Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2003-01-09
2004-06-22
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C514S529000
Reexamination Certificate
active
06753445
ABSTRACT:
The present invention relates to antibacterials; more specifically to mutilins. Pleuromutilins are naturally occurring antibiotics which have antimycoplasmal activity and modest antibacterial activity. We have found mutilins having the principal ring structure of naturally occurring pleuromutilins which have improved antimicrobial, e.g. antibacterial activity.
In one aspect the present invention provides a compound selected from 14—O—[(cycloalkyl-sulfanyl)acetyl]mutilins; 14—O—[(cycloalkyl-alkyl-sulfanyl)acetyl] mutilins; 14—O—[(cycloalkoxy)acetyl] mutilins; and14—O—[cycloalkyl-alkoxy)acetyl] mutilins; such as 14—O—[(aminocycloalkyl-sulfanyl)acetyl]mutilins; 14—O—[(aminocycloalkyl-alkyl-sulfanyl)acetyl] mutilins; 14—O—[(aminocycloalkoxy)acetyl] mutilins; and 14—O—[(aminocycloalkyl-alkoxy)acetyl] mutilins; preferably 14—O—[(aminocycloalkyl-sulfanyl)acetyl]mutilins; e.g. cycloalkyl is preferably (C
3-12
)cycloalkyl; cycloalkoxy is preferably (C
3-12
)cycloalkoxy; alkyl is preferably (C
1
)alkyl; and alkoxy is preferably (C
1-4
)alkoxy.
In another aspect the present invention provides a compound of formula
wherein
R is hydrogen;
R
1
is hydrogen or a group of formula
wherein
X is sulphur, oxygen or NR
10
, wherein R
10
, is hydrogen or alkyl; and
R
9
is amino, alkyl, aryl or heterocyclyl; and, if X is oxygen, R
9
is additionally hydrogen;
Y is sulphur or oxygen;
R
2
is hydrogen or one or more substituents, e.g. including substituents such as conventional in organic, e.g. (pleuro)mutilin, chemistry;
R
4
is hydrogen or alkyl;
R
5
is hydrogen or alkyl;
R
3
and R
3
′ are hydrogen, deuterium, or halogen;
R
6
, R
7
and R
8
are hydrogen or deuterium;
m is a number selected from 0 to 4;
n is a number selected from 0 to 10; and
p is a number selected from 0 to 10; with the proviso that n plus p are at least 1 and
preferably less than 13.
In formula I, preferably
R is hydrogen;
R
1
is hydrogen or a group of the formula −C(=X)R
9
,
wherein X is oxygen; and
R
9
, is alkyl, e.g. (C
1-8
)alkyl, such as (C
1-4
)alkyl, unsubstituted or substituted alkyl, e.g. substituted by groups which are conventional in organic, e.g. pleuromutilin, chemistry, such as one or more amino; e.g., if R
9
is alkyl substituted by amino, R
9
is preferably the residue of an amino acid, e.g. valine, e.g. said residue includes that part of an amino acid which remains if the carboxylic group is split off;
Y is sulphur;
R
2
is hydrogen;
R
4
, R
5
, R
3
, R′
3
, R
6
, R
7
, and R
8
are hydrogen;
m is o;
n is 3 or4;
p is 0 or 1; and
p plus n is 3 or4.
In another aspect, the invention provides a compound of the formula I
p
wherein R
1p
is hydrogen or the residue of an amino acid; e.g. valyl; e.g. R
1p
is a group of formula —CO—R
9p
wherein R
9p
is the residue of an amino acid which remains if the carboxylic group is split off.
In formula I
p
a group —NH—R
1p
may be in any position of the cyclohexyl ring system and is preferably in position 2, 3, or 4. Amino acid in the meaning of Rap includes any amino acid, preferably valine; and R
9p
is preferably a group —CH(NH
2
)—CH(CH
3
)
2
. The amine group in said amino acid residue may be unprotected or protected, e.g. by appropriate amino acid protection groups, e.g. such as conventional, for example tert.butoxycarbonyl; and is preferably unprotected.
