Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-28
2004-08-31
Wang, Shengjun (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S330000, C514S183000, C540S001000, C546S242000, C546S245000, C546S246000, C546S001000, C546S184000
Reexamination Certificate
active
06784193
ABSTRACT:
The present invention relates to compounds having e.g. antimicrobial, e.g. antibacterial, activity; more specifically the present invention relates to mutilins.
In one aspect the present invention provides a compound of formula
wherein
R is hydrogen or alkyl;
R
1
is hydrogen or a group of formula
wherein
X is sulphur, oxygen, NR
10
, wherein R
10
is hydrogen or alkyl, or N
+
(R′
10
)
2
wherein R′
10
is alkyl in the presence of an appropriate anion;
R
9
is amino, alkyl, aryl, heterocyclyl or mercapto; and, if X is oxygen, R
9
is additionally hydrogen;
R
2
is arylene or heterocyclene;
R
4
is hydrogen or alkyl;
R
5
is hydrogen or alkyl;
R
3
and R
3
′ are hydrogen or deuterium,
R
6
, R
7
and R
8
are hydrogen or deuterium; or
R and R
2
together with the nitrogen atom to which they are attached form non-aromatic heterocyclene and R
1
is a group of formula
wherein X and R
9
are as defined above.
R is hydrogen or alkyl, e.g. (C
1-4
)alkyl; preferably hydrogen.
R
1
is hydrogen or a group of formula —C(═X)R
9
, e.g. a group of formula —C(═X)R
9
.
X is sulphur, oxygen, NR
10
, wherein R
10
is hydrogen or alkyl, e.g. (C
1-4
)alkyl, or N
+
(R′
10
)
2
wherein R′
10
is alkyl, e.g. (C
1-4
)alkyl, in the presence of an appropriate anion; preferably oxygen.
R
9
is amino, alkyl, alkoxy, e.g. (C
1-4
)alkoxy; aryl, heterocyclyl or mercapto; e.g. a group of formula —S—R
12
, wherein R
12
is alkyl, e.g. (C
1-4
)alkyl; and, if X is oxygen, R
9
is hydrogen, amino, alkyl, alkoxy, aryl, heterocyclyl or mercapto.
R
9
is preferably alkyl, e.g. (C
1-8
)alkyl, such as (C
1-4
)alkyl, e.g. unsubstituted or substituted alkyl, e.g. substituted by groups which are conventional in pleuromutilin chemistry, e.g. one or more amino, halogen, such as fluoro, e.g. trifluoroalkyl, such as trifluoromethyl; guanidinyl, hydroxy, heterocyclyl, e.g. including a 5 or 6 membered ring containing 1 or 2 nitrogen atoms; e.g. imidazolyl. If R
9
is alkyl substituted by amino, R
9
is preferably the residue of an amino acid, e.g. including valine, histidine, arginine, pipecolinic acid, e.g. said residue includes that part of an amino acid which remains if the carboxylic group is split off.
Or R
9
is preferably heterocyclyl, e.g. 5 or 6 membered heterocyclyl, e.g. containing one or two heteroatoms; e.g. selected from nitrogen; e.g. condensed with a further ring (system), e.g. the further ring system including phenyl; preferably piperidinyl, pyrrolidinyl, pyrrolyl, pyridinyl, benzimidazolyl, quinolinyl, triazolyl; e.g. unsubstituted heterocyclyl or substituted heterocyclyl, e.g. substituted by one or more alkyl, e.g. methyl; hydroxy, amino, nitro, a group COOR
13
, wherein R
13
is alkyl, e.g (C
1-4
)alkyl, such as tert.butyl; e.g. preferably substituted by one or more alkyl hydroxy, amino, nitro.
If R
9
is heterocyclyl, e.g. piperidinyl, hydrogen atoms of the heterocyclyl ring, e.g. in piperidinyl; the hydrogen atom attached to the nitrogen atom of the ring system may be replaced by deuterium.
Amino in the meaning of R
9
includes a free amine group, alkyl- and dialkylamine and amine substituted by —COOR
11
, wherein R
11
is alkyl, preferably (C
1-4
)alkyl. R
2
is arylene, such as phenylene, e.g. unsubstituted arylene or substituted arylene, e.g. substituted by groups which are conventional in pleuromutilin chemistry; e.g. one or more hydroxy, alkyl, e.g. (C
1-4
)alkyl; halogen, e.g. fluoro; trifluoroalkyl; nitro; or heterocyclene. Heterocyclene as used herein is a heterocyclic ring, wherein two bonds are the bonds to the vicinal nitrogen and sulphur group in a compound of formula I. Preferably R
2
is arylene, e.g. unsubstituted arylene or arylene substituted by one or more groups which are conventional in pleuromutilin chemistry, e.g. alkyl, e.g. (C
1-4
)alkyl, such as methyl; halogen such as fluoro; trifluoroalkyl, such as trifluoromethyl. Arylene and heterocyclene in the meaning of R
2
are bound to a sulphur atom and to —N(R)(R
1
) in a compound of formula I. These two bonds may be vicinal or in another position, e.g. in ortho, para or meta position; in the corresponding ring system. Heterocyclene is preferably bound to the sulphur atom and to —N(R)(R
1
) in a compound of formula I via carbon atoms of heterocyclene.
