CA2122429A1 - Use of bradykinin antagonists for the preparation of a medicament for the prophylaxis of treatment of arteriosclerosis - Google Patents
Use of bradykinin antagonists for the preparation of a medicament for the prophylaxis of treatment of arteriosclerosisInfo
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- CA2122429A1 CA2122429A1 CA002122429A CA2122429A CA2122429A1 CA 2122429 A1 CA2122429 A1 CA 2122429A1 CA 002122429 A CA002122429 A CA 002122429A CA 2122429 A CA2122429 A CA 2122429A CA 2122429 A1 CA2122429 A1 CA 2122429A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/043—Kallidins; Bradykinins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
Abstract Use of bradykinin antagonists for the preparation of a medicament for the prophylaxis or treatment of arterio-sclerosis The use of bradykinin antagonists for the prophylaxis and treatment of arteriosclerosis is described. The bradykinin antagonists to be used are distinguished by a content of the amino acids D-Tic, D-Phe, D-Dic, D-Thi or D-Nal in position 7 of the peptide.
Description
2~2~429 aOECHST AKTI~NGESELLSC~AFT H0~ 93/F 118 Dr.VF/St DESCRIPTION
Use of bradykinin antagonist~ for the preparation of a medicament for the prophylaxiR or treatment of arterio~
sclerosis The invention relates to the u~e of bradykinin antago-nists ~or the treatment and preventive treatment of arterio~clero~is. Bradykinin and related peptide~ are potent inflammation- and pain-generating and vasoactive endogenou~ sub~ta~ces.
Surprisingly, it has now been found that bradykinin antagonists are ~uitable therapeutics for the prevention and treatment of arterioscleroRisO
Suitable bradykinin antagonists arP, inter alia, the peptides of the fonmula I
Z-P-A-~-C-E-F-K-~D)Q-G-M-F'~
in which:
Z is al) hydrogen, [C1-C8)-alkyl~ (C1-Ca)-alkanoyl, (cl-c8)-alkoxycarbonyl~ ( C3_CB ) -CYC1Oa1kY1, ( C4-C9 ) -cycloalkanoyl~ or ~C,-C8)-alkylsul~onyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 vr 3 identical or different radical fxom the series comprising carboxyl, NHR(l), [( Cl-C4 ) -al~yl]-N~(l) or ~(C6-~,0)-aryl-( C~-C4 ) alkyl]NR(1), in which R(l) i3 hydrogen or a urethane protective group, (C1-C4)-alkyl t ( C~-C~ )-alkylami~o, (C6-C,0)-aryl~lCl-C4~-alkylamino, hydroxyl, ( Cl-C4 ) -alkoxy, halogen, , ~ : .
:
21~2~29 `- ~
. -" , di-(C1-Cg~-alkylamino, di-[( C6-C10 ) -axyl-~Cl-C43]-alkylamino, carbamoyl, phthalimido, l,8-naphthalimido, sul-famoyl, ( C~-C4 ) -alkoxycarbonyl, (C6-C,4)-aryl and ~Cs-C~ aryl-(Cl-Cs)-alkyl, or in which in each ~ase 1 hydrogen atom i8 optionally replaced by a radical from the seri~s Comprising ( C3-Ca ) -cyc loalkyl, ( Cl-C6 ) -alkyl-~ulfonyl, (C~-C6)-alkylsulfinyl, (C6-Cl~)-aryl-(C1-C4)-allcylsul~onyl, )-aryl-(cl-c~)-alkyl~ulfin (C6-Cl4)-aryl, (c6-c~)-aryloxy~
( C3-cl3 ) -heteroaryl and ~ C3-C~3 ~ -heteroaryloxy a~d 1 or 2 hydrogen atome are replaced by 1 or 2 identical or different radicals from the ~eries comprising carboxyl, amino, (Cl-Ca)-alkylamino, hydroxyl, (C1 c4)~alkoxy, halogen, di-~cl-cfl )-alkylamino t carbamoyl t sulf~moyl, (cl-c4)-alkoxycarbonyl~
(~6~Cl4)-aryl and (C6-C,4)-aryl-( Cl~C5 1 -~lkyl;
a2) (C6-Cl4)-aryl, ~C7-Cls~-aroyl, IC6-Cl4~-~rylsul-fonyl, (C3-C13)-heteroaryl or ~c3-C13)-h~t~ro-aroyl;
a3) carbamoyl, whi~h can optionally be ~ubstituted on the nitrogen by (C~-Cg)-alkyl, (C6-Cl4)-aryl ox (Cc-Cl~)-aryl-(Cl-Cs)-alkyl; ~ ~:
and in which, in the radical~ defi~ed under al)~ a2~
and a3) ~ the aryl, hetersaryl, aroyl, aryleul~onyl and heteroaroyl groupg are optionally sub~tituted hy :~:
1, 2, 3 or 4 radical~ from the ~erie~ comprising _ carboxyl, amino, nitro, ~C~-Ca~-alkylamino, hydroxyl, ~C,-C~)-alkyl, (C~-C6)-alkoxy, ~ C6-C14 ) -aryl J ( c7-cls ) -aroyl~ halogen, cyano, di-(Cl-C8)-alkylamino, carbamoyl, sulfamoyl and (cl-c6)-alkoxycarbonyl;
P i8 a direct bond or a radical of the formula II
-NR(2)-(U)-CO~
in which R(2) i~ hydrogen, methyl or a urethane protec-tive group, U iS ~ C3-C~ )-cycloalkylidene, (C6-C14~-aryl idene, (C3-C13~-heteroarylidene or ( C6-C14)-aryl-( C,-C6)-alkylidene, which can option-ally be substitUted~ or [C~R(3) ]n in which n i8 1 - 8, preferably 1 - 6, R(3) independently of one another are hydrogen, ~Cl-C6 ) -alkyl, ~ C3-C8 ) -cycloalkyl, (C6-Cl4)-aryl or (C3-C13)-heteroaryl, which, with th2 excep-tio~ of the hydrogen, are in each ca~e optiQnally monosubRtituted by amino, ~ub~tituted amino, amidino, suh~tituted amidi~o, hydroxyl, carboxyl, carbamoyl, guanidin~, ~ub~tituted guan-idino, ureido, ~ubRtit~t~d ureido, mercapto, ~ethyl-mercapto, phenyl, 4-chloro-phenyl, 4~fluorophenyl, 4-nitrophenyl~ 4-methoxyphenyl, 4-hydroxyph~nyl, phthalimido, 1,8-naphthalimido~ 4-imid-azolyl, 3-indolyl, ~-thienyl, 3-thienyl~ 2-pyridyl, 3-pyridyl or cyclohexyl, 2~22~29 : - 4 -in which ~ubstituted amino i preferably -N(A')-Z, substituted amidino is preferably -lNH=~C-NH-Z, ~ubstituted guanidino is prefer-ably -N(A'~C[=N(A')] N~-Z and 3ubstituted ureido i9 preferably -CO-N(A')-Z, in which the radicals A' independently of one another are hydrogen or z, in which z is a~ defined under a,) or a2);
or in which R(2) and R(3), together with the atom~
carrying these, form a mono-, bi- or tricyclic ring 3y~tem having 2 to 15 carbon atoms;
A i~ as defined for P;
B is a ba~ic amino acid in the L- or D-configuration, which can be substituted in the side chain;
C is a compound of the formula IlIa or IIIh G'-G'-Gly G'-NH-(CH2)p-CO
(IIIa) (IIIb) in which p is 2 to 8 and the radicals G' independently of one another are a radical of the formula IY ;~.