In another aspect, the present invention provides a compound which is:
14—O—[(aminocyclohexan-2-yl-sulfanyl)acetyl]mutilin,
14—O—[(aminocyclohexan-3-yl-sulfanyl)acetyl]mutilin,
14—O—[(aminocyclohexan-4-yl-sulfanyl)acetyl]mutilin,
14—O—[(N-valyl-aminocyclohexan-2-yl)sulfanyl)-acetyl]-mutilin,
14—O—[(N-valyl-aminocyclohexan-3-yl)sulfanyl)-acetyl]-mutilin, or
14—O—[(N-valyl-aminocyclohexan-4-yl)sulfanyl)-acetyl]-mutilin; including
14—O—[(N-(R)-valyl-(R)-aminocyclohexan-2(R)-yl)sulfanyl)-acetyl]-mutilin,
14—O—[(N-(R)-valyl-(R)-aminocyclohexan-2(S)-yl)sulfanyl)-acetyl]-mutilin,
14—O—[(N-(R)-valyl-(R)-aminocyclohexan-3(R)-yl)sulfanyl)-acetyl]-mutilin,
14—O—[(N-(R)-valyl-(R)-aminocyclohexan-3(S)-yl)sulfanyl)-acetyl]-mutilin;
14—O—[(N-(R)-valyl-cis-aminocyclohexan-4-yl)sulfanyl)-acetyl]-mutilin, and
14—O—[(N-(R)-valyl-trans-aminocyclohexan-4-yl)sulfanyl)-acetyl]-mutilin, e.g., in free (base) form or in the form of a salt, such as a hydrochloride.
Preferred compounds include: 14—O—[(aminocyclohexan-4-yl-sulfanyl)acetyl]mutilin and 14—O—[(N-valyl-aminocyclohexan-4-yl)sulfanyl)-acetyl]-mutilin. More preferred is 14—O—[(N-valyl-aminocyclohexan-4-yl)sulfanyl)-acetyl]-mutilin.
A compound provided by the present invention is hereinafter designated as “A compound of the present invention”. The present invention includes a compound of the present invention, e.g. including a compound of formulae I and I
p
, in free (base) form and in the form of a salt, e.g. in the form of a solvate.
In another aspect, the present invention provides a compound of the present invention in the form of a salt, e.g. and in the form of a salt and in the form of a solvate, or in the form of a solvate.
A salt of a compound of the present invention includes a pharmaceutically acceptable salt, e.g. including a metal salt or an acid addition salt. Metal salts include for example alkali or earth alkali salts; acid addition salts include salts of a compound of the present invention with an acid, e.g. hydrogen fumaric acid, fumaric acid, naphthalin-1,5-sulfonic acid, hydrochloric acid, and deuterochloric acid; preferably hydrochloric acid or deuterochloric acid.
A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in unsolvated form; and vice versa.
A compound of the present invention may exist in the form of isomers and mixtures thereof; e.g. a compound of the present invention may contain asymmetric carbon atoms and may thus exist in the form of diastereoisomeres and mixtures thereof. For example, in a compound of formula I
p
, wherein the group —NH—R
1p
is in position 2 or 3 of the cyclohexyl ring, the carbon atom of the cyclohexyl ring which is attached to the side chain of the mutilin ring and the carbon atom of the cyclohexyl ring to which the group —NH—R
1p
is attached are both asymmetric carbon atoms. A compound of formula I
p
wherein the group —NH—R
1p
is in position 2 or 3 of the cyclohexyl ring may thus exist in (R) and (S) configurations in respect to both of these carbon atoms. For example, if R
1p
is the residue of an amino acid, that amino acid may comprise asymmetric carbon atoms. E.g., if R
1p
is valyl, the carbon atom to which the amine group of said valyl is attached is an asymmetric carbon atom. A compound of formula I
p
wherein R
1p
is valyl may thus exist in (R) and in (S) configurations in respect to said valyl carbon atom.
Isomeric or diastereoisomeric mixtures may be separated as appropriate, e.g. according to conventional methods, to obtain pure isomers or diastereoismers, respectively. The present invention includes a compound of the present invention in any isomeric and diasteroisomeric form and in any isomeric and diastereoisomeric mixture. Preferably the configuration in the mutilin ring of a compound of formula I is the same as in a naturally produced pleuromutilin.
A compound of the present invention may be obtained as appropriate, e.g. according to, e.g. analogously, to any conventional method. E.g., 14-O-[(cycloalkyl-sulfanyl)acetyl]mutilins; 14—O—[(cycloalkyl-alkyl-sulfanyl)acetyl] mutilins; 14—O—[(cycloalkoxy)acetyl] mutilins; and 14—O—[(cycloalkyl-alkoxy)acetyl] mutilins of the present invention may be prepared by reacting a 14—O—[(mercapto)acetyl
Ascher Gerd
Berner Heinz
Biochemie Gesellschaft m.b.H.
Furman Diane E.
Killos Paul J.
Thallemer John D.
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