AU624153B2 - Substituted azacyclohexyl derivatives - Google Patents

Description

the invention the subject of the application.

DECLARED at Basle, Switzerland on June 6, 1989 /7 ~W.

CIBA-GEIGY AG Werner Waldeg Single Signature bspcal 2.88 521 WW

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V

To: The Commissioner of Patents Our Ref: 1 27,9680 Patents~24 COMPLETE SPECIFICAkrION

(ORIGINAL)

FORM p Application Num~ber Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: 4; C

C

t 4 1

A;

Applicant(s): Ciba-Geigy AG Klybeckstrasse 141 4002 BASLE

SWITZERLAND

I';

I

Address for Service: Complete specification for ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSV! 2000 the invention entitled "Substituted azacyclohexyl derivatives".

V

I

I;

The following statement is a full description best method of performing it known to me:of this invention., includ~ing the 1-

F

-la The present invention relates to novel substituted azac,,yclohexyl derivatives of rifamycins ,of formula R2 YH3 YH 3

YH

3 At.

H3*6H X 00 13 A2 anRat3hro nwic h tutrleeets-lA-- A-4 n AsAG are eahehln r Cyeeo heeeet A-A-3n A- 99H 3

\R

and sathe maufcre tn hreof. tutra lmnt A-A- I3- n TheA, barc nu~ehg ofyeeo vn eo the eiglyteecr esp ns to lA2 tht s d for A eae, inc USyln Pant No.A6 4 i00 077. nXis\R- r a 6i f. alky or yd!,oge, al is n alphaic hdrocrbonradcal ~r ab-on, R ii; 2 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 compounds of this invention contain at least one basic centre they are 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 Ci-C 4 alkanecarboxylic acids that are unsubstituted or substituted, for example, by halogen, for example acetic acid; or'such as unsaturated or saturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid; hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, for example aspartic acid or glutamic acid; or aromatic carboxylic acids, for example benzoic acid; or with organic sulfonic acids, such as unsubstituted or, for example, halo-substituted, Ci-C4alkane- or aryl-sulfonic acids, for example methanesulfonic acid, bromobenzenesulfonic acid or toluenesulfonic acid. Corresponding acid addition salts can also be formed with a basic centre that may be present in

~I

i ii

B

RiO ii r a ;tii i/ ii q~ SCf C.

C t 9 *i 9 99 9 c 9 9 9 949; addition (for example X Further, the compounds of the invention 9 9 *9 containing an acid phenolic hydroxy group can form salts with bases, for example alkali metal salts, such as sodium or potassium salts, iti addition, corresponding internal salts can, be formed. Salts that 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.

An aliphatic hydrocarbon radical is especially alkylene, alkenylene or alkynylene, the multiple bonds preferably being located in a position higher than the a-position to the piperazine nitrogen atom (X in ui saturated radicals.

w; (i

U,

L i I Acyl is derived, for example, from an organic carboxylic acid or fo-M ~a substituted carbonic acid. Such radicals are, for example, unsubstituted or, for example, halo- or aryl-substituted (CI-C 7 -)alkanoyl, or unsubstituted or, for example, halo-, (CI-0 7 -)alkyl-, (C 1

-C

7 -)alkoxy-, hydroxy-, (C 2

-C

8 -)alkanoyloxy-, trifluoromethyl- and/or nitro-substituted carbocyclic airoyl, such as benzoyl or naphthoyl, or heterocyclic aroyl, such as monocyclic, 5- or 6-membered monothia-, monooxa-, or monoazaaroyl, for example (2-)thenoyl, (3-)furoyl, nicotinoyl or isonicotinoyl.

A suitable acyl radical derived from a substituted carbonic acid is, for example, (CI-C7-)alkoxycarbonyl, or aminocarbonyl that is unsubstituted or mono- or di-substituted, for example, by (C 1

-C

7 -)alkyl.

A cycloal,4phatic 'hydrocarbon radical is especially cycloalkyl, cycloalkenyl or rycloaflcynyl, it being possible for such radicals to contain, in addition, one or more, such as 2 or 3, alkyl groups, especially lower alkyl.

tt #4 9**

S.

S

S

Aryl is derived, for example, from a mono- or poly-cyclic, such as bicyo~ic, C-ring system that contains at least one aromatic ring, such as S phenyl, biphenylyl, such as 3- or, especially, 4-biphenylyl, or :*,naphthyl, st!!:i as 1- or 2-naphthyl, and is unsubstituted or mono- or poly-substituted, for example di- or tni-substituted, for example by ial en, -)alkyl, alkoxy, bydroi-y, (C-CB-)alkanoyloxy, t cifl uoromethyl and/or. nitro.

4'4 Hleteroaryl is especially monocyclic 5- or 6-membered monoaza- monooxa- or monothia-aryl, such as pyrrolyl, N-alkylpyrrolyl, pynidyl, N-oxidopyridyl, furyl or thi-#inyi and is unsubstituted or mono- or poly-tubstituted, such as di- or tri-substituted, for example as indicated for The general definitions used hereinbefore and hereinafter have, unless defined otherwise, especially the following meanings: 9 fi->~i 1 -4- Alkyl is especially CI-C7alkyl and is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl and also includes corresponding pentyl, hexyl and heptyl radicals. CI-Ci~alkyl is preferred.

Al1kylene is, for example, Cl-C,2alkylene, especially CI-C 7 alhylene, and is st raight -chain or branched and is, for example, methylene, ethylene, propylene or butylene as well as 1,2-propylene, 2-methyl-1,3-propylene or 2,2-dimethyl-1 ,3-propylene. Ca-Ci~alkylene, especially methylene, is preferred.

kct Alkenylene is especially C 3

-C

7 alkenylene, is straight-chain or branched (r and is, for example 1,3-prop-2-enylene, 1,4-but-2- or 1,4-but-3-enylene, l-but-2-pnylene, 2,4-but-3-enylene, 1,5-pent-2-, or -4-eyee n 4 also corresponding hexenylene and heptenylene radicals. is preferred.

Alkynylene is especially C3-C7alkynylene and i6 straighl-chain or Sbranched, and is, for example, 1,3-prop-2-ynylene, 1,4-but-2-or 1,4-but- ,~3-ynylene, 1,5-pent-2-, or -5-ynylene, and also corres",nding hexynylene and beptynylene radicals. C 3

-C

5 alkynylene is preferred.

Halogen is especially halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine, and also iodine.

CycJloalkyl is especially C3-C7cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloponty. and cyclohexyl are preferred.

Cycloalkenyl is especiall~y C3-C7cycloalkenyl and contains especially one, or also (from CO, two double bonds, for example cycloprop-2-en-1-yls cyclobut-2-en-l-yl, cyclobut-1,3-dien-1-yl, cyc lope n t-2-en- 1-yl, -3-en-l-yl, -2,4-dien-1-yl, cyclohex-2--en-1-yl, -3-en-1-yl or -2,4-dien- 1-yl, -1,3-dien-1-yl or -2 ,5-dien-l-yl, or also a corresponding cyclohepteny). radical.

I:

:1 f Cycloalkynyl is especially Ca-C 7 cycloalkynyl and contains especially a triple bond, and is, for example, cyclopent-2-yn-1-yl, cyclobut-2-yn- 1-yl, cyclopent-2-yn-1-yl or -3-yn-1-yl, cyclohex-2-yn-1-yl or -3-yn- 1-yl, or a corresponding heptynyl radical.

Alkanoyl is especially C 2 -Calkanoyl and is, for example, acetyl, propionyl, butyryl, isobutyryl oz pivaloyl. Branched 0 3 -C6alkanoyl, especially pivaloyl, is preferred.

Alkoxy is especially Ci-C 7 alkoxy and is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy. Cj-Cialkoxy is e' preferred.

In alkanoyloxy, alkanoyl has the meanings given hereinbefore.

a: i In alkoxycarbonti alkoxy has the meanings given hereinbefore.

r 9 Pyrrolyl is, for example, 2- or 3-pyrrolyl, pyridyl is, for example, 3- or 4-pyridyl, 1-oxido-pyridyl is, for example, 1-oxido-2-, or A, -4-pyridyl, furyl is, for example, 2- or 3-furyl and1 thienyl is, for S example 2- or 3-thienyl.

*0* 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. It has now been found that the coma S pounds of formula I and the pharmaceutically acceptable salts thereof do not e-hibit any corresponding antibiotic activity in the conventional pharmacological test models fcr assessment.

Surprisingly, however, they do have a significant lipid-lowering activity, which can be demonstrated in animal tests, preferably caried out on mammals, for example rats. Thus, the lowering of very low dcnsity, low density and high density liv proteihs (VLDL, LDL and HDL) in serum can be demonstrated q two test procedures, in male rats with genetic hypercholesterolaemia (procedure A) and in normolipaemic rats of both sexes (procedure 1).

-I p 6- Albino rats having a body weight of 180-240 g and with free access to standard rat feed and drinking water are used. For procedure A, the rats are Sprague Dawley progeny of the Tif:RAI strain and, for procedure B, are animals of the IVa-WI Wistar strain. The test compound is administered orally to groups of 8 to 10 rats, daily for 5 consecutive days, in a polyethylene glycol solution (average molecular weight: 400). Two hours after the final administration the animals, anaesthetised with ether, are sacrificed by being bled from the throat. For a period of 16 hours before being sacrificed the animals receive no more food. To the combined serum of 2 t6 3 rats there are added a 0.05 aqueous solution of ethylenediaminetetraacetic acid-and a 0.01 aqueous solution of thiomersal.

Using an ultracentrifuge, the serum lipoproteins are separated by centrifuging for 24 hours at 78 000 g, 78 000 g or 109 000 g in salt solutions with densities of 1.006 and 1.040, respectively, and are analysed enzymatically for their content of cholesterol and triglycerides S using test systems supplied, for example, by Sigma Chemical Co.

(St. Louis, MO, USA).

a* a a S The test for antibiotic activity is carried out, for example, on the one hand in vitro by determining the mean effective concentration EC5o for the inhibition of the RNA polymerase of Escherichia coli, as well as the minimum inhibitory concentration MIC in the conventional plate test, and, on the other hand, in vivo by determining the ED 5 a (effective dose that is life-preserving for 50 of the test animals) in infected mice and rats. The microorganisms used for this purpose are especially Mycobacterium tuberculosis TB H 3 7Rv and Staphy)ococcus aureus. When using S compounds having a lipid-lowering indication, an antibiotic activity is a, Sconsidered a disadvantage, as it can lead to the formation of strains of 0 *0 microorganisms that are resistant to antibiotics, especially in the case of long-term administration.

'I i i| C above-mentioned tests.

Thus, for example, it can be shown that, depending on the test procedure, Ithe minimum above-described test methods, the c ompounds o f the invention when administered repeatedly inthe dos age range of from about 0.1 to about 10 mg/kg, and above-mentionrase is still not attained with 00 g/ml, and the for various pathogenic strains of Staphylococcus aureus is higher than 130 pg/ml.

Thus, for example, iabout 000can be shown that, depending on the test procedure,mally required for a corresponding effect. Even under in vivo conditions using the inimum effective dose ofccus ure the compounds of the invention when antibiotic activity when administered in a single dose is from about to about 10 mg/kg, and this invention can be used, for example, as hypolipidaemic agents for the that aent 50-0 lowerlipidaeng of te LDL fraction can be achieved by repeaterid sclerosis, for example when hyperlipoproteinaemia is a risk factor.

