DERIVES DE LA RIFAMYCINE

DERIVATIVES OF RIFAMYCIN

Abrégé anglais

PROCESS FOR THE MANUFACTURE OF NEW ANTIBIOTICALLY ACTIVE
COMPOUNDS
Abstract of the Disclosure
The invention refers to a process for the manufacture
of selected 3-amino-rifamycin S and -SV derivatives, the amino
group being of the aliphatic type, and more precisely being
a 4R-1-piperazinyl- radical which is optionally substituted
at the C-atoms by lower alkyl groups, and wherein R represents
a hydrocarbon radical of the formula
(III) <IMG> ,
wherein Z1 - Z3 represent various hydrocarbon groups, including
aromatic and cycloaliphatic groups, and Z' and Z" are optionally
hydrogen or lower alkyl groups. These new compounds possess
beyond a high general antibiotic action an especially high
anti - tuberculosis effect, and are distinguished by a low
toxicity.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the manufacture of rifamycin S compounds (I) which are
substituted in the 3-position by an aliphatically substituted amino group
and have the following formula
(I) <IMG>
and their corresponding hydroquinones, the rifamycin SV derivatives (compounds
II), wherein A denotes a 4R-1-piperazinyl radical which is optionally substit-
uted at the C atoms by lower alkyl groups, and wherein R represents a hydro-
carbon radical with not more than 35C atoms of the formula
(III) <IMG>

in which n = 0 or 1, and Z1 represents, when taken alone,
a. an unsubstituted lower alkyl or lower alkenyl group,
b. a lower alkyl or lower alkenyl groups substituted by
a) phenyl or phenylsubstituted by 1 to 3 lower alkyl groups
or halogen atoms or
b) C3-C8 cycloalkyl or C3-C8 cycloalkenyl
c) phenyl or phenyl substituted by 1 to 3 lower alkyl groups
or halogen atoms
c) C3-C8 cycloalkyl or C3-C8 cycloalkeny]
Z2 represents, when taken alone, hydrogen, or a lower alkyl or
lower alkenyl group,
Z3 represents, when taken alone, a lower alkyl or lower alkenyl
group,
Z' and Z'', when taken alone, each represent hydrogen or an
alkyl group of 1-4 carbon atoms,
Z3 taken together with Z'' represents a double bond,
Z2 taken together with Z3 represents a lower alkylidene or lower
alkenylidene groups,
Z1 taken together with Z3 represents an unsubstituted lower alky-
lene or lower alkenylene groups,
Z1 taken together with Z2 represents a lower alkylene or lower
alkylene group in the case that Z3 taken together with Z''
represents a double bond,
with the proviso that the cycloaliphatic groups mentioned, or
those formed by an alkylene or alkenylene group Z1+Z3 or Z1+Z2
together with the C atom indicated in formula (III) to which Z1,
Z2 and Z3 are bonded, include such having unsubstituted cyclo-
- 31 -

aliphatic rings as well as such whose rings are substituted
by alkyl groups having 1 to 4 C atoms, and such in which
two nonadjacent C atoms of the ring are bonded to one another
directly or through an alkylidene or alkylene group having
1-4 C atoms and such in which another cycloaliphatic ring
having from 3 to 5 C atoms is spirocyclically attached to one
C atom of the ring, with the proviso that all such cycloali-
phatic groups have not more than a total of 12 carbon atoms
and from 3 to 8 ring carbon atoms, any lower alkyl, alkenyl,
alkylidene or alkenylidene group containing from 1 to 7
carbon atoms or R represents the allyl group, and their salts
and quaternary ammonium salts, characterised in that rifamy-
cin S is reacted with an amine of the formula HA, wherein A
has the same meaning as above, or that 3-(1-piperazinyl)-rifamy-
cin S or SV, which can optionally be substituted by lower alkyl
radicals at the C atoms of the piperazinyl radical, is reacted
with an alkylating agent which is suitable for the N-alkylation
of piperazines and introduces the radical R, R having the
above meaning, and that the resulting 3-amino-substitution
product of rifamycin S or rifamycin SV is isolated and/or,
if desired, before or after isolation a resulting hydroquinone is
oxidised to the quinone or a resulting quinone is reduced to
the hydroquinone and/or a resulting compound is converted into
a salt.
- 32 -

2. Process according to Claim 1, characterised in
that rifamycin S is reacted in an organic solvent which is
free from hydroxyl groups.
3. Process according to Claim 2, characterised in that
a solvent of low polarity is used.
4. Process according to Claim 3, characterised in that
a halogenated aliphatic hydrocarbon is used.
5. Process according to Claim 3, characterised in
that an ether is used.
6. Process according to Claim 5, characterised in
that dioxane is used.
7. Process according to Claim 1, characterised in that
an excess of amine is used and the reaction is carried out
at between room temperature and 100°.
8. Process according to Claim 1, characterised in
that rifamycin S is reacted with the amine without using a
solvent.
9. Process according to claim 1, characterised in that
the alkylating agent used is a compound of the formula XR,
wherein R has the above meaning and X denotes a halogen atom
or the radical of an oxygen-containing inorganic acid.
10. Process according to Claim 9, characterised in that
an alkylating agent of the formula XR is used, wherein X
denotes chlorine, iodine or bromine.
- 33 -

11. Process according to Claim 9, characterised in that
mono-esters or di-esters of sulphuric acid or of fluoro-
sulphonic acid with an alcohol ROH, wherein R has the meaning
indicated in Claim 9, are used.
12. Process according to Claim 9, characterised in
that the reaction is carried out in the presence of a base.
13. Process according to Claim 12, characterised in that
a strongly basic, non-nucleophilic tertiary amine is used as
the base.
14. Process according to Claim 13, characterised in that
ethyl-diisopropyl-amine is used as the base.
15. Process according to Claim 9, characterised in that
the reaction is carried out in an inert solvent.
16. Process according to Claim 15, characterised in that
a chlorinated aliphatic hydrocarbon is used as the inert
solvent.
17. Process according to Claim 15, characterised in that
an alcohol is used as the inert solvent.
18. Process according to Claim 9, characterised in that
the reaction is carried out at temperatures between room tem-
perature and approx. 100°.
19. Process according to Claim 12, characterised in
that approx. 1 mol of each of the reactants and of the base
is used.
- 34 -

20. Process according to Claim 1, characterised in
that a resulting hydroquinone is oxidised to the corresponding
quinone by means of hydrogen peroxide, ammonium persulphate
or potassium ferricyanide.
21. Process according to Claim 1, characterised in that
a resulting quinone is reduced to the hydroquinone by means
of ascorbic acid or a salt of this acid.
22. Process according to Claim 21, characterised in that
the reduction is carried out in the reaction mixture before
isolating the desired process product.
23. Process according to Claim 21, characterized in that
the reduction is carried out in the reaction mixture before
isolating the desired process product.
24. Process according to one of Claims 1, 6 and 7,
characterised in that the piperazinyl radical is un-
substituted at the carbon atoms.
25. Process according to anyone of Claims 9, 10 or 11,
characterized in that alkylating agents are used wherein the
piperazinyl radical is unsubstituted at the carbon atoms.
26. Process according to anyone of Claims 12, 13, or
14, characterized in that alkylating agents are used wherein
the piperazinyl radical is unsubstituted at the carton atoms.
27. Process according to anyone of claims 20, 21 or
22, characterized in that alkylating agents are used wherein the
piperazinyl radical is unsubstituted at the carbon atoms.
- 35 -

28. Process according to one of claims 1, 6 and 7, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein cycloalkyl or cycloalkenyl groups in the radical R have 5-6 ring C
atoms.
29. Process according to one of claims 9, 10 or 11, characterized in
that alkylating agents are used wherein cycloalkyl oder cycloalkenyl groups
in the radical R have 5-6 ring C atoms.
30. Process according to one of claims 12, 13 or 14, characterized in
that alkylating agents are used wherein cycloalkyl or cycloalkenyl groups in
the radical R have 5-6 ring C atoms.
31. Process according to one of claims 20, 21 or 22, characterized in
that starting rifamycins S or SV derivatives or alkylating agents are used
wherein cycloalkyl or cycloalkenyl groups in the radical R have 5-6 ring C-
atoms.
32. Process according to one of claims 1, 6 and 7, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein a phenyl group in the radical R is substituted by 1 to 3 methyl groups.
33. Process according to one of claims 9, 10 or 11, characterized in
that alkylating agents are used wherein a phenyl group in the radical R is sub-
stituted by 1 to 3 methyl groups.
36

34. Process according to one of claims 12, 13 or 14,
characterised in that alkylating agents are used wherein a
phenyl group in the radical R is substituted by 1 to 3 methyl
groups.
35. Process according to one of claims 20, 21 or 22,
characterised in that starting rifamycin S or SV derivatives
or alkylating agents are used wherein a phenyl group in the
radical R is substituted by 1 to 3 methyl groups.
36. Process according to one of Claims 1, 6 and 7, cha-
racterised in that starting rifamycin S or SV derivatives
or alkylating agents are used wherein a lower alkyl,alkyli-
dene,alkenyl or alkylene groups in the radical R has 1-4 or
2-4 C atoms respectively.
37. Process according to one of claims 9, 10 or 11, cha-
racterised in that alkylating agents are used wherein a lower
alkyl, alkylidene, alkenyl or alkylene group in the radical R
has 1-4 or 2-4 C atoms respectively.
38. Process according to one of claims 12, 13 or 14,
characterised in that alkylating agents are used wherein a
lower alkyl, alkylidene, alkenyl or alkylene group in the
radical R has 1-4 or 2-4 C atoms respectively.
- 37 -