~NR(4)-CHR(~)-CO- ~IV) in which R(4) and R(5) t together with the atoms carrying these, form a heterocyclic mono-~ bi- or tricyclic ring ~ystem having 2 to 15 caxbon atoms;
is the radical of a nQutral, acid or basic, 2122~2~ :
_ 5 _ aliphatic or alicyclic-aliphatic amino acid;
khe radicals F independently of one another are the radical of a neutral, acid or basic, aliphatic or aromatic ~mino acid, which can ~e ~ubstituted in the 5side chain, or a direct bond;
(D)Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, which can optionally be substituted by halogen, methyl or methoxy, or a radical of the following formula (V~
R
~ ~V~ ~
N~ :
O ' in which 0 X i8 oxygen or sulfur or a direct ~ond;
R is hydrogen, (C,-C8)-alkyl, (C3-C8)-cycloalkyl, ~ ~
(C6-Cl4)-aryl or (C6-Cl4)-aryl-l C~-C4 ~ -alkyl, in ~ -which the alicyclic xadic~l can optionally be substituted by halogen, methyl or methoxy;
15 G is as defined above for G' or a direct bond;
F' is as defined for ~, a radical -~H-~CH2)9-, where q is 2 to 8~ or, if G i8 not a direct bond, a direct bond;
I is -OH, -NH2 or NHC2H~;
K is the radical ~NH-(C~2)~-CO- where x is 1 to 4, or a direck bond and i6 as defined for F, and physiologically tolerated salt~ thereofO
.. :, , , Suitable bradykinin anta~onists are described, for example, in the Patent Publication~ EP 370 453, EP 472 220, WO 92/18155, WO 92/18156 and WO 92/17201 [Cortech; bradykinin aIltagoni~t~ of the ~onmula X(~KA)~, 5 in which X is a bonding member, BKA i8 the peptide ~hain of a bradykinin ~ntagoni~t and n i8 an integer greater than 1; bradykinin antagoni~ts of the formula X(BKA); and bradykinin antagonists of the formula (Y)(X)~BKA) where Y is a ligand which i~ an antagoni~t or an ~gonist for a non-bradykinin receptor].
Particularly fiuitable peptides of the formula I are those in which:
Z is hydrogen or i9 as defined under a,), a2) or a3), P i~ a bond or a radical of the formula II
-NR(2)-(U)-CO- (II~
where U i~ CHR(3) and R~3) is as defined ~bove, R(2) is H or CH3, A is a bond.
Particularly preferred compounds of the formula I are those in which~
Z i8 hydrogen or i~ a8 defined under al), a2) or a3), P i~ a bond or a radical of the formula II
-NR(2)-tU)-cO- (II) whexe U i8 CHR(3) and where the radical~ R(3) independently o one another are hydrogen, (C~-C6)-alkyl, (C3-C0~-cycloalkyl, (C6-C14)-aryl or ( C3-C,3)-heteroaryl, which, with the xception of the hydrogen, are in each case option-ally monosubstituted by 2~2242~ ~
, ~
amino, ~ubstituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, ~ub-stituted guanidino, ureido, mer-capto/ methylmcrcapto, phenyl, 4-chlorophenyl~ 4-fluorophenyl, 4-nitrophenyl, 4 methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imi-dazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, and in which ~ubstitut2d amino i3 prefer-ably -N(A')-Z and substituted guanidino i~ preferably -N(A')-C[-N(A')]-~-Z~ in which the radicals A' independently of one another are hydrogen or Z, in which Z
i~ as defined under al) or a2);
or in which R~2~ and R(3), together with the atoms carrying these, form a mono-, bi-2 0 or tricyclic ring ~ystem having 2 to 15 carbon atom ;
R(2) is H or C~3 A i~ a bond, ~D)Q is D-Tico (R)-Arginyl-~S)-arginyl-(S)-prolyl-(2S,4R~-hydroxypro-lyl ) glycyl- ( S ) - ~ 3- ( 2~thienyl ) ~lanyl ~ - ~ 5 ) -seryl ( R 3 -[ (1,2,3,4-tetrahydro~3~ uinolyl)carbonyl3-( 2S, 3aS, 7aS ) r ( hexahydro-2-indolinyl)carbonyl]-(S)-arginine N-acetate, which carrie~ the INN name iaatibant 3~ acetate and i~ also called HOE 140, i~ espPcially suit-able.
The bradykinin antagonist~ are used in a ~uitable ac~min-istration form as medicaments for the treatment of atherosslerosis.
Suitable pharmaceutical preparations compri~e an active amount of the bradykinin ~ntagoni~t - individually or in combination - together with an inorganic or organic pharmaceutically usable excipient.
The preparation can be used enterally, parenterally -such a~, for example, ~ubcutaneously, intramu~cularly or intravenou~ly - sublingually, epi~utaneously, nasally, rectally, intravaginally, intrabuccally or by inhalation.
The dosage of the active compound depend~ sn the warm-blooded ~pecie~, the body weight, age and the method ofa~ministration.
The pharmaceutical preparations of the present invention are prepared in solution ~ mixing, granulating or tablet-coating processes which are known per ~e.
For the oral use form or for application to the mucosae, the active compounds are mixed with the additives custom~
ary for this purpose, such as sxcipients, stabilizer~ or inert diluent~, and are brought by customary method~ into suitable dosage forms, such as tablet~, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily su~pen-sio~s or aqueous, alcoholic or oily ~olutions. Inert excipients which can be used, are, for example, gum arabic, magnesia, magnesium carbonate, pota88ium phos-phate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch~ Formulation can be effected in either dry or moist granul~ form. Possible oily excipient~ or solvent~ are, for example, vegetable or animal oils, such as sunflower oil and cod-liver oil.
A preparation for topical u~e can be in the form o~ an aqueous or oily solution, lotion, emul~ion or jelly, ointment or greasy ointment or, i~ possibleO in ~pray form, it being po~sible to improve the aclhe~lsn, if appropriate, by addition of a polymer.
For the intranasal use form, the compounds are mixed with 2122~29 g the additives customary for this purpose, such as stabi-li~ers or inert diluents, and brought by cu~tomary methods into suitable dosage forms, such a~ aqueous, alcoholic or oily suspensions or aqueous, lcoholic or oily solutions. Chelating agents, ethylenediamine~
N,~,~',N'-tetraacetic acid, citric acid, tartaric acid or ~alts thereof can b~ added to aqueous intranasal formula-tions. ~he nasal ~olutions can be admini~tered by mean~
of metered atomizer~, or as nasal drops with a viscosity-lncreasing content or na~al gel~ or nasal cream~.