Accordintration of 0 g/khe compounds of formula I and the pharmaceuticase have acceptable salts thereof can be used, for example, as pharmaceutical virtually no antibiotichypolactivity; an E nts for the i nhibition of hyper- S plymerase is still not attained with 100 mlb, and o and the Cfor variouss when hyperlipoproteinaemia is a risk factor. The invention further relates to pathogenic strains of Staphylococcus aureu is highe preparation of130 g/m medicamnts, especalues are about 10hypol0 times higher than ncentrations norallyle is required for a corresponding effect. Even under in vivo conditions using agmice infected wior thStaphyloeutic and prophylatic t he compoun exhibits nommeial antibiotic activity when administered in a single dose of 200 mg/kg. manuf Especiallycture on account f their LDL-lowering active subans al fals wity, the compund of this this invention can be used, r example, as hyplipidaemic agents for he treatment of hyperlipidaemiae, mainly of types Ha and lib, and arteriosclerosis, 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 hyper- J lipidaemiae, mainly of types Iha and lIb, and of arteriosclerosis when i hyperlipoproteinaemia is a risk factor. The invention further relates to S* the use oC the compounds of the invention for the preparation of medicamnts, especially hypolipidaemic agents and antiarteriosclerosis ji agents, and for therapeutic and prophylactic treatment. The commercial ,j manufacture of tha active substances also falls within the scope of this JE invention. j -8- The invention relates especially to compounds of formula I and salts thereof in which -A 3

A

4

-A

5

R

2

R

3 and R4 have the meanings given, X is or XN, alk is alkylene, R, is hydrogen or acyl, R 5 is hydrogen, cycloalkyl or aryl, and R 7 is hydrogen.

The invention relates especially to compounds of formula I and salts thereof in which -A 1

-A

2

-A

3 -A5-A 6

R

2

R

3 and R 4 have the meanings given, X is >C(R6) or \.-ard Rs is hydrogen or alkyl, alk is KJalkylene, alkenylene or alkynylene, the multiple bond being located in a position higher than the ca-position to the piperazine nitrogen (x Ris UnF'jbstituted or halo- or phenyl-substiue aknobnzy, naphthoyl or monocyclic 5- or 6-membered monoaza-, monooxa- or monothiaaroyl, alkoxycarbonyl, or aminocarbonyl that is unsubstituted or mono- or 72 :di--substitutl~d by alkyl, Rs is hydrogen, cycloal1kyl, cycloalkenyl, cycloalkynyl, phenyJ, biphenylyl, naphthyl, monocyclic 5- or 6-membered monoaza-, monrioxa- or monothia-aryl and R 7 is, hydrogen or alkyl, each of S the aromatir, radicals, independently of tht, others, being unsubstituted or mono- or poly-substituted by halogc,,-, alkyl, alkoxy, hydroxy, alkanoyloxy, -trifluoromethy. and/or nitro.

C The invention relates erpqcially to compounds of formula I and salts thereof in which -A 3 As-A6-, R2, R3 and R4 have the 9meanings given, X is C(R6) Or and RG is hydrogen or Cl-C7alkyl, alk is CI-Cl2alkyJlenet C3-C 7 alkenylene. Or~ 3-C 7 alkynylene, the multiple bond being located in a position higher than the a-position to the piperazine o nitrogen atom, RI is unsubstituted or halo- or phenyl-substituted. Cz-Csalkanoyl, benzoyl, naphthoyl or monocyclIc 5- or 6-membered monoaza-, moriooxa- or nonothia-aroyl, Ci-C 7 alkoxycarbonyl, or aminocarbonyl that is unsubstituted or mono- or di-substituted by Cl-C 7 alkyl, R5 is hydrogen, C3-Cicycloalkyl, C 3

-C

7 cycl.oalkenyl, C 3 -C7cycloal~ynyl, phenyl, biphenylyl, naphthyl., pyrroly]., N-Cl,-C7alk.ylpyxrrolyl, pyridy.., 1-oxidopyridyl, furyl or thienyl, and R 7 is hydrogen or C 1 7 alkyl, each of the aromatic -9radicals, independently of the others, being unsubstituted or mono- or poly-substituted by halogen, CI-C 7 alk CI-C 7 alkoxy, hydroxy, C 2 -Caalkanoyloxy, trifluoromethyl and/or nitro.

The inventiLon relates especially to compounds of, formula I and salts thereof in which -AI-A2-, -A 3 A4-, -A 5

R

3 and R4 have the meanings given, X is CH- or alk CI-O 7 alkylene, R 1 is

C

2

-C

8 alkanoyl that is unsubstituted or substituted by halogen or by phany. which may contain halogen, C 1

-C

7 alkyl, C1-C7alkoxy, hydroxy,

C

2 -Caalkanoyloxy, trifluoromethyl and/or nitro, unsubstituted or halo-, Ci-C 7 alkyl-, CI-C 7 alkoxy-, hydroxy-, C 2 -Coalkanoyloxy-, trifluoromethyland/or nitro-substituted benzoyl, naphthoyl or monocyclic 5- or 6-membered monoazao-, monooxa- or monothia-aroyl, Cl-C7alkoxycarbonyl, or t 4 aninocarbonyl that is unsubstituted or mono- or di-substituted by Ql-C7- *.:alkyl, R5 is hydrogen, C3-C 7 cycloalkyl, or phenyl, biphenylyl or naphthyl each of which is unsubstituted or mono- or poly-substituted by halogen, CVC7alkyl, Cl-C7alkoxy, hydroxy, C2-Cakanoyloxy, trifluoromethy.

and/or by nitro, and R 7 is hydrogen.

The invention relaes especially to compounds of formula I and salts thereof in which -Al-A 2

-A

3 -As-A6-1 R21 R3 and R4 have the meanings given, X is C(R6) or and R6 is hydrogen or 0 1 -G7alkyl, alk is Cl-Cl~alkylene, such as Cl-C7alkylene, C3-C 7 alkenylene or C 3 -C7alkynylene, the multiple bond being lo'cated in a position higher than the a-position to the piperazine nitrogen atom, Ri is hydrogen or 03-C$alkanoyl, Rs is hydrogen, G 3 -C7cycloalkyl, C3-C7cycjoalkenyl, or phenyl, biphenylyl, naphthyl, thienyl, furyl or pyridyl each of which is unsubstituted or substituted by halogen, CI-C7alkyl, CI-C7alkoxy and/or by trifluoronethyl, and R7 is hydrogen or Cl-C7alkyl.

The invention relates especially to compounds of formula I and salts thereof in which -Ai-A2-, -A 3

-A

4 -As-A6-, R3 and R4 have the meanings given, X is CH-~ >4 RI is C3-Csalkanoyl, especially pivaloyl, R2 is 09 acetyl, on the one hand alk is CI-C 7 alkylene, such as, 2-methyl--l,3propylene, and Rs is hydrogen, or o~n the other hand alk is Ca-C4alkylene, especially methylene, and R 5 is 03-C6cycloalkyl, such as cycl(.:hexyl, C3-C6,cycloalkerlyl, such as cyclohex-3-en-1-yl, unsubstituted or CI-C4alkyl-substituted, especially methyl-substituted, phenyl, such as or 2,4,6-trimethylphenyl, biphenylyl, such as 4-biphenylyl, naphthyl, such as 2-naphthyl, or thienyl, such as 2-thienyl, and R 7 is hydrogen or Cj~-C~.alkyl, such a..q methyl.

The invention relates especially to compounds of formula I and salts thereof in which -A 3

-A

5 R3 and R4 have the meanings given, Ri is hydrogen or C2-Cealkanoyl, especially branched C 3 -Cs alkanoyl, R 2 is acetyl1, X is allk is Cl-C7alkylene, especially Cl-Ct~alkylene, R5 is hydrogen, C 3 -C7cycloalkyl, or phenyl, biphenylyl or ,:naphthyl each of which is unsubstituted or mono- or poly-substitu.ted by Ci-CltalkYl or halogen, and R 7 is hydrogen.

f49The invention relates especially to compounds of formula I and salts 0 41 theireof in which the structural elements -Ai-A2-, -A 3 -A4- and -As-A6have the meanings given, Pq is branched, C3-Csalkanoyl, such as pivaloyl, is acetyl, R 3 and R4 have the meanings given, X is alk is Cv"C~alkylene, such as methylene, R 5 ts C3-C7cycloalkyl, such as cyclohexyl, C3-C7cycloalkenyl, such as cyclohex-3-en--yl, or phenyl mono- or poly-substituted, suach as di- or tri-substituted, by Ci-Calkyl, such as methyl, such as 2-methylphenyl, or 2, 6-dime thylphenyl or 2, 4 ,6-trimethylphenyl, and R 7 is on the one hand hydrogen, Or On the other hand Oi,-C. ilkyl, such as methyl, The invention relates especially to compounds of formula I and salts thereof in which the structural elements -At-Az-, -A3-A4- and -As-A6- and the variables RI and R have the meanings given, alk is Ci-Co.lkylenet such as methylene, 2,3-propylene or 2-methyl-1,3-propylene, Ri is hydrogen or branched C3-06alkanoyl, stV,ch as pivaloyl, Rz is acetyl, is R6 is hydrogen, CI-C~cycloalkyl, such asccoeyphanyl o 2',',6-tri-Cl-Gz~alkylphenyl, such as 2,4fi -Jan ethylphenyl, and R 7 is hydrogen.

The invention relates especially to compounds of formula I and salts thereof in which the structural elements -Al-A 2

-A

3 -A4- and -Aq-A 6 have the meanings given, X is R 2 is hydrogen or a~cetyl, R 3 and R 4 together are a bond, and on the one hand alk is CI-C~+alkylene, especially ?-methyl-1,3-propylene and Rs is hydrogen, or on the other hand alk is methylene and R5 is 2,4,6-tri-Ci--C4alkylphenyl, especially 2,4,6-trimethylphenyl, and R 7 is in each case hydrogeni.

The invention relates especially to compounds of formula I and salts thereof in which the structural elements -A 3 -A4- and -A 5 -Asa.'have the meanings given, X is R 2 is acetyl, R3 and R4 together 44 lylne are a bond or each is hydrogen, and on the one hand alk is Cj-~lyee especially 2-methyl-1,3-propylene, and R5 is hydrogen, or on the other **hand alk is methylene and Rs is 2,4,6-tri-Cl-C4alkylphenyl, especially off 2, 4, 6-t rime thylphenyl, and R7 is in each case C 1 -Cr~alkyl, such as methyl.

The inveintion relates especially to compounds of formula I and salts 44** thereof in which the structural elements -A 3 -A4- and -A5-A6- are each vinylene, or the elements -Ai-A 2

-A

3 -A4- are butA-It3-diorr-1,4-diy1 and -As-A 6 is ethylene, X is CHalk is Cl-Ct~alkylee, bpecially m retbylene or 2,3-propylene, RI is branched C 3 -Csalkanoyl, especially pivaloyl, R 2 is acetyl, R3 and R4 together are a bond and Rs is hydrogen, or also cyclohexyl or phenyl, and R7 is hydrogen.

The invention relates especially to compounds of formula I and salts thereof in 4hich the structuiral elements .T-Ai-A 2 -o -A3-A4- and -As-A6- are each vinylene, or the elements -Ai-Az-A 3 are buta-1,3-dienI-1,4-diy1 and -As-A6- is ethylene, X is >,Ri is hydrogen or branchrd C 1-C6 7 -2 alkanoyl, especially pivaloyl., R 2 is acetyl, R3 and R4. together are bond, alk is Ca-Ckalkyllane, eaopRcially 2-inethyl-1,3--propyl, and R(5 is.

hydrogen, o r alk is Ca-Ci~alkylene, especially methylene and R 5 is 2,4,6-tri-Cl-C~alkylphenyl, espatially 2,4,6-trimethyiphenyl, and R(7 i S hydrogen.

The invention relates especially to compounds of formula I and salts the~reof in which X is -Al-A 2 and -IA 3 -A4- are each ethylene and

-A

5

-A

6 is vinylene or ethylene, RI is branched C3-Csalkanoyl, especially pivaloyl, R2 is acetyl, R(3 and R4 together are a bond or each is hydrogen, on the one hapd alk is CI-C~al}kylene, espeq~ially methylene, and, R6 is 2,4,6-trimethylphenyl, or on the other hand al) s Cj-Ci~alkylene, espiecial2ly 2-methyl-1,3--propylene, and Rs is hydroget., and R 7 is *~hydrogon.

Vie invention relates especially to compounds of formula I and salts Sthereof in which -A 1

-A

3 -A4- and -As-As- are each ethylene~j X is Ri is pivaloyl, R 2 is acetyl, R3 and R4 together are a bond or each is hydrogen, alk-Rs is 2,4,6-trimethylbenzyl, and R(7 is hydrogen.

**The condititons of exclusion mentioned at the b _,inning apply also to the 00 above-defined compounds of formula I and salts ther'pof.

