CA2355251A1 - New .beta.-amide and .beta.-sulfonamide carboxylic acid derivatives, their preparation and their use as endothelin receptor antagonists - Google Patents
New .beta.-amide and .beta.-sulfonamide carboxylic acid derivatives, their preparation and their use as endothelin receptor antagonists Download PDFInfo
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- CA2355251A1 CA2355251A1 CA002355251A CA2355251A CA2355251A1 CA 2355251 A1 CA2355251 A1 CA 2355251A1 CA 002355251 A CA002355251 A CA 002355251A CA 2355251 A CA2355251 A CA 2355251A CA 2355251 A1 CA2355251 A1 CA 2355251A1
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Abstract
The invention relates to carboxylic acid derivatives of formula (I), in whic h the substituents have the following meanings: R1 is tetrazol or a group (a); W and Z, can be identical or different and are nitrogen or methine, provided that if W and Z are methine, then Q is nitrogen; X is nitrogen or CR9; Y is nitrogen or CR10; Q is nitrogen or CR11, provided that if Q is nitrogen then X is CR5 and Y is CR10; R2 and R3 are identical or different and are possibly substituted phenyl or naphthyl or phenyl or naphthyl which are linked in an ortho position via a direct bond, a methlyene, ethylene or ethenylene group, an oxygen or sulfur atom or a SO2-, NH- or N-alkyl group or possibly substituted C5-C6-cycloalkyl; R4 is a rest (b) or (c); and R5 is hydrogen, C 1- C4-alkyl. The invention further relates to their preparation and their use a s endothelin receptor antagonists. The invention also relates to compounds of formula (II) and a structural fragment of formula (d) in which the rests R1, R2, R3, R4 and R5 have the meanings given in claim no. 1 and to their use as structural elements in an endothelin receptor antagonist.
Description
NEW ~3-AMIDE AND L3-SULFONAMIDE CARBOXYLIC ACID
DERIVATIVES. THEIR PREPARATION AND THEIR USE AS
ENDOTHELIN RECEPTOR ANTAGONISTS
The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelia exists is three isoforms, ET-1, ET-Z and ET-3. "Endothelia" or "ET" hereinafter refers to one or all isoforms of endothelia.
Endothelia is a potent vasoccnstzictor and has a strong effect on vessel tone. It is known that this vasoconst=fiction is caused by binding of endothelia to its receptor (Nature, ~, 411-415, 1988; FEeS Letters,~23 , 440-444, 19A8 and 8iochem. eiophys. Res.
Coauuun . . 1~. 8 6 B-8 7 5 . 19 8 A ) .
Elevated or abnormal release of endothelia causes persistent vasoconstriction in peripheral. serial and cerebral blood vessels, which may result in disotders. As reported in the literature, errdothelin is involved in a number of disorders. These include:
hypertension, acute myocardial-infarct, pulte~onary hyper-tension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis. asthma and prostate cancer (J.~vaseular-.Med. Biology 2, 207 (1990), J. Am. Med. Associat3.on 264, 2868 (1990), lvature 344, 114 (1990), N. Engl. J. Med. 32~, ZOS (1989), !'. Engl. J. Med. ,~28. 1732 (1993), Nephron 6~, 373 (1994), Stroke ~5_, 904 (1999), Nature ~, 759 (1993), J. Mol.
Cell. Cazdiol. Z7, A239 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944,(1995)).
At least two endothelia receptor subtypes, ~T, and ETa receptors, are curreatly,described in the literature (Nature ~$, 730 (1990), Nature 348, 732 (1990)). Accordingly, substance8 trhich inhibit tlse binding of endothelia to one or both receptors ought to antagonize the physiological effects of endothelia and therefore represent valuable drugs.
DE 19726146.9 describes the preparation of l3-amino and !i-azido carboxylic acid derivatives and their use as endothelia receptor antagonists. Further investigation has revealed that related aromatic carboxamides and sulfonamide derivatives have advantageous properties in relation to receptor affinity and receptor binding profile. The present patent relates to the preparation and use the=eof.
Z
The invention relates to J3-amido and !3-sulfonamido carboxylic acid derivatives of the formula I
R4 Rz w-x S N~C 0 ~ ~Q
i I z =y Rs Ri R
Where Eil is tetrazolyl or a group O
C-~R
where R has the following meaning:
a) a radical OR6, Where R6 is:
hydrogen, the cation of an alka7.i metal, the canon of an alkaline earth metal or a physiologically tolerated organic ammonium ion such as tertiary C1-C~-alkylaau~onium oz the aaanoaium ion ; .
C3-Cs-cycloalkyl. Ci-Ce-alkyl, CHZ-ghenyl. Which may be ~5 substituted by one or mo=e of the following radicals:
halogen, aitro, eyano, C1-Cg-alkyl, Cl-C~-haloalkyl, hydroxyl, Cl-C'-alkoxy, me=capto, C1-C~-alkylthio, amino, 'NB~C1-C,-alkyl , N(C1-Ca-alkyl)z;
3o a C3-CA-alkenyl o= C3-Ce-alkynyl group, it being possible far these groups in turn to car=y one to five halogen atoass;
Rs can furthermore be a phenyl radical Which may carry one to five~haloqen atoms andlor ova to three of the following 35 .radicals: vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl. C1-Cs-alkoxy, mereapto, C1-C,-alkylthio, amino, Ng(C1-C4-alkyl), N(Ci-C4-alkyl)z: , b) a 5-membered heteroaromatic systet~ linked via a nitrogen qp atom, suca as pyrrolyl. pYrazolyl, imidazolyl and triazolyl, erhich may carry one or two halogen atoms or one or two C1-C~-alkyl or one or zoo Cl-C4-alkoxy groups:
q5 c) a group _ C - ~ C~~ ~p 5 g, where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and R~ is to C1-Cd-alkyl. C3~Ca-cycloalkyl, C3-C'-alkenyl, C3-CB-alkynyl or phenyl, Which may be substituted by one or more, eg. one to three, of the following radicals:
halogen, nit=o, cyano, C1-Cq-alkyl, hydro~rl, C1-Cq-alkoxy, Gl-Cq-alkylthiv, amino, NH(C1-Cs-alkyl). N(CI-Ca-alkyl)Z.
mercapta;
d~ a radical p - N 5 - ga H II
O
whe=e RB is:
Cl-C4-alkyl. C3-C,-alkenyl, C3-Ca-alkynyl, C3-Ce-cycloalkyl, it being possible for these radicals to carry .a C1-C,-alkoxy.
3p C1-C,-alkylthio and/or a phenyl radical as mentioned under c);
Ci-C,-haloalkyl or phenyl, u~substituted or substitated in particular as mentioeed under c).
The_other substituents have the folloaring meanings:
W and Z, ~rhich may be identical or different a=e:
nitrogen or methine; with the proviso that Q = nitrogen if W
90 and 2 = methine;
g is nitrogen or CR9:
Y , is nitrogen or CRS°;
Q is nitrogen or CRI~; ~,rith the proviso chat X = CR9 and Y
CRlo if Q = nitrogen;
Rz and R3, which may be identical or difFerent, are:
' phenyl or naphthyl, each of which may be substituted by one or more of the following radier~ls: halogen, vitro, cyano, hydroxyl, mercapto, C1-C,-alkyl, CZ-C,-alkenyl, C=-C4-alkynyl, CI-C,-haloalkyl, C1-C,-alkoxy, phenoxy,, C=-C°-haloalkoxy, C1-C,-alkylthio, amino, NH(C1-C9-alkyl), N(C~-C°-alkyl)2 yr phenyl which may be substituted one or more times, eg. one to three times, by halogen, vitro, eyano, C1-C,-alkyl, Gl-Ca-haloalkyl, Ci-C,-alkoxy, Ci-C,-haloelkoxy or C1-C,-alkylthio; or I5 ' phenyl or naphthyl wdieh ase linked together in ortho positions by a direct linkage, a methyleae, ethylene oz ethenyleae group, an oxygen or sulfur atom or an SOZ, pe or N-alkyl group;
C5-C6-cyeloalkyl, it being possible for these radicals to be substituted in each case vne or more times by; halogen, hy3roxyl, mereapto, carboxyl, vitro, eyano, C1-C~-alkyl,.
C=-Cq-alkenyl, C2-C°-alkynyl, Cl-C~-alkoxy, C1-C,-alkylthio, IS Cl-C,-haloalkoxy;
R° a) a radical 30 Riz with R1~ phenyl, naphthyl or a five- or six-rnembered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, 35 ,, it being possible for said radicals to be substituted one or more times by: halogen, vitro, cyano, hydroxyl, mercapto, C1-C°-alkyl, C1-C°-hydroxyalkyl, Cl,-C°-haloalkyl, Ci-C4-alko~cy, C~-C°-alkylcarbonyl, carboxyl, 40 Cl-C4-haloalkoxy, C1-C4-alkylthio,~amino, NH(C1-Ca-alkyl), N(C1-C,-Slkyl)2, BZN50~, (CI-C9-alkyl)NHSOZ, (C1-C4-alkyl)ZNSOZ, or phenoxy or phenyl, each of which may be substituted one or more times, e.g. one to three times, by 45 halogen, vitro, eyana, C1-Ca-alkyl, C1-Ca-haloalkyl, CI-C9-alkoxy, C1-ca-haloalkoay and/or Cl-C9-alkylthio b) a radical -S- Ria to with R13 C1-C9-alkyl. C1-C4-haloalkyl o= phenyl, it being possible for the phenyl radical in turn to carry one to five halogen atoms and/or one to three of the follcwi~g radicals: C1-C~-alkyl, C1-Ca-haloalkyl, C1-Ge-alkoxy, CL-C,-haloalkoxy and/or C1-Cq-alkylthio;
RS is hydrogen, C1-C4-alkyl:
Zo R~ and Rla(~,rhich may be identical or different) are:
hydrogen, halogen, Cl-C,-alkoxy, Cl-C'-haloalkoxy, C3-C6-alkenyloxy. C3-C6-alkynyloxy, C1-C,-alkylthio, Cl-C9-alkylcarbonyl, Ci-C4-alkoxycarbonyl, hydroxyl, N82, NH(Cl-G~-alkyl), N(Ci-C~-alkyl)Z;
CI-C4-alkyl, CI-C~-alkenyl. C=-C,-alkynyl, it being possible for these radicals to be Substituted by halogen, hydroxyl, mercapto, carboxyl, cyano;
or CRS or CRla is linked to CR11 as indicated for R11 to give a 5- or 6-membeted ring, R~i . is hydrogen, halogen, C1-C,-alkoxy, Cl-C~-haloalkoxy, C3-Cd-alkenyloxy, c3-cs-alkynyloxy, Cy-C4-alkylthio, C1-Ci-alkylcarbonyl, Cl-Ca-alkoxycarbonyl, P8(C1-Ca-alkyl), N(C1-C4-alkyl)z, hydroxyl, carboxyl, cyano, amino, me=captv;
C~-C,-alkyl, CZ-CQ-alkenyl, CZ-Ca-alkynyl, it Deing possible for these radicals to be substituted one or more times by:
halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C1-CQ-alkoxy;
~5 , or CR11 forms together With CRS or CRi° a 5- or 6-meaibered alkylene or alkenylene ring which may be substituted by one or two C1-C4-alkyl groups, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur. -NH
or -N(C1-Cq-alkyl).
The definitions applying herein and hereafter are:
an alkali metal is, for example, lithium. sodium, potassium;
as alkaline,earth metal is, for example, calcium, magnesium, barium;
organic ammonium ions are protonated amines such as ethanolamine, diethanolamine, ethyleaediamine, diethylamine or piperazine;
C3-Cs-cycloalkyl is, fot example, cyclopropyl, cyclobutyl, cyclopeatyl, cyelohexyl, cycloheptyl or cyclooctyl;
~i-ce-haloalkyl can be linear or branched, eg. fluoromethyl, d~fluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, I0 2-fluoroethyl, 2.Z-difluoroethll, 2,2,2-trifluoroethyl, Z-chloro-2,2-difluoroethyl, Z,2-dichloro-Z-fluoroethyl, Z,2,Z-ttichloroethyl or pentafluoroethyl;
Ci-Ca-haloalkoxy can be linear or branched, eg- difluorornethoxy, Z5 trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetraflucroethoxy, 2,2,2-trifluotvethoxy, Z-cttloro-1,1,2-trifluoroethoxy, Z-fluoroethoxy or pentafluoroethoxy;
30 ~y-C4-alkyl can be linear or branched, ag. methyl, ethyl, 1-propyl, 2-propyl, Z-methyl-Z-propyl, 2-methyl-1-propyl, 1-butyl or Z-Dutyl;
C2-C,-alkenyl can be linear or brapched, eg. ethenyl, 35 1-p=open-3-yl, l-prvpen-2-yl, 1-pxopen-1-yl, Z-methyl-1-propenyl, 1-buzenyl or 2-butenyl;
C=-C,-alkynyl can be linear or branched, eg'. ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
40 Gl-Ca-alkoxy can be linear or branched, eg, methoxy, ethoxy, ptopoxy, 1-methylethoacy, butoxy, 1-methylpropoxy, Z-methylpropoxy or l,i-dimethylethoxy;
Cs-Cs-alkenYloxy can be linear or branched, eg. allyloxy, 45 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-8lkynyloxy eaa be linear or branched, eg. 2-propyn-1-yloxy, Z-butyn-I-yloacy or 3-butyn-Z-yloxy; .
C1-C9-alkylthio can be linear or branched, eg. methylthio, ethylthio, propylthio, 1-methylethylthio, butyltnio, ' 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-CS~alkylcarbonyl can be linear or branched, eg. acetyl, ethylcarbonyl o= 2-propylcarbonyl;
C1-CB-alkyl can be linear or branched, eg. C1-Ca-alkyl, pentyl, hexyl, heptyl or octyl;
C3-Ce-alkenyl can be linear or branched, eq. 1-propen-3-yl, I-propen-2-yl, 1-propen-l-yl, 2-methyl-1-propeoyl, 1-buten-4-yZ, 2-bates-3-yl, 1-peatet~-5-yl, 1-hexes-6-yl, 3-hexes-6-yl, 2-hepten-7-yl or 1-octen-B-yl;
G3-CB-alkynyl can be linear or bra»ched, eg. 1-propyn-1-yl, 1-jp=opyn-3-yl, 1-butya-4-yl, Z-burins-4-yl, Z-pentyn-5-y', 3-hexyn-6-yl, 3-heptyn-7-yl, 2-oetyn-B-yl;
Halogen is, far example, flucrine, chlorine, bromine, iodine.
The invention further relates to those compounds from Which the compounds of the formula I can be liberated (called prodrugsl.
Preferred prodrugs are those ~rhose release takes place under conditions prevailing in certain compartments of the body, eg. in the stomach, intestine, blood circulation, liver.
The compounds I and the irate=mediates for preparing them, eg, II
and I=I, may have one or more asymtnetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or pure diastereomers or as mixture thereof. It is preferred to use an enantioanerically pure compound as active ingredient.
the invention further relates to the use of the abovementioned carboxylic acid derivatives to produce drugs, in particular to produce inhibitors of ETa andloz ETB receptors. =he novel compounds are suitable as antagonists as defined at the outset.
The compounds according to the invention with formula I can be prepared via the routes described in DE 19726146.9.
A possible alternative to this is preparation via intermediates of the general formula III; these derivatives can be synthesized either by reducing azides of the formula II (see DE 19726146.9) by generally known methods oz by opening the oxazoline derivatives of the general formula IV Which are described in Wo 95/07266.
RZ Rz . R3 Ri H R R=
p C-OH < N 0 io 3 R~ R3 Rl , IV
zi xrz The oxaxoline derivatives of the formula Iv can he opened by treatment with aqueous solutions of strong acids such as ' hydrochlori.c acid, hydrobromic acid, sulfuric acid, perchloric Z5 acid, trifluoroaeetic acid, toluenesulfonic acid, ~nethane'ulfonic acid or trifluvramethanesulfonic acid in the presence of a suitable solubiliZer. All water-miscible solvents can be used for this purpose as long as they are inert toward the reagents used.
a0 Examples of such solubilizers are alcohols such as methanol, ethanol. n-propanol, isopropanol; ethers such as tetrahydrofuran or dioxane; nitrites sued as acetvnitrile or propionitrile;
amides such as dimethylformarnide -or ~aia~etbylacetamide; sulfoxides and 3ulfones such as dimethyl sulfoxide.: carboxylic acids such as 25 acetic acid or propionic acid.
