HK1060119B - Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use - Google Patents

Description

diphenylazetidinone derivatives, process for their preparation, medicaments containing these compounds and their use

The invention relates to substituted diphenylazetidinones, their physiologically acceptable salts and physiologically functional derivatives.

Diphenylazetidinones (e.g. ezetimibe) and their use for the treatment of hyperlipidemia and arteriosclerosis and hypercholesterolemia have been described [ see Drugs of the Future2000, 25 (7): 679-685)].

It is an object of the present invention to provide other compounds having therapeutically useful lipid-lowering effects. In particular, the object of the present invention was to find new compounds which absorb to a very low extent compared to the compounds described in the prior art. Very low absorption is understood to mean an intestinal absorption of less than 10%, preferably less than or equal to 5%. In particular, the absorption of the new compound should be less than that of ezetimibe. Pharmaceutically active compounds that are absorbed to a very low extent generally have much lower side effects.

The present invention therefore relates to compounds of formula I and pharmaceutically acceptable salts thereof,

wherein

R1, R2, R3, R4, R5 and R6 are independently (C)₀-C₃₀) -alkylene-L, wherein one or more carbon atoms in the alkylene group may be replaced by-O-, - (C ═ O) -, -CH ═ CH-, -C ≡ C-, -N ((C ≡ C) — (C-)₁-C₆) -alkyl) -or-NH-substituted;

H、F、Cl、Br、I、CF₃、NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) Alkyl radical]₂、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl or O- (C)₁-C₆) -alkyl, wherein one, more or all of the hydrogens of the alkylene group may be substituted by fluorine;

SO₂-NH₂、SO₂NH(C₁-C₆) Alkyl, SO₂N[(C₁-C₆) -alkyl radical]₂、S-(C₁-C₆) Alkyl, S- (CH)₂)_n-phenyl, SO- (C)₁-C₆) Alkyl, SO- (CH)₂)_n-phenyl, SO₂-(C₁-C₆) Alkyl, SO₂-(CH₂)_n-phenyl, wherein n ═ 0-6 and phenyl can be substituted up to two times by: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂；

NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、NH(C₁-C₇) -acyl, phenyl, O- (CH)₂)_n-phenyl, wherein n ═ 0-6, wherein the phenyl ring may be mono-to trisubstituted with the following groups: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

L is

Rx, Ry, Rz independently of one another are H, F, Cl, Br, I, CF₃、NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) Alkyl radical]₂、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl or O- (C)₁-C₆) Alkyl radicals in which one, more than one of the alkylene radicals is presentOne or all of the hydrogens may be replaced by fluorine;

SO₂-NH₂、SO₂NH(C₁-C₆) Alkyl, SO₂N[(C₁-C₆) -alkyl radical]₂、S-(C₁-C₆) Alkyl, S- (CH)₂)_n-phenyl, SO- (C)₁-C₆) Alkyl, SO- (CH)₂)_n-phenyl, SO₂-(C₁-C₆) Alkyl, SO₂-(CH₂)_n-phenyl, wherein n ═ 0-6 and phenyl can be substituted up to two times by: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂；

NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、NH(C₁-C₇) -acyl, phenyl, O- (CH)₂)_n-phenyl, wherein n ═ 0-6, wherein the phenyl ring may be mono-to trisubstituted with the following groups: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R1 to R6 must mean in each case (C)₀-C₃₀) -alkylene-L, wherein one or more carbon atoms in the alkylene group may be replaced by-O-, - (C ═ O) -, -CH ═ CH-, -C ≡ C-, -N ((C ≡ C) — (C-)₁-C₆) -alkyl) -or-NH-substituted.

Preference is given to compounds of the formula I in which at least one of the radicals R1 to R6 means (C)₀--C₃₀) -alkylene-L, wherein one or more carbon atoms in the alkylene group may be substituted by-O-, - (C ═ O) -, or-NH-.

Particular preference is given to compounds of the formula I in which one of the radicals R1 or R3 is (C)₀-C₃₀) -alkylene-L, wherein one or more carbon atoms in the alkylene group may be substituted by-O-, - (C ═ O) -, or-NH-.

