Note: Descriptions are shown in the official language in which they were submitted.
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1
Bis-basic compounds as tryptase inhibitors, processes for preparing them and
their use as pharmaceutical compositions
The present invention relates to bis-basic compounds of general formula (I)
B' -Ar' -X' -A r2-X2-A-X3-A r3-X4-A-4-B 2
(I)
wherein the groups B', B2, Ar', Ar2, Ar3, Ar4, X', X2, X3, X4 and A may have
the
1o meanings given in the following description and in the claims, processes
for
preparing them and their use as pharmaceutical compositions, particularly as
pharmaceutical compositions with a tryptase-inhibiting activity.
Tryptase inhibitors may be used in the production of pharmaceutical
compositions
which are used to prevent and/or treat inflammatory and/or allergic
conditions.
The object of the present invention is therefore to provide new compounds
which
have a tryptase-inhibiting activity and may be used to prevent and treat
conditions in
which tryptase inhibitors may have a therapeutic value.
The compounds according to the invention are bis-basic compounds of general
formula (I)
B' -A r' -X' -A r2-X 2-A-X 3-A r3-.X 4-A r4- B z
(I )
wherein
B' and B 2 which may be identical or different denote -C(=NR')-NR"H, -CH2NH2,
-CH2CH2NH2 or -NH-C(=NH)-NH2;
3o R' and R" which may be identical or different denote hydrogen, OH, -COR2or
-COOR2;
R 2 denotes hydrogen, Cl -C1 g-alkyl, aryl or aryi-Cl -C6-alkyl;
Ar', Ar2, Ar3, Ar4 and aryl
which may be identical or different denote C6-Cl p-aryl, which may
optionally be mono- to tetrasubstituted by one or more groups selected
frpm among C3-Cl p-cycloalkyl, F, Cl , Br, I, OH, OR3, SR3, NR3R4, .
COOR3, Cl-Cg-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, whilst in the
^
CA 02391085 2002-05-10
2
substituents C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen
atoms may optionally be replaced by F or OR3, or
a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three
carbon atoms may be replaced by one or more heteroatoms selected
from among oxygen, nitrogen and sulphur and which may optionally be
mono- to tetrasubstituted by one or more groups selected from among
C1-C10-cycloalkyl, F, CI, Br, I, OH, OR3, SR3, NR3R4, COOR3, C1-C6-
alkyl, C2-C6-alkenyl and C2-C6-alkynyl, whilst in the substituents
C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen atoms may
optionally be replaced by F or OR3;
R3 and R4 which may be identical or different denote hydrogen or a group
selected from among Cl-C6-alkyl and C3-C6-cycloalkyl wherein one or
more hydrogen atoms may optionally be replaced by F;
X',Xz;X3andX4
which may be identical or different denote a bridge selected from
among -(CH2)n-, -(CH2),,O-, -(CH2)n-S-, -(CH2)nNR3- and -(CH2)^3R4-
where n=1 or 2;
A denotes a group selected from among C2-C16-alkylene and C2-C16-
alkenylene, wherein optionally one or more hydrogen atoms may be
replaced by one or more groups selected from among F, R3, OR3 and
COOR3, or A denotes C2-C16-alkynylene, or
A denotes -(CH2); D-(CH2)R,-, whilst in the alkylene groups -(CH2),- and
-(CH2)m one or two hydrogen atoms may optionally be replaced by
C1-C6-alkyl and wherein
D denotes aryl or C3-C10-cycloalkyl wherein one or more hydrogen
atoms may optionally be replaced by one or more groups selected
from among F, R3 and OR3
and I and m, which may be identical or different, denote 0, 1, 2, 3 or
4, or
D denotes -0-, -S- or -NR3-
and I and m, which may be identical or different, denote 2, 3 or 4;
or
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3
A denotes -G1- ( CH2 ) r-G2-, if X2 or X" denote
-(CH2) ,,-, A may also denote -El- (CH2) r-Gl- or -E1- (CH2) r-E2-,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G1 and G2 which may be identical or different
denote a single bond or C3-Clo-cycloalkyl, but if r=0 or r=1
Gl and G2 cannot simultaneously represent a single bond;
E1 and E2 which may be identical or different
denote C3-Clo-aza-cycloalkyl which contains one or two
nitrogen atoms, wherein at least one N-atom is bound to X2 or
x3 =(CH2)nr
optionally in the form of their racemates, enantiomers,
diastereomers, tautomers and mixtures thereof, and optionally
the pharmacologically harmless acid addition salts thereof.
According to one aspect of the present invention,
there is provided a compound of general formula (IA)
B~ B 2
\ /
~
/ o I\ \ O \~
XZ A-x3
(IA)
wherein:
Bl and Bz which are identical or different, denote
-C ( =NRi ) -NR"H, -CH2NH2i -CH2CH2NH2 or -NH-C ( =NH ) -NH2;
R1 and R" which are identical or different, denote
hydrogen, OH, -COR2 or -C00R';
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3a
R2 denotes hydrogen, C1-C18-alkyl, aryl or
aryl-Cl-CE.-alkyl;
X2 and X3 which are identical or different, denote
a bridge selected from the group consisting of -(CH2)õ-,
- ( CH,) r,0-, - ( CH2) õ-S-, - ( CH2 ) NR3- and - (CH2) nN+R3R9- where n=1
or 2;
A denotes a group selected from the group
consisting of C2-C16-alkylene and C2-C16-alkenylene, wherein
one or more hydrogen atoms are optionally replaced by one or
more groups selected from the group consisting of F, R3, OR3
and C00R3, or A denotes CZ-C16-alkynylene, or
A denotes -(CHz) 1-D- (CH2) n,-, wherein, in the
alkylene groups -(CH2) 1- and -(CHZ) m-, one or two hydrogen
atoms are optionally replaced by Cl-C6-alkyl and wherein
D denotes aryl or C3-C10-cycloalkyl wherein one or
more hydrogen atoms are optionally replaced by one or more
groups selected from the group consisting of F, R3 and OR3
and 1 and m, which are identical or different, denote 0, 1,
2, 3 or 4, or
D denotes -0-, -S- or -NR3-
and 1 and m, which are identical or different,
denote 2, 3 or 4;
or
A denotes -G1- (CH2) r-Gz-, and if X2 or X3 denote
-(CH2) õ-, A denotes -Gl- (CHz) r-G2-, -El- (CHz) -G1- or
-E1- ( CH2 ) r-Ez- ~
wherein r denotes 0, 1, 2, 3, 4, 5 or 6,
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3b
GI and G2 which are identical or different, denote
a single bond or Cj-Clo-cycloalkyl, and if r=0 or r=1, G1 and
G2 cannot simultaneously represent a single bond; and
E1 and E` which are identical or different, denote
C3-C10-aza-cycloalkyl which comprises one or two nitrogen
atoms, wherein at least one N-atom is bound to X2 or
X3= (CH2) n,
or a racemate thereof, an enantiomer thereof, a
diastereomer thereof, a tautomer, a mixture thereof, or a
pharmacologically acceptable acid addition salt thereof.
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3c
Preferred compounds of general formula (I) are those wherein
B' and B2 which may be identical or different denote -C(=NR')-NR"H, -CH2NH2,
-CH2CH2NH2 or -NH-C(=NH)-NH2;
R' and R" which may be identical or different denote hydrogen, OH, -COR2or
-COOR2;
R 2 denotes hydrogen, C1-C14-alkyl, aryl or aryl-Cl-Cg-alkyl;
Ar', Ar2, Ar3, ArA and aryl
which may be identical or different, denote C6-C10-aryl which may
optionally be mono- to tetrasubstituted by one or more groups selected
from among C3-C8-cycloalkyl, F, Cl, Br, I, OH, OR3, NR3R4, COOR3,
C1-C6-alkyl, C2-C6-alkenyi and C2-C6-alkynyl, whilst in the
substituents C1-C6-alkyl and C2-C6-alkenyl one or more hydrogen
atoms may optionally be replaced by F, or
a 5-10-membered mono- or bicyclic heteroaryl ring, wherein up to three
carbon atoms may be replaced by one or more heteroatoms selected
from among oxygen, nitrogen and sulphur and
which may optionally be mono- to tetrasubstituted by one or more
groups selected from among F, OR3, COOR3 or C1-C6-alkyl, wherein in
^
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the substituent C1-C6-alkyl one or more hydrogen atoms may
optionally be replaced by F;
R3 and R4 which may be identical or different denote hydrogen or a group
selected from among C1-C6-alkyl and C3-C6-cycloalkyl wherein one or
more hydrogen atoms may optionally be replaced by F;
X', X2, X3 and X4
which may be identical or different denote a bridge selected from
among -(CH2)n-, -(CH2)nO-, -(CH2),-S-, -(CH2)nNR3- and -(CH2),N+R3R4-
where n=1 or 2;
,-.. A denotes a group selected from among C2-C14-alkylene and C2-C10-
alkenylene, wherein optionally one or more hydrogen atoms may be
replaced by one or more groups selected from among F, R3, OR3 and
COOR3, or A denotes C2-C10-alkynylene, or
A denotes -(CH2),-D-(CH2)m , whilst in the alkylene groups -(CH2)1- and
-(CH2)R; one or two hydrogen atoms may optionally be replaced by
C1-C6-alkyl and wherein
D denotes aryl or C3-C8-cycloalkyl wherein one or more hydrogen
atoms may optionally be replaced by one or more groups selected
from among F, R3 and OR3
and I and m, which may be identical or different, denote 0, 1, 2, 3 or
4, or
~--,
D denotes -0-, -S- or -NR3-
and I and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes -G'-(CHZ)-G2-,
if X2 or X3 represents -(CH2)n-, A also denotes
-E'-(CH2)r G'- or -E'-(CH2)r-E2-,
wherein
r denotes the number 0, 1, 2, 3, 4, 5 or 6,
G' and G2 which may be identical or different denote a single bond or
C3-C8-cycloalkyl, but if r=0 or r=1 G' and G2 cannot simultaneously
represent a single bond;
a
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E' and Ez which may be identical or different denote C3-C8-aza-
cycloalkyl which contains one or two nitrogen atoms, wherein at
least one N-atom is bound to X2 or X3 =(CHA,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
5 mixtures thereof, and optionally the pharmacologically harmless acid
addition salts
thereof.