39. Process according to one of claims 20, 21 or 22, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein a lower alkyl, alkylidene, alkenyl or alkylene group in the radical
R has 1-4 or 2-4 C atoms respectively.
40. Process according to one of claims 1, 6 and 7, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein the group A according to claim 1 denotes a 4R-1-piperazinyl radical
which is unsubstituted at the C atoms and wherein R has one of the following
formulae:
<IMG> <IMG>
(IV) (V)
<IMG>
<IMG>
(VI) (VII)
wherein n = 1 or 2 and V1 and V2 each denote an alkyl or alkenyl group with
1 - 4 C atoms, V3 denotes hydrogen or an alkyl or alkenyl group with 1-4
atoms or together with V2 denotes an alkylidene or alkenylidene group with
1-4 C atoms, Ph denotes a phenyl group which is unsubstituted or substituted
by chlorine or bromine atoms and/or methyl groups, Cy denotes a cycloalkyl or
cycloalkenyl group with 5-6 ring C atoms, wherein the ring can optionally be
substituted by lower alkyl groups with 1-4 C atoms, Py denotes a cycloalkyl
or cycloalkenyl group of this type or a phenyl group as defined above and
"Alk" denotes a straight-chain or branched alkylene group with 2-4 C atoms or
38

an alkylidene group with 1-4 C atoms.
41. Process according to one of claims 9, 10 or 11, characterized in
that alkylating agents are used wherein the piperazinyl radical is unsubstitu-
ted at the C atoms and wherein R has one of the following formulae:
<IMG> <IMG>
(IV) (V)
<IMG>
<IMG>
(VI) (VII)
wherein n = 1 or 2 and V1 and V2 each denote an alkyl or alkenyl group with
1 - 4 C atoms, V3 denotes hydrogen or an alkyl or alkenyl group with 1-4 atoms
or together with V2 denotes an alkylidene or alkenylidene group with 1-4 C
atoms, Ph denotes a phenyl group which is unsubstituted or substituted by
chlorine or bromine atoms and/or methyl groups, Cy denotes a cycloalkyl or
cycloalkenyl group with 5-6 ring C atoms, wherein the ring can optionally be
substituted by lower alkyl groups with 1-4 C atoms, Py denotes a cycloalkyl
or cycloalkenyl group of this type or a phenyl group as defined above and
"Alk" denotes a straight-chain or branched alkylene group with 2-4 C atoms
or an alkylidene group with 1-4 C atoms.
42. Process according to one of claims 12, 13 or 14, characterized in
that alkylating agents are used wherein the piperazinyl radical is unsubstitut-
ed at the C atoms and wherein R has one of the following formulae:
39

<IMG> <IMG>
(IV) (V)
<IMG> <IMG>
(VI) (VII)
wherein n = 1 or 2 and V1 and V2 each denote an alkyl or alkenyl group with
1 - 4 C atoms, V3 denotes hydrogen or an alkyl or alkenyl group with 1-4 atoms
or together with V2 denotes an alkylidene or alkenylidene group with 1-4 C
atoms, Ph denotes a phenyl group which is unsubstituted or substituted by
chlorine or bromine atoms and/or methyl groups, Cy denotes a cycloalkyl or
cycloalkenyl group with 5-6 ring C atoms, wherein the ring can optionally be
substituted by lower alkyl groups with 1-4 C atoms, Py denotes a cycloalkyl
or cycloalkenyl group of this type or a phenyl group as defined above and
"Alk" denotes a straight-chain or branched alkylene group with 2-4 C atoms or an
alkylidene group with 1-4 C atoms.
43. Process according to one of claims 20, 21 or 22, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein the piperazinyl radical is unsubstituted at the C atoms and wherein
R has one of the following formulae:
<IMG>
<IMG>
(IV) (V)

<IMG> <IMG>
(VI) (VII)
wherein n = 1 or 2 and V1 and V2 each denote an alkyl or alkenyl group with
1 - 4 C atoms, V3 denotes hydrogen or an alkyl or alkenyl group with 1-4 atoms
or together with V2 denotes an alkylidene or alkenylidene group with 1-4 C
atoms, Ph denotes a phenyl group which is unsubstituted or substituted by
chlorine or bromine atoms and/or methyl groups, Cy denotes a cycloalkyl or
cycloalkenyl group with 5-6 ring C atoms, wherein the ring can optionally be
substituted by lower alkyl groups with 1-4 C atoms, Py denotes a cycloalkyl
or cycloalkenyl group of this type or a phenyl group as defined above and
"Alk" denotes a straight-chain or branched alkylene group with 2-4 C atoms
or an alkylidene group with 1-4 C atoms.
44. Process according to one of claims 1, 6 and 7, characterized in that
starting rifamycin S or SV derivatives or alkylating agents are used wherein
the group A according to claim 1 denotes a 4R-1-piperazinyl radical which is
unsubstituted at the C atoms and wherein R has the following formula
<IMG> (VIII)
wherein n = 1 or 2 and m = 1-4 and W1, W2 and W3 denote methyl groups, which
are optionally present on any desired ring C atom, their derivatives which
are monounsaturated in the cycloaliphatic ring, and derivatives of these com-
pounds having a bridged cycloaliphatic ring, the bridge being a methylene,
ethylene or isopropylidene group or a direct C,C-bond.
45. Process according to one of claims 9, 10 or 11, characterized in
that alkylating agents are used wherein the piperazinyl radical is unsubstitu-
41

ted at the C atoms and wherein R has the following formula
<IMG>
(VIII)
wherein n = 1 or 2 and m = 1-4 and W1, W2 and W3 denote methyl groups, which
are optionally present on any desired ring C atom, their derivatives which are
monounsaturated in the cycloaliphatic ring, and derivatives of these compounds
having a bridged cycloaliphatic ring, the bridge being a methylene, ethylene
or isopropylidene group or a direct C,C-bond.
46. Process according to one of claims 12, 13 or 14, characterized in
that alkylating agents are used wherein the piperazinyl radical is unsubstituted
at the C atoms and wherein R has the following formula
<IMG>
(VIII)
wherein n = 1 or 2 and m = 1-4 and W1, W2 and W3 denote methyl groups, which
are optionally present on any desired ring C atoms, their derivatives which
are monounsaturated in the cycloaliphatic ring, and derivatives of these com-
pounds having a bridged cycloaliphatic ring, the bridge being a methylene,
ethylene or isopropylidene group or a direct C,C-bond.
47. Process according to one of claims 20, 21, or 22, characterized in
that starting rifamycin S or SV derivatives or alkylating agents are used
wherein the piperazinyl radical is unsubstituted at the C atoms and wherein R
has the following formula
<IMG>
(VIII)
42

wherein n = 1 or 2 m = 1-4 and W1, W2 and W3 denote methyl groups, which are
optionally present on any desired ring C atom, their derivatives which are
monounsaturated in the cycloaliphatic ring, and derivatives of these compounds
having a bridged cycloaliphatic ring, the bridge being a methylene, ethylene
or isopropylidene group or a direct C,C-bond.
43

48. Process according to anyone of claims 1, 6 and 7,
wherein rifamycin S is reacted with 4-isobutyl-piperazine and
3-(4-isobutyl-1-piperazinyl)-rifamycin SV is isolated optio-
nally after reduction of the reaction mixture, e.g. with
ascorbic acid, and the product obtained is oxidized prior
or after isolation to the corresponding quinone, if 3-(4-
isobutyl-l-piperazinyl) rifamycin S is required.
49. Process according to anyone of Claims 9-11, wherein
there is used an alkylating agent introducing the isobutyl
group in the N'-position of 3-(piperazinyl-1)-rifamycin SV,
and 3-(4-isobutyl-1-piperazinyl)-rifamycin SV is isolated,
and this product is oxidized to the corresponding quinone,
if 3-(4-isobutyl-l-piperazinyl)-rifamycin S is required.
50. Process according to anyone of Claims 12-14, wherein
there is used an alkylating agent introducing the isobutyl
group in the N'-position of 3-(piperazinyl-1)-rifamycin SV,
and 3-(4-isobutyl-1-piperazinyl)-rifamycin SV is isolated,
and this product is oxidized to the corresponding quinone,
if 3-(4-isobutyl-1-piperazinyl)-rifamycin S is required.
51. Process according to anyone of Claims 1, 6 and 7,
wherein rifamycin S is reacted with 4-methallyl-piperazine and
3-(4-methallyl-1-piperazinyl)-rifamycin SV is isolated,
optionally after reduction of the reaction mixture, e.g.
with ascorbic acid, and the product obtained is oxidized
to the corresponding quinone, if 3-(4-methallyl-1-piperazinyl)-
-rifamycin S is required.
52. Process according to anyone of Claims 9-11, wherein
there is used an alkylating agent introducing the methallyl
44

