CS347091A3 - Substituted azoles, process of their preparation and their use - Google Patents

Description

-777 JUDr. W35IO & VŠETEČKAadvokát -1

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Substituted azoles, process for their production and their use

The present invention relates to substituted azoles, to a process for their preparation and to their use.

BACKGROUND OF THE INVENTION Elid-A-324377, EP-A-253310, EP-A-28834 and EP-A-323341 disclose imidazole, pyrrole, pyrazole or triazole derivatives and their use as angiotensin-II receptor antagonists.

New azole-like compounds have now been found, surprisingly, with the highly potent antigiotensin-II receptor antagonist both in vitro and in vivo.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula I J-a-t-e

x · / v2 refers to 2. [C 3 -C 10] -alkenyl, -2- (C 3 -C 10) -alkynyl; - (C 6 -C 12) cycloalkylalkyl, (C 8 -C 12) cycloalkylalkynyl, C (C 2 -C 4) -cycloalkylalkynyl, 9 - (CE 2) mB- (CB 2) n-E 4, 10 benzyl, 11 a residue, defined as under b / 1, 2, 3,, or 9, which is monosubstituted by COgHy 12. residue defined as b / 1, 2, 3 - or 9 »k d 1 or all the H atoms are substituted with fluorine, or the 13 th residue defined under b / 10, which is substituted on the phenyl by 1 or 2 identical or different halogen, alkoxy or nitro radicals $ c / & 1. hydrogen, 2. halogen, 3. nitro, 4. θν ^ + Ι »5. SP5, 6. pentafluorophenyl, 7. cyano, 8. (C ^-C / /-alkoxy, benzyloxy, 9. phenyl,. 10. phenyl- (C1-C6) -alkyl, 11. (C1-C4) alkyl, 12. (C1-C4-alkenyl), 13. phenyl-C3-8-alkenyl, -3-14. imidazolyl- (CE 2) m, 15, 1, 2, 3-triazolyl- (CH 2) n -, 16 - tetzazolyl- (CH 2) m -, 17 - (CH 2) o-1-CHR 7 -R 5, 18. - (CH 2) o -O-CO-R 3, 19. - (CH 2) OS-R 6, 20. -S (O) - R 6, 21. -CH = CH- (CH 2) m -CHR 3 -E 6, 22 -CH 2 = CH- (CH 2) m -CO-R e, 23 -CO-R 8, 24. -CH = CH- (CE 2) m -O-CO-H 7, 25 - (CH 2) m -CH / CH3 / -C0-R8, 26. - / CH2 / o-C0-R8, 27.- / CIL / -OC-HH-R9,

d ° IIB 28. - / CH 9 / -NR 7 -C-OR 9,

* ° M

B 29. «/ H2 / 0-O7-C0-KHR9, 30. - / CH2 / 0-ra7-so2a9, 31. - / CEL / -UR7-C-R9

° NB 32. - / CH2 / nB, 33. - / CH2 / n-0-] J02, 34. -CH2-N3, 35. - / CH2 / n.IiO2, 36. -CH = N-NE5R7, 37 phthalimido- (CH 2) n -, -4-

-5-42. Phenyl-SO8-NH-HeCH-

d / E3 44. - / CH2 / n-SO2-NET-CO-NE6E9, 45. - / CH2 / o-S02E9, 46th residue defined as c / 9 · or 10th which is substituted on phenyl 1 or 2 the same or different radicals from the halogen, hydroxyl, meta, trifluoromethyl, COg, and phenylene radicals, as defined under c / 11, 12. or 20 wherein 1 or all H atoms are substituted with fluoro, or a 48 residue defined as under 15 is substituted with the same or different radicals from the methoxycarbonyl and alkyl series; 1. hydrogen, 2. (C1-C6) -alkyl, 3. (C1-C6) -cycloalkyl, (4) phenyl, (5) benzyl or (6) a residue defined under d / 2, wherein 1 to all H atoms are substituted fluorine; -6- e / 1 * hydrogen, 2. (C 1 -C 8) allyl, 3 (C 1 -C 8) -cycloalkyl, 4 "(C 8 -C 4) alkenyl or 5 (C 2 -C 4) -alkynyl) i (E5) hydrogen, (C1-C6) -alkyl, 3. (C1-C6) -cycloalkyl, (4) phenyl or (5) benzyl; (g) (1) hydrogen, (2) (C 1 -C 8) alkyl, (3) C 1 -C 6 Acycloalkyl, (4) C 8 -C 12 / -aryl, preferably phenyl, (5) benzyl, 6 (C 1 -C 8) heteroaryl which it may be partially or completely hydrogenated, preferably 2-pyrimidinyl, 7. (C 1 -C 4 -alkanoyl, 8) (C 1 -C 4) -heteroaryl-C 1 -C 6 / -alkyl, the heteroaryl moiety being - or completely hydrogenated, or 9 · residue defined as g / 4, 6. or 8, substituted by 1 or 2 identical or different radicals from the series halogen, hydroxy group, methoxy group, nitro group, cyano group, COgE4, -NE, and trifluoromethyl, h? R? 1. hydrogen, -7-2. (C1-C6) -alkyl, 3. (C1-C6) -cycloalkyl, 4. (C6-C12) -aryl- (C1-C6) -alkyl ,. preferably benzyl, 5-phenyl or 6. (C 1 -C 8) -he-bexoazyl, i / R 8 1. hydrogen, (C 2 -C 6) -alkyl, (3) C 6 -C 8 / - cycloalkyl, 4. phenyl- / CE2 / q-, 5. OH5, 6. 01¼12 or / -

7 · -HD 1 / E 9 1. (C 1 -C 6) -alkyl, 1-adamantyl, 3-1-naphthyl, 4-1-naphthylethyl, 5-phenyl- (CH 2) 4 - or 6th residue defined below j / 1 *, wherein 1 to all H atoms are substituted with fluoro; Or R and R are taken together with the N atom carrying -8- / -0 -012 k / R10 to be cyano, nitro or CO2r7; C 1 -C 6 -alkyl, 3-phenyl, 4-phenyl or 5-ethylbenzyl, m / NR 4 is O or CH 2; n / is hydrogen, (C 1 -C 6) -alkyl or phenyl; o / AO 2 - (C 8 -C 24) "polyl moiety or (i) C 1 -C 8 / -heteroaryl, which may be either aromatic, partially or fully hydrogenated, or a residue of an fused heterocycle having 8 to 10 ring atoms in which up to 9 ring atoms are C atoms, and A can be substituted with up to three identical non-boron residues from the 1 series. halogen, 2 oxo, 3 nitroso, 4 nitro, 5 cyano, 6 hydroxy, 7 / C C 1 -C 6 -alkyl, 9-C 8 -C 8 -alkanoyl, 9-O-O-alkanoyloxy, 10. C 12 -C 11, 11-methanesulfonylamino, 12-trifluoromethanesulfonylamino, 13- CO-NE-OR9, 14. -SO2-ER6R7, 15.-ch2-or7, 16. (C8-C12) -aryl, 17. (C3-C8) -cycloalkyl, 18. (G1-C5-C7). -alkyloxy group, 19. (C 1 -C 6) -heteroaxyl, 20. COgR 3, 21. HR6R7, 22nd sulfo group, 23. -SO2 R3, 24. -SO2-ER7-CO-35R6R9, 25. -NR7-CO-KR6-SO2-OH2-R5, 26. -C / CS * -O-0