Particularly preferred are compounds of general formula (I), wherein
B' and B2 which may be identical or different denote -C(=NR')-NR''H, -CH2NH2,
-CH2CH2NH2 or -NH-C(=NH)-NH2;
R' and R" which may be identical or different denote hydrogen, OH, -COR2or
-COOR2;
R2 denotes hydrogen, Cl -Cl p-alkyl or aryl-Cl -Cq,-alkyl;
Ar', Ar2, Ar3, Ar4 and aryl
which may be identical or different, denote
phenyl or naphthyl which may optionally be mono-, di- or trisubstituted
by one or more groups selected from among F, OR3, NR3R4, COOR3 or
Cl-Cg-alkyl, wherein in the substituent Cl-Cg-alkyl one or more
hydrogen atoms may optionally be replaced by F or OR3;
R3 and R4 which may be identical or different denote hydrogen or a group
selected from among cyclopropyl, cyclopentyl, cyclohexyl and Cl-Cq.-
alkyl wherein one or more hydrogen atoms may optionally be replaced
by F;
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X', X2, X3 and X4
which may be identical or different denote a bridge selected from
among -(CH2)n-, -(CH2)nO-, -(CH2)n-S-, -(CH2)nNR3- and -(CH2)nN`R3R4-
where n=1 or 2, preferably where n=1;
A denotes C2-C12-alkylene wherein optionally one or more hydrogen
atoms may be replaced by one or more groups selected from among F,
OR3 and COOR3, or
io A denotes -(CH2),-D-(CH2),,,-, whilst in the alkylene groups -(CH2)1- and
-(CH2)m one or two hydrogen atoms may optionally be replaced by a
C1-C4 group and wherein
D denotes a group selected from among phenyl, cyclopentyl and
cyclohexyl wherein one or more hydrogen atoms may optionally be
replaced by one or more groups selected from among F, R3 and
OR3
and I and m, which may be identical or different, denote 0, 1, 2, 3 or
4,
or
D denotes -O- or -NR3-
and I and m, which may be identical or different, denote 2, 3 or 4;
or
A denotes -G'-(CH2)r-G2-,
if X2 or X3 represents -(CHZ)r,-, A also denotes
-E'-(CH2)r-G'- or -E'-(CH2)r-E2-
wherein
r denotes the number 0, 1, 2, 3 or 4,
G' and G2 which may be identical or different denote a single bond,
cyclopentyl, cyclohexyl or cycloheptyl, if r=0 or r=1 G' and G2
cannot simultaneously represent a single bond;
E' and E2 which may be identical or different denote a group selected
from among pyrrolidine, imidazolidine, piperidine and piperazine,
wherein at least one N-atom is bound to X2 or X3 =(CHA,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
mi
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7
Of particular importance according to the invention are compounds of general
formula (I) wherein
B' and B 2 which may be identical or different denote -C(=NR')-NR''H, -CH2NH2,
-CH2CH2NH2 or -NH-C(=NH)-NHZ;
R' and R" which may be identical or different denote hydrogen, OH, -COR2 or
-COOR2, preferably hydrogen or OH,
R2 denotes hydrogen, C1-C6-alkyl or benzyl;
Ar', Ar2, Ar3 and Ar4 which may be identical or different, denote
phenyl which may optionally be mono-, di- or trisubstituted by one or
... more groups selected from among F, OR3, NR3R4, COOR3 or C1-C4-
alkyl, wherein in the substituent C1-C4-alkyl one or more hydrogen
atoms may optionally be replaced by F;
R3 and R4 which may be identical or different denote hydrogen or a group
selected
from among cyclopropyl, cyclopentyl, cyclohexyl and C1-C4-alkyl,
wherein one or more hydrogen atoms may optionally be replaced by F;
X', X2, X3 and X4
which may be identical or different denote a bridge selected from
among -(CH2)n-, -(CH2)nO-, -(CH2)n_S-, -(CH2)nNR3- and -(CH2)nN+R3R4-
where n=1 or 2, preferably where n=1; or
A denotes C2-C12-alkylene wherein one or more hydrogen atoms may
optionally be replaced by one or more groups selected from among F,
OR3 and COOR3, or
3o A denotes -(CH2),-D-(CH2)m-, whilst in the alkylene groups -(CHz); and
-(CH2)m one or two hydrogen atoms may optionally be replaced by a
methyl group and wherein
D denotes a group selected from among phenyl and cyclohexyl
wherein optionally one or more hydrogen atoms may be replaced
by one or more groups selected from among F, R3 and OR3
and I and m, which may be identical or different, denote 0, 1, 2 or 3,
or
D denotes -0- and I and m, which may be identical or different,
denote 2 or 3;
o
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8
or
A denotes -G'-(CH2)r G2-,
if X2 or X3 represents -(CH2)n- A also denotes
-E'-(CH2),-G'- or -E'-(CHz)~-EZ-
wherein
r denotes the number 0, 1, 2 or 3,
G' and G2 which may be identical or different denote a single bond,
cyclopentyl or cyclohexyl, but if r=0 or r=1 G' and G2 cannot
simultaneously represent a single bond;
E' and E2 which may be identical or different denote piperidine or
piperazine, wherein at least one N-atom is bound to X2 or X3 =
(CHA,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
Also of significance according to the invention are compounds of general
formula (I),
wherein
B' and B2 which may be identical or different denote -C(=NR')-NH2, -CH2NH2 or
-CH2CH2NH2;
R' denotes hydrogen, OH, -COR2or -COOR2, preferably hydrogen or OH,
R2 denotes hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl or benzyl;
Ar', Ar2, Ar3 and Ar4 , which may be identical or different, denote phenyl;
X', X2, X3 and X4 which may be identical or different denote a bridge selected
from
among -(CH2)n-, -(CH2),,O-, -(CH2)nNH-, -(CH2),NMe-, -(CH2),NEt-,
-(CHANprop-, -(CHANcyclopropy-, -(CH2)nNBu- and -(CHZ)nN+(Me)2-
where n=1;
A denotes C2-C12-alkylene which may optionally be substituted by a
group selected from among OH, COOH and COOMe, or
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9
-(CH2); D-(CH2)m , whilst in the alkylene groups -(CH2),- and -(CHZ)m one
or two hydrogen atoms may optionally be replaced by methyl and
wherein
D denotes phenyl or cyclohexyl which may optionally be substituted
by methyl and I and m, which may be identical or different, denote
0, 1,2or3,
or
D denotes -0- and I and m, which may be identical or different,
represent 2 or 3;
or
A denotes -G'-(CH2)r7G2-,
if X2 or X3 denotes -(CH2)n- A may also denote
-E'-(CH2)r-G'- or -E'-(CH2)r-E2-,
wherein
r denotes the number 0, 1, 2 or 3,
G' and G2 which may be identical or different denote a single bond or
cyclohexyl, but if r=O or r=1 G' and G2 cannot simultaneously
represent a single bond;
E' and EZ which may be identical or different denote piperidine or
piperazine, wherein at least one N-atom is bound to X2 or X3 =
(CH2),,,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
Also preferred are compounds of general formula (IA)
B B2
0 ~ 3 ~ ~ ~
x2-A-X
(IA)
wherein B1, B2, A, X2 and X3 have the meanings given hereinbefore and
hereinafter,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
CA 02391085 2002-05-10
Of particular importance are the compounds of general formula (I) or (IA)
according
to the invention wherein
the grouping B'-Ar'-X'-Ar2-X2- denotes a group selected from among
B B
\ I ~
B~ B~ N
H
a \ ~ / \
0
~ / N- N-
B Me B~ \ (iv)
r-- ~
o
/ O ( and
B1 =~ (v) Me/ Me (vi) N-
~
O
5 (vii) O- Me
the grouping -X3-Ar3-X4-Ar4-B2 denotes a group selected from among
O B2 O B2
(i') / Bz -N\ (ii') a B2 " o
iv '
-N (iii') 2 N ( ' B2
Me B
o ~
~
N, \ I -N ~ and
~ Me (v') gz (vi')
Me
O/
\ I
Me
-O
(vii')
wherein
^
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11
B' and BZ which may be identical or different denote -C(=NR')-NR'`H, -CH2NH2,
-CH2CH2NH2 or -NH-C(=NH)-NH2;
R' and R" which may be identical or different denote hydrogen or OH,
preferably
hydrogen;
A denotes a bridging group which is selected from among
(viii) C4-Cl p-alkylene which may optionally be substituted by COOH,
(ix) (x) (xi)
(xii) (xiii) (xiv)
Me Me Me N J
(xv) (xvi) and
(xvii)
or
A may also denote
N N
(xviii)
if the grouping B'-Ar'-X'-Ar2-X2- represents the group
B
o
(i)
and the grouping -X3-Ar3-X4-Ara-Bz represents the group
^
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12
B2
O\/ I
(i')
or
A may also denote
-N N
(xix)
if the grouping of the two groups B'-Ar'-X'-Ar2-X2- and -X3-Ar3-X4-Ar4-B2
represents the group (i) or (i') which is bound directly to the piperazine-
nitrogen of the group A,
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
lo thereof.