group in N'-position of 3-(piperazinyl-1)-rifamycin SV, and
3-(4-methallyl-1-piperazinyl)-rifamycin SV is isolated, and
this product is oxidized to the corresponding quinone, if
3-(4-methallyl-1-piperazinyl)-rifamycin S is required.
53. Process according to anyone of Claims 12-14, wherein
there is used an alkylating agent introducing the methallyl
group in N'-position of 3-(piperazinyl-1)-rifamycin SV, and
3-(4-methallyl-1-piperazinyl)-rifamycin SV is isolated, and
this product is oxidized to the corresponding quinone, if
3-(4-methallyl-1-piperazinyl)-rifamycin S is required.
54. Process according to anyone of Claims 1, 6 and 7,
wherein rifamycin S is reacted with 4-cyclohexylmethyl-piperazine
and 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV is iso-
lated, optionally after reduction of the reaction mixture,
e.g. with ascorbic acid, and the product so obtained is oxidized,
prior or after isolation, to the corresponding quinone, if
3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S is required.
55. Process according to anyone of Claims 9-11, wherein
there is used an alkylating agent introducing the cyclohexyl-
methyl group in the N'-position of 3-(piperazinyl-l)-rifamycin
SV, and 3-(4-cyclohexylmethyl-1-piperazinyl-)-rifamycin SV is
isolated, and this product is oxidized to the corresponding
quinone, if 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin
is required.
56. Process according to anyone of Claims 12-14, wherein
there is used an alkylating agent introducing the cyclohexyl-
methyl group in the N'-position of 3-(piperazinyl-1)-rifamycin
SV, and 3-(4-cyclohexylmethyl-1-piperazinyl-)-rifamycin SV is

isolated, and this product is oxidized to the corresponding
quinone, if 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin
is required.
57. Process according to anyone of Claims 1, 6 and 7,
wherein rifamycin S is reacted with a member selected from the
group consisting of
4-(2-ethylbutyl)-piperazine
4-(2-methylbutyl)-piperazine
4-allyl-piperazine
4-(2-methyl-2-pentenyl)-piperazine
4-(2-ethyl-2-butenyl)-piperazine
4-(2-ethyl-2-hexenyl)-piperazine
4-(2,3-dimethyl-2-butenyl)-piperazine
4-(2-ethylbutyl)-piperazine
4-(1,2-dimethylpropyl-piperazine
4-(3-methylbutyl)-piperazine
4-(2-methylpentyl)-piperazine
4-(3-methylpentyl)-piperazine
4-neopentyl-piperazine
4-(3,3-dimethylbutyl)-piperazine
4-(3-phenyl-2 propenyl)-piperazine
and the corresponding 3-(4-alkyl- or alkenyl-l-piperazinyl)-
rifamycin SV are isolated, optionally after reduction of the
reaction mixture, e.g. with ascorbic acid, and the products
so obtained are oxidised, prior or after isolation, to the
corresponding quinones, if the corresponding rifamycin S deri-
vatives are required.
58. Process according to anyone of Claims 9-11, wherein there
is used an alkylating agent RX introducing in N'-position of
46

the 3-(piperazinyl-l)-rifamycin SV, the group R selected frorn
the group consisting of the radicals
<IMG>
and the corresponding 3-(4-alkyl or alkenyl-l-piperazinyl)-
rifamycin SV derivatives are isolated, and the products so
obtained are oxidized to the corresponding quinones, if the
corresponding rifamycin S derivatives are required.
59. Process according to anyone of Claims 12-14,wherein there
is used an alkylating agent RX introducing in N'-position of
the 3-(piperazinyl-l)- rifamycin SV, the group R selected from
the group consisting of the radicals
<IMG>
47

and the corresponding 3-(4-alkyl or alkenyl-l-piperazinyl)-
rifamycin SV derivatives are isolated, and the products so
obtained are oxidized to the corresponding quinones, if the
corresponding rifamycin S derivatives are required.
60. Process according to anyone of Claims 1, 6 and 7,
wherein rifamycin S is reacted with a member selected from
the group consisting of
4-cyclopropylmethyl-piperazine
4-cyclobutylmethyl-piperazine
4-cyclopentylmethyl-piperazine
4-(2-phenylpropyl)-piperazine
4-cycloheptylmethyl-piperazine
4-(3-cyclohexen-1-yl)-piperazine
4-(2-norbornylmethyl)-piperazine
4-cyclooctylmethyl-piperazine
4-(4-methylcyclohexyl-methyl)-piperazine
4-(2-benzyl-propyl)-piperazine
and the corresponding 3-(4-alkyl- or alkenyl-l-piperazinyl)-
rifamycins SV are isolated, optionally after reduction of the
reaction mixture, e.g. with ascorbic acid, and the products
so obtained are oxidised, prior or after isolation, to the
corresponding quinones, if the corresponding rifamycin S deri-
vatives are required.
48

61. Process according to anyone of Claims 9-11, wherein
there is used an alkylating agent XR introducing in N'-
position of the 3-(4-piperazinyl-1)-rifamycin SV the group R
selected from the group consisting of the radicals
4-cyclopropylmethyl
cyclobutylmethyl
cyclopentylmethyl
2-phenyl-propyl
cycloheptylmethyl
3-cyclohexen-1-yl
2-norbornylmethyl
cyclooctylmethyl
methylcyclohexyl
2-benzylpropyl
and the corresponding 3-(4-alkyl- or -alkenyl l-piperazinyl)-
rifamycin SV are isolated, and the products so obtained are
oxidized to the corresponding quinones if the corresponding
rifamycin S derivatives are required.
62. Process according to anyone of Claims 12-14, wherein
there is used an alkylating agent XR introducing in N'-
position of the 3-(4-piperazinyl-1)-rifamycin SV the group R
selected from the group consisting of the radicals
4-cyclopropylmethyl
cyclobutylmethyl
cyclopentylmethyl
2-phenyl-propyl
49

cycloheptylmethyl
3-cyclohexen-1-yl
2-norbornylmethyl
cyclooctylmethyl
methylcyclohexyl
2-benzylpropyl
and the corresponding 3-(4-alkyl- or -alkenyl l-piperazinyl)-rifamycin SV are
isolated, and the products so obtained are oxidized to the corresponding
quinones if the corresponding rifamycin S derivatives are required.
63. Process according to claim 1, wherein rifamycin S is reacted with
4-isobutyl-piperazine in dioxane, using an excess of this amine, and the
reaction is carried out at room temperature or slightly elevated temperature
up to 100°, and 3-(4-isobutyl-1-piperazinyl)-rifamycin SV is isolated, option-
ally after reduction of the reaction mixture, e.g. with ascorbic acid, and the
product obtained is oxidized, prior or after isolation, to the corresponding
quinone, if 3-(4-isobutyl-1-piperazinyl)-rifamycin S is required.
64. Process according to claim 1, wherein 3-(piperazinyl-l)-rifamycin SV
is reacted with isobutyl bromide in the presence of ethyl-diisopropylamine in
a chlorinated aliphatic hydrocarbon or an alcohol, at a temperature between
room temperature and approx. 100°, using approx. 1 mol of each of the reactants,
and the 3-(4-isobutyl-1-piperazinyl)-rifamycin SV obtained is isolated or is
oxidized to the corresponding quinone, if 3-(4-isobutyl-1-piperazinyl)-ri-
famycin S is required.
65. Process according to claim 1, wherein rifamycin S is reacted with
4-methallyl-piperazine in dioxane, using an excess of this amine, and the
reaction is carried out at room temperature or slightly elevated temperature
up to 100°, and 3-methallyl-1-piperazinyl)-rifamycin SV is isolated, option-
ally after reduction of the reaction mixture, e.g. with ascorbic acid, and
the product obtained is oxidized, prior or after isolation, to the correspond-
ing quinone, if 3-(4-methallyl-1-piperazinyl)-rifamycin S is required.

66. Process according to claim 1, wherein 3-(piperazinyl-1)-rifamycin
SV methallyl bromide is reacted with isobutyl bromide in the presence of ethyl-
diisopropylamine in a chlorinated aliphatic hydrocarbon or an alcohol, at a
temperature between room temperature and approx. 100°, using approx.1 mol of
each of the reactants, and the 3-(4-methallyl-1-piperazinyl)-rifamycin SV
obtained is isolated or is oxidized to the corresponding quinone, if 3-(4-
methallyl-l-piperazinyl)-rifamycin S is required.
67. Process according to claim 1, wherein rifamycin S is reacted with
4-cyclohexylmethyl-piperazine in dioxane, using an excess of this amine, and the
reaction is carried out at room temperature or slightly elevated temperature
up to 100°, and 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV is isolated,
optionally after reduction of the reaction mixture, e.g. with ascorbic acid,
and the product obtained is oxidized, prior or after isolation, to the corres-
ponding quinone, if 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S is required.
68. Process according to claim 1, wherein 3-(piperazinyl-1)-rifamycin
SV is reacted with isobutyl bromide in the presence of ethyl-diisopropylamine
is a chlorinated aliphatic hydrocarbon or an alcohol, at a temperature between
room temperature and approx. 100°, using approx. 1 mol of each of the reactants,
and the 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV obtained is isolated
or is oxidized to the corresponding quinone, if 3-(4-cyclohexylmethyl-1-
piperazinyl)-rifamycin S is required.
69. A product selected from the group consisting of rifamycin S of the
formula
51