Nebuliz~r~ or compres~ed ga~ pack~ u~ing inert carriergases can be utilized for inhalative use.
For intravenous, subcutaneous, epicutaneous or intradermal administration, the active compounds or physiologically tolerated salts thereof are dissol~ed, suspended or emul~ified, if de~ired with the pharmaceuti-cally customary auxiliarie~, for example for i~otoni-cizing or p~ adjustment, as well as 801ubilizing ayent~, mulsifiers or other auxiliaries.
Becau~e of the short half-lives of ~ome of the medic-aments de6crib~d in body fluids, it is appropriate to ll~e injectable sustained release formulations. Medicame~t forms which can be u~ed ars, for example, oily crystal sllspensions, microcapsules~ rods or implants, it bei~g possible for the latter to be built up from ti~su~-tolerated polymers, in particular biodegradable polym~r~, such a~, for example, tho~e ba~ed on polylacti.c acid/polyglycolic acid copolymer or human albuminO
'rhe active do~e is at least 0.001 mg/kg/day, pre~erably at lea~t 0.01 mg/kg/day, in particular at lea~t 0.1 mg/kg/day to not more than 3 mg/kg/day, prefera~ly to not more than 1 mg/kg/day of body weight, ba~ed on an adult weighing 75 kg.
Investigation of the activity of br~dykinin antagonistss 2122~29 Arteriosclerotic changes to the ves el walls were induced in rabbits by feeding with a cholesterol-containing diet.
Rabbiks were protected by treatment with HOE 140.
Arterio~clerotic changes to the vessel walls were greatly reduced.
Te~t m~thod:
The test was carried out with white rabbits (New Zealand) of the male ~ex weighing 3 - 4 kilogram~ in accordance with the published methods of A. Kisanuki, Y. Asada, K. Hatakeyama, T. Hayashi and A. Sumiyosh:i: Contributions o~ the Endothe}ium to Intimal Thicke~ing in ~ormo-cholesterolemic and Hypercholesterolemic Rabbit~
Arteriosclerosis and Thrombosis ~1992), 12; 1198 - 1205 and J. Cooke, A. Singer, P. Tsao, P. Zera, R. Rowan and M. Billingham: Antiatherogenic Effects of L Arginine in the Hyperchol~sterolemic Rabbi~ ~1992), 90; 1168 - 1172.
After a week under standard rabbit food ~Altromin 2834, Lage-~ippe, Germany), two groups of 15 rabbits each were fed with a cholesterol-rich diet for three months. The diet contained 0.25% of cholesterol and 3% of coconut oil. One of the two group~ was additionally giYen a subcutaneou~ continuous infu ion of ~OE 140 via implanted 06motic minipumps throughou the entire period of three months. The dose was 100 ~g/kg/day.
~:
Another group of 15 rabbits give~ a ~on-atherogenic normal diet ~erved a~ the negative control~ Food and water were given ad libitum. The evidence that the do~e of HOE 140 chosen can inhibit the action of endogenous kinins was provided via inhibition of the antihyper-tensive action of exogenous bradykinin. At th~ end o~ thetest, after treatment for three months~ the animal~ were anesthetized and the basal blood pressure was measured.
The basal blood pres3ure was between 100 an~ 110 mm ~g.
After measurement ~f the basal blood pressure~ br~dykinin was injected intraart~rially as a bolus in a dose of 10 ng. In the animals with normal food~ this led to a drop in blood pressure of 21 mm ~g, and in the animals 2122~29 with an atherogenic diet, the drop in blood pressure was 24 mm Hg. In rabbit~ with an atherogenic diet treated with HOE 140, the blood pressure dropped only by 3.7 mm ~g, which indicated effective inhibition of the action of bradykinin by ~OE 140.
Thereafter, the rabbit~ were sacrificed with a high dose of pentobarbital (40 mg/kg) and a complete autopsy was performed. The athero~clerotic plaques were rendered vi~ible by oil red O (C26~24N4O), their extent was deter-mined by means of an image analyzer and the percentageplaque size in the aorta was determined. The cholesterol fractions (HDL, LDL and VLDL) in the serum were further-more determined with the aid of ultracentrifugation.
Results , Evaluation of the arteriosclerotic changes:
Aortas of rabbit~ under normal food showed no arterio~
sclerotic vascular ~hang s at all. Aortas of rabbit~ with cholesterol-containing food showed pronounced vascular changes in the form of atherosclerotic plaques. Surpris-ingly, HOE 140 showed antiatherosclerotic actions:atherosclerotic changes in the aortic arch and the aortic sections in the thorax and abdomen were lower by far in the animals given HOE 140 with the atherogenic diet (Table 1).
Action on ~erum lipids: LDL and VLD~ were greatly reduced by HO~ 1~0 and were ~carcely di~tingui~hable from lipid values of the controls with normal, non-atherogenic food (Table 2). The HDL values were sig~ificantly increased in the animals with cholesterol-rich food. Treatment with HOE 140 ~howed no influence on the~e parameters.
Conclu~ion:
Bradykinin antagonists reduce ~erum lipids and have .. . . - ,. , .. ..
2122~29 pronounced antiatheroscl~rotic action~. On the basi~ of these actions, they are ~uitable for the therapy and preventive treatment of arterio~clerosisO
Table 1 Plaque~ in the aorta: area in perc~nt of the intima area (mean ~ S.~.M.) Normal diet Atherogenic Atherogeni~
diet diet ~ ~OE
140 :
Aortia arch 0 44.3 ~ 4092 23.4 i 5.4 : :~
Thoracic 0 12.3 ~ 4.0 1.6 aorta Abdominal 0 10 ~ 8 ! 3 ~ 2 1 ~ 4 + O n 6 10 aorta 1 Abdominal 0 14.6 ~ 1/9 700 ~ 1.5 aorta 2~ -1 and 2 = fir~t and, re~pectlvely, ~econd ~ectlon ~able 2 Ser~m lipoprotein fractions (~g/ml~
~Mean~ ~ S~EoM~ ) Normal diet Atherogeni~ Atherogenic :~
diet diet ~ ~OE
140 ~:
LDL 257 ~ 63 2950 ~ 329 168 ~ 21 VLDL 330 ~ 64 2837 ~ 163 250 ~ 12 HDL 2871 ~ 23 5703 ~ 610 4981 ~ 576
Use of bradykinin antagonist~ for the preparation of a medicament for the prophylaxiR or treatment of arterio~
sclerosis The invention relates to the u~e of bradykinin antago-nists ~or the treatment and preventive treatment of arterio~clero~is. Bradykinin and related peptide~ are potent inflammation- and pain-generating and vasoactive endogenou~ sub~ta~ces.
