'C (decomposition).

C

49

H

63

N

3 0 10 mol. wt.: 853 (found, MS, FD).

21 co H C C I \-CH, o CH3 H 3

C

Example 4: 10 equivalents of pivaloyl chloride are added to a solution of the target product described in Example 3 in pyridine and the mixture is allowed to stand at room temperature until analysis by thin-layer chromatography shows that no more starting material can be detected in the reaction product. The reaction mixture is then rapidly concentrated to dryness by evaporation under a high vacuum and the residue is taken up in methylene chloride. The methylene chloride extract is washed in succession with a solution of citric acid, a buffer solution of pH 7, and a saturated solution of sodium chloride. The methylene chloride extract is dried and concentrated by evaporation to give a red residue which is 25-deacetyl-8-0-pivaloyl-3- [4-(2,4,6-trimethylbenzyl piperazin--yl 1,15-oxy-rifamycin of formula I in which R 1 is pivaloyl, R 2 is hydrogen and R 3 is methyl.

C

5 4

H

7 1

N

3 0 1 1 mol. wt.: 937 (found, MS,FD).

HI-NMR

(CDC13, 360 MHz): signal of the pivaloyl group at 1.41 (s, 9H, CH 3

C).

O-i 1 V CH3 Ha Exml :1 qiaet f iaolclrd r de i to ouino h tre rdc ecrbdi xml inprdn n h itr salwdt tn tro tempratre nti anaysi bythi-layr cromtogaph h ~i -22-

HO

H

3 CO 6H C H

CH

3 ?Rl CH3 R, is pivaloyl I IH3C\ 4 HC Example 5: 4 g of 8-0,N-dipivaloyl-3-[4-(2,4,6-trimethylbenzyl)piperazin-1-yl]-rifamycin S (prepared in accordance with WO 87/02361, Example 1) are heated, with the exclusion of light, in 70 ml of isopropanol in a bomb tube for 4 hours at 100 The solvent is then removed under vacuum and the dark red residue is chromatographed over 600 g of silica gel (Merck) with petroleum ether/ethyl acetate The substances contained in the first two zones are discarded. The red fraction immediately following contains the target product of Example 1. Further target product present in the chromatography column is eluted with ethyl acetate/methanol and chromatographed once more for further purification. The eluates are concentrated by evaporation, to give the 8-O-pivaloyl-l-deoxy-15-deoxo- 1,15-oxy-3-(2,4,6-trimethylbenzyl)piperazin-1-yl]-rifamycin characterised in Example 1.

Example 6: Capsules containing as active ingredient 250 mg of, for example, the compound of formula I in which

R

1 is pivaloyl, R 2 is acetyl and R 3 is 2,4,6-trimethylphenyl, can be prepared as follows: phenyl, can be prepared as follows:, 1_ LI 23 Composition (for 1000 capsules):

I

active ingredient 250.0 g corn starch 50.0 g polyvinylpyrrolidone 15.0 g magnesium stearate 5.0 g ethanol q.s.

The active ingredient and the corn starch are mixed and the mixture is moistened with a solution of the polyvinylpyrrolidone in 50 g of ethanol. The moist mixture is passed through a sieve having a mesh width of 3 mm and dried at 45°. The dry granulate is passed through a sieve having a mesh width of 1 mm and mixed with 5 g of magnesium stearate. The mixture is filled in 0.320 g portions into size 0 dry-fill capsules.

The other compounds prepared according to the Examples can also be used as active components in similar manner.

Example 7: 250 g of an active ingredient according to any one of Examples 1 to 5 and 1750 g of finely triturated suppository base cocoa butter) are thoroughly mixed and then the mixture is melted. 1000 suppositories of 2 g are cast from the melt which is kept homogeneous by stirring. Each suppository contains 250 mg of active ingredient.

Qi

M-

'YNT O.

1

**T

A

Claims (17)

1. Gempeundo of formula I H3 pHa YHa3 R0\ H 3 CO\\ 6H H H i CH 3 (I) SCH3 SH 3 i 3 6 OH H./ H3 0 H3 and salts thereof in which R 1 is hydrogen or trialkyl- acetyl, R 2 is hydrogen or acetyl and R 3 is alkyl.

2. A compound according to claim 1 of formula I or a salt thereof in which R 1 represents tri-C 1 -C 7 alkylacetyl, especially tri-CI-C 4 alkylacetyl, and R 3 represents C 1 -C 7 alkyl, especially C 1 -C 4 alkyl.

3. A compound according to claim 1 or 2 of formula I or a salt thereof in which R 1 represents pivaloyl.

4. A compound according to any one of claims 1 to 3 of formula I or a salt thereof in which R 3 represents methyl.

A compound according to claim 1 of formula I or a salt thereof in which R 1 represents pivaloyl and R 3 represents methyl.