Also of special importance are the compounds of general formula (I) according
to the
invention wherein
the grouping B'-Ar'-X'-Ar2-X2- denotes a group selected from among
B1 B1
I\ I~
~
B1 B1 N
I \ I \ H
.-. \
/ 0 \ and
N-
Me
Me
the grouping -X3-Ar3-X4-Ar4-B2 denotes a group selected from among
^
CA 02391085 2002-05-10
13
/ 62 cr 62 o ~ I o 01) 62 and -NH (n ) / BZ
O / I O ~
-N N
(,
Me v~ )
Me
wherein
,...
B' and B2 which may be identical or different denote -C(=NR')-NR"H or -CH2NH2,
s R' and R" which may be identical or different denote hydrogen or OH,
preferably
hydrogen;
A denotes a bridging group which is selected from among
(viii) C4-C1 p-alkylene,
- / I
(ix) (x)
(xii) (xiii)
and
Me Me Me
(xv)
or
A may also denote
_N N
(xviii)
if the grouping B1-Ar1-X1-Ar2-X2- denotes the group (i)
CA 02391085 2002-05-10
14
and the grouping -X3-Ar3-X4-Ar4-B2 denotes the group (i`),
optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
Particularly preferred are the compounds of general formula (IA1)
B B2
/
X2 A_X3 o\ I
o I ~ I \
14-1 1411
( IA1 )
...
wherein B', B2, A, X2 and X3 have the meanings given hereinbefore and
hereinafter,
io optionally in the form of their racemates, enantiomers, diastereomers,
tautomers and
mixtures thereof, and optionally the pharmacologically harmless acid addition
salts
thereof.
Particularly preferred are the compounds of general formula (I), (IA) or
(IA1), wherein
-X2-A-X3- denotes a group of the formula
-CH2 Na N-CH2
,~..
Compounds of general formula (I) wherein B' and B2 which may be identical or
different denote -C(=NR')-NR''H are so-called prodrugs if neither R' nor R"
denotes
hydrogen. After being taken by the patient these prodrugs can be converted by
the
body, on the basis of a functionality which can be cleaved in vivo, into the
therapeutically active compounds of general formula (I) wherein B' and B 2
which may
be identical or different denote -C(=NH)NH2.
The term alkyl groups (including those which are part of other groups) denotes
branched and unbranched alkyl groups with 1 to 18 carbon atoms, preferably 1-
14,
most preferably 1-10 carbon atoms, unless otherwise stated. Examples include
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl, etc. Unless
otherwise
stated, the above terms propyl, butyl, pentyl, hexyl, heptyl and octyl, etc.,
also
include all the possible isomeric forms. For example, the term propyl also
includes
CA 02391085 2002-05-10
the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-
butyl, iso-
butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl,
neopentyl, etc. In
some cases common abbreviations are also used to denote the abovementioned
alkyl groups, such as Me for methyl, Et for ethyl etc.
5
Examples of alkylene groups are branched and unbranched alkylene bridges
having
1 to 18 carbon atoms, preferably 1- 14 carbon atoms, most preferably 1- 10
carbon
atoms. These include, for example: methylene, ethylene, propylene, butylene,
etc.
Unless otherwise stated, the above terms propylene, butylene, etc. also
include all
lo the possible isomeric forms. For example, the term propylene includes the
two
isomeric bridges n-propylene and dimethylmethylene, the term butylene includes
n-
butylene, 1-methylpropylene, 2-methylpropylene, 1.1-dimethylethylene, 1.2-
dimethylethylene etc.
15 The term alkenyl groups (including those which are part of other groups)
denotes
branched and unbranched alkenyl groups having 2 to 16 carbon atoms, preferably
2
to 10 carbon atoms, most preferably 2 to 6 carbon atoms, if they contain at
least
one double bond, for example the abovementioned alkyl groups as well, provided
that they contain at least one double bond, such as for example vinyl
(provided that
no unstable enamines or enolethers are formed), propenyl, iso-propenyl,
butenyl,
pentenyl, hexenyl.
The term alkynyl groups (including those which are part of other groups)
denotes
branched and unbranched alkenyl groups having 2 to 16 carbon atoms, preferably
2
to 10 carbon atoms, most preferably 2 to 6 carbon atoms, provided that they
have at
least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl,
hexynyl.
In the abovementioned alkyl groups, alkylene groups and alkenyl groups, one or
more hydrogen atoms may optionally be substituted by the groups specified in
the
definitions. By the phrase "several substituted hydrogen atoms" is meant the
substitution of at least 2 hydrogen atoms. When the substituent is fluorine
all the
hydrogen atoms of the alkyl, alkylene and alkenyl groups may optionally be
replaced.
Examples of cycloalkyl groups with 3 - 10 carbon atoms include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and
cyclodecyl, which may also be substituted by branched or unbranched alkyl
having 1
to 4 carbon atoms, hydroxy and/or halogen or as hereinbefore defined.
.
CA 02391085 2002-05-10
16
In the abovementioned cycloalkyl groups one or more hydrogen atoms may
optionally be substituted by the groups mentioned in the definitions. By the
phrase
"several substituted hydrogen atoms" is meant the substitution of at least 2
hydrogen
atoms. When the substituent is fluorine all the hydrogen atoms of the
cycloalkyl
group may optionally be replaced.
Fluorine, chlorine, bromine or iodine is generally referred to as halogen.
The term C3-C1 0-aza-cycloalkyl groups denotes 3- to 10-membered cycloalkyl
lo groups which contain one or two nitrogen atoms. These include, for example,
pyrrolidine, imidazolidine, piperidine, piperazine, azepan, diazepans, etc.,
each of
which, unless otherwise specified, may also be substituted by branched or
~., unbranched alkyl with 1 to 4 carbon atoms, hydroxy and/or halogen or as
hereinbefore defined.
Examples of 5-1 0-membered mono- or bicyclic heteroaryl rings in which up to
three
carbon atoms may be replaced by one or more heteroatoms selected from among
oxygen, nitrogen or sulphur include for example furan, thiophene, pyrrole,
pyrazole,
imidazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine,
oxazole,
isoxazole, thiazole, thiadiazole, oxadiazole, wherein each of the
abovementioned
heterocycles may optionally also be condensed onto a benzene ring and wherein
these heterocycles may be substituted as specified in the definitions.
The term C6-C10-aryl denotes an aromatic ring system with 6 to 10 carbon
atoms,
which, unless otherwise stated, may for example carry one or more of the
following
substituents: C1-C6-alkyl, C1-C6-alkyloxy, halogen, hydroxy, mercapto, amino,
alkylamino, dialkylamino, CF3, cyano, nitro, -CHO, -COOH, -COO-CI-C6-alkyl,
-S-C1-C6-alkyl. The preferred aryl group is phenyl.
"=0" denotes an oxygen atom linked via a double bond.
In the abovementioned definitions, unless otherwise specified, all the
definitions
given for the groups -Ar'-, -Ar2-, -Ar3- and -Ar4- should be regarded as two-
bonded
groups which may be linked to the two adjacent functions in three possible
substitution patterns (ortho, meta and para). Meta- and para-substitution are
preferred.
In the abovementioned definitions, unless otherwise specified, all the
definitions
given for the groups -X'-, -X2-, -A-, -X3- and -X - should be regarded as two-
bonded
^
CA 02391085 2002-05-10
17
groups which may be linked to the two adjacent functions in two possible
orientations. Preferably, -X'- denotes -O-(CHZ)n-, -S-(CH2)n- or -NR3-(CH2),-
particularly -O-CH2 ; and -X4- denotes -(CH2),-0-, -(CH2)-S- or -(CH2)-NR3-n,
particularly -CH2 O-.
According to another aspect, the present invention relates to the use of the
above-
defined compounds of general formula (I) as pharmaceutical compositions. In
particular, the present invention relates to the use of the compounds of
general
to formula (I) for preparing a pharmaceutical composition for the prevention
and/or
treatment of diseases in which tryptase inhibitors may have a therapeutic
benefit.