4 The invention relates especially to the novel compounds mentioned 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 carrie9d out in a manner known pgre n copies fo example, a) for the preparation of compounds of formula I th salts thereof in which X reprisen 's reacting a com pound of formula 'aj1 4 A1 V j 13 (Iha), or a salt thereof in hich X is with a compound of formula a a.

a a. a 9 a a a.

a, a, sa.

a.

a a.

a a a S a. a a a. a a~ a a..

9 a. a a a a a.

Z-alk-Rs (Irb) in which Z is reactive esterified hydroxy or b) for the preparation of compounds of formula I and salts thereof in which R 2 is acetyl and R3 and R 4 together are a bond, cycrlising a compound of formula 'jYH3 YJH3

YH

3

*R

2 0 5 H Aa 3 in which R1 is acyl and R'1 is hydrogen or acyl, or 2

I

14s A44 HjH 3H H 3 R0\

C

H

3 O H A z ~C0 (IV)

L

6 Ri 0 /~CH 3

H

3 and, if desired, converting a comrpound of formula I obtainable by the 4process or in another manner, or, a salt thereof, into a different compound of the invention or a salt thereof, or converting a free compound 0 of formula I obtainable by the process into a salt and/or a salt .:obtainable, by the process into the free compound o! formula I or intn a different salt and, if desired, separating a mixture of isomers obtainable in accordance with the process.

,Salts of the starting materials of formulae Ila and III that conta Ilzz k, acid phenolic hydr6xy group are corresponding salts w3,th bases of the kind indicatedI hereinbefore, whereas starting compoun~ds of formula Ilb *~:that, have one or 1-wo basic centres can form correspondinZ acid ad~dition salts similar to the acid addition salts of formula I.

Reactive esterif ied hydroxy, for example Z, is specially hildroxy esterified withi a strong inorganic acid or organic sulfonic acid, and is, for examiple, ha. ogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxyt hal~osulf onyloxy, for example fluorosulfonyl- :oxy, Cj-C, alkanesulfonyloxy that is unsubstx'tubed or substituted, for example, by halogen, for example methanesulfomyloxy or trifluoromethanesulfonyloxy, Ct-C 7 cycloalkanesulfonyloxy, for example cyclohexanesulforqrloxy, or benzenesulfonyloxy that is umsubstituted or substituted, for example, by C 1 -C7alkyl or halogen, for example p-bromobenzenesulfonyloxy or p-troluenesulfonyloxy.

0 15 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 dilusnt or a mixture thereof, the process being carried out, as required, with ciooling, at room temperature or with heating, for example in a temperattie range of approximately from -800 to the boiling temperature of the reaction medium, preferably from about -10° to about +180'C and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

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

S* 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 r example tri-lower alkylamines, basic heterocycles and carbocyclic amines, S such as ethyl diisopropylamine, triethylamine, pyridine, bicyclo[ 4 .3.0]non-5-ene (D3N), as well as 1,8-diazabicyclo[5.4.0]undec- S 7-ene (DBU).

The starting material of formula HIa can be prepared in a manner known S er se, for example by the reaction of 3-halo-rifamycin S with piperazine protected in position 4 (for example analogously to U 4 005 077), subsequent acylation to corresponding 1-0-acyl- or 1,8-di-C ,acyl-rifamycin S SV derivatives, and cyclisation in accordance with Variant Finally, the protecting group is removed.

S*.

*a Variant b): R! and R' are each acyl, especially pivaloyl.

i alkynylene, the multiple bonds preferably being located in a position jhigher than the a-position to the piperazine nitrogen atom (X in i u Tsaturated radicals.

a 16 The cyclisation of compounds of formula III is advantageously carried out with heating, for example in a temperature range of approximately from to the boiling temperature of the reaction system, for example up to approximately 180 0 C, such as in a temperature range of from approximately 1000 to approximately 170 0

C.

The cyclisation of compounds of formula III for example in which the structural elements -Ai-AZ-, -A 3 -A4- and -As-As- are each ethylene, can of course also be carried out at room temperature.

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 amine of formula SHN >-alk-R (Ia).

The reaction is carried out especially with an excess of the amine of Sformula IIIa, for example in a temperature range of from about 0' to about 100C, a mixture of the quinone and hydroquinone form being formed.

This mixture can be converted into the corresponding hydroquinone (RI H) (derivative of rifamycin SV) by reduction, for example by S catalytic hydrogenation. 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 n n Voon which Ri is acyl and is hydrogen or RI and R' are acyl can be obtained. If the structural elements -Ai-A 2

-A

3 -A4- and are each vinylene, such compounds can be converted (also at the precursor rtage), for example by catalytic hydrogenation, in each case depending on lo: the choice of reducing agents and take up of the H2 equivalents, into the corresponding tetrahydro form (-AI-A 2 and -A 3 -A4- are each ethylene and i As-As is vinylene) or hoxahydro form (-A 1 -A2- and -A 3 -A4- and -As-AG- are each ethylene).

-1 i l 1 1 The general definitions used hereinbefore and hereinafter have, unless defined otherwise, especially the following meanings: 0

I

,'i 7~ 7';-i I, 1 i 17 r

J

i I :t i 1~

S

Variant c): The cyclisatkon is carried out especially by heating or irradiating the starting material.

The reaction is preferably carried out 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 or pyridine.

If the reaction temperature is too low, the reaction proceeds very slowly, but at too high a temperature a considerab t proportion of undesired side-products are produced. A suitable Vbinperature range is, 0• for example, from about 50° to about 90°C, the temperature preferably S being about 750C.

I

C

@4 *c19 *1 p Ce *i C CC 4 *C c: The irradiation is carried out in a manner known per se, for example using conventional radiation sources, such as microwave radiation.

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 y H1 YH 3 R 2 0 \H L (IVa) I1i cyclobut-2-en-1-yl, cyclobut-1,3-dien-1-yl, cyclopent-2-en-1-yl, -3-en-l-yl, -2,4-dien-1-yl, cyclohex-2-en-1-yl, -3-en-l-yl or -2,4-dien- 1-yl, -1,3-dien-1-yl or -2,'5-dien-l-yl, or also a corresponding cycloheptenyl radical.

Ii ~d V ;a Irr~l~ I 18 with an acylating agent with which the triacetyl group can be introduced into positions 8 and 14, such as pivaloyl chloride.

The invention relates also to the novel compounds obtainable in accordance with the above 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 the structural elements -Ai-A2-, -A3-A4and -A 5 -A6 are each vinylene, or -A 1

-A

2 and -A 3 -A4- are each ethylene and -As-A6- is vinylene, can be converted by reduction, for example by catalytic hydrogenation, into the corresponding tetrahydro (-AI-A 2 and t* -A3-A 4 are each ethylene and -As-As- is vinylene) or the corresponding hexahydro derivatives -A 3 -A4- and -As-As- are each ethylene).

S The hydrogenation of the multiple bonds is, for example, carried out in the presence of hydrogenation catalysts, there being suitable for this purpose, for example, noble metals or derivatives thereof, for example S" oxides, such a* nickel, Raney nickel, palladium, platinum oxide, which if appropriate can be carried on a substrate, for example on carbon or calcium carbonate. For homogeneous catalysis, the catalysts used are especially also complex rhodium compounds, for example tris-(triphenyl- 4 phosphine)-rhodium(I) chloride. The hydrogenation may be carried out especially at pressures of from 1 to approximately 100 at. The corresponding hexahydro derivatives can be further hydrogenated by catalytic hydrogenation to form octahydro derivatives of formula I in which R 3 and R4 are each hydrogen. If R 3 and RI together are a bond, this double bond can also be hydrogenated selectively in the presence of further double bonds in the Ansa ring using a suitable hydride, especially sodium borohydride. The reaction conditions may be so selected that first of all 16,17,18,19-tetrahydro derivatives are obtained (catalyst, for example Pd/C) and from these, or from correspondingly unsaturated starting materials, the 16,17,18,19,28,29-hexahydro compounds can be obtained directly and then convertedto the corresponding octahydro derivatives by the absorption of a further Hz equivalent (catalyst, for example, PtO 2 '1 '2

L

4 i out on mammals, for example rats. Thus, the lowering of very low density, low density and high density li iproteins (VLDL, LDL and HDL) in serum can be demonstrated io two test procedures, in male rats with genetic hypercholesterolaemia (procedure A) and in normolipaemic rats of both sexes (procedure 19 compounds of formula in which R3 and R4 are each hydrgen, for example

-I

Irrespective of the degree of hysrogenation of the structural elementsNaH

-A-A

2

-A

3 -A it is possible for compounds of formula I in radicals (alk or Rs) to be hydrogenated simultaneously during the hydrogenation reaction. In order to avoid undesirable side reactions, it is advantageous to use correspondingly hydrogenated compounds of formula IIa as starting materials and proceed in accordance with Variant a).

If alk and the cycloaliphatic hydrocarbon radical R5 in compounds of formula are unsaturated hydrocarbon radicals, the multiple bonds can *0 be saturated in a manner known per se. The hydrogenation of multiple bonds is effected, for example, by cat c atalytic hydrogenation in the S" presence of hydrogenation catalysts, thfre being suitable for this 4* purpose, for example, noble metals and derivatives thereof, for example *a oxides, such as nickel, Raney nickel, palladium, platinum oxide, which may, if desired, be carried on a substrate, for example carbon or calcium carbonate. The hydrogenation can be carried out preferably at pressures S* of from 1 to approximately 100 at.

SCompounds of formula I in which R is hydrogen can be acylated in a ,o 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 6 i a formic acid ester, an activated carboxylic acid ester, such as cyanomethyl ester, nitrophenyl ester, or a polyhalophenyl ester, for example pentachlorophen l ester. The reaction with the carboxylic acid or a salt thereof is advantageously 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 c i4 Y' iuc an fo i 'pl aci choie ^anyrds 20 out in the presence of a base. Similarly, the acetyl radical Rz 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 RI can be replaced by hydrogen by treatment with strong bases, such as alkali metal hydroxides. The acyl radical R 1 can also 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 .t se. Thus, for example, acid addition salts of compounds of formula (I) are obtained by treatment with an acid or with a suitable ion exchange reagent. Salts can be converted in customary manner into the free S compounds; acid addition salts, for example, by treatment with a suitable g o* basic agent.

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

ft.

i Owing to the close relationship between the novel compounds in free form S' and in the form of their salts, hereinbefore and hereinafter references to free compounds or their salts .;hall also, where appropriate with regard to context, include the corresponding salts or free compounds *t ft respectively.

The novel compounds, including the salts in the case of salt-forming compounds thereof, 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 4A v r I: I *r 4 9c 09 99 9 9: 9 .94, i4 9 9 9 94 99 9,49 94 9 9 9* 9u 9 *9 9 9* 21 asymmetric carbon atoms they may be in the form of pure optical isomers, such as antipodes, or in the form of mixtures of isomers, such as racemates, mixtures of diastereoisomers or mixtures of racemates.

Resulting mixtures of racemates can be separated in known marner 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 diastereo'isomeric salts, for example by reaction of a basic end product racemate with an optically active acid, such as a carboxylic acid, for example tartatic 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 enantiomer can be freed by the action of suitable agents. It is advantageous to isolate the more active enantiomer.

When the Ci6-C17- and Clo-C 19 -double bonds (-AI-A2- and -A 3 ethylene) are hydrogenated an additional asymmetrically substituted C-atom (C-16) results. Accordingly there exist in addition two different stereoisomeric arrangements at the C-16 atom, the R- and S-configuration, respectively, according to the Cahn-Ingold-Prelog nomenclature system.

The hydrogenation of the 1-deoxy-15-deoxo-l,15-oxy-rifamycins proceeds practically stereospecifically with respect to C-16. To obtain the other stereoisomeric form with respect to C-16, it is necessary, for example, to start from corresponding hydro derivatives of formula III in which Ri and Rj are hydrogen, to separate the stereoisomoric forms concerned,

V~

h! 1* -22 for example by conventional chromatographic methods, and 'hn to acylate accordingly the so-obtainable compounds of formula III and carry out the i cyclisation, for example in accordance with Variant b).