6. A compound according to claim 1 of formula I or a salt thereof in which R 1 represents pivaloyl, R 2 represents I i acetyl and R 3 represents methyl. i mm

7. A compound according to claim 1 of formula I or a salt thereof in which R, represents hydrogen, R 2 represents acetyl and R 3 represents methyl.

8. A compound according to claim 1 of formula I or a salt thereof in which R, and R 2 each represent hydrogen and R 3 represents methyl.

9. A compound according to claim 1 of formula I or a salt thereof in which R, represents pivaloyl, R 2 is hydrogen and R 3 represents methyl.

A compound according to any one of claims 1 to 9 in the form of a pharmaceutically acceptable salt.

11. Pharmaceutical preparations comprising as active ingredient a compound according to any one of claims 1 to 9 in free form or in the form of a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent S 20 or excipient.

12. A method for the treatment of hyperlipidaemia and arteriosclerosis, which comprises administering a S: compound according to any one of claims 1 to 9 in free form or in the form of a pharmaceutically acceptable salt thereof.

13. A process for the preparation of a compound according to any one of claims 1 to 9, which comprises reacting a compound of formula q2021,wpftdisk58,25345.I25 I 26- H 3 jH3 YH 3 CH 3 H, C I II H 3 0 or a salt thereof, with a compound of formula p3 Z-CHZ- k-R3 r H 3 (hb wherein Z is reactive esterified hydtoxy, or b) for the preparation of compounds of formula I and salts thereof in which R, is trialkylmethylcarbonyl and R 2 is acetyl, heating a compound of formula R 2 H 3 YH 3 YH 3 R 2 H 3 CO 6JH O\ CH 3 CCH H 3 H. 3 H 3 05&3 or c) heating or irradiating a compound of formula P ,A4 I' -27 CHi o« H, *I I .H B .H HCO Ry (IV) 00 I II 0 2 6 -*R3 ees and, if desired, converting a compound of formula I obtainable by the process or in another manner, or a salt thereof, into a different compound of the invention or a salt thereof, or converting a free compound of formula I obtainable by the process into a salt and/or a salt obtainable by the process into the free compound of formula I or into a different salt.

14 The compound of Formula I said compound substantially as herein described with reference to any one of Examples 1 to A pharmaceutical preparation substantially as herein described with reference to Example 6 or Example 7. DATED this 19th day of March 1992. CIBA-GEIGY AG By their Patent Attorneys DAVIES COLLISON CAVE S920121,wpftdisk58,25345.127 1 j I, I *i 28 4-17107/-/16742/MA 1916 Substituted azacyclohexyl derivatives Abstract The invention relates to the preparation of substituted azacyclohexyl derivatives of rifamycins of the formula R 2 H~3 SYH3 YH 3 8 3 C0 .3 ?3 0 5i3 and salts thereof in which R, is hydrogen or trialkyl- acetyl, R 2 is hydrogen or acetyl and R 3 is alkyl, which exhibit valuable pharmacological properties. I?' j 1~ INTERNATIONAL SEARCH REPORT PC./CH 88/00198 International Application No I. CLASSIFICATION OF SUBJECT MATTER (If several classification symbols apply, Indicate all) 4 According to Intrnational Patent Classification (IPC) or to both National Classification and IPC Int.Cl C 07 D 498/18; A 61 K 31/495; 09 D 498/18, 323:00 307:00, 263:00) II. FIELDS SEARCHED Minimum Documentation Searched 7 Classification System Classification Symbols A Int.Cl1 C 07 D 498/00; A 61 K 31/00 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched a iii. DOCUMENTS CONSIDERED TO BE RELEVANT 9 Category I Citation of Document, 1 with indication, where appropriate, of the relevant passages 12 Relevant to Claim No. 13 Y WO, A, 87/02361 (CIBA-GEIGY) 23 April 1987 1,13 see claims 1,8 Y Chemical Pharmaceutical Bulletin, volume 33, 1 No. 5, 1985, (TOKYO, JP), M. Taguchi et al.:"Chemical modification of the amide group of rifamycin S", pages 2133-2136, see formula 8 Special categories of cited documents: 1o later document published after the international filing date document defining the general state of the art which is not or priority date and not in conflict with the application but considered to be of particular relevance cited to understand the principle or theory underlying the invention earlier document but published on or after the international v _io. "E lier document but published on r ater the nternational "X document of particular relvance; the claimed invention cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or Involve an inventive step which is cited to establish the publication date of another "Y documet of particular relevancethe clamed nvention citation or other special reason (as specified) document of particular relevance; the claimed Invention cannot be considered to involve an Inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but In the art. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 16 January 1989 (16.01.89) 2 February 1989(02.02.89) International Searching Authority Signature of Authorized Officer EUROPEAN PATENT OFFICE Form PCT/ISA/210 (second sheet) (January 1985) Sm m 7Q L';Ji i i I;; International Appllcation No.PCT/CH 88 00198 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET i I V.I OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE This international search report has not been established In respect of certain claims under Article 17(2) for the following reasons: 1.R Claim numbers.1.4...., because they rmlate to subject matter not required to be searched by this Authority, namely: See Patent Cooperation Treaty, rule 39.1(iv); Claim because they relate to parts of the International application that do not comply wHh the prescribed requlre- mants to such an extent that no meaningful Internatloial search can be carried out, speciflaly: Claim num because they are dependent claims nd are not drafted In accordnce with tte second and thd sentences of PCT Rute 6.4(a). Vl.- OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions In this International application as follows: t1.[ As all required additional search fees were timely paid by the applicant, this International search report covers all searchable claims of the International application. 2. As only some of the required additional search fees were timely paid by the applicant, this intrnational search report covers only those claims of the International application for which fees were paid, specifically claims: M. No required additional search fees were timely paid by the applicant. Consequently, this International sarch report is restricted to the Invention first mentioned In the claims; it Is covered by claim numbers: SAs all searchable claims could be searched without effort justifying an additional fee, the International Searching Authority did not invite payment of any additional fee. Remark on Protest SThe additional search fees were accompanied by applicant's protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISA/210 (supplemental sheet (January 1985) .i i i 1~-11 i. -L i .:i I I ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. CH 8800198 SA 24684 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 26/01/89 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information.