27. II. Phosphonooxy, -O-P-OE, 28. 'PO2 E2, 29. -KH-P0 / OH / 2.30-S / O / R6, 31. -CO-R8 and 32. -C0-ER6R9 j -10

p / I 1. single bond 2. -C0-3 -CH2-4-O- 5. -NR21-7 -C0-KR21-8 -NR21-C0-9 -O-CH2-10. -ch2-o- 11. -s-oh2-

12. -CH2-S 13. -EH-CR20R22- 14. -1JR21-SO2- 15. so2-nr21- 16. -CR20R22-KH- 17. -CH = CH- 18. -CP = CP-, 19. -CB = CP-, 20. -CP = CH-, 21. -CH2-CH2- 22. -CP2-CP2-, 23. -CB / OR3 / -, 24. -CB / OCOR5 / - 25. - C-, II 23 26. -C- B24 / X OB2? or -11- q. / E residue 1. 0

II 27. -S -IIo

provided that if X = Y → CH does not indicate COOH E14 2.

/ CH2on -12- r / B stands for O, KB? or S is a (C 1 -C 4) -alkanediyl; t / R14 is -COgR3, -CH8COgR3, -BO3Hg, -SO4H or tetrazolyl; u / m is an integer from 0 to 5% v / n is. an integer of 1 to 5 w / o is an integer of 1 to 10; z / r is 0.1 or 2, and y / v is an integer of 1 to 6: as well as their physiologically tolerable salts.

Alkyl, alkenyl or alkynyl may be linear, unbranched, and this is similar to the radicals derived therefrom, such as alkanoyl or alkoxy.

Cycloalkyl is also understood to mean alkyl substituted rings. For example, C 6 -C 12 / -aryl is phenyl, naphthyl or biphenylyl, preferably phenyl. This applies similarly to the residues derived therefrom, such as aroyl or aralkyl.

In particular, the term "C 1 -C 4 -heteroaryl" refers to radicals which are derived from phenyl or naphthyl, in which one or more O-groups are replaced by H and / or at least two adjacent CH-groups are replaced by S, NH or O / o. creating a five-member aromatic ring. Furthermore, there may also be 1 or both atoms of the condensation site of a hicyclic radical (as in indolizinyl / atom K).

These are, for example, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalatinyl , quinoxalinyl, quinazolinyl, quinoline-13-linyl ·

By fused heterobicyclic is meant, in particular, a bicyclic ring system of 8 to 10 ring atoms, of which up to 9 ring atoms are C atoms in which the two-atom atoms are common members of both rings. One or both of these rings formally derive from benzene in which one or more CH- groups are substituted for H, O + and S + and / or wherein two adjacent CH-groups are / to form a five-membered aromatic ring / replaced with S, HH or 0 ·

These are, for example, benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnamine, benzthiazole, benzthiazole-1,1-dioxide, coumarin, chroman, benzoxazole, benzisothiazole, benzodiazine, benz-triazole, benztriazine, benzoxazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, imidazothiazole, pyrazolopyridine, thienopyridine and pyrrolo-pyrimidine. The heterobicyclic may also be partially or fully hydrogenated. Preferably, the ring remains aromatic, with benzane heterobicyclic being particularly preferred. In the case of residues containing S and / or partially saturated radicals, the bicyclic may, for example, be oxo-substituted as in the case of the benz-1,2,3-triazinone residue.

The term physiologically tolerable salts of the general formula (I) refers to both their organic and organic salts as described in Remington Pharmaceutical Sciences, 17th edition, page 1418 (1985).

Based on the physical and chemical stability and solubility of the acid groups, among others, the sodium salts, the potassium salts, the calcium salts and the ammonium salts of the probazic group are preferred, among others, salts of -14-salt, sulfuric acid, phosphoric acid, acids carboxylic acids or sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid. Preferred are compounds of formula I, kdea / Σ is R, Y is CR1 2 * and Z is CR2, β is CR2, YN and Z are CR2, c // is CR2, Y is CR2 and ZH is j or d / X.xatxxraa Y and Z is now R · Further, the compounds of formula I are preferred in each case and a (R 1) (C 3 -C 10) -alkyl, (C 2 -C 6) -alkenyl, (C 3 -C 10) -alkynyl 4. (C 1 -C 8) -cycloalkyl, (5) benzyl, (6) benzyl which is substituted as defined above or

7. - / 0B2 / BB- / C ^ / n-E4 5 6 * 8 9 S b / E2 1. hydrogen, 2 · halogen, 3 «nitro group, 4 · ° nν2ν + 1» 5. SF5 6. pentafluorophenyl C 7 -C 8 -alkoxy, benzyloxy, 9. Phenyl, 10 Phenyl- (C 1 -C 4) -alkyl, -15 11. C 1 -C 4 -Q 2 -alkecyl, 13-phenyl-C 2 -C 4 -alkenyl, 14 1-imidazolyl- (CH 2) m -, 15 1,2,3-triazoles 1- (1 H) -4- , 16. tetrazolyl- (CH 2) ff -1 - 17. - / CH 2 - 0-1 -CHR 7 -OR 5, 18. - / CH 2 / o -O-C 0 R 3, 19. -COR 8, 20. - / CH 2 / O- CO-R 6, 21. -S / O / R 6, 22. -CH = CH- (CH 2) m -CHR 3 -OR 6, -CH 2 = CH- (CH 2) m -CO-R 8; CH 2 (O-NH-CO-OR 9, 25 - (CH 2) -RH-SO 9 -R 9, 26 - (CH 2) n R 27 - / CE 2 / o-SO 3 R 9, 28 - / CH 2 / n-SO 2 - NH-CO-HR6R9 or a 29th residue, as defined under b / 9, 10, 11, 12 or 15, which is substituted with a residue as defined above under 0/46, 47. or 48} c / R 8 hydrogen, (C 1 -C 5) -alkyl, OR 5, IfiW 2 or morpholine a new group} d / T represents 1. single bond, 2. -00- 3. -COUR 21 -, 4. -CH 2 - CE2-, -16- 5. -O21-C0-, 6 · -Ο-CHg-, 7. -CH2-0-, 8. -S-CH2-, 9. -ce2-s- , 10. - nh-ch2-, 11. -ch2-nh-, 12. -CH = CE-, or 0