R
4
is hydrogen or alkyl; preferably hydrogen or (C
1-4
)alkyl, e.g. methyl.
R
5
is hydrogen or alkyl, preferably hydrogen or (C
1-4
)alkyl such as methyl; e.g. unsubstituted alkyl or substituted alkyl, e.g. substituted by hydroxy; more preferably R
5
is hydrogen.
R
3
and R′
3
are hydrogen or deuterium, preferably hydrogen. R
6
, R
7
and R
8
are hydrogen or deuterium.
If R
1
is a group of formula —C(═X)—R
9
, R and R
2
together with the nitrogen atom to which they are attached may form non-aromatic heterocyclene, e.g. having 5 to 6 ring members and one heteroatom, e.g. nitrogen; preferably including piperidinyl, pyrrolidinyl, preferably piperidine. Preferably said heterocyclene is bound to the sulphur group and to the —N(R
1
) group in a compound of formula I via heterocyclene carbon atoms.
If not otherwise defined herein heterocyclyl or heterocyclene includes a 5 or 6 membered ring having 1 to 4 heteroatoms selected from S, O and N; e.g. N; optionally condensed with a further ring (system), e.g. condensed with a phenyl ring; e.g. or condensed with a heterocyclyl ring, e.g. including quinoline, purine. Heterocycl(ene) includes unsubstituted or substituted heterocycl(ene), e.g. substituted by groups which are conventional in pleuromutilin chemistry, e.g. including alkyl; hydroxy, amino, nitro, a group COOR
13
, wherein R
13
is alkyl. Alkyl includes (C
1-8
)alkyl, e.g. (C
1-4
)alkyl. Aryl includes phenyl.
In another aspect the present invention provides a compound of formula I, wherein
R is hydrogen;
R
1
is hydrogen or a group of formula
wherein X is sulphur, oxygen, NR
10
, wherein R
10
is hydrogen or alkyl, or N
+
(R′
10
)
2
wherein
R′
10
is alkyl in the presence of an appropriate anion; e.g. Cl
−
;
R
9
is amino, alkyl, heterocyclyl or mercapto; and, if X is oxygen, R
9
is additionally hydrogen;
R
2
is phenylene;
R
4
is hydrogen or alkyl;
R
5
is hydrogen;
R
3
and R
3
′ are hydrogen;
R
6
, R
7
and R
8
are hydrogen or deuterium; or
R and R
2
together with the nitrogen atom to which they are attached form non-aromatic heterocyclene and R
1
is a group of formula
wherein X is oxygen and R
9
is alkyl.
In another aspect the present invention provides a compound of formula
wherein R
1s
is hydrogen or a group of formula
e.g. a group of formula
wherein R
6s
is hydrogen or deuterium;
R
2s
is hydrogen, methyl or tert-butyl;
R
7s
is hydrogen or methyl; and
R
3s
, R
4s
and R
5s
are hydrogen or deuterium; and a compound of formula
wherein R
3ss
, R
4ss
and R
5ss
are hydrogen or deuterium.
A compound of formula I includes a compound of formulae Is and Iss.
In another aspect the.present invention provides a compound of formula I, e.g. including a compound of formula Is and Iss in the form of a salt, or in the form of a salt and in the form of a solvate, or in the form of a solvate.
In another aspect the present invention provides
14-O-(3-amino)phenyl-sulfanylacetyl)-mutilin, e.g. in free form or in the form of a salt, e.g. with hydrochloric acid;
14-O-(3-amino)phenyl-sulfanylacetyl)-2,2,4-trideutero-mutilin, e.g. in free form or in the form of a salt, e.g. with hydrochloric acid or with deuterochloric acid;
14-O-(3-(piperidin-2-yl-carbonylamino)-phenyl-sulfanylacetyl)mutilin, e.g. in free form or in the form of a salt, e.g. with hydrochloric acid;
14-O-(3-(piperidin-2-yl-carbonylamino)phenyl-sulfanylacetyl) -2,2,4-trideutero-mutilin, e.g. in free form or in the form of a salt, e.g. with hydrochloric acid or deuterochloric acid;
14-O-(3-(piperidin-2-yl-carbonylamino)-2,5-dimethyl-phenylthio-methylcarbonyl)mutilin, e.g. in free form or in the form of a salt, e.g. with hydrochloric acid;
14-O-(3-(piperidin-2-yl-carbonylamino)-2,5-dimethyl-phenylthio-
Ascher Gerd
Berner Heinz
Hildebrandt Johannes
Furman Diane E.
Sandoz GmbH
Thallemer John D.
Wang Shengjun
LandOfFree
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