MXPA02001702A - Substituted piperazine derivatives, the production thereof and their utilization as medicaments - Google Patents

Abstract

The invention relates to substituted piperazine derivatives of general formula (I), wherein Ra to Re and n have the meaning defined in claim 1. The invention also relates to the isomers and salts of said substituted piperazine derivatives, especially to their physiologically acceptable salts which represent valuable inhibitors of microsomal triglyceride transfer protein (MTP), the medicaments containing said compounds, their utilization and the production thereof.

Description

Ri denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group of 1 to 3 carbon atoms, wherein the hydrogen atoms may be substituted wholly or partially by fluorine atoms, a hiaroxy group, alkoxy group of 1 to 4 carbon atoms, phenylalkoxy of 1 to 3 carbon atoms, carboxy, alkoxycarbonyl of 1 to 3 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms, N, N-di- (alkyl of 1 to 3 atoms) carbon) -aminocarbonyl, nitro, amino, alkylamino of 1 to 3 carbon atoms, di- (alkyl of 1 to 3 carbon atoms) -amino, phenyl- (alkyl of 1 to 3 carbon atoms) -amino, N - (alkyl of 1 to 3 carbon atoms) -phenyl- (alkyl of 1 to 3 carbon atoms) -amino, alkyl-carbonylamino of 1 to 3 carbon atoms, N- (alkyl of 1 to 3 carbon atoms) - (C 1 -C 3 alkyl) carbonylamino, alkylsulfonylamino of 1 to 3 carbon atoms or N- (C 1 -C 3 alkyl) - (alkyl of 1 to 3 carbon atoms) carbon) -sulfonylamino, and R2 denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group of 1 to 3 carbon atoms or R1 and R2, together, denote a methylenedium group, a heteroaryl group, a heteroaryl or a monocyclic group or phoenix _., each of which is substituted by a phenyl or monocyclic heteroaryl group, while the phenyl portions mentioned in the above may each be substituted by a fluorine atom, chlorine or bromine, and the phenyl portions mentioned in the foregoing and the heteroaryl groups may each be substituted by an alkyl group of 1 to 3 die carbon atoms, wherein the hydrogen atoms may be substituted wholly or partially by fluorine atoms, by an idroxy group, alkoxy of 1 to 3 carbon atoms, carboxy, alkoxycarbonyl of 1 to 3 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms or N, N-di- (alkyl of 1 to 3 carbon atoms) carbon) -aminocarbonyl, Rb denotes a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, Rc denotes a hydrogen atom, an alkyl group of 1 to 10 carbon atoms, cycloalkyl of 3 to 7 carbon atoms or cycloalkyl (from 3 to 7 carbon atoms) -alkyl of 1 to 3 carbon atoms, wherein the hydrogen atoms in each case may be substituted wholly or partially by fluorine atoms, a phenyl, naphthyl or heteroaryl group, optionally substituted by fluorine, chlorine or bromine atoms, by an alkyl group of from 1 to 3 carbon atoms, wherein the hydrogen atoms may be substituted totally or partially by fluorine atoms, by a hydroxy group, alkoxy of 1 to 3 atoms carbon, carboxy, alkoxycarbonyl) of 1 to 3 carbon atoms, aminocarbonyl, alkylaminocarbonyl of 1 to 3 carbon atoms or N, N-di- (alkyl of 1 to 3 carbon atoms) -aminocarbonyl, for a cycloalkyleneimino group from 3 to 7 members, while the methylene group in the 4-position of a cycloalkyleneimino group of 6 or 7 members can be further substituted by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, imino or N- (C 1 -C 3 alkyl) -imino group, by a nitro, amino, alkylamino group of 1 to 3 carbon atoms, di- (alkyl of 1 to 3 carbon atoms) -am..no, alkylcarbonylamino of 1 to 3 carbon atoms, N- (alkyl of 1 to 3 carbon atoms) - (alkyl) of 1 to 3 carbon atoms) -carbonylamino, alkylsulfonylamino of 1 to 3 carbon atoms or N- (alkyl of 1 to 3 carbon atoms) - (alkyl of 1 to 3 carbon atoms) -sulfonylamino, Rd indicates a group phenyl, naphthyl or heteroaryl optionally substituted by a fluorine, chlorine or bromine atom, by an alkyl group of 1 to 3 carbon atoms, wherein the hydrogen atoms may be completely or partially substituted by fluorine atoms, by a hydroxy group , alkoxy of 1 to 3 carbon