II 13 · -S-, 0 and other residues and variants are defined as above. and / R (C 1 -C 4) alkyl, or (C 1 -C 6) alkenyl, b / R 2 is 1. hydrogen, 2 chloro, 3 bromo, 4. 5 · pentafluorophenyl, 6 / C 1 -C 6 -alkoxy, benzyloxy -pine, 7. -S / O / rB6, 8 · SR5, 9. / ch2 / 0-1-che7-oh5, 10. / CH2 / O-0-C0-E3, 11. -C0R8, 12. - / CH2 / o.C0.R8, 13. -CH2-HH-C0-R8, -17- c / R3a / r6e / R7i / R8

gZ R9h / A 14. - / CE2 / o-NH-SO2-R9, 15. -CH = CE-CHR3-OR6, 16. tetrazolyl- (CH2) m-, 17.- / CH2 / nSO2-NH-eO -NR 6 R 9, 18. - (CH 2) o -SO 3 R 9 or 19 · optionally hydroxy substituted C 1 -C 6 -C 8 -alkyl, preferably hydroxymethyl; is hydrogen or (C1-C4-alkyl) is hydrogen, (C1-C4-alkyl), (C1-C4-alkanoyl) phenyl which may optionally be substituted by 5 or 2 identical or different radicals from the series halogen, hydroxy, methoxy, nitro, cyano, CO 3 R 3 and trifluoromethyl, or (C 1 -C 6) heteroaryl, which may be partially or fully hydrogenated, preferably 2-pyrimidyl; hydrogen, (C 1 -C 6) -alkyl, ZC 1 -C 4 -Z-heteroaryl, or (C 6 -C 12) -aryl- (C 1 -C 4 -Z-alkyl) is hydrogen, (C 1 -C 4) - alkyl, OR 3 or morpholino is CR 1, C 1 -C 6 alkyl or phenyl; is a (C1-C4) -Z2-aryl radical or Y (Z2) -Z2-Z-heteroaryl, which may be either aromatic or partially or fully hydrogenated, or [7] represents a radical of 8 to 10 atoms in the ring, of which up to 9 ring atoms are C 1, wherein A 1 can be substituted by up to 3 identical or -13- different radicals from the series halogen, nitro-6,7 na, cyano, hydroxy, -SE B1, phenyl, -S / O / rR6 and - CO 2 R 3} 1 / T represents a single bond, -O-O-, -O-RHCO-, OCH 2 - or O

II -s-

II o and other residues and variants are defined as above.

Compounds of formula (I) are preferred and are (R 1) (C 1 -C 5) -alkyl. b / R 2 is hydrogen, chloro, methoxy, -S / O / R 6 or benzyloxy, o (R 4) hydrogen or (C 1 -C 4) -alkyl, d / R 4 and R 4, which are the same or different and are hydrogen or (C 1 -C 4 -alkyl, e) R 4 is hydrogen. (C 1 -C 6) -alkyl, phenyl or 4-tolyl f / R 14 -COOH, -SO 4 H or 5-tetrazolyl g / A phenyl or the remainder of the heteroated heteroaryl with 8 to 10 ring atoms, of which up to 9 atoms, the ring is C, wherein A may be substituted with up to 2 identical or different halogen, nitro, cyano, phenyl, -S / O / XR $ and -COgR ^, h / B O, RH or S radicals, i / 1 -ch2-, j / r is 0.1 or 2, k / q is 0, -19- 1 / T is a single bond, m / m is 0,1,2 or 3 and η / n is 1 , 2 or 3 and X, Y and Z are as defined above.

The invention also relates to a process for the preparation of compounds of the formula I

1-A-I-E-

in which the compounds of general formula II

H where f 1, χ, χ and z are defined as above, alkylate with -20

The compounds of formula (III) UIATE (III), wherein I, A, T, E are defined as above and U is a volatile group, or temporarily / temporarily / introduced protecting groups, and the compounds of formula (I) obtained are optionally converted in their physio logically tolerable salts. Preferred Volatile Groups U is its nucleofugal group (s). Angew. Chem. 72 (1960) 71) as halogen, p-toluenesulfonate, mesylate or triflate.

The process for preparing the precursors of compounds of formula (II) is known, inter alia, from U.S. Pat. No. 4,355,044EB-A-324,377 and EB-A-323,841.

Other methods are described in G * I * abbe, Chem. T. Brodsky in "The Chemistry of the Azi-do Group", Viley, New York, 1971, p. 331} H. Wamhoffv · Comprehensive Heterooyclic Chemistry, S. KatrizkyEd., Bergamon Bress, New lork (1964).

The alkylation of azoles of the general formula II is, for example, the corresponding benzyl halides, benzyl tosylates, benzyl mesylates or triflates or the corresponding alkyl halides, alkyl tosylates, alkyl mesylates or alkyl triflates.

The synthesis of derivatives such as benzofurans, benzthiophenes, and indoles with a benzyl-CH 2 - group has been described, inter alia, by R.B. Dikson et al. in J.Med. Chem. 29, 1637 (1986), and ibid. 29, 1643 (1986). The production of benzimidazoles, benzothiazoles, benzodiazines, benzopyrones, benzothiazolones, benzotriazines, benzoxazines, benzoxazoles, as described in the above-mentioned " Comprehensive He-Terooyclic Chemistry ", S. Katritzky Ed., Bergamon Bress, -21-

Kew York (1984).

The alkylation is carried out analogously to the known methods.

The azole derivative of formula (II) is metallated in the presence of a base. Preferred bases are metal hydrides of formula MH such as lithium hydride, sodium hydride or potassium hydride, for example in DME or DMSO as a solvent or metal alkoxide of formula MCE, wherein E is methyl, ethyl, t-butyl and the reaction is carried out in a suitable alcohol, DME or DMSO. The azole salts formed are dissolved in an aprotic solvent such as DME or DMSO and made up with a suitable amount of alkylating agent.

An alternative possibility for deprotonation of atoll derivatives is, for example, reaction with potassium carbonate in DME or DMSO

The reaction is carried out at temperatures below the temperature to the boiling point of the reaction mixture, preferably between + 20 ° C to the boiling point of the reaction mixture for about 1-10 hours.

Synthesis of E14 fragments of Formula II

A is performed by the addition of metallized isonitriles / Angew. Chem. 86,878 (1974), 89, 351/1977 for the acid chlorides of general formula III in inert solvents at 78 ° C to -15 ° C to the boiling point of the solvent, preferably in diethyl ether or THE at -78 ° C to 0 ° c. -22-

A-I-C 0 -C 1 Synthesis of fragments of Formulas IV and V

(VI), (V), is carried out in principle by known alkylation of aryl-acetic acid derivatives or arylaetonitriles, analogously to ethers such as diethyl ether, THP or dimethoxyethane with sIDA at -78 ° C or with KOtBu at room temperature in t-butanol ·

The compounds of formula (I) according to the invention act antagonistically on angiotensin II receptors and can therefore be used for the treatment of angiotensin-dependent hypertension -II ·

Further applications include cardiac insufficiency, cardioprotection, myocardial infarction, cardiac hypertrophy, arteriosclerosis, nephropathy, renal failure as well as vascular brain diseases such as transitoric ischemic attacks and stroke.

Renin is a proteolytic enzyme from the aspartyl pro-class, which, due to various stimuli / volume depletion, nitrogen deficiency, stimulation of β-receptors, is secreted from jixtaglomerular kidney cells into the bloodstream. There, decapeptide angiotensin I is cleaved from angiotensinogen excreted by the angiotensin converting enzyme (ACE) in angiotensin II. Angiotensin II plays an important role in regulating blood pressure, increasing the blood vessel contraction by direct blood pressure. stimulates the secretion of aldosterone from the adrenal gland and increases in this way, by inhibiting the secretion of natria extracellular liquid volume, which contributes to the increase in blood pressure, and the effects of the post-receptor are, among other things, stimulation of phosphoinositol / release of Cα, activation of protein kinase C / a nacAMB-dependent hormone receptor facilitators.