Very particular preference is given to compounds of the formula I in which one of the radicals R1 or R3 is- (CH)₂)_0-1-NH-(C＝O)_0-1-(C₃-C₂₅) -alkylene- (C ═ O)_0-1-NH-L, wherein one or more carbon atoms of the alkylene group may be substituted by oxygen atoms.

One of the radicals R1-R6 is bonded to the L radical preferably in a meta position to the ring C of the L radical.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications due to their increased solubility in water compared to the starting or base compound. These salts should have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as: hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and salts of organic acids such as: acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothioric, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric, and trifluoroacetic acid. For pharmaceutical purposes, the use of chloride salts is very particularly preferred. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. magnesium and calcium salts).

Also included within the scope of the invention are salts with pharmaceutically unacceptable anions which may be useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications such as in vitro applications.

As used herein, the term "physiologically functional derivative" refers to any physiologically acceptable derivative of a compound of the present invention, such as an ester, which is capable of forming (directly or indirectly) such a compound or an active metabolite thereof upon administration to a mammal, such as a human.

Another aspect of the present invention is a prodrug of a compound of the present invention. Such prodrugs can be metabolized in vivo to provide the compounds of the invention. These prodrugs may or may not be active themselves.

The compounds of the invention may also exist in various polymorphic forms, for example as amorphous or crystalline polymorphic forms. The scope of the present invention includes all polymorphic forms of the compounds of the invention, which form a further aspect of the invention.

As used herein, all references below to compounds of formula (I) "refer to compounds of formula I above, their salts, solvates and physiologically functional derivatives.

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal drugs for the treatment of impaired lipid metabolism, particularly hyperlipidemia. The compounds of formula I are also suitable for regulating serum cholesterol levels and for the prophylaxis and treatment of atherosclerosis.

The compounds of formula (I) may also be administered in combination with other active compounds.

The amount of compound of formula (I) required to achieve the target biological effect depends on a variety of factors, such as the particular compound selected, the intended application, the mode of administration, and the clinical condition of the patient. In general, the daily dosage will be in the range of from 0.1mg to 100mg (usually 0.1mg to 50mg) per kg body weight per day, for example O.1 to 10 mg/kg/day. For example, a tablet or capsule may contain 0.O1-100mg, usually 0.02-50 mg. In the case of pharmaceutically acceptable salts, the weight data set forth above is based on the weight of the diphenyl-thia * ion derived from the salt. For the prophylaxis or treatment of the above-mentioned symptoms, the compounds of formula (I) may be used as such, but preferably they are present in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with the other composition components and not deleterious to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may be present, including other compounds of formula (I). The pharmaceutical composition of the present invention can be prepared by a known pharmaceutical method which is basically mixing the components with a pharmaceutically acceptable carrier and/or adjuvant.

The pharmaceutical compositions of the invention are those suitable for oral or peroral (e.g. sublingual) administration, although the most suitable mode of administration will depend in each particular case on the nature and severity of the condition to be treated and on the type of compound of formula (I) used in each case. Coated formulations and coated delayed release formulations are also included within the scope of the present invention. Acid and bowel resistant formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be present as separate units: such as capsules, cachets, lozenges or tablets, which in each case contain the compound of formula (I) in the specified amount; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. As noted above, these compositions may be prepared according to any suitable pharmaceutical method which includes contacting the active compound with a carrier, which may consist of one or more additional ingredients. Generally, the compositions are prepared by the following method: the active compound is uniformly and homogeneously mixed with the liquid and/or finely divided solid carrier, and the product is then shaped if desired. For example, tablets may be prepared by compressing or forming a powder or granules of the compound, if desired, with one or more additional components. Compressed tablets may be produced by the following process: the compounds are compressed into a free-flowing form such as a powder or granules, and mixed with a binder, lubricant, inert diluent and/or surfactant (s)/dispersant(s) in a suitable machine if desired. Shaped tablets may be produced by shaping in a suitable machine a powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges comprising a compound of formula (I) and a flavoring agent, conventional sucrose and acacia or tragacanth, lozenges comprising a compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Suitable further active compounds for the combined preparation are: all antidiabetic agents described in Roten Liste 2001, Chapter 12. They can be combined in particular with the compounds of the formula I according to the invention to achieve a synergistic effect. The active compounds can be administered to a patient by administering them individually or in the form of a combined preparation of a plurality of active compounds contained in a medicament.