atoms, carboxy L, alkoxycarbonyl of 1 to 3 carbon atoms, aminocarbonyl, alkylamino nocarbonyl of 1 to 3 carbon atoms or N, N-di- (alkyl of 1 to 3 carbon atoms! to incarboxyl, by a 3 to 7 membered cycloalkyleneimino group, while the methylene group in the 4-position of a 6 or 7 membered cycloalkyleneimino group may be further substituted by an oxygen or sulfur atom, by a sulfinyl, sulfonyl group , imino c N- (C 1-3 alkyl) -imino, by a group nLtro, amino, alkylamino of 1 to 3 carbon atoms, di- (alkyl of 1 to 3 carbon atoms) -amino, alkylcarbonylamino of 1 to 3 carbon atoms, N- (alkyl of 1 to 3 carbon atoms) - (alkyl of 1 to 3 carbon atoms) -carbonylamino, alkylsulfonylamino of 1 to 3 carbon atoms or N- (alkyl of 1) to 3 carbon atoms) - (C 1-3 alkyl) -sulfonylamino, and Re indicates a carboxy group, an alkoxycarbonyl group of 1 to 6 carbon atoms or cycloalkoxycarbonyl of 3 to 7 carbon atoms, wherein the The carbon atom of the alkoxycarbonyl group bound to the oxygen atom is a primary or secondary carbon atom and wherein the alkyl or cycloalkyl portion of both groups can be substituted from the 2-position relative to the oxygen atom, by an alkoxy group of 1 to 3 carbon atoms, amino, alkylamino of 1 to 3 carbon atoms or di- (alkyl of 1 to 3 carbon atoms) -amino, a phenylalkoxycarbonyl group of 1 to 3 carbon atom or heteroaryl-alkoxycarbonyl of 1 to 3 carbon atoms, while the heteroaryl groups in the foregoing are 6-membered heteroaryl groups containing one, two or three nitrogen atoms, and 5-membered heteroaryl groups, which contain an imino group optionally substituted by an alkyl group of 1 to 3 carbon atoms, an oxygen or sulfur, or a free group optionally substituted by an alkyl group of 1 to 3 carbon atom and one oxygen or sulfur atom, or 1 or 2 nitrogen atoms:.

Preferred compounds of the general formula I above are those in which Re is as defined in the above, n denotes the number 3, 4 or 5, Ra indicates a phenyl group which is substituted by the groups? and R2, while Rt denotes a hydrogen, chlorine or bromine atom, an alkyl group of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, benzyloxy, carboxy, akyloxycarbonyl of 1 to 3 carbon atoms, nitro , amino, acetamino or methanesulfonylamino, and R, indicates a hydrogen atom, chlorine or bromine, or a methyl group, or Ri Y 2 / together, indiban a methylenedioxy group, a biphenyl group the rual may be substituted by a fluorine atom , chlorine or bromine, by a methyl, methoxy or trifluoromethyl group, a pyridyl, pyrimidyl, pyrazomyl, pyridazinyl or thienyl group, optionally substituted by a phenyl group, or a phenyl group thereof substituted by a thienyl, thiazolyl, pyrrolyl, imidazyl, or pyridyl or a benzimidazolyl group, Rb denotes a hydrogen atom, Rc denotes an alkyl group of 1 to 3 carbon atoms or phenyl, and Rd denotes a phenyl group optionally substituted by a fluorine or chlorine atom, or per a methyl or methoxy group, the isomers and the Seles of the irs. Particularly preferred compounds of the general formula I above are those in which Re is as defined above, n denotes the number 3 or 4, Ra denotes a nyl group which is substituted by the groups R and R2, in those which Rx indicates an atom of hydrogen, chlorine or bromine, an alkyl group of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or benzyloxy, and R2 denotes a hydrogen, chlorine or bromine atom, or a methyl group, a biphenyl group which may be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or trifluoromethyl group, a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thienyl group, optionally substituted by a phenyl group, or a phenyl group substituted by a thienyl, thiazolyl, pyrrolyl, imidazole, pyridyl or benzimidazolyl group, Rh denotes a hydrogen atom, Rc denotes an alkyl group of 1 to 3 carbon atoms, and methylene, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol of the general formula V used as a solvent, optionally in the presence of an acid such as hydrochloric acid or sulfuric acid , or in the presence of a dehydrating agent, for example, in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2, 2-d: methoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexyl-carbodiimide, N, '-dicyclohexylcarbodiimide / N-hydro i- succinimide, N, N'-dicyclohexylcarbodii id a / 1-hydrox i-benzotriazole, 2- (lH-benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium tetrafluoroborate, tetrafluorobfrate 2- (lH -benzotriazol-1-yl '. 