<IMG>
(I)
and its corresponding hydroquinone, the rifamycin SV derivative, wherein A
denotes a 4R-1-piperazinyl radical which is optionally substituted at the C
atoms by lower alkyl groups, and wherein R represents a hydrocarbon radical
with not more than 35 C atoms of the formula
(III) <IMG>
in which n = 0 or 1, and Z1 represents, when taken alone, a. an unsubstituted
lower alkyl or lower alkenyl group, b. a lower alkyl or lower alkenyl groups
substituted by a) phenyl or phenylsubstituted by 1 to 3 lower alkyl groups or
halogen atoms or b) C3-C8 cycloalkyl or C3-C8 cycloalkenyl c) phenyl or phenyl
substituted by 1 to 3 lower alkyl groups or halogen atoms c) C3-C8 cycloalkyl
or C3-C8 cycloalkenyl, Z2 represents, when taken alone, hydrogen, or a lower
alkyl or lower alkenyl group, Z3 represents, when taken alone, a lower alkyl or
lower alkenyl group, Z' and Z", when taken alone, each represent hydrogen or
an alkyl group of 1-4 carbon atoms, Z3 taken together with Z" represents a
double bond, Z2 taken together with Z3 represents a lower alkylidene or lower
alkenylidene groups,
52

Z1 taken together with Z3 represents an unsubstituted lower alky-
lene or lower alkenylene groups,
Z1 taken together with Z2 represents an lower alkylene or lower
alkylene group in the case that Z3 taken together with Z''
represents a double bond,
with the proviso that the cycloaliphatic groups mentioned, or
those formed by an alkylene or alkenylene group Z1+Z3 or Z1+Z2
together with the C atom indicated in formula (III) to which Z1,
Z2 and Z3 are bonded, include such having unsubstituted cyclo-
aliphatic rings as well as such whose rings are substituted
by alkyl groups having 1 to 4 C atoms, and such in which
two nonadjacent C atoms of the ring are bonded to one another
directly or through an alkylidene or alkylene group having
1-4 C atoms and such in which another cycloaliphatic ring
having from 3 to 5 C atoms is spirocyclically attached to one
C atom of the ring, with the proviso that all such cycloali-
phatic groups have not more than a total of 12 carbon atoms
and from 3 to 8 ring carbon atoms, any lower alkyl, alkenyl,
alkylidene or alkenylidene group containing from 1 to 7
carbon atoms, or R represents the allyl group, and their salts
and quaternary ammonium salts, whenever prepared or produced
according the process of any of claims 1, 6 and 9 or a process
which is an obvious chemical equivalent thereof.
70. The 3-(4-isobutyl-1-piperazinyl)-rifamycin SV whenever
prepared or produced by the process of claim 63 or a process
which is an obvious chemical equivalent thereof.
53

71. The 3-(4-isobutyl-1-piperazinyl)-rifamycin S when-
ever prepared or produced by the process of claim 63 or a
process which is an obvious chemical equivalent thereof.
72. The 3-(4-isobutyl-1-piperazinyl)-rifamycin SV when-
ever prepared or produced by the process of claim 64 or a
process which is an obvious chemical equivalent thereof.
73. The 3-(4-isobutyl-1-piperazinyl)-rifamycin S whenever
prepared or produced by the process of claim 64 or a process
which is a obvious chemical equivalent thereof.
74. The 3-(4-methallyl-1-piperazinyl)-rifamycin SV
whenever prepared or produced by the process of claim 65 or
a process which is an obvious chemical equivalent thereof.
75. The 3-(4-methallyl-1-piperazinyl)-rifamycin S whenever
prepared or produced by the process of claim 65 or a process
which is an obvious chemical equivalent thereof.
76. The 3-(4-methallyl-1-piperazinyl)-rifamycin SV whenever
prepared or produced by the process of claim 66 or a process
which is an obvious chemical equivalent thereof.
77. The 3-(4-methyallyl-1-piperazinyl)-rifamycin S whenever
prepared or produced by the process of claim 66 or a process
which is an obvious chemical equivalent thereof.
78. The 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV
whenever prepared or produced by the process of claim 67
or a process which is an obvious chemical equivalent thereof.
54

79. The 3-(4-cyclohexylmethyl-l-piperazinyl)-rifamycin S
whenever prepared or produced by the process of claim 63
or a process which is an obvious chemical equivalent thereof.
80. The 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV
whenever prepared or produced by the process of claim 68
or a process which is an obvious chemical equivalent thereof.
81. The 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S
whenever prepared or produced by the process of claim 68
or a process which is an obvious chemical equivalent thereof.
82. Process according to anyone of claims 9-11, wherein
there is used an alkylating agent introducing the isobutyl
group in the N'-position of 3-(piperazinyl-1)-rifamycin S,
and 3-(4-isobutyl-1-piperazinyl)-rifamycin S is isolated,
and this product is reduced to the corresponding hydroquinone,
if 3-(4-isobutyl-1-piperazinyl)-rifamycin SV is required.
83. Process according to anyone of Claims 12-14,
wherein there is used an alkylating agent introducing the
isobutyl group in the N'-position of 3-(piperazinyl-1)-
rifamycin S, and 3-(4-isobutyl-1-piperazinyl)-rifamycin S
is isolated, and this product is reduced to the corresponding
hydroquinone, if 3-(4-isobutyl-l-piperazinyl)-rifamycin SV is
required.
84. Process according to claim 1, wherein 3-( piperazinyl-
l)-rifamycin S is reacted with isobutyl bromide in the presence
of ethyl-diisopropylamine in a chlorinated aliphatic hydro-

carbon or an alcohol, at a temperature between room temperature
and approx. 100°, using approx. 1 mol of each of the reactants,
and the 3-(4-isobutyl-1-piperazinyl)-rifamycin S obtained is
isolated or is reduced to the corresponding hydroquinone,
if 3-(4-isobutyl-1-piperazinyl)-rifamycin SV is required.
85. Process according to anyone of claims 9-11,
wherein there is used an alkylating agent introducing the
methallyl group in the N'-position of 3-(piperazinyl-1)-
rifamycin S, and 3-(4-methallyl-1-piperazinyl)-rifamycin S
is isolated, and this product is reduced to the corresponding
hydroquinone, if 3-(4-methallyl-1-piperazinyl)-rifamycin SV
is required.
86. Process according to anyone of claims 12-14,
wherein there is used an alkylating agent introducing the
methallyl group in the N'-position of 3-(piperazinyl-1)-
rifamycin S, and 3-(4-methallyl-1-piperazinyl)-rifamycin S
is isolated, and this product is reduced to the corresponding
hydroquinone, if 3-(4-methallyl-1-piperazinyl)-rifamycin SV
is required.
87. Process according to claim 1, wherein 3-(piperazinyl-
l)-rifamycin S is reacted with methallyl bromide in the presence
of ethyl-diisopropylamine in an chlorinated hydrocarbon or
an alcohol, at a temperature between room temperature and approx.
100°, using approx. 1 mol each of the reactants, and the 3-(4-
methallyl-l-piperazinyl)-rifamycin S is isolated or is reduced
to the corresponding hydroquinone, if 3-(4-methallyl-1-piperazin-
yl)-rifamycin SV is required.
56

88. Process according to anyone of claims 9-11, wherein
there is used an alkylating agent introducing the cyclohexyl-
methyl group in the N'-position of 3-(piperazinyl-1)-rifamycin S,
and 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S is iso-
lated, and this product is reduced to the corresponding hydro-
quinone, if 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV
is required.
89. Process according to anyone of Claims 12-14, wherein
there is used an alkylating agent introducing the cyclohexyl-
methyl group in the N'-position of 3-(piperazinyl-1)-rifamycin S,
and 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S is isolated,
and this product is reduced to the corresponding hydroquinone,
if 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV is required.
90. Process according to claim 1, wherein 3-(piperazinyl-
l)-rifamycin S is reacted with cyclohexylmethyl bromide in the
presence of ethyl-diisopropylamine in a chlorinated aliphatic
hydrocarbon or an alcohol, at a temperature between room
temperature and approx. 100°, using approx. 1 mol of each of
the reactants, and the 3-(4-cyclohexylmethyl-1-piperazinyl)-
rifamycin S obtained is isolated or is reduced to the corres-
ponding hydroquinone, if 3-(4-cyclohexylmethyl-l-piperazinyl)-
rifamycin SV is required.
91. The 3-(4-isobutyl-1-piperazinyl)-rifamycin S whenever
prepared or produced by the process of claim 84 or a process
which is an obvious chemical equivalent thereof.
92. The 3-(4-isobutyl-l-piperazinyl)-rifamycin SV whenever
57

prepared or produced by the process of claim 84 or a process
which is an obvious chemical equivalent thereof.
93. The 3-(4-methallyl-1-piperazinyl)-rifamycin S
whenever prepared or produced by the process of claim 87 or
a process which is an obvious chemical equivalent thereof.
94. The 3-(4-methallyl-1-piperazinyl)-rifamycin SV
whenever prepared or produced by the process of claim 87 or
a process which is an obvious chemical equivalent thereof.
95. The 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S
whenever prepared or produced by the process of claim 90 or
a process which is an obvious chemical equivalent thereof.
96. The 3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin SV
whenever prepared or produced by the process of claim 90 or
a process which is an obvious chemical equivalent thereof.
58