Antidiabetic agents include insulin and insulin derivatives, such as Lantus^*Or HMR 1964, GLP-1 derivatives such as those disclosed in Novo Nordisk A/S in WO 98/08871, and orally hypoglycemic active compounds.

Oral hypoglycemic active compounds preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers (such as those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861), insulin sensitizers, liver enzyme inhibitors involved in the stimulation of carbohydrate neogenesis and/or hepatic glucose breakdown, glucose uptake modulators, compounds that modulate lipid metabolism such as antihyperlipidemic active compounds and antilipidemic active compounds, compounds that reduce food intake, PPAR and PXR agonists, and active compounds that act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA reductase inhibitor such as simvastatin (simvastatin), fluvastatin (fluvastatin), pravastatin (pravastatin), lovastatin (lovastatin), atorvastatin (atorvastatin), cerivastatin (cerivastatin), rosuvastatin (rosuvastatin).

In one embodiment of the invention, the compounds of formula I are administered in combination with cholesterol absorption inhibitors such as ezetimibe, tiquinane, pamaquside.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR-gamma agonist such as rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), JTT-501, GI 262570.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR-alpha agonist such as GW 9578, GW 7647.

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR- α/γ agonist such as GW 1536, AVE 8042, AVE 8134, AVE 0847.

In one embodiment of the invention, the compound of formula I is administered in combination with a fibrate such as fenofibrate, clofibrate, bezafibrate (benzafibrate).

In one embodiment of the invention, the compound of formula I is administered in combination with an MTP inhibitor such as Bay13-9952, BMS-201038, R-103757.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor, such as HMR 1453.

In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as Bay 194789.

In one embodiment of the invention, the compounds of formula I are administered in combination with a polymeric bile acid adsorbent such as cholestyramine (cholestyramine), colesolvam.

In one embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor inducing agent, such as HMR1171, HMR 1586.

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor such as avasimibe (avasimibe).

In one embodiment of the invention, the compound of formula I is administered in combination with an antioxidant such as OPC-14117.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor such as NO-1886.

In one embodiment of the invention, the compound of formula I is administered in combination with an ATP citrate lyase inhibitor, such as SB-204990.

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor, such as BMS-188494.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein (a) antagonist such as Cl-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipase inhibitor, such as orlistat (orlistat).

In one embodiment of the invention, the compound of formula I is administered in combination with insulin.

In one embodiment, the compounds of formula I are administered in combination with a sulfonylurea, such as tolbutamide, glibenclamide, glipizide or gliclazide (gliclazid).

In one embodiment, the compound of formula I is administered in combination with a biguanide, such as metformin.

In another embodiment, the compound of formula I is administered in combination with a meglitinide such as repaglinide.

In one embodiment, the compound of formula I is administered in combination with a thiazolidinedione such as troglitazone (troglitazone), ciglitazone (ciglitazone), vicinal glitazone (pioglitazone), rosiglitazone (rosiglitazone) or a compound disclosed in WO 97141097 by dr. reddy's research focus, particularly 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione.

In one embodiment, the compounds of formula I are administered in combination with an α -glucosidase inhibitor, such as Miglitol (Miglitol) or bayer (acarbose).

In one embodiment, the compounds of formula I are administered in combination with an active compound that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glibenclamide, glipizide (gliazide) or repaglinide (repaglinide).

In one embodiment, the compound of formula I is administered in combination with more than one of the above compounds, for example in combination with sulfonylureas and metformin, sulfonylureas and bayer (acarbose), repaglinide (repaglinide) and metformin, insulin and sulfonylureas, insulin and metformin, insulin and troglitazone (trovastatin), insulin and lovastatin (lovastatin), and the like.