On the basis of the investigations in the test procedure described at the beginning for determining the lipid-lowering properties of the compounds of the invention, it was ascertained that one of the two possible stereoisomeric arrangements with respect to C-16 is responsible for an especially high degree of inhibition of the level of cholesterol. It has not until now been possible to ascertain the absolute configuration at C-16 for these stereoisomers.

i o* Accordingly, the present invention relates especially to the compounds of formula I described at the beginning and in the Examples, and the salts Sthereof, in which there is such a stereoisomeric arrangement at C-16.

*e 9* 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 diastereoisomers, racemates or antipodes or, especially, is formed under the reaction conditions.

The reaction product is isolated from the reaction mixture obtainable in accordance with the process and worked up in a manner known per se, for example by dilution with water, and/or optionally by neutralisation or slight acidification (up to approximately pH 3) with an aqueous acid, such as an inorganic or organic acid, for example a mineral acid or, advantageously, cittic aci), and addition of a water-immiscible solvent, such as a chlorinated hydrocarbon, for example chloroform or inethylene chloride, the reaction product changing into the organic phase from which it can be obtained in purified form in conventional manner, for example by drying, concentration of the solvent by evaporation, and crystalli- i! sation and/or chromatography of the residue, or by other conventional purification methods. If the above reaction results, for example, in a mixture of acylated compounds or diastereoisomeric forms, this can be 1 -ii i i.

i 23 resolved in a manner known per se, for example by means of fractional crystallisation, chromatography etc. into the desired individual acyl compounds or diaste'eoisomeric forms, respectively.

In the process of this invention it is preferred to use those starting materials that lead to the compounds 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 AI-A2,

A

3 'As-A 6 R R 2 R, R4, Rs, Rs, X and alk having the meanings given for the respective preferred compound groups 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 combination with other active substances, as agents for the therapeutic S, treatment, that is 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 50, mg/kg of body weight, which doses may be exceeded in acute cases, are administered to warm-'looded animals. The e.

invention also relates by analogy to the corresponding method of medical F treatment.

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

i 24 The pharmaceutical preparations of the invention, which 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 daily dose of the active ingredient depends on age and individual condition and also on the mode of administration.

The novel pharmaceutical preparations contain, for example, from about to about 80 preferably from about 20 to about 60 of the active ingredient, Pharmaceutical preparations of the invention for Senteral or parenteral administration are, for example, those in dosage Sunit forms, such as drag6es, 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, o confectioning, dissolving or lyophilising methods. For example, pharmaceutical preparations for oral administration can be obtained by S 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 adjunctst to form S* tablets or dragee cor; 4 oi Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or S calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, maize, 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 algini, acid or a salt thereof, such as sodium alginate. Adjuncts are especially solvents, flow-regulating agents and lubricants, for example silicic acid, 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, polyvinyl- 25 pyrrolidone, 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 drag6e 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-fill 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 S 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.

*a Suitable rectally administrable pharmaceutical preparations are, for o.,as example, suppositories that consist of a combination of the active S* ingredient with a suppository base matorial. Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possiblk to use gelatin rectal capsules that contain a combination of the active ingredient with a base material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydro- 44 carbons.

There are suitable for parenteral administration especially aqueous solutions of an active ingredient in water-soluble form, for example a water-4oluble salt, and also suspensions of the active ingredient, such as corresponding oil' 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 tri- i glycerides, are used, or aqueous injection suspensions that contain I i i I 1 which X represenvs NN-, reacting a compound of formula 0 ''E Al visco sity-inc rea sing substances, for example sodium carboxymethylcellulose, sorhPitol and/or dextran, and, where appropriate, also The dosage of the active ingredient depends on the species of warmblooded animal, the age and individual condition, as well as on the mode of administration. Normally, in the case of oral admi,nistration an approximate daily dose of about 150 mg to about 1500 mg, advantagerusly in several equal partial doses, will be admintstered to a warm-blooded animal weighing about 75 kg, The following Exa,,.ples illustrate the :above-described it~vention, b~t in no w ,y limi~t the scope thereof. Temperatures are in degrees Celsius. The SNMR spectra were advantageovsly, taken at elevated temperatures I espec- 4A~: ially at abou t 80 0 C. in DMSO; the chemical shifts of the signal,- are gVen in ppm.

chemical namne of the basic structure from which the rifamycin derivativL- of the present invenition are derived Is as follows: 1-deoxy-15deoxco-1,15-oxy-r'Ifamycin, and the associated structural formula may be :0"V illustrated as follows: YH 3 YH3 YH 3

H

3 C-'0 6 33 N 25 1 I I 0 647 CHH1 34 4~ 3.

13r 11 i 1.1 27 t

I

I

8 ~W 89 8 *8* 89 88 9 9889 88 98 9 a 8 88 98 9 8 84 8 i 9, 8 8 9 4~ 8 8** 8 4 88 84 9~ 8 Eaml, A solution of 2 g of 8-0-pivaloyl-l-deoxy-15-deoxo-1,l5-oxy- 3-14-(2,4,6-trimethylbenzyl)-piperazin-1-yll-rifamycin of formula I in which the structural elements "A-A 2

-A

3 -A4- and -A 5 AG- are each vinylene, X is X Ialk is methylene, R, is pivaloyl, R 2 is acetyl,

R

3 and R4 together are a bond and Rs is 2,4,6-trimethylphenyl and R7 is hydrogen is hydrogenated in 100 ml of ethanol in the presence of 0.2 g of palladium on carbon (10 at 250 and normal pressure until the absorption of hydrogen is complete. The catalyst is then removed by filtration and the solvent is concentrated by evaporation under vacuum.

The dark red residue is chromatographed on 200 g of silica gel with the eluant petroleum ether/ethyl acetate Two rapidly migrating redcoloured bands, followed by one strong red main band, are observed, The eluate of this red main band is collected. and concentrat ed by evaporation. The residue consists of epimerically pure 16,17,18,19-tetrahydro-8-0-pivaloyl-l-deoxy-15-deoxo-1 ,15-oxy-3-14-(2 6-trimethylbenzyl)-piperazin-1-yl]-rifamycin of formula I in which the structural elements -AI-A and -A-j-A4- are each ethylene and is ethylene, X is N alk is methylenev R, is pivaloyl, R2 is acetyl, R3a and R4 together are a bond, R 5 is 2, 4,6- trime thylphenyl and R7 is h"ydrogen.

C561177N301; 'MOl, Wt.: 983 (found, MS), 'H-NU{R (360 MHz, DMSO): signal for CH 3 -30 at 1.4 ppm 3H).

3u I 0, \N1 N$ N>-CI12- 3 ii The starting A mixtur~e ofc4 r ,famycin SV rilamycin SV material can be pr~epared as follows! 5 g of 3- 4, 6-t rime thylbenzyl) -piLperaz in-I -yl] [cf. EP 244 398, Example 2; the preparation of other compounds used 'in tlie following Examples is desuribed, for S; 28 Qexample, in US 4 005 077], 50 ml of dry pyridine and 4.5 ml of pivaloyl I chloride is kept at 50°C for 30 minutes. The solvent is theii removed by evaporation under, vacuum. The oily residue is dissolved in ethyl acetate and the solution is washed with 2N hydrochloric acid, with e 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/hT--ne, yielding 1,8-di-0-pivaloyl-3- [4-(2,4,6-trimethylbenzyl)-piperazin-1-yl]-rifamycin SV with a melting point of 203-204°C.

C6hlie3N3014; mol. wt.: 1081 (found, MS) The 1,8-di-0-pivaloyl compounds used in the following Examples can be S. prepared in an analogous manner.

g of 1,8-di-0-pivaloyl-3-[ 4-(2,4,6-trimethylbenzyl)-piperazin-1-yl]rifamycin SV are dissolved with the application of heat in 1000 ml of 0 hl 2-methoxyethanol and refluxed under nitrogen for 5 hours. The solvent is r i then concentrated by evaporation in vacuo and the residue is crystallised twice from methanol. 8-0-pivaloyl-l, deoxy-15-deoxo- 15--oxy-3-[4-(2,4,6trimethylbenzyl)-piperazin-l-yl]-Eifamycin of formula I in which the *n structural elements -A3-A4- and -As-A6- are each vinylene, X is alk is methylene, R is pivaloyl, R2 is acetyl, Ra and R4 S together are a bond, R is 2,4, 6-trimethylphenyl and R7 is hydrogen, is hobtained. M.p. 160-165° (crystallisation from ethanol).

C56H73N3012; M 979, found 979; 1H-NMR (360 MHz, CDCLa, TMS): t r1.49 9H, pivaloyl at 0-8).

uExample 2 A solution of 1 0 g of the target product of Example 1 in 800 ml of ethanol is hydrogenated for 1 hour in the presence of 1.2 g of sulfuric acid and 1 g of Pt2O at 25°C and normal pressure. After that time 1 equivalent of hydrogen (230 ml) has been taken up. The catalyst is removed by filtration, the filtrate is neutralised by the addition of aqueous sodium bicarbonate solution, a saturated solution of sodium chloride is added and the hydrogenation product is extracted by repeated shaking with ethyl acetate. After-dying and concentrating the ethyl i i 11 1 -29acetate extract by evaporation, the residue is purified t y chrcLe',togr,7prhy 4 in the manner described in Example 1 The red material obtained in the" strong main band is epimerically pure 16,17,18,19,28,29-hexsahydro-8-0pivaloyl- 1-deoxy- 1 5-deoxo-1, 1 5-oxy- 3- 4- 2, 4, 6- trime thylben zyl) piperazin-1-yl]-rifamycin of formula I in which the structural elements -Al-A 2

-A

3 -A4- and -As-A6- are each ethylene, X is >,alk is methylene, R, is pivaloyl, R 2 is acetyl, R 3 and R4. together are a bond, Rs is 2, 4 6-t rime thylphenyl and R 7 is hydrogen. C56H 7 9

N

3

O

1 2 Mo1. Wt-: 985 (found, MS, FD). 1H-NMR (360 MHz, DMS0): all signals of vinylic protons'have disappeared.

H C O

H

3 jll3

YH

3

H

3 CO i !HI 4 t 4 *~CH 3

~H

3 C\ A Ii 3

C\

H

3

H

3

C~

6o Excample 3: In a manner analogous, for example, to that described in Example 2, 5 g of 8-0-pivaloyl-l-deoxy-1 5-deoxo-1 ,15-oxy-3-E 2,4,6trimethylbenzyl)-piperazin-1--yl]-rifamycin of formula I in which the structural elements -A 1

-A

3 -A4- and -A 5 -AG- are each vinylene, X is alk is methylene, R 1 is pivaioyl, R 2 is acetyl, R3 afid R4 together are a bond, R 5 is 2,4,6-t rime thyiphenyl and, R7 is hydroge-n are Sdissolved in 500 ml. of ethanol and hydrogenated in the presence oE 0.5 g of PtO2, and 0.7 g of sulfuric acid at room temperature and norm4 pressure until 4 equivalents of hydrogen (-~460 ml) have been taken up.

The catalyst is removed by filtration, the filtrate is neutralised by aqueous sodium bicarbonate solution, a saturated solution of sodium chloride is added and the hydrogenation product is extracted by repeated shaking with ethyl acetate. After dryi.-g, and concentrating the ethyl acetate extract by evaporat~on, the residue is dissolved in ether. After each ethylene).

rfmcno fomlIinwihtesrcua elmet -A rstain forc somer ie N,15,16,17,8,19,28rom-ethdrormcolourlys pifamycins ofl fra I2- o in dwh chothestutrlo lmntn).- 2 and -As- 6 -arM01 eahWthylne 98 isond aS, ismehyee).i 0 YH3 YH3 ?113

H

3

H

3 CO cH 113,- C\ H3 113 H 3

C~

SExample 4: In a manner analogous, for example, to that described in 2 Example 1 in the manufacture of the starting material, there is obtained from 1 ,8-di-0-pivaloyl-3-f,4-(l-naphthyl-methyl)-piperazin-1-yl]-rifamycin SV by heating for 5 hours in 2-methoxyethanol, deoxo-1 ,15-oxy-3-[4-(1-na'phthyl-methyl)-piperazin-1-yl]-nifamycim of formula I in which the structural elements -Al-Az-, -A 3 and -A-Aare each vinylene, X is alk is methylene, R 1 is pivaloyl, R2 is acetyl, R3 and R4 together are a bond, Rs is 1-naphthyl and R7 is hydrogen, which crystallises from methanol/water in the form of red crystals. H.p. 207'.