Description

105~934
The subject of the present invention is the manufacture of new deri-
vatives of rifamycin S and SV of high antibiotic activity. These derivatives
are the rifamycin S compounds (I) which are substituted in the 3-position by
an aliphatically substituted amino group and have the following formula
32 31
fH3 CH3
CH3COO ~ 24 OH ~ CH3
(1) 34 CH3 ~ ~ 15
13
and their corresponding hydroquinones, the rifamycin SV derivatives (compounds
II), wherein A denotes a 4R-l-piperazinyl radical which is optionally sub-
stituted at the C atoms by lower alkyl groups, and wherein R represents a
hydrocarbon radical with not more than 35 C atoms of the following formula
CH ~ H~ -C ~ Z
-2-

" 1055934
in which n = O or 1, and Zl represents, when talcen alone,
a. an unsubstituted lower alkyl or lower alkenyl group,
b. a lower alkyl or lo~er alkenyl groups substituted by
a) phenyl orphenyl.substituted by 1 to 3 lower alkyl gro~lps
or halogen atoms or
b) C3-C8 cycloalkyl or C3-C8 cycloalkenyl
c) phenyl or phenyl substituted by 1 to 3 lower alkyl groups
or halogen atoms
c) C3-C8 cycloalkyl or C3-C8 cycloalkenyl
Z2 represents, ~hen taken alone, hydrogen, or a lower alkyl or
lower alkenyl group,
Z3 represents, when taken alone, a lower alkyl or lower al.kenyl
group,
Z' and Z " , when taken alone, each represent hydrogen or an
alkyl group of 1-4 carbon atoms,
Z3 taken together with Z " represents a double bond,
Z2 taken together with Z3 representsa lower alkyli.dcne or lower
alkenylidene groups, `
Zl taken together with Z3 represents an unsubstituted lo~er alky-
lene or lo-~er alkenylene groups,
Zl taken together with Z2 represents a lower alkylene or lower
alkylene group in the case that Z3 ta~en together witll Z "
represents a double bond,
with the proviso ~hat the cycloaliphatic groups mentioned, or
those formed by an alkylene or alkenylene group Zl+z3 or Zl~-z2
together with the C a~-om indicated in formul.a (III) LO ~,hich Z
Z2 and Z3 are bonded, include such having unsuhs~ituted cyclo-
~ 2a -

`"` 1(~55934
aliphatic rings as well as sucl~ wllose rings are s~bstitutcd
~y alkyl groups having 1 to 4 C atoms, and such in whic~l
two nonadjacent C atoms of tlle ring are bonded to one another
directly or through an alkylidene or allcylene group having
1-4 C atoms and such in which another cycloaliphatic ring
having ~rom 3 to 5 C atoms is spirocyclically a~ached to one
C atom of the ring, Witll the proviso that all such cycloali~
~hatic groups have not more than a total of 12 carbon atoms
and from 3 to 8 ring carbon atoms, any lower alkyl, alkenyl,
alkylidene or alken~lidene group containing from 1 to 7
carbon atoms or R represents the allyl group, and their salts
and qua~ernary ammonium salts, characterised in that rifamy-
cin S is reacted ~itll an amine of the formula ~, wherein A
has the same meaning as above, or that 3-(1-piperazinyl)-rifamy-
cin S or SV, which can optionally be substituted by lower alkyl
radicals at the C atoms o~ the piperazinyl radical, is reacted
with an alkylating agent which is suitable for the N-alkylation
of piperazines and introduces the radical R, R having the
above meaning, and that the resulting 3-amino-substitution
product of ri~amycin S or rifamycin SV is isolated and/or,
if desired, before or after isolation a resulting hydroquinone is
oxidised to the quinone or a resulting quinone is reduced to
the hydroquinone and/or a resulting compound is converted into
a salt.
By alkenyl or cycloalkenyl, or alkenylidene or
alkenylene groups, there are to be understood hydrocarbon
radicals with one or more double bonds.
Lower alkyl, lower alkenyl and lower alkylidene or
lower alkenylidene groups are those with up to 7 C atoms,

` ` 1055g34
An alkylene or alkenylene group Zl ~ Z3 together with the C atom of the above-
mentioned formula, to which it is bonded, forms a cycloalkyl or cycloalkenyl
group with a total of not more than 12 C atoms, and here again a cycloalkenyl
group is to be understood as a group with one or more double bonds. Prefer-
ably, straight or branched alkylene groups can be used which accordingly form
cycloalkyl radicals with 3 8 ring C atoms and above all 5-6 ring C atoms or
cycloalkenyl radicals with, preferably, 5-8 ring C atoms. Straight-chain
alkylene groups or alkenylene groups together with the abovementioned C atoms
of the above formula give unsubstituted cycloaliphatic rings and in the case
of branched alkylene groups the rings formed are substituted by alkyl groups,
especially lower alkyl groups with 1-4 C atoms, above all methyl groups. Such
cycloalkyl groups with 3-8 C atoms in the ring are, for example, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 2,6-di-
methylcyclohexyl or 3,5-dimethylcyclohexyl groups or 1-methyl-4-isopropylcyclo-
hexyl (p-menthyl) or l-methyl-3-isopropylcyclohexyl (m-menthyl) groups.
Examples of cycloalkenyl groups which should be mentioned are: 1-
cyclopenten-l-yl, 2-cyclopenten-1-yl,
_~,~, -4-

~ 055934
3-cyclopenten-l-yl, 2,4-cyclopentadien-l-yl, l-cyclohexen-l-yl,
2-cyclohexen-l-yl, 3-cyclohexen-l-yl, 1,3-cyclohexadien-l-yl
and 1,4-cyclohexadien-l-yl, l-p-menthen-4-yl, 2-p-menthen-l-yl,
3-p-men~hen-l-~Jl or optionally other isomers of this grou~, or
corresponding compounds with ~JO double bonds, such as the
hydrocarbon radicals of the terpinenes, of the phellandrenes,
of the limonenes or of the menthadienes.
A cycloalkyl or cycloalkenyl group which may repre-
sent the radical Zl or occur in this radical or represent Zl
+ Z2 together with the C-atom to which this group is bonded,
can also be unsubstituted or substituted by lower alkyl
groups and has not morethan 12 C atoms and is,
above all, a cycloalkyl radical lit~ 3-8 ring C atoms and
especially 5-6 ring C atoms or a cycloalkenyl radical with
-8 ring C atoms, these radicals being unsubstituted or
substituted by lower al~yl groups, especially ~ith 1-4 C
atoms, above all methyl groups, and can be, ~or example, one
of ~he specific groups of this type whlch have just been
mentioned.
The cycloalkyl or cycloalkenyl groups can also be
bridged directly or via a lower alkylidene or alkylene group,
with 1-4 C atoms, such as a methylene, ethylene or isopropyli-
dene group, or can be spirocyclically substituted by another
cycloaliphatic ring having 3 to 5 ring C atoms. Such groups
are, for example, the hydrocarbon radicals of bicyclohexanes,
bicycloheptanes or bicyclooctanes and their
derivatives substituted by lower

1055934
alkyl groups, such as the hydrocarbon radicals of the
bicyclic terpenes of the thujane, pinane or bornane group.
me abovementioned phenyl radicals can be unsub-
stituted or substituted by halogen, such as, for example, by
chlorine, fluorine or bromine, or by lower alkyl radicals,that
is to say those with 1-7 C atoms, especially by methyl
groups.
me group R has preferably not more than 35 C atoms
and in particular has between 4 and 16 C atoms.
Lower alkyl groups Z' and Z" in the indicated
formula (III) are those with 1-7 C atoms, especially 1-4 C
atoms, such as one of those mentioned above, but above all
methyl groups.
Amongst the compounds (I) and (II) there are
especially to be singled out those in which the group A
denotes a 4R-l-piperazinyl radical which is unsubstituted
at the C atoms and wherein R has one of the following
formulae:
Ph
- (CH2~ - C ~ -- (CH~ ~ C - V2
V3 . 3
, '. - .
(IV) (V)
-- 6 --

.1055934
C, y . CAlk) Py
- ~CH~ - C - V~ ~ CH ) - C V
3 V3
(~I) (VII)
wherein n = l or 2 and Vl and V2 each denote æn alkyl or
alkenyl group with 1-4 C atoms, V3 denotes hydrogen or an
alkyl or alkenyl group with 1-4 C atoms, or, together with
V2 denotes an alkylidene or alkenylidene group
with 1-4 C atoms, Ph denotes a phenyl group which is
unsubstituted or substituted by chlorine or bromine atoms
and/or methyl grou~s, Cy denotes a c~cloalXyl or cyclo-
alkenyl group with 5-8 ring C atoms, wherein the ring can
optionally be substituted by lo~"er alkyl groups wlth 1-4 C
atoms, Py denotes a cycloalkyl or cycloal~enyl group of this
type or a p~enyl group as defined above and "Alk" denotes
a straight-chain or branched alXylene group with 2-4 C atoms
or an alkylidene group with 1-4 C atoms. The said alkyl,
alkenyl, alkylidene or alkenylidene groups with 1-4 C atoms
are, for example, those mentioned above, in particular, methyl,
ethyl or propyl groups, or vinyl or allyl or methallyl groups
or methylene, ethylidene,propylidene or isopropylidene groups
or vinylidene or 2-propen-1-ylidene groups~ The said alkylene
group with 2-4 C atoms is in particular an ethylene or
L~,