In another embodiment, the compound of formula I is administered in combination with a CART agonist, NPY agonist, MC4 agonist, orexin (orexin) agonist, H3 agonist, TNF agonist, CRF BP agonist, urocortin agonist, β 3-agonist, MSH (melanocyte stimulating hormone) agonist, CCK agonist, serotonin reuptake inhibitor, mixed serotonin and noradrenergic compounds, 5HT agonist, bombesin agonist, galanin antagonist, growth hormone releasing compound, TRH agonist, uncoupling protein 2-or 3 modulator, leptin (leptin) agonist, DA agonist (bromocriptin), dopexin), lipase/amylase inhibitor, PPAR modulator, RXR modulator, or TR-B agonist.

In one embodiment of the invention, the further active compound is leptin.

In one embodiment of the invention, the other active compound is dextroamphetamine or amphetamine.

In one embodiment of the invention, the further active compound is fenfluramine (fenfluramine) or dexfenfluramine (defefluramine).

In another embodiment, the other active compound is a tramadol (sibutramine).

In one embodiment, the other active compound is orlistat (orlistat).

In one embodiment, the other active compound is mazindol or phentermine.

In one embodiment, the compound of formula I is mixed with fibers, preferably insoluble fibers such as Caromax^*The administration is combined. And Caromax^*Can be provided in one formulation or administered separately with the compound of formula I and Caromax^*. Here, Caromax^*It can also be administered in the form of a food, such as a bakery or milk bar. The compound of formula I is compared to Caromax alone^*In addition to its potentiating effect, especially that associated with LDL cholesterol lowering, it is also characterized by an improved tolerability.

It is to be understood that each suitable combination of a compound of the invention with one or more of the above-mentioned compounds and optionally one or more other pharmacologically active substances is to be considered as being included within the scope of the present invention.

The invention also provides mixtures of stereoisomers of formula I and pure stereoisomers of formula I, mixtures of diastereomers of formula I and pure diastereomers. The mixture is separated by chromatography.

Preferred are racemic and enantiomerically pure compounds of formula I of the following structure:

preference is also given to compounds of the formula I in which the L radical has the following meaning:

the present invention also provides a process for the preparation of a compound of formula I, said process comprising obtaining a compound of formula I by a process analogous to the reaction scheme below.

R4' is (C)₀-C₃₀) Alkylene, where one or more carbon atoms in the alkylene may be replaced by-O-, - (C ═ O) -, -CH ═ CH-, -C ≡ C-, -N ((C ≡ C))₁-C₆) -alkyl) -or-NH-substituted.

Alternatively, the binding to the L group may be through ring a or ring C.

The following examples serve to illustrate the invention in more detail without limiting the invention to the products and embodiments described in the examples.

Example IV

N-4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzyl-N' - {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-2-ylamino) -propyl ] -phenyl } -adipamide (14)

a)5- {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-2-ylamino) -propyl ] -phenylcarbamoyl } -pentanoic acid (13)

Preparation started from 1.5g of 3- (2-amino-phenyl) -1-phenyl-2-pyridin-2-yl-3- (pyridin-2-ylamino) -propan-1-ol, 3.4g of adipic acid, 1.04g of dicyclohexylcarbodiimide and 640mg of benzotriazol-1-ol, analogously to example Iiif), product molecular weight 524.6 (C)₃₁H₃₂N₄O₄)；MS(ESI+)：525(M+H⁺)：(ESI-)：523(M-H⁺)

b) N-4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzyl-N' - {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1 (pyridin-2-ylamino) -propyl ] -phenyl } -adipamide (14)

Preparation is analogous to example III starting from 300mg of 4- (4-aminomethyl-phenyl) -1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxy-propyl in 25mg of tetrahydrofuran]-azetidin-2-ol, 372mg 5- {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-2-ylamino) -propyl]-phenylcarbamoyl } -pentanoic acid, 155mg dicyclohexylcarbodiimide and 120mg benzotriazol-1-ol, chromatography: SiO 2₂Dichloromethane/methanol 10: 1; product molecular weight 929.1 (C)₅₆H₅₄F₂N₆O₅)；MS(ESI+)：929(M+H⁺)