The reaction in this case is preferably carried out at a temperature in the range between 0°C and the boiling point of the solvent or solvent a~.ixture.
Compounds according to the invention in ~rhich RqRSN is aromatic or hetezoaromatic carboxamido can be prepared, for example, by acylating III oe the nitrogen or, alternatively, acylating both the amino group and the hydroxyl group in III and then 35 eliminating the ester acyl group using generally known methods.
For this purpose, the compound of the general fonttula III is reacted with tl~e acylating reagent in the molar ratio of 1=1 to 1:6.in the presence of a suitable diluent. All solvents which are inert toward the reagents used can be used for this purpose.
RZ O Rx FI N C O I= ~ H
H w~ R N C OH
~ H
Ri R3 Ri v Examples of such solvents oz diluents are aliphatic, al icyclic and aromatic hydrocarbons, Which may in each ease optionally be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and tricl~lotoethylene, ethers such as diisopropyl ether, dibutyl etAer, methyl tent-butyl ethe=, dioxane and tetrahydrofuran, nitriles ouch as acetonitrile and prnpfonitrile, amides such as dimethyltormanide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfaaes such as dimethyl sulfoxide and sulfolane.
Z0 The reaction in this case is preferably carried out at a temperature in the range between o°C and the boiling point of the solvent or solvent mixture.
The presence of a zeaction catalyst may be~advantageous. A
Z5 suitable catalyst in this case is, for example, dia~ethylaminopyridine.
the resulting compounds of the general formula V are converted into the B-amido carboxylic acid derivatives according to the 30 iwention by zeacting the compounds of the general formula V faith neterocycles of the general formula VI.
~n1_X W_X
p + ~ Ri 4 --~~ ~ Q -~1 R' g C 0 --~~ . Q
35 3 Rl Z =Y
2=Y
VI
Ia R~' in formula vI is halogen or R15-501-, where R15 can be 40 C1-C4-alkyl, C1-C,-haloalkyl or phenyl, and the definitions of W, X, Y, Z and Q are those given at the outset. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. a base ~rhich deprotonates the intermediate V, at a temperature in the range from room 45 temperature to the boiling point of the solvent.
l Compounds of the formula v= are known, and some of them can be bought or they can be prepared in a generally known manner.
zf al in compounds of the general formula Ia is an ester, the ester group can be cleaved with acid or base or by hydrogenolysis to give the free carboxylic acids with R1 ~ COOH. Compounds of the type Ia with Ri = C008 can, however, also be obtained directly by dep=vtonating the intermediate V in which R1 = COON with three equivalents of a suitablQ base and reacting with compounds of the general formula VI. Once again, the reaction cakes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solveat.
The base which caa be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.
sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an orgaaou~etallic~compouad such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.
The~compounds according to the invention of the general formula I
in which R4R5N is sulfonarnido can be obtained from anuLnee of the general formula VII and are prepared as described in DE
I9~~61.46_9. For this purpose, VII i,s reacted by generally known methods irith suLfonyl halides and, if Ri is an ester, the ester group is cleaved arith acid or base or by hydrogenolysi5.
Rz Rx R Hi X II ~ H u1 R
8 N ~ C O---~~ ~~Q ~ R13-5-N C -O ~ ~ Q
Z
IR1 8=Y ~~ N I Z=Y
Ra R7 Ib Compounds o! the formula I caa also be prepared by startiDg front the appropriate carboxylic acids, i.e. compounds of the formula I
in which Ri is COON, first converting them in a conventional way in an activated form, such as an acid halide, anhydride ar imidazolide, and then reacting the latter orith a~ appropriate hydro~cyl compound HOR6 oz sulfonamide BiNSO2Re . This reaction can be carried out in conventional solvents and often requites the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act in the presence of a dehydrating agent such as a carbodiimide on the hydroxyl compound or the sulfonamide.
It is additionally possible to prepare compounds of the formula I
by starting from the salts of the appropriate carboxylic acids, i.e, from compounds of the formula I in' which R1 is a group Coots, where H can be an alkali metal cation or the equivalent of an S alkaline earth metal cation_ These salts can be reacted With many ' compounds of the formula R-D where D is a conventional nucleofugie leaving group, for example halogen such as chlorine, bromine, iodine or optioeally halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl .such as toluenesulfonyl aid methylsulfoeyl or another equivalent leaving group. Compounds of the formula R-D with a reactive substituent D
are known or can easily be obtained with general expert knowledge. This reaction can be carried out in the conventional solvents and is advantageously performed in the presence of a base, in erhich case those mentioned above are suitable.
~ompouads of the forinula I in which Rt is tetrazolyl can be prepared according to the methods described is WO 96/11914 from the corresponding carboxylic acids (formula I with R1 ~ COOH).
In some cases, it is necessary to use generally knocan protective group techniques to prepare the compounds I according to the invention. If, for exaa~le. R4RSN = 9-8o-phenyl-CONS-, the hydroxyl group can initially be protected as benzyl ether, which is then cleaved az a suitable stage in the reaction sequence.
Compounds of the formula I and v can be obtained in enantiornerically pure form by carrying out a classical raeersate resolution ~rith suitable enantiomerically pure bases, such as those described in wo 96/11914, ~rith racemic or diastereomeric compounds of the formula I and v.
Glith a view to the biological effect, preferred carboxylic acid derivatives of the general formula I - both as~pure enantiomers or pure diasteteomers and as mixtures thereof ~ are those in which the substitueaes have the following meanings:
R1 is tetrazolyl or a group O
C-R
in ~ohich R has the following meaning:
a) a radical OR6, in Which R6 is:
hydrogen, the cation of as alkali metal, the cation of an alkaline earth metal, a physSologically tolerated organic ammonium ion such as tertiary C1-Ca-alkylaraswnium or the ananonium ion;
C3-Ce-cycloalkyl, Cl-Ce-alkyl, CHi-phenyl, which can be substituted by one or more of the follo~ring radicals:
halogen, C~-C4-alkyl, Cl-C!-haloalkyl, hydroxyl, C1-C~-alkoxy, mercapto, C1-C,-alkylthio, NH(Cl-C4-alkyl), N(Cl-C,-alkyl)?;
to a C3-CB-alkenyl or a C3-Ce-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
Rs can also be a phenyl radical Which can carry vse to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C~-haloalkyl, hydro~cyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, NH(C1.-~4-alkyl), N(Cl~~a-alkyl)?;
D) a 5-membered heteroaromatic system trhich is linked via a nitrogen atom, such as pytazolyl, imidaaolyl and triazolyl, which a~ay carry one or tmo halogen atoms or one or two ~ C~-C,-alkyl or. one or two C1-C,-alkoacy groups;
c~ a,group (o)r ' I
- O - ( C8~ )p S R' 3o is Which k can assume the values 0, 1 and Z, p can assume the values 1, 2, 3 and 4, and ~!~ is ci-C,-alkyl, C3-C,-cycloalkyl, C3-Ce-alkenyl, C3-Ce-alkynyl or pdenyl Which can be substituted by one or more, e.g. one to , three, of the following radicals:
halogen, C1-C9-alkyl, hydroxyl. C1-C~-alkoxy, CZ-Ca-alkylthio, NR ( C1-Ca-alkyl ) . N ( Cl--C4-alkyl ) z . a~ereapto;
d ) ~ a radical O
-N 5- Ae N
O
in which Re is:
Cl-C9-alkyl, C3-Ca-alkenyl, C3-CB-alkyayl, Cj-C8-cycloalkyl, it being possible for these radicals to carry a Cl-Ca-alkcxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
Cl-C,-haloalkyl or phenyl, optionally substituted in particular as mentioned under c);
W and 2 (which may be identical or different):
nitrogen or methine; with the proviso that Q = nitrogen i.f W
and Z = methine;
X nitrogen or CR9;
Y nitrogen or CR»; ' Q nitrogen or CRil: With the proviso that X = CR9 and x =
CRl° if Q ~ nitrogen;
Rx and R3 (which may be identical or different):
phenyl or naphthyl. each of which may be substituted by one Z5 or mote of the following radicals: halogen, eyano, hydroxyl.
mercapzo, C1-Cq-alkyl, C1-C4-haloalkyl,~Cl-C~-alkoxy, phenoxy, Cl-C4-halvalkoxy. Cl-Cq-alkylthio, amino, Na(Cl-C~-alkyl), N(C1-t4-alky112 or phenyl, ~rhich may be substituted one or more times, e.g. one to three times, by halogen, cyano, C1-Ca-alkyl, Ci-C4-haloalkyl, cl-Ca-alkoxy, Cl-Cq-haloalkoxy or Cl-C4-alkylthiop or phenyl or naphthyl, which are linked together in ortha positions by direct linkage, a methylene, ethylene or .etheaylene group. an oxygen or sulfur atorn,or an 50i, NH er N-alkyl group;
Rd a) a radical ~z R
With Rlz phenyl, naphthyl or a five-~or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for said radicals to be substituted one or more times by halogen, eyano, hydroxyl, mercapto, CI-Cq-alkyl, C1-C~-hydroxyalkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, Cl-Ca-haloalkoxy, Cl-Cd-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyllZ~ AzNSaz~
(Cl.Cq-alkyl)NHSOZ, (Cl-C4-alkyl)ZNSOZ, or phenoxy ' ~ or phenyl, each of which may be substituted one or more times, e_g. one to three rimes, by halogen, eyano, Cl-C,-alkyl. C1-C9-haloalkyl, C1-C4-alkoxy, C1-Ca-haloalko~cy.and/or Ci-Cq-alkylthio;
b1 a radical O
-I5,_ Ri3 O
with Rl3 C~-Cq-alkyl, Cl-C4-haloalkyl or phenyl, it being possible fvr tha phenyl sadieal in turn tv carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-Cq-haloalkyl, C1-C~-alkoxy;
R5 hydrogen, methyl;
R9 and Rl~(which may be identical or different):
. hydrogen, halogen, C1-Cq-alkoxy, C1-Cq-?raloal3co~cy, C1-Ca-alkylthio, D~8(C1-Ca-alkyl), N(C1-Ca-alkyl)t;
C1-C,-alkyl. CZ-C,-alkenyl, it being possible fo= these =adieals to be substituted by halogea, hydroacyl, .mereapto, cyano;
or CR9 or CR1~ is linked to CRL1 as indicated fo= R11 to give a 5- or 6-membered ring;
R11 hydrogen, halogen, C1-C4-alkoxy, Cl-Ca-haloalkoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(Ci-C4-alkyl)Z, eyano;
cl-C4-alkyl, CZ-Ca-alkenyl, it being possible for each of these radicals to he substituted one or more times by:
halogen, cyano, C1-ca-alkoxy;
~ 15 or GR11 forma together with CR9 or CR1°~a 5- or 6-membered alkylene or alkenylene ring v~ie?r may be substituted by one or two C1-C,-alkyl groups, and in ~rhich in each case one ar more methylene groups may be teplaeed by oxygen, .
sulfur, -Nii or -NtCl-C~-alkyl).
particularly preferred compounds of the formula I - both as pure enantiomers oz pure diastereomers and as mixtures thereof - are those in which the substituents have the following meanings:
Ra is tetraaolyl or a group C-R
is which R has the following meaning:
a) a radical OR6, in which R6 is.
Zo ' hydrogen, the cation of an al.7eali metal. ~e cgtion of an ' alkaline earth metal or the ammonium iorr:
C1-C8-alkyl, CB=-phenyl, Which can be substituted by one Z5 . or more of the following radicals: halogen, C1-C4-alkyl, C1-C~-haloalkyl, C1-Ca-alkoxy:
R6 can fuzthertnore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the 3o follooring radicals: C1-CQ-alkyl. C1-Cs-haloalkyl.
C1-C4-alkoxy~
b) a 5-membered heteroaromatic system linked via a nitrogcn~
atom, such as imidazolyl and triazvlyl, which may carry 35 ' one or !WO halogen atoms, or one or two Cl-C,-alkyl or one or two C1-C4-alkoxy groups:
c) a group (il)k 4o -O-- (C8i)p S R' in which k may assume the values 0, l and 2, p may assume s5 the values 1, 2. 3 and 4, and R~ is Cl-C4-alkyl, C3-CB-cycloalkyl or phenyl Which may be substituted'by one or more, e.g_ one to three, of the folloW,irg radicals:
halogen, CI-Cq~alkyl, Cl-C4-alkoxy;
d ) a radic al O
SI
- N - --- R' N
O
in which Re is.
l5 Cl-C4-alkyl, C3-Ce-eyeloelkyl, it being possible for these radicals to carry a cl-C~-alkoxy and/oz a phenyl radical as mentioned under c);
Z0 Cl-.C4-haloalkyl oz phenyl, optionally substituted, ici particular as mentioned under c);
W and Z (which may be identical or different):
Z5 , nitrogen or methine; with the proviso that Q m nitrogen if W and Z = methine;
X ,nitrogen or CR9; . .
Y nitrogen o= CRlo 30 Q nitrogen or CR11; with the proviso that X ~ CRS and Y
= CR1~ if Q = nitrogen;
RZ and Rj (which may be identical or different phenyl groups which may be substituted by one or more of 35 the following radicals: halogen, C1-Cq-alkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, phenoxy, C1-C9-alkylthio, NH(C1-Cq-alkyl), N(C~-C9-alkyl)z or phenyl, which may ba substituted one or more times, e.g. one to three times, by halogen, C1-co-alkyl, C1-C9-haloalkyl, C1-C~-alkoxy or 40 Ci-Cq-alkylthio; os phenyl groups which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or snlfar atom or an SOz-, 45 NH- or I~-alkyl group;
R4 a) a radical D
giz Nith Rlz phenyl or a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms andlor one sulfur or oxygen atom, it being possible for said radicals to be substituted one or more times by: halogen, hydroxyl, Cl-Ca-alkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, Cl-C9-haloalkoxy, phenoxy, Cl-Ca-alkylthio, NH(C1-c4-alkyl), N(C1-Cq-alkyl)?, (C1-Ca-alkyl)N850z, cl-C4-alkyl ) zpSOz or phenyl rrhieh can be substituted one or more times, e.g. one to three times, by halogen, Cl-C~-alkyl; C1-Ca-haloalkyl, ' Cl-Cd-alkoxy and/or C1-C4-haloalkoay;
D) a radical ' O
- S _ Ri3 O
with Rl~ C1-C4-alkyl, C1-C,-haloalkyl or phenyl. it being po9sible for the phenyl radical in tu=r to ea==y one to five halogen atoms and/or otie to three of the following radicals: C1-C~-alkyl, Cl-C4-haloalkyl. Cl-Ca-alkoxy;
RS hydrogen, methyl;
R9 and Rla(vhieD may be identical or different):
hydrogen, C1-C4-alkoxy, C1-C4-alkylehio, N(Cl-C~-alkyl)i;
C1-Ca-alkyl, it being possible for these radicals to be substituted by halogen;
or CR9 or CRl° is linked with CRil as indicated for R11 to forea a 5- o= 6-me~nbered ring;
f8 R11 hydrogen, C1-C,-alkoxy, C1-Ca-alkylthio, cyano;
G1-C4-alkyl, it being possible for these radicals in each case to be substituted one or more times by halogen;
or CRil forms together with CR9 or CRl~ a 5- or 6-membered alkylene or alkeoylene ring which may be substituted by one or two Cl-C4-alkyl groups and in which, fn each case, one oz more methylene groups can be replaced by oxygen, sulfur, -NH or -p(Ca-C4-alkyl).
The compounds of the present invention offer a~novel potential treatment of hypertension, pulmonary hypertension, myocardial infarct, chronic heart failure, angina pectoris, acute/ch;tonic kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxia-induced organ failure, intzavascular coagulation, ~estenosis after angioplaaty, benign prostate hyperplasis, ischemic and intoxication-induced ZO kidney failaze or l~ype.rtension. cgclosporine-induced kidney failure, erectile dysfunction, metastasis and gror.rth of mesenchymal tumors, cancer, prostate cancer, contrast agent-induced kidney failure, pancreatitis, gastrointestinah ulcers.