105~93Y
trimethylene group. A cycloalkyl or cycloalXenyl group Cy
is, in particular, a group of this type with 5-6 ring C
atoms, that is to say a cyclopentyl or cyclohexyl group, or
a corresponding mono-unsaturated and/or lower alXyl-
substituted hydrocarbon radical, such as, for example, one
of those mentioned above. Preferably, 1-3 of the substitu-
ents mentioned are optionally present in ~he said phenyl
groups or cycloalkyl rings. The latter can also be
bridged as described above and are then, say, radicals of
the abovementioned t-;pe, for example radicals of the bi-
cyclic terpenes which have been mentioned.
A class of compounds (I) and (II) -~rhich is a~so
preferred are compounds in which the group A denotes a
4R-l-piperazinyl radical which is unsubstituted at the C
atoms and wherein R has the following formula:
~2~ ; ~ 'r2
(~III)
wherein n = 1 or 2 and m = 1-4, and W1, W2 and W3 denote

1055934
methyl groups, which are optionally present at any desired ring C atom,
their derivatives which are monounsaturated in the cycloaliphatic ring of
the formula VIII, and derivatives of these compounds having a bridged cyclo-
aliphatic ring, the bridge being a methylene, ethylene or isopropylidene group
or a direct C,C bond. Examples of saturated and unsaturated cycloaliphatic
rings according to the formula VIII are to be found amongst those generally
mentioned above for the compounds (I) and (II). In particular, in these com-
pounds, m = 1 or 2~ Such rings, if they are substituted, particularly carry
1-2 methyl groups~
Amongst the compounds of the present invention having the partial
formulae ~III) - (VIII) for the radical R according to the above definition,
compounds of particular importance are those wherein n = 1, and in turn parti-
cularly those in which the radicals Vl - V3, Py, Cy and "Alk" in the formula
(VII) have the meaning specified above or in the formula VIII the cycloali-
phatic ring is a cyclopentyl or

1055934
cyclohexyl rin~ or a corresponding radical which is mono-
unsaturated and/or substituted by methyl groups, especially
1-2 methyl groups.
The new compounds (I) and (II) include, for example,
3-(4-isobutyl-1-piperazinyl)-rifamycin S and SV, 3-[4-(2-
ethylbutyl)-l-piperazinyl]-rifamycin S and SV, 3-[4-(2-
methylbutyl)-l-piperazinyl]-rifamycin S and SV, 3-[4-(2-
methylpentyl)-l-piperazinyl]-rifamycin S and SV, 3-[4-(2-
phenylpropyl)-l-piperazinyl]-rifamycin S and SV, 3-(4-
methallyl-l-piperazinyl)-rifamycin S and SV, 3-[4-(2-methyl-
3-butenyl)-1-piperazinyl]-rifamycin S and SV, 3-(4-cyclo-
hexylmethyl-l-piperazinyl)-rifamycin S and SV, 3-[4-(4-
methylcyclohexylmethyl)-l-piperazinyl]-rifamycin S and SV,
3-[4-(4-tert. butylcyclohexylmethyl)-l-piperazinyl]-
rifamycin S and SV, 3-[4-(4-isobutylcyclohexylmethyl)-1-
piperazinyl]-rifamycin S and SV, 3-[4-(4-isopropylcyclo-
hexylmethyl)-l-piperazinyl]-rifamycin S and SV, 3-[4-(3-
methylcyclohexylmethyl)-l-piperazinyl]-rifamycin S and SV,
3-[4-(3,4-dimethylcyclohexylmethyl)-1-piperazinyl]-rifa-
mycin S and SV, 3-[4-(3,5-dimethylcyclohexylmethyl)-1-
piperazinyl]-rifamycin S and SV, 3-[4-(3-cyclohexenylmethyl)-
].-piperazinyl]-rifamycin S and SV, 3-(4-cyclopropylmethyl-
l-piperazinyl)-rifamycin S and SV, 3-(4-cycloheptylmethyl-
l-piperazinyl)-rifamycin S and SV, 3-[4-(2-cyclohexylpropyl)-
l-piperazinyl]-rifamycin S and SV or 3-[4-(2-cyclohexyl-
butyl-l-piperazinyl]-rifamycin S and SV, 3-(4-cyclooctyl-
methyl-l-piperazinyl)-rifamycin S and SV,-3-[4-(2-methyl-
cyclohexylmethyl)-l-piperazinyl]-rifamycin S and SV and
-- 10 --

1055934
3-[(bicyclo[2.2.1]hept-2-yl-methyl)-l-piperazinyl]-rifamycin
S or SV.
3-Aminorifamycin S and SV compounds having an anti-
biotic action are already known. Thus French Patent No.
1,490,18~ describes rifamycin S and SV compounds which are
substituted in the 3-position by an amino group of aliphatic
character. These compounds have a high antibiotic action
and in particular also exhibit an anti-tuberculosis effect.
The compounds of the present invention are now distinguished,
relative to the compounds described in the said French patent
and also relative to other known rifamycin derivatives having
an anti-tuberculosis action, by having a greater anti-
tuberculosis action, as can be demonstrated in animal experi-
ments, for example on mice. Thus the compounds, when
administered perorally to mice infected with Mycobacterium
bovis, show a pronounced tuberculostatic action in doses of
between l mg/kg and 40 mg/kg. For example, 3-(4-isobutyl-
l-piperazinyl)-rifamycin SV in this test shows an ED50 f
l mg/kg. 3-(4-Cyclohexylmethyl-l-piperazinyl)-rifamycin SV
in the same test also shows an ED50 of l mg/kg. In addition,
the compounds are distinguished by very great therapeutic
breadth in that a significant toxicity only manife ts itself
at a very high dose. Thus, for example, the oral LD50 in
the case of the last-mentioned specific compounds is greater
than 5,000 mg/kg.
The high anti-tuberculosis action can also be demon-
strated by in vitro experiments. Thus the minimum inhibi-
tory concentration in vitro against Mycobacterium bovis is
-- 11 --

~055934
30 times lower in the case of the abovementioned 3-(4-
isobutyl-l-piperazinyl)-rifamycin SV than in the case of the
known tuberculostatic rifamycin medicament Rifampicin,
namely 3-(4-methyl-1-piperazinyl-iminomethyl)-rifamycin SV.
The compounds also have a good anti-bacterial action,
as can also be demonstrated in animal experiments, for
example on mice. Thus they show a pronounced an-tibacterial
action on mice infected with staphylococci, when administered
perorally in doses of between 0.2 and 40 mg/kg.
The new compounds can therefore be used as medica-
ments, above all for tubercular infections, but also for
other infections such as, for example, leprosy, or infections
caused by pyogenic germs, such as, for example, staphylo-
cocci. The new compounds are~however~ also valuable inter-
mediate products for the manufacture of other useful
materials, especially of pharmacologically active compounds.
The new compounds according to the present invention
can be obtained in a manner which is in itself known, for
example in accordance with the indications in the above-
mentioned French patent, that is to say by reacting rifamycin
S with the amine which corresponds to the group to be intro-
duced into the 3-position.
According to another process, for example, the
piperazinyl radical which is unsubstituted or substituted at
the C atoms is first introduced in the abovementioned manner
into the 3-position of rifamycin S or rifamycin SV and the
radical R is then introduced into the N'-position of the
piperazinyl radical by reaction with an alkylating agent.

1055934
The process for the manufacture of the compounds I
and II of the present application is characterised in that
rifamycin S is reacted with an amine of the formula HA,
wherein A has the same meaning as above or that 3~
piperazinyl)-rifamycin S or SV, which can optionally be sub-
stituted by lower alkyl radicals at the C atoms of the
piperazinyl radical, is reacted with an alkylating agent
which is suitable for the N-alkylation of piperazines and
introduces the radical R, R having the above meaning, and
that the resul-ting 3-amino-substitution product of rifamycin
S or rifamycin SV is isolated and/or, if desired, before or
after isolation a resulting hydroquinone is oxidised to the
quinone or a resul~ing quinone is reduced to the hydro-
quinone and/or a resulting compound is converted into a salt.
The reaction of rifamycin S with the amine HA is
suitably carried out in an organic solvent which is free from
hydroxyl groups, preferably of low polarity, such as halo-
genated aliphatic hydrocarbons, such as methylene chloride or
chloroform, esters or ethers, such as, for example, ethyl
r~ ~ellosol~e ~
~'~ acetate, butyl acetate, amyl acetate or collosolv~ or in
tetrahydrofurane and above all in dioxane. If the amine to
be reacted is liquid, it is possible to dispense with the
addition of a solvent. Suitably, an excess (~-10 mols) of
amine is used. The reaction is advantageously carried out
a-t room temperature or, for example if it takes place slowly,
at an elevated temperature, for example at between room
temperature and 100. The course of the reaction can be
followed by thin layer chromatography.
- 13 -
~c ffa~e~7ark