Example XIII

(1- {2- [8- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -octanoylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (27)

a)8- {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl- -1 (pyridin-2-ylamino) -propyl ] -phenylcarbamoyl } octanoic acid (26)

C₃₄H₃₈N₄O₄(566.72)MS(ESI)567(M+H)

b) (1- {2- [8- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -octanoylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (27)

C₆₁H₆₁F₅N₆O₇(1085，19)MS(ESI)971(M+H)

Example XIV

(1- {2- [8- (3- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -octanoylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-ylammonium trifluoroacetate (28)

C₆₁H₆₁F₅N₆O₇(1085.19)MS(ESI)971(M+H)

Example XV

(1- {2- [11- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -undecenylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (30)

a)11- {2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-2-ylamino) -propyl ] -phenylcarbamoyl } -undecanoic acid (29)

C₃₇H₄₄N₄O₄(608.82)MS(ESI)609(M+H)

b) (1- {2- [11- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -undecanoylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (30)

C₆₄H₆₇F₅N₆O₇(1127，28)MS(ESI)1013(M+H)

Example XVI

(1- {2- [11- (3- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -undecanoylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-ylpropyl) -pyridin-2-yl-ammonium trifluoroacetate (31)

C₆₄H₆₇F₅N₆O₇(1127.28)MS(ESI)1013(M+H)

Example XVII

(1- {2- [2- (2- {2- [ (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -ethoxy) -acetylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (33)

a) {2- [2- ({2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-2-ylamino) -propyl ] -phenylcarbamoyl } -methoxy) -ethoxy ] -ethoxy } -acetic acid (32)

C₃₃H₃₆N₄O₇(600.68)MS(ESI)591(M+H)

b) (1- {2- [2- (2- {2- [ (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -ethoxy) -acetylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl) -pyridin-2-yl-ammonium trifluoroacetate (33)

C₆₀H₅₉F₅N₆O₁₀(1119.17)MS(ESI)1005(M+H)

Example XVIII

(1- {2- [2- (2- {2- [ (3- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -ethoxy) -acetylamino ] -phenyl } -3-hydroxy-3-phenyl-2-pyridin-2-ylpropyl) -pyridin-2-yl-ammonium trifluoroacetate (34)

C₆₀H₅₉F₅N₆O₁₀(1119.17)MS(ESI)1005(M+H)

Example XIX

{1- [2- (2- {2- [ (4- {1- (4-fluorophenyl) -3- [3- (4-fluoro-phenyl) -3-hydroxypropyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -acetylamino) -phenyl ] -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl } -pyridin-2-yl-ammonium trifluoroacetate 36

C₃₁H₃₂N₄O₆(556.62)MS(ESI)557(M+H)

a)2- ({2- [ 3-hydroxy-3-phenyl-2-pyridin-2-yl-1- (pyridin-1-ylamino) propyl ] -phenylcarbamoyl } -methoxy) -ethoxy ] -acetic acid (35)

b) {1- [2- (2- {2- [ (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxy-propyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -acetylamino) -phenyl ] -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl } -pyridin-2-yl-ammonium trifluoroacetate (36)

C₅₈H₅₅F₅N₆O₉(1075.11)MS(ESI)961(M+H)

Example XX

{1- [2- (2- {2- [ (3- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxy-propyl ] -4-oxo-azetidin-2-yl } -benzylcarbamoyl) -methoxy ] -ethoxy } -acetylamino) -phenyl ] -3-hydroxy-3-phenyl-2-pyridin-2-yl-propyl } -pyridin-2-yl-ammonium trifluoroacetate (37)

C₅₈H₅₅F₅N₆O₉(1075.11)MS(ESI)961(M+H)

The activity of the compounds of formula I of the invention was determined using the following method.