Surprisingly, it has now been found that bradykinin antagonists are ~uitable therapeutics for the prevention and treatment of arterioscleroRisO
Suitable bradykinin antagonists arP, inter alia, the peptides of the fonmula I
Z-P-A-~-C-E-F-K-~D)Q-G-M-F'~
in which:
Z is al) hydrogen, [C1-C8)-alkyl~ (C1-Ca)-alkanoyl, (cl-c8)-alkoxycarbonyl~ ( C3_CB ) -CYC1Oa1kY1, ( C4-C9 ) -cycloalkanoyl~ or ~C,-C8)-alkylsul~onyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 vr 3 identical or different radical fxom the series comprising carboxyl, NHR(l), [( Cl-C4 ) -al~yl]-N~(l) or ~(C6-~,0)-aryl-( C~-C4 ) alkyl]NR(1), in which R(l) i3 hydrogen or a urethane protective group, (C1-C4)-alkyl t ( C~-C~ )-alkylami~o, (C6-C,0)-aryl~lCl-C4~-alkylamino, hydroxyl, ( Cl-C4 ) -alkoxy, halogen, , ~ : .
:
21~2~29 `- ~
. -" , di-(C1-Cg~-alkylamino, di-[( C6-C10 ) -axyl-~Cl-C43]-alkylamino, carbamoyl, phthalimido, l,8-naphthalimido, sul-famoyl, ( C~-C4 ) -alkoxycarbonyl, (C6-C,4)-aryl and ~Cs-C~ aryl-(Cl-Cs)-alkyl, or in which in each ~ase 1 hydrogen atom i8 optionally replaced by a radical from the seri~s Comprising ( C3-Ca ) -cyc loalkyl, ( Cl-C6 ) -alkyl-~ulfonyl, (C~-C6)-alkylsulfinyl, (C6-Cl~)-aryl-(C1-C4)-allcylsul~onyl, )-aryl-(cl-c~)-alkyl~ulfin (C6-Cl4)-aryl, (c6-c~)-aryloxy~
( C3-cl3 ) -heteroaryl and ~ C3-C~3 ~ -heteroaryloxy a~d 1 or 2 hydrogen atome are replaced by 1 or 2 identical or different radicals from the ~eries comprising carboxyl, amino, (Cl-Ca)-alkylamino, hydroxyl, (C1 c4)~alkoxy, halogen, di-~cl-cfl )-alkylamino t carbamoyl t sulf~moyl, (cl-c4)-alkoxycarbonyl~
(~6~Cl4)-aryl and (C6-C,4)-aryl-( Cl~C5 1 -~lkyl;
a2) (C6-Cl4)-aryl, ~C7-Cls~-aroyl, IC6-Cl4~-~rylsul-fonyl, (C3-C13)-heteroaryl or ~c3-C13)-h~t~ro-aroyl;
a3) carbamoyl, whi~h can optionally be ~ubstituted on the nitrogen by (C~-Cg)-alkyl, (C6-Cl4)-aryl ox (Cc-Cl~)-aryl-(Cl-Cs)-alkyl; ~ ~:
and in which, in the radical~ defi~ed under al)~ a2~
and a3) ~ the aryl, hetersaryl, aroyl, aryleul~onyl and heteroaroyl groupg are optionally sub~tituted hy :~:
1, 2, 3 or 4 radical~ from the ~erie~ comprising _ carboxyl, amino, nitro, ~C~-Ca~-alkylamino, hydroxyl, ~C,-C~)-alkyl, (C~-C6)-alkoxy, ~ C6-C14 ) -aryl J ( c7-cls ) -aroyl~ halogen, cyano, di-(Cl-C8)-alkylamino, carbamoyl, sulfamoyl and (cl-c6)-alkoxycarbonyl;
P i8 a direct bond or a radical of the formula II
-NR(2)-(U)-CO~
in which R(2) i~ hydrogen, methyl or a urethane protec-tive group, U iS ~ C3-C~ )-cycloalkylidene, (C6-C14~-aryl idene, (C3-C13~-heteroarylidene or ( C6-C14)-aryl-( C,-C6)-alkylidene, which can option-ally be substitUted~ or [C~R(3) ]n in which n i8 1 - 8, preferably 1 - 6, R(3) independently of one another are hydrogen, ~Cl-C6 ) -alkyl, ~ C3-C8 ) -cycloalkyl, (C6-Cl4)-aryl or (C3-C13)-heteroaryl, which, with th2 excep-tio~ of the hydrogen, are in each ca~e optiQnally monosubRtituted by amino, ~ub~tituted amino, amidino, suh~tituted amidi~o, hydroxyl, carboxyl, carbamoyl, guanidin~, ~ub~tituted guan-idino, ureido, ~ubRtit~t~d ureido, mercapto, ~ethyl-mercapto, phenyl, 4-chloro-phenyl, 4~fluorophenyl, 4-nitrophenyl~ 4-methoxyphenyl, 4-hydroxyph~nyl, phthalimido, 1,8-naphthalimido~ 4-imid-azolyl, 3-indolyl, ~-thienyl, 3-thienyl~ 2-pyridyl, 3-pyridyl or cyclohexyl, 2~22~29 : - 4 -in which ~ubstituted amino i preferably -N(A')-Z, substituted amidino is preferably -lNH=~C-NH-Z, ~ubstituted guanidino is prefer-ably -N(A'~C[=N(A')] N~-Z and 3ubstituted ureido i9 preferably -CO-N(A')-Z, in which the radicals A' independently of one another are hydrogen or z, in which z is a~ defined under a,) or a2);
or in which R(2) and R(3), together with the atom~
carrying these, form a mono-, bi- or tricyclic ring 3y~tem having 2 to 15 carbon atoms;
A i~ as defined for P;
B is a ba~ic amino acid in the L- or D-configuration, which can be substituted in the side chain;
C is a compound of the formula IlIa or IIIh G'-G'-Gly G'-NH-(CH2)p-CO
(IIIa) (IIIb) in which p is 2 to 8 and the radicals G' independently of one another are a radical of the formula IY ;~.
~NR(4)-CHR(~)-CO- ~IV) in which R(4) and R(5) t together with the atoms carrying these, form a heterocyclic mono-~ bi- or tricyclic ring ~ystem having 2 to 15 caxbon atoms;
is the radical of a nQutral, acid or basic, 2122~2~ :
_ 5 _ aliphatic or alicyclic-aliphatic amino acid;
khe radicals F independently of one another are the radical of a neutral, acid or basic, aliphatic or aromatic ~mino acid, which can ~e ~ubstituted in the 5side chain, or a direct bond;
(D)Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, which can optionally be substituted by halogen, methyl or methoxy, or a radical of the following formula (V~
R
~ ~V~ ~
N~ :
O ' in which 0 X i8 oxygen or sulfur or a direct ~ond;
R is hydrogen, (C,-C8)-alkyl, (C3-C8)-cycloalkyl, ~ ~
(C6-Cl4)-aryl or (C6-Cl4)-aryl-l C~-C4 ~ -alkyl, in ~ -which the alicyclic xadic~l can optionally be substituted by halogen, methyl or methoxy;
15 G is as defined above for G' or a direct bond;
F' is as defined for ~, a radical -~H-~CH2)9-, where q is 2 to 8~ or, if G i8 not a direct bond, a direct bond;
I is -OH, -NH2 or NHC2H~;
K is the radical ~NH-(C~2)~-CO- where x is 1 to 4, or a direck bond and i6 as defined for F, and physiologically tolerated salt~ thereofO
.. :, , , Suitable bradykinin anta~onists are described, for example, in the Patent Publication~ EP 370 453, EP 472 220, WO 92/18155, WO 92/18156 and WO 92/17201 [Cortech; bradykinin aIltagoni~t~ of the ~onmula X(~KA)~, 5 in which X is a bonding member, BKA i8 the peptide ~hain of a bradykinin ~ntagoni~t and n i8 an integer greater than 1; bradykinin antagoni~ts of the formula X(BKA); and bradykinin antagonists of the formula (Y)(X)~BKA) where Y is a ligand which i~ an antagoni~t or an ~gonist for a non-bradykinin receptor].