105593~
In the reaction of ~ piperazinyl-rifamycin S or SV
or of its abovementioned C-methyl homologues with the alkyl-
ating agen-t mentioned, alkylating agen-ts of the formula XR
are used in particular, wherein X denotes a halogen, such
as, for example, chlorine, bromine or iodine, or the radical
of an oxygen-containing inorganic acid, such as a sulphuric
acid or sulphurous acid, or of a halogenosulphuric acid, such
as, in particular, fluorosulphonic acid. Such alkylating
agents are thus, for example, alkyl halides, such as, for
example, the bromides, iodides or chlorides of the hydro-
carbon radical R, or the R-monoesters or R-diesters of sul-
phuric acid or of fluorosulphonic acid.
The reaction of the said rifamycin compound with
these alkylating agen-ts is preferably carried out in the pre-
sence of a base, especially of a strongly basic, non-
nucleophilic tertiary amine, in particular an amine of the
formula
,,/ 1
X N
\X
wherein X denotes a lower alkyl group and Xl and X2 each
denote a bulky aliphatic hydrocarbon radical. The groups
Xl and X2 are, for example, lower alkyl groups with 1-12 C
atoms, preferably with 1-7 C atoms, which have a br~nched
carbon chain, whilst X preferably denotes a lower alkyl group
with 1-7 C a-toms. Above all, the so-called Hunig s base 7
that is to say ethyl-diisopropylamine, is used.
The reac-tion is advantageously carried o~t in an

1055934
inert solven-t, such as, in particular, a chlorinated ali-
phatic hydrocarbon, for example methylene chloride, or an
alcohol 7 such as methanol, at ternperatures between room
temperature and approx. 100, using 1 mol each of the rifa-
mycin compound and of the alkylating agent and also prefer-
ably adding the base in an equimolar ratio. The reaction
time varies according to the reactants and can be from half
an hour to 24 or 48 hours.
The starting materials for the process methods des-
cribed above are known or can be manufactured in a manner
which is in itself known. For example, 3-piperazino-
rifamycin SV to be used as a possible starting material, is
obtained according to the process of the abovementioned
French patent from rifamycin S and piperazine, with sub-
sequent reduction by means of ascorbic acid.
The reaction product is frequently present in the
reaction partially in the form of the quinone and partially
in the form of the hydroquinone. It is advantageous to
convert the reaction product into a single compound in this
respect before working up, that is to say to oxidise the
hydroquinone present to the quinone or reduce the quinone
present to the hydroquinone, and then to isolate the 3-amino-
derivative in either one or the other form. The oxidation
is advantageously carried out with inorg&nic oxidising agents,
preferably potassium ferricyanide and the reduction is prefer-
ably carried out with ascorbic acid or Na dithionite.
The isolation of the reaction product from the reac-
tion mixtures thus obtained or from the reaction mixtures
- 15 -

1055934
obtained in the first place is carried out in a manner
which is in itself known, for example by dilution with water
and/or if appropriate by neutralisation with an aqueous acid,
for example mineral acid or advantageously citric acid, and
addition of a water-immiscible solven-t, such as, for example,
a chlorinated hydrocarbon, for example chloroform or methylene
chloride, whereupon the reaction product passes into the
organic phase from which it can be obtained in a pure form
by the customary methods, that is to say drying, evaporation
and crystallisation and/or chromatography or o-ther customary
methods of purification.
The quinones or hydroquinones thus obtained can
easily be converted into one another, for example by treat-
ment with the abovementioned reducing agents or oxidising
agents.
The quinones are in most cases compounds of a violet-
red colour. The hydroquinones are mos-tly yellow in colour
and crystallise well. The hydroquinones form metal sal-ts,
for example alkali metal salts. With acids, the quinones
and the hydroquinones form acid addition salts and under
certain circumstances also quaternary ammonium salts, especi-
ally with esters of lower alkanols with hydrogen halide
acids, sulphuric acidsor sulphonic acids. To form acid
addition salts, acids suitable for forming therapeutically
usable sal-ts are employed, above all. As examples of these
there may be mentioned: hydrogen halide acids, sulphuric
acids, phosphoric acids, nitric acid and perchloric acid ;
aliphatic, alicyclic, aromatic or heterocyclic carboxylic
- 16 -

~055934
acids or sulphonic acids, such as formic acid, acetic acid,
propionic acid, succinic acid, glycollic acid, lactic acid,
malic acid, tartaric acid, citric acid, ascorbic acid, maleic
acid, hydroxymaleic acid or pyruvic acid; phenylacetic acid,
benzoic acid, p-aminobenzoic acid, anthranilic acid, p-
hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid,
embonic acid, methanesulphonic acid, ethanesulphonic acid,
hydroxyethanesulphonic acid and ethylenesulphonic acid;
halogenobenzenesulphonic acids, toluenesulphonic acids, naph-
thalenesulphonic acids or sulphanilic acid; methionine,
tryptophan, lysine or arginine.
These or other salts of the new compounds, such as,
for example, the picrates, can also serve f~r purification
of the bases obtained, by conver-ting the bases into salts,
isolating these and again liberating the bases from the salts.
Because of the close relationship between the bases in the
free form and in the form of their salts, the free bases are,
in the preceding and following text, where appropriate also
to be understood as the corresponding salts, in respect of
general sense and intended use.
The new compounds can be used, for example, in the
form of pharmaceutical preparations. These contain the
compounds mixed with a pharmaceutical organic or inorganic,
solid or liquid excipient suitable for enteral, topical or
parenteral administration. Suitable materials for forming
the excipien-t are those which do not react with the new com-
pounds, such as, for example, water, gelatine, lactose,
starch, stearyl alcohol, magnesium stearate, talc7 vegetable

lOS5934
oils, benzyl alcohols, gum, propylene glycol, polyalkylene
glycols, white petroleum jelly, cholesterol or other known
medicinal excipients. The pharmaceutical preparations can
be, for example, in the form of tablets, dragees, ointments,
creams or capsules or in a liquid form, as solutions, sus-
pensions or emulsions. They are optionally sterilised
and/or contain auxiliaries, such as preservatives, stabi-
lisers, wetting agents or emulsifiers, solubilising agents
or salts for regulating the osmotic pressure or buffers.
They can also contain yet other therapeutically valuable
substances. The preparations are obtained according to
customary methods.
The new compounds can also be used in veterinary
medicine, for example in one of the abovementioned forms.
The invention also relates to those embodiments of
the process described above for the manufacture of the new
3-amino-rifamycin compounds, in which a compound obtainable
as an intermediate product at any stage is used as the
starting material and the missing process steps are carried
out, or the starting materials are formed under the reaction
conditions.
The invention is described in the examples which
follow.
Exam~le l
90 g of rifamycin S are dissolved in a mixture of
100 ml of dioxane and 96 g of l-isobutylpiperazine and the
solution is left to stand at room temperature for 28 hours.
After this time, water is added, the mixture is acidified
- 18 -

1055934
with citric acid and the reaction product is taken up with chloroform. The
chloroform solution is washed with sodium chloride solution, dried with mag-
nesium sulphate and evaporated. The residue is dissolved in methanol, aqueous
concentrated ascorbic acid solution is added dropwise until a light yellow
colour is achieved, and the mixture is left to stand. After a short time,
3-(4-isobutyl-1-piperazinyl)-rifamycin SV separates out in yellow crystals
which after two recrystallisations from chloroform-methanol-water melt at 170C.Further quantities are to be found in the last ~wo mother liquors.
W spectrum in 0.01 N alcoholic HCl, maxima in nm (logf): 228(4,53),
298(4.28) and 433(3.90).
Example ?
Analogously to the description in Example 1, 90 g of rifamycin S
are reacted with 100 g of 1-(2-ethylbutyl) piperazine, and 3~4-(2-ethylbutyl)-
l-piperazinyl]~rifamycin SV is thus obtained.
Example 3
Analogously to the description in Example 1, 90 g of rifamycin S are
reacted with 100 g of 1-~2-methylbutyl)-piperazine, and 3-[4-(2-methylbutyl)-1
-piperazinyl]-rifamycin SV is thus obtained.
Example 4
Pharmaceutical preparations, in the form of pushfit capsules, con-
taining 3-(4-isobutyl-1-piperazinyl)-rifamycin SV as the antibiotic.
-19-

1055934
Composition
3-(4-Isobutyl-l-piperazinyl)-rifamycin SV 50.00 mg
Lactose 100.00 mg
Ethylcellulose 1.50 mg
Stearic acid 1.50 mg
153.00 mg
Manufacture
1) The active substance is mixed with the lactose_
2) The ethylcellulose is dissolved in a 10-fold
quantity of methylene chloride,
3) Mixture 1) is moistened with solution 2) and beaten
through a sieve of 3-5 mm mesh width and dried at a tempera-
ture not exceeding 40C.
4) The dry granules are beaten through a sieve of
0.5 mm mesh width and mixed with pulverulent stearic acid.he mixture is then filled into push-fit capsules of size 2.
Example 5
30 g of l-cyclohexylmethylpiperazine are added to a
solution of 30 g of rifamycin S in 100 ml of dioxane and the
mixture is left to stand at room temperature until the
initially violet-blue colour of the reaction mixture has
changed to orange-brown. Water is then added and the mix-
ture is acidified with citric acid. The desired reaction
product is taken up with chloroform. After drying and
evaporating the chloroform solution, the residue which remains
is dissolved in a little methanol and concentrated aqueous ascorbic
acid solution is added dropwise until the ini-tially dark
coloration o~ the methanol solution has become golden yellow.
_ 20 -