Cholesterol absorption + as measured using mouse, rat and hamster excreta³Effect of H-taurocholic acid excretion

NMRI mice, Wistar rats or Golden Syrian hamsters (group n-4-6) were kept in metabolic cages where they were allowed to eat standard food (Altromin, lage (lippe)). In administration of a radiotracer(s) ((¹⁴C-cholesterol), the food was removed and the animals were acclimatized to the hurdle.

In addition, use³H-TCA (taurocholic acid) (e.g., μ Ci/mouse to 5 μ Ci/rat) labeled animals, 24 hours later orally administered test food: (¹⁴C-Cholesterol, at Intralipid^*20，Pharmacia-Upjohn)。

Cholesterol absorption test: intralipid of 0.25 ml/mouse was administered orally by gavage^*20(Pharmacia-Upjohn) (0.1 mg cholesterol insert 0.25. mu. Ci¹⁴C-cholesterol).

Test substances were prepared in 0.5% methylcellulose (Sigma)/5% Solutol (BASF, Ludwigshafen), respectively, or in suitable excipients. The test substance was administered in a volume of 0.5 ml/mouse. Test food was consumed immediately after the test substance administration (with¹⁴C-Cholesterol labeled Intralipid) (Cholesterol uptake assay).

Feces were collected over a 24 hour period: measurement after 24 hours¹⁴C-cholesterol and³fecal excretion of H-taurocholic acid (TCA).

The liver was removed and homogenized and aliquots were incinerated in oximate (Model 307, Packard) to determine the absorbed/absorbed¹⁴The amount of C-cholesterol.

Evaluation of

Stool sample:

the total weight was determined, the sample was replenished with water to a defined volume, then homogenized, and an aliquot was evaporated to dryness and incinerated in an oximate (Model 307, from Packard, for incinerating radiolabeled samples): from radioactivity³H-H₂O and¹⁴C-CO₂respectively deducing excretion³H-taurocholic acid and¹⁴the amount of C-cholesterol (dual isotope technique). ED as dose from dose-effect curves according to the control group of concurrent treatments₂₀₀Values were interpolated as the dose at which TCA or cholesterol excretion doubled.

Liver sample:

absorbed by the liver¹⁴The amount of C-cholesterol is based on the dose administered. ED from dose-Effect curves according to control group₅₀Interpolation of values into the liver¹⁴Dosage at which C-cholesterol absorption is halved (50%).

The following ED₅₀The values represent the activity of the compounds of formula I of the invention.

EXAMPLE No. ED₅₀(liver) [ mg/mouse]

XVI 0.03

XVIII 0.3

XIX 0.1

As can be seen from the table, the compounds of formula I have a very good cholesterol lowering effect.

Biological absorption

Bioabsorption of compounds of formula I was determined using a Caco cell model (a.r. hilgerset, Caco-2 cell nanolayers as a model for drug transport across the intestinal mucosa, Caco-2 cell monolayer as a model for drug transport across the intestinal mucosa), pharm. res.1990, 7, 902).

From the data determined, it can be seen that the absorption of the compound of formula I of the invention is significantly lower than that described in the prior art (control structure):

comparative example

Apparent partition coefficient

P_app [cm/s] 4.88×10^-06

(according to Lit. Hilgers)

Estimated human biological absorption of 100%

Comparative structure:

Ezetimibe

Claims (7)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein R1 is- (CH)₂)_0-1-NH-(C＝O)_0-1-(C₃-C₂₅) Alkylene- (C ═ O)_0-1-NH-L, wherein one or more carbon atoms of the alkylene group may be replaced by oxygen atoms,

r2, R3, R4, R5, R6 are independently H, F;

l is

R_x，R_y，R_zIs H.

2. A medicament comprising one or more compounds as claimed in claim 1.

3. A process for the preparation of a medicament containing a compound as claimed in claim 1, said process comprising mixing the active compound with a pharmaceutically acceptable carrier and bringing the mixture into a form suitable for administration.

4. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment of hyperlipidemia.

5. The use of a compound as claimed in claim 1 for the preparation of a medicament for lowering serum cholesterol concentrations.

6. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment of atherosclerosis.

7. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment of insulin resistance.