C

57

H

69

N

3 0 12 Mo1. Wt-: 987 (found, MS, F49).

-31-

H

3 Y~H3cYH3K R* CH3 3 Example 5: in a manner analogous, for example, to that described in Exi'ile 1 in the manufacture of the starting material, there is obtained $04 piva),oyl-1-deoxy-15-deoxoi 15-oxy-3-(4-isobutyl-l-piperazinyl)-rifamycinl of formula I in which the structural elements -Al-A 2

-A

3 -A4- and 5

-A

6 are each vinylene, X is N alk is 2-methyl=.1,3-propylene, RI is pivaloyl, R 2 is acetyl, R3 and R4 together are a bond, and R5 and

R

7 are hydrogen, having a melting point of 187-188' (crystallised from :methanol/water), Qs CoHiN 3 0 1 2 MOl, Wt-: 903 (found, MS, FD). IHNM (360 "iz, ODC1 3 signals of the isobutyl group at 0.92 (6H1, (Cii 3 )2ClJ); 2.16 2H1, CHzN).

\o/ H307\2C:H:;, _3H301 YR1 CU 3 H13 Example 6: In a manner analdgolus, for example, to that described in Example 3, hydrogenation of 8-0-pivaloyl-l-deoxy'15-d60x0-l,15-oxy-3-( 4 isobu tyl-I -pipe razinyl) -rifamyc in of formula I in which the structural -32elements -A 1

-A

3 -A4- and -As--A 6 are each vinylei~j, X is N, alk is 2-methyl-1,3-propylene, R 1 is pivaloyl, R 2 is acetyl, R 3 and R4 together are a bond, and R 5 and R 7 are hydrogen, with PtO 2 in ethanol with the addition of sulfuric acid, yields N,15,16,17,18,19,28,29-octahydro-8-0-pivaloyl-deoxy-15-deoxo-1 ,1 5-oxy-3-(4-isobutyl-1pipe razinyl),-rif amycin of formula I in which the structural elements -Ai-A 2

-A

3

-A

4 and -As-A 6 are each ethylene, X i's R, is pivaloyl, R 2 is acetyl, R 3 and R4 are eac,> hydrogen, R 5 and R 7 are hydrogen, and alk is 2-methyl-i ,3-propylene. Recrystallisation of the faintly reddish coloured crystals from hexane yields colourless square platelets melting at from 150 to 160%0.

C s oH 7 7

N

3 0 1 2 mol M1-Wt: 911 (found, MS, FD).

*3 Example 7: In a manner analogous, for example, to that described in Example I in the manufacture of the starting material, there is obtained from 1 8-di-O-pivaloyl- 3- [4-(4-pbenylbenzyl) -1 -pipe ra zinyl]I-rif amycin SV by heating for 5 hours in 2-methoxyethanol under nitrogen, 1-cdeoxy-15-deoxo-1 ,15-oxy-3-14-(4-phenylbenzyl)-l-piperazinyl)-rifamycin of formula I in which the structural elements, -Al-Az-, -A 3

-A

4 and -As-A6- are each vinylene, X is RN-, alk is methylene, R, is pivaloyl, R2 is acetyl, R3 and R4 together are a bond, R5, Ls 4-bipheriylyl and R 7 i S hydrogen. The compound crystallises from hexane/ether in the form of red Ar crystals that melt from 140'.

C59H 7 1N 3 Oiz; Mo1. Wt.: 1013 (found, MS, FAB).

Example 8: A 5 methanolic solution of NaBHi. is added dropwise to a solution, in 20 ml of methanol, of 1 g of 16,17,18,19-tetrnhydro-8-0pivaloyl-1-deoxy-15-deoxo-1 ,15-oxy-3-[4-(2,4,6-trimethylbenzyl)-1pipe raz inyl) -rif amycin ofT formula I in which the structural elements -Aa-A2-, -A 3 -A4- are each ethylene and -AS-As- is vinylene, X is>alk is methylene, R1 is pivaloyl, R2 is acetyl, R3 and R4 together are a bond, R5 is 2, 4,6- trime thylphenyl and R 7 is hydrogen, until the reaction solution has lost its red colour. The reaction solution is then acidified a salt thereof is advantageously carried 'out with removal of water, for 4 example azeotropic. removal of the water of reaction, or by treatment with h a suitable condensing agent, for example N,N'Tdicyclohexylcarbodiimide.

The reaction with a reactive acid derivative is- advantageously carrlhed 33 wit aqeu4sobcaistrtd alslto sadd stutua el nt 44,A2 an-A r ahehln n A5- is with yleus a~ scorbicyacid, Rste iall soluion iseyl adde, a nl the areacon prouct iaken up is2wit re tlcete.fewahnteehy Eaetae extac with bufe solutdHios pdded, ding overrnt Nasolutiand cncentringo teetylacetaae extac bml oeaoaio, of 5,1171of9 hahro8-0-pivaoy1-1 -de oxy- 1 5-de oxo- 1 5-oxy 24, 6-t riimethylbe y)bn-1pipe razinyl -rif amyc in of formula I isotne in which thestuurlemns strctal- eleme- ns -AS-Ar,- ade-each are eachXethylene and-A-s is vnlekismethylene, R is pivaloyl, R 2 is acetyl, R13 a. nd R4 oehrar od Reahh~rgnadR is 2,44,6-t rime thylphenyl adR (ddyw reatio soluti6.3o(d Is H-29)ie wonly 2sgalseofs vinyric proton slft;n 5.79 wase and H-satu1.39ed auover matl sltio ar, added3.Te reamtle 9:xur 0. i fsoi aken isaed with stycttirrng to axtsoluio ith offerahydouraon o H7 re vrX and 100oncfeethnolaot5edo yildn Opiaol1-dyr--piallldeoxy-1 5-deoxo-1 4 -riehybyl-4trmthlzy)lpiperaziny~l)-rifamycin of formula I in which the srcua liet structal lms-iA-, -A 3 and~ -As-A 6 are each v nylene, Xi 1,aki X sXaki methylenfe, RI is pivaloyl, R is acetyl, R 3 adRtgheaR a bndR are a IR 5 yrgadR is 2,-rmt ey and 6-t ie hyogen AfTe 10umintne them .pale-yellowis rea tn soluing is acliiie woith aquou Csolution, and wat. and satund, aqeS, FD). soluion are0 added 5,7 J -34.

Example 10:In a manner analogous, for example, to that described in Example I in the manufacture of the starting material, there is obtained from 1 ,8-di-0-pivaloyl-3-[4-(2 rifamycin, 8-0-pivaloyl-l-deoxy-15-deoxo-l ,15-oxy-3-[4-(2 benzyl)-l-pliperazinylll-rifainycin'of formula I in which the structural elements -Aa-Az-, -A 3 aqnd -As-A 6 are each vinylene, X is Ialk is methylene, Ri. is pivaloyl, R2 is acetyl, R 3 and R4 together are a bond, R 5 is 2,5-dimethylphenyl and is hydrogen, m.p. 2200 (crystqllised from methanol).

C

5

SH

7 jN30a 2 mol. wt.: 965 (found, MS, DCI). 'H-NM{R spectrum (3 O MHz, DMSO-d6): signals of the 2,5-dimethylbenzyl group at 3.48 (-1-,2.27 and 2.32 (arom. CHOla as well as 7.09 (1 arom. H) and 7.0 (centr. AB, S2 arom. H) ppm.

g's Exaimple 11: In a manner analogous, for example, to that described in o *Example 1 in the manufacture of the starting material, there is obtained *from 1 ,8-di-0-pivaloyl-3-(4-benzyl-1-piperazinyl)-rifamycin, 8-0-pivaloyl-l-deoxy-15-deoxlo-1 ,15-oxy-3-(4-benzyl-1-piperazinyt)- :rifamycin of formula I in which the structural elements -A 1 -A2-, -A3-Aic- and -As-AG- are each vinylene, X is XR 1 is pivaloyl, is 4 acetyl, R3 and R4 together are a bond, alk is methylene, R5 is phenyl and 0 s R 7 is hydrogen. The compound crystallises from methanol/water in the form of thin crystalline platelets that melt at fromi 181-182'.

C53H6 7

N

3 0 1 2; M0o1. Wt-: 937 (found, MS, FAB).

*.:Example 12:. In a manner analogous, for example, to that described in Exanple 1 in the manufacture of the starting material, there is obtained from 1 ,8-di--pivaloyl3-(4-cyclohexylmethyl--piperazinyl)rifamycin, 8-0-pivaloyl-1-deoxy-15-deoxo-1 ,15-oxy-3-(4-cyclohexylmethyl-lpiperazinyl)-rifamycin of formula I in which the structur~al elements -Ai-A2-, -Ai-A4- and -A6-A6- are each vinylene, X is X ,alk is methyl.ene., R, is pivaloyl, R 2 is acetyl, R3 and R4. together are a. bond, Rs is cyclohexyl and R 7 is hydrogen. The compound crystallises from methanol in the form of platelets that melt at from 155-156'.

to start from corresponding hydro derivatives of formula III in which Ri and R'1 are hydrogen, to separate the stereoisomeric forms concerned,

I,

C

53

H

73

N

3 0 12 mol. wt.: 943 (found, MS, DCI).

Example 13: In a manner analogous, for example, to that described in Example 1 in the manufacture of the starting material, there is obtained from 1 ,8-di-0-pivaloyl-3-[4-(cyclohex-3-en-1-ylmethyl)-1-piperazinyl)rifamycin SV, 8-0-pivaloyl-l-deoxy-15-deoxo-1,15-oxy-3-[4-(cyclohex-3-en- 1-ylmethyl)-1-piperainyl)-rifamycin of formula I in which the structural elements -A 1

-A

2

-A

3 -A4- and -As-A 6 are each vinylene, X is alk is methylene, KR is pivaloyl, R 2 is acetyl, R3 and R4 together are a bond, R 5 is cyclohex-3-enl-yl and R 7 is hydrogen. The compound crystallises from methanol in the form of rhomboidal platelets, which with previous sintering melt at ~165'.

r C53H 7 1

N

3 0 1 2 mol. wt.: 941 (found, MS, DCI).

8H-NMR (360 MHz, DMSO-d6): 5.66 2H, 2 olef. H in cyclohexene), 2.26 N-CH2-CH overlayered with s at 2.24 of CH3-30) ppm.

The starting material can be prepared as follows: a) 2 g of N-(cyclohex-3-en-1-ylmethylethy)-piperazine are added to a solution of 5 g of 3-bromorifamycin S in 50 ml of tetrahydrofuran and left to stand for 30 minutes at 20'. The whole is then acidified by the addition of aqueous citric acid solution and the reaction product is taken up in ethyl acetate. Drying and concentration of the ethyl acetate extract by evaporation yields a dark residue. This is dissolved in methanol and aqueous ascorbic acid solution is added dropwise thereto, The solution o •turns yellow during the course of this and, after a short period, 3-[4- (cyclohex-3-en-1-ylmethyl)-piperazin-1-yll-rifamycin SV precipitates in the form of yellow-coloured crystals that melt at 170-172, b) A mixture of 5 g of 3-[4-(cyclohex-3-en-1-ylmethyl)-piperazin-1-yl]rifamycin SV, 50 ml of dry pyridine and 4.5 ml of pivaloyl chloride is iL' heated at 500 for 30 minutes. The solvent is then evaporated in vacuo.

The oily residue is dissolved in ethyl acetate and washed with 2N hydrochloric acid, with buffer solution of pH 7 and wi' h a solution of sodium chloride, After drying and concentrating by evaporation, a yellow residue l m n l Im mmi 4 -36of crude 1 ,8-di-O-pivaloyj.-3-[4-(cyclohex-3-en-l-vlmethyl)-lpiperazinyl]-rifamycin SV is obtained, which is further processed without being further purified.