It is preferred according to the invention to use compounds of general formula
(I) for
the purpose mentioned above, for preparing a pharmaceutical composition for
the
prevention and/or treatment of inflammatory and/or allergic diseases.
It is particularly preferable to use the compounds of general formula (I) as
mentioned
above for preparing a pharmaceutical composition for the prevention and/or
treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis,
atopic
dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders,
Crohn's
disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung
(ARDS) and
arthritis.
It is also advantageous to use the compounds of general formula (I) as
mentioned
above for preparing a pharmaceutical composition for the prevention and/or
treatment of fibroses such as lung fibrosis, fibrosing alveolitis and
scarring,
coliagenoses such as lupus erythematodes and scierodermia as well as
arteriosclerosis, psoriasis and neoplasm.
One possible method of obtaining the compounds of general formula (I)
according to
the invention with the aid of and using conventional chemical methods of
synthesis is
diagrammatically shown hereinafter.
Method A
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2-X2-A-X3-Ar3-X4-Ar4-B2
(I)
wherein B' and BZ denote -C(=NH)-NH2, imidoesters of general formula (II)
CA 02391085 2002-05-10
18
RO-C (= N H)-Ar' -X' -Ar2-X2-A-X3-Ar3-X4-Ar4-C (= N H)-O R
(fi)
wherein R denotes C1-Cg-alkyl, are reacted with ammonia.
The reaction is preferably carried out in an organic solvent at temperatures
between
about 0 C and the boiling temperature of the reaction mixture, preferably
between
ambient temperature and about 100 C or the boiling temperature of the solvent
used,
if this is lower. Suitable solvents are polar organic solvents, preferably
alcohols, most
preferably methanol, ethanol or propanols. If the starting materials are
sufficiently
acid-stable the reaction may take place via the corresponding acid imide
chlorides
instead of via the imidoesters.
Method B1
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2-X2-A-X3-Ar3-X4-Ar4-B2
(I)
wherein B' and B2 denote -C(=NOH)-NH2, compounds of general formula (III)
NC-Ar'-X'-Ar2-X2-A-X3-Ar3-X4-ArA-CN
(IIl)
are treated with hydroxylamine in the presence of carbonates or alkoxides of
the
alkali or alkaline earth metals in solvents such as methanol, ethanol, n-
propanol or
isopropanol, possibly in admixture with dioxan or tetrahydrofuran. The
alkoxides may
be prepared from the alkali metals or metal hydrides and the corresponding
alcohol.
The reaction is preferably carried out at 20-100 C, most preferably at the
boiling
temperature of the solvent used.
Method B2
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2-Xz-A-X3-Ar3-X4-Ara-B2
(I)
wherein B' and B2 denote -C(=NH)-NH2, amidoximes of general formula (I)
wherein
B' and B2 denote -C(=NOH)-NHZ are reduced.
Catalytic hydrogenation is suitable for the reduction, particularly with Raney
nickel,
palladium or platinum in a lower alcohol, e.g. methanol, ethanol or propanols.
Appropriately the amidoxime is dissolved in a polar solvent, e.g. methanol,
ethanol,
CA 02391085 2002-05-10
19
propanols, tetrahydrofuran or dimethylformamide, with the addition of the
calculated
amount of the acid whose salt is desired as the end product, and hydrogenated
at
ambient temperature under gentle pressure from 1 bar, e.g. at 5 bar, until the
uptake
of hydrogen has ceased.
..-~
CA 02391085 2002-05-10
Method C
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2 -X2-A-X3-Ar3-X4-Ar-B2
5 (I)
wherein B' and B2 denote -C(=NH)-NH2, compounds of general formula (111)
N C-A r' -X' -A rz-X2-A-X3-A r3-X4-A rA-C N
(III)
lo are reacted with Li-hexamethyldisilazane. Suitable solvents for the
reaction are
nonpolar and polar aprotic solvents such as for example toluene, ether or
tetrahydrofuran at temperatures of -80 C to 120 C. To cleave the silyl groups
inorganic and organic acids are used such as HCI, HBr, HZSO4, sulphonic acids
such
as p-toluenesulphonic acid, benzenesulphonic acid or methanesulphonic acid,
15 carboxylic acids such as formic acid, acetic acid or trifluoroacetic acid
at
temperatures of 0 C to 100 C.
Method D
In order to prepare compounds of general formula (I)
B' -Ar' -X' -Ar2-X2-A-X3-Ar3-X4-Ar4-B2
(1)
wherein B' and B2 may have the meanings given hereinbefore, compounds of
general formula (IV and (V)
PG-B'-Ar'-X'-Ar2-CHO (IV)
OHC-Ar3-X4-Ar4-BZ-PG (V)
wherein PG may denote a protecting group suitable for protecting amines, which
may also be present twice, are reacted with a diamine with subsequent
reduction of
the C=N- double bonds thus formed. Suitable amino protecting groups PG which
may be mentioned here include for example alkoxycarbonyl, particularly tert-
butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl, 2,2,2-
trichloroethyloxycarbonyl etc.
For the reaction, aldehydes of formula (IV) and (V) are reacted with diamines
in
aprotic solvents such as toluene, dichloromethane, ethyl acetate, ether,
tetrahydrofuran etc. at temperatures of -80 C to 120 C. The subsequent
reduction
CA 02391085 2002-05-10
21
may be carried out with complex hydrides such as for example LiAIH4, Li-
alkoxyhydrides, NaBH4, NaBHCN3, NaBH(OAc)3, etc.
For the reaction with primary amines NaBH4 is preferably used, while for
secondary
amines NaBH(OAc)3 is preferred. The solvents used may be polar solvents such
as
DMF, alcohols such as methanol, ethanol, propanols etc. and water. The
temperature is kept in a range from -30 C to 100 C. For cleaving the hydride
complexes, organic and inorganic acids are used, such as HCI, HBr, H2SO41
formic
acid, acetic acid, sulphonic acids such as p-toluenesulphonic acid,
benzenesulphonic
acid or methanesulphonic acid in polar solvents such as ethyl acetate,
methanol,
io ethanol, propanols, water, DMF, acetonitrile.
Finally, the protecting groups are cleaved, particularly with inorganic or
organic acids
or by hydrogenolysis or using other methods known from the prior art which are
,,. conventionally used for cleaving specific protecting groups.
Method E
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2 -X2-A-X3-Ar3-X4-Ar~-B2
(I)
wherein B' and B2 may have the meanings given hereinbefore, compounds of
general formula (VI) and (VII)
PG-B'-Ar'-X'-Arz-CH2Y (VI)
YCH2-Ar3-X4-Ar4-B2-PG (VI I)
r1
wherein PG may denote a protecting group used to protect amines, which may
also
be present twice and
Y denotes fluorine, chlorine, bromine or iodine or a C1-C4-alkyl- or an
arylsulphonate group
are reacted with a diamine or a dialcohol. Suitable amino protecting groups PG
which may be mentioned here include for example alkoxycarbonyl, particularly
tert-
butyloxycarbonyl, benzyloxycarbonyl, 2-trimethylsilylethyloxycarbonyl, 2,2,2-
trichloroethyloxycarbonyl etc.
The reaction is carried out with basic adjuvants such as for example alkali
metal or
alkaline earth metal hydroxides, alkali metal or alkaline earth metal
carbonates,
C1-C4-alkali metal alkoxides in solvents which are inert under the reaction
conditions
used, such as formamides - preferably dimethylformamide (DMF) -, C1-C4-alkyl
esters of carboxylic acids - preferably ethyl acetate or ethyl formate -,
aromatic or
^
CA 02391085 2002-05-10
22
aliphatic hydrocarbons - preferably toluene - or in branched or unbranched
C1-C4-alcohols.
In the final reaction step, the protecting groups are cleaved, particularly
with
inorganic or organic acids or by hydrogenolysis or using other methods known
from
the prior art which are conventionally used for cleaving specific protecting
groups.
Method F
In order to prepare compounds of general formula (I)
B'-Ar'-X'-Ar2-X2-A-X3-Ar~-X4-Ar4-B2
(I)
wherein B' and B 2 denote -C(=NR')-NH2 with R'#H, compounds of general formula
,.. (I), wherein B' and B2 denote -C(=NH)-NH2, are reacted with chloroformates
or acyl
halides or corresponding anhydrides. For this, the bis-benzamidines in
solvents such
as toluene, ether, dichloromethane, DMF, ethyl acetate, water at temperatures
of 0 C
to 120 C are combined with acyl halides or acid anhydrides, with the addition
of a
basic substance such as triethylamine, cyclic amines such as DBU, or pyridine.
The
amines may also be used as solvents. Two-phase mixtures such as e.g.
water/toluene or water/dichloromethane are also suitable for the reaction.
2o The compounds of formula (I) wherein B' and B2 denote -C(=NR')-NH2 (with
R'#H)
may also be prepared from the acylated amidines (IV) and (V) according to
Method
D and E. In this case the group R' acts as the protecting group PG.
There is no need here to cleave the protecting group PG as mentioned in Method
D
and E.