The invention further relates to combination products consisting of endothelin.receptor antagonists o~ the formula'I and inhibitors of~the resin-aagiotensin system. Inhibitors of the resin-angiotensin system are resin inhibitors, angiotensin Z=
ant8gonists and, in particular, angiotensin converting enzyme (ACE) inhibitors.
These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.
The good effect of the compounds can be shown in the following teats:
Receptor-binding studies Cloned human ETA or ET8 receptor-expressing C80 cells were employed for binding studies.
- ~ 'i'9 Membrane preparation.--.
The ETa or ET8 receptor-e~cpressing CHO cells were grown is Dt~iEH
NUT MIX F12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (FRA Laboratories GtnbH, Lint, No. A15-022), 1 ml~i glutamine . (Gibeo No. 25030-024), 100 U/ml penicillin and 100 )tg/ml streptnmycia (Sigma No. P-07.81). After 48 hours, the cells were washed with PBS and incubated with 0.05 trypsin-containing PHS
at 37°C for 5~ minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300 x g.
For membrane preparation, the cells Were adjusted to a concentration of l0e cells/ml of buffer (50 mri Tris-8C1 Duffer, pB
7_4) and then disintegrated with ultrasound (Branson 5onifier 250, 40-70 seconds/eonstant output 20).
83.nding assays Z0 For the ETa and ETa receptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris-5C1.~ pe 7.4 eith 5 mrl ' , MnCl2, 40 ~g/ml bacitraeia and 0.2% HSA) in a concentration of 50 ~:g of protein per assay mixture and incubated with ZS pM
yxsl~_gTl (HTA receptor assayl or ZS pM I1~5I7-FTC (ZTa receptor assay) in the presence and absence of test suDstanee at 25°C. The nonspecific bind~g Was determined using 10-1 M E"ry. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skat=on cell harvester (5katron, Lier, Nox~rayl separated free and bound radioliqand, and the filters were washed e.rith ice-cold Tris-HC1 buffer, pH 7.4 with 0.2% HSA. The radioactivity collected on the filters was quantified using a Packard 2200 GA
liquid scintillation counter_ Testing of ET antagonists in vivo:
Male SD tats weighing 250 - 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed_ The carotid artery and jugular vein were cathezeri2ed.
In control animals, intravenous administzation of 1 mglk9 ETl results in a marked rise in blood pressure r,~hich persists for a lengthy period.
The test animals received i_v. injection (1 ml/kg) of the test compounds 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
' Oral testing of ET receptor antagonists:
Male narmotensive tats (Sprague Dawlcy, Janvier) Weighing 250-350 g axe pretreated with the test substances orally. 80 l0 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure)~and the jugular vein (administration of big endothelin/.endothelin 1) are catheterized.
15 After a stabilization period, big endothelin (z0 (tg/kg, admin.
vol. 0.5 ml/kg) or ET1 (0.3 ~.g/kg, admin. vol. 0.5 atl/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The marked and long-lasting changes in blood pressure are calculated as the area under the curve ZO (AQC). To detereu.ne the antagonistic effect of the test substances, the ADC for the animals treated with substance is compared with the AUC for the control animals.
Tre novel compounds can be admiriistered orally or parenterally Z5 (subcutaneously, intravenously. intramuscularly, intraperitoneally) in a conventional way. Administration can also tekg place orith vapors or sprays tbrough the nasvpharyngesl space.
The .dosage depends on the age, condition and weight of th~
patient and on the mode of administration. As a rule, the daily dose of active ingredient is from about 0.5 to 50 mglkg of body weight on oral administration and from about 0.1 to 10 tng/kg of body weight art parenteral administration.
The novel compounds can be administered in conventional solid or liquid pharmaceutical form" eg. as uneoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulator, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slo~,ring agents. antioxidants and/. or propellant gases (cf. H. Sucker et al.: PharmaZeutisehe Technologic, Thieme-Verlag, Stuttgart. 1991)_ Tha administration forms obtained i~ this way~AOrmally contain from 0.1 to 90% by weight of active ingredie~.
Synthesis Examples ' s Example l:
tiethyl 3-amino-Z-hydroxy-3,3-dipheaylpropionate to O.Z g of a 10~ palladium/carboa hydrogenation catalyst gas added to a solution of methyl 3-azido-2-hydroxy-3,3-diphenylpropioaate (5.71 g; 19.2 aanol) in methanol (100 ml). The mixture was stirred under a hydrogen atmosphere at zoom temperatu=e for 48 hours; the catalyst was rhea filtered off and the solvent was distilled off.
i5 The residue Was taken up in 5% strength aqueous citric acid and ' the resulting solution eras extracted r~ith ether. The aqueous phase ~as~then made alkalise with dilute sodium hydroxide solution and again extracted ~rith ether. The extracts obtained from the alkaline phase were dried over magnesium sulfate,~and 20 solvent was removed in vacuo. 4.03 g (14.9 muiol, 77% yield) t'f the pure amine were obtained.
~ (200 M8a): 7.5 (m. 2 E1): 7.2-7.4 (m. 9 H). 5_0 (s, 1 H): 4.2 (s br, 1 E1). 3.4 (s, 3 ti): 2.0-2.9 (s bz, 2 Hl.
as Example 2:
2-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2.2-diphenylethyl 4-meehoxybenzaate 8yridine (1.17 g; 14.7 mmoll. a spatula tip of di,methylarninopyridine, and pare-methoxybenzoyl chloride (2.52 g, 14.7 mmol) were successively added to a solution of methyl 3-amine-Z-hydroxy-3,3-diphenylpropioaate (2.00 g, 7.37 mmol) in dichlorornethane (10 ml). The mixture Was stirzed at room temperature for 4 hours and then, for vorkup, mixed ~rith mater aad~extracted With ether. The combined organic phases were washed with aqueous citric acid and saturated brine and then dried over magnesium sulfate. The solvent was evaporated off is vacuo to afford the crude bisacylation product. Which was employed without further purification (1.37 g; 28% yield ~rith a purity of BZ%
according to HPLC).
Example 3:
Methyl 2-hydroxy-3-(4-methoxpbenzoylamino)-3,3-diphenylpropionate Z-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2,Z-diphenylethyl 4-rnethoxybenZOate (1.37 g; 2.08 mtnol with a parity of eZ%) vas dissolved in methanol (20 ml), and potassium carbonate (B63 mg, 6. Z5 uunol) vas added. The resulting mixture was stirred at room temperature for 16 hours and the solvent Was removed in vacuo.
id The residue vas taken up in water and extracted With ether; a colorless solid precipitated during this and was isolated by .
filtration and was identical to the title compound. The aqueous phase was then extracted again with ethyl ac~tate. The organic phases were combined aad dried over magnesium sulfate, and the solvent was removed in vacuo_ The crude product vas purified Dy crystallization from diehloromethaae/ether/n-hexane, resulting in a colorless solid (503 mg; 60$ yield).
Example 4.
eeazyl 2-hydroxy-3-(4-methoxybenzoylaa~ino)-3,3-diphenyl-propionate 2_11 ml of a 1 molar sodium hydroxide solution were added to a 15 solution of methyl Z-hydroxy-3-(4-methoxybenzoylamino)-3,3-di-phenylpropionate (503 mg; 1. Z4 mmol) in 1:2 water/tetrahydrvfuran (50 ml) and Stirred at room temperature for 60 hours. The sta=ting material had been substantially.coavezted after this: to complete the reaction, 1 molar sodi~un hydroxide solution (Z.11 30 ail) vas added again. and stirring was continued for one hour. The mixture Was diluted with water, extracted with ether, acidified with citric acid and again extracted with ether. The extracts obtained from the acidic phase were dried ever magnesium sulfate and the solvent was removed in vacuo. The residue (406 mg) eras 35 taken up in dimethylformamide (ZO ml), and potassium carbonate (179 mg: 1.30 mmol) and benzyl bromide (195 mg; 1.14 mmol) Were successively added. The resulting mixture vas stirred at room temperature for 20 hours and then 5% strength aqueous citric acid gas added. After dilution with water, ext=action r.ras carried out 40 with dichloromethane and then With ether (product is only moderately soluble in ether). The combined organic extracts were thoroughly washed With water aad then with saturated brine and dried over magnesium sulfate, and the solvent was removed in vacuo. Traces of benzyl bromide and dimethylformamide were 45 removed by washing the residue with a little 1:1 ether/n-hexane.
Qe? mg (?9$) of the pure benzyl ester were obtained.
Example 5:
Bentyl 2-14,6-diethyl[1,3,5]triazin-Z-yloxy)-3-(4-methoxy-bentoyla~no)-3,3-diphenylpropionate Poeassi~un carbonate (80 mq; 0.58 mmol) and 2-chloro-4,6-diethyl-[1,3.5]t=iazine (74 mg; 0_43 Col) were successively added to a solution of. beezyl . . . . .~ , : t 2-hydroxy-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate (139 to sng, 0 .29 nmol ) in dimethylformatni.de ( 15 ml ) . The mixture vas heated to 6D°C and stirred at this temperature for .4 hours. The reaction Haas stopped by adding 5% strength citric acid (10 ml).
Dilution with water Nas followed by extraction With ether, and the combined organic phases ~~rere washed with saturated brine and dried oyez magnesium sulfate. The solvent was distilled off; the residua was purified by flash chromatograpby (eluent: ethyl acetate irr cyclohexane 30-50%). 124 mg of the target compound Were obtained with a purity of 90% (accordiaq to BYLC) (63%
. yield).
Example 6:
2-(4,6-Diethyl[1,3,5]triazin-Z-yioxy)-3-(9-metlioxybenzoylamino)-3,3-diphenylpropionic acid (I-4) A 10% palladium/carbon hydrogenation catalyst (spatula tip) was added to a solution of benzyl 2-(4.6-diethyl-(1,3,5]triazin-2-yloxy)-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate 1124 mg, 0.18 a~ol with a purity of 90%) in ethyl acetate (15 ml) and stirred under a hydrogen atu~osphere at room temperature for 3 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from dichloromethane/ether/n-hexane, resulting in 99 mg (73% yield) of the pure carboxylic acid.
1H_~1(yg (200 l~iflz): 7.8 (m. 3 H1: 7.6 ldd. 2 H): 7.1-7_4 (m, 8 R); 6_9 (d, Z H); 6.fi (s, 1 8); 3.B (s. 3 H); 2.7 (q, 4 H); 1.2 it, 6 H).
ESI-MS : h' - 526 .
The folloaring were synthesized analogously:
2-(4,6-Diethyl[1,3,5]triazin-2-yloxy)-3-(3,5-dimethoxybenzoyl-amino)-3,3-diphenylpropivnic acid (I-327) 1H-NMR (200 l~lliz): 7.9 (s.l e); 7.6 (m. 2 H), 7.2-7,5 (m. B H): 6.9 (d, z H); 6.7 (s. 1 H). 6.6 (t. 1 H1: 3.B (s, 6 B): 2.7 (q. 4 8) 1.2 (t. 6 H)-. 24 ESI-MS: M~ = 556.
3-(3,5-Dimethoxybenzoylamino)-Z-(4,6-dimethyl-Z-pyrimidinyloxy)-3,3-diphenylpropionie acid (I-248) 1H-NMR (Zo0 t~iz): A.l (s Dr. 1 N): 7.7 (m, 2 H); 7_Z-7.5 (sn. 8 H):
7.0 (d, 2 H); 6.70 (s, 1 a); 6.65 (s, 1 a): 6.60 (t, 1 g); 3.8 (s, 6 p); .2.3 (s, 6~ R) .
EST-MS: M' = 5Z7.
3-8enzoylatnino-2-(4,6-dimethyl-2-pyrimidinyloxy)-3,3-diphenyl-p=opionie acid (I-66) 1g-gMg ( Z 0 0 I~JAz ) : 8 . Z ( s br, 1 H ) : 7 . 8 ( ai, 2 8 ) : 7 . 6 (:n.
Z 8 ) t 7.1-7.5 (gin. 11 H); 6.70 (s, 1 H): 6.6S (s. 1 8): ~2~3 (s, 6 R).
ESI-h5: M- ~ 467.
z-( 4, 6-Dimethyl-2-pY=i~dioyloxy)-3-( 4-mec,hylbenzoyla~nino)-3.3-diphenylpropionic acid (I-199) Zo (Z00 ~z): e.o (s br. 1 H): 7.7 (d, Z S); 7.6 (m. Z M):
7.1-7.5 (m. l0 S); 6.7 ~s, 2 H)s 2,4 (s, 3 H): Z~3 (s~ 6 ESI-M5 : !t' - 4 B 1.
Example 7_ Henayl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-ca=boxylate Boron trifluoride etherate (8.04 g; 56.7 mmvll vas cautiously added to a solution of beezyl 3,3-diphenyloxirane-Z-carboxylate (10.D g; 28.3 rnmol) in acetonitrile (10D ml). The cttixture vas ' stirred at room temperature for an hour and then concentrated in a rotary evaporator. The residue eras taken up in water, saturated with sodium chloride aad extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent ~sas removed in vacuo; the residue (13.5 g) vas employed further Without purificasion-Example e:
Benzyl 3-amino-2-hydroXy-3,3-diphenylpropionate Benzyl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-carboacylate (13.5 g; crude) was stirred in a miacture of methanol (25 ml), Water (50 ml) and concentrated hydzochlorie acid (50 ml) at t'oom teznpesature for 60 hours. The solution vas then decanted off the undissolved t~taterial: the residue Was stirred in the 2'S
abovementioned mixture again fot three hours. Recantation gas repeated; the remaining residue was discarded. The two liquid phasres weze eomb~ined and adjusted to pB e-9 with sodium hydroxide solution, whereupon crystallization started. The crystals were washed with ether and filtered aff with suction; 4.65 g of the required amino alcohol were obtained in 97$ purity_ lE~-NMR (Z00 MHz)s T.4 (m, Z 8); 7_1-7.3 (a~, 11 H); 7.0 (m, 2 H); 5.0 (s, 1 9); 4.9 (d, 1 )i); 4.7 (d, 1 EI): 1.9-Z.5 (s br, Z ~1).
Example 9:
Benzyl 2-hydzoxy-3,3-diphenyl-3-(4-trifluvromethylbenzoylamino)-propionate pyridine ( 99 mg; 1. 00 aunol ) . a spatula tip of ditnethylauiino-pyridiae, and pare-trifluoromethylbenzoyl chloride (215 mg, 1.00 miool) were successively added to a solution of benzyl 3-amino-2-hyd=oxy-3,3-diphenylpropionate (365 mg: 1.00 mmol) in ZO dichloromethane (50 ml). The mixture vas sti=zed at room temperature for 60 hours sad then Worked up by extracting with dilute citric acid. The organic phase was dried over magnesium Sulfate, and the solvent Was removed in vacuo..The residue (540 mg) Haas taken up in chlorofarm (50 m1) ard. after additiae of pyridine ( 36 mg, 0 . 45 tnn~ol ) and a few crystals of dimethylarninopyridine, refluxed for 4 hours. After cooling, working up was carried out by extraction with dilute citric acid_ zhe organic phase gas dried over magnesium sulfate, and the solvent eras removed in vacuo_ The residue ~,ras crystallized from ethe=/n-hexane; 235 mg (45s yield) of the pure product were obtained.