Example 14: A methanolic solutioii of 8-O-pivaloyl-l-deoxy-15-deoxo-1,15oxy-3-[4-(2,4,6-trimethylbenzyl)-l-piperazinyl]-N,15,16,17,18,19,28,29octahydrorifamycin of formula I in which the structural elements -Ai-A 2

-A

3 -A4- and -AS-A 6 are each ethylene, X is alk is methylene, R, is pivaloyl, R2 is acetyl, R 3 R4 and R7 are each hydrogen and Rs is 2,4,6-trimethylphenyl (target product of Example 3) is acidified with excess aqueous solution of L(+)-ascorbiQ acid, diluted Swith a large amount of water and extracted by shaking with ethyl acetate.

4 In the course of this, the ascorbic acid salt of the octahydro derivative passes into the ethyl acetate phase. After drying over Na2SO 4 and concen- Strating the ethyl acetate solution by evaporation, the ascorbate of *pipe razinyl 15, 16,17,18,19, 28, 29-octahydrorif amycin of formula I in which the structural elements -Al-A 2

-A

3 -A4- and -As-As- are each ethylene, X is alk is methyle~a, R 1 is pivaloyl, R2 is acetyl, R3, ,,R4 and R 7 are each hydrogen and RS is 2,4,6-trimethylphonyl remains, in the form of a colourless lacquer. On the addition of ether t'e compound **crystallises from ethyl acetate in the form of long thin prisms that melt at approximately 2000 with decomposition.

Example 15: In a manner, analogous, for example, to that described in Example 14, there is obtained from 8-0-pivaloyl-l-deoxy-15-deoxo-1,15hydrorifamycin SV (target product of Example 8) the ascorbic acid salt of the compound of formula I in which the st'- tural elements -Al-A2- and

-A

3 -A4- are each ethylene and -A5-A6-- is vinylene, X is alk is methylene, Ri is pivaloyl, R2 is acetyl, PR3, R4 and R7 are each hydrogen an~d R 5 is 2,4,6-trimethylphenyl. The salt forms cqlourless prisms having a melting point of 175' (decomposition), (r ~i.

37 C t t

C~

4. *4 4@ S

E

5,54 S S S .5 5 S *4 i S S 4'445 Example 16: 10 ml of pivaloyl. chloride are added dropwise, at 00, with stirring, to a solution of 10 g of 16,17,18,19,28,29-hexahydro-3-[4- (2,4,6-trimethylbenzyl)-1-piperazinyl]-rifamycin (diastereoisomeric mixture) in 100 ml of pyridinq and the reaction solution is left to stand at room temperature for 4 hours.'Water is then added, the whole is acidified with dilute hydrochloric acid and the reaction product is taken up in ethyl acetate, The ethyl acetate extract is washed with dilute acid, with buffer solution of pH1 7 and with a saturated solution of sodium. chloride, then driecd over Na2SO. and concentrated by evaporation in vacuo. The residue contains the 2 diastereoisomeric, red-coloured hexahlydro ta. rivatives, which are separated by chroin.atography: when chromatography is repeated on 1 kg of silica gel with the eluant n-hexane/ethyl acetate 3:1, the more rapidly migrating of the 2 redcoloured, bands in this system is isolated. It contains diastereoisomerically pure 16,17,18,19,28,29-hexahydro-8-0--pivaloyl-1-deoxy-15-deoxo- 1 ,15-oxy-3-14-(2,4,6-trimethylbenzyl)-piperazin-1-yl]-rifamycin of formula I, in which the structural elements -Ai-A2-, -A 3 -A4- and -A 5 s-A6are each ethylene), X is >,alk is methylenei R, is pivaloyl, R 2 is acetyl, Rj and R4, together are a bond, R5 is 2,4,6-tirimethylpbenyl and R 7 is hydrogen, which is diastereoisomeric to the target prodoct of Example 2.

C56H79N30iZ; mol. Wt.: 985 (found, M(S, FAB)., The starting material can bo prepared, for eXample, as follows; 0.5 g of PtO2 is added to a solution of 3 g of 3-(4-(2,4,6-trimethylbenzyl)piperazin-1-yl]-rifamycin SV in 300 ml of ethanol, and the whole is hydrogenated for 13 hours at room temperature and under normal pressure.

The catalyst. is then filtered off through a layer of kieseiguhr, the filtrate is concentrated to dryness by evaporation# and the residue .1s crystallised in a mixture of ethyl acetate and diethyl ether, yielding 3-(4-('4,4,6-.trimothylbenzyl)-piperazin-1-yl]1-16,17,18,19,28,29-hexahydrotifamycin SV (epimeric mixtuire) in the form Qf yellow-coloured crystals that decompose above 250'; mass spectrum: m/z 920 (H 1) corresponding to the empirical formula CsIH 7 3N5012-

S

55 4* -38- Example 17: An approximately 1 solution of NaBII4 in methanol is slowly added dropwise at room temperature, with stirring, to a solution of 3 g of the target product of Example 16 in 50 ml of methanol until the initially deep-red colour of the reaction mixture has disappeared completely and the mixture has taken on a pale-yellow colour. The mixture Lo then diluted with a large amount of water, the reduced material is tak~en up in ether, the ethereal solution is washed with buffer solution of pH 7 and with a saturated solution of sodium chloride, dried with Xa 2 S04. and concentrated by evaporation, The almost colourless residue is crystallised several times fr6m ether, resulting in N,15,16,17,18,28,29- -deoxy-I 5-deoxo-1 xy-3- 4, 6-trime thy!" ben zyl) -pipe razin-1 -yl ]-rif amycin of formula I in which the structural S elements -Ali-A2-, -A 3

-A

4 and -As-A 6 are each ethylene, X is alk is methylene, RI is pivaloyl, Rz is acetyl, R3 4nd R4. are each hydrogen and R6 is 2,4,6-trimethylphenyl, which is diastereoisomeric to Sthe target product of Example 3, The colourless crystals melt at .234-2350, C 5 611 8 1

N

2 0 1 2; M01. Wt, 987 (found, US, DCI)# I11-NM.R spectrum (360 MHz, DMSO-dG, PPM): no more vinylic f-signals present; differences from the spectrum of the diastereoisomeric compound (target product of .'Example 5) only in the region of the high field, for eXamplal; -0.28 (d, 3H1); 0.29 311); 0.60 311) and 0.78 '-3H1, 4 Ana ngmty groups); 1.40 Example 18: A 10 so-Lution of' freshly prepared 8-0-'pivaloyl-3"[ 4 4 6 .trimethylbenzyl)-1 -pipe raiyI.]-rif amyqin SV in toluene is heated at for 15 minutes in a pressure ves!;ql, The to~luene is then evaporated. The ':material remaining is crystallised frotn methanol/watet, The ystals obtained after crystallising twice, having a melting point of 1750, are 1-deoxy-15-deoxo-1 ,15-oxy-3-(4-(2,4,6-trimethylbenzyl) -1-piperazinylh, rifamycin of formula I in which the structural elements -AI-A2-f

-A

3

-A

4 and -A446~- are each vinylenet X is >,RI is hydrogen, RI is acetyl, R 3 and R4. together are a bond, alk is methyloe, R$ is 2,4,6-trimothylphenyl and R7 is hydrogen., The starting material can be prepared, for example, as follows: a) 1.5 g of pivalic acid r:hlorvId- (1.13 equivalents) are added dropwise, with stirring, to a solution of 10 g of 3-[4-(2,4,6-trimethylbenzyl)-1piperazinyl] -rifamycin S in 100 mi of pyridine and the whole is allowed to react for 10 minutes at 200. 10 ml of methanol are then added to the reaction mixture and the whole is stirred for a further hour and subsequently concentrated to dryness by evaporation in vacuo. The residue is dissolved in ethyl acetate and the ethyl acetate solution is washed with aqueous sodium bicarbonate solution and a saturated solution of sodium chloride, dried over Na 2

SO

4 and concentrated by evaporation.

8-0-pivaloyl-3- 4-(2,4,6-trimethylbenzyl)-1-piperazinyl]-rifamycin S remains, which is crystallised from ether in the form of blue-black sr crystals having a melting point of 191-193 (decomposition), (sintering t at about 162, and again at about 1750).

b) The resulting quinone is dissolved in toetraydrofuran and while stirring well, there is added to the solution an excess of zinc dust and, dropwise, 1 hydrochloric acid until the reaction mixture has taken on a yellow colour. The reaction mixture is then filtered, the tetrahydrofuran solution is washed twice with saturated sodium chloride solution, dried with sodium sulfate and rapidly concentrated by evaporation in vacuo at S low temperotare. The yellow residue consists of 8-0-pivaloyl-3-(4-(2,4,6trimethylbjnyl) -I1-pipera inyl rifamycin SV, which can be used directly in tha4 form for the ring closure reaction. The material crystallises from ether in the form of orange-yellow crystals that melt at about 1650 r with decomposition.

t Example 19: A solution of 1,8-di-0-pivaloyl-3-[2-methyl4- 4 (2 4 ,6-trimethylbenzyl)-piporazin-1-yl-riamycin in 8 mi of 2-methoxyethanl is heated under reflux under nitrogen. After heating for 5 hourss the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel, oluted with ethyl acetate/hexane 1:4 to 2.3. 8-o0-pivaloy--deoxy-15-doxo-1,15-oxy-3d2-mthyl- 4 4 ,6-trimethylbenzyl) -piperazin-I-yl -rifamycin of formula I is obtained in whi L -i r 1 i.L &3J 13 V11

I

Cr

(C

4 I 3- #14 44 14 9 1949 99 4.

9 9 .9.9 9.

.9 9 99 9 9 99 99 *9 9 4* 9 99 *4 94 9 9 99 9 40 the structural elements -Aa-A 2

-A

3 -A4- and -A5-A6- are each vinylene, R, is pivaloyl, P2 is acetyl, R3 and R 4 together are a bond, alk is methylene, R 5 is 2,4,6-trimethyiphenyl and R 7 is hydrogen, Isomer A(in respect of the R 7 methyl) -containing C atom of the piperazine ring): melting point:*140 0 (decomp.), NMR (300 MHz, CD 3 OD): 6.80 2H1).

Is,=er B (in respect of the R 7 (q imethyl)-containing C atom of the piperazinei _ng)o: melting point: 140' (decomp.), NMR (300 MHz, CD 3 OD): 6.85 (sj 2H-).

The starting material can be prepared as follows: At room temperature, a mixture of 1.34 g mmol) of 1-trimethyl-3methyl-piperazine and 1.17 ml (8,17 mmol) of teiethylamine inp 160 ml of tetrahydrofuran is added dropwise, at a raptd dripy.ing speed, to a solution of 4.45 g (5.75 mmot) of 3-bromo-rifamycin S in 160 ml of tetrahyrdrofur f. After 10 minutes thin layer chromatography shows that there is no ioore starting material in the reac-tion mixcture, The solvent is removed under reduced pressure and a dork solid residue is obtained which is chromatogra! bad in a silica gel flash column with methylene chloride and 4 methanol as eluants. In this manner 3-.[2-methyl-4-(2,4,6-trimetbylber-.zyl)-piperazin-1-yl]-rifamycin S is obt~ained.

(270 MHz, CD 3 OD): 6.78 (211, s), A solution of 2.14 g (109.8 mmol) of sodium ascorbate in methanol/water ml each) is added dropwise to a solution of 1 g (1.08 mmol) of 3-[2me thyl-4- 4, 6-t rime thylbenzyl) -piper azin-yl I rif amycin S in 40 ml of methanol at room temperature. When the addition is complete, the reaction mixture is stirred for A hour, tj~e colour changing from red to orange.

Thin-layer chromatography in W~ )metbanol/methylene chloride shows that There is u) mote starting material present. Insoluble material is fil :ered off, hmd the filtrate is rapidly concentrated to dryness by evaporation. The residue is partitioned between methylene chloride aoid saturated NaH-C03 solution. The P-ganic extract is washed with a solution of s -dium rhloride, dried Over M9gS04 s nd concentrated, resulting in the 7 '7 4

A

-41 hydroquinone form (SV) as a pair of diastereoisomers in respect of the R 7 (me~thyl) containing C atom of the piperaziie ring, in the form of a yellow solid.