Patent document Publication Patent family Publication cited in search report date member(s) date WO-A- 8702361 23-04-87 EP-A- 0244398 11-11-87 i For more details about this annex see Official Journal of the European Patent Office, No. 12/82 _i i i -i INTERNATIONALER RECHERCHENBERICHT Internationales Aktenzeichen PCT/ CI 88 /00198 1. KLASSIFIKATION DES ANMELDUNGSGEGENSTANOS (bel mehreran Klasslflkationssymbolon sind all. anzugeben) 6 Nach der Internationalen Paten tklasaifikatio n (IPC) oder nach der nationalen Kiassifilcation und der IPC IntCJ- C 07 D 498/18; A 61 K 31/495; (C 09 D 498/18, 323:00, S307:00, 263:00) 11. ENS RCLAIGRE VEROPFENTIHNGN Art Knnzechnun derVerofentlchung 1 ,aaeiterfoirer ihunetr Agbedr aigbice eie 2 er.Aspuh r siehe C1price4, 1985 (TD o 49/ 0;A 61K 31 0 M. Tagchit eit al.:idetp~stf "C eicald mordf icatioen, sofhs th md rupt ofe rciarnySchi Sfaleite siehe Fosrel e 8 Besondeal KaearticnutancaleBubeneniVetBanndlichunge M VeTfnlcundedagemine Sad "rheikcT'Sater m ediffichunt ienac deonefainae n definiert, aber nicht ala besanders bedeutsam anzusehen ist meldedatum oder dem Priorititsdatum veroffentlictit worden ltees okumntdasfedch eat m aer ach em ntena- ist und mit der Anmeldung nicht kallidiert, sondern nut zum ""Atonale Ankmddteofent lich ecoh rt adenc da iten Verstandinis des der Etfindlung zugrundeliegenden Prinzips tionlenAnmededtumverdfenlict wodenistoder der ihr zugrundeliegenden Theorie angegeben it Veroffentlichung, die geeignet ist, omnen Prioritatsanspruch Veroffentlichung on besonderer Bedeutung; die beanspruch. zweifelhaft etacheinen zu lessen, odor durch die das Vetaf- t ricugkn ih l e drafefneice kg fentlichungsdatum elner anderen im Recherchenbeticht ge- t berfind kanchta arneder u ridrice ag nannten Nkr~ffentlichung beiegt werden soil odor die aus eiekirbnhnnbtahotwre anderen besonderen Grund angegeben ast (Wie ausgefdhrt) Votdffentlichung van besonderet Bedoutung; die beanspruch. er~fenlicung diesic au eie mndlihe ffebarng, to Erfindung kann nicht als auf etfinderischer Tdtigkoit be- e Vefentlicung, ine Asich aug ein aindce Offenbarn ruhend bettachtet warden, wonn die Votoffentlichung mit beie etun.enAuelugooanteMLahe einer oder mehteten andoron Veroffontlichungen dieter Kate- bozehtgonie in Vetbindlung gebracht wird uncs diese Vetbindlung fUr Vetoffentlichung, die vor dem intetnatioalen Anmeldeda- linen Fachmann naholiegond ist turn, abet nach dam beanspruchten Priorititadaturn vordffent- ~VrfetihndeMtle eslo aetaii t licht warden ast VVrfetihndeMtie esle aetaii IV. BESCHEINIGUNG Datum des Abschiusses der intetnationalen Rechotche Absendlodatumn des internatianalen Recherchenbetichta