1055934
After brief standing, 3-(4-cyclohexylmethyl-1-piperazinyl)-
rifamycin SV crystallises and is obtained completely pure
after two recrystallisations from chloroform-methanol-water.
Melting point 176-178C. The mother liquor of the first
crystallisation contains almost exclusively rifamycin SV
alongside the desired reaction product.
UV spectrum in 0.01 N alcoholic HCl, maxima in nm
(log~): 228(4.53), 298(4.28) and 433(3.90).
Example 6
Following an analogous procedure to that described
in the preceding example, 25 g of rifamycin S in 40 ml of
dioxane with 30 g of l-cyclopropylmethylpiperazine give
3-(4-cyclopropylmethyl-1-piperazinyl)-rifamycin SV, which
after three crystallisations from chloroform-methanol-water
is obtained in yellow crystals of melting point 217C.
W spectrum in 0.01 N alcoholic HCl, maxima in nm (log):
225(4.54), 272(4.30) and 430(3.81).
Example 7
Pharmaceutical preparations, in the form of push-
fit capsules, containing 3-(4-cyclohexylmethyl-1-piperazinyl)-
rifamycin SV as the antibiotic.
Composition
3-(4-Cyclohexylmethyl-l-piperazinyl) rifamycin SV 100.00 mg
Lactose 50.00 mg
Ethylcellulose 1.50 mg
Stearic acid 1.50 mg
153.00 mg
- 21 -

1055934
Manufacture
1) The active subs-tance is mixed with the lactose.
2) The ethylcellulose is dissolved in a 10-fold
quantity of me-thylene chloride.
3) Mixture 1) is moistened with solution 2) and beaten
through a sieve of 3-5 mm mesh width and dried at a tempera-
ture not exceeding 40C.
4) The dry granulès are beaten through a sieve of
0.5 mm mesh width and mixed with pulverulent stearic acid.
The mixture is then filled into push-fit capsules cf size 2.
Example 8
20 g of rifamycin S are dissolved in a mixture of
100 ml of dioxane and 27 g of N-methallylpiperazine and the
solution is left to stand at room temperature for 35 hours.
After this time, water is added, the mixture is acidified
with citric acid and the reaction product is taken up
with chloroform. The chloroform solution is washed with
sodium chloride solution, dried over sodium sulphate and
evaporated. me residue is dissolved in methanol,aqueous oonoen-
trated ascorbic acid solution is added dropwise until a
light colour is achieved and the mixture is left to stand.
After a short time, 3-(4-methallyl-1-piperazinyl)-rifamycin
SV separates out in yellow crystals which after two
recrystallisations from chloroform-methanol-water melt
at 172-174C. Further amounts are to be found in the last
t~o mother liquors.
W spectrum in 0.01 N alcoholic HCl, maxima in nm
(log&): 229 (4.59), 298 (4.31) and 435 (3.90).
- 22 -

1055934
Example 9
Analogously to the description in Example 8, 10 g
of rifamycin S are reacted with 12 g of l-allylpiperazine
and 3-[4-allyl-1-piperazinyl]-rifamycin SV of melting point
174-177C is thus obtained.
W spectrum (recorded as in Example 8):228 (4.60),
297 (4.32) and 435 (3.91).
Example_l0
Analogously to the description in Example 8, 10 g
of rifamycin S are reacted with 10 g of N-(2-methyl-2-pen-
tenyl)-piperazine and 3-[4-(2-methyl-2-pentenyl)-1-pipera-
zinyl]-rifamycin SV of melting point 164-166C is thus
obtained.
W spectrum (recorded as in Example 8):228 (4.58),
298 (4.30) and 435 (3.92).
Example 11
Analogously to the description in Example 8, 20 g
of rifamycin S are reacted with 20 g of N-(2-ethyl-2-
butenyl)-piperazine and 3-[4-(2-ethyl-2-butenyl)-1-pipera-
zinyl]-rifamycin SV of melting point 174-175C is thus
obtained.
W spectrum (recorded as in Example 8):229 (4.60),
298 (4.33) and 435 (3.93).
Example 12
Analogously to the description in Example 8, 15 g
of rifamycin S are reacted with 16 g of N-(2-ethyl-2-
hexenyl)-piperazine and 3-[4-(2-ethyl-2-hexenyl)-1-
piperazinyl]-rifamycin SV of mel-ting point 153-156C is
- 23 -

1055934
thus obtained.
UV spectrum (recorded as in Example 8): 229 (4.61),
298 (4.33) and 435 (3.94).
Example 13
Analogously to the description in Example 8, 20 g
of rifamycin S are reacted with 20 g of N - (2,3-dimethyl-2-
butenyl)-piperazine and 3-C4-(2,3-dimethyl-2-butenyl)-1-
piperazinyl]-rifamycin SV of melting point 171-174C is
thus obtained.
W spectrum (recorded as in Example 8):230 (4.60),
300 (4.33) and 435 (3.93).
Example 14
Analogously to the description in Example 8, 10 g
of rifamycin S are reacted with 11 g of N-(2-ethylbutyl)-
piperazine and 3-[4-(2-ethylbutyl)-1-piperazinyl]-rifamycin
SV of melting point 168-170C is thus obtained.
- W spectrum (recorded as in Example 8):228 (4.47),
299 (4.32) and 435 (3.94).
Example 15
A mixture of 55 ml of ethanol, 1 ml of water, 1.15 g
of cyclobutylmethyl bromide (2 equivalents) and 2.5 ml
(approx. 2 equivalents) of Hunig's base (ethyl-diisopropyl-
amine) is added to 3 g of 3-(1-piperazinyl)-rifamycin SV and
the solution is warmed under reflux for 20 hours. After
this time, water is added, the mixture is acidified with
citric acid and the reaction product is taken up w th chloro-
form. The chloroform solution is washed with sodium
chloride solution, dried with sodium sulphate and evaporated.
- 24 ~

~QSS934
The residue is dissolved in methanol, a few drops of aqueous
concentrated ascorbic acid solution are added and the mix-
ture is left to stand. After a short time 3-(4-cyclobutyl-
methyl-l-piperazinyl)-rifamycin SV separa+es out in yellow
crystals which after two recrystallisations from chloroform-
methanol-water slowly decompose above 195C. Further
quantities are to be found in the last two mother liquors.
W spectrum in 0.01 N alcoholic HCl, maxima in nm
(logÇ): 230 (4.58), 299 (4.30) and 435 (3.90).
~ . .
Analogously to the description in Example 15, 5 g
of 3-(1-piperazinyl)-rifamycin SV are reacted with 2.1 g
(2 equivalents) of cyclopentylmethyl bromide and 2.5 ml
(2 equi~alents) of Hùnig base and 3-(4-cyclobutylmethyl-1-
piperazinyl)-rifamycin SV of melting point 180-185C
(decomposition) is thus obtained.
W spectrum: 228 (4.58), 298 (4.31) and 435 (3.92)
(recorded as in Example 8).
Example 17
Analogously to the description in Example 15, 10 g
of rifamycin S are reacted with 10 g of N-(1,2-dimethyl-
propyl)-piperazine and 3-[4-(1,2-dimethylpropyl)-1-
piperazinyl]-rifamycin SV of melting point 184-186C is
thus obtained
W spectrum: 230 (4,58), 299 (4.33) and 435 (3.93)
(recorded as in Example 8).
Example 18
If rifamycin S is reacted in the manner indicated
- 25 -

~055934
below with the N-substituted piperazines listed in the
first column of the table which follows, the rifamycin SV
derivatives substituted in the 3-position by the corresponding
N'-substituted l-piperazinyl radical are obtained, which have
the physical data listed in the table.
- 26 -

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- 27 -

1055934
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Manufacture: 1055934
The stated amount of amine is added to a solution
of -the stated amount of rifamycin S in -the stated amount of
dioxane and the mixture is left to stand at room temperature
until the initially violet-blue colour of the reaction mixture
has changed -to orange-red. Water is then added and the mix-
ture is acidified with citric acid. The desired reaction
product is taken up in chloroform. After drying and
evaporating the chloroform solution, the residue which remains
is dissolved in a little methanol and concentrated aqueous
ascorbic acid sollltion is added dropwise until the initially
dark coloration of the methanol solution has changed to golden
yellow. After brief standing, the desired product crystal-
lises and is obtained completely pure after two recrystal-
lisations from chloroform-methanol-water. For melting
points, see the table. The mother liquor from the first
recrystallisation contains almost exclusively rifamycin SV
alongside the desired reaction product.
The substituted piperazines which figure as starting
materials in the table can in general be obtained by reaction
of the particular alkyl bromides with piperazine in a manner
which is in i-tself known.
In some cases it is advisable to use, instead of
a bromide, the corresponding tosylate; thus, for example,
N-~neopentyl)-piperaz-ne mentioned above can be obtained by
reaction of piperazine with neopen-tyl -tosylate.
~ - 29 _

105S934
SUPPLEMENTARY DISCLOSURE
The following Example also illustrates the invention.
Example 18
The compounds obtained in Examples 1, 3 and 5 are oxidized in the following
manner to the corresponding quinone derivatives. The hydroquinone derivative
is dissolved in aqueous methanolic sodium hydrogen carbonate solution, and
this solution is treated with chloroform and an aqueous solution of potas-
sium ferricyanide solution in excess. After strongly mixing the solution
for 5 minutes, it is acidified with citric acid and the chloroform layer is
separated. After evaporating the chloroform, the residue is crystallised in
ether. The quinones obtained have the following melting points:
3-(4-isobutyl-1-piperazinyl)-rifamycin S F 178 - 179C
3-4[-(2-methylbutyl)-1-piperazinyl]-rifamycin S F 168 - 169C
3-(4-cyclohexylmethyl-1-piperazinyl)-rifamycin S F 188 with decomposition.
-29a-
~,~
~ J