Method G
In order to prepare compounds of general formula (I)
B' -A r' -X' -A r2-X2-A-X3-A r3-X 4-A r4- B 2
(I)
wherein B' and B 2 denote -CHZ NH2, the corresponding nitrile compounds of
general
formula (III)
N C-Ar' -X' -Ar2-XZ-A-X3-Ar3-X4-Ar4-C N
(III)
are reduced, either by catalytic hydrogenation in solvents such as methanol,
ethanol,
higher alcohols, DMF or water, with catalysts such as Raney nickel, Pd/C,
platinum,
or with hydride reagents, such as NaBH41 Ca(BH4)2, LiAIH4 and other Al- or B-
hydrides at temperatures of 0-100 C and pressures of 760 Torr or more.
^
CA 02391085 2002-05-10
23
The abovementioned methods A-G are suitable for synthesising both symmetrical
and non-symmetrical compounds of general formula (I).
Some methods of preparing the compounds of general formula (I) according to
the
invention are described in more detail hereinafter, by way of example. The
Examples
which follow serve only as a detailed illustration, without restricting the
subject of the
invention.
Example 1 (Method B1):
NOH
HzN
/ O I~ N I~ I~le / I
/^ \% M. N O ~
I / NHZ
OH
1.4 g of sodium carbonate and 1.83 g of hydroxylamine x HCI in 10 ml H20 were
added dropwise to 2.3 g of the corresponding dinitrile in 80 ml of ethanol and
refluxed for 3h. The suspension formed was suction filtered and washed with
ethanol. The crystals were chromatographed over silica gel 60 with
acetonitrile/dichloromethane/formic acid/H20 70:20:15:10. After conversion
into the
base with 2N NaOH and extracting with ethyl acetate, the substance was
suspended
in methanol and combined with dilute methanesulphonic acid. The solution was
concentrated and slowly crystallised with ether. 0.7 g were obtained in the
form of
the trimethanesulphonate. M.p. 210-212 C.
'H-NMR(250 MHz, DMSO-d6):5=9.66(2H, s, OH); 7.84-7.07 (2OH, m, aryl-H); 5.75
(4H, s, NH2), 5.12 (4H, s, OCH2 ); 3.57; 3.55 (8H, 2s,N-CH2-); 2.36 (6H, s, N-
CH3);
2.11 (9H, s, CH3 C=O).
CA 02391085 2002-05-10
24
Example 2 (Method C):
H
HZN I \
/ p p I\ / I
/ / O \ O \
I / NHZ
H
1.74 g of the corresponding dinitrile were dissolved in 75 THF and 20 ml of
lithium
hexamethyidisilazane (1 M) in THF were added dropwise under nitrogen. After
the
addition of another 25 ml of THF and heating to 45 C, the solution was stirred
for 12
h at ambient temperature. 18 ml of 4N hydrochloric acid were slowly added
dropwise
with cooling at 0 C. The THF was distilled off, water was added and the
crystals were
suction filtered and washed with water. The dihydrochloride was converted into
the
io base with 2N NaOH in DMF. This base was chromatographed over 160 g of
silica gel
60 (acetonitrile/chloroform/ glacial acetic acid/water: 75:20:10:7.5).
Yield: 0.73 as the diacetate. M.p.: 221 C.
'H-NMR(250 MHz, DMSO-d6):8=9.92 (8H, broad, -C(=NHZ{')NH2); 8.03-7.25 (20H, m,
aryl-H); 5.33 (4H, s, OCH2-); 4.64; 4.63 (8H, 2s, -CHZ O-CHZ ); 1.74 (6H, s,
CH3 C=0).
Example 3 (Method D):
HZN
0 \ N~'\~N \ I O \
~^ I / H ~ / NHz
0.49 g of diaminoethane in 2 ml dichloromethane were taken and 0.8 g of 3-[4-
(N-
Boc-aminomethyl)-phenyloxymethyl]-benzaldehyde (70 %) were added. After
heating
to 80 C and cooling, 10 ml of ethanol were added and the solution was combined
with 100 mg of NaBH4 at 0-5 C. After 12 h at ambient temperature, the mixture
was
acidified with 1 ml of 2N HCI at 0-5 C and after 2 h the precipitated crystals
were
suction filtered. After dissolving in HCI/ethyl acetate, DMF and methanol, the
mixture
was heated and after 12 h evaporated down. The residue was taken up in
methanol
and the crystals were suction filtered. Yield: 0.33 g.
'H-NMR(250 MHz, CD3OD):8=7.75-7.10 (16H, m, aryl-H); 5.19 (4H, s, OCH2-);
3o 4.32(4H, s, N-CH2-phenyl); 4.09 (4H, s, CH2NH2); 3.47 (4H, s, N-CH2CH2-N).
CA 02391085 2002-05-10
Example 4 (Method E):
HZN ~ Q /
~/o "'ep ~~ p
Me NH
s
3.75 g of N-Boc-2-[4-(3-chlormethyl-benzyloxy-)phenyl]ethylamine, 0.72 g of
2,5-
5 diamino-2,5-dimethyl-hexane, 1.4 g of potassium carbonate and 0.1 g of
potassium iodide in 15 ml of DMF were stirred for 6 h at an internal
temperature of 75 C and for a further 7 h at 140 C. The suspension was
evaporated down, the residue was taken up in water and extracted with ethyl
acetate. The organic phase dried over Na2SO4 was evaporated down and the
To residue was chromatographed over silica gel 60 with
dichloromethane/methanol/conc. ammonia 65:35:5. The Boc-protected
compound was dissolved in 10 ml of ethyl acetate and mixed with 10 ml of 3M
HCI in ethyl acetate and stirred for 24 h. The crystals precipitated were
recrystallised from 50 ml of ethanol. Yield: 0.22 g in the form of the
15 tetrahydrochloride. M.p.: 270 C (decomposition).
'H-NMR(250 MHz, CD30D):5=7.85-6.98 (16H, m, aryl-H); 5.16 (4H, s, OCH2-); 4.30
(4H, s, N-CH2-phenyl); 3.15; 2.90 (8H, 2m, N-CH2 CHZ phenyl); 1.95 (4H, s, C-
CH2CH2 ); 1.52 (12H, s, CH3-C-CH3).
20 Example 5 (Method F):
EtOOCI-C~o HZN ye ` N O
NHZ
4y, COOEt
0.3 g of the corresponding bis-benzamidine were dissolved as the base in a
little
absolute ethanol. 50 ml of dichloromethane and 0.115 g of ethyl chloroformate
were
25 added thereto and at ambient temperature 1 ml of triethylamine was added
dropwise.
After 2 h the mixture was extracted twice with 50 ml of water. The organic
phases
were evaporated down and chromatographed over silica gel 60
(acetonitrile/dichloromethane/formic acid/H20 70:20:15:10). The product was
taken
up in water, combined with sodium hydroxide solution, extracted with 100 ml of
ethyl
acetate, dried and evaporated down. Yield: 85 mg in the form of a colourless
oil.
'H-NMR(250 MHz, CDCI3):8=8.50 (4H, s, NH2); 8.02-6.96 (16H, m, aryl-H); 5.18
(4H,
s, OCH2 ); 4.25 (4H, qu, J=7.0 HZ, OCH2-CH3); 4.10 (4H, s, N-CH2-phenyl); 2.80-
1.07
^
CA 02391085 2002-05-10
26
(12H, m, N-CH2(CH2)4-CH2-N); 2.55 (6H, s, N-CH3); 1.28 (6H, t, J=7.0 HZ, OCH2
CH3).
Example 6 (Method G):
HzN
NHZ
1.16 g of the corresponding dinitrile in 60 ml DMF were hydrogenated with the
addition of methanolic ammonia solution and Raney nickel for 6 h at 5 bar and
60 C.
The catalyst was removed by suction filtering and the solvent was eliminated.
The
lo residue was dissolved while hot in 100 ml of DMF and after cooling down the
solution
was suction filtered. The filtrate was dissolved in 50 ml of DMF, the
calculated
amount of ethereal hydrochloric acid was added, the solvent was distilled off
and
stirred with ethanol. The residue was converted into the base using conc.
ammonia
and chromatographed over 70 g of silica gel 60
(acetonitrile/chloroform/glacial
acetic acid/water 75:20:10:7.5).
Yield: 0.24 g in the form of the diacetate. M.p.: 148 C.
'H-NMR(250 MHz, DMSO-d6):5=7.44-6.86 (20H, m, aryl-H); 5.08 (4H-OCH2-); 4.60
(6H, s, CH3); 4.52; 4.51 (8H, 2s, -CH2 O-CHz-); 3.69 (4H, s, CH2-NH2); 1.81
(6H, s,
CH3-C=O).
The following compounds, inter alia, were also obtained analogously to the
examples
of synthesis described above and according to synthesis methods A-G:
~~--
Example 7 (Method G):
H2N I I NHZ
0 I% INtt 0
H Fi
'H-NMR(250 MHz, CD3OD):8=7.72-7.07 (16H, m, aryl-H); 5.20 (4H, s, OCH2); 4.25
(4H, s, N-CH2-phenyl); 4.10 (4H, s, CH2-NH2); 3.09 (4H, m, N-CH2(CH2)3-CH2-N);
1.89-1.40 (6H, m, N-CH2(CH2)-).