Particularly fiuitable peptides of the formula I are those in which:
Z is hydrogen or i9 as defined under a,), a2) or a3), P i~ a bond or a radical of the formula II
-NR(2)-(U)-CO- (II~
where U i~ CHR(3) and R~3) is as defined ~bove, R(2) is H or CH3, A is a bond.
Particularly preferred compounds of the formula I are those in which~
Z i8 hydrogen or i~ a8 defined under al), a2) or a3), P i~ a bond or a radical of the formula II
-NR(2)-tU)-cO- (II) whexe U i8 CHR(3) and where the radical~ R(3) independently o one another are hydrogen, (C~-C6)-alkyl, (C3-C0~-cycloalkyl, (C6-C14)-aryl or ( C3-C,3)-heteroaryl, which, with the xception of the hydrogen, are in each case option-ally monosubstituted by 2~2242~ ~
, ~
amino, ~ubstituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, ~ub-stituted guanidino, ureido, mer-capto/ methylmcrcapto, phenyl, 4-chlorophenyl~ 4-fluorophenyl, 4-nitrophenyl, 4 methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imi-dazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, and in which ~ubstitut2d amino i3 prefer-ably -N(A')-Z and substituted guanidino i~ preferably -N(A')-C[-N(A')]-~-Z~ in which the radicals A' independently of one another are hydrogen or Z, in which Z
i~ as defined under al) or a2);
or in which R~2~ and R(3), together with the atoms carrying these, form a mono-, bi-2 0 or tricyclic ring ~ystem having 2 to 15 carbon atom ;
R(2) is H or C~3 A i~ a bond, ~D)Q is D-Tico (R)-Arginyl-~S)-arginyl-(S)-prolyl-(2S,4R~-hydroxypro-lyl ) glycyl- ( S ) - ~ 3- ( 2~thienyl ) ~lanyl ~ - ~ 5 ) -seryl ( R 3 -[ (1,2,3,4-tetrahydro~3~ uinolyl)carbonyl3-( 2S, 3aS, 7aS ) r ( hexahydro-2-indolinyl)carbonyl]-(S)-arginine N-acetate, which carrie~ the INN name iaatibant 3~ acetate and i~ also called HOE 140, i~ espPcially suit-able.
The bradykinin antagonist~ are used in a ~uitable ac~min-istration form as medicaments for the treatment of atherosslerosis.
Suitable pharmaceutical preparations compri~e an active amount of the bradykinin ~ntagoni~t - individually or in combination - together with an inorganic or organic pharmaceutically usable excipient.
The preparation can be used enterally, parenterally -such a~, for example, ~ubcutaneously, intramu~cularly or intravenou~ly - sublingually, epi~utaneously, nasally, rectally, intravaginally, intrabuccally or by inhalation.
The dosage of the active compound depend~ sn the warm-blooded ~pecie~, the body weight, age and the method ofa~ministration.
The pharmaceutical preparations of the present invention are prepared in solution ~ mixing, granulating or tablet-coating processes which are known per ~e.
For the oral use form or for application to the mucosae, the active compounds are mixed with the additives custom~
ary for this purpose, such as sxcipients, stabilizer~ or inert diluent~, and are brought by customary method~ into suitable dosage forms, such as tablet~, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily su~pen-sio~s or aqueous, alcoholic or oily ~olutions. Inert excipients which can be used, are, for example, gum arabic, magnesia, magnesium carbonate, pota88ium phos-phate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch~ Formulation can be effected in either dry or moist granul~ form. Possible oily excipient~ or solvent~ are, for example, vegetable or animal oils, such as sunflower oil and cod-liver oil.
A preparation for topical u~e can be in the form o~ an aqueous or oily solution, lotion, emul~ion or jelly, ointment or greasy ointment or, i~ possibleO in ~pray form, it being po~sible to improve the aclhe~lsn, if appropriate, by addition of a polymer.
For the intranasal use form, the compounds are mixed with 2122~29 g the additives customary for this purpose, such as stabi-li~ers or inert diluents, and brought by cu~tomary methods into suitable dosage forms, such a~ aqueous, alcoholic or oily suspensions or aqueous, lcoholic or oily solutions. Chelating agents, ethylenediamine~
N,~,~',N'-tetraacetic acid, citric acid, tartaric acid or ~alts thereof can b~ added to aqueous intranasal formula-tions. ~he nasal ~olutions can be admini~tered by mean~
of metered atomizer~, or as nasal drops with a viscosity-lncreasing content or na~al gel~ or nasal cream~.
Nebuliz~r~ or compres~ed ga~ pack~ u~ing inert carriergases can be utilized for inhalative use.
For intravenous, subcutaneous, epicutaneous or intradermal administration, the active compounds or physiologically tolerated salts thereof are dissol~ed, suspended or emul~ified, if de~ired with the pharmaceuti-cally customary auxiliarie~, for example for i~otoni-cizing or p~ adjustment, as well as 801ubilizing ayent~, mulsifiers or other auxiliaries.
Becau~e of the short half-lives of ~ome of the medic-aments de6crib~d in body fluids, it is appropriate to ll~e injectable sustained release formulations. Medicame~t forms which can be u~ed ars, for example, oily crystal sllspensions, microcapsules~ rods or implants, it bei~g possible for the latter to be built up from ti~su~-tolerated polymers, in particular biodegradable polym~r~, such a~, for example, tho~e ba~ed on polylacti.c acid/polyglycolic acid copolymer or human albuminO
'rhe active do~e is at least 0.001 mg/kg/day, pre~erably at lea~t 0.01 mg/kg/day, in particular at lea~t 0.1 mg/kg/day to not more than 3 mg/kg/day, prefera~ly to not more than 1 mg/kg/day of body weight, ba~ed on an adult weighing 75 kg.
Investigation of the activity of br~dykinin antagonistss 2122~29 Arteriosclerotic changes to the ves el walls were induced in rabbits by feeding with a cholesterol-containing diet.
Rabbiks were protected by treatment with HOE 140.
Arterio~clerotic changes to the vessel walls were greatly reduced.
