Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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WO 2004/069266 PCT/EP2004/000550
1
Use of bradykinin-B2 receptor antagonists for treating osteoarthrosis
The invention relates to the use of peptides having bradykinin-antagonistic
action for the production of pharmaceuticals for the treatment of
degenerative joint diseases.
In degenerative joint diseases such as osteoarthrosis, a slowly progressing
destruction of the joint takes place, which is caused in particular by the
proteolytic degradation of collagen by collagenases. Collagenases belong
to the superfamily of the metalloproteinases (MP) or matrix metalloprotein-
ases (MMPs). MMPs are capable of degrading fibrillar and nonfibrillar
collagen and proteoglycans, which are all important constituents of the
cartilaginous matrix. MMP 3 is involved in the biological degradation of the
extracellular matrix and is found in increased levels in patients with
osteoarthrosis, which is why particular importance is ascribed to MMP 3 in
the degradation of the joint matrix in osteoarthrosis (Manicourt et al. (1994)
Arthritis and Rheumatism 37:1774-83).
Bradykinin is a naturally occurring nonapeptide which has some
pharmacological effects which lead to inflammation and pain. Peptides
having bradykinin-antagonistic action have already been described in
European patent EP 0 370 453 131. It is further known that peptides having
bradykinin-antagonistic action can be employed in the treatment of
osteoarthritis or rheumatoid arthritis (AU 638 350). Osteoarthritis and
rheumatoid arthritis are joint diseases having severe inflammatory phases
in the course of the disease. Lerner et al. (Arthritis and Rheumatism (1987),
30, 530-540) report that, in the context of rheumatoid arthritis, bradykinin
may actually enhance bone resorption, but does not stimulate the
degradation of the cartilaginous matrix itself.
In the attempt to find active compounds for the treatment of degenerative
joint diseases, it has now been found that the peptide employed according
to the invention inhibits the release of MMPs such as MMP-3 (and MMP-1
and MMP-13). As a result, the matrix degradation can be inhibited
significantly more effectively than only by the inhibition of MMPs
themselves which have already been released or formed in the tissue.
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2
The invention therefore relates to the use of the compound of the formula I
A-B-X-E-F-K-(D)-TIC-GM-M-F'-l (I)
for the production of pharmaceuticals for the treatment of degenerative joint
diseases, in which:
A a,) is a hydrogen atom, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C,-C8)-
alkoxycarbonyl or (C1-C8)-alkylsulfonyl, in which in each case
1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or
three identical or different radicals from the group consisting
of carboxyl, amino, (C1-C4)-alkyl, (C1-C4)-alkylamino,
hydroxyl, (C1-C3)-alkoxy, halogen, di-(C1-C4)-alkylamino,
carbamoyl, sulfamoyl, (C,-C4)-alkoxycarbonyl, (C6-C12)-aryl
and (C6-C12)-aryl-(C1-C5)-alkyl,
or in which in each case 1 hydrogen atom is optionally
replaced by a radical from the group consisting of (C3-C8)-
cycloalkyl, (C1-C4)-alkylsulfonyl, (C1-C4)-alkylsulfinyl, (C6-C12)-
aryl-(C1-C4)-alkylsulfonyl, (C6-C12)-aryl-(C1-C4)-alkylsulfinyl,
(C6-C12)-aryloxy, (C3-C9)-heteroaryl and (C3-C9)-heteroaryloxy
and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or
different radicals from the group consisting of carboxyl,
amino, (C,-C4)-alkylamino, hydroxyl, (C,-C4)-alkoxy, halogen,
di-(C1-C4)-alkylamino, carbamoyl, sulfamoyl, (C,-C4)-
alkyloxycarbonyl, (C6-C12)-aryl and (C6-C12)-aryl-(C,-C5)-alkyl,