CA 02391085 2002-05-10
27
Example 8 (Method D):
HZN N~ H / I
I ~ N N ~ O ~
Hz
~li N
'H-NMR(250 MHz, CD3OD):5=7.62-7.02 (16H, m, aryl-H); 5.14 (4H, s, OCH2-); 4.20
(4H, s, H-CH2-phenyl); 4.06 (4H, s, CH2-NH2); 2.99 (4H, m, N-CHz (CH2),o CHZ
N);
1.82-1.17 (20H, m, N-(CH2)1 o-).
Example 9 (Method D):
H2N Ilik
e M H /
H Me N \ I `
/ Me I NH2
'H-NMR(250 MHz, CD3OD):8=7.93-7.19 (16H, m, aryl-H); 5.28 (4H, s, OCH2-); 4.33
1o (4H, s, N-CH2-phenyl); 4.13 (4H, s, CH2-NH2); 2.03-1.38 (8H, m, C-(CH2)4-
C); 1.48
(12H, s, C-(CH3)2).
Example 10 (Method D):
HZN I% ` I NHz
o
'H-NMR(250 MHz, CD3OD):8=7.63-6.85 (20H, m, aryl-H); 5.10; 5.04(4H, 2s, OCH2);
4.40; 4.18; 4.01 (8H, 3s, N-CH2); 3.20; 2.95 (4H, 2m, H-CH2CH2-N).
Example 11 (Method D):
H2N ~ \
I ~ N H ` (
IV ~ / NHZ
'H-NMR(250 MHz, CD3OD):5=7.70-7.03 (16H, m, aryl-H); 5.15 (4H, s, OCH2-); 4.20
(4H, s, N-CH2-phenyl); 4.05 (4H, s, CH2-NH2); 2.82 (4H, d, J=5.8 Hz, CH2-CH);
2.00-
0.95 (10H, m, cyclohexyl-H).
CA 02391085 2002-05-10
28
Example 12 (Method D):
HZN I \ NH2
~
'H-NMR(250 MHz, CD3OD):5=7.76-7.07 (16H, m, aryl-H); 5.19 (4H, s, OCH2); 4.37
(1 H, m, CH-OH); 4.29 (4H, s, N-CH2-phenyl); 4.09 (4H, s, CH2-MH2); 3.16 (4H,
m,-
CH2 CHOH-CH2 ).
Example 13 (Method D):
HZN M NH2
~H \ o
Me
'H-NMR(250 MHz, CD3OD):8=7.70-7.05 (16H, m, aryl-H); 5.15 (4H, s, OCH2); 4.23
(4H, s, N-CH2-phenyl); 4.07 (4H, s, CH2-NH2); 3.02 (4H, S, -CH2 C-CHz ); 1.11
(6H, s,
CH3-C-CH3).
Example 14 (Method D):
HZN ~\ e Me a / ~
e QNH2
'H-NMR(250 MHz, CD3OD):8=7.88-7.17 (16H, m, aryl-H); 5.27 (4H, s, OCH2); 4.31
(4H, s, N-CH2-phenyl); 4.13 (4H, s, CH2-NH2); 1.93 (4H, s, C-CH2CH2-C); 1.51
(12H,
s, CH3 C-CH3).
Example 15 (Method D):
H2N \ / I NH2
'H-NMR(250 MHz, CD3OD):5=7.79-7.13 (20H, m, aryl-H; 5.22 (4H, s, OCH2); 4.28
(8H, s, N-CH2-phenyl); 4.11 (4H, s, CH2-NH2):
Example 16 (Method D):
H2N
o
NHZ
'H-NMR(250 MHz, CD30D):5=7.60-7.00 (20H, m, aryl-H); 5.14 (4H, s, OCH2); 4.15
(8H, s, N-CH2-phenyl); 4.04 (4H, s, NH2-CH2).
^
CA 02391085 2002-05-10
29
Example 17 (Method D):
H H
H2N 10~ NHZ
o
'H-NMR(250 MHz, DMSO-d6):5=9.54 (4H, s, NH2+); 9.23; 9.09 (8H, 2s, -
C(=NH2+)NH2); 7.90-7.15 (16H, m, aryl-H); 5.22 (4H, s, OCH2); 4.11 (4H, N-CH2-
phenyl); 2.83 (4H, m, N-CH2(CH2)3-CH2-N); 1.54-0.90 (6H, m, N-CHZ (CHZ)3 ).
Example 18 (Method D):
HZN Me Me
rINH 2
,=- Me N I / O
'H-NMR(250 MHz, CD3OD):5=7.89-7.20(16H, m, aryl-H); 5.28 (4H, s, OCH2); 4.39;
io 4.33 (4H, 2s, N-CH2-phenyl); 4.15 (4H, s, CH2-NH2); 2.43-1.30 (9H, m,
cyclohexyl);
1.56 (3H, s, C-CH3); 1.50 (6H, s, CH3 C-CH3).
Example 19 (Method D):
HZN rINH2
o I %
'H-NMR(250 MHz, CD3OD):5=7.68-6.93 (16H, m, aryl-H); 5.08 (4H, s, OCH2); 4.19
(4H, s, N-CH2-phenyl); 4.02 (4H, s, CH2-NH2); 3.08 (2H, m, N-CH-cyclohexyl);
2.30-
0.88 (20H, cyclohex-CHZ cyclohex-H).
Example 20 (Method D):
HZN lqk NHZ
---Crr, I ; o
0/^ i m
'H-NMR(250 MHz, CD3OD):5=7.85-7.13 (16H, m, aryl-H); 5.23 (4H, s, OCH2); 4.31
(4H, s, N-CH2-phenyl); 4.11 (4H, s, CH2-NH2); 3.12 (4H, m, N-CHZ cyclohexyl);
2.33-
0.73 (10H, m, cyclohexyl-H).
CA 02391085 2002-05-10
Example 21 (Method D):
NHZ
HZN I ~ 0
N~N I ,0
0-0 ~
~
w
/
'H-NMR(250 MHz, CD3OD):8=7.93-7.15 (16H, m, aryl-H); 5.28 (4H, s, OCH2); 4.35
(4H, s, N-CH2-phenyl); 4.14 (4H, m, CH2-NH2); 3.76-3.46 (12H, m, NCH2CH2
pip.).
5
Example 22 (Method D):
HzN Nzt / NH2
/
'H-NMR(250 MHz, DMSO-d6):5=9.54 (4H, s, NH2); 9.23; 9.09 (8H, 2s,
C(=NH2+)NHZ);
7.90-7.15 (16H, m, aryl-H); 5.22 (4H, s, OCH2); 4.11 (4H, N-CH2-phenyl); 2.83
(4H,
1o m, N-CH2(CH2)3-CH2-N); 1.54-0.90 (6H, m, N-CHZ (CH2)3 ).
Example 23 (Method D):
H H
HZN I ~ NHz
I~ N N I~ O
'~ 0 \
'H-NMR(250 MHz, CD3OD):5=7.88-7.16 (16H, m, aryl-H); 5.27 (4H, s, OCH2); 4.24
15 (4H, s, N-CH2-phenyl); 3.05 (4H, m, N-CHZ-(CHZ)5 CHz-N-); 1.89-1.27 (1OH,
m, N-
CH2(CH2)5 );
Example 24 (Method D):
NH
HZN `~ Me /
~/ O \ N N ztts ~ p ~
/ Me I / NHZ
H
20 'H-NMR(250 MHz, CD3OD):5=7.85-7.15 (16H, m, aryl-H); 5.27 (4H, s, OCH2-);
4.51;
4.29 (4H, m, N-CH2 phenyl); 3.20 (4H, m, N-CH2 (CH2)4 CH2 N); 2.81 (6H, s, N-
CH3);
2.03-1.35 (8H, m, N-CH2-(CH2)4 ).
CA 02391085 2002-05-10
31
Example 25 (Method D):
NH
HZN \ H ~
p \
~ / NHz
H
'H-NMR(250 MHz, CD3OD):8=7.98-7.26 (16H, m, aryl-H); 5.32 (4H, s, OCH2 ); 4.28
(4H, s, N-CH2-phenyl); 3.08 (4H, m, N-CHZ (CH2)4-CHZ N); 1.89-1.32 (8H, m, N-
CH2-
(CH2)a-)=
Example 26 (Method D):
H
H2N
Iao I ~ ~N \ I 0 0 NHz
NH
'H-NMR(250 MHz, CD3OD):5=7.80-7.13 (16H, m, aryl-H); 5.22 (4H, s, OCH2); 4.22
lo (4H, s, N-CH2 pheny!); 2.90 (4H, d, J=7.4 Hz, N-CHZ cyclohexyl); 2.13-0.93
(10H, m,
cyclohexyl-H).