NHR 300 M4Hz, CD 3 OD): 6. 99 2H-, isomer 6 .95 2H1, isomer B) At 00, 25 mg of dime thylaminopyridine and 0. 32 ml of triethylam2,qc are added to a solution of 1.02 g (1.08 mmol) of 3 -[2-methyl-4-(2,4,6-tri- X me thylben zyl) -pipe ra zin-1 -yl I-rif amycin SV in 20 ml of methylene chloride and thn, dropwise, 0.27 ml (2.20 mmol) of pivaloyl chloride in 6 ml of methyj,ene chloride is added. The reaction mixture is washed with saturaed NaHiCO 3 solution, NaCI solvtion, dried over MgS04. and concentrated. The crude product is separated by means of flash chromatography on silica gel, ethyl acetate/hexane 3:1 being used as eluant. There are thua obtained in tespect Of the R 7 methyl) -containing C atom of the piperazine ring, 2 isomers of 1,8-di-0-pivaloyl-3-[2-mnethyl-4-(?46ti methylbenzyl)-pJperazin-1-yl)-rifamycin.

Isomer A: NNR 14-z, CD 3 0D): 6.8 2H1); 1.81 311); Rf 0.76 91 *f ethyl acetate/hexane 1:1) Isomer B: N-MR (211 MHz, CD 3 0D): 6.75 211); 1,7 3H1); Rf 0.71 ethyl acetate/bexane 1:1) Example 20: A solution of 50 mg of isomer A according to Example 19, mg of Pt02, 0.02 ml of acetic acid ai.d 2 ml of ethyl acetate is hydrogenated for 4 hours at 50 Psi of hydrogen. The catalyst is filtered off and the crude, faintly orange-coloured product is concentrated, and ~.:then purified by flash chromatography on silica gel using hexane:ethyl acetate 2:1 to 1:1 as eluant. After trituration with ether N,lS, 1 6 1 l 7 ,18,19,28,29-octahydro-l-deoxy-15-deoxo-1,15-oxy-8-o-pivaloyl- 3-[(2-me thyl-4- 4,6- trime thylbenzy'A) -pipe razin-1 -yl]1-rif amycin, m~po 229-21130, is obtained. NMR (300 MHz, CD 3 OD): 5.76 111); 2.81 (br. d, 2h1) and 2.88 (br. t, 211).

aqueous sodium bicarbonate solution, a saturated solution of sodi-im chloride is added and the hydrogenation product is extracted by repeated shaking with ethyl acetate. *After--&ying and concentrating, the ethyl 42 Example 21: In a manner analogous, for example, to that described in Example 1 in the manufacture of the starting material, there is obtai ned from 1 ,8-di-0-pivaloyl-3-114-(4-penten-1-yl)-l-piperazinyl]-rifamycin, 8-0-pivaloyl-1-deoxy-1 5-deoxo-1 ,1 5-oxy-3- 4-penten-1-yl)-lpiperazinyl]- Iifamycin of formul4 I in which the structural elements

-A

1

-A

2 4

-A

3

-A

4 and -A 5

-A

6 are each vinylene, X is alk is methylene, RI is pivaloyl, R 2 is acetyl, R 3 and R4 together are a bond, Rs is 3-butenyl and R 7 is hydrogen. The compound crystallises from methanol in the form of platelets that melt at 1400. C 5 1 11 6 9

N

3 0 1 2 mol.

wt.: 915 (found, MS, DCI) 1 H-NMR spectrum (360 MHz, DMSQ-d6): signals of the Olefinic side chain in multiplets, centred at: 1.58 (211), 2.09 (211), 2.48 (2H1) and also 4.95 C (together with d of H1-25, together with 2H), 5.04 (11) and 6.86 (111) ppm, Example 22: The following compounds can be prepared in a manner analogous, far example, to that described in one of the preceding F e xamples: 8-Q-piPaloyl-l-deoxy-15-deoxo-1 ,1 5-oxy-3-1 4 3-dimethylbenzyl)piperazin-1-yl)-rifamycin, :8-0-pivaloyl-1 -deoxy-1 5-deoxo-1 ,1 5-oxy-3- 2,6-dime thylbenzyl)piperazin-1-yl)-rifamycin, 8-0-pivaloyl--1-deoxy-15-deoxo-1,15-oxy-3 -[4-t2-(2,4,6-trimethylpbenyl)boa* ethylI-piperazin-1-yl)-rifamycin, 8-0-pivaloyl-1-deoxy-15-deox-o-I ,15-oxy-3-L4-[l-(2,4,6-trimqathylphenyl)ethylJI-piperazin-1 -yl)-rif amycin, :8-0-pivaloyl-l-deoxy-I 5-deoxo-1 15-oxy- [4-(2-ietoxybenzyl piperazin-l yl)-rifamycin, 8-0-pivaloyl--deQocy-15-dleoxo-1 ,15'-oxy-[4-(2,4,6-trimethylphenyl)piperazin-1-yl] -rfamycin.

Example 23: Capsules containing as active ingredient 250 mg of, for example, the compound of formula I in which the structural elements

-A

1

-A

3 -A4- and -As-AG- are each ethylene, X is )Nalk is S43 methyldne, RI is pivaloyl, R2 is acetyl, R 3 and R4 together are a bond, Rs is 2,4,6-trimethylphenyl and R 7 is hydrogen, can be prepared as Sfollows: Composition (for 1000 capsules): 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.

r 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 S mesh width of 1 mm and mixed with 5 g of magnesium stearate. The mixture.

is introduced in 0.320 g portions into size 0 dry-fill capsules.

The other compounds prepared according to Examples 1 to 22 can also be used as active components in similar manner.

I

i I It I i 1 i Sil

Claims (16)

1. Compounds of formula I p r if, L2 CH 3 .3 A~7 C C C t~ C* 4~1 4 1 #8 .4, *8 8, S. 1b4 0 84 and salts thereof in which the structural elements -A 1 -A 2 -P. 3 and -As-A 6 are each ethylene or vinylene or the elements -A 1 -A 2 and -A3-A4-are each ethylene and -A5-A 6 is vinylene, X is R6- or X- and R 6 is alkyl or hydrogen, alk is an aliphatic hydrocarbon radical or a bond, RI is hydrogen or acyl, R 2 is hydrogen or acetyl, R 3 and R4 together are -a bond or each is hydrogen, Rs is hydrogen, a cycloaliphatic; hydrocarbon radical, aryl or heteroaryl and R 7 is hydrogen or alkyl, with the proviso that when -A 1 -A 2 -A 3 -A4- and -As-As- are each vinylene, X is R 1 is hydrogen or trialkylacetyl, R 2 is hydrogen or acetyl, R 3 and R 4 together are a bond and alk is methylene, R5 is other than 2, 6-dimethyl-4-alkylphenyl.

2. A compound according to claim 1. of formula I, and salts thereof, in which -A 1 -A 3 -As-As-, R 2 R 3 and R 4 have the meanings given, X is C11- or alk is alkylene, R 1 is hydrogen or acyl, R5 is hydrogen, cycloalkyl or aryl, and R 7 is hydrogen.

3. A compound a co66r,,,ng to claim I of formula I, and salts thereof, in which -A 3 R 2 91 ,_Ond R4 have the meanings given, p Y: is C(R6) or and R6 is hydrogen or alkyl, alk is alkylene, alkenylene or alkynyleme, the multiple bond being located in a position higher than the a-position to the piperazine nitrogen R, is unsubstituted or halo- or phenyl-substituted aJlkanoyl, benzoyl, naphthoyl or monocyclic 5- or ,6-membered monoaza-, monooxa- or monothia-aroyl, alkoxycarbonyl, or aminocarbonyl that, is unsubstituted or mono- or di- substituted by alkyl, Rs is hydrogen, cycloalkyl, cycloalkenyl, cyclo- alkynyl, phenyl, biphenylyl, napkthyl, nonocyclic 5- or 6-membered nonoaza-, monooxa- or monothia-aryl and R 7 is hydrogen or alkyl, each of the aromatic radicals, independently of the others, being unsubstituted or mono- or poly-substituted by halogen, q;lkyl; alkoxy, hydroxy, :.*alkanoyloxy, trifluoronethyl and/or nitro.

4. A compound according to claim 1 of formula I, and salts thereof, in which -A 1 -A 2 -A 3 -As-A 6 R2, R 3 and R4. have the meanings given, :9:9:R r ndR is hydrogen or C -C alkyl alk is CI-C 1 2 X is /XR)o -adR ~y alkylene, C3-C 7 alkenylene or C 3 -C 7 alkynylene, the multiple bond being located in a position higher than the ax-position to the piperazine :nitrogen atom, R, is unsubstituted or halo- or phenyl-substituted C2-C8- alkanoyl, benzoyl, naphthoyl or uonocyclic 5- or 6-menbered nonoaza-, nonooxa- or monothia-aroyl, Ca-C~alkoxycarbonyl, or aminocarbonyl that is *:..*unsubstituted or mono- or di-substituted by Ca-C 7 alkyl, RS is hydrogen, C3-C7cycloalkyl, C 3 -C 7 cycloalkenyl, C3-C7cycloalkynyl, phenyl, biphenyl- yl, naphthyl, pyrrolyl, N-C1-C7alkylpyrrolyl, pyridyl, I-oxidopyridyl, :furyl or thienyl, and R7 is hydrogen or CI-C~alkyl, each of the aromatic **:radicals, independently of the others, being unsubstituted'or mono- or poly-substituted by halogen, Cl-C7alkyl, CI-C 7 alkoxy, hydroxy, C2-CS- alkanoyloxy, trifluoromethyl and/or nitro. A compound according to claim I of formula I, arnd salts thereof, in which -Ai-A 2 -A 3 -As-A 6 R2, R 3 and R4 have the meanings given, X is HC~- or alk is Cl-C7alkylene, R, is 0 2 -Cealkanoyl that is 6> 1* E~ 94 6 40 9 .4 49 .9 0