The affinity of the compounds of formula (I) for the antigiotensin II receptors can be determined by measuring the suppression of the β-angiotensin β 1 -receptor or β-H-angiotensin-II in the glomerulos / adrenal membrane membranes. buffer at pH 7.4. To prevent degradation of r-dioligands during incubation, peptidase-inhibiting aprotinin is added. Approximately 14,000 cpm of tra-cerus with a specific activity of 74 TBq / mmol / A is used in Aaersham Buchler / and the amount of the 50-tracer-binding receptor protein. The reaction is started by adding 50 µl of a membrane suspension to 100 µl of buffer + aprotinin; With or without 50 µl of angiotensin II or antagonist antagonist and 5 µl of tracer · Bo incubation time of 60 minutes at 25 ° C bound and free radioligand

divides in a filtration experiment with Whatmann GBICB filters on Skatron - cell collectors ·

Nonspecific binding is prevented by treating the filter with 0.3% polyethyleneimine pH 10 / Sigma # 3143 /. The radioactivity in the gamma scintillator is determined to be a radioligand suppression rate of $ 6. receptor. The values which indicate the concentration of inhibitor required to suppress 50 µg of ligand are determined by Chem. et.al. J.Theor. Biol. £ 2. 253 (1970). These move through the compounds of Formula I in the region of 10 ”4-10” θ · ·

To determine the antagonistic effect of the general formula I, their effect can be measured by increasing the blood pressure induced by angiotensin-II in narcotized Sprague-Dawley rats. The narcotics serve Na-thiobarbital / Trapanal, Byk Gulden / in the distance of 100 mg / kg i.p.- I.v. the application is made to the jugular vein / tail vein. Blood pressure is measured in a.oarotis.First, the animals are pre-prepared with pentolinium tartrate (10 .mu.g / kg .mu.m) to achieve a higher blood pressure / ganglion block. AHG II / Hypertensin, CIBA / is administered i.v. in a volume of 0.1 ml / 100 g at 10 min intervals. The dose is 0.5 µg / kg. The compounds of the formula I are dissolved in distilled water and applied at doses of 0.1; 1; 10 and 100 mg / kg intravenously or intraduodenally.

The compounds of formula I are effective in the range of 0.1 to 100 mg / kg.

The present invention also relates to pharmaceutical compositions consisting of a compound of formula (I) and a number of active ingredients such as diuretics or non-steroidal antiinflammatory drugs. The compounds of formula (I) may also be used as diagnostics for the renin-angiotensin system.

The pharmaceutical preparations contain effective amounts of the active compound of the formula I and optionally other active ingredients together with an inorganic or organic pharmaceutical carrier. The use may be intravenous, intravenous, subcutaneous or oral. The dosage of the active ingredient depends on the type of warm-blooded, the body weight, the age and the type of application.

The pharmaceutical compositions of the present invention are made by known dissolution, mixing, granulating or draining techniques.

For oral use, the active compounds are formulated together with customary additives such as carriers, stabilizers, or inert diluents by mixing them with the usual methdases, into suitable forms for administration, such as tablets, dragees, plugs / capsules, aqueous, alcoholic, or oily suspensions or aqueous, alcoholic or oily solutions. For example, gum arabic, magnesia, magnesium carbonate, camphosphate, milk sugar, glucose, magnesium stearyl fumarate or starch, especially corn starch, can be used as inert carriers. The preparation can be carried out as a dry and wet granulate. Suitable ooolics carriers or solvents are vegetable or animal oils, such as sunflower oil and fish.

For subcutaneous or intranasal administration, the active compounds or their physiologically tolerable salts, optionally together with substances customary for them, as solubilizers, emulsifiers and other auxiliaries, adjust the forms of solutions, suspensions or emulsions. for example, ethanol, propanediol, or glycerin, sugar solutions such as glucose solutions, mannitol solutions, or a mixture of the various solvents mentioned.

List of abbreviations: DMF N, N-dimethylformamide NBS N-bromosuccinimide -26- AIBN OL, 3L-azobisobutyronitrile was electron impact DCI chemical desorptionion ET room temperature EE ethyl acetate / EtOAc / LIP diisopropyl ether THE tetrahydrofuran m.p. melting point MTB methyl 1-tert-butyl ether SdPxx boiling point at xx torres Et 3 M triethylamine MS mass spectrum PAB Past atom bombardment IDA lithium diisopropylamide The following examples illustrate the invention without limiting it. EXAMPLE 11 1- (4- (1-Carboxy-1-cyclopentyl) benzyl) -2-n-butyl-4-chloro-5-formylimidazole a / ethyl 1- (p-tolyl) cyclopentanecarboxylic acid 10 g of 1- (p-tolyl) -cyclopentanecarboxylic acid are suspended in 200 ml of ethanol, slowly added to 4.3SOClg and refluxed for 24 hours. Excess SOCl 2 is removed in vacuo, taken up in 100 ml of EE, washed twice with 50 ml of a saturated aqueous solution of HagCO 3 and dried over MgSO 4. The solvent was then removed in vacuo and 11.3 g of the title compound were obtained as pale brown crystals with m.p. : 47 ° C. b) 1- (4-Bromo-4-phenyl-cyclopentanecarboxylic acid) ethyl ester 2.5 g of 1- (p-tolyl) -cyclopentanecarboxylic acid ethyl ester ethyl ester, 1.94 g of NBS and 200 mg of benzoyl peroxide are boiled in 50 ml of chlorobenzene 3 hours at reflux ·

The solvent is then removed in vacuo, taken up in 300 ml of EE, washed once with 5 ml of an aqueous solution of Na2SO4 and twice with saturated aqueous HCO3 solution and dried over Na2SO4. The solvent is then removed in vacuo to give 3.2 g of the title compound as oil E2 / SiO2; EE / heptane 1: 4 (= 0.50 MS / DCI): 311 (M + 1) - [1- [4- (1-ethoxycarbonyl-1-cyclopentyl) -Eenzyl] -2-n-butyl-4- Chloro-5-formylimidazole 342 mg of 1- (4-bromomethyl) -phenyl-piperidineparboxylic acid ethyl ester, 187 mg of 2-n-butyl-4-chloro-5-formylimidazole and 138 mg of K2CO3 are mixed in 10 ml of BMP 22 The mixture was diluted with 100 mL of EE, washed with 1 x 50 mL of H 2 O and 5% aqueous EaCl, dried over H 2 SO 4, and the solvent removed in vacuo to give the title compound as a colorless oil (240 mg).

Hf / SiO 2: BIP / MTB 1: 1 / = 0.68 MS / DCI /: 417 / M21 / d / 1 - [4- (1-carboxy-1-cyclopentyl) benzyl-7-2-n- butyl 4-chloro-5-imidylimidazole 115 mg of 1- (4- (1-ethoxycarbonyl-1-cyclopentyl) benzyl) -2-n-butyl-4-chloro-5-formylimidazole; 28-

NaOH is heated in 8 mL of EtOH for 29 h at reflux. Ethanol was removed in vacuo, diluted with 30 mL of EgO and washed with 10 mL of DIE. Then it was adjusted to pH = 1-2 and extracted twice with 50 mL of EE. Dry over EtOAc and remove the solvent in vacuo. Chromatography on silica gel gave 68 mg of the title compound as a light brown solid.

M.p. : 134 ° C

Hf / SiO 2: MTB / = 0.30 MS / UCI / i 339 / M + 1 /

The title compounds of Examples 2 and 3 were synthesized analogously to Example 1 via the methyl ester. EXAMPLE 2 1- 1- (4- (1-Carboxy-1-cyclohexyl) -benzyl-7-n-butyl-4-chloro-5-formylimidazole. cyclohexyl 1-benzyl-N-2-n-butyl 4-methoxy-5-formylimidazole 670 mg 1- (7'4- (1-methoxycarbonyl-1-cyclohexyl) -benzyl-7-2-n-butyl The 4-chloro-5-formyl-5-imidazole is reacted as described in Example 1d). 300 mg of the title compound of Example 2 was obtained

Ef / SiO 2; MTB / DIP 1: 1 = 0.35 MS / DCI / 403 / M + 1 / M.p. 147 ° C as well as 160 mg of the title compound of Example 3

Bf / SiO 2: MTB / DIP 1: 1 / = 0.25 MS / DCI /: 399 / M + 1 /

T, 167 ° C -29- which are chromatographed on silica gel with MIB / DIP1: 1. Example 4 1- (4- (2-Chloro) oxy) -1,4-dimethyl-cyclohexyl- (7-benzyl) -2-n-butyl-4-chloro-5-formylimidazole; tolyl 4,4-dimethylcyclohexanecarbonitrile 27.6 g of potassium t-butylate are taken up in 200 ml of t-butanol and heated to reflux, a solution consisting of 32 g of 5-dihromone is added dropwise during 1 hour. -3,3-dimethylpentane and 16.3 ml of 4-tolylacetonitrile in 100 ml of butanol were refluxed for 4 hours, the solvent was removed in vacuo and the residue was taken up in 200 ml of saturated aqueous NaHCO3 solution. 200 ml of HIB, extracted twice with 200 ml of MTB each time, dried over Na2SO4 and the solvent removed in vacuo to give a colorless oil (9.7 g).

0.20 135-140 ° C MS (DCI): 228 (M + 1 / b) 1p-tolyl-4,4-dimethylcyclohexanecarboxylic acid 4.0 g of 1β-tolyl-4,4-dimethylcyclohexanecarbonitrile 3; 0 g of EOH is refluxed in 50 ml of diethylene glycol 3 hours. It is allowed to cool, poured onto 100 ml of 0.1 n NaOH and washed twice with 30 ml of LIP each time. It is then adjusted to pH = 1-2 with HCl and extracted 3 times with 100 ml of diethyl ether each time. Drying over Na2SO4 and removal of the solvent in vacuo. Drying over Na2SO4 and removal of the solvent in vacuo. 4.0 g of pale yellow crystals are obtained.

M.p. : 128 [deg.] C. MS (DCI): 241 (M +) -30-c / 1p-tolyl-4,4-dimethylcyclohexanecarboxylic acid ethyl ester 4.0 g of 1p-tolyl-4,4-dimethylcyclohexanecarboxylic acid dissolved in 50 ml of ethanol and make up with 1.5 ml of SO 2 Cl 2. It is stirred at 50 ° C for 3 hours, then at reflux for 3.5 hours. The solvent is removed in vacuo, taken up in 200 ml of EE and washed with 3 x 50 ml of saturated aqueous EagCO 3 solution. Dry over Na 2 SO 4 and the solvent is removed in vacuo to give 5.0 g of slightly soiled brown oil which is used without cleaning. MS / DCI / 275 / M + 1 / d / 1- (4-Bromomethyl) -phenyl-4,4-dimethyl-cyclohexanecarboxylic acid ethyl ester 5.0 g 1p-tolyl-4,4-dimethyl-cyclohexanecarboxylic acid ethyl ester, 2.9 NBS and 50 mg of benzoyl peroxide are refluxed in 50 ml of chlorobenzene for 1.5 h. The solvent was then removed in vacuo, taken up in 200 mL of EE, washed once with 100 mL of saturated aqueous Na 2 SO 4 solution and 1X NaCl solution. Dry over K 2 SO 4 and remove the solvent in vacuo to give 5.4 g of a brown oil.

Rf / SiOg; EE / heptane 1: 8 / - 0.39 MS / DCI /: 353 / M + 1 /

The next reaction is carried out analogously to Examples 1c and 1d to give 1- (4 -) - carboxy-1- (4,4-dimethyl) -cyclohexyl-7-benzyl) -2-n-butyl-4-chloro-5-formylimidazole. .

Rf / SiO2; DIP (= 0.16 MS / DCI): 431 (M + 1) Example 5 1- (4-Chi-5-thirazolyl) cyclohexyl-7-benzyl [-2-n-butyl-4-chloro-5-hydroxymethyliroidazole -31- and [1- (4-tolyl) -cyclohexanecarbonitrile

The compound was synthesized analogously to Example 3 and /

τ · ν · 0.3 = 95-100 ° C MS / LCI /: 200 / M + 1 / b / 1- (4-bromomethylphenyl) -cyclohexanecarbonitrile

The compound was synthesized analogously to Example 3d.

Ef / SiO 2; SE / Hep 1: 4 / = 0.46 MS / LCI / 278 / M + 1 / c / 1 - [4- (1-cyano-1-cyclohexyl) -benzyl-2-n-butyl-4- chloro-5-formylimidazole

The compound was synthesized analogously to Example 1c.

Rf (SiO2, LIP) = 0.33 MS (LCI): 384 (M + 1) (d) -1- [4- (1-cyano-1-cyclohexyl) benzyl-7-2-n-butyl-4-chloro- 5-hydroxymethylimidazole 1.0 g 1- [4- (1-cyano-1-cyclohexyl) -benzyl-pyr-2-n-butyl-4-chloro-5-formylimidazole and 400 mg of KBH3 are dissolved in 25 ml of methanol 5h NaHSO4 solution was added slowly until pH = 2, the ethanol was removed in vacuo and extracted three times with 50 ml of SE. Removes 1.0 g of a colorless oil.

Rf / SiO2; MTB = 0.54 MS / LCI: 386 (M + 1) - [1- (4- (7) -1 "(2-trimethylstanyl-5-tetrazolyl) -1-cyclohexyl-7-benzyl) -2-n -butyl-4-chloro-5-hydroxymethylimidazole 1.1 g 1- (74- (1-cyano-1-cyclohexyl) benzyl-7-n-butyl-4-chloro-5-hydroxymethylimidazole and 1.1 g trimethyltin azide is boiled in 25 ml of toluene under reflux for 48 h. The solvent is removed in vacuo and the residue is used without further purification, -32- (triphenylmethyl-5-tetrazolyl) -1-cyclohexyl-17-benzyl 2-n-butyl, 4-chloro, 5-hydroxymethylimidazole

The unpurified title compound of Example 5 (5) was dissolved in 7 mL of CH 3 Cl 2 and 1.5 mL of 0.35 mL of 10 µL was added.

NaOH and stirred for 5 minutes at room temperature, 900 mg of trityl chloride was added by Eotom and stirred for 3 days at room temperature. Dilute with 100 mL of EE, wash twice with 10 mL of 0.1 N NaOH and twice with 10 mL of saturated aqueous NaCl solution, dry over Na 2 SO 4 and remove the solvent in a vacuum, silica gel MTB / DH? 1: 1 gives 400 mg of the title compound as a white foam.

Rf (SiO2); DII / MTB 1: 1 / 0.32 MS / EAB / 677 (M + 1 / g) 1- [4- (1-tetrazolyl) -1-cyclohexyl-7-bentyl] -2-n-butyl-4 -chloro-5-hydroxymethylimazole 400 mg 1- (4-tert-1-triphenylmethyl-5-tetrazolyl) -1-cyclohexyl-7-benzyl) -2-n-butyl-4-chloro-5-hydroxymethylimidazole and 300 µl of a 4 n aqueous hydrochloric acid solution are dissolved in 4 ml of methanol and stirred at room temperature for 2 hours. The residue was diluted with 10 mL of H 2 O, the methanol was removed in vacuo and adjusted to pH 13.3 with 2 N NaOH, washed with 5 mL of toluene each time, then adjusted to pH = 4 with 10% KH 2 O 4 and extracted 3 times. always 50 mlEE. Dry over Na 2 SO 4 and remove the solvent in vacuo. Eotom is digested in an ultrasonic bath, filtered and washed twice with 2 ml of EE each time. The residue was dried in a gentle vacuum to give 170 mg of the title compound as colorless crystals. M.p. : 179 ° C / decomposition

Ef / SiO 2 EE / MeOH 10: 1 / s 0.44 -33- MS / FAB /: 429 / M + 1 / Example β 1-4- / 4-carboxy-5-oxazoyl / -b en zyl-7 " 2-n-butyl-4-chloro-5-formylimidazole and 4-bromomethylbenzoic acid methyl ester

50 g of p-tolylcarboxylic acid methyl ester, 60 g of NBS and 200 mg of benzoyl peroxide are suspended in 300 ml of chlorobenzene and heated gently under reflux. The reaction proceeds vigorously, is allowed to cool again, the chlorobenzene is removed in vacuo and the residue is distilled. 68 g of the title compound are obtained in the form of colorless crystals, [lambda] 15 ° C / SiO 2, EE / heptane 1: 4 / = 0.50MS / BCI /: 299 / M + 1 / b / 4-bromomethylbenzoic acid 5.0 g 4-bromomethyl-benzoic acid methyl ester is suspended in 15 ml of 48% aqueous HBr solution and refluxed for 30 minutes. NaHCO3 is adjusted to pH = 8 and washed twice with DIB. The aqueous phase is then adjusted to pE = 2 with NaESO4 and extracted with 3 times 150 ml of EE. Dry over Na 2 SO 4 and remove the solvent in vacuo to give 3.8 g of the title compound as colorless, hygroscopic crystals.

M.p. : 45 ° C

Bf / SiO 2; EE (= 0.43 MS / BCI): 215 / M + 1 / c / 4-bromomethylbenzoyl chloride 3.8 g of 4-bromomethylbenzoic acid was suspended in 10 ml of SOClg and refluxed for 1 h. it is dried in a fine oven and the crude is used further. d) 5- [4-Bromomethyl] -benzyl-4-methoxycarbonyloxazole

The crude product of Example 5c) was dissolved in 50 ml of anhydrous with 5 ml of Et2O. At 5 [deg.] C., 1.8 ml of methyl isocyanoate are added dropwise and the mixture is stirred at room temperature for 3 days. It is then diluted with 300 ml of EB, washed 3 times with 100 ml of 0.7 M KH2 PO4, 3 x 100 ml of saturated aqueous KaHCO3 solution and 1 x 100 ml of NaCl solution, dried over K2SO4 and the solvent is removed in vacuo. Silica gel chromatography with MIB yields 2.0 g of yellow crystals.

M.p. 79 ° C

Kf / SiO 2; MIB / * 0.36 e / l- [4- (4-methoxycarbonyl-5-oxazolyl) benzyl] -2-n-butyl-4-chloro-5-formylimidazole 296 mg 5- (4-bromomethyl) benzyl 4-methoxycarbonyloxazole, 187 mg of 2-u-butyl-4-chloro-5-formylimidazole and 139 mg of KgCO3 are mixed in 10 ml of BMP 21 h at room temperature. ml of saturated aqueous HHCO3 and 1 x 50 ml of an aqueous solution of BaCl, dried over Na2SO4 and the solvent removed in vacuo. Silica gel chromatography with MTB / DIP 1: 1 afforded 250 mg of a colorless oil.

Ef / SiO 2; MTB / DIP 1: 1 = 0.35 MS / DCI / 402 / M + 1 / [1 - [[4- (4-carboxy-5-oxazolyl) benzyl-7-2-n-butyl-4- Chloro-5-formylimidazole 240 mg 1 - (4 ') - 4-Methoxycarbonyl-5-oxazolyl-benzyl (7-2-n-butyl-4-chloro-5-formylimidazole is dissolved in 15 ml of methanol, make up 2, 5 ml of a 1N aqueous solution of BaOH and stirred at room temperature for 20 hours, then the methanol was removed in vacuo, diluted with 20 ml of HgO and washed twice with 10 ml of DEP each time. 50 ml of EI each, dried over Na2SO4 and the solvent removed in a vacuum. Chromatography on silica gel with EE / glacial acetic acid 10: 1 affords 90 mg of pale yellow foam. = 0.16MS / DCI / 388 / M + 1 /

Claims (10)

cilíiar. SSNoS VOICEWIND THE IW PRAGUE 1, ZITT £ 5 —36— P A T E K I 0 V YEARS "ll ^ d ~ λΛΉΓ20 1λΖΞΊν .AJEdI ανπη In which a / X, Y and Z are the same or different and are N or CR 2, b / R 1 is 1. (C 2 -C 10) -alkyl, 2 (C 1 -C 4 -C 6 alkenyl, 3) (C 1 -C 10) -alkynyl, 1. Compounds of formula I '16 IX L ‘' ypo 2. A compound of formula (I) according to claim 1, wherein: Χ, Ν, Y CE2 and Z CE2, b / X CE2, YH and Z CE2, c / X CE2, 2 CE2 and ZN or -48 d / XY and Z Η, as well as its physiologically tolerable salts. Or (b) R2 (R2) A compound of formula (I) according to claim 1, wherein: 1. (C1-C10) -alkyl, (2-C03-O) -alkenyl, 3. (C3-C10) -alkynyl 4. (C 3 -C 6) -cycloalkyl, (5) benzyl, (6) benzyl, which is substituted as defined in claim 1 or (7) - (O) H 2 (n-E-H 3 / n -E 4) 1 hydrogen, 2. halogen, 3rd nitro group 4 * CvP2v + 1 2. -CO- 3. -CORR21-, 3. -CH2-, 4. -0- 5. -S- 4. A compound of formula (I) according to one of claims 1 to 3, wherein a / C 1 -C 4 -Z-alkyl, ΖΟ ^ -ΟγΖ-βϋβ ^ Ι or ZC 1 -C 4 Z-alkynyl, hZ E ^ 1 hydrogen, 2. chlorine, 3. bromine, 4 · θνΙ'2ν + 1 sv β 1 · 2 or 3, 5, 5, pentafluorophenyl, 6 · Z 2 -C 2 -C 4 -alkoxy, benzyloxy, 4. -CH 2 -CH 2 -, 4. OR 3, 5. (C 1 -C 6 Acycloalkyl, 6) (C 1 -C 10) -ycloalkylalkyl, (7) C 1 -C 10 -cycloalkylalkenyl, (8) C 1 -C 4 -C 2 -cycloalkylalkynyl, 10-benzyl, 11 a residue defined as under b / 1, 2, c / R 2, 3 or which is monosubstituted with CO 2 R 2; A 12th residue, defined as under b / 1, 2, 3, or 9, wherein 1 to all H atoms are substituted with fluoro, or a 13th residue, defined under b / 10. which is substituted on phenyl by 1 or 2 identical or different halogen radicals, (C 1 -C 6) alkoxy and nitro, (1) hydrogen, (2) halogen, (3) nitro, (4) CvP 2v + 1, A compound of formula (I) according to one of claims 1 to 4, wherein: E1 / C3-C5-alkyl, pb / E is hydrogen, chloro, methoxy, benzyloxy or -S / O / rE6, c / E ^ is hydrogen or (C 1 -C 4 -alkyl, d / E 4 and E 4) are the same or different and are hydrogen, or (C 1 -C 4) -alkyl, e / E 4 is hydrogen, N - (C 1-6 alkyl) , phenyl or 4-t-allyl, f / E14 is -C00E, -E0 ^ E2, -SO4E or 5-tetrazolyl, g / A is phenyl or a fused heterocycle residue with 8 to 10 ring atoms, z wherein -53-9 ring atoms are C, wherein A may be substituted with up to 2 identical or different halogen, nitroso-pina, cyano, phenyl, -S / O / rB ^ and -CO2e3 radicals, h / B is O, NH or S, i / I is -CH 2 -, j / r is 0,1 or 2, k / q is 0, 1 / T is a single bond, m / m is 0,1,2 or 3a n / is 1,2 or 3 and Σ, Y, Z are as defined in the preceding claims, as well as its physiologically tolerable salts, 5. -RR21-C0-, 6. -0-0Η2 «, -50- 5. Si> 5 6. Pentafluorophenyl, γ. cyano, 8. (C 1 -C 6) -alkoxy, benzyloxy, 9-phenyl, 10-phenyl-O-O-C 1-6 -alkyl, 11. (C 1 -C 10) -alkyl, 12. / C 3 -C 10 n-alkenyl, 13. phenyl- (C 2 -C 8) -alkenyl, 14. 1-imidazolyl- (CH 2) m- -49-15. 1, 2,3-triazolyl- (CH 2) o - 16. Cf2 / m- 17. - / CH2 / 0-1-CHB7-OR5 18. - / CH2 / o-O-C0E3, 19. -COR8, 20. - / CH2 / o-C0-R8, 21. -S / 0 / rR6, -CH = CH- / CE 2 / m-OHR 3 -OR 6, 23. -CH2 = CH- (CH2) 2-m-CO-R8, 24. - (CE2) -RH-CO-R9, 25. - (CH2) o-NH-SO2-R9, 26. - (CH2) nE, 27. - (CH 2) o -SO 3 R 9, 28. - (CH 2) n -SO 2 -HH-CO-R 6 R 9 or the 29 th residue defined as b / 9 », 10, 11, 12. or 15, which is substituted as the residue described under (46), (47). or 48} c / R 8 represents hydrogen, (C 1 -C 4) alkyl, OR 9, NR 4 R 4, or a morpholino group; d / T means 1. single bond, 2. -00-, 5. OR1 2 3 4 5 6 *, 6. 0¾12 or j / R 9 * or R 8 is 1. (C 1 -C 8 alkyl), 2-adamantyl, 3-naphthyl, 4-1-naphthylethyl, 5-phenyl- (CH 2) q- or 6-residue defined under j / 1 Where 1 to all H atoms are substituted by fluorine 8 and R is taken together with the N atom which is -43- -NR T Ω Ύ k / R is cyano, nitro or CC 1 R 1, R 1 and R 2 are the same or different and are 1. hydrogen, 2. (C 1 -C 4) -alkyl,, 3-phenyl, 4-benzyl or 5 C 1-6 -methylbenzyl; m / D is NR 8, O or CE 8; n (R 1) is hydrogen, (C 1 -C 4) -alkyl or phenyl; or (C 1 -C 8) heteroaryl, which may be either aromatic, partially hydrogenated, or completely hydrogenated, or is a ring-fused heterocycle having from 8 to 10 atoms in the ring of which up to 9 ring atoms are G atoms, wherein A may be substituted by up to 3 identical or different 1-residue residues, halo, 2-oxo, 3-nitroso, 4. a nitro group, -44 ', 5'-cycloalkyl, 6-hydroxy, 7'-C (4) -alkyl, 8. (C 1 -C 6) -alkanoyl, 9-C 6 -C 6 -alkanooyloxy 10. CO2F3, 11. m < 5 > -sulfonylamino, 12. trifluoromethanesulfonylamino, 13. -CO-NH-OR9, 14. -SO2-NR6R7, 15. -CH 2 -OR 7, 16. (C 6 -C 12) -aryl, (17 / C 3 -C 8) -cycloalkyl. 18. (O-C ^-C alko-alkoxy, 19. C ^ -C-Cghheteroaryl, 20. COR3, 21. NR6R7, 22nd sulfo, 23. -SO ^ R3, 24. -SO2-NR7-C0-KR6R9, 25. -HR7-CO-NR6-302-CH2-R5, 26. -C (C) 3 / 20H, O-27. "Phosphonooxy, -O-OH -OH, 11 OH 28. -RG3H2, 29. -HH-RO / OH / 2, -45- 30. -S (O) - (R) -16, 31. -CO-R8 and 32. -CO-HR6R9; p / I means a single bond, 5. SE5, 6. pentafluorophenyl, 7 · cyano group, 8 · alkoxy group ina, benzyloxy group, 9. phenyl, 10. phenyl- O-O-O-alkyl, 11. O-O-O-alkyl group; 12. (C 1 -C 10) -alkenyl, (13) phenyl- (C 2 -C 8) -alkenyl 14. 1-imidazolyl- (CH 2) m -, 15, 1,2-triazolyl- (CH 2) n - , 16. tetrazolyl- (CH 2) m- 17. - (CH 2) Oel-CHR 7 -Of 5, 18. - / CH 2 / o-O-CO-E 3, 19. - / CH 2 / OS-R 6, 20. - S / 0 / r-E6 21. -CH = CH- / CH2 / m-CBE3-OE6, -38- 22. -CH2 = CH- / CH2 / m-C0-ES, 23. -GO-E8 24. -CH = CH- / CE2 / m-O-CO-E7, 25. - (CH2) m-CH / CH3 / -CO-E8 26. - / CH2 / o-CO-E8 27. - / CHO / -OC-NH-E9, 0 IIB 28. - / CH- / -NE7-C-OE9, ° IIB 29. - / CH2 / O-NK7-CO-HBE9, 30. - / CH2 / o -NE7-S02E9, 31.- / CHO / -O7-C-E9, B32 .- / CH2 / nE, 33.- / CH2 / n-O-NO2, 34. -CH2-K3, 35.- / CH2 / n-NO2, 36. -CE = ME5E7, 37. phthalimido- / CE2 / n -39- 41. - (CH2) o-1-C0 OCH 42. Phenyl-SOg-NH-KeCH-, 40- 44. - (CH2) n-SO2-HR7-CO-KR6R9, 45. - (CE2 / o-SO2R9, 46th residue defined as under o / 9 · or 10.) which is substituted on phenyl by 1 or 2 identical or different radicals from the series halo, hydroxy, methoxy, trifluoromethyl, and Rg, and phenyl, as defined under c / 11, 12. or 20. wherein 1 to all H atoms are substituted with fluoro, or a 48th residue defined as c / 15, which is substituted with I or 2 by the same non-boron residues of the methoxycarbonyl (- (- (-) - alkyl; R3 is hydrogen, 2. (C1-C8) -alkyl, 3. (C1-C8) -cycloalkyl, (4) phenyl, (5) benzyl or (6) a residue defined under d / 2, wherein 1 to all H is substituted with fluoro; e / R 4 is hydrogen, -41- (C 2 -C 8) alkyl, (3) C 1 -C 6 Acycloalkyl, (4) C 4 -C 4 -alkenyl or 5 (C 2 -C 4) - hydrogen, 2. (C1-C8) -alkyl, 3. (C3-C8) -cycloalkyl, (4) phenyl or (5) benzyl; - C 1-6 alkyl, - (C 1 -C 6) acycloalkyl, (4) C 6 -C 4 Aaryl, 5. Benzyl, 6 '(C 1 -C 6) ketexoaryl, which may also be partially or completely hydrogenated; Aalkanoyl, 8. (C 1 -C 6) heteroaryl-Aq-C 1-6 alkyl, wherein the heteroaryl moiety may also be partially or completely hydrogenated, or the 9th residue defined as g / 4, 6, or 8 substituted with 1 or 2 identical or differentresidues from the series halogen, hydroxy, methoxy, nitro, cyano, CO 2, -NO 2, B '' '2 and trifluoromethyl; h / 1. hydrogen, 2. (C 1 -C 8 alkyl), (3) C 1 -C 6 Acycloalkyl, -42- (R 8) 4 (C 8 -C 12) -aryl- (C 1 -C 8) -alkyl, 5 · phenyl or 6 / C 1 -C 4 -Z-heteroaryl, 1. hydrogen, 2. (C 1 -C 6) -alkyl, 3. (C 1 -C 6) -ylo-cycloalkyl, 4-phenyl- (CH 2) 2 -, A process for the preparation of compounds of formula I according to one of the claims 1 to 5, characterized in that the compounds of the formula II wherein E 1, X, ϊ and Z are as defined above, alkylthio compounds of formula III -54-UIATE / III / wherein kde.Α, Τ, Ε are defined as above and U is a volatile group, optionally temporarily introduced by a protecting group. the groups are again cleaved and the compounds of formula (I) obtained are optionally converted into their physiologically tolerable salt. 6. -NR21-7 -C0-NR21-, A compound according to any one of claims 1 to 5 for use as a medicament. 7. -SZOZrE6, 7 · -CHg-O-t 8. -S-CHg-, The compound of claim 7 for use as a blood pressure lowering agent. 8. SP5, 9. Ζ0Η2Ζο-1-0ΗΕ7-0Ε5, 10. Z0E2Zo-0-CO-b3, 11. -C0E8, -51- 12. - / CH2 / o -C0-E8, 13. -CH2-NE-CO-E8, 14. - (CH2) o-HH-SO2-R9, 15. -ch = gh-che3-oe6, 16. tetrazolyl- (CH2) m- 17. - / CH2 (nS02-NH-CO-EE6E9, 18.- / CH2 / q-SO3E9 or 19-) optionally hydroxy-substituted (C1-C6) -alkyl, preferably hydroxymethyl, [epsilon] / E3 is hydrogen or (C1-C6) alkyl; N-alkyl; E is hydrogen, (C 1 -C 6) -alkyl, (C 1 -C 4) -alkanoyl, phenyl, which may optionally be substituted by 1 or 2 identical or different halogen, hydroxy radicals - p ina, methoxy, nitro, cyano, CO 2 f 3 and trifluoromethyl or (C 1 -C 6) heteroaryl, which may also be partially or fully hydrogenated; e / E? is hydrogen, (C 1 -C 6) -alkyl, (C 1 -C 6) -hetero-aryl, or (C 6 -C 2) -aryl- (C 1 -C 2) -alkyl is / E 8 is hydrogen, C1-6-alkyl, OE3 or morpholino, g / E9 is CE4- (C1-C6) -alkyl or phenyl; h / A means. / / C -C-C ^ / / aryl or / / / C /-C ^-heteroaryl, which may be either aromatic or partially or fully hydrogenated or -52-aryl / a radical of a fused heterobicyclic with 8 "to 10 atoms in the ring of which up to 9 ring atoms are C atoms, wherein A may be substituted with up to 3 identical or different halogen, nitro-group, cyano, hydroxy, -NE R, phenyl, -S / O radicals (rE6 and -CO2E3) 1 / T represents a single bond, -O-, -G0-, -NECO-, -OCE2-, or O-8, and other radicals and variants are defined as in the preceding claims, and and its physiologically susceptible salts. 8. -NR21-C0- 9. -o-ch2- 10. -ch2-o- 11. -s-ch2- 12. -CH2-S- 13. -NH-CR20R22- 14. -NR21-S02- 15. S02-RR21- 16. -CR20R22-KH- 17. -CH = CH- 18. -CR = CR-, 19. -CH = CP-, 20. -CP = CH-, 21. -CH2-CH2-, 22. -cf2-c: f2-, 23. -CH / OR3 / -, -46- 24. -CB / OCOR5 / - 26. 25 R240 OR 25 or 27. OΠ -S-II O q. / 32 means the remainder provided that in the case of X = Y = CH R44 unknown COOH, τ / Β means Ο, NO? netto S; s / 1 denotes / C 1 -C 4 Z-alkanedi! ; t / E 14 is -CO 9 E 3, -CH 2 CO 2 E 3, -EO 4 H 8, -SO 4 H or tetrazolyl; 10; xZ r is 0,1 or 2, and yZ v is an integer from 1 to 6; as well as their physiologically tolerable salts. A pharmaceutical composition comprising at least one compound according to one of claims 1 to 5, 7 and 8. 9. -CH ^ "» 10. -ne-ce2-, 11. -ch2-nh-, 12. -CE = CE-, or O-13 -S-t-O and other residues and variants are defined as in the foregoing claims, as well as their physiologically tolerable salts. 10. Process for the preparation of a composition according to claim 9, characterized in that one or more compounds of the formula I or their physiologically tolerable salts are treated together with physiologically acceptable carriers and optionally further additives and auxiliaries. a suitable form for administration.