Te~t m~thod:
The test was carried out with white rabbits (New Zealand) of the male ~ex weighing 3 - 4 kilogram~ in accordance with the published methods of A. Kisanuki, Y. Asada, K. Hatakeyama, T. Hayashi and A. Sumiyosh:i: Contributions o~ the Endothe}ium to Intimal Thicke~ing in ~ormo-cholesterolemic and Hypercholesterolemic Rabbit~
Arteriosclerosis and Thrombosis ~1992), 12; 1198 - 1205 and J. Cooke, A. Singer, P. Tsao, P. Zera, R. Rowan and M. Billingham: Antiatherogenic Effects of L Arginine in the Hyperchol~sterolemic Rabbi~ ~1992), 90; 1168 - 1172.
After a week under standard rabbit food ~Altromin 2834, Lage-~ippe, Germany), two groups of 15 rabbits each were fed with a cholesterol-rich diet for three months. The diet contained 0.25% of cholesterol and 3% of coconut oil. One of the two group~ was additionally giYen a subcutaneou~ continuous infu ion of ~OE 140 via implanted 06motic minipumps throughou the entire period of three months. The dose was 100 ~g/kg/day.
~:
Another group of 15 rabbits give~ a ~on-atherogenic normal diet ~erved a~ the negative control~ Food and water were given ad libitum. The evidence that the do~e of HOE 140 chosen can inhibit the action of endogenous kinins was provided via inhibition of the antihyper-tensive action of exogenous bradykinin. At th~ end o~ thetest, after treatment for three months~ the animal~ were anesthetized and the basal blood pressure was measured.
The basal blood pres3ure was between 100 an~ 110 mm ~g.
After measurement ~f the basal blood pressure~ br~dykinin was injected intraart~rially as a bolus in a dose of 10 ng. In the animals with normal food~ this led to a drop in blood pressure of 21 mm ~g, and in the animals 2122~29 with an atherogenic diet, the drop in blood pressure was 24 mm Hg. In rabbit~ with an atherogenic diet treated with HOE 140, the blood pressure dropped only by 3.7 mm ~g, which indicated effective inhibition of the action of bradykinin by ~OE 140.
Thereafter, the rabbit~ were sacrificed with a high dose of pentobarbital (40 mg/kg) and a complete autopsy was performed. The athero~clerotic plaques were rendered vi~ible by oil red O (C26~24N4O), their extent was deter-mined by means of an image analyzer and the percentageplaque size in the aorta was determined. The cholesterol fractions (HDL, LDL and VLDL) in the serum were further-more determined with the aid of ultracentrifugation.
Results , Evaluation of the arteriosclerotic changes:
Aortas of rabbit~ under normal food showed no arterio~
sclerotic vascular ~hang s at all. Aortas of rabbit~ with cholesterol-containing food showed pronounced vascular changes in the form of atherosclerotic plaques. Surpris-ingly, HOE 140 showed antiatherosclerotic actions:atherosclerotic changes in the aortic arch and the aortic sections in the thorax and abdomen were lower by far in the animals given HOE 140 with the atherogenic diet (Table 1).
Action on ~erum lipids: LDL and VLD~ were greatly reduced by HO~ 1~0 and were ~carcely di~tingui~hable from lipid values of the controls with normal, non-atherogenic food (Table 2). The HDL values were sig~ificantly increased in the animals with cholesterol-rich food. Treatment with HOE 140 ~howed no influence on the~e parameters.
Conclu~ion:
Bradykinin antagonists reduce ~erum lipids and have .. . . - ,. , .. ..
2122~29 pronounced antiatheroscl~rotic action~. On the basi~ of these actions, they are ~uitable for the therapy and preventive treatment of arterio~clerosisO
Table 1 Plaque~ in the aorta: area in perc~nt of the intima area (mean ~ S.~.M.) Normal diet Atherogenic Atherogeni~
diet diet ~ ~OE
140 :
Aortia arch 0 44.3 ~ 4092 23.4 i 5.4 : :~
Thoracic 0 12.3 ~ 4.0 1.6 aorta Abdominal 0 10 ~ 8 ! 3 ~ 2 1 ~ 4 + O n 6 10 aorta 1 Abdominal 0 14.6 ~ 1/9 700 ~ 1.5 aorta 2~ -1 and 2 = fir~t and, re~pectlvely, ~econd ~ectlon ~able 2 Ser~m lipoprotein fractions (~g/ml~
~Mean~ ~ S~EoM~ ) Normal diet Atherogeni~ Atherogenic :~
diet diet ~ ~OE
140 ~:
LDL 257 ~ 63 2950 ~ 329 168 ~ 21 VLDL 330 ~ 64 2837 ~ 163 250 ~ 12 HDL 2871 ~ 23 5703 ~ 610 4981 ~ 576
Claims (5)
1. The use of a bradykinin antagonist or one of its physiologically tolerated salts for the preparation of a medicament for the prophylaxis or treatment of arteriosclerosis.
2. The use as claimed in claim 1 of a bradykinin antagonist of the formula I
Z-P-A-B-C-E-F-K-(D)Q-G-M-F'-I (I) in which Z is a1) hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl, (C3-C8)-cycloalkyl, (C4-C9)-cycloalkanoyl, or (C1-C9-alkyl-sulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or
Z-P-A-B-C-E-F-K-(D)Q-G-M-F'-I (I) in which Z is a1) hydrogen, (C1-C8)-alkyl, (C1-C8)-alkanoyl, (C1-C8)-alkoxycarbonyl, (C3-C8)-cycloalkyl, (C4-C9)-cycloalkanoyl, or (C1-C9-alkyl-sulfonyl, in which in each case 1, 2 or 3 hydrogen atoms are optionally replaced by 1, 2 or
3 identical or different radicals from the series comprising carboxyl, NHR(1), [(C1-C4)-alkyl-]-NR(1) or [(C6-C10)-aryl-(C1-C4)-alkyl]NR(1), in which R(1) is hydrogen or a urethane protective group, (C1-C4)-alkyl, (C1-C8)-alkylamino, (C6-C10)-aryl-(C1-C4)-alkylamino, hydroxyl, (C1-C4)alkoxy, halogen, di-(C1-C8)-alkylamino, carbamoyl, phthalimido, 1,8-naphthalimido, sul-famoyl, (C1-C4)-alkoxycarbonyl, (C6-C14)-aryl and (C6-C14)-aryl-(C1-C5)-alkyl, or in which in each case 1 hydrogen atom is optionally replaced by a radical from the series comprising (C3-C8)-cycloalkyl, (C1-C6)-alkyl-sulfonyl, (C1-C6)-alkylsulfinyl, (C6-C14)-aryl-(C1-C4)-alkylsulfonyl, (C6 C14)-aryl-(C1-C4)-alkylsulfinyl, (C6-C14)-aryl, (C6-C14)-aryloxy, (C3-C13)-heteroaryl and (C3-C13)-heteroaryloxy and 1 or 2 hydrogen atoms are replaced by 1 or 2 identical or different radicals from the series comprising carboxyl, amino, (C1-C8)-alkylamino, hydroxyl, (C1-C4)-alkoxy, halogen, di-(C1-C8)-alkylamino, carbamoyl, sulfamoyl, (C1-C4)-alkoxycarbonyl, (C6-C14)-aryl and (C6-C14) aryl-(C1-C5)-alkyl;
a2) (C6-C14)-aryl, (C7-C15)-aroyl, (C6-C14)-aryl-sulfonyl, (C3-C13)-heteroaryl or (C3-C13)-heteroaroyl;
a3) carbamoyl, which can optionally be sub-stituted on the nitrogen by (C1-C8)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C5)-alkyl;