1, 1, 3, 3-1 et rame ti luronio / 1 -hidroxibenzot ria zol, N, N' carbonyldiimidazole or triphenylfpsfina / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C. The reaction of a corresponding reactive compound of general formula IV such as esters, imidazolides or halides with an alcohol of the general formula V is preferably carried out in a corresponding alcohol as solvent, optionally in the presence of another solvent such as methylene chloride or a protecting group for a carboxyl group can be a trimethylsilyl, methyl ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and the protecting groups for an amino, alkylamino or imino group can be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl group, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl, and additionally, for the amino group, a phthalyl group Any optionally used protecting group is subsequently removed, for example, by hydrolysis in an aqueous solvent, for example in water, isopropanol / water, acid acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, or aprroically, for example, in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C. However, a silyl group can also be separated using tetrabutylammonium fluoride as described above. However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is, for example, hydrogenolytically separated, for example with hydrogen in the presence of a catalyst such as palladium / activated carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid , optionally triglycerides labeled for fluorescence at a high enough concentration to cause self-extinction of the fluorescence. When the donor and acceptor particles are incubated with an MTE source, the fluorescence-labeled triglycerides are transferred from the donor particles to the acceptor. This leads to an increase in fluorescence in the sample. Solubilized liver microsomes of several species (eg rat) can be used as the source MTP. MTP inhibitors can be identified such as substances which reduce the transfer of triglycerides labeled by fluorescence in comparison with a control mixture, without inhibitor. In view of the biological properties mentioned in the above, the compounds of general formula I and the physiologically acceptable salts thereof are particularly suitable for lowering the plasma concentration of lipoproteins containing atherogenic apolipoprotein B (apoB) such as chylomicrons or lipoproteins of very low density (VLDL), or both, as well as residues thereof such as low density lipoprotein LDL) or lipoprotein (a) (Lp (a)), or arabos to treat hyperlipidemias, to prevent and treat atherosclerosis and the sequelae 5 clinics thereof, and to avoid and treat related disorders such as diabetes mellitus, adiposity and pancreatitis, oral administration is preferred. phase transfer catalyst such as tetrabutylammonium iodide in a solvent such as, for example, water, DMF, toluene or mixtures thereof at temperatures between 20 and 130 ° C.

The protecting group is separated using methods known from the literature and produces a compound of the general formula VII. The following examples are designed to illustrate the invention: Example 1 Methyl 2-methyl-2-phenyl-5- (4 • phenyl-piperazin-1-yl) -pentanoate to. Methyl 2-phenylpropionate 50 g (0.3 mole) of 2-phenylpropionic acid are dissolved in 375 ml of methanolic hydrochloric acid and stirred for 14 hours at temrj > environmental environment. The solvent is removed and the residue is extracted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic phases are extracted with water and saturated saline, dried over magnesium sulfate and reduced by evaporation. Yield: 51 g (9 .8 ° of theory).