1H-NMR (200 Mgz): 7.7 (d. ~ H): 7.5 (d, Z H); 7.2-7.4 (m, 13 A); 7,1 (d, z H~; 5.5 (d b=, 1 e); s.o (on. 2 H): 4.6-4.6 (s br, 1 H)_ Example 10:
Benzyl 2-(4,6-dimethyl-2-pysimidinyloxy)-3,3-Biphenyl-3-(4-tri~luoromethylbenzoylamino)propionate Potassium carbonate (100 mg; o.7Z mu~ol) and 2-methylsulfonyl-4,6-dia~ethylpyrimidine (96 mg; 0.51 mmol) were successively added to a solution of benzyl 2-Qydroxy-3,3-Biphenyl-3-(4-trifluoro-methylbenzoylamino)propionate (ZZO mg, 0.42 mmol) it dimethylformamide (15 ml)_ The enixtuze was heated to 80°c and stirred at this temperature for one hour. The reaction was stopped by adding dilute citric acid acrd Water (200 ml)_ After ' 26 extraction with ether, the organic phase vas dried over magnesium sulfate and concentrated in vaeuo. The residue vas crystalli2ed from ether/n-hexane; 158 mg (60$) of the pure title compound were obtained.
Example 11:
1~
2-(4,6-Dirnethyl-2-pyrimidinYloxyl-3,3-diphenyl-3-(4-trifluoro-methylbenzoylamino)propionic acid (I-ZO1) A 10% palladiurn/carbon hydrogenation catalyst (spatula tip) vas added to a solution of benzrl 2-(9,6-dimethyl-2-pyzimidinyloxy)-3,3lBiphenyl-3-(9-trifluoromettrylbenzoylamino)propionate (150 mg, 0.24 am,ol) in ethyl acetate (50 nl), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue vas crystallized from etbe=/n-hexane, resulting in 100 mq (78%) of the pure carboxylic acid.
lH-PMR (200 MHx)a 8.3 (s br, 1 A); 7.9 ( d, 2 H); 7.7 gym, 4 H);
_ 7,1-7.4 (m. 8 a): 6.7 (s, 1 Hi; 6.6 (s, 1 g); 2.3 (s, 6 8).
ESI-rlS: !!~ = 535, The follotaing were prepared analogously;
3-(3,4-Dimethoxybenzoylamino)-2-(4,6-dimethyl-2-pyrimidinyloxy)-3.3-diphenylpropionic acid (I-48) 1H-pMit (200 LiHz): 8.Z (s br, 1 H); 7.? (m. 2 8); 7.1-7.5 (m, l0 R);
DERIVATIVES. THEIR PREPARATION AND THEIR USE AS
ENDOTHELIN RECEPTOR ANTAGONISTS
The present invention relates to novel carboxylic acid derivatives, their preparation and use.
Endothelia is a peptide which is composed of 21 amino acids and is synthesized and released by vascular endothelium. Endothelia exists is three isoforms, ET-1, ET-Z and ET-3. "Endothelia" or "ET" hereinafter refers to one or all isoforms of endothelia.
Endothelia is a potent vasoccnstzictor and has a strong effect on vessel tone. It is known that this vasoconst=fiction is caused by binding of endothelia to its receptor (Nature, ~, 411-415, 1988; FEeS Letters,~23 , 440-444, 19A8 and 8iochem. eiophys. Res.
Coauuun . . 1~. 8 6 B-8 7 5 . 19 8 A ) .
Elevated or abnormal release of endothelia causes persistent vasoconstriction in peripheral. serial and cerebral blood vessels, which may result in disotders. As reported in the literature, errdothelin is involved in a number of disorders. These include:
hypertension, acute myocardial-infarct, pulte~onary hyper-tension, Raynaud's syndrome, cerebral vasospasms, stroke, benign prostate hypertrophy, atherosclerosis. asthma and prostate cancer (J.~vaseular-.Med. Biology 2, 207 (1990), J. Am. Med. Associat3.on 264, 2868 (1990), lvature 344, 114 (1990), N. Engl. J. Med. 32~, ZOS (1989), !'. Engl. J. Med. ,~28. 1732 (1993), Nephron 6~, 373 (1994), Stroke ~5_, 904 (1999), Nature ~, 759 (1993), J. Mol.
Cell. Cazdiol. Z7, A239 (1995); Cancer Research 56, 663 (1996), Nature Medicine 1, 944,(1995)).
At least two endothelia receptor subtypes, ~T, and ETa receptors, are curreatly,described in the literature (Nature ~$, 730 (1990), Nature 348, 732 (1990)). Accordingly, substance8 trhich inhibit tlse binding of endothelia to one or both receptors ought to antagonize the physiological effects of endothelia and therefore represent valuable drugs.
DE 19726146.9 describes the preparation of l3-amino and !i-azido carboxylic acid derivatives and their use as endothelia receptor antagonists. Further investigation has revealed that related aromatic carboxamides and sulfonamide derivatives have advantageous properties in relation to receptor affinity and receptor binding profile. The present patent relates to the preparation and use the=eof.
Z
The invention relates to J3-amido and !3-sulfonamido carboxylic acid derivatives of the formula I
R4 Rz w-x S N~C 0 ~ ~Q
i I z =y Rs Ri R
Where Eil is tetrazolyl or a group O
C-~R
where R has the following meaning:
a) a radical OR6, Where R6 is:
hydrogen, the cation of an alka7.i metal, the canon of an alkaline earth metal or a physiologically tolerated organic ammonium ion such as tertiary C1-C~-alkylaau~onium oz the aaanoaium ion ; .
C3-Cs-cycloalkyl. Ci-Ce-alkyl, CHZ-ghenyl. Which may be ~5 substituted by one or mo=e of the following radicals:
halogen, aitro, eyano, C1-Cg-alkyl, Cl-C~-haloalkyl, hydroxyl, Cl-C'-alkoxy, me=capto, C1-C~-alkylthio, amino, 'NB~C1-C,-alkyl , N(C1-Ca-alkyl)z;
3o a C3-CA-alkenyl o= C3-Ce-alkynyl group, it being possible far these groups in turn to car=y one to five halogen atoass;
Rs can furthermore be a phenyl radical Which may carry one to five~haloqen atoms andlor ova to three of the following 35 .radicals: vitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, hydroxyl. C1-Cs-alkoxy, mereapto, C1-C,-alkylthio, amino, Ng(C1-C4-alkyl), N(Ci-C4-alkyl)z: , b) a 5-membered heteroaromatic systet~ linked via a nitrogen qp atom, suca as pyrrolyl. pYrazolyl, imidazolyl and triazolyl, erhich may carry one or two halogen atoms or one or two C1-C~-alkyl or one or zoo Cl-C4-alkoxy groups:
q5 c) a group _ C - ~ C~~ ~p 5 g, where k can assume the values 0, 1 and 2, p the values 1, 2, 3 and 4, and R~ is to C1-Cd-alkyl. C3~Ca-cycloalkyl, C3-C'-alkenyl, C3-CB-alkynyl or phenyl, Which may be substituted by one or more, eg. one to three, of the following radicals:
halogen, nit=o, cyano, C1-Cq-alkyl, hydro~rl, C1-Cq-alkoxy, Gl-Cq-alkylthiv, amino, NH(C1-Cs-alkyl). N(CI-Ca-alkyl)Z.
mercapta;
d~ a radical p - N 5 - ga H II
O
whe=e RB is:
Cl-C4-alkyl. C3-C,-alkenyl, C3-Ca-alkynyl, C3-Ce-cycloalkyl, it being possible for these radicals to carry .a C1-C,-alkoxy.
3p C1-C,-alkylthio and/or a phenyl radical as mentioned under c);
Ci-C,-haloalkyl or phenyl, u~substituted or substitated in particular as mentioeed under c).
The_other substituents have the folloaring meanings:
W and Z, ~rhich may be identical or different a=e:
nitrogen or methine; with the proviso that Q = nitrogen if W
90 and 2 = methine;
g is nitrogen or CR9:
Y , is nitrogen or CRS°;
Q is nitrogen or CRI~; ~,rith the proviso chat X = CR9 and Y
CRlo if Q = nitrogen;
Rz and R3, which may be identical or difFerent, are:
' phenyl or naphthyl, each of which may be substituted by one or more of the following radier~ls: halogen, vitro, cyano, hydroxyl, mercapto, C1-C,-alkyl, CZ-C,-alkenyl, C=-C4-alkynyl, CI-C,-haloalkyl, C1-C,-alkoxy, phenoxy,, C=-C°-haloalkoxy, C1-C,-alkylthio, amino, NH(C1-C9-alkyl), N(C~-C°-alkyl)2 yr phenyl which may be substituted one or more times, eg. one to three times, by halogen, vitro, eyano, C1-C,-alkyl, Gl-Ca-haloalkyl, Ci-C,-alkoxy, Ci-C,-haloelkoxy or C1-C,-alkylthio; or I5 ' phenyl or naphthyl wdieh ase linked together in ortho positions by a direct linkage, a methyleae, ethylene oz ethenyleae group, an oxygen or sulfur atom or an SOZ, pe or N-alkyl group;
C5-C6-cyeloalkyl, it being possible for these radicals to be substituted in each case vne or more times by; halogen, hy3roxyl, mereapto, carboxyl, vitro, eyano, C1-C~-alkyl,.
C=-Cq-alkenyl, C2-C°-alkynyl, Cl-C~-alkoxy, C1-C,-alkylthio, IS Cl-C,-haloalkoxy;
R° a) a radical 30 Riz with R1~ phenyl, naphthyl or a five- or six-rnembered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, 35 ,, it being possible for said radicals to be substituted one or more times by: halogen, vitro, cyano, hydroxyl, mercapto, C1-C°-alkyl, C1-C°-hydroxyalkyl, Cl,-C°-haloalkyl, Ci-C4-alko~cy, C~-C°-alkylcarbonyl, carboxyl, 40 Cl-C4-haloalkoxy, C1-C4-alkylthio,~amino, NH(C1-Ca-alkyl), N(C1-C,-Slkyl)2, BZN50~, (CI-C9-alkyl)NHSOZ, (C1-C4-alkyl)ZNSOZ, or phenoxy or phenyl, each of which may be substituted one or more times, e.g. one to three times, by 45 halogen, vitro, eyana, C1-Ca-alkyl, C1-Ca-haloalkyl, CI-C9-alkoxy, C1-ca-haloalkoay and/or Cl-C9-alkylthio b) a radical -S- Ria to with R13 C1-C9-alkyl. C1-C4-haloalkyl o= phenyl, it being possible for the phenyl radical in turn to carry one to five halogen atoms and/or one to three of the follcwi~g radicals: C1-C~-alkyl, C1-Ca-haloalkyl, C1-Ge-alkoxy, CL-C,-haloalkoxy and/or C1-Cq-alkylthio;
RS is hydrogen, C1-C4-alkyl:
Zo R~ and Rla(~,rhich may be identical or different) are:
hydrogen, halogen, Cl-C,-alkoxy, Cl-C'-haloalkoxy, C3-C6-alkenyloxy. C3-C6-alkynyloxy, C1-C,-alkylthio, Cl-C9-alkylcarbonyl, Ci-C4-alkoxycarbonyl, hydroxyl, N82, NH(Cl-G~-alkyl), N(Ci-C~-alkyl)Z;
CI-C4-alkyl, CI-C~-alkenyl. C=-C,-alkynyl, it being possible for these radicals to be Substituted by halogen, hydroxyl, mercapto, carboxyl, cyano;
or CRS or CRla is linked to CR11 as indicated for R11 to give a 5- or 6-membeted ring, R~i . is hydrogen, halogen, C1-C,-alkoxy, Cl-C~-haloalkoxy, C3-Cd-alkenyloxy, c3-cs-alkynyloxy, Cy-C4-alkylthio, C1-Ci-alkylcarbonyl, Cl-Ca-alkoxycarbonyl, P8(C1-Ca-alkyl), N(C1-C4-alkyl)z, hydroxyl, carboxyl, cyano, amino, me=captv;
C~-C,-alkyl, CZ-CQ-alkenyl, CZ-Ca-alkynyl, it Deing possible for these radicals to be substituted one or more times by:
halogen, hydroxyl, mercapto, carboxyl, cyano, amino, C1-CQ-alkoxy;
~5 , or CR11 forms together With CRS or CRi° a 5- or 6-meaibered alkylene or alkenylene ring which may be substituted by one or two C1-C4-alkyl groups, and in which in each case one or more methylene groups may be replaced by oxygen, sulfur. -NH
or -N(C1-Cq-alkyl).
The definitions applying herein and hereafter are:
an alkali metal is, for example, lithium. sodium, potassium;
as alkaline,earth metal is, for example, calcium, magnesium, barium;
organic ammonium ions are protonated amines such as ethanolamine, diethanolamine, ethyleaediamine, diethylamine or piperazine;
C3-Cs-cycloalkyl is, fot example, cyclopropyl, cyclobutyl, cyclopeatyl, cyelohexyl, cycloheptyl or cyclooctyl;
~i-ce-haloalkyl can be linear or branched, eg. fluoromethyl, d~fluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, I0 2-fluoroethyl, 2.Z-difluoroethll, 2,2,2-trifluoroethyl, Z-chloro-2,2-difluoroethyl, Z,2-dichloro-Z-fluoroethyl, Z,2,Z-ttichloroethyl or pentafluoroethyl;
Ci-Ca-haloalkoxy can be linear or branched, eg- difluorornethoxy, Z5 trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetraflucroethoxy, 2,2,2-trifluotvethoxy, Z-cttloro-1,1,2-trifluoroethoxy, Z-fluoroethoxy or pentafluoroethoxy;
30 ~y-C4-alkyl can be linear or branched, ag. methyl, ethyl, 1-propyl, 2-propyl, Z-methyl-Z-propyl, 2-methyl-1-propyl, 1-butyl or Z-Dutyl;
C2-C,-alkenyl can be linear or brapched, eg. ethenyl, 35 1-p=open-3-yl, l-prvpen-2-yl, 1-pxopen-1-yl, Z-methyl-1-propenyl, 1-buzenyl or 2-butenyl;
C=-C,-alkynyl can be linear or branched, eg'. ethynyl, 1-propyn-1-yl, 1-propyn-3-yl, 1-butyn-4-yl or 2-butyn-4-yl;
40 Gl-Ca-alkoxy can be linear or branched, eg, methoxy, ethoxy, ptopoxy, 1-methylethoacy, butoxy, 1-methylpropoxy, Z-methylpropoxy or l,i-dimethylethoxy;
Cs-Cs-alkenYloxy can be linear or branched, eg. allyloxy, 45 2-buten-1-yloxy or 3-buten-2-yloxy;
C3-C6-8lkynyloxy eaa be linear or branched, eg. 2-propyn-1-yloxy, Z-butyn-I-yloacy or 3-butyn-Z-yloxy; .
C1-C9-alkylthio can be linear or branched, eg. methylthio, ethylthio, propylthio, 1-methylethylthio, butyltnio, ' 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylethylthio;
C1-CS~alkylcarbonyl can be linear or branched, eg. acetyl, ethylcarbonyl o= 2-propylcarbonyl;
C1-CB-alkyl can be linear or branched, eg. C1-Ca-alkyl, pentyl, hexyl, heptyl or octyl;
C3-Ce-alkenyl can be linear or branched, eq. 1-propen-3-yl, I-propen-2-yl, 1-propen-l-yl, 2-methyl-1-propeoyl, 1-buten-4-yZ, 2-bates-3-yl, 1-peatet~-5-yl, 1-hexes-6-yl, 3-hexes-6-yl, 2-hepten-7-yl or 1-octen-B-yl;
G3-CB-alkynyl can be linear or bra»ched, eg. 1-propyn-1-yl, 1-jp=opyn-3-yl, 1-butya-4-yl, Z-burins-4-yl, Z-pentyn-5-y', 3-hexyn-6-yl, 3-heptyn-7-yl, 2-oetyn-B-yl;
Halogen is, far example, flucrine, chlorine, bromine, iodine.
The invention further relates to those compounds from Which the compounds of the formula I can be liberated (called prodrugsl.
Preferred prodrugs are those ~rhose release takes place under conditions prevailing in certain compartments of the body, eg. in the stomach, intestine, blood circulation, liver.
The compounds I and the irate=mediates for preparing them, eg, II
and I=I, may have one or more asymtnetrically substituted carbon atoms. Compounds of this type can exist as pure enantiomers or pure diastereomers or as mixture thereof. It is preferred to use an enantioanerically pure compound as active ingredient.
the invention further relates to the use of the abovementioned carboxylic acid derivatives to produce drugs, in particular to produce inhibitors of ETa andloz ETB receptors. =he novel compounds are suitable as antagonists as defined at the outset.