16. Ja Inuar 1989 -2 FEB 1989 Internatianale Recherchenbehorde Utemrschrift des bevollmctt 5 Icledklee e Europiiaches Patentrnt M. VAN MOL Formblott PCT/ISA/21 0 (Blatt 2) (Januar 1985) I. I. I nternationales Aktenzel 11 PCT/CH 88/00198 t WEITERE ANGABEN ZU BLATT 2 V. BEMERKUNGEN ZU DEN ANSPRUCHEN, DIE SICH ALS NICHT RECHERCHIERBAR ERWIESEN HABENI GemaSg Artikel

17 Absatz 2 Buchstabe a sind bestimmte Anspr~che aus folgenden Gr~nden nicht Gegenstand der internationalen Recherche gevvesen: rn 14 1. F Anspr~che Nr well sie sich auf Gegenst~nde beziehen, die zu recherchieren die Behorde nicht verpflichtet ist, nimlich Siehe Vertrag Qber die internationale Zusainmenarbeit auf dem Gebiet des Patentwesens, Rege. 39.l(iv). 2. 0 Ansprilche Nr well sle sich auf Teile der internationalen Anmeldlung beziehen, die den vorgeschriebenen Anforderunger so wvenig entsprechen. deRg eine sinnvolle internationale Recherche nicht durchgef~hrt werden kann, namlich, 3. D Anspriiche Nr weil sle abh~ngige Anspriiche und nicht entsprechend Satz 2 und 3 der Regel 6.4 a) PCT abgefa~t %Ind. Vi.I BEMVERKUNGEN BEI MANGELNDER EINHEiTLICHKEIT DER ERFINDUNG 2 Die Internationale Recherchenbeharde hat festgestellt, dall diese internationale Anmeldlung mehrere Erfindlungen enthalt; 1. D Da der Anmelder alle erforderlichen zusdtzlichen Recherchengebghren rechtzeitig entrichtet hat, erstreckt sich der internationale Recherchenbericht auf alle recherchierbaren Ansprdche der internationalen Anmeldung. 2. D Da der Anmelder nur einige der erforderlichen zusatzlichen Recherchengeb~ihren rechtzeitig entrichtet hat, erstreckt sich der interna- tionale Recherchenbericht nur auf die Anspriche der internationalen Anmeldung, fUr die GebUhren gezahit warden sind, namlich 3. D1 Der Anmelder hat die erforderlchen zusaitzlichen Recherchengeb~hren nicht rechtzeitig entrichte t. Der internationale Recherchen. bericht beschr-inkt sich dlaher auf die in den Anspruchen zuerst erwahnte Erfindung; sle ist in folgendlen AnsprUchen erfa~t: 4. D: Da f~r alle recherchierbaren Anspriche elne Recherche ohne einen Arbeitsaufwand durchgefiihrt werdlen konnte, der elne zu- saezliche RecherchengebUhr gerechtfertigt hatte, hat die Internationale Recherchenbehorde elne soiche GebUhr nicht verlangt. Bemneriung hinsichtllch eines Widerspruchs E] Die zusdtzlchen GebUhren wurden yamn Anmelder unter Widerspruch gezahit. 0 Die Zahiung zusaSzlicher Gebuhren erfolgte ohne Wdrpuh V a Forniblatt PCT/ISA/210 (Ergainzungsbogen 2) (Januar 1985) OIL- 11 ANHANG ZUM INTERNATIONALEN RECHERCHENBERICHT (3BER DIE INTERNATIONALE PATENTANMELDUNG NR. CH 8800198 SA 24684 In diesem Anhang sind die Mitglieder der Patentfamilien der im obengenannten internationalen Recherchenbericht angcruhfrten Patentdokuniente angegeben. Die Angaben fiber die Familieninitglieder entsprecben dem Stand der Datei des EuropAischen Patentamnts am 26/01/89 Diese Angaben dienen nur zur tUnterrichtung und erfolgen obne Gewihr. un Recberchenbericht angeiuhrtes Patentdokument Datum der Veroffentlichung Mitglied(er) der Patentfarnilie Datum der Veroffentlichung WO-A- 8702361 23-04-87 EP-A- 0244398 11-11-87 Fuir nahere Einzelheiten zu diesem Anhang :siehe Amtshlatt des EuropAischen Patentamts, Nr.12/82 IL