It is prepared in a manner analogous to Example 2, starting from methyl 1- (2-bromo-phenyl) -piperazine-methyl-2-methyl-1,2-phenyl-pentanoate. Yield: 0.3 g (38.4% of theory), C23H29BrN202 (M = 445. < 0) Calculated: moleoular peak (M) = 444/446 Found: molecular peak (M) = 444/446 Example 9 Methyl 2-methy1-2-phenyl-5- [4- (4-bromo-phenyl) -piperazin-1-yl] -pentanoate It is prepared in a manner analogous to Example 2, starting from methyl 1- (bromo-phenyl) -piperazinayf-bromo-2-methyl 1-2-phenol-pentanoate. Yield: 0.25 g (32% of theory), C23H29BrN202 (M = 445. < 0) Calculated: peak mole oular (MP = 444/446 Found: mollecular peak (M) = 444/446 Example 10 2-methyl-2-phenyl-5- [4- (2-methyl-phenyl) -piperazin-l-ii: methyl pentanoate (18) 5- [4- (2'-Fluoro-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of isopropyl (19) 5- [4- (4'- methyl chloro-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate (20) 5- [4- (4'-chloro-biphenyl-4-yl-piperazin-1) -yl] -2-methyl-2-phenyl-pentanoate of et (21) 5- [4- (4'-chloro-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl propyl pentanoate (22) 5- [4- (4'-Chloro-biphenyl-4-yl-p? perazin-1-yl] -2-methyl-2-phenyl-pentanoate of is-propyl (23) 5- [4- (3'-Chloro biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of me: yl (24) 5- [4- (3'-chloro-biphenyl- 4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of et (25) 5- [4- (3'-chloro-biphenyl-4-yl-piperazin-1-yl] - 2-methyl-2-phenyl-pentanoate of prppyl (26) 5- [4- (3'-chloro-biphen? L-4-yl-piperaz? N-1-? L] -2-methyl-2-phenyl- isyl propyl pentanoate (27) 5- [4- (2'-Chloro-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoic acid methyl ester (28) 5- [ 4- (2'-Chloro-biphenyl-4-yl) -piperazine-1-? L] -2-methyl-2-phenyl-pentanoate of et (29) 5- [4- (2'-chloro-biphenyl-4-yl) -piperazm-1-yl] -; prilic methyl-2- phenyl-pentanoate (42) 5- [4- (2'-trifluoromethyl-biphenyl-4-yl) -piperazin-1-yl] -2-methyl-2-phenyl-pentanoate isopropyl (43) 5- [4- (4 ' methyl-methyl-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate (44) 5- [4- (4'-methyl) biphenyl-4-ii-piperazin- 1-yl] -2-methyl-2-phenyl-pentanoate ethyl (45) 5- [4- (4'-methyl-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl propyl pentanoate (46) 5- [4- (4'-methyl biphenyl-4-yl-piperazin-l-yl] -2-methyl-2-phenyl-pentanoate isopropyl (47) 5- [4- ( 3'-methyl-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of me (48) 5- [4- (3'-methyl biphenyl-4? - piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of et UO (49) 5- [4- (3'-methyl biphenyl-4-yl-piperazin-1-yl] -2-methyl-2 pr-opyl phenyl-pentanoate (50) 5- [4- (3'-methyl-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate is isopropyl (51) 5 - [4- (2-methyl-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate, mehyl (52) 5- [4- (2'-methyl-biphenyl-4 -yl-pi? erazin-l-il] -2-methyl-2-phenyl-pentanoate d ety (53) 5- [4- (2'-methyl biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of pripyl .66) 5- [4- (2'-methoxy-biphenyl-4-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of isopropyl (67) 5- [4- (4'- methyl fluororbiphenyl-3-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate; 68) 5- [4- (4'-fluorohbiphenyl-3-yl-piperazin-1-yl] -2 ethyl-methyl-2-phenyl-pentanoate (69) 5- [4- (4'-Fluoro-biphenyl-3-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate propyl (70) ) 5- [4- (4'-fluororbiphenyl-3-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of isopropyl (71) 5- [4- (3'-fluoro-biphenyl- Methyl 