The compounds according to the invention with formula I can be prepared via the routes described in DE 19726146.9.
A possible alternative to this is preparation via intermediates of the general formula III; these derivatives can be synthesized either by reducing azides of the formula II (see DE 19726146.9) by generally known methods oz by opening the oxazoline derivatives of the general formula IV Which are described in Wo 95/07266.
RZ Rz . R3 Ri H R R=
p C-OH < N 0 io 3 R~ R3 Rl , IV
zi xrz The oxaxoline derivatives of the formula Iv can he opened by treatment with aqueous solutions of strong acids such as ' hydrochlori.c acid, hydrobromic acid, sulfuric acid, perchloric Z5 acid, trifluoroaeetic acid, toluenesulfonic acid, ~nethane'ulfonic acid or trifluvramethanesulfonic acid in the presence of a suitable solubiliZer. All water-miscible solvents can be used for this purpose as long as they are inert toward the reagents used.
a0 Examples of such solubilizers are alcohols such as methanol, ethanol. n-propanol, isopropanol; ethers such as tetrahydrofuran or dioxane; nitrites sued as acetvnitrile or propionitrile;
amides such as dimethylformarnide -or ~aia~etbylacetamide; sulfoxides and 3ulfones such as dimethyl sulfoxide.: carboxylic acids such as 25 acetic acid or propionic acid.
The reaction in this case is preferably carried out at a temperature in the range between 0°C and the boiling point of the solvent or solvent a~.ixture.
Compounds according to the invention in ~rhich RqRSN is aromatic or hetezoaromatic carboxamido can be prepared, for example, by acylating III oe the nitrogen or, alternatively, acylating both the amino group and the hydroxyl group in III and then 35 eliminating the ester acyl group using generally known methods.
For this purpose, the compound of the general fonttula III is reacted with tl~e acylating reagent in the molar ratio of 1=1 to 1:6.in the presence of a suitable diluent. All solvents which are inert toward the reagents used can be used for this purpose.
RZ O Rx FI N C O I= ~ H
H w~ R N C OH
~ H
Ri R3 Ri v Examples of such solvents oz diluents are aliphatic, al icyclic and aromatic hydrocarbons, Which may in each ease optionally be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, ethyl chloride and tricl~lotoethylene, ethers such as diisopropyl ether, dibutyl etAer, methyl tent-butyl ethe=, dioxane and tetrahydrofuran, nitriles ouch as acetonitrile and prnpfonitrile, amides such as dimethyltormanide, dimethylacetamide and N-methylpyrrolidone, sulfoxides and sulfaaes such as dimethyl sulfoxide and sulfolane.
Z0 The reaction in this case is preferably carried out at a temperature in the range between o°C and the boiling point of the solvent or solvent mixture.
The presence of a zeaction catalyst may be~advantageous. A
Z5 suitable catalyst in this case is, for example, dia~ethylaminopyridine.
the resulting compounds of the general formula V are converted into the B-amido carboxylic acid derivatives according to the 30 iwention by zeacting the compounds of the general formula V faith neterocycles of the general formula VI.
~n1_X W_X
p + ~ Ri 4 --~~ ~ Q -~1 R' g C 0 --~~ . Q
35 3 Rl Z =Y
2=Y
VI
Ia R~' in formula vI is halogen or R15-501-, where R15 can be 40 C1-C4-alkyl, C1-C,-haloalkyl or phenyl, and the definitions of W, X, Y, Z and Q are those given at the outset. The reaction preferably takes place in an inert solvent or diluent with the addition of a suitable base, i.e. a base ~rhich deprotonates the intermediate V, at a temperature in the range from room 45 temperature to the boiling point of the solvent.
l Compounds of the formula v= are known, and some of them can be bought or they can be prepared in a generally known manner.
zf al in compounds of the general formula Ia is an ester, the ester group can be cleaved with acid or base or by hydrogenolysis to give the free carboxylic acids with R1 ~ COOH. Compounds of the type Ia with Ri = C008 can, however, also be obtained directly by dep=vtonating the intermediate V in which R1 = COON with three equivalents of a suitablQ base and reacting with compounds of the general formula VI. Once again, the reaction cakes place in an inert solvent and at a temperature in the range from room temperature to the boiling point of the solveat.
The base which caa be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, e.g.
sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an orgaaou~etallic~compouad such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.
The~compounds according to the invention of the general formula I
in which R4R5N is sulfonarnido can be obtained from anuLnee of the general formula VII and are prepared as described in DE
I9~~61.46_9. For this purpose, VII i,s reacted by generally known methods irith suLfonyl halides and, if Ri is an ester, the ester group is cleaved arith acid or base or by hydrogenolysi5.
Rz Rx R Hi X II ~ H u1 R
8 N ~ C O---~~ ~~Q ~ R13-5-N C -O ~ ~ Q
Z
IR1 8=Y ~~ N I Z=Y
Ra R7 Ib Compounds o! the formula I caa also be prepared by startiDg front the appropriate carboxylic acids, i.e. compounds of the formula I
in which Ri is COON, first converting them in a conventional way in an activated form, such as an acid halide, anhydride ar imidazolide, and then reacting the latter orith a~ appropriate hydro~cyl compound HOR6 oz sulfonamide BiNSO2Re . This reaction can be carried out in conventional solvents and often requites the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act in the presence of a dehydrating agent such as a carbodiimide on the hydroxyl compound or the sulfonamide.
It is additionally possible to prepare compounds of the formula I
by starting from the salts of the appropriate carboxylic acids, i.e, from compounds of the formula I in' which R1 is a group Coots, where H can be an alkali metal cation or the equivalent of an S alkaline earth metal cation_ These salts can be reacted With many ' compounds of the formula R-D where D is a conventional nucleofugie leaving group, for example halogen such as chlorine, bromine, iodine or optioeally halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyl .such as toluenesulfonyl aid methylsulfoeyl or another equivalent leaving group. Compounds of the formula R-D with a reactive substituent D
are known or can easily be obtained with general expert knowledge. This reaction can be carried out in the conventional solvents and is advantageously performed in the presence of a base, in erhich case those mentioned above are suitable.
~ompouads of the forinula I in which Rt is tetrazolyl can be prepared according to the methods described is WO 96/11914 from the corresponding carboxylic acids (formula I with R1 ~ COOH).
In some cases, it is necessary to use generally knocan protective group techniques to prepare the compounds I according to the invention. If, for exaa~le. R4RSN = 9-8o-phenyl-CONS-, the hydroxyl group can initially be protected as benzyl ether, which is then cleaved az a suitable stage in the reaction sequence.
Compounds of the formula I and v can be obtained in enantiornerically pure form by carrying out a classical raeersate resolution ~rith suitable enantiomerically pure bases, such as those described in wo 96/11914, ~rith racemic or diastereomeric compounds of the formula I and v.
Glith a view to the biological effect, preferred carboxylic acid derivatives of the general formula I - both as~pure enantiomers or pure diasteteomers and as mixtures thereof ~ are those in which the substitueaes have the following meanings:
R1 is tetrazolyl or a group O
C-R
in ~ohich R has the following meaning:
a) a radical OR6, in Which R6 is:
hydrogen, the cation of as alkali metal, the cation of an alkaline earth metal, a physSologically tolerated organic ammonium ion such as tertiary C1-Ca-alkylaraswnium or the ananonium ion;
C3-Ce-cycloalkyl, Cl-Ce-alkyl, CHi-phenyl, which can be substituted by one or more of the follo~ring radicals:
halogen, C~-C4-alkyl, Cl-C!-haloalkyl, hydroxyl, C1-C~-alkoxy, mercapto, C1-C,-alkylthio, NH(Cl-C4-alkyl), N(Cl-C,-alkyl)?;
to a C3-CB-alkenyl or a C3-Ce-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
Rs can also be a phenyl radical Which can carry vse to five halogen atoms and/or one to three of the following radicals:
C1-C4-alkyl, C1-C~-haloalkyl, hydro~cyl, C1-C4-alkoxy, mercapto, C1-C4-alkylthio, NH(C1.-~4-alkyl), N(Cl~~a-alkyl)?;
D) a 5-membered heteroaromatic system trhich is linked via a nitrogen atom, such as pytazolyl, imidaaolyl and triazolyl, which a~ay carry one or tmo halogen atoms or one or two ~ C~-C,-alkyl or. one or two C1-C,-alkoacy groups;
c~ a,group (o)r ' I
- O - ( C8~ )p S R' 3o is Which k can assume the values 0, 1 and Z, p can assume the values 1, 2, 3 and 4, and ~!~ is ci-C,-alkyl, C3-C,-cycloalkyl, C3-Ce-alkenyl, C3-Ce-alkynyl or pdenyl Which can be substituted by one or more, e.g. one to , three, of the following radicals:
halogen, C1-C9-alkyl, hydroxyl. C1-C~-alkoxy, CZ-Ca-alkylthio, NR ( C1-Ca-alkyl ) . N ( Cl--C4-alkyl ) z . a~ereapto;
d ) ~ a radical O
-N 5- Ae N
O
in which Re is:
Cl-C9-alkyl, C3-Ca-alkenyl, C3-CB-alkyayl, Cj-C8-cycloalkyl, it being possible for these radicals to carry a Cl-Ca-alkcxy, C1-C4-alkylthio and/or a phenyl radical as mentioned under c);
Cl-C,-haloalkyl or phenyl, optionally substituted in particular as mentioned under c);
W and 2 (which may be identical or different):
nitrogen or methine; with the proviso that Q = nitrogen i.f W
and Z = methine;
X nitrogen or CR9;
Y nitrogen or CR»; ' Q nitrogen or CRil: With the proviso that X = CR9 and x =
CRl° if Q ~ nitrogen;
Rx and R3 (which may be identical or different):
phenyl or naphthyl. each of which may be substituted by one Z5 or mote of the following radicals: halogen, eyano, hydroxyl.
mercapzo, C1-Cq-alkyl, C1-C4-haloalkyl,~Cl-C~-alkoxy, phenoxy, Cl-C4-halvalkoxy. Cl-Cq-alkylthio, amino, Na(Cl-C~-alkyl), N(C1-t4-alky112 or phenyl, ~rhich may be substituted one or more times, e.g. one to three times, by halogen, cyano, C1-Ca-alkyl, Ci-C4-haloalkyl, cl-Ca-alkoxy, Cl-Cq-haloalkoxy or Cl-C4-alkylthiop or phenyl or naphthyl, which are linked together in ortha positions by direct linkage, a methylene, ethylene or .etheaylene group. an oxygen or sulfur atorn,or an 50i, NH er N-alkyl group;
Rd a) a radical ~z R
With Rlz phenyl, naphthyl or a five-~or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for said radicals to be substituted one or more times by halogen, eyano, hydroxyl, mercapto, CI-Cq-alkyl, C1-C~-hydroxyalkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, Cl-Ca-haloalkoxy, Cl-Cd-alkylthio, amino, NH(C1-C4-alkyl), N(C1-C4-alkyllZ~ AzNSaz~
(Cl.Cq-alkyl)NHSOZ, (Cl-C4-alkyl)ZNSOZ, or phenoxy ' ~ or phenyl, each of which may be substituted one or more times, e_g. one to three rimes, by halogen, eyano, Cl-C,-alkyl. C1-C9-haloalkyl, C1-C4-alkoxy, C1-Ca-haloalko~cy.and/or Ci-Cq-alkylthio;
b1 a radical O
-I5,_ Ri3 O
with Rl3 C~-Cq-alkyl, Cl-C4-haloalkyl or phenyl, it being possible fvr tha phenyl sadieal in turn tv carry one to five halogen atoms and/or one to three of the following radicals: C1-C4-alkyl, C1-Cq-haloalkyl, C1-C~-alkoxy;
R5 hydrogen, methyl;
R9 and Rl~(which may be identical or different):
. hydrogen, halogen, C1-Cq-alkoxy, C1-Cq-?raloal3co~cy, C1-Ca-alkylthio, D~8(C1-Ca-alkyl), N(C1-Ca-alkyl)t;
C1-C,-alkyl. CZ-C,-alkenyl, it being possible fo= these =adieals to be substituted by halogea, hydroacyl, .mereapto, cyano;
or CR9 or CR1~ is linked to CRL1 as indicated fo= R11 to give a 5- or 6-membered ring;
R11 hydrogen, halogen, C1-C4-alkoxy, Cl-Ca-haloalkoxy, C1-C4-alkylthio, NH(C1-C4-alkyl), N(Ci-C4-alkyl)Z, eyano;
cl-C4-alkyl, CZ-Ca-alkenyl, it being possible for each of these radicals to he substituted one or more times by:
halogen, cyano, C1-ca-alkoxy;
~ 15 or GR11 forma together with CR9 or CR1°~a 5- or 6-membered alkylene or alkenylene ring v~ie?r may be substituted by one or two C1-C,-alkyl groups, and in ~rhich in each case one ar more methylene groups may be teplaeed by oxygen, .
sulfur, -Nii or -NtCl-C~-alkyl).
particularly preferred compounds of the formula I - both as pure enantiomers oz pure diastereomers and as mixtures thereof - are those in which the substituents have the following meanings:
Ra is tetraaolyl or a group C-R
is which R has the following meaning:
a) a radical OR6, in which R6 is.
Zo ' hydrogen, the cation of an al.7eali metal. ~e cgtion of an ' alkaline earth metal or the ammonium iorr:
C1-C8-alkyl, CB=-phenyl, Which can be substituted by one Z5 . or more of the following radicals: halogen, C1-C4-alkyl, C1-C~-haloalkyl, C1-Ca-alkoxy:
R6 can fuzthertnore be a phenyl radical which may carry one to five halogen atoms and/or one to three of the 3o follooring radicals: C1-CQ-alkyl. C1-Cs-haloalkyl.
C1-C4-alkoxy~
b) a 5-membered heteroaromatic system linked via a nitrogcn~
atom, such as imidazolyl and triazvlyl, which may carry 35 ' one or !WO halogen atoms, or one or two Cl-C,-alkyl or one or two C1-C4-alkoxy groups:
c) a group (il)k 4o -O-- (C8i)p S R' in which k may assume the values 0, l and 2, p may assume s5 the values 1, 2. 3 and 4, and R~ is Cl-C4-alkyl, C3-CB-cycloalkyl or phenyl Which may be substituted'by one or more, e.g_ one to three, of the folloW,irg radicals:
halogen, CI-Cq~alkyl, Cl-C4-alkoxy;
d ) a radic al O
SI
- N - --- R' N
O
in which Re is.
l5 Cl-C4-alkyl, C3-Ce-eyeloelkyl, it being possible for these radicals to carry a cl-C~-alkoxy and/oz a phenyl radical as mentioned under c);
Z0 Cl-.C4-haloalkyl oz phenyl, optionally substituted, ici particular as mentioned under c);
W and Z (which may be identical or different):
Z5 , nitrogen or methine; with the proviso that Q m nitrogen if W and Z = methine;
X ,nitrogen or CR9; . .