Example 27 (Method D):
HzN I \ e M
r
/ O \ N N \ I O
~/ Ms Me NHz
,,^ H
'H-NMR(250 MHz, DMSO-d6):5=10.15; 9.20; 8.37 (12H, 3s, NH2); 7.99-7.11 (16H,
m,
aryl-H); 5.22 (4H, s, OCH2-); 4.00 (4H, s, N-CH2-phenyl); 1.91-1.12 (4H, m, -C-
CH2CH2-C); 1.30 (12H, s, -C(CH3)2 CH2-CH2 C(CH3)Z ).
Example 28 (Method D):
H
HzN H(\ o o/ I NHz
\
/
'H-NMR(250 MHz, CD3OD):8=8.03-7.23 (20H, m, aryl-H); 5.33 (4H, s, OCH2); 4.31
(8H, s, N-CH2-phenyl).
^
CA 02391085 2002-05-10
32
Example 29 (Method D):
HZN I ~
X
/ `,
NHz
NH
'H-NMR(250 MHz, CD3OD):8=8.03-7.29 (20H, m, aryl-H); 5.37 (4H, s, OCH2); 4.40
(8H, s, N-CH2-phenyl).
Example 30 (Method D):
Me
H
O N `
~ ~ 0
HZN "
iIIyNH2
Me NH
'H-NMR(250 MHz, CD3OD):8=7.96-7.19 (16H, m, aryl-H); 5.32 (4H, s, OCH2-);
4.43;
4.41 (4H, m, N-CH2-phenyl); 3.15 (8H, m, N-CHZ (CHZ )a-CHZ N; N-CH2-
CH2CH2CH3);
lo 2.03-1.22 (16H, m, N-CH2 (CH2)a, N-CH2CH2CH2CH3); 0.95 (6H, m, N-(CH2)3-
CH3).
Example 31 (Method D):
HzN I;Zt ye
O `
Me NHz
'H-NMR(250 MHz, CD3OD):5=7.74-7.00 (16H, m, aryl-H); 5.17 (4H, s, OCH2-); 4.40
(4H, s, N-CH2-phenyl); 4.05 (4H, s, CH2-NH2); 3.18 (4H, m, N-CH2(CH2)4-CH2-N);
2.77
(6H, s, N-CH3); 1.95-1.36 (8H, m, N-CH2(CH2)1).
Example 32 (Method D):
NH H
HZN I~ 00~ NHz
/ ~~ a ~i 1 ~
~
'H-NMR(250 MHz, CD3OD):8=7.91-7.10 (16H, m, aryl-H); 5.23 (4H, s, OCH2-); 4.24
(4H, s, N-CH2-phenyl); 2.86 (3H, m, NH-CH-; N-CH2-CH2CH2); 2.05-1.24 (6H, m, N-
CHZ CH2CH2);
^
CA 02391085 2002-05-10
33
Example 33 (Method D):
HZN T
M a \ ~ o\
/ e Me ~/ NHZ
NH
'H-NMR(250 MHz, DMSO-d6):5=9.61; 9.56; 9.38 (12H, 3, s, NH2; C(=NH2+)NH2);
8.22-7.43 (16H, m, aryl-H); 5.34 (4H, s, OCH2-); 4.28 (4H, s, N-CH2-phenyl);
2.05-
1.27 (8H, m, C-CHZCHZ CH2CH2 C); 1.49 (12H, s, CH3 C-CH3).
Example 34 (Method D):
H
H2N
^ / O I \ N
/ ~.
N \ I O 0 NH2
NH
'H-NMR(250 MHz, CD3OD):5=7.80-7.06 (16H, m, aryl-H); 5.18 (4H, s, OCH2-); 3.48
io (4H, s, N-CH2-phenyl); 2.97-0.92 (18H, m, pip-H).
Example 35 (Method E):
HzN\/I \
~ \ \ r
/ Me Ne \
~/
NHZ
'H-NMR(250 MHz, CD3OD):5=7.88-7.02 (20H, m, aryl-H); 5.21 (4H, s, OCH2-);
4.55;
4.43 (8H, 2s, N-CH2-phenyl); 3.16; 2.93 (8H, 2m, N-CH2CH2-phenyl); 2.75 (6H,
s, N-
CH3).
Example 36 (Method B1):
11OH
H2N
o
NH2
I
N'OH
CA 02391085 2002-05-10
34
'H-NMR(250 MHz, DMSO-d6):5=13.16 (2H, s, C=N-OH); 11.33 (4H, s, NH2); 10.26
(4H, s, NH2); 7.86-7.22 (20H, m, aryl-H); 5.31 (4H, s, OCH2-); 4.21 (8H, s, N-
CH2-
phenyl).
Example 37 (Method F):
~,COOMe
H2N I \ e
M H /
/ O \ N N \ I O \
Me
/ Me NHZ
'COOMe
'H-NMR(250 MHz, DMSO-d6):8=9.14 (8H, s, NH2); 8.11-7.04 (16H, m, aryl-H); 5.19
(4H, s, OCH2-); 4.11 (4H, s, N-CH2-phenyl); 3.59 (6H, s, OCH3); 1.60-1.15 (8H,
m, C-
(CH2)4; 1.31 (18H, s, CH2-C-CH3);
Example 38 (Method G):
HzN I \
LJ Me Ne \ I O N.
NHZ
'H-NMR(250 MHz, CD3OD):5=7.76-7.06 (20H, m, aryl-H); 5.19 (4H, s, OCHZ );
4.51;
4.38 (8H, 2s, N-CH2-phenyl); 4.05 (4H, s, CH2-NH2); 2.72 (6H, s, N-CH3).
Example 39 (Method D):
H H % HZN / I NHs
~~ `
~~ -
'H-NMR(250 MHz, DMSO-d6):5=9.80; 9.42; 9.19 (12H, 3s, NH2+, C(=NH2{')NH2);
7.97-7.13 (16H, m, aryl-H); 5.22 (4H, s, OCH2-); 4.20 (4H, s, N-CH2-phenyl);
3.75;
2o 3.06 (8H, 2m, N-CH2-CH2 O).
Example 40 (Method D):
H
HZN I~`` Me e H
/ NH
O Me x
~
CA 02391085 2002-05-10
'H-NMR(250 MHz, DMSO-d6):8=9.31; 9.11; 9.09 (12H, 3s, NH2+, C(=NH2i')NH2);
8.00-7.15 (16H, m, aryl-H); 5.23 (4H, s, OCH2); 4.11 (4H, s, N-CH2-phenyl);
2.37-
0.83 (9H, m, pip-H); 1.38 (6H, s, C(CH3)2); 1.29 (3H, s, C-CH3).
5 Example 41 (Method D):
H
HZN I ~
/ o Me
Me N \ O 0 NHZ
lly
NH
'H-NMR(250 MHz, CD3OD):5=7.80-7.06 (16H, m, aryl-H); 5.18 (4H, s, OCH2-); 3.48
(4H, s, N-CH2-phenyl); 2.97-0.92 (18H, m, pip-H).
Example 42 (Method E):
HZN I ~
\v
O~~N
N `~ I O
NHZ
'H-NMR(250 MHz, CD3OD):5=7.43-6.85 (16H, m, aryl-H); 5.15 (4H, s, OCH2); 3.49
(4H, s, N-CH2-phenyl); 2.88-0.93 (26H, m, CH2 CHZ NH2; pip.-H).
Example 43 (Method D):
HZN I ~ (J~ / ~ NH2
H/ O '~.
l~ o
Example 44 (Method D):
HZN ` Nt~ NH2
/ O I~ N N / I O /
H H
CA 02391085 2002-05-10
36
Example 45 (Method D):
HsN \ H
i
/ 0,^ \ N N \ 0 I\
H NHz
Example 46 (Method E):
NHZ
HZN +
I;ao H
/ Ilk
MeNM=~/=N ~ ,
li
Example 47 (Method D):
,.-. HZN \ H /
~ / N ~ 0
O \
/ H NH2
Example 48 (Method D):
HZN \
/ a \ ~ \
/NHZ
Example 49 (Method D):
HZN I \ I \ NHZ
'~ O I\ N N Q
H
Example 50 (Method D):
\ H (:"-i N
HZ
\ ~ I / 0 H2N I / H \ ~
Example 51 (Method D):
N O/ I NHZ
N~
~ ~
\ .J
HZN I
CA 02391085 2002-05-10
37
Example 52 (Method D):
HZN IRS. I \ NHZ
/ H H \
Example 53 (Method B1):
NOH
HZN
N
Me e O QNH2
NOH
Example 54 (Method G):
~
HZN I \
o ,.