and in which, in the radicals defined under a1), a2) and a3), the aryl, heteroaryl, aroyl, aryl-sulfonyl and heteroaroyl groups are optionally substituted by 1, 2, 3 or 4 radicals from the series comprising carboxyl, amino, nitro, (C1-C8)-alkylamino, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C7-C15)-aroyl, halogen, cyano, di-(C1-C8)-alkylamino, carbamoyl, sulfamoyl and (C1-C6)-alkoxycarbonyl;
P is a direct bond or a radical of the formula II
-NR(2)-(U)-CO- (II) in which R(2) is hydrogen, methyl or a urethane protec-tive group, U is (C3-C8)-cycloalkylidene, (C6-C14)-aryl-idene, (C3-C13)-heteroarylidene or (C6-C14)-aryl-(C1-C6)-alkylidene, which can option-ally be substituted, or [CHR(3)]n, in which n is 1 - 8, preferably 1 - 6, R(3) independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C3)-cycloalkyl, (C6-C14)-aryl or (C3-C13)-heteroaryl, which, with the excep-tion of the hydrogen, are in each case optionally monosubstituted by amino, substituted amino, amidino, substituted amidino, hydroxyl, carboxyl, carbamoyl, guanidino, substituted guan-idino, ureido, substituted ureido, mercapto, methyl-mercapto, phenyl, 4-chloro-phenyl, 4-fluorophenyl,
a2) (C6-C14)-aryl, (C7-C15)-aroyl, (C6-C14)-aryl-sulfonyl, (C3-C13)-heteroaryl or (C3-C13)-heteroaroyl;
a3) carbamoyl, which can optionally be sub-stituted on the nitrogen by (C1-C8)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C5)-alkyl;
and in which, in the radicals defined under a1), a2) and a3), the aryl, heteroaryl, aroyl, aryl-sulfonyl and heteroaroyl groups are optionally substituted by 1, 2, 3 or 4 radicals from the series comprising carboxyl, amino, nitro, (C1-C8)-alkylamino, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy, (C6-C14)-aryl, (C7-C15)-aroyl, halogen, cyano, di-(C1-C8)-alkylamino, carbamoyl, sulfamoyl and (C1-C6)-alkoxycarbonyl;
P is a direct bond or a radical of the formula II
-NR(2)-(U)-CO- (II) in which R(2) is hydrogen, methyl or a urethane protec-tive group, U is (C3-C8)-cycloalkylidene, (C6-C14)-aryl-idene, (C3-C13)-heteroarylidene or (C6-C14)-aryl-(C1-C6)-alkylidene, which can option-ally be substituted, or [CHR(3)]n, in which n is 1 - 8, preferably 1 - 6, R(3) independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C3)-cycloalkyl, (C6-C14)-aryl or (C3-C13)-heteroaryl, which, with the excep-tion of the hydrogen, are in each case optionally monosubstituted by amino, substituted amino, amidino, substituted amidino, hydroxyl, carboxyl, carbamoyl, guanidino, substituted guan-idino, ureido, substituted ureido, mercapto, methyl-mercapto, phenyl, 4-chloro-phenyl, 4-fluorophenyl,
4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 1,8-naphthalimido, 4-imid-azolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, in which substituted amino is preferably -N(A')-Z, substituted amidino is preferably -(NH=)C-NH-Z, substituted guanidino is prefer-ably N(A')-C[=N(A')]-NH-Z and substituted ureido is preferably -CO-N(A')-Z, in which the radicals A' independently of one another are hydrogen or Z, in which Z is as defined under a1) or a2);
or in which R(2) and R(3), together with the atom carrying these, form a mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms;
A is as defined for P;
B is a basic amino acid in the L- or D-configur-ation, which can be substituted in the side chain;
C is a compound of the formula IIIa or IIIb G'-G'-Gly G'-NH-(CH2)p-CO
(IIIa) (IIIb) in which p is 2 to 8 and the radicals G' independently of one another are a radical of the formula IV
-NR(4)-CHR(5)-CO- (IV) in which R(4) and R(5), together with the atoms carrying these, form a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms;
E is the radical of a neutral, acid or basic, aliphatic or alicyclic-aliphatic amino acid;
the radicals F independently of one another are the radical of a neutral, aaid or basic, aliphatic or aromatic amino acid, which can be substituted in the side chains or a direct bond;
(D) Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, which can optionally be substituted by halogen, methyl or methoxy, or a radical of the follow-ing formula (V) (V) in which X is oxygen or sulfur or a direct bond;
R is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C5-C14)-aryl or (C6-C14)-aryl-(C1-C4)-alkyl, in which the alicyclic radical can optionally be substituted by halogen, methyl or methoxy;
G is as defined above for G' or a direct bond;
F' is as defined for F, a radical -NH-(CH2)q-, where q is 2 to 8. or, if G is not a direct bond, a direct bond;
I is -OH, -NH2 or NHC2H5;
K is the radical -NH-(CH2)x-CO- where x is 1 to 4, or a direct bond and M is as defined for F, or one of its physiologically tolerated salts.
3. The use as claimed in claim 2 of a bradykinin antag-onist of the formula I in which:
Z is hydrogen or is as defined under a1), a2) or a3), P is a bond or a radical of the formula II
-NR(2)-(U)-CO- (II) where U is CHR(3) and R(3) is as defined above, R(2) is H or CH3, A is a bond.
4. The use as claimed in claim 2 of a bradykinin antag-onist of the formula I in which:
Z is hydrogen or is as defined under a1), a2) or a3), P is a bond or a radical of the formula II
-NR(2)-(U)-CO- (II) where V is CHR(3) and where the radicals R(3) independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C6-C14)-aryl or (C3-C13)-heteroaryl, which, with the exception of the hydrogen, are in each case option-ally monosubstituted by amino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, sub-stituted guanidino, ureido, mer-capto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imi-dazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, and in which substituted amino is prefer-ably -N(A')-Z and substituted guanidino is preferably -N(A')-C[=N(A')]-NH-Z, in which the radicals A' independently of one another are hydrogen or Z, in which Z
is as defined under a1) or a2);
or in which R(2) and R(3), together with the atoms carrying these, form a mono-, bi-or tricyclic ring system having 2 to 15 carbon atoms;
R(2) is H or CH3, A is a bond, (D)Q is D-Tic.