Y nitrogen o= CRlo 30 Q nitrogen or CR11; with the proviso that X ~ CRS and Y
= CR1~ if Q = nitrogen;
RZ and Rj (which may be identical or different phenyl groups which may be substituted by one or more of 35 the following radicals: halogen, C1-Cq-alkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, phenoxy, C1-C9-alkylthio, NH(C1-Cq-alkyl), N(C~-C9-alkyl)z or phenyl, which may ba substituted one or more times, e.g. one to three times, by halogen, C1-co-alkyl, C1-C9-haloalkyl, C1-C~-alkoxy or 40 Ci-Cq-alkylthio; os phenyl groups which are linked together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or snlfar atom or an SOz-, 45 NH- or I~-alkyl group;
R4 a) a radical D
giz Nith Rlz phenyl or a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms andlor one sulfur or oxygen atom, it being possible for said radicals to be substituted one or more times by: halogen, hydroxyl, Cl-Ca-alkyl, C1-Cq-haloalkyl, Cl-Ca-alkoxy, Cl-C9-haloalkoxy, phenoxy, Cl-Ca-alkylthio, NH(C1-c4-alkyl), N(C1-Cq-alkyl)?, (C1-Ca-alkyl)N850z, cl-C4-alkyl ) zpSOz or phenyl rrhieh can be substituted one or more times, e.g. one to three times, by halogen, Cl-C~-alkyl; C1-Ca-haloalkyl, ' Cl-Cd-alkoxy and/or C1-C4-haloalkoay;
D) a radical ' O
- S _ Ri3 O
with Rl~ C1-C4-alkyl, C1-C,-haloalkyl or phenyl. it being po9sible for the phenyl radical in tu=r to ea==y one to five halogen atoms and/or otie to three of the following radicals: C1-C~-alkyl, Cl-C4-haloalkyl. Cl-Ca-alkoxy;
RS hydrogen, methyl;
R9 and Rla(vhieD may be identical or different):
hydrogen, C1-C4-alkoxy, C1-C4-alkylehio, N(Cl-C~-alkyl)i;
C1-Ca-alkyl, it being possible for these radicals to be substituted by halogen;
or CR9 or CRl° is linked with CRil as indicated for R11 to forea a 5- o= 6-me~nbered ring;
f8 R11 hydrogen, C1-C,-alkoxy, C1-Ca-alkylthio, cyano;
G1-C4-alkyl, it being possible for these radicals in each case to be substituted one or more times by halogen;
or CRil forms together with CR9 or CRl~ a 5- or 6-membered alkylene or alkeoylene ring which may be substituted by one or two Cl-C4-alkyl groups and in which, fn each case, one oz more methylene groups can be replaced by oxygen, sulfur, -NH or -p(Ca-C4-alkyl).
The compounds of the present invention offer a~novel potential treatment of hypertension, pulmonary hypertension, myocardial infarct, chronic heart failure, angina pectoris, acute/ch;tonic kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxia-induced organ failure, intzavascular coagulation, ~estenosis after angioplaaty, benign prostate hyperplasis, ischemic and intoxication-induced ZO kidney failaze or l~ype.rtension. cgclosporine-induced kidney failure, erectile dysfunction, metastasis and gror.rth of mesenchymal tumors, cancer, prostate cancer, contrast agent-induced kidney failure, pancreatitis, gastrointestinah ulcers.
The invention further relates to combination products consisting of endothelin.receptor antagonists o~ the formula'I and inhibitors of~the resin-aagiotensin system. Inhibitors of the resin-angiotensin system are resin inhibitors, angiotensin Z=
ant8gonists and, in particular, angiotensin converting enzyme (ACE) inhibitors.
These combination products are particularly suitable for treating and preventing hypertension and its sequelae, and for treating heart failure.
The good effect of the compounds can be shown in the following teats:
Receptor-binding studies Cloned human ETA or ET8 receptor-expressing C80 cells were employed for binding studies.
- ~ 'i'9 Membrane preparation.--.
The ETa or ET8 receptor-e~cpressing CHO cells were grown is Dt~iEH
NUT MIX F12 medium (Gibco, No. 21331-020) with 10% fetal calf serum (FRA Laboratories GtnbH, Lint, No. A15-022), 1 ml~i glutamine . (Gibeo No. 25030-024), 100 U/ml penicillin and 100 )tg/ml streptnmycia (Sigma No. P-07.81). After 48 hours, the cells were washed with PBS and incubated with 0.05 trypsin-containing PHS
at 37°C for 5~ minutes. This was followed by neutralization with medium, and the cells were collected by centrifugation at 300 x g.
For membrane preparation, the cells Were adjusted to a concentration of l0e cells/ml of buffer (50 mri Tris-8C1 Duffer, pB
7_4) and then disintegrated with ultrasound (Branson 5onifier 250, 40-70 seconds/eonstant output 20).
83.nding assays Z0 For the ETa and ETa receptor-binding assay, the membranes were suspended in incubation buffer (50 mM Tris-5C1.~ pe 7.4 eith 5 mrl ' , MnCl2, 40 ~g/ml bacitraeia and 0.2% HSA) in a concentration of 50 ~:g of protein per assay mixture and incubated with ZS pM
yxsl~_gTl (HTA receptor assayl or ZS pM I1~5I7-FTC (ZTa receptor assay) in the presence and absence of test suDstanee at 25°C. The nonspecific bind~g Was determined using 10-1 M E"ry. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skat=on cell harvester (5katron, Lier, Nox~rayl separated free and bound radioliqand, and the filters were washed e.rith ice-cold Tris-HC1 buffer, pH 7.4 with 0.2% HSA. The radioactivity collected on the filters was quantified using a Packard 2200 GA
liquid scintillation counter_ Testing of ET antagonists in vivo:
Male SD tats weighing 250 - 300 g were anesthetized with amobarbital, artificially ventilated, vagotomized and pithed_ The carotid artery and jugular vein were cathezeri2ed.
In control animals, intravenous administzation of 1 mglk9 ETl results in a marked rise in blood pressure r,~hich persists for a lengthy period.
The test animals received i_v. injection (1 ml/kg) of the test compounds 30 min before administration of ET1. To determine the ET-antagonistic properties, the changes in blood pressure in the test animals were compared with those in the control animals.
' Oral testing of ET receptor antagonists:
Male narmotensive tats (Sprague Dawlcy, Janvier) Weighing 250-350 g axe pretreated with the test substances orally. 80 l0 minutes later, the animals are anesthetized with urethane, and the carotid artery (for measuring the blood pressure)~and the jugular vein (administration of big endothelin/.endothelin 1) are catheterized.
15 After a stabilization period, big endothelin (z0 (tg/kg, admin.
vol. 0.5 ml/kg) or ET1 (0.3 ~.g/kg, admin. vol. 0.5 atl/kg) is given intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. The marked and long-lasting changes in blood pressure are calculated as the area under the curve ZO (AQC). To detereu.ne the antagonistic effect of the test substances, the ADC for the animals treated with substance is compared with the AUC for the control animals.
Tre novel compounds can be admiriistered orally or parenterally Z5 (subcutaneously, intravenously. intramuscularly, intraperitoneally) in a conventional way. Administration can also tekg place orith vapors or sprays tbrough the nasvpharyngesl space.
The .dosage depends on the age, condition and weight of th~
patient and on the mode of administration. As a rule, the daily dose of active ingredient is from about 0.5 to 50 mglkg of body weight on oral administration and from about 0.1 to 10 tng/kg of body weight art parenteral administration.
The novel compounds can be administered in conventional solid or liquid pharmaceutical form" eg. as uneoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulator, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slo~,ring agents. antioxidants and/. or propellant gases (cf. H. Sucker et al.: PharmaZeutisehe Technologic, Thieme-Verlag, Stuttgart. 1991)_ Tha administration forms obtained i~ this way~AOrmally contain from 0.1 to 90% by weight of active ingredie~.
Synthesis Examples ' s Example l:
tiethyl 3-amino-Z-hydroxy-3,3-dipheaylpropionate to O.Z g of a 10~ palladium/carboa hydrogenation catalyst gas added to a solution of methyl 3-azido-2-hydroxy-3,3-diphenylpropioaate (5.71 g; 19.2 aanol) in methanol (100 ml). The mixture was stirred under a hydrogen atmosphere at zoom temperatu=e for 48 hours; the catalyst was rhea filtered off and the solvent was distilled off.
i5 The residue Was taken up in 5% strength aqueous citric acid and ' the resulting solution eras extracted r~ith ether. The aqueous phase ~as~then made alkalise with dilute sodium hydroxide solution and again extracted ~rith ether. The extracts obtained from the alkaline phase were dried over magnesium sulfate,~and 20 solvent was removed in vacuo. 4.03 g (14.9 muiol, 77% yield) t'f the pure amine were obtained.
~ (200 M8a): 7.5 (m. 2 E1): 7.2-7.4 (m. 9 H). 5_0 (s, 1 H): 4.2 (s br, 1 E1). 3.4 (s, 3 ti): 2.0-2.9 (s bz, 2 Hl.
as Example 2:
2-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2.2-diphenylethyl 4-meehoxybenzaate 8yridine (1.17 g; 14.7 mmoll. a spatula tip of di,methylarninopyridine, and pare-methoxybenzoyl chloride (2.52 g, 14.7 mmol) were successively added to a solution of methyl 3-amine-Z-hydroxy-3,3-diphenylpropioaate (2.00 g, 7.37 mmol) in dichlorornethane (10 ml). The mixture Was stirzed at room temperature for 4 hours and then, for vorkup, mixed ~rith mater aad~extracted With ether. The combined organic phases were washed with aqueous citric acid and saturated brine and then dried over magnesium sulfate. The solvent was evaporated off is vacuo to afford the crude bisacylation product. Which was employed without further purification (1.37 g; 28% yield ~rith a purity of BZ%
according to HPLC).
Example 3:
Methyl 2-hydroxy-3-(4-methoxpbenzoylamino)-3,3-diphenylpropionate Z-(4-Methoxybenzoylamino)-1-methoxycarbonyl-2,Z-diphenylethyl 4-rnethoxybenZOate (1.37 g; 2.08 mtnol with a parity of eZ%) vas dissolved in methanol (20 ml), and potassium carbonate (B63 mg, 6. Z5 uunol) vas added. The resulting mixture was stirred at room temperature for 16 hours and the solvent Was removed in vacuo.
id The residue vas taken up in water and extracted With ether; a colorless solid precipitated during this and was isolated by .
filtration and was identical to the title compound. The aqueous phase was then extracted again with ethyl ac~tate. The organic phases were combined aad dried over magnesium sulfate, and the solvent was removed in vacuo_ The crude product vas purified Dy crystallization from diehloromethaae/ether/n-hexane, resulting in a colorless solid (503 mg; 60$ yield).
Example 4.
eeazyl 2-hydroxy-3-(4-methoxybenzoylaa~ino)-3,3-diphenyl-propionate 2_11 ml of a 1 molar sodium hydroxide solution were added to a 15 solution of methyl Z-hydroxy-3-(4-methoxybenzoylamino)-3,3-di-phenylpropionate (503 mg; 1. Z4 mmol) in 1:2 water/tetrahydrvfuran (50 ml) and Stirred at room temperature for 60 hours. The sta=ting material had been substantially.coavezted after this: to complete the reaction, 1 molar sodi~un hydroxide solution (Z.11 30 ail) vas added again. and stirring was continued for one hour. The mixture Was diluted with water, extracted with ether, acidified with citric acid and again extracted with ether. The extracts obtained from the acidic phase were dried ever magnesium sulfate and the solvent was removed in vacuo. The residue (406 mg) eras 35 taken up in dimethylformamide (ZO ml), and potassium carbonate (179 mg: 1.30 mmol) and benzyl bromide (195 mg; 1.14 mmol) Were successively added. The resulting mixture vas stirred at room temperature for 20 hours and then 5% strength aqueous citric acid gas added. After dilution with water, ext=action r.ras carried out 40 with dichloromethane and then With ether (product is only moderately soluble in ether). The combined organic extracts were thoroughly washed With water aad then with saturated brine and dried over magnesium sulfate, and the solvent was removed in vacuo. Traces of benzyl bromide and dimethylformamide were 45 removed by washing the residue with a little 1:1 ether/n-hexane.
Qe? mg (?9$) of the pure benzyl ester were obtained.
Example 5:
Bentyl 2-14,6-diethyl[1,3,5]triazin-Z-yloxy)-3-(4-methoxy-bentoyla~no)-3,3-diphenylpropionate Poeassi~un carbonate (80 mq; 0.58 mmol) and 2-chloro-4,6-diethyl-[1,3.5]t=iazine (74 mg; 0_43 Col) were successively added to a solution of. beezyl . . . . .~ , : t 2-hydroxy-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate (139 to sng, 0 .29 nmol ) in dimethylformatni.de ( 15 ml ) . The mixture vas heated to 6D°C and stirred at this temperature for .4 hours. The reaction Haas stopped by adding 5% strength citric acid (10 ml).
Dilution with water Nas followed by extraction With ether, and the combined organic phases ~~rere washed with saturated brine and dried oyez magnesium sulfate. The solvent was distilled off; the residua was purified by flash chromatograpby (eluent: ethyl acetate irr cyclohexane 30-50%). 124 mg of the target compound Were obtained with a purity of 90% (accordiaq to BYLC) (63%
. yield).
Example 6:
2-(4,6-Diethyl[1,3,5]triazin-Z-yioxy)-3-(9-metlioxybenzoylamino)-3,3-diphenylpropionic acid (I-4) A 10% palladium/carbon hydrogenation catalyst (spatula tip) was added to a solution of benzyl 2-(4.6-diethyl-(1,3,5]triazin-2-yloxy)-3-(4-methoxybenzoylamino)-3,3-diphenylpropionate 1124 mg, 0.18 a~ol with a purity of 90%) in ethyl acetate (15 ml) and stirred under a hydrogen atu~osphere at room temperature for 3 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue was crystallized from dichloromethane/ether/n-hexane, resulting in 99 mg (73% yield) of the pure carboxylic acid.
1H_~1(yg (200 l~iflz): 7.8 (m. 3 H1: 7.6 ldd. 2 H): 7.1-7_4 (m, 8 R); 6_9 (d, Z H); 6.fi (s, 1 8); 3.B (s. 3 H); 2.7 (q, 4 H); 1.2 it, 6 H).
ESI-MS : h' - 526 .
The folloaring were synthesized analogously:
2-(4,6-Diethyl[1,3,5]triazin-2-yloxy)-3-(3,5-dimethoxybenzoyl-amino)-3,3-diphenylpropivnic acid (I-327) 1H-NMR (200 l~lliz): 7.9 (s.l e); 7.6 (m. 2 H), 7.2-7,5 (m. B H): 6.9 (d, z H); 6.7 (s. 1 H). 6.6 (t. 1 H1: 3.B (s, 6 B): 2.7 (q. 4 8) 1.2 (t. 6 H)-. 24 ESI-MS: M~ = 556.
3-(3,5-Dimethoxybenzoylamino)-Z-(4,6-dimethyl-Z-pyrimidinyloxy)-3,3-diphenylpropionie acid (I-248) 1H-NMR (Zo0 t~iz): A.l (s Dr. 1 N): 7.7 (m, 2 H); 7_Z-7.5 (sn. 8 H):
7.0 (d, 2 H); 6.70 (s, 1 a); 6.65 (s, 1 a): 6.60 (t, 1 g); 3.8 (s, 6 p); .2.3 (s, 6~ R) .
EST-MS: M' = 5Z7.
3-8enzoylatnino-2-(4,6-dimethyl-2-pyrimidinyloxy)-3,3-diphenyl-p=opionie acid (I-66) 1g-gMg ( Z 0 0 I~JAz ) : 8 . Z ( s br, 1 H ) : 7 . 8 ( ai, 2 8 ) : 7 . 6 (:n.
Z 8 ) t 7.1-7.5 (gin. 11 H); 6.70 (s, 1 H): 6.6S (s. 1 8): ~2~3 (s, 6 R).
ESI-h5: M- ~ 467.
z-( 4, 6-Dimethyl-2-pY=i~dioyloxy)-3-( 4-mec,hylbenzoyla~nino)-3.3-diphenylpropionic acid (I-199) Zo (Z00 ~z): e.o (s br. 1 H): 7.7 (d, Z S); 7.6 (m. Z M):
7.1-7.5 (m. l0 S); 6.7 ~s, 2 H)s 2,4 (s, 3 H): Z~3 (s~ 6 ESI-M5 : !t' - 4 B 1.
