LT3369B - Substituted beta-lactam compounds useful as hypocholesterolemic agents and processes for the preparation thereof - Google Patents

Abstract

The formula of new compounds:<IMAGE>whereA is -CH=CH-B; -C=C-B; -(CH2)p-X-B, where p is 0-2 and X is a connection, -NH- or -S(O)0-2; heteroaryl or benzo-condensed heteroaryl are changed without distinction; -C(O)-B; or<IMAGE>;D is B'-(CH2)mC(O)-, where m is 1-5; B'-(CH2)q-, where q is 2-6; B'-(CH2)e-Z-(CH2)z-, where Z is -O-, C(O)-phenyl. -NR8- or -S(O)o-2-, e is 0-5 and r is 1-5 on condition that e and r sum is 1-6; B'-(alkenyl)-; B'-(alkadienyl)-; B'(CH2)t-Z-(alkenyl), where t is 0-3, on condition that the sum of t and the carbonic atoms in the alkenylene chain is 2-6; B'-(CH2)f-V-(CH2)g-, where V is cycloalkylene, f is 1-5, and g is 0-5, on the condition that the sum of f and g is 1-6; B'(CH2)a-Z-(CH2)b-V-(CH2)d-, where a, b and d is 0-6, on the condition that the sum a, b and d is 0-6; T-(CH2)s-, where T is cycloalkyl, and s is 1-6; naphthyl methyl or hetero aryl methyl without distinction;B is phenyl without distinction;B' naphthyl, heteroaryl without distinction or heteroarylmethyl without distinction;R is hydrogen, fluorine, alkyl, alkenyl, alkynyl or B-(CH2)h-, where h is 0-3;R4 is phenyl, indanyl, benzofuranyl, tetrahydronaphtyl, pyridyl, pyrizinyl, pyrimidinyl or chinolyl without distinction;are discovered, and also its use by the hypocholesterolemic agents; the method for use of the compounds of the II formula<IMAGE>whereR20 is phenyl without distinction, naphthyl without distinction, heteroaryl or benzo-condensed heteroaryl without distinction.R21, R22 and R23 are independently chosen from H or R20;E, F and G independently is a connection; cycloalkylene, alkylene; alkenylene; alkynylene; the changed alkylene, alkenylene or alkynylene chain, inserted alkylene, alkenylene or alkynylene chain; or inserted alkylene, alkenylene or alkynylene chain, changed by one or more surrogates; or one from R21-E and R22-F is chosen from the group, which consists of halogen, OH, alkoxy, -OC(O)R5, -NR10R11, -SH or -S(alkyl);R5 is alkyl, phenyl, R14-phenyl, benzyl or R14-benzyl;R10 and R11 are independently chosen from H and lower alkyl, or pharmaceutically their own salt, in a pharmaceutically proper carrier, as a hypocholesterolemic agent is also discovered.

Description

R 20 is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted heteroaryl, or optionally substituted benzo-fused heteroaryl,

R 21, R 22 and R 23 are independently selected from H or R 20;

E, F and G are independently a bond; cycloalkylene, alkylene; alkenylene; alkynylene; substituted alkylene, alkenylene or alkynylene chain, alkylene, alkenylene or alkynylene chain inserted; or an alkylene, alkenylene or alkynylene chain substituted with one or more substituents; or one of R 21 -E and R 22 -F is selected from the group consisting of halogen, OH, alkoxy, -OC (O) R 5, -NR 10 R 11, -SH or -S (alkyl);

R8 is alkyl, phenyl, Ru-phenyl, benzyl or Ru-benzyl;

R 10 and R 11 are independently selected from H and lower alkyl, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier as a hypocholesterolemic agent is also disclosed.

i

The present invention relates to substituted β-lactams used as hypocholesterolemic agents for the treatment and prevention of atherosclerosis and for the preparation of β-lactams.

Atherosclerotic coronary heart disease is the leading cause of death and cardiovascular disease in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes, heredity, male sex, smoking and serum cholesterol. Total cholesterol levels above 225-250 mg / dl are associated with a significant increase in risk.

Cholesterol esters are the most important component of atherosclerotic lesions and the most important form of cholesterol accumulation is in the cells of the arterial wall. The formation of cholesterol esters is also the most important part of the intestinal absorption of nutrient cholesterol. Internal cholesterol esterification in cells is catalyzed by the enzyme acyl-CoA: cholesterol acyl transferase (ACAT, EC2.3.1.26). Thus, inhibition of ACAT can inhibit the increase in the formation of atherosclerotic lesions, reduce the accumulation of cholesterol esters in the arterial wall, and block the intestinal absorption of nutrient cholesterol.