a2) is (C3-C8)-cycloalkyl, carbamoyl,
which can optionally be substituted on the nitrogen by (C1-
C6)-alkyl or (C6-C12)-aryl,
(C6-C12)-aryl, (C6-C12)-aryloyl, (C6-C12)-arylsulfonyl or (C3-C9)-
heteroaryl or (C3-Cg)heteroaryloyl, where in the radicals
defined under a,) and a2) heteroaryl, aryloyl, arylsulfonyl and
heteroaryloyl in each case is optionally substituted by 1, 2, 3
or 4 different radicals from the group consisting of carboxyl,
amino, nitro, hydroxyl, cyano, (C1-C4)-alkylamino, (C,-C4)-
alkyl, (C1-C4)-alkoxy, halogen, di-(C,-C4)-alkylamino,
carbamoyl, sulfamoyl and (C,-C4)-alkoxycarbonyl, or
a3) is a radical of the formula II,
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R(1)-N-CH-C- 11
O
R(2) R(3)
where
R(1) is defined as A under a,) or a2),
R(2) is a hydrogen atom or methyl,
R(3) is a hydrogen atom or (C1-C6)-alkyl, where alkyl is
unsubstituted or monosubstituted by amino, substituted
amino, hydroxyl, carbamoyl, guanidino, substituted guanidino,
ureido, mercapto, methylmercapto, phenyl, 4-chlorophenyl,
4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxy-
phenyl, phthalimido, 4-imidazolyl, 3-indolyl, 2-thienyl,
3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl,
where substituted amino is a radical -NH-A- and substituted
guanidino is a radical -NH-C(NH)-NH-A-, in which A is as
defined under a,) or a2);
B is Arg, Lys, Orn, 2,4-diaminobutyroyl or an L-homoarginine
radical,
where in each case the amino or the guanidino group
of the side chain can be substituted by an A as
described under a,) or a2);
X is a compound of the formula Illa or Illb
G'-G'-Gly (llla)
G'-NH-(CH2)n-CO (Iilb),
in which G' independently of one another is a radical of the
formula IV
R(4) R(5) O
f 11 IV
-N-CH- C-
in which R(4) and R(5) together with the atoms carrying
these is a heterocyclic mono-, bi- or tricyclic ring system
having 2 to 15 carbon atoms, and n is 2 to 8;
E is the radical of phenylalanine,
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which is optionally substituted by halogen in the 2-, 3-
or 4-ring position, or
is tyrosine, 0-methyltyrosine, 2-thienylalanine, 2-pyridyl-
alanine or naphthylalanine;
F independently of one another is the radical of a neutral, acidic
or basic aliphatic or aromatic amino acid,
which can be substituted in the side chain,
or is a covalent bond;
(D)-Tic is the radical of the formula V
C
H
V
N
G is G' or a covalent bond;
F is the radical of a basic amino acid Arg or Lys in the L or D
form or a covalent bond,
where the guanidino group or amino group of the side chain
can be substituted by A as defined under a1) or a2),
or is a radical -NH-(CH2),- where n is 2 - 8,
or a covalent bond;
I is -OH, -NH2 or NHC2H5;
K is the radical -NH-(CH2)X CO where x is 1 to 4 or a covalent
bond;
M is defined as F,
and its physiologically tolerable salts.
A further subject of the invention is also the use according to the invention
of the compound of the formula I, in which:
B is Arg, Orn or Lys,
where the guanidino group or the amino group of the
side chain is unsubstituted or can be substituted by
(C1-C8)-alkanoyl, (C7-C13)-aryloyl, (C3-C9)-heteroaryl-
oyl, (C1-C8)-alkylsulfonyl or (C6-C12)-arylsulfonyl, where
the aryl, heteroaryl, aryloyl, arylsulfonyl and hetero-
aryloyl radicals can be substituted as described above
under a2) by optionally 1, 2, 3 or 4 identical or different
radicals;
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E is phenylalanine, 2-chiorophenylalanine, 3-chlorophenyl-
alanine, 2-fluorophenylalanine, 3-fluorophenylalanine,
4-fluorophenylalanine, tyrosine, 0-methyltyrosine or
/8-(2-thienyl)alanine;
K is a covalent bond and
M is a covalent bond.