Example 7_ Henayl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-ca=boxylate Boron trifluoride etherate (8.04 g; 56.7 mmvll vas cautiously added to a solution of beezyl 3,3-diphenyloxirane-Z-carboxylate (10.D g; 28.3 rnmol) in acetonitrile (10D ml). The cttixture vas ' stirred at room temperature for an hour and then concentrated in a rotary evaporator. The residue eras taken up in water, saturated with sodium chloride aad extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and the solvent ~sas removed in vacuo; the residue (13.5 g) vas employed further Without purificasion-Example e:
Benzyl 3-amino-2-hydroXy-3,3-diphenylpropionate Benzyl 2-methyl-4.4-Biphenyl-4,5-dihydrooxazole-5-carboacylate (13.5 g; crude) was stirred in a miacture of methanol (25 ml), Water (50 ml) and concentrated hydzochlorie acid (50 ml) at t'oom teznpesature for 60 hours. The solution vas then decanted off the undissolved t~taterial: the residue Was stirred in the 2'S
abovementioned mixture again fot three hours. Recantation gas repeated; the remaining residue was discarded. The two liquid phasres weze eomb~ined and adjusted to pB e-9 with sodium hydroxide solution, whereupon crystallization started. The crystals were washed with ether and filtered aff with suction; 4.65 g of the required amino alcohol were obtained in 97$ purity_ lE~-NMR (Z00 MHz)s T.4 (m, Z 8); 7_1-7.3 (a~, 11 H); 7.0 (m, 2 H); 5.0 (s, 1 9); 4.9 (d, 1 )i); 4.7 (d, 1 EI): 1.9-Z.5 (s br, Z ~1).
Example 9:
Benzyl 2-hydzoxy-3,3-diphenyl-3-(4-trifluvromethylbenzoylamino)-propionate pyridine ( 99 mg; 1. 00 aunol ) . a spatula tip of ditnethylauiino-pyridiae, and pare-trifluoromethylbenzoyl chloride (215 mg, 1.00 miool) were successively added to a solution of benzyl 3-amino-2-hyd=oxy-3,3-diphenylpropionate (365 mg: 1.00 mmol) in ZO dichloromethane (50 ml). The mixture vas sti=zed at room temperature for 60 hours sad then Worked up by extracting with dilute citric acid. The organic phase was dried over magnesium Sulfate, and the solvent Was removed in vacuo..The residue (540 mg) Haas taken up in chlorofarm (50 m1) ard. after additiae of pyridine ( 36 mg, 0 . 45 tnn~ol ) and a few crystals of dimethylarninopyridine, refluxed for 4 hours. After cooling, working up was carried out by extraction with dilute citric acid_ zhe organic phase gas dried over magnesium sulfate, and the solvent eras removed in vacuo_ The residue ~,ras crystallized from ethe=/n-hexane; 235 mg (45s yield) of the pure product were obtained.
1H-NMR (200 Mgz): 7.7 (d. ~ H): 7.5 (d, Z H); 7.2-7.4 (m, 13 A); 7,1 (d, z H~; 5.5 (d b=, 1 e); s.o (on. 2 H): 4.6-4.6 (s br, 1 H)_ Example 10:
Benzyl 2-(4,6-dimethyl-2-pysimidinyloxy)-3,3-Biphenyl-3-(4-tri~luoromethylbenzoylamino)propionate Potassium carbonate (100 mg; o.7Z mu~ol) and 2-methylsulfonyl-4,6-dia~ethylpyrimidine (96 mg; 0.51 mmol) were successively added to a solution of benzyl 2-Qydroxy-3,3-Biphenyl-3-(4-trifluoro-methylbenzoylamino)propionate (ZZO mg, 0.42 mmol) it dimethylformamide (15 ml)_ The enixtuze was heated to 80°c and stirred at this temperature for one hour. The reaction was stopped by adding dilute citric acid acrd Water (200 ml)_ After ' 26 extraction with ether, the organic phase vas dried over magnesium sulfate and concentrated in vaeuo. The residue vas crystalli2ed from ether/n-hexane; 158 mg (60$) of the pure title compound were obtained.
Example 11:
1~
2-(4,6-Dirnethyl-2-pyrimidinYloxyl-3,3-diphenyl-3-(4-trifluoro-methylbenzoylamino)propionic acid (I-ZO1) A 10% palladiurn/carbon hydrogenation catalyst (spatula tip) vas added to a solution of benzrl 2-(9,6-dimethyl-2-pyzimidinyloxy)-3,3lBiphenyl-3-(9-trifluoromettrylbenzoylamino)propionate (150 mg, 0.24 am,ol) in ethyl acetate (50 nl), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was then filtered off and the solvent was distilled off in vacuo. The residue vas crystallized from etbe=/n-hexane, resulting in 100 mq (78%) of the pure carboxylic acid.
lH-PMR (200 MHx)a 8.3 (s br, 1 A); 7.9 ( d, 2 H); 7.7 gym, 4 H);
_ 7,1-7.4 (m. 8 a): 6.7 (s, 1 Hi; 6.6 (s, 1 g); 2.3 (s, 6 8).
ESI-rlS: !!~ = 535, The follotaing were prepared analogously;
3-(3,4-Dimethoxybenzoylamino)-2-(4,6-dimethyl-2-pyrimidinyloxy)-3.3-diphenylpropionic acid (I-48) 1H-pMit (200 LiHz): 8.Z (s br, 1 H); 7.? (m. 2 8); 7.1-7.5 (m, l0 R);
6.8 (d, 1 e): 6.7 (s, i g); 6.6 ~s, 1 E1); 3.9 (s, 3 B); 3.8 (s, 3 R1: 'Z.3 (s, 6 S).
ES.I-MS: H' ~ 527, 3-(3,4-Difluorobenzoylaruino)-2-(4,6-dimethyl-2~py=imidinyloxy)-3,3-diphenylpropionic acid (I-340) 1H-NMR (200 l~z): B.Z~Is Dr. 1 8): 7.5-?.8 (m. 5 H): 7.1-7.4 (m, 88); 6.7 (s, 1 H): 6.6 (s. 1 H); 2.3 (s, 6 R).
ESI-MS: M' = 503.
2-(9,6-Dimethyl-2-pyriatidinyloxy)-3-(4-fluorobenzoylamino)-3,3-diphenylpropionic acid (I-170) 1H-NriR (200 M8z): B.2 (s br, 1 H): 7.8 (dd, Z H): 7.6 (m, Z H);
ES.I-MS: H' ~ 527, 3-(3,4-Difluorobenzoylaruino)-2-(4,6-dimethyl-2~py=imidinyloxy)-3,3-diphenylpropionic acid (I-340) 1H-NMR (200 l~z): B.Z~Is Dr. 1 8): 7.5-?.8 (m. 5 H): 7.1-7.4 (m, 88); 6.7 (s, 1 H): 6.6 (s. 1 H); 2.3 (s, 6 R).
ESI-MS: M' = 503.
2-(9,6-Dimethyl-2-pyriatidinyloxy)-3-(4-fluorobenzoylamino)-3,3-diphenylpropionic acid (I-170) 1H-NriR (200 M8z): B.2 (s br, 1 H): 7.8 (dd, Z H): 7.6 (m, Z H);
7.0-7.5 (m, 10 H); 6.7 (s, 1 B); 6.6 (s, 1 H): 2.3 (s, 6 H).
ESI-MS: M' = 985.
Example 12:
Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methanesulfonyl-ami.no-3,3-diphenylp=opionate Methanesulfonyl chloride (53 mg. 0.73 mmol). pyridine (82 mg;
1.04.aanol) and dimethylaminopyridine (spatula tip) were added to a solution of methyl 3-amino-2-(4,6-dirnethoxy-Z-pyrimidinyl-oxy)-3,3-diphenylpropionate (213 mg: 0.52 mcrol) in dichloromethane (15 ml). The mixture was stirzed at room temperature for one Week. Because conversion was incomplete, a further 0.20 mole equivalent of methanesulfonyl ehlozide was , added, and stinting w86 again carried out at room temperature for three days. For ~oorkup. the mixture a~as diluted dith ether and washed successively pith dilute citric acid, $odiutn bicarbonate solution and saturated brine. The organic phase was dried over magnesium sulfate, and the solvent was removed in vacuo. The citric acid extract was neutralized and extracted with ether; the organic phases obtained therefrom were dried and evaporated as described above. The residue (206 mg) was employed further wsthoat further workup.
Example 13:
Z5 2-1A.6-Dimethoxy-Z-pytimidiayloxy)-3-methanesulfonylamino-3,3-di-phenylpropionic acid (I-156) 0.5o ml of a 1 molar sodium hydroxide solution gas added to a solution of methyl 2-(4.6-dimethoxy-2-pyrimidinyloxy)-3-methane-3o sulfonylamiao-3,3-diphehylpropionate (1B1 mg, crude) in 1:Z
wate=/tetrahydrofuzan (30 rnl), and the mixture Was stixred at room temperature'for 5 days. =o complete the reaction, a further 0.5 wale equivalent of 1 mole= sodium hydroxide solution was added, and the mixture was again stirred for 29 hours. After the 35 dilution with eater and extraction with ether the aqueous phase was acidified with citric acrd and again extracted with ether.
The extracts obtained from the acidic phase were dried over magnesium sulfate, and the solvent Was removed in vacuo.
Crystallization of the residue from dichlozomethane/n-hexane 40 afforded the pure target compound (71 mg: 33% yield owe= two stages).
lg-pMg (200 MRz): 7.6-7.7 (m. Z H); 7_3-7.S (m. B H), 6_S (s, 1 B)7 6.3 (s br, 1 H). 5.8 (s, 1 H): 3.9 (s, 6 H). 2.Z (s, 3 8).
45 E5=-HS: M' - 973.
The coc~pounds Listed in Table 1 can be prepared analogously or as desc=ibed in the qerreral part.
l0 ~ ' N
Z Z.'..Z Z Z vT.Z ZZ Z Z Z Z Z w . ~ . J - a ' a a ?1 .~
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y y y ~
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t U Ua a G U aa a aa a V a V a a =a z x N
U V
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C ~1?.C G C CW.C ?~?vC G C G.G.C
V 4r101W Q1I1 V rl~1LIN 411 1 11 s ~,o .e.er ~.~..s oo s r s w w P.G.N GL04GII1 ~ NN i1G 0.1 1 Or 1 iId1 1 1 '~1~iI 10Ip1 1 1 -./ I
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al CI0141 O:r1.1n ~ ..~.-I~n G rl.-/G L .C.-1..1 r1t~1~ ? w'~~r~~ Glr?W1a O~W ~.?~'~1 G CC C C C CC 1 GC I t I C C G
aldm alv al11m w mal~.w w m m al r ,c~ .cr r .~r 1 tG 1 1 I s s t p.WW CLG C~W0.a~ iL0.a v~v 0.i>.G.
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Example 14:
Receptor bindir~g data were measured for the compounds listed S below using the binding assay described aboQe.
Tt~e results are shown in Table 2.
Table 2 Receptor binding data (R; values) ~o~mpound ETp [ nM ] ETB [ n!s ]
' I-C 74 2100 I-66 63 >3000 I-156 337 >10000 -Z0 I-ZOl 84 500 =-Z48 18 930
ESI-MS: M' = 985.
Example 12:
Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methanesulfonyl-ami.no-3,3-diphenylp=opionate Methanesulfonyl chloride (53 mg. 0.73 mmol). pyridine (82 mg;
1.04.aanol) and dimethylaminopyridine (spatula tip) were added to a solution of methyl 3-amino-2-(4,6-dirnethoxy-Z-pyrimidinyl-oxy)-3,3-diphenylpropionate (213 mg: 0.52 mcrol) in dichloromethane (15 ml). The mixture was stirzed at room temperature for one Week. Because conversion was incomplete, a further 0.20 mole equivalent of methanesulfonyl ehlozide was , added, and stinting w86 again carried out at room temperature for three days. For ~oorkup. the mixture a~as diluted dith ether and washed successively pith dilute citric acid, $odiutn bicarbonate solution and saturated brine. The organic phase was dried over magnesium sulfate, and the solvent was removed in vacuo. The citric acid extract was neutralized and extracted with ether; the organic phases obtained therefrom were dried and evaporated as described above. The residue (206 mg) was employed further wsthoat further workup.
Example 13:
Z5 2-1A.6-Dimethoxy-Z-pytimidiayloxy)-3-methanesulfonylamino-3,3-di-phenylpropionic acid (I-156) 0.5o ml of a 1 molar sodium hydroxide solution gas added to a solution of methyl 2-(4.6-dimethoxy-2-pyrimidinyloxy)-3-methane-3o sulfonylamiao-3,3-diphehylpropionate (1B1 mg, crude) in 1:Z
wate=/tetrahydrofuzan (30 rnl), and the mixture Was stixred at room temperature'for 5 days. =o complete the reaction, a further 0.5 wale equivalent of 1 mole= sodium hydroxide solution was added, and the mixture was again stirred for 29 hours. After the 35 dilution with eater and extraction with ether the aqueous phase was acidified with citric acrd and again extracted with ether.
The extracts obtained from the acidic phase were dried over magnesium sulfate, and the solvent Was removed in vacuo.
Crystallization of the residue from dichlozomethane/n-hexane 40 afforded the pure target compound (71 mg: 33% yield owe= two stages).
lg-pMg (200 MRz): 7.6-7.7 (m. Z H); 7_3-7.S (m. B H), 6_S (s, 1 B)7 6.3 (s br, 1 H). 5.8 (s, 1 H): 3.9 (s, 6 H). 2.Z (s, 3 8).
45 E5=-HS: M' - 973.
The coc~pounds Listed in Table 1 can be prepared analogously or as desc=ibed in the qerreral part.
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Example 14:
Receptor bindir~g data were measured for the compounds listed S below using the binding assay described aboQe.
Tt~e results are shown in Table 2.
Table 2 Receptor binding data (R; values) ~o~mpound ETp [ nM ] ETB [ n!s ]
' I-C 74 2100 I-66 63 >3000 I-156 337 >10000 -Z0 I-ZOl 84 500 =-Z48 18 930
Claims (10)
1. A .beta.-amido or .beta.-sulfonamido carboxylic acid derivative of the formula I
where the substituents have the following meanings:
R1 tetrazolyl or a group R:
a) a radical OR6, in which R6 is:
hydrogen, C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl,it being possible for said radicals optionally to be substituted, C3-C8-alkenyl or a C3-C8-alkynyl group optionally substituted or phenyl optionally substituted, b) a 5-membered heteroaromatic system linked via a nitrogen atom, e) a group in which k may assume the values 0, 1 and 2, p may assume the values 1, 2, 3 and 4, and R7 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or optionally substituted phenyl.
d) a radical in which R8 is:
C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical, C1-C4-haloalkyl or phenyl, optionally substituted.
W and Z, which may be identical or different:
nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;
X, nitrogen or CR9:
Y nitrogen or CR10;
Q nitrogen or CR11; with the proviso that X = CR9 and Y =
CR10 if Q = nitrogen;
R2 and R3, which may be identical or different:
phenyl or naphthyl, optionally substituted, or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, as oxygen or sulfur atom or an SO2, NE
or N-alkyl group, C5-C6-cycloalkyl, optionally substituted;
R4 a) a radical with R12 phenyl, naphthyl or a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for said radicals optionally to be substituted;
b) a radical with R13 C1-C4-alkyl, C1-C4-haloalkyl, C1-4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl or phenoxy, it being possible for the phenyl radicals optinally to be substituted;
R5 hydrogen, C1-C4-alkyl;
R9 and R10(which may be identical or different):
hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals optionally to be substituted, or CR9 or CR10 is linked to CR11 as indicated below to give a 5- or 6-membered ring;
R11 hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, hydroxyl, carboxyl, cyano, amino, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals optionally to be substituted;
or CR11 forms together with CR9 or CR10 a 5-or 6-membered alkylene or alkenylene ring which may optionally be substituted, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(C1-C4-alkyl), and the physiologically tolerated salts, and the possible enantiomerically pure and diastereomerically pure forms, excepting the following compounds:
2-(6-Ethyl-2 methyl-4-pyrimidinyloxy)-3-(4-methoxybenz-oylamino)-3,3-diphenylpropionic acid 2-(2,6-Dimethyl-4-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(6-methoxy-2-methyl-4-pyr-imidinyloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(6-methoxy-5-methyl-2-pyr-azinyloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-Z-(5-methoxy-6-methyl[1,2,4]-triazin-3-yloxy)-3,3-diphenylpropionic acid 2-(4-Ethyl-6-methyl[1,3,5]triazin-2-yloxy)-3-(4-methoxy benzoylamino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(5-methoxy-6-methyl-3-pyr-idazinyloxy)-3.3-diphenylpropionic acid 2-(4,6-Dimethyl[1,3,5]triazin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6-methyl[1,3,5]-triazin-2-ylozy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-5,6-dihydrofuro-[2.3-d)pyrimidin-2-yloxy)-3,3-diphenylpropionic acid 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 2-(4-Ethyl-6-methyl-2-pyrimidinyloxy)-3-(4-methoxybenz-oylamino)-3,3-diphenylpropionic acid 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6-methyl-2-pyr-imidinyloxy)-3,3-diphenylpropionic acid 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-hydroxybenzoyl-amino)-3,3-diphenylpropionic acid 2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(4-methylsulf-anylbenzoylamino)-3,3-diphenylpropionic acid 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(4-nitrobenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Chlorobenzoylamino)-2-(4-ethyl-6-methyl-2-pyr-imidinyloxy)-3,3-diphenylpropionic acid 3-(4-Ethylbenzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionic acid 3,3-Bis-(4-fluorophenyl)-3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-dihydrofuro[2,3-d]pprimidin-2-yloxy)-propionic acid 3-(4-Chlorobenzoylamino)-2-(4,6-dimethyl[1,3,5)tri-azin-2-yloxy)-3,3-diphenylpropionic acid 3-(3,4-Dimethoxybenzoylamino)-2-(4-methoxy-6-methyl-[1,3,5]triazin-2-yloxy)-3,3-diphenylpropionic acid 3-(3,4-Dimethoxybenzoylamino)-2-(4-ethyl-6-methyl-[1,3,5)triazin-2-yloxy)-3,3-diphenylpropionic acid 3-(4-Chlorobenzoylamino)-2-(5-methozy-6-methyl-3-pyri-dazinyloxy)-3,3-diphenylpropionic acid 3-(3,4-Dichlorobenzoylamino)-2-(6-methoxy-5-methyl-2-pyrazinyloxy)-3,3-diphenylpropionic acid 3-(9-Hydroxy-3-methoxybenzoylamino)-2-(5-methoxy-6-methyl(1,2,4]triazin-3-yloxy)-3,3-diphenylpropionic acid 3-(3-Chlorobenzoylamino)-2-(2,6-dimethyl-4-pyrimidinyl-oxy)-3,3-diphenylpropionic acid 3-(2-Chlorobenzoylamino)-2-(6-methoxy-2-methyl-4-pyr-imidinyloxy)-3,3-diphenylpropionic acid 2-(6-Ethyl-2-methyl-4-pyrimidinyloxy)-3-(9-nitrobenz-oylamino)-3,3-diphenylpropionic acid.
where the substituents have the following meanings:
R1 tetrazolyl or a group R:
a) a radical OR6, in which R6 is:
hydrogen, C3-C8-cycloalkyl, C1-C8-alkyl, CH2-phenyl,it being possible for said radicals optionally to be substituted, C3-C8-alkenyl or a C3-C8-alkynyl group optionally substituted or phenyl optionally substituted, b) a 5-membered heteroaromatic system linked via a nitrogen atom, e) a group in which k may assume the values 0, 1 and 2, p may assume the values 1, 2, 3 and 4, and R7 is C1-C4-alkyl, C3-C8-cycloalkyl, C3-C8-alkenyl, C3-C8-alkynyl or optionally substituted phenyl.
d) a radical in which R8 is:
C1-C4-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or a phenyl radical, C1-C4-haloalkyl or phenyl, optionally substituted.
W and Z, which may be identical or different:
nitrogen or methine; with the proviso that Q = nitrogen if W and Z = methine;
X, nitrogen or CR9:
Y nitrogen or CR10;
Q nitrogen or CR11; with the proviso that X = CR9 and Y =
CR10 if Q = nitrogen;
R2 and R3, which may be identical or different:
phenyl or naphthyl, optionally substituted, or phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, as oxygen or sulfur atom or an SO2, NE
or N-alkyl group, C5-C6-cycloalkyl, optionally substituted;
R4 a) a radical with R12 phenyl, naphthyl or a five- or six-membered heteroaromatic system comprising one to three nitrogen atoms and/or one sulfur or oxygen atom, it being possible for said radicals optionally to be substituted;
b) a radical with R13 C1-C4-alkyl, C1-C4-haloalkyl, C1-4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, phenyl or phenoxy, it being possible for the phenyl radicals optinally to be substituted;
R5 hydrogen, C1-C4-alkyl;
R9 and R10(which may be identical or different):
hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, hydroxyl, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals optionally to be substituted, or CR9 or CR10 is linked to CR11 as indicated below to give a 5- or 6-membered ring;
R11 hydrogen, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, C3-C6-alkenyloxy, C3-C6-alkynyloxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl, NH(C1-C4-alkyl), N(C1-C4-alkyl)2, hydroxyl, carboxyl, cyano, amino, mercapto, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, it being possible for these radicals optionally to be substituted;
or CR11 forms together with CR9 or CR10 a 5-or 6-membered alkylene or alkenylene ring which may optionally be substituted, and in which in each case one or more methylene groups can be replaced by oxygen, sulfur, -NH or -N(C1-C4-alkyl), and the physiologically tolerated salts, and the possible enantiomerically pure and diastereomerically pure forms, excepting the following compounds:
2-(6-Ethyl-2 methyl-4-pyrimidinyloxy)-3-(4-methoxybenz-oylamino)-3,3-diphenylpropionic acid 2-(2,6-Dimethyl-4-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(6-methoxy-2-methyl-4-pyr-imidinyloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(6-methoxy-5-methyl-2-pyr-azinyloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-Z-(5-methoxy-6-methyl[1,2,4]-triazin-3-yloxy)-3,3-diphenylpropionic acid 2-(4-Ethyl-6-methyl[1,3,5]triazin-2-yloxy)-3-(4-methoxy benzoylamino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(5-methoxy-6-methyl-3-pyr-idazinyloxy)-3.3-diphenylpropionic acid 2-(4,6-Dimethyl[1,3,5]triazin-2-yloxy)-3-(4-methoxy-benzoylamino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6-methyl[1,3,5]-triazin-2-ylozy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-5,6-dihydrofuro-[2.3-d)pyrimidin-2-yloxy)-3,3-diphenylpropionic acid 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 2-(4-Ethyl-6-methyl-2-pyrimidinyloxy)-3-(4-methoxybenz-oylamino)-3,3-diphenylpropionic acid 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-methoxybenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Methoxybenzoylamino)-2-(4-methoxy-6-methyl-2-pyr-imidinyloxy)-3,3-diphenylpropionic acid 2-(4,6-Dimethyl-2-pyrimidinyloxy)-3-(4-hydroxybenzoyl-amino)-3,3-diphenylpropionic acid 2-(4-Methoxy-6-methyl-2-pyrimidinyloxy)-3-(4-methylsulf-anylbenzoylamino)-3,3-diphenylpropionic acid 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-(4-nitrobenzoyl-amino)-3,3-diphenylpropionic acid 3-(4-Chlorobenzoylamino)-2-(4-ethyl-6-methyl-2-pyr-imidinyloxy)-3,3-diphenylpropionic acid 3-(4-Ethylbenzoylamino)-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionic acid 3,3-Bis-(4-fluorophenyl)-3-(4-methoxy-benzoylamino)-2-(4-methoxy-5,6-dihydrofuro[2,3-d]pprimidin-2-yloxy)-propionic acid 3-(4-Chlorobenzoylamino)-2-(4,6-dimethyl[1,3,5)tri-azin-2-yloxy)-3,3-diphenylpropionic acid 3-(3,4-Dimethoxybenzoylamino)-2-(4-methoxy-6-methyl-[1,3,5]triazin-2-yloxy)-3,3-diphenylpropionic acid 3-(3,4-Dimethoxybenzoylamino)-2-(4-ethyl-6-methyl-[1,3,5)triazin-2-yloxy)-3,3-diphenylpropionic acid 3-(4-Chlorobenzoylamino)-2-(5-methozy-6-methyl-3-pyri-dazinyloxy)-3,3-diphenylpropionic acid 3-(3,4-Dichlorobenzoylamino)-2-(6-methoxy-5-methyl-2-pyrazinyloxy)-3,3-diphenylpropionic acid 3-(9-Hydroxy-3-methoxybenzoylamino)-2-(5-methoxy-6-methyl(1,2,4]triazin-3-yloxy)-3,3-diphenylpropionic acid 3-(3-Chlorobenzoylamino)-2-(2,6-dimethyl-4-pyrimidinyl-oxy)-3,3-diphenylpropionic acid 3-(2-Chlorobenzoylamino)-2-(6-methoxy-2-methyl-4-pyr-imidinyloxy)-3,3-diphenylpropionic acid 2-(6-Ethyl-2-methyl-4-pyrimidinyloxy)-3-(9-nitrobenz-oylamino)-3,3-diphenylpropionic acid.
2. The use of the .beta.-amido and .beta.-sulfonamido carboxylic acid derivatives as claimed in claim 1 for treating diseases.
3. The use of the compounds I as claimed in claim 2 as endothelin receptor antagonists.
4. The use of the .beta.-amido and .beta.-sulfonamide carboxylic acid derivatives I as claimed in claim 1 for producing drugs for treating diseases in which elevated endothelin levels occur.
5. The use of the .beta.-amido and .beta.-sulfonamido carboxylic acid derivatives I as claimed in claim 1 for treating chronic heart failure, restenosis, high blood pressure, pulmonary hypertension, acute/chronic kidney failure, erectile dysfunction, cerebral ischemia, benign prostate hyperplasia and prostate cancer.
6. The use of the .beta.-amido and .beta.-sulfonamido carboxylic acid derivatives I as claimed in claim 1 is combination with:
inhibitors of the resin-angiotensin system such as resin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors; mixed ACE/neutral endopeptidase (NEP) inhibitors; .beta. blockers.
inhibitors of the resin-angiotensin system such as resin inhibitors, angiotensin II antagonists and, in particular, angiotensin converting enzyme (ACE) inhibitors; mixed ACE/neutral endopeptidase (NEP) inhibitors; .beta. blockers.
7, A pharmaceutical preparation for oral, parenteral and intraperitoneal administration containing at least one carboxylic acid derivative I as claimed in claim 1 with a single dose, besides conventional pharmaceutical ancillary substances.
8. A compound of the formula II
in which the radicals R1, R2, R3, R4 and R5 have the meanings stated in claim 1.
in which the radicals R1, R2, R3, R4 and R5 have the meanings stated in claim 1.
9. The use of compounds of the formula II, in which the radicals R1, R2, R3, R4 and R5 have the meanings stated in claim 1, as starting material for synthesizing endothelin receptor antagonists.
10. A structural fragment of the formula in which the radicals R1, R2, R3, R4 and R5 have the meanings stated in claim 1, as structural element in an endothelin receptor antagonist.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19858779A DE19858779A1 (en) | 1998-12-18 | 1998-12-18 | New 3-acylamino-propionic acid and 3-sulfonylamino-propionic acid derivatives useful as endothelin receptor antagonists in treatment of e.g. cardiovascular and renal disorders, migraine and cancer |
| DE19858779.1 | 1998-12-18 | ||
| PCT/EP1999/009679 WO2000037450A1 (en) | 1998-12-18 | 1999-12-09 | NEW β-AMIDE AND β-SULFONAMIDE CARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE AS ENDOTHELIN RECEPTOR ANTAGONISTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2355251A1 true CA2355251A1 (en) | 2000-06-29 |
Family
ID=7891778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002355251A Abandoned CA2355251A1 (en) | 1998-12-18 | 1999-12-09 | New .beta.-amide and .beta.-sulfonamide carboxylic acid derivatives, their preparation and their use as endothelin receptor antagonists |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1140867A1 (en) |
| JP (1) | JP2002533330A (en) |
| KR (1) | KR20010101279A (en) |
| CN (1) | CN1334806A (en) |
| AR (1) | AR023353A1 (en) |
| AU (1) | AU3036400A (en) |
| BG (1) | BG105618A (en) |
| BR (1) | BR9916331A (en) |
| CA (1) | CA2355251A1 (en) |
| CZ (1) | CZ20012186A3 (en) |
| DE (1) | DE19858779A1 (en) |
| HK (1) | HK1042095A1 (en) |
| HU (1) | HUP0201321A3 (en) |
| IL (1) | IL143451A0 (en) |
| NO (1) | NO20013000L (en) |
| SK (1) | SK8682001A3 (en) |
| TR (1) | TR200101780T2 (en) |
| WO (1) | WO2000037450A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8304403B2 (en) | 2005-11-23 | 2012-11-06 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0301892A3 (en) * | 2000-11-17 | 2005-06-28 | Warner Lambert Company Llc Mor | Pharmaceutical compositions for treatment of sexual dysfunction and their preparation |
| EP2712865B1 (en) * | 2009-07-10 | 2016-03-16 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8912700D0 (en) * | 1989-06-02 | 1989-07-19 | Shell Int Research | Herbicidal compounds |
| DE4329911A1 (en) * | 1993-09-04 | 1995-03-09 | Basf Ag | Substituted lactic acid derivatives with an N-organic radical in the beta position |
| TR199901416T2 (en) * | 1996-12-18 | 1999-08-23 | Basf Aktiengesellschaft | Heterocyclic carbonicacyte térevleri. |
| DE19726146A1 (en) * | 1997-06-19 | 1998-12-24 | Basf Ag | New ß-amino and ß-azidopcarboxylic acid derivatives, their preparation and use as endothelin receptor antagonists |
-
1998
- 1998-12-18 DE DE19858779A patent/DE19858779A1/en not_active Withdrawn
-
1999
- 1999-12-09 CA CA002355251A patent/CA2355251A1/en not_active Abandoned
- 1999-12-09 BR BR9916331-4A patent/BR9916331A/en not_active Application Discontinuation
- 1999-12-09 KR KR1020017007615A patent/KR20010101279A/en not_active Application Discontinuation
- 1999-12-09 TR TR2001/01780T patent/TR200101780T2/en unknown
- 1999-12-09 CN CN99814580A patent/CN1334806A/en active Pending
- 1999-12-09 JP JP2000589522A patent/JP2002533330A/en active Pending
- 1999-12-09 EP EP99964533A patent/EP1140867A1/en not_active Withdrawn
- 1999-12-09 AU AU30364/00A patent/AU3036400A/en not_active Abandoned
- 1999-12-09 IL IL14345199A patent/IL143451A0/en unknown
- 1999-12-09 WO PCT/EP1999/009679 patent/WO2000037450A1/en not_active Application Discontinuation
- 1999-12-09 SK SK868-2001A patent/SK8682001A3/en unknown
- 1999-12-09 HU HU0201321A patent/HUP0201321A3/en unknown
- 1999-12-09 CZ CZ20012186A patent/CZ20012186A3/en unknown
- 1999-12-17 AR ARP990106523A patent/AR023353A1/en unknown
-
2001
- 2001-06-15 NO NO20013000A patent/NO20013000L/en not_active Application Discontinuation
- 2001-06-18 BG BG105618A patent/BG105618A/en unknown
-
2002
- 2002-05-31 HK HK02104116.9A patent/HK1042095A1/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8304403B2 (en) | 2005-11-23 | 2012-11-06 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
| US8642576B2 (en) | 2005-11-23 | 2014-02-04 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| DE19858779A1 (en) | 2000-06-21 |
| HUP0201321A3 (en) | 2003-02-28 |
| IL143451A0 (en) | 2002-04-21 |
| JP2002533330A (en) | 2002-10-08 |
| BG105618A (en) | 2002-01-31 |
| NO20013000L (en) | 2001-08-15 |
| WO2000037450A1 (en) | 2000-06-29 |
| HUP0201321A2 (en) | 2002-12-28 |
| AU3036400A (en) | 2000-07-12 |
| EP1140867A1 (en) | 2001-10-10 |
| SK8682001A3 (en) | 2002-08-06 |
| TR200101780T2 (en) | 2001-11-21 |
| CZ20012186A3 (en) | 2002-07-17 |
| BR9916331A (en) | 2001-09-11 |
| HK1042095A1 (en) | 2002-08-02 |
| AR023353A1 (en) | 2002-09-04 |
| CN1334806A (en) | 2002-02-06 |
| NO20013000D0 (en) | 2001-06-15 |
| KR20010101279A (en) | 2001-11-14 |
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