9.. 0* 9 9 9. *9 4 9 0444 90 94 9 94 99 9 04 .4 9 0440 .4 9 9 49 04 0 4. 94 46 unsubstituted or substituted by halogen or by phenyl which may cojitain halogen, C 1 -C 7 alkyl, Cl-C~alkoxy, hydroxy, C2-Csalkanoyloxy, trifluoro- methyl and/or nitro, unsubstituted or halo-, Cl-C~alkyl-, CI-C~alkoxy-, hydroxy-, C2-Caalkanoyloxy-, trifluoromethyl-, and/or nitro-substituted beozoyl, naphthoyl or monocyclic 5- or 6-membered monoazao-, mor-,oxa- or monothia-aroyl, Cl-C7alkoxycarbonyl, or aminocarbonyl that is unsub- stituted or mono- or di-substituted by CI-C 7 alkyl, Rs is hydrogen, C 3 -C 7 cycloalkyl, or phenyl, biphenylyl or naphthyl each of which is unsub- stituted or mono- or poly-substituted by halogen, CI-C 7 alkyl, CI-C 7 alk- oxy, hydroxy, C2,-Csalkanoyloxy, trifluoromethyl and/or by nitro, and R7 is hydrogen. 6. A compound according to claim 1 of formula I, and salts thereof, in which -Al-A 2 -A3-A 4 -As-As-, R 2 R 3 and R4 have the meanings given, X is C(Gor N- and R6 is hydrogen or Cl-C 7 alkyl, alk is Cl-C 1 2 alk- ylene, such as Cl-C7alkylene, C3-C7alkenylene or C3-C7alkynylene, the multiple bond being located in a position higher than the c-position to the piperazine nitrogen atom, I is hydrogen or C3-C6alkanoyl, Rs is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkemyl, or phenyl, biphenylyl, naphthyl, thienyl, furyl or pyridyl each of which unsubstituted or sub- stituted by halogen, Cl-C 7 alkyl, CI-Clal~oxy and/or by trMSluoromethyl, and R7 is hydrogen or Cl-C 7 alkyl. 7. A compound according to claim 1 of formula I, and salts thereof, in which -AI-A 2 -A 3 R 3 and R4 have the meanings given, X is >1H- or >,RI is C3-C6alkanoyl, especially pivaloyl, R 2 is acetyl, on the one hand alk is C3-C7aklkylene, such as 2-methyl-1,3-propylene, and Rs is hydrogen, or, on the other hand alk is CI-C~alkylene, especially nethylene, and Rs5 is C3-Cscycloalkyl, such as cyclohexyl, C3-C6CYClO- alkemyl, such as cyclohex-3 .en-1-yl, unsubstituted or Cl-CL~alkyl-sub- stituted, especially methyl-substituted, phenyl, such as 2,5-dimethylb. or 2,4, 6-t rime thylphenyl, biphenylyl, such as 4-biphenylyl, naphthyl, such as 2-naphthyl, or thienyl, Ach as 2-thienyl, and RI is hydrogen or Ci-Ci~alkyl, such as methyl. I, 4* 9* 9. 99 9* 9 .9 9. 9 9* 9* .9 *9 9 94 9e S 99 .9 9 9 .944 47 8. A compound according to claim 1 of formula I, and salts thereof, in which -Ai-A 2 -A 3 -As-A 6 R 3 and have the meanings give~n, R, is hydrogen or C- 2 -Caalkanoyl, especially branchied C 3 -C6alkanoyl, R 2 is acetyl, X is X ,alk is Cl-C 7 alkylene, especially Cl-C~.alkylene, Rs is hydrogen, C 3 -C 7 cycloalkyl, or phenyl, biphenylyl ornaphthyl each of which is unsubstitu~ed or mono- or poly-substituted by Cl-Ci~alkyl or halogen, and R 7 is hydrogen. 9. A compound according to claim 1 of formula I, and salts thereof, in which the structural elements -A 1 -A 3 -A 4 and -AB-AG- have the meanings given, RI-is branched C 3 -Csalkanoyl, such as pivaloyl, R2 is acetyl, R 3 and R4 have the meanings given, X is alk is C 1 -C~alk- ylene, such as methylene, R5 is 0 3 -C 7 cycloalkyl, such as cyclohexyl, C3-C7cycloalkenyl, such as cyclohex-3-en-1-yl, or phenyl mono- or poly- substituted, such as di- or tni-substituted, by Cl-Cialkyl, such as methyl, such as 2-imethylphenyl, 2,5- or 2,6-dinethylphenyl or 2,4,6-trimethyiphenyl, and R7 is on the one hand hydrogen, or on the other hand CI-C~.alkyl, such as methyl.

10. A compound according to claim 1 of formula I, and salts thereof, in which the structural elements -Ai-A 2 -A3-A4- and -As-A6- and the variables R3 and Ri 4 have the meanings given, alk is Cl-Ci4alkylene, such as methylene, 2,3-propylene or 2-methyl-1,3-propylene, RI is hydrogen or branched C 3 -Csalkanoyl, such as pivaloyl, RZ is acetyl, X is X Rs is hydrogen, C3-Cscycloalkyl, such as cyclohexyl, phenyl or 2,4,6-t i- Cl-Ci~alkylphenyl, such as 2,4,6-trimethylphenyl, and R 7 is hydrogen.

11. A compound according to claim 1 of formula I, and salts thereof, in which the struct,,ral elements -Ai-Az-, -A3-A4- and -As-As- have the meanings given, X is R2 is hydrogen or acetyl, R3 and R4 together .9 9 9* 99 99 9 9* 99 VV are a bond, and o n, the one band alk is CI-C~.alkylene, especially 2 -methyl--1,3-propylene and Rs is hydrogen, or on the other hand alk is methylene and RS is 2, 4 6 -tri-C--Ci~alkylphenyl, especially 2 4 ,6-tri- methyiphenyl, and R 7 is in each case hydrogen.

12. A compound according to claim 1 of formula I, and salts thereof, in which the structural elements -Ai-A2-, -A 3 -A 4 and -As-A 6 have the meanings given, X is )NR 2 is acetyl, R 3 and R 4 together are a, bond or each is hydrogen, and on the one hand alk is C1-C4alkylene, especially 2-methyl-1,3-propylene, and R5 is hydrogen, or on the other hand alk is methylene and Rs is 2,4,6-tri-Cl-Ci 4 alkylphenyl, especially 2, 4 ,6-tri- methyiphenyl, and R7 is in each case Cl-C~.alkyl, such as methyl.

13. A compound according to claim 1 of formula 1, and salts there'-f, in which the structural elements -Ai-A 2 -A 3 -A 4 and -As-A6- are each vinylene, or the elements -Ai-A2-A 3 -A 4 are buta-1,3-dien-1,4-diyl. and 6 is ethylene, X is CH1-, alk is Cl-C~alkylene, especially methylene or 2,3-propylene, RI is branched C 3 -Csalkanoyl, especially *pivaloyl, RZ is acetyl, R 3 and R4 together are a bond and Rs is hydrogen, S or also cyclohexyl or phenyl, and R 7 is hydrogen. ~14. A compound, according to claim 1 of formula I, and salts thereof, in which the structural elements -AI-A 2 -A 3 -A4- and -As-A 6 are each vinylene, or the elements -Al-Az-A 3 are buta-1,3-dien-1,4-diyl and 6 is ethylene, X is )NRX is hydrogen or branched C3-Co- *'14 alkanoyl, especially pivaloyl, R~2 is acetyl, R3 and R4 together 'are a bond, alk is CI-C4alkylene, especially 2-methyl-1,3-propyl, and Rs is hydrogen, or alk is C 1 -C4alkylene, especially methylene and R 5 is 2,4,6-tri-c 1 -C~alkylphenyl, especially 2,4,6-trimethylphenyl, and R 7 is hydrogen. 49 A compound according toclaim 1 of formula I, and salts thereof, in wihX iX IA-2 and -A 3 -A 4 are each ethylene and -At-A6- is vinylene ar ethylene, R 1 is branched C3-C6ai-kanoylj especially pivaloyl, R 2 is acetyl, and R4 together are a bond or each is hydrogen, on the one hand alk is CI-Ci~alkylene, especially methylene, and Rs is 2,4,6-tni- methylphenyl, and on the other hand alk is Cl-C& 1 alkylene, especially 2 -methyl-1,3-propylehe, and I's is hydrogen, and R 7 is hydrogen.

16. A compound according to claim 1 of formula I, and salts thereof, in which -Al-A 2 -A 3 -A4- and -As-A 6 are each ethylene, X is >NRI is pivaloyl, R 2 is acetyl, R3 and R4 together are'a bond or each is 0hydrogen, alk-1R 5 is 2, 4,6-t rime thylbenzyl, and R1 7 is hydrogen.

17. 1 6 ,17,18,19-tetrahydro-8-O-pivaloyl-l-deoxy-15-deoxo-11,15-oxy-3- 4 -(2,4,6-trimethylbenzyl)-piperazin-1-yl]-rifamycinI or l 6 ,1 7 ,18,19,28,29-hexahydro-8-O-pivaloyl-1-deoxy-15-deoxo-1 ,15-oxy-3- i4- 4,6- trime thylbenzyl) -pipertazin-1 -yl I-rif amycin; or S. 0 N, 15,16, 17,18,19, 28, 29-oc tahydro-8-O-pivaloyl-I -deoxy-1 5-deoxo- 'oxy-3- 4 4, 6-t rime thylbenzyl) -pipe razin- -yl I-rif amycin; or 8-Q-pivaloyl-1-deoxy-15-deoxo-1 ,15-oxy-3-t4-(1-naphthyl-methyl)- :pipetazin-1-yl]-rifamycin; or S* 8-Q-pivaloyl-l-deoxy-1 5-deoxo-1, 15-.oxy-3-(4-sbtlppeai.lyl rifamyctn; or N,15,16,17,18,19,28,29-octahydro-8-O-pivaloyl-1-deoxy-15-deoxo-1,15- oxy-3-(4-isobutyl-l-pltpQrazinyl)-rifamycint or 8-O-pivaloyl-1-deoxy-15-deoxo-1 ,15-oxy-3-(4-(phenylbontyl)-1- pipe razinyl -rif amycint, or N, 15,16,17 ,18,19-hexahydro-8-O--pivaloyl-1-deoxy-15-deoxo-1 15-oxy-3- 4,6- trime thylbenzyl) -1 -piperazinylI-rif amycin;, or N, 15-dihydro-8-0-pivaloyl-l1-deoxy-1 5-deoxo-1 ,1 5-oxy-3-f 2 6-tri- me thylbenzyl -pipe razinyl I-rif amycin; or 8-Q-pivaloyl-l -deoxy-1 5-deoxo-1 ,1 5-oxy-3-( 5-dimethylbenzy1) -1- piperazinyl]-rifamycin; or 8-0-pivaloyl--deoxy-15-deoxo-1 1 5-oxy-3-(4-benzyJ-l-pipe razinyl) rifamycin ;or 4 44 4 4~$4 t tr 4 4 444; 49 ii 4; 4 9 *9*9 9. *9 9 99 9 9 9. 99 9 9994 94 9 09 94 94 9 99 9'* 8-O-pivgloyl- 1-deoxy- 15-cleoxo-1 ,15-oxy- 3- (4-cyclohexylme thyl-1 pipe razinyl1) -rif amycin or 8-0-pivaloyl-1 -deoxy-1 5-deoxo-1 1 5-oxy.-3-f cyclobex-3-en-11-yJ.- methyl)-1-peorazinyl)-rifamycLn; or 8-O-pivaloyl-1-deoxy-15-ieoxo-1 ,15-oxy-3-(,2-methyl-4-(2, 4 6-tri- methylbenzyl)-piperazin-1-yl)-rifamycin, or N,15,16,17 ,18,1 9,28, 29-octahydro-l-deoxy-1 5-deoxo-1 ,1 5'oxy-8-0- pivaloyl-3- eqthyl-4- 4,6-t rime thylbenzyl) -piperazin-1 -rif amycin or salts theredpf.

18. A compound *ztlcordU~ng to any one of claims 1-1L7 in the formi of te (16S) isomer, A compound according to any one of claims 1-17 in the form of the (16R) isomer. A compound according to any one of claims 1-19 in the form of an ascorbic acid salt. p LL_ ~c t C t 4* 'I Oee 9. #9 0 4499 4. 99 09 0 4 9494 .9 94 9 49 9 9 4 94 4 .44 .9 .4 9444 *4 0 9 94 b4 94 0 *9 .4 *4 51

21.A compound according to any one of claims 1-19 in the form of a pharmaceutically acceptable salt.

22. Pharmaceutical preparations containing a compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof together with customary adjuncts and additives.

23. A method of treating hyperlipidaemia a.nd arteriosclerosis which comprises administering a compound according to any one of claims 1- 24 or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount.

24. A process for the preparation of a compound according to any one of clawims 1 -21, which comprises a) for the preparation of compounds of formula I and salts thereof in which X represents reacting a compound of formula YH 3 YH3 YH3 S3 R (IIa, I R H 0. 7- or a salt thereof in which X is with a compound of formula Z-alk-Rs (IIb) in which Z is reactive esterifivd hydroxy or il f -52- b) for the preparation of compounds of formula I and salts thereof in which Rz is acetyl and R3 and R4 together are a bond, cyclising a compound of formula (III) 4 I i tt t a 4# et 4t Ia I I 0~ #4 a 4 4~ I a ~I I .1 *i4~ I I a, a a 40 I 44 4* S WI I 44 in which R1. is acyl and R" is hydrogen or acyl, or c) cyclising a compound of for~mula J\A 2 CH 3 IV) k-R 8 A7 and, if dererd, converting a compound of formula I obtainable by the process or in another manner, or a splt 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 and$ if desired, separating a mixture of isomers obtainable in accordance with the process. FO 7,4IDH/sm* p. xl 'Jo 14 .0 6 1 11 'V 'If 'r I C 0268d/NNG -53 A substituted azacyclohexyl derivative of rifamycins of the formula 1, or a salt thereof, substantiaClly as herein described with reference to anyone of the e'namples thereof. ")?AVED this 9th day of March, 1992. CIBA-GEIGY AG By Its Patent Attorneys AVIES COLLISON CAVE It t 1 4 It 11 4 I I I. 4 44 I 1 44 44 4, *4 4* 4 o 4 4 9*4*44 9 9*44*4 V T 'I a