The invention further relates to the use according to the invention of
the compound of the formula I, in which:
A is a hydrogen atom, (D)- or (L)-H-Arg, (D)- or (L)-H-Lys or
(D)- or (L)-H-Orn;
B is Arg, Orn or Lys,
where the guanidino group or the amino group of the
side chain can be substituted by a hydrogen atom, (C1-
C8)-alkanoyl, (C6-C12)-aryloyl, (C3-Cg)-heteroaryloyl,
(C1-C8)-alkylsulfonyl or (C6-C12)-arylsulfonyl, where the
aryl, heteroaryl, aryloyl, arylsulfonyl and heteroaryloyl
radicals can optionally be substituted by 1, 2, 3 or 4
identical or different radicals from the group consisting
of methyl, methoxy and halogen;
C is Pro-Pro-Gly, Hyp-Pro-Gly or Pro-Hyp-Gly;
E is Phe or Thia;
F is Ser, Hser, Lys, Leu, Val, Nle, Ile or Thr;
K is a covalent bond
M is a covalent bond
G is the radical of a heterocyclic ring system of the formula IV,
selected from the radicals of the heterocycles pyrrolidine (A),
piperidine (B), tetrahydroisoquinoline (C), cis- or trans-
decahydroisoquinoline (D), cis-endo-octahydroindole (E), cis-
exo-octahydroindole (E), trans-octahydroindole (E), cis-endo-,
cis-exo-, trans-octahydrocyclopentano[b]pyrrole (F), or
hydroxyproline (V);
F is Arg;
I is OR
The invention also relates to the use according to the invention of a
compound of the formula I, which is selected from the group:
H-(D)-Arg-Arg-Pro-Hyp-Giy-This-Ser-(D)-Tic-Oic-Arg-OH,
H-(D)-Arg-Arg-Pro-Pro-Gly-This-Ser-(D)-Tic-Oic-Arg-OH,
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H-(D)-Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH,
H-(D)-Arg-Arg-Hyp-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH and
H-(D)-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D)-Tic-Oic-Arg-OH.
The invention also relates to the use according to the invention of
D-arginyl-L-arginyl-L-prolyl-L-prolylglycyl-3-(2-thienyl)-L-alanyl-L-seryl-
(3R)-
1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-(2S,3aS,7aS)-octahydro-1 H-
indole-2-carbonyl-L-arginine; which is also known under the name
HOE 140.
The term "(C1-C8)-alkyl" is understood as meaning hydrocarbon radicals
whose carbon chain is straight-chain or branched and contains 1 to 8
carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tertiary-butyl, pentyl, isopentyl, neopentyl, hexyl, 2,3-dimethylbutyl,
heptyl,
neohexyl or octyl.
The term "halogen" is understood as meaning fluorine, chlorine, bromine or
iodine.
The term "(C3-C8)-cycloalkyl" is understood as meaning radicals which are
derived from 3- to 8-membered monocycles such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term "-(C6-C12)-aryl" is understood as meaning aromatic hydrocarbon
radicals having 6 to 14 carbon atoms in the ring. -(C6-C12)-aryl radicals are,
for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl,
biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl
or fluorenyl. Biphenylyl radicals, naphthyl radicals and in particular phenyl
radicals are preferred aryl radicals.
The term "(C3-C9)-heteroaryl" is to be understood as meaning radicals such
as acridinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzo-
tetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl,
4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydro-
quinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2,3-b]-tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl,
indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl),
isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,
oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
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piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyroazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,
pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl,
pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetra-hydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thia-diazinyl, 1,2,3-thiadiazolyl, 1,2,4-
thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thia-diazolyi, thianthrenyl,
thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,
triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl
and
xanthenyl.
Pyridyl; such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl; such as 2-
pyrrolyl
and 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl; thiophenyl, thienyl; such
as
2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl,
isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl,
isoindolyl,
benzofuranyl, benzothiophenyl, 1,3-benzodioxolyl, indazolyl, benzimid-
azolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl,
isochromanyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido-
imidazolyl, pyridopyridinyl, pyridopyrimidinyl, purinyl and pteridinyl are
preferred.
The peptides employed according to the invention are prepared as
described in EP 0 370 453 131.
On account of the pharmacological properties, the compounds according to
the invention are suitable for the selective prophylaxis and therapy of
degenerative joint diseases such as osteoarthrosis, spondylosis or
chondroporosis after joint trauma or relatively long immobilization of a joint
after meniscus or patella injuries or torn ligaments. The term
"osteoarthrosis" is understood as meaning a disease which chiefly
develops in connection with a disparity between the strain on and the load
capacity of the individual joint components and joint tissues, which is
associated with increasing destruction of the cartilage and which is in the
main not inflammatory. Damage to the joint cartilage, such as fraying,
demedullation and hyalinization, followed by reactive changes in the
subchondral bone, and also capsule changes, is prominent in the
pathology. The term "spondylosis" is understood as meaning an arthrosis of
the vertebral bodies, with this arthrosis being characterized by a
noninflammatory loss of cartilage from the vertebral bodies and
intervertebral disks.
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The pharmaceuticals according to the invention can be administered by
inhalative or transdermal administration or by subcutaneous, intraarticular,
intraperitoneal or intravenous injection. Intraarticular administration or
topical application is preferred.
Suitable solid or pharmaceutical preparation forms are, for example,
suspensions, emulsions, or injectable solutions, and preparations having
protracted release of active compound, in whose preparation customary
excipients are used.