Few β-lactam compounds suitable for cholesterol reduction and / or inhibition of cholesterol lesion formation in mammalian artery walls have been reported. U.S. Pat. 4983597 discloses Nsulfonyl-2-azetodinones as anticholesterolemic agents and Ram et al. Indian J. Chem. Sect. B 29B, 12 (1990), p. 1134-7, discloses ethyl 4- (2-oxoazetidin-4-yl) phenoxy-alkanoates as hypolipidemic agents. EP no. Publication 264231 discloses 1LT 3369 B-substituted-4-phenyl-3- (2-oxoalkylidene) -2-azetidinones as inhibitors of platelet aggregation.

The novel hypocholesterolemic compounds of the present invention are represented by Formula ^N 'n

O R4 wherein A is -CH = CH-B;

-CsC-B;

(CH _{2) p} -XB, wherein p is 0,1 or 2 and X is a bond, -NHarba -S (0) _o _ _2;

heteroaryl, benzo-fused heteroaryl, W-substituted heteroaryl or W-substituted benzo-fused heteroaryl, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazylin, imidazole, thiazolyl, pyrazolyl, thienyl, oxanyl, N-oxides, and wherein W is 1-3 substituents on ring carbon atoms selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkandioyl, lower alkyl lower alkandioilo, allyloxy, -CF _3, -OCF _3, benzyl, R ₁₄ -benzyl, benzyloxy, R ₁₄ -benziloksilo, phenoxy, R ₁₄ -fenoklsilo, dioxolanyl, NO _2, -NR ₁₀ R n, NR ₁₀ R ₁₁ (lower alkyl ) -, NR, NR _n (lower alkoxy) -, OH, halogeno, -NHC (O) OR _5, -NHC (O) R _5, R _e o ₂ SNH-, (R ₆ O ₂ S) ₂ N- , S (O) ₂ NH ₂ , -S (O) O-2 R ₁₀ , tert -butyldimethyl silyloxymethyl, -C (O) R ₁₂ and

-ch ₂ -n

R ₁₃ , and wherein the substituents on the substituted nitrogen atoms in the heteroaryl ring, when present, are selected from the group consisting of lower alkyl, lower alkoxyl, -C (O) OR ₅ , -C (O) R ₅ , OH, NR ₁₀ R ₁₁ (lower alkyl) -, NR ₁₀ R ₁₁ (lower alkoxy) -, S (O) ₂ NH ₂ and -C (O) -B; with

R ₁₃ wherein k is 1 or 2;

D is B '- (CH ₂ ) _m C (O) -, wherein m is 1, 2, 3, 4 or 5;

B '- (CH ₂ ) _q -, wherein q is 2, 3, 4, 5ar 6;

B '- (CH ₂ ) _e -Z- (CH ₂ ) _r - wherein Z is -O-, -C (O) -, phenylene

-NR ₈ - or -S ( _O ) _o . ₂ ~, e is 0, 1, 2, 3, 4 or 5, and r is

1, 2, 3, 4 or 5, provided that the sum of e and r is 1,

2, 3, 4, 5 or 6;

B '- (C ₂ -C ₆ alkenylene) B' - (C ₄ -C ₆ alkadienylene) -;

B '- (CH ₂ ) _t -Z- (C ₂ -C ₆ alkenylene) -, wherein Z is as defined above, ot is 0, 1, 2 or 3, with the proviso that t and the number of carbon atoms in the alkenylene the sum in the chain is equal to 2, 3, 4, 5 or 6;

B '- (CH ₂ ) _f -V- (CH ₂ ) _g - wherein C is C ₃ -C ₆ cycloalkylene, f is 1, 2, 3, 4 or 5, og is 0, 1, 2, 3, 4 or 5, provided that the sum of f and g is 1, 2, 3, 4, 5 or 6;

B '- (CH ₂ ) _t -V- (C ₂ -C ₆ alkenylene) alkenylene)

-ar

B '- (C ₂ -C ₆

V- (CH ₂ ) _t -, wherein V and t are as defined above, provided that the sum of t and the number of carbon atoms in the alkenylene chain is equal to 2, 3, 4, 5 or 6;

B '- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d -, wherein Z and V are as defined above, oa, b and d are independently 0, 1, 2, 3 , 4, 5 or 6, provided that the sum of a, b and d is 0, 1, 2, 3, 4, 5 or 6;

T- (CH ₂ ) _s -, wherein T is cycloalkyl of 3-6 carbon atoms and S is 1, 2, 3, 4, 5 or 6; or naphthylmethyl, heteroarylmethyl, W-substituted heteroarylmethyl, where heteroaryl and W are as defined above;

B is

r ₂ r ₃

B 'is naphthyl, heteroaryl or W-substituted heteroaryl, where heteroaryl is as defined above, or

R is hydrogen, fluoro C _x -C ₁₅ alkyl, C ₁ -C ₁₅ alkynyl or B- (CH ₂ ) _h -, wherein h is 0, 1, 2 or 3;

R _1f R ₂ and R _{3 are} independently selected from the group consisting of H, lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl (lower alkoxyimino) lower alkