MXPA01001246A - New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists - Google Patents

Abstract

The invention relates to new carboxylic acid derivatives of the formula (I), where the substituents have the meaning given in the description, their production and their use as endothelin-receptor antagonists.

Description

SECONDARY CHAINS CETO, AND ITS PREPARATION AND USE AS ANTAGONISTS OF THE ENDOTHELINE RECEPTOR The present invention relates to novel carboxylic acid derivatives, their preparation and use. Endothelin is a peptide constructed of 21 amino acids, which is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following, "endotelma" or "ET" designates one or all endothelin isoforms. Endothelin is a potent vasoconstrictor and has a strong effect on vascular tone. It is known that this vasoconstriction is caused by the binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys., Res. Commun., 154, 868. -875, 1988). The increased or abnormal release of endothelin causes a lasting vascular contraction in the peripheral blood vessels, kidney and brain, which can lead to diseases. As reported in the literature, endothelin is involved in a number of conditions. These include: hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's syndrome, cerebral vasospasm, seizure, benign prostate hypertrophy, arteriosclerosis and asthma (J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 114 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med. 3 ^ 28, 1732 (1993), Nephron 66, 373 (1994), Stroke 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell, Cardiol.27, A234 (1995), Cancer Research 56, 663 (1996)). At least two endothelin receptor subtypes, the ETA and ETB receptors, have been described in the literature at present (Nature 348, 730 (1990), Nature 348, 732 (1990)). Consequently, substances that inhibit the binding of endothelin to both receptors must antagonize endothelin physiological effects and thus be valuable pharmaceuticals. Mixed endothelin receptor antagonists are those compounds which bind to the ETA and ETB receptors with approximately equal affinity. Approximately there is an equal affinity to the receptors when the quotient of the affinities is greater than 0.05 (preferably 0.1) and smaller than 20 (preferably 10). Patent application DE 19636046.3 describes antagonists of mixed ETA / ETB receptors. The spacer Q (see formula XX) which corresponds in length to an alkyl chain of C2-C4, is important for these compounds.

Antagonists of the mixed receptors are also obtained with the spacer Q = COCR7R8 (see formula I) - The object of the invention is to identify compounds that bind with approximately equal affinity to ET receptors? and ETB and have more advantageous properties compared to the known endothelin receptor antagonists already known. The invention relates to acid derivatives carboxylic acids of the formula I. wherein the substituents have the following meanings: R1 is tetrazole [sic] or a group OR II C-R R is an OR radical, in which R is hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal, a physiologically tolerable organic ammonium ion such as C 1 -C 4 tertiary alkylammonium or the ammonium ion; C3-Ca cycloalkyl, Ci-Cs alkyl, CH2 phenyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, C? -C4 alkyl, C1-C4 haloalkyl, hydroxyl , C1-C4 alkoxy, mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; a C3-C6 alkenyl group or a C3-C6 alkynyl, wherein these groups on the other hand can carry from one to five halogen atoms; A phenyl radical which can carry from one to five halogen atoms and / or one to three of the following radicals: nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, C alkoxy; -C, mercapto, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2; B) a 5-membered heteroaromatic which is linked by means of a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, and which may carry one or two halogen atoms, or one or two C1-alkyl C4, [lacuna] or one or two C1-C4 alkoxy groups, c) a group rt¡áb *? UMU * ^, j ~ 4tol *? »* tÍMt? > k »^^^^^^ in which k [lacuna] assumes the values of 0, 1 and [sic] 2, p [lacuna] assumes the values of 1, 2, 3 and [sic] 4 and R10 is C1-C4 alkyl, C3 cycloalkyl -C8, C3-C6 alkenyl, C3-C6 alkynyl or phenyl, which can be substituted by one or more, for example one to three, of the following radicals: halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, C1-C4 alkoxy, C1-C4 alkylthio, mercapto, amino, NH (C1-C4 alkyl), N (alkyl of d) a radical wherein R 11 is: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, wherein these radicals can carry a C 1 -C 4 alkoxy, C1-C4 alkylthio and / or a phenyl radical as mentioned under c); phenyl which can be substituted by one to three of the following radicals: halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, hydroxyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mercapto, amino, NH (C 1 -C 4 alkyl), N (C? -C4 alkyl) 2; R 2 is hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4) alkyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, hydroxyalkyl of C? ~ C4, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy or C1-C4 alkylthio, or CR2 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring; X is nitrogen or methine; And it's nitrogen or methine; Z is nitrogen or CR 12 in which R 12 is hydrogen, halogen, C 1 -C 4 haloalkyl or C 1 -C 4 alkyl or CR12, together with CR2 or CR3, forms a 5 or 6 membered alkylene or alkenylene ring, which can be substituted by one or two C1-C4 alkyl groups, and in which one or more methylene groups can be replaced in each case by oxygen, sulfur, -NH or N (C 1 -C 4 alkyl), wherein at least one of the X, Y or Z members in the ring is nitrogen; R 3 is hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4) alkyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, haloalkyl of C 1 -C 4, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkylthio, or CR 3 is linked to CR 12 as indicated under Z to give a 5- or 6-membered ring; R 4 and R 5 (which may be identical or different) are: phenyl or naphthyl, each of which may be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, C 1 -C 4 alkyl , C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, phenoxy, carboxyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, amino, NH (C 1 -C 4 alkyl) -C 4), N (C 1 -C 4) alkyl or phenyl which can be mono- or polysubstituted, for example mono- to trisubstituted, by halogen, nitro, cyano, C 1 -C 4 alkyl, haloalkyl of C3- 0 C4, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio; phenyl or naphthyl, which are connected to each other in the ortho position by means of a direct bond, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or a S02, NH or N-alkyl group; C3-Ce cycloalkyl; R6 is C3-C8 cycloalkyl, wherein these radicals in each case can be mono- or polysubstituted by: halogen, hydroxyl, mercapto, carboxyl, nitro, cyano, C? -C4 alkoxy, C? -C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C4 alkylthio, C1-C4 haloalkoxy, C-C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, alkylcarbonylalkyl of C3-Ce, carboxamide, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2, or phenyl which may be mono- or polysubstituted, for example 5 mono to trisubstituted, by halogen, nitro, cyano, alkyl art jys ^^ C1-C4, haloalkyl of C1-C4, alkoxy of C1-C4, haloalkoxy of Ci-C4 or alkylthio of C1-C4; phenyl or naphthyl each of which can be substituted by one or more of the following radicals: halogen, R15, nitro, mercapto, carboxyl, cyano, hydroxyl, amino, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 alkenyloxy, C 1 -C 4 haloalkyl, C 3 -C 6 alkynyloxy, C 1 -C 4 alkylcarbanyl, C 1 -C 4 alkoxycarbonyl , carboxamide, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 1 -C 4) alkyl, dioxomethylene, dioxoethylene or phenyl, they can be mono- or polysubstituted, for example mono to trisubstituted, by halogen, nitro, cyano, C 1 -C 4 alkyl, Ci-C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio; a five or six member heteroaromatic, comprising one to three nitrogen atoms and / or a sulfur or oxygen atom, which may carry from one to four halogen atoms and / or one or two of the following radicals: alkyl of C1-C4, C2-C alkenyl, C1-C4 haloalkyl, C? -C alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, phenyl or phenoxy, wherein the phenyl radicals in turn can carry from one to five halogen atoms and / or one to three of the following radicals: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy and / or C 1 alkylthio C4; ^ ¡^ HH R7 and R8 (which may be identical or different) are: hydrogen, C1-C4 alkyl; R15 is C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkoxy, each of which bears one of the following radicals: hydroxyl, carboxyl, amino, NH (C1-C4 alkyl), N (alkyl) of C? -C4) 2, carboxamide or CON (C 1 -C 4 alkyl) is sulfur or oxygen The following definitions apply here and in the following text: An alkali metal is, for example, lithium, sodium or potassium; alkaline earth metal is, for example, calcium, magnesium or barium, C3-C8 cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, haloalkyl of C1-C4, can be linear or branched, such as, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2, 2 Dichloro-2-fluoroethyl, 2, 2, 2-trichloroethyl or pentafluoroethyl; haloalkoxy of C 1 -C 4 can be linear or branched, such as, for example, difluoromethoxy, triftitomethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,2, trifluoroethoxy , 2-fluoroethoxy or pentafluoroethoxy; C 1 -C 4 alkyl can be linear or branched, such as, for example, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl or 2-butyl; C2-C4 alkenyl may be linear or branched, such as, for example, ethenyl, l-propen-3-yl, l-propen-2-10 yl, 1-propenyl-yl, 2-methyl-l- propenyl, 1-butenyl or 2-butenyl; C2-C4 alkynyl may be linear or branched, such as, for example, ethynyl, 1-propyn-1-yl, l-propyn-3-l, l-butin-4-yl or 2-butin-4-yl; C 1 -C 4 alkoxy can be linear or branched, such as, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy; C3-C6 alkenyloxy may be linear or branched, such as, for example, allyloxy, 2-buten-1-yloxy or 3-buten-2-yloxy; C3-C6 alkynyloxy may be linear or branched, such as, for example, 2-propynyl-yloxy, 2-butynyl-yloxy or 3-butynyl-2-yloxy; C 1 -C 4 alkylthio may be linear or branched, such as, for example, methylthio, ethylthio, propylthio, 1- Methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio or 1,1-dimethylolithio; C 1 -C 4 alkylcarbonyl can be linear or branched, such as, for example, acetyl, ethylcarbonyl or 2-propylcarbonyl; C 1 -C 4 alkoxycarbonyl can be linear or branched, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl or n-butoxycarbanyl; C -C8 alkylcarbonylalkyl can be linear or branched, such as, for example, 2-oxoprop-1-yl, 3-oxobut-1-yl or 3-oxobut-2-yl; Ci-Cs alkyl can be linear or branched, such as, for example, C 1 -C 4 alkyl, pentyl, hexyl, heptyl or octyl; halogen is, for example, fluorine, chlorine, bromine or iodine. The invention further relates to those compounds of which the compounds of the formula I can be released (so called prodrugs). Preferred prodrugs are those in which release takes place under those conditions prevailing in certain body compartments, for example, in the stomach, intestine, blood circulation or liver. The compounds I and also the intermediates for their preparation, such as, for example, II, III, IV, V and VI, may have one or more asymmetrically substituted carbon atoms. Such compounds may be present as pure enantiomers or pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as an active compound is preferred. The invention further relates to the use of the aforementioned carboxylic acid derivatives for the production of drugs, in particular for the production of inhibitors for the ETA and ETB receptors. The compounds according to the invention are suitable as mixed antagonists, as defined in the beginning. The preparation of the compounds having the general formula IV in which is sulfur or oxygen can be carried out as described in WO 96/11914. In this reaction, the last keto group is protected as a cyclic acetal; however, other protecting groups are also conceivable, such as, for example, dimethylacetal.

II III IV The compounds of the formula IV can be taken in enantiomerically pure form starting from enantiomerically pure compounds of the formula II and reacting them with compounds of the formula III as described in WO 96/11914. In addition, the enantiomeric compounds of formula IV can be obtained by carrying out a classical resolution with suitable enantiomerically pure bases using racemic compounds or d astereomepcos of formula IV. The suitable bases of this type are, for example, 4-chlorofemletilamine and bases such as those mentioned in WO 96/11914. The preparation of compounds of the general formula II is described in WO 96/11914, while compounds of the General formula III are either known or can be synthesized by generally known methods, such as, for example: S N 2.) Deprotection R "3.) Acetalization III The carboxylic acid derivatives of the general formula IV can then be reacted with compounds of the general formula V, substances of the type VI are obtained.

In the formula V, Rld e s halogen or R17-S02-, where R, 17 can be C? -C alkyl, C1-C4 haloalkyl or phenyl. In addition, at least one of the X or Y or Z members in the ring is nitrogen. The reaction preferably takes place in an inert solvent or diluent with addition of a suitable base, i.e. of a base which produces a deprotonation of intermediate IV, in a temperature range from room temperature to the boiling point of the solvent. Compounds of the type VI with R1 = COOH can be obtained directly in this form if the intermediate IV, in which R1 is COOH, is deprotonated using two equivalents of a suitable base and reacting it with compounds of the general formula V. Here also , the reaction takes place in an inert solvent and in a temperature range from room temperature to the boiling point of the solvent. Examples of such solvents or diluents are aliphatic, alicyclic and aromatic hydrocarbons, each of which may optionally be chlorinated, such as, for example, hexane, cyclohexane, petroleum ether, naphtha, lt1f? iift ^ rr.iftiti-tfí ^ -ir iiti «ít ^ ittr r x > ^ "^^^ || X Benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichlorethylene, ethers, such as, for example, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, propylene oxide , dioxane 5 and tetrahydrofuran, nitriles such as, for example, acetonitrile and propionitrile, acidic amides, such as, for example, dimethylformamide, dimethylacetamide and N-methylpyrrolidone, and sulfoxides and sulfones, such as, for example, dimethyl sulfoxide and sulfolane. The compounds of the formula V are known, in some cases commercially available or can be prepared in a generally known manner. The base used may be an alkali metal or alkaline earth metal hydride, such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, for example sodium or potassium carbonate, an alkali metal hydroxide or alkaline earth metal such as sodium or potassium hydroxide, an organometallic compound such as butyl- lithium or an amide alkali metal such as lithium diisopropylamide or lithium amide. The compounds according to the invention, in which the substituents have the meanings indicated under the general formula I, can be finally prepared eliminating the keto protecting group in the compounds of the Formula VI In the case of ethylene glycol acetal, *** this can be carried out by acid hydrolysis.

VI R-C -C-W- -Hc-o- (7 -íz The compounds of type I can be further synthesized by means of compounds having the formula VII The compounds having the general formula VII can then be reacted with Gpgnard reagents to give the compounds of the formula I The compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie compounds of the formula I in which R1 is COOH, and first converting these in the customary manner into an activated form such as an acid halide, an anhydride or imidazole and then reacting this with an appropriate hydroxyl compound HOR9. This reaction can be carried out in the usual solvents and frequently requires the addition of a base, those previously mentioned being suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide. In addition, the compounds of the formula I can also be prepared by starting from the salts of the corresponding carboxylic acids, ie of compounds of the formula I in which R 1 is a COOM group, wherein M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R9-A, where A is a customary nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl optionally substituted by halogen, alkyl or haloalkyl, such as, for example, toluenesulfonyl and methylsulfonyl or other equivalent leaving group. Compounds of the formula R9-A having a reactive substituent A are known or easy to obtain using general expert knowledge. This reaction can be carried out in the customary solvents and is advantageously carried out with the addition of a base, suitable those mentioned above. In some cases, the use of generally known protective group techniques are necessary for the preparation of the compounds I according to the invention. If, for example, R6 is 4-hydroxyphenyl, the hydroxyl group can be protected first as a benzyl ether, which is then split at an appropriate stage in the reaction sequence. The compounds of the formula I in which R1 is tetrazole [sic] can be prepared as described in WO 96/11914. With respect to the biological action, the carboxylic acid derivatives of the general formula I both as pure enantiomers or pure diastereomers or as a mixture thereof are preferred in which the substituents have the following meanings: R 2 is hydrogen, N (C 1 -C 4 alkyl) 2, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio , C1-C4 haloalkyl, X-C4 haloalkoxy, hydroxymethyl or CR2 is linked to CR12 as indicated under Z to give a 5- or 6-membered ring; X is nitrogen or methine; And it is nitrogen or metma; Z is nitrogen or CR12, in which R12 is hydrogen, fluorine, trifluoromethyl or methyl or CR12, together with CR2 or CR3, forms a 5- or 6-membered alkylene or ring MI ^^^^ MBMMjaiiÉ ^ alkenylene which can be replaced by one or two methyl groups, and in which a methylene group in each case can be replaced by oxygen or sulfur, such as -CH2-CH2-0-, -CH2 -CH2-CH2-0-, -CH = CH-0-, -CH = CH-CH20-, -CH (CH3) -CH (CH3) -0-, -CH = C (CH3) -0-, - C (CH3) = C (CH3) -0- or -C (CH3) = C (CH3) -S; at least one of the members X, Y or Z in the ring is nitrogen; R 3 is hydrogen, N (C 1 -C 4 alkyl), C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, hydroxymethyl or CR3 binds to linked CR as indicated under Z to give a ring of 5 or 6 members; R4 and R5 (which may be identical or different) are: phenyl or naphthyl, each of which may be mono- to trisubstituted by halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-6 alkoxy C 4, phenoxy, C 1 -C alkylthio, NH (C 1 -C 4 alkyl) or N (C 1 -C 2) alkyl or phenyl, which may be mono- to trisubstituted, by halogen, cyano, C 1 -C 6 alkyl, C4, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio; or phenyl or naphthyl, each of which can be attached to each other in the ortho position by means of a direct bond, a methylene group, ethylene, ethenylene, an oxygen or sulfur atom or a group S02-, NH-, or N-alkyl, C5-C15 cycloalkyl; R6 is C3-C8 cycloalkyl, wherein these radicals [sic] in each case can be mono- to trisubstituted by: halogen, C1-C4 alkoxy, C? -C4 alkyl, C1-C4 alkylthio, haloalkoxy C1 -C 4, C 1 -C 4 alkoxycarbonyl, or phenyl which may be mono- to trisubstituted, by halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or alkylthio C3.-C4; phenyl or naphthyl, each of which may be mono- to trisubstituted by halogen, R15, cyano, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C? -C4 alkylcarbonyl, C1-C4 alkoxycarbonyl, alkoxy of C 1 -C 4, C 1 -C 4 haloalkoxy, phenoxy, C 1 -C 4 alkylthio, NH (C 1 -C 4 alkyl), N (C 2 -C 4 alkyl) 2, dioxomethylene, dioxoethylene or phenyl which may be mono- to trisubstituted by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio; a heteroaromatic of five or six members, comprising one to three nitrogen atoms and / or a sulfur or oxygen atom, which may carry one or two halogen atoms and / or one or two of the following radicals: C1-C4, C 1 -C 4 alkoxy, trifluoromethoxy, C 1 -C 4 alkylthio, phenyl or phenoxy, wherein the phenyl radicals themselves can carry from one to five halogen atoms and / or from one to three of the following radicals : C1-C4 alkyl, haloalkoxy i¿SiiB¿.XX. ' of C1-C4 and / or C1-C4 alkylthio; R7 and R8 (which may be identical or different) are: hydrogen, C1-C4 alkyl; R15 is methyl, ethyl, methoxy or ethoxy, each of which carries one of the following radicals: hydroxyl, carboxyl, arrimo, NH (C1-C4 alkyl), N (C1-C4 alkyl) 2, carboxamide or CON (C? -C) alkyl 2; W is sulfur or oxygen. Particularly preferred compounds of the formula I - both as pure enantiomers or pure diastereomers or as a mixture thereof - are those in which the substituents have the following meanings: R 2 is trifluoromethyl, C 1 -C 4 alkyl, C 1 - alkoxy C4, C1-C4 alkylthio, or CR2 is linked to CR12 as indicated by ba or Z to give a 5- or 6-membered ring; X is nitrogen or methine; And it's nitrogen or methine; Z is nitrogen or CR12, in which R12 is hydrogen, fluorine, or methyl or CR12, together with CR2 or CR3, forms a 5 or 6 membered alkylene or alkenylene ring, in which a methylene group in each case can be replaced by oxygen or sulfur, such as -CH2-CH2-S-, -CH = CH-0-, -CH2-CH2-S- [sic]; at least one of the members X, Y or Z in the ring is nitrogen; R3 is trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio or CR3 is linked to CR12 as indicated by ba or Z to give a 5- or 6-membered ring; R 4 and R 5 (which may be identical or different) are: phenyl or naphthyl, each of which may be mono- to trisubstituted, by halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenoxy or phenyl , which may be mono-a trisubstituted by halogen, C? -C4 alkyl or Ci-C4 alkoxy; or phenyl or naphthyl, which can be attached to each other in the ortho position by a direct bond, a methylene, ethylene or ethenylene group or a S02 group; cyclohexyl; R6 is cyclohexyl which may be mono- to trisubstituted by C1-C4 alkoxy, C1-C4 alkyl, halogen or phenyl, which may be mono- to trisubstituted by halogen, C1-C4 alkyl, C- alkoxy C4; phenyl or naphthyl, which in each case may be mono to trisubstituted by halogen, R15, C1-C4 alkyl, C1-C4 haloalkyl, acetyl, C1-C4 alkoxycarbonyl, C1-C4 alkoxy, phenoxy, C1 alkylthio -C 4, dioxomethylene, dioxoethylene or phenyl, which can be mono- to trisubstituted by halogen, C 1 -C 4 alkyl, C 1 alkoxy S α JA ^ t ** C4, or C 1 -C 4 alkylthio; R7 and R8 (which may be identical or different) are: hydrogen, C1-C4 alkyl; R15 is methoxy or ethoxy, each of which bears one of the following radicals: hydroxyl, carboxyl, carboxamide or CON (C? -C4 alkyl) 2; W is sulfur or oxygen. The compounds of the present invention offer a novel therapeutic potential for the treatment of hypertension, high pulmonary blood pressure, myocardial infarction, angina pectoris, arrhythmia, acute / chronic renal failure, chronic heart failure, renal insufficiency, cerebral vasospasm, cerebral ischemia. , subarachnoid hemorrhages, migraine, asthma, arteriosclerosis, endotoxic attack, organ failure induced by endotoxin, intravascular coagulation, restenosis after angioplasty and bypass operations, benign prostate hyperplasia, ischemic renal failure or hypertension and renal insufficiency or hypertension caused by intoxication , metastasis and growth of mesenchymal tumors, renal failure induced by contrast agent, pancreatitis and gastrointestinal ulcers. The invention further relates to combinations of endothelin receptor antagonists of the Formula I and inhibitors of the renin-angiotensin system. The inhibitors of the renin-angiotensin system are renin inhibitors, angiotensin II antagonists and inhibitors of the enzyme that converts angiotensin (ACE). Combinations of endothelin receptor antagonists of the formula I and ACE inhibitors are preferred. The invention further relates to combinations of endothelin receptor antagonists of the formula I and beta-blockers. The invention further relates to combinations of endothelin receptor antagonists of the formula I and diuretics. The invention further relates to combinations of endothelin receptor antagonists of the formula I and substances which block the action of VEGF (vascular endothelial growth factor). Such substances are, for example, antibodies directed against VEGF or specific binding proteins or alternatively low molecular weight substances which can specifically inhibit the release of VEGF or receptor binding. The combinations mentioned above can be administered simultaneously or sequentially. Both can be used in a single pharmaceutical formulation or alternatively in separate formulations. The form of administration can also be different, for example endothelin receptor antagonists can be administered orally and VEGF inhibitors can be administered parenterally. These combinations of preparations are especially suitable for the treatment and prevention of hypertension and its sequelae, and for the treatment of heart failure. The invention further relates to a structural fragment of the formula in which the radicals R1, R4, R5, R5, R7, R8 and W have the above-mentioned meaning. Such structural fragments are suitable as structural constituents of endothelin receptor antagonists, in particular receptor antagonists of endothelin mixed. The invention further relates to endothelin receptor antagonists consisting of a structural fragment of the formula twenty wherein the radicals R1, R2, R3, R4, R5, R7, R8, W, X, Y and Z have the meanings mentioned above, covalently linked to a group which has a molecular weight of at least 40, preferably at least 77. The good action of the compounds can be shown in the following experiments: Receptor binding studies CHO cells expressing human cloned ETTA or ETB receptors were used for binding studies.

Membrane preparation CHO cells expressing ETA or ETB receptors were proliferated in DMEM NUT MIX F? 2 medium (Gibco, No. 21331-020) with 10% fetal calf serum (PPA Laboratories GmbH, Linz, No. A15-022), 1 mM glutamine (Gibco No. 25030-024), 100 U / ml penicillin and 100 μg / ml streptomycin (Gibco, Sigma No. P-0781). After 48 hours, the cells were washed with PBS and incubated at 37 ° C t ^? i? ^^ t ^ iM ?? t to ^ i ^ for 5 minutes with PBS containing 0.05% trepsin. The mixture was then neutralized in medium and the cells were harvested by centrifugation at 300 x g. For the membrane preparation, the cells were adjusted to a concentration of 10 8 cells / ml regulator (50 mM regulator tris HCL [sic], pH 7.4) and then disintegrated by means of ultrasound (Branson Sonifier 250, 40-70 seconds / constant output 20).

Linkage tests For binding tests of ETA and ETB receptors, the membranes were suspended in incubation buffer (50 mM tris HCl, pH 7.4 with 5 mM MnCl2, 40 μg / ml bacitracin and 0.2% BSA) a concentration of 50 μg of protein per test batch and incubated at 25 ° C with 25 pM of [1251] -ET! (ETA receptor test) or 25 pM [1251] -ET3 (ETB receptor test) in the presence and absence of the test substance. The non-specific link was determined with 10"M ETi, after 30 minutes, the free radioligand and the linked [sic] separated by filtration through glass fiber filters GF / B (Whatman, England) on a Skatron cell sampler (Skatron, Lier, Norway) and the filters were washed with regulator ice-cold tris, pH 7.4 containing 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter. Test of the ET antagonists in vivo: SD male rats weighing 250-300 g were anesthetized with amobarbital, artificially breathed, vagotomized and outlandish. The carotid artery and the jugular vein were catheterized. In control animals, intravenous administration of 1 μg / kg of ET1 leads to an increase in the distinctive blood pressure, which lasts for a relatively long period. The test compounds were injected i.v. (1 mg / kg) within the animals tested 30 minutes before administration of ETl. For the determination of the antagonistic properties of ET, the changes in blood pressure in the test animals were compared with those of the control animals. p.o. test of the mixed ETA and ETB antagonists: Male normotonic rats weighing 250-350 g (Sprague Dawley, Janvier) are pretreated orally with the test substances. 80 minutes later, the animals are anesthetized with urethane and the carotid artery is catheterized (for measurement of blood pressure) as well as the jugular vein (administration of large endothelin / endothelin 1). After a stabilization phase, large endothelin (20 μg / kg, admin volume 0.5 ml / kg) or ET1 (0.3 μg / kg, admin volume 0.5 ml / kg) is administered intravenously. Blood pressure and heart rate are recorded continuously for 30 minutes. Clear and long-term blood pressure changes are calculated as the area under the curve (AUC). For the determination of the antagonistic action of the test substances, the AUC of the animals treated with substances is compared with the AUC of the control animals. The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a customary manner. Administration can also be carried out through the nasopharynx using vapors or sprinklers. The dose depends on the age, condition and weight of the patient and the type of administration. As a rule, the daily dose of active compound is between about 0.5 and 50 mg / kg of body weight in the case of oral administration and between about 0.1 and 10 mg / kg of body weight in the case of parenteral administration. The novel compounds can be used as solids or liquids in customary pharmaceutical administration forms, for example, as tablets, film-coated tablets, capsules, powders, sugar-coated tablet granules, suppositories, solutions, Xnguentos, creams or sprinklers. These are prepared in a customary way. In this case, the active compounds can be processed using customary pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, delayed release agents, antioxidants. and / or propellants (see H. Sucker et al .: Pharmazeutische Technologie [Pharmaceutical Technology], Thieme-Verlag, Stuttgart, 1991). The manner of administration thus obtained normally contains the active compound in an amount of 0.1 to 90% by weight.

Synthesis Examples Example 1 Methyl 2-hydroxy-3, 3-diphenyl-3- (2-phenyl- [1,3] -dioxolan-2-yl-methoxy) propionate. P-Toluenesulfonic acid (0.50 g, 0.27 rrrmoles) was added with cooling to ice to a solution of 2-phenyl- [1, 3] -dioxolan-2-ylmethanol (1.98 g, 11.0 mmol) and 3, 3-diphenyl methyl -2, 3-epoxypropionate (4.71 g, 13.2 mmol, purity according to HPLC: 71%) in anhydrous dichloromethane (100 ml) and the mixture was stirred at 0 ° C for 15 minutes. The resulting solution was washed with sodium hydrogen carbonate solution, and the organic phase was separated and dried over magnesium sulfate. After filtering the drying agent, the solvent was removed by distillation; the crude unrefined oily (4.70 g) was reacted traditionally without purification additional.

Use 2 Acid 2-hydroxy-3,3-diphenyl-3- (2-phenyl- [1,3] dioxolan-2-methoxy) -propionic acid Methyl 2-hydroxy-3- ( 2-phenyl) - [1, 3] -d-oxolan-2-l-methoxy) -3,3-diphenyl propionate (4.60 g, unrefined) in dioxane / water 2: 1 (45 ml) and treated with sodium hydroxide (300 mg, 7.50 mmol). The mixture was heated to 40 ° C and stirred for one hour. To make it diluted with water (150 ml) and extracted twice with ethyl acetate. The aqueous phase was acidified with citric acid and extracted twice with ethyl acetate. The extracts obtained from the acidification were dried over magnesium sulfate and the solvent was removed by distillation. 4.00 g of an oil without Refining was obtained, which were further reacted without further purification.

EXAMPLE 3 2- (Methoxy-6-methylpyrimidn-2-yloxy) -3,3-diphenyl-3- (2-phenyl- [1,3] d-oxolan-2-ylmethoxy acid) propionic Sodium hydride at 50% strength (240 mg, 5.00 mmol) was added in 3 portions over the course of 3 minutes to a solution of 2-hydroxy-3- (2-phenyl- [1, 3] -dioxolan- 2-methoxy) -3,3-diphenylpropionic acid (1.00 g, 1.62 mmol at 68% purity according to HPLC) in anhydrous DMF (15 ml). The mixture was stirred for 5 minutes and then 2-methanesulfonyl-4,6-dimethylpyrimidine (421 mg, 2.00 mmol) was added in portions. The mixture was stirred at room temperature for 16 hours. For working up, the contents of the flask were poured over ice water. They were then acidified with citric acid and extracted twice with ether. The organic extracts were dried over magnesium sulfate and the solvent was removed by distillation. 1.75 g of an oil remained, which was further purified by flash chromatography and subsequent crystallization from ether / n-hexane. The title compound was obtained as a colorless solid (750 mg, 85% yield). X-NMR (200 MHz, CDC13): 7.5-7.7 ppm (2H, m), 7.2-7.4 (13H, m), 6.3 (1H, s), 6.2 (1H, s), 4.2-4.4 (2H, m ), 4.1 (1H, d), 3.9 (3H, s), 3.8-4.0 (2H, m), 3.6 (1H, d), 2.4 (3H, s).

Example 4 2- (4-Methoxy-6-methylpyrim-din-2-yloxy) -3- (2-oxo-2-phenylethoxy) -3,3-diphenylpropionic acid p-Toluenesulfonic acid (50 mg) was added to a Solution of 2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3- (2-phenyl- [1,3] -dioxolan-2-ylmethoxy) -3,3-diphenylpropionic acid (600 mg, 1.11 mmol) ) in dioxane / water 1: 1 (20 ml) and the resulting mixture was stirred at 80 ° C for 2 hours. After cooling, the mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulfate and the solvent was removed by distillation. The residue (550 mg) which remained, was purified by crystallization from ether / n-hexane, subsequent flash chromatography and crystallization from ether / n-hexane again. The title compound was obtained as a crystalline solid (163 mg, 30% yield). X-NMR (200 MHz, CDC13): 7.2-7.9 ppm (15H, m), 6.2 (2H, broad s), 5.1 (2H, m), 3.7 (3H, s), 2.2 (3H, s). ESI-MS: M + = 498 The following compounds were prepared analogously: Example 5 2- (4,6-Dimethylpyrimidin-2-yloxy) -3- (2-oxo-2-phenylethoxy) -3,3-diphenylpropionic acid XH- NMR (200 MHz, CDC13): 7.8 ppm (2H, d), 7.2-7.7 (13H, m), 6.7 (1H, s), 6.3 (1H, s), 5.2 (1H, d), 4.9 (1H, d), 2.3 (6H, s). ESI-MS: M + = 482 Example 6 3- [2- (4-Bromophenyl) -2-oxoethoxy] -2- (4,6-dimethylpyrimidin-2-yloxy) -3,3-diphenylpropionic acid * X- NMR (200 MHz, CDC13): 7.7 ppm (2H, d), 7.6 (2H, d), 7.2-7.5 5 (10H, m), 6.7 (1H, s), 6.2 (1H, s), 5.1 (1H , d), 4.9 (1H, d), 2.3 (6H, s). ESI-MS: M + = 560 Example 7 10 3- [2- (4-Bromophenyl) -2-oxoethoxy] -2- (4-methoxy-6-methylpyrimidin-2-ylox?) -3,3-diphenylpropionic acid X-NMR acid (200 MHz, CDC13): 7.7 ppm (2H, d), 7.6 (2H, d), 7.2-7.5 (10H, m), 6.2 (1H, s), 6.0 (1H, s), 5.2 (1H, d), 4.9 (1H, d), 3.7 (3H, s), 2.2 (3H, s). ESI-MS: M + = 576 * In the synthesis of substituted 4-bromophenyl derivatives, boron trifluoride etherate was used in place of p-toluenesulfonic acid for the cleavage of the final acetal. Example 8 Benzyl 2-hydroxy-3- [(methoxymethylcarbamoyl) met0x1] -3,3-diphenylpropionate Boron trifluoride etherate 25 (0.10 ml) was added slowly to a solution, cooled to -78 ° C, of 2-hydroxy -W- ^^^^^ gjí¡gggM ~ t ^^ itü ^^ ^ aá methoxy-? 7-met? L-acetamida (1.19 g, 10.0 mmoles) and benzyl 3,3-diphenyl-2, 3-epoxy -propionate (3.88 g, 11.0 mmol, purity according to HPLC: 94%) in anhydrous dichloromethane (100 ml). The mixture was stirred for two hours and during this time it was gradually heated to -20 ° C, and the reaction was stopped by the cautious addition of aqueous sodium hydrogencarbonate solution. The organic phase was washed with sodium hydrogencarbonate solution and dried over magnesium sulfate. After filtering the drying agent, the solvent was removed by distillation; the residual crude oil (5.50 g) was reacted further by purification.

EXAMPLE 9 Benzyl 3- [(methoxymethylcarbamoyl) methoxy] -2- (4-methoxy-6-methyl-15 pyrimidin-2-yloxy) -3,3-diphenylpropionate A solution of benzyl 2-hydroxy? -3- [(methoxymethylcarbamoyl) -methoxy] -3,3-diphenylpropionate (1.35 g, unrefined) was treated with ice-cold potassium carbonate (365 mg, 2.64 mmol) and, after 10 minutes, with 2- 20 methanesulfon? -4-methoxy-6-methyl-pipmidine (320 mg, 1.45 mmol). Subsequently, it was stirred at 0 ° C for 30 minutes and then at room temperature for 16 hours. The mixture was diluted with water, acidified with citric acid and extracted twice with ether. The combined organic phases are [sic] washed with water pushed back and dried ^ gS ^^ to ^ - ^. ^^^? ^^^^ ._ É ^^^ i ^ M ^^ on magnesium sulfate. After distilling off the solvent, a foam (1.60 g) remained, which was purified by flash chromatography and subsequent crystallization from ether / n-hexane; 650 mg of the title compound was obtained.

Example 10 Benzyl 3- [2- (3,4-dimethoxyphenyl) -2-oxoethoxy] -2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3,3-diphenylpropionate A 1-molar solution of bromide of 3,4-dimethoxyphenylmagnesium in tetrahydrofuran (0.60 ml) was added at room temperature to a solution of benzyl 3- [(methoxymethylcarbamoyl) -methoxy] -2- (4-methoxy-6-methylpyrimidin-2-yloxy) -3, 3 -diphenylpropionate (250 mg, 0.38 mmol, purity according to HPLC: 86%) in anhydrous tetrahydrofuran (25 ml). After stirring for 10 minutes, only partial conversion was observed, therefore a 1-molar solution of 3,4-dimethoxyphenylmagnesium bromide in tetrahydrofuran (0.60 ml) was added by dripping again. The mixture was stirred for an additional 10 minutes, then the solvent was evaporated. The residue was extracted into ethyl acetate / ether 1: 2. After filtering the undissolved matter, the solvent was removed by distillation, and the oily residue (400 mg) was purified by flash chromatography. The title compound was obtained as a foam (125 mg, 49% yield with 95% purity according to HPLC). X-NMR (400 MHZ, CDC13): 7.5-7.7 ppm (4H, m), 7.4 (2H, d), 7.2-7.3 (9H, m), 6.9 (2H, d), 6.8 (1H, d), 6.3 (1H, s), 6.2 (1H, s), 5.4 (1H, d), 5.0 (2H, m), 4.7 (1H, d), 3.9 (6H, s), 3.7 (3H, s), 2.3 (3H, s). The compounds in Table I can be prepared analogously or as described in the general section.

Example 11 The receptor binding data for the compounds listed below were measured as in the binding test described above. The results are shown in Table 2. 15 Table 2 Receiver link data (Ki values) OR

Claims (8)

1. A carboxylic acid derivative of the formula I where the substituents have the following 5 meanings: R1 is tetrazole [sic] or a group 0 II C -R [lacuna] a) a radical OR9, in which R9 is: hydrogen, the cation of an alkali metal, the cation of an alkaline earth metal or a physiologically tolerable organic ammonium ion; C3-C8 cycloalkyl, C? -C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, CH2 phenyl or phenyl each of which is optionally substituted; 15 b) a 5-membered heteroaromatic which is bonded by means of a nitrogen atom; c) a group in which k can assume the values 0, 1 and [sic] 2, p can assume the values 1, 2, 3 and [sic] 4 and R10 is C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 3 alkenyl -C6, C3-C6 alkynyl or optionally substituted phenyl; d) a radical wherein R 11 is: C 1 -C 4 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 8 cycloalkyl, wherein these radicals can carry a C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and / or a phenyl radical; phenyl which is optionally substituted; R 2 is hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4) alkyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy or C 1 -C 4 alkylthio, or CR 2 is linked to CR 12 as indicated above to give a 5- or 6-membered ring; X is nitrogen or methine; 20 And it's nitrogen or methine; Z is nitrogen or CR12, in which R12 is hydrogen or C1-C alkyl or CR12, together with CR2 or CR3, forms a 5 or 6 membered alkylene or alkenylene ring, which may be optionally substituted, and in which one or more methylene groups in each case can be replaced by oxygen, sulfur, -NH or -N (C1-C4 alkyl); R 3 is hydrogen, hydroxyl, NH 2, NH (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 9 haloalkyl) C4, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, or CR3 binds to CR12 as indicated above to give a 5 or 6 membered ring; R4 and R5 (which may be identical or different) are: phenyl or naphthyl, each of which is optionally substituted, phenyl or naphthyl, which are linked to each other in the ortho position by a direct bond, a methylene group, ethylene or ethylene, an atom of oxygen or sulfur or a group S02, NH or N-alkyl, C3-C8 cycloalkyl, which is optionally substituted, R6 is optionally substituted C3-C8 cycloalkyl, phenyl or naphthyl which are substituted ~ a «optionally; a heteroaromatic of five or six members, comprising one to three nitrogen atoms and / or a sulfur or oxygen atom, and which may be optionally substituted; R7 and R8 (which may be identical or different) are: Hydrogen or C? -C alkyl; W is sulfur or oxygen.

2. A pharmaceutical preparation comprising at least one carboxylic acid derivative I as claimed in claim 1.

3. The use of carboxylic acid derivatives as claimed in claim 1 for the treatment of diseases.

4. The use of the compounds I as claimed in claim 1, as endothelin receptor antagonists.

5. The use of the carboxylic acid derivatives I as claimed in claim 1, for the production of drugs for the treatment of diseases in which the elevation of endothelin levels occurs.

6. The use as claimed in claim 5, for the treatment of chronic heart failure, restenosis, high blood pressure, high pulmonary blood pressure, acute / chronic renal failure, cerebral ischemia, benign prostatic hyperplasia and prostate cancer.

7. A pharmaceutical combination preparation comprising a carboxylic acid derivative as claimed in claim 1 and an inhibitor of the renin-angiotensin system or a mixed ACE / neutral endopeptidase (NEP) inhibitor or a β-blocker.

8. The use of compounds of formula IV R * I H R-C -C-W-C C- OH IV wherein the radicals R1, R4, R5, R6, R7, R8 and W have the meanings indicated in claim 1, as intermediates [sic] for the synthesis of endothelin receptor antagonist. 9 The use of a structural fragment of the formula in which the radicals R1, R4, R5, R6, R7, R8 and W have the meanings indicated in claim 1, as a structural constituent of an endothelin receptor antagonist. jjte8M aógógicos | BJ¡ij 10 The use of a structural fragment of the formula wherein the radicals R1, R2, R3, R4, R5, R7, R8, W, X, Y and Z have the meanings indicated in claim 1, as a structural constituent in an endothelin receptor antagonist. 11. A compound of the formula Via wherein the radicals R1, R2, R3, R4, R5, R6, R7, R8, W, X, Y and Z have the meanings indicated in claim 1, and R18 and R19 have the following meanings: R18 and R19 ( which may be identical or different) are: C 1 -C 4 alkyl or R 18, together with R 19, form a bridge of ethylene or propylene which can be optionally substituted by one to four methyl groups. ^ s ^ j. ^ s ^ ¡i ^