Preferably, the pharmaceutical preparations are prepared and administered
in dose units, each unit containing as active constituent a certain dose of
the compound of the formula I according to the invention. In the case of
injection solutions in ampoule form, this dose can be up to approximately
300 mg, but preferably approximately 10 to 100 mg, in the case of injection
solutions for intraarticular treatment up to approximately 300 micrograms,
preferably 100 micrograms.
For the treatment of an adult patient, depending on the activity of the
compound according to formula I, daily doses of approximately 0.01 mg/kg
to 10 mg/kg of active compound are indicated in the case of systemic
administration, in the case of the administration of injection solutions daily
doses of 0.001 mg/kg to 0.005 mg/kg of active compound are indicated and
in the case of topical or inhalative administration, daily doses of 0.01 mg/kg
to 5 mg/kg of active compound are indicated. Under certain circumstances,
however, higher or lower daily doses may also be appropriate. The daily
dose can be administered either by single administration in the form of an
individual dose unit or else a number of smaller dose units or by multiple
administration of subdivided doses at specific intervals.
The invention is illustrated below with the aid of examples.
The abbreviations used for the amino acids correspond to the three-letter
code customary in peptide chemistry, as is described in Europ. J. Biochem.
138, 9 (1984). Further abbreviations used are listed below.
Oic octahydro-1 H-indole-2-carbonyl
Thia 2-thienylalanyl
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Tic 1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl
HOE 140 was prepared as described in EP 0 370 453 B1.
Pharmacological examples
For the analysis of the disease-modifying action of HOE140 in a cell culture
model relevant to cartilage, the MMP3 expression was analyzed in the
chondrosarcoma cell line SW 1353 (ATCC: HTB 94). For the experiments,
SW1353 cells were cultured under standard conditions (37 C, 5% CO2) in
DMEM-Glutamax with 10% of fetal calf serum (FCS) in plastic culture
bottles. After detrypsinization of the cells, 50,000 cells were inoculated per
well of a 96-well flat-bottom plate in medium without FCS and preincubated
with the compound HOE140 in an incubator. After one hour, the cells were
stimulated by addition of human IL1-(3 (0.1 ng/ml, Roche) in a total volume
of 300 pl. After incubation for 24 hours under standard conditions, the cell
culture supernatant was taken off, centrifuged for 5 minutes and frozen at
-20 C until further analysis. The MMP3 expression in the cell culture
supernatants was then analyzed by means of a commercial MMP3 ELISA
test system (Amersham) according to the instructions of the manufacturer.
In parallel to this, a WST cytotoxicity test was carried out with the
remaining
cells. For this, the commercial test system of Roche was used and the
measurement was carried out according to the instructions of the
manufacturer's protocol.
Table 1 below shows the results.
Bradykinin increases the MMP3 release by more than 30%. This increased
release of MMP3 was inhibited by HOE140 in a dose-dependent manner.
Table 1 MMP- 3 release from SW cells
MMP-3 release
Relative values
based on
Stimulation parameter MW SD starting value
(OD 450 nm)
unstimulated 93 20
I L 1 a (0.05 n /ml 328 17 100
IL1a + bradykinin 0.1 pM) 433 32 132.0
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IL1a + bradykinin (0.1 NM) 458 50 139.6
+ 0.05 M HOE140
IL1a + bradykinin (0.1 NM) 371 8 113.1
+ 0.1 pM HOE140
IL1a + bradykinin (0.1 pM) 309 18 94.2
+ 0.5 pM HOE140
IL1a + bradykinin (0.1 NM) 306 27 93.3
+1 pM
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SEQUENCE LISTING
<110> Sanofi-Aventis Deutschland GmbH
<120> Use of Bradykinin-B2 Receptor Antagonists for Treating
Osteoarthosis
<130> 9982-895
<140> CA 2,514,152
<141> 2004-01-23
<150> DE 103 04 994.0
<151> 2003-02-07
<160> 1
<170> Patentln version 3.3
<210> 1
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Description of Artificial Sequence: Peptide with D-Amino Acid
<220>
<221> misc feature
<222> (1)..(1)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc feature
<222> (6)..(6)
<223> Xaa can be any naturally occurring amino acid
<220>
<221> misc_feature
<222> (8)..(9)
<223> xaa can be any naturally occurring amino acid
<400> 1
Xaa Arg Pro Pro Gly Xaa Ser Xaa Xaa Arg
1 5 10