I / HZ
Example 55 (Method F):
NCOOEt
HZN ~ ` Me / ~
/ O I
/ ~ N N OI /\
Me NHZ
NCOOEt
Example 56 (Method B1/B2):
NH
H2N I \
o~
I / NHZ
NH
Example 57 (Method F):
NCOOMe
HZN I \
/ O I N
N O Q NHZ
NCOOMe
^
CA 02391085 2002-05-10
38
Example 58 (Method F):
NCOOEt
HZN I \
/ O I \ N
/
N O \
I / NHZ
NCOOEt
Example 59 (Method F):
NCOO-n-Bu
H2N I \
/ O I \ N
/
N \ O \
I / NH2
NCOO-n-Bu
Example 60 (Method F):
NCOO-n-Hex
HZN I \
/ O I \ N
/
N \ I O \
NH2
NCOO-n-Hex
Example 61 (Method F):
NCOO-Benzyl
H2N I \
/ O I \ N
/
N \ ( O \
I / NH2
NCOO-Benzyl
^
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39
Example 62 (Method D):
NH
HZN
/ o (\ %N
Ni O
I \
/ NHZ
NH
Example 63 (Method D):
NH
HzN I \
/ O I \ H
,%
H \ I O
NH2
H
Example 64 (Method D):
NH
HZN I \ N / I
/ O I \ o \
/ N ~ / NHZ
NH
Example 65 (Method D):
NH
HzN I \
/ O \ H I\ N /
~N H O
\
LL(NH2
NH
Example 66 (Method B1):
rH
HZN
o j o ~\
.- / o \ o ,~
NHZ
OH
CA 02391085 2008-07-17
27400-239
Example 67 (Method B1):
HO
HZN
/ O I \ N
N \ I O
I NHZ
1
N, O H
Example 68 (Method G):
I \
H 2 N
/ O I \ N
N \ I O \
NHZ
The compounds according to the invention are characterised by their tryptase-
inhibiting activity. This ability to inhibit tryptase was investigated using
the test
described below.
TM
The measurement is carried out in Tris HCI buffer (100 mM), which additionally
io contains calcium (5 mM) and heparin (100 mg/mi), at pH 7.4. The standard
used is
rh beta tryptase which may be obtained commercially from Promega, for example.
The substrate used is N-p-tosyl-Gly-Pro-Lys-para-nitroaniline in a
concentration of
0.6 mM. The substrate is digested with tryptase to form p-nitroaniline which
can be
measured at 405 nm. Usually, an incubation period of 5 minutes and an
incubation
15 temperature of 37 C are chosen. The enzyme activity used is 0.91 U/mI. The
TM
measurements are carried out in an Autoanalyser (Cobas Bio) made by Hofmann
LaRoche. The potential inhibitory substances are used in concentrations of 10
PM in
the screening, the inhibition of the tryptase being given in percent. The IC5o
(concentration at which 50% of the enzyme activity is inhibited) is determined
at over
2o 70 % inhibition. After 5 minutes' pre-incubation of the potential
inhibitory
substances, the substrate is added to start the reaction, the formation of p-
nitroaniline being taken as a measurement of the enzyme activity after 5
minutes,
after testing the linearity.
25 The IC50 values obtained for the compounds according to the invention are
shown in
Table 1.
CA 02391085 2002-05-10
41
Table 1:
Example salt form IC50 value [nM]
2 diacetate 19
7 tetrachloride 4.3
tetrachloride 35
11 tetrachloride 4
14 tetrachloride 13
tetrachioride 23
16 tetrachloride 12
17 tetrachloride 1.4
18 tetrachloride 10.7
19 tetrachloride 10
~ 20 tetrachloride 7.1
22 tetrachloride 27.4
23 tetrachloride 1.1
24 tetrachloride 3.1
tetrachloride 1.2
26 tetrachloride 0.8
27 tetrachloride 1.7
28 tetrachloride 5.3
29 tetrachloride 1.7
tetrachloride 6.8
31 tetrachloride 13
32 tetrachloride 32.4
,t. 33 tetrachloride 2.5
34 tetrachloride 0.8
tetrachloride 31.6
39 tetrachloride 12
tetrachloride 5
41 tetrachloride 4.6
42 tetrachloride 30.9
56 diacetate 19
62 tetrachloride 41
63 tetrachloride 0.74
64 tetrachloride 1.1
65 tetrachloride 0.59
68 tetrachloride 2.5
CA 02391085 2002-05-10
42
The tryptase inhibitors according to the invention may be administered orally,
transdermally, by inhalation or parenterally. The compounds according to the
invention occur as active ingredients in conventional preparations, for
example in
compositions which consist essentially of an inert pharmaceutical carrier and
an
effective dose of the active substance, such as for example tablets, coated
tablets,
capsules, powders, solutions, suspensions, emulsions, syrups, suppositories,
transdermal systems, etc. An effective dose of the compounds according to the
invention is between 1 and 100, preferably between I and 50, most preferably
between 5-30 mg/dose for oral administration, and between 0.001 and 50,
preferably
between 0.1 and 10 mg/dose for intravenous or intramuscular administration.
For
inhalation, according to the invention, solutions containing 0.01 to 1.0,
preferably 0.1
to 0.5 % active substance are suitable. For administration by inhalation the
use of
powders is preferred. It is also possible to use the compounds according to
the
invention as a solution for infusion, preferably in a physiological saline or
nutrient
saline solution.
The compounds according to the invention may be used on their own or in
conjunction with other active substances according to the invention,
optionally also in
conjunction with other pharmacologically active substances. Suitable
preparations
include for example tablets, capsules, suppositories, solutions, elixirs,
emulsions or
dispersible powders.
Suitable tablets may be obtained, for example, by mixing the active
substance(s)
with known excipients, for example inert diluents such as calcium carbonate,
calcium
phosphate or lactose, disintegrants such as corn starch or alginic acid,
binders such
as starch or gelatine, lubricants such as magnesium stearate or talc and/or
agents
for delaying release, such as carboxymethyl cellulose, cellulose acetate
phthalate, or
polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced
analogously
to the tablets with substances normally used for tablet coatings, for example
collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve
delayed
release or prevent incompatibilities the core may also consist of a number of
layers.
Similarly the tablet coating may consist of a number or layers to achieve
delayed
release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof
according
to the invention may additionally contain a sweetener such as saccharine,
cyclamate,
glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanilline
or
CA 02391085 2002-05-10
43
orange extract. They may also contain suspension adjuvants or thickeners such
as
sodium carboxymethyl cellulose, wetting agents such as, for example,
condensation
products of fatty alcohols with ethylene oxide, or preservatives such as
p-hydroxybenzoates.
Solutions for injection are prepared in the usual way, e.g. with the addition
of
preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal
salts of
ethylenediamine tetraacetic acid, and transferred into injection vials or
ampoules.
1o Capsules containing one or more active substances or combinations of active
substances may for example be prepared by mixing the active substances with
inert
carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for
this purpose, such as neutral fats or polyethyleneglycol or the derivatives
thereof.
A therapeutically effective daily dose is between 1 and 800 mg, preferably 10 -
300
mg per adult.
2o The Examples which follow illustrate the present invention without
restricting its
scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
active substance 100 mg
lactose 140 mg
corn starch 240 mg
polyvinyl pyrrolidone 15 mg
magnesium stearate 5 mg
500 mg
The finely ground active substance, lactose and some of the corn starch are
mixed
together. The mixture is screened, then moistened with a solution of
polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The
granules, the
remaining corn starch and the magnesium stearate are screened and mixed
together. The mixture is compressed to produce tablets of suitable shape and
size.
^
CA 02391085 2002-05-10
44
B) Tablets per tablet
active substance 80 mg
corn starch 190 mg
lactose 55 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg
sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg
400 mg
,.- The finely ground active substance, some of the corn starch, lactose,
microcrystalline
cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened
and
worked with the remaining corn starch and water to form a granulate which is
dried
and screened. The sodium-carboxymethyl starch and the magnesium stearate are
added and mixed in and the mixture is compressed to form tablets of a suitable
size.
C) Coated tablets per coated tablet
Active substance 5 mg
Corn starch 41.5 mg
Lactose 30 mg
Polyvinylpyrrolidone 3 mg
Magnesium stearate 0.5 mg
80 mg
The active substance, corn starch, lactose and polyvinylpyrrolidone are
thoroughly
mixed and moistened with water. The moist mass is pushed through a screen with
a
1 mm mesh size, dried at about 45 C and the granules are then passed through
the
same screen. After the magnesium stearate has been mixed in, convex tablet
cores
with a diameter of 6 mm are compressed in a tablet-making machine . The tablet
cores thus produced are coated in known manner with a covering consisting
essentially of sugar and talc. The finished coated tablets are polished with
wax.
CA 02391085 2002-05-10
D) Capsules per capsule
Active substance 50 mg
5 Corn starch 268.5 mg
Magnesium stearate 1.5 mg
320 mg
The substance and corn starch are mixed and moistened with water. The
10 moist mass is screened and dried. The dry granules are screened and mixed
with
magnesium stearate. The finished. mixture is packed into size 1 hard gelatine
capsules.
E) Ampoule solution
active substance 50 mg
sodium chloride 50 mg
water for inj. 5 ml
The active substance is dissolved in water at its own pH or optionally at pH
5.5 to 6.5
and sodium chloride is added to make it isotonic. The solution obtained is
filtered
free from pyrogens and the filtrate is transferred under aseptic conditions
into
ampoules which are then sterilised and sealed by fusion. The ampoules contain
5
mg, 25 mg and 50 mg of active substance.
F) Suppositories
Active substance 50 mg
Solid fat 1650 mg
1700 mg
The hard fat is melted. At 40 C the ground active substance is homogeneously
dispersed. It is cooled to 38 C and poured into slightly chilled suppository
moulds.