or in which R(2) and R(3), together with the atom carrying these, form a mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms;
A is as defined for P;
B is a basic amino acid in the L- or D-configur-ation, which can be substituted in the side chain;
C is a compound of the formula IIIa or IIIb G'-G'-Gly G'-NH-(CH2)p-CO
(IIIa) (IIIb) in which p is 2 to 8 and the radicals G' independently of one another are a radical of the formula IV
-NR(4)-CHR(5)-CO- (IV) in which R(4) and R(5), together with the atoms carrying these, form a heterocyclic mono-, bi- or tricyclic ring system having 2 to 15 carbon atoms;
E is the radical of a neutral, acid or basic, aliphatic or alicyclic-aliphatic amino acid;
the radicals F independently of one another are the radical of a neutral, aaid or basic, aliphatic or aromatic amino acid, which can be substituted in the side chains or a direct bond;
(D) Q is D-Tic, D-Phe, D-Dic, D-Thi or D-Nal, which can optionally be substituted by halogen, methyl or methoxy, or a radical of the follow-ing formula (V) (V) in which X is oxygen or sulfur or a direct bond;
R is hydrogen, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C5-C14)-aryl or (C6-C14)-aryl-(C1-C4)-alkyl, in which the alicyclic radical can optionally be substituted by halogen, methyl or methoxy;
G is as defined above for G' or a direct bond;
F' is as defined for F, a radical -NH-(CH2)q-, where q is 2 to 8. or, if G is not a direct bond, a direct bond;
I is -OH, -NH2 or NHC2H5;
K is the radical -NH-(CH2)x-CO- where x is 1 to 4, or a direct bond and M is as defined for F, or one of its physiologically tolerated salts.
3. The use as claimed in claim 2 of a bradykinin antag-onist of the formula I in which:
Z is hydrogen or is as defined under a1), a2) or a3), P is a bond or a radical of the formula II
-NR(2)-(U)-CO- (II) where U is CHR(3) and R(3) is as defined above, R(2) is H or CH3, A is a bond.
4. The use as claimed in claim 2 of a bradykinin antag-onist of the formula I in which:
Z is hydrogen or is as defined under a1), a2) or a3), P is a bond or a radical of the formula II
-NR(2)-(U)-CO- (II) where V is CHR(3) and where the radicals R(3) independently of one another are hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C6-C14)-aryl or (C3-C13)-heteroaryl, which, with the exception of the hydrogen, are in each case option-ally monosubstituted by amino, substituted amino, hydroxyl, carboxyl, carbamoyl, guanidino, sub-stituted guanidino, ureido, mer-capto, methylmercapto, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, phthalimido, 4-imi-dazolyl, 3-indolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or cyclohexyl, and in which substituted amino is prefer-ably -N(A')-Z and substituted guanidino is preferably -N(A')-C[=N(A')]-NH-Z, in which the radicals A' independently of one another are hydrogen or Z, in which Z
is as defined under a1) or a2);
or in which R(2) and R(3), together with the atoms carrying these, form a mono-, bi-or tricyclic ring system having 2 to 15 carbon atoms;
R(2) is H or CH3, A is a bond, (D)Q is D-Tic.
5. The use of a bradykinin antagonist for the prepara-tion of a medicament for the prophylaxis or treat-ment of arteriosclerosis as claimed in claim 2, wherein the bradykinin antagonist is (R)-arginyl-(S)-arginyl-(S)-prolyl-(2S,4R)-hydroxyprolyl)glycyl-(S)-[3-(2-thienyl)alanyl]-(S)-seryl-(R)-[(1,2,3,4-tetrahydro-3-isoquinolyl)carbonyl]-(2S,3aS,7aS) [(hexahydro-2-indolinyl)carbonyl]-(S)-arginine N-acetate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4314073.4 | 1993-04-29 | ||
| DE4314073 | 1993-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2122429A1 true CA2122429A1 (en) | 1994-10-30 |
Family
ID=6486700
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002122429A Abandoned CA2122429A1 (en) | 1993-04-29 | 1994-04-28 | Use of bradykinin antagonists for the preparation of a medicament for the prophylaxis of treatment of arteriosclerosis |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0623350A1 (en) |
| JP (1) | JPH06312940A (en) |
| AU (1) | AU677290B2 (en) |
| CA (1) | CA2122429A1 (en) |
| HU (1) | HUT66820A (en) |
| IL (1) | IL109447A0 (en) |
| NO (1) | NO941562L (en) |
| TW (1) | TW301608B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9492495B2 (en) | 2010-05-14 | 2016-11-15 | Max-Delbrueck-Centrum Fuer Molekulare Medizin | Therapeutic use of agonists or antagonists of bradykinin receptor 1 or 2, for modulation collateral blood vessel growth |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2739553B1 (en) | 1995-10-06 | 1998-01-02 | Oreal | USE OF BRADYKININE ANTAGONISTS TO STIMULATE OR INDUCE HAIR GROWTH AND / OR STOP THE HAIR LOSS |
| EP2420245A1 (en) * | 2010-08-18 | 2012-02-22 | Max-Delbrück-Centrum Für Molekulare Medizin | Therapeutic use of agonists or antagonists of bradykinin receptor 1 or 2, for modulation collateral blood vessel growth |
| CN103992383B (en) * | 2014-06-27 | 2017-05-17 | 杭州阿诺生物医药科技股份有限公司 | Method for preparing icatibant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3604873A1 (en) * | 1986-02-15 | 1987-08-20 | Basf Ag | METHOD FOR PRODUCING 2,6-BIS (HYDROXYMETHYL) -PYRIDINE-2,6-BIS- (N-METHYLCARBAMATE) |
-
1994
- 1994-03-28 TW TW083102681A patent/TW301608B/zh active
- 1994-04-21 EP EP94106197A patent/EP0623350A1/en not_active Withdrawn
- 1994-04-27 IL IL10944794A patent/IL109447A0/en unknown
- 1994-04-27 AU AU60737/94A patent/AU677290B2/en not_active Ceased
- 1994-04-28 NO NO941562A patent/NO941562L/en unknown
- 1994-04-28 CA CA002122429A patent/CA2122429A1/en not_active Abandoned
- 1994-04-28 JP JP6090789A patent/JPH06312940A/en active Pending
- 1994-04-28 HU HU9401226A patent/HUT66820A/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9492495B2 (en) | 2010-05-14 | 2016-11-15 | Max-Delbrueck-Centrum Fuer Molekulare Medizin | Therapeutic use of agonists or antagonists of bradykinin receptor 1 or 2, for modulation collateral blood vessel growth |
Also Published As
| Publication number | Publication date |
|---|---|
| HU9401226D0 (en) | 1994-08-29 |
| NO941562D0 (en) | 1994-04-28 |
| JPH06312940A (en) | 1994-11-08 |
| AU677290B2 (en) | 1997-04-17 |
| IL109447A0 (en) | 1994-07-31 |
| EP0623350A1 (en) | 1994-11-09 |
| HUT66820A (en) | 1995-01-30 |
| AU6073794A (en) | 1994-11-03 |
| TW301608B (en) | 1997-04-01 |
| NO941562L (en) | 1994-10-31 |
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