3-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate (72) 5- [4- (3'-Fluororbiphenyl-3-yl-piperazin-1-yl] -2-methyl Ethyl 2-phenyl-pentanoate; 73) 5- [4- (3'-fluororbiphenyl-3-yl-piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of prppyl (74) 5- [ 4- (3'-Fluorohbiphenyl-3-ii -piperazin-1-yl] -2-methyl-2-phenyl-isopropyl 75-pentanoate) 5- [4- (2'-fluoro-biphenyl-3-yl-piperazin- l -yl] -2-methyl-2-phenyl-pentanoate methyl (76) 5- [4- (2'-fluoro-biphenyl-3-yl-piper azm- • l-ill-2-methyl-2- phenyl-pentanoate et: lo (77) 5- [4- (2'-Fluoro-biphenyl-3-yl-piperazin-l-yl] -2-methyl-2-phenyl-pentanoate propyl (114) 5- [4- (2'-methyl-biphenyl-3? L) -p? Perazin-l-? L] -2-methyl-2-phenyl-pentanoate of isopropyl (115) methyl 5- [4- ('-methoxybiphenyl-3-yl) -piperazin-1-yl] -2-methyl-2-phenyl-pentanoate 116) 5- [4- (4'-methoxy) ethyl β-phenyl-3-yl) -piperazin-l-yl] -2-methyl-2-phenyl-pentanoate (117) 5- [4- (4'-methoxy-biphenyl-3-yl) -piperazine-1 -yl] -2-methyl-2-phenyl-pentanoate propyl (118) 5- [4- (4'-methoxy-biphenyl-3-yl) -piperazin-1-yl] -2-methyl-2-phenyl isopropyl pentanoate (119) 5- [4- (3 '-methoxy-biphenyl- • 3-yl) -p? perazin-1-yl. Methyl-9-methyl-2-phenyl-pentanoate (120) 5- [4- (3'-methoxy-biphenyl-3-yl) -piperazin-1-yl] -2-methyl-2-phenyl- etS-lo pentanoate (121) 5- [4- (3'-methoxy biphenyl-3-yl piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of propyl (122) 5- [4- ( 3'-methoxy-biphenyl-3-yl) -piperazin-1-yl] -2-methyl-2-phenyl-pentanoate of isopropyl (123) 5- [4- (2'-methoxy-bifeml-piperazin-1- il] -2-methyl-2-phenyl-pentanoate of mehyl (124) 5- [4- (2'-methoxy-biphen? l • 3-yl) -piperaz? n- 1-? l] -2-methyl Ethyl-2-phenyl-pentanoate 125) 5- [4- (2'-methoxy | -biphenyl-3- ii) -p? Pera z m- 1-? L] -2-methyl-2-phenyl-pentanoate propyl Found: molecular peak (M) '= 456 The following compounds can be prepared using the method described in Example 32: (1) 5- [4- (4-chloro-phenyl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoic acid ethyl ester (2) 5- [4- (4-chloro-phenyl) - piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate propyl (3) 5- [4- (4-chloro-phenyl) -piper to zin-1-yl] -2-ethyl-2- isopropyl phenyl-pentanoate (4) 5- (4-biphenyl-4-yl-1-pipe to zin-l-yl] -2-ethyl-2-phenyl-pentanoate ethyl (5) 5- (4-biphenyl) -4-yl-piperazin-l-yl] -2-et? L-2-phenyl-pentanoate propyl (6) 5- (4-biphenyl-4-yl-piperazin-1-yl) -2- isopropyl ethyl-2-phenyl-pentanoate (7) ethyl 5- (4-biphenyl-3-yl-piperazin-l-yl) -2-ethyl-2-phenyl-pentanoate (8) 5- (4-) biphenyl-3-i-1-piperazin-1-yl] -2-ethyl-2-f in propyl-il-pentanoate (9) 5- (4-biphenyl-3-y-piperazin-1-yl) -2-et i 1-2- isopropyl phenyl-pentanoate (10) 5- [4- (4'-Fluoro-biphenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of met: the (35) ethyl 5- (4- (4'-trifluoromethyl-bi-phenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (36) 5- [4- (4 ' -trifluc rometil-bifeni1-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate propyl (37) 5- [4- (4'-trifluoromethyl-bipheni-4-yl) - piperazin-l-yl] -2-ethyl-2-phenyl-pentanoate ie isopropyl (38) 5- [4- (3'-trifluoromethyl-bipheni-4-yl) -piperazin-1-yl] -2-ethyl- 2-phenyl-pentanoate ie methyl (39) 5- [4- (3'-trifluoromethyl-bi-phenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (40) ) 5- [4- (3'-trifluoromethyl-1-biphenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate ie propyl (41) 5- [4- (3'-trifluoromethyl) -bi-pheny1-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of isopropyl (42) 5- [4- (2'-trifluoromethyl-biphenyl-4-yl) -piperazine- 1-yl] -2-ethyl-2-phenyl-pentanoate ie methyl (43) 5- [4- (2'-trifluoromethyl-bipheni-4-yl) -piperazin-1-yl] -2-eti1-2- phenyl-pentanoate ae et i lo (44) 5- [4- (2'-tri-fluqrometi-1-bi-phenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pe propyl n-natoate 45) 5- [4- (2'-trifluororneti-1-bi-phenyl-4-yl) -piperazin-; il] -2-ethyl-2-phenyl-pentanoate ie isopropyl (46) 5- [4- (4'-methyl biphenyl-4-yl) -piperazin-] -yl] -2-ethyl-2-phenyl-pentanoate of mettlo (59) 5- [4- (4'-methoxy-bi-phenyl-1-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of eti; or (60) 5- [4- (4'-methoxy-biphenyl-4-yl) -piperazin-1-yl] -2-eti1-2-phenyl-pentanoate propyl (61) 5- [4- ( Isopropyl 4'-methoxy-biphenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (62) 5- [4- (3'-methoxy-bi-pheny1-4-yl) ) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of met: lo (63) 5- [4- (3'-methoxy-biphenyl-4-yl) -piperazin-1-yl] -2- Ethyl-2-phenyl-pentanoate of eti: o (64) 5- [4- (3'-methoxy-bi-phenyl-4-yl) -piperazin-1-yl] -2-ethyl-2- propyl phenyl-pentanoate (65) 5- [4- (3'-methoxy-bi-phenyl-4-yl) -piperazin-1-yl] -2-eti-1-phenyl-isopropyl-isopropyl ester (66) - [Methyl 4- (2'-methoxy-bi-phenyl-1-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (67) 5- [4- (2'-methox β-biphenyl-4-yl) -piperazi-1-yl; .9_ ethyl ethyl-2-phenyl-pentanoate (68) 5- [4- (2'-methoxy-biphenyl-4-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate propyl (69) 5- [4- (2'-methoxy-biphenyl -Dioerazin-1-yl] -2-ethyl-2-phenyl-pentanoate of isopropyl (70) 5- [4- (4'-fluoro-biphenyl- 3-yl) -piperazin-l-yl] -2-ethyl-2-phenyl-pentanoate methyl (71) 5- [4- (4 * -fluoro) -bifeni-l, 3-yl) -p,? -zinzin-1-yl] -2-ethyl-2-phenyl-pentanoate, or (72) 5- [ 4- (4'-Fluoro (-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate, propyl 73) 5- [4- (4'-fluoro-biphenyl-3 -Il) -piperazin-l-yl] -2-ethyl-2-phenyl-isopropyl pentanoate (74) 5- [4- (3'-fluoro-biphenyl-3-yl) -piperaz-1-yl] 2-ethyl-2-phenyl-pentanoate of metho (75) 5- [4 -. (3'-fluoro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl- ethyl pentanoate 76) 5- [4- • fluoro-bif eni-3-yl) -piperazyl-l -yl] -2-ethyl-2-phenyl-pentanoate of propyl 77) 5- [4- (3 -fluoro β-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of isopropyl 78) 5- [4- (2'-fluoro-biphenyl-3-yl) -piperazin-1- il] methyl 2-ethyl-2-phenyl-pentanoate 79) 5- [4- (2'-fluoro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate ethyl (80) 5- [4- (2'-Fluoro-bi-phenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of prooyl (81) 5- [4- ( 2'-Fluoro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of iso-ropyl (82) 5- [4- (4'-chloro-bi-pheny1- il I-pipera in-l-il] -2-ethyl-2-phenyl-pentanoate methylo (83) 5- [4- (4'-Chlore-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of eti? Lo (84) 5- [4- ( 4'-Chloro-bipheni-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate propyl (85) 5- [4- (4'-chloro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-isopropyl pentanoate (86) 5- [4- (3'-Chloro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl Mettlo-2-phenyl-pentanoate (87) 5- [4- (3'-Chloro-biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of eti-P (88) ) 5- [4- (3'-Chloro-biphenyl-3-yl) -piperazin-1-yl] -2-eti1-2-phenyl-pentanoate of pro-oyl (89) 5- [4- (3 '-) chlore • biphenyl-3-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate is isopropyl (90) 5- [4- (2'-chloro-biphenyl-3-yl) -piperazine -l-yl] -2-ethyl-2-phenyl-pentanoate methyl (91) 5- [4- (2'-chloro-biphenyl-3-yl) -piperazin-1-yl] -2-eti1-2- Phenyl-pentanoate of ethyl (92) 5- [4- (2'-Chlore-bi-phenyl-3-yl) -piperazyl-1-yl] -2-ethyl-2-phenyl-pentanoate of pro-oyl ( 93) 5- [4- (2 '-chlore • bi faith ni i- 3- il) -piperaz iso-oryl (1-yl) -2-ethyl-2-phenyl-pentanoate (94) 5- [4- (4'-trifluor-romethyl-bi-phenyl-3-yl) -piperazin-1-yl] - 2-eti1-2-phenyl-pentao moat *: ie met i lo 131) 5-. { 4- [3- (1H-iimidazol-4-yl) -phenyl] -piperazin-1-yl} Methyl -2-eti1-2-phenyl-pentanoate (132) 5-. { 4- [3- (lH-pyrrol-2-yl) -phenyl] -piperazin-1-yl} Methyl -2-ethyl-2-phenyl-pentanoate (133) 5-. { 4- [3- (1H-be? Zoimidazol-2-yl) -phenyl] -piperazin-1-yl} -2-ethyl-1-2-phenyl-pentanoate of methyl 134; 5-. { 4- [4-thiazol-2-yl-phenyl] -piperazin-1-yl-methyl-2-phenyl-pentanoate methyl (135) 5-. { 4- [4-thiophen-3-yl-phenyl) -? Iperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of metj. lo (136) 5-. { 4- [4- (1H-imidazol-4-? 1) -phenyl] -piperazin-1-yl} Methyl -2-ethyl-2-phenyl-pentanoate (137) 5-. { 4- [4- (lH-pyrrol-2-yl) -phenyl] -piperazin-1-yl-ethyl-2-ethyl-2-phenyl-pentanoate (138) 5-. { 4- [4- (lH-benzoimidazol-2-yl) -phenyl] -piperazin-1-yl} Methyl -2-ethyl-2-phenyl-pentanoate (139) methyl 5- [4- (4-pyridin-2-yl-phenyl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (140) 5- [4- (6-phenyl-L-pyridin-2-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-β-methanoate of methlo 141) 5- [4- (4-phenyl- p.rimid? n-2-yl) -piperazin-1-yl] ethyl-2-phenyl-pentanoate of metho 142) 5- [4- (2-phenyl-pyrimidin-5-yl) -piperazin- 1- il] methyl 2-ethyl-2-phenyl-pentanoate (143) Methyl 5- (4- (5-phenyl) pyridin-2-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (144). 5- [4- (5-phenyl, -thiophen-2-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate of methyl (145) 5- [4- (5-phenyl. methyl-oxazol-2-yl) -piperazin-1-yl] -2-ethyl-2-phenyl-pentanoate (146) 5- (4- [2,2 '] bi> iridinyl-6-yl-piperazin -l-yl) -2-ethyl-2-phenyl-pentanoate methyl (147) 5- (4-biphenyl-1-piperazm-1-yl) -2-ethyl-2- (4-fluoro-phenyl) -methyl pentanoate (148) methyl 5- (4-biphenyl- • -yl-piperazin-l-yl] -2-ethyl-2- (4-fluoro-phenyl) -pentanoate Example 34 2, 2-di feni 1-5- (4- phenyl-1-piperaz n-l-yl) -pentanoate methyl to. 3.3-diphenyl-tetrahydro-pyran-2-one One drop of 33 ml f 0.053 mole) of a 1.6 molar solution of n-but-llithium in hexane is added dropwise to a solution of 5 g (0.024 mole) of diphenylacetic acid in 50 ml of tetrahydrofuran under nitrogen at -10. ° C and stirred for 30 minutes at 0 ° C. Then 3 ml (0.03 moles) I 1.3- were added at 0 ° C.

Claims (1)

1. ethyl-2-phenyl-pentanoate methyl and (c) methyl 5- (4-biphenyl-3-yl-piperazin-1-yl) -2-ethyl-2-phenyl-β-entanoate, and isomers and salts of the same. 5. Physiologically acceptable salts of the compounds, as described in claims 1 to 4 6. Medicaments, which contain a compound, as described in at least one of claims 1 to 4 or a salt, as described in claim 5, optionally together with one or more inert carriers or diluents, or both. 7. The use of a compound, according to at least one of claims 1 4, or a salt, as described in claim 5, for the preparation of a medicament having an effect of lowering the plasma concentrations of heterogeneous lipoproteins Process for preparing a medicament, as described in claim 6, characterized in that a compound according to at least one of claims 1 to 4 or a salt, as described in claim 5, is incorporated in one or more inert carriers or diluents, or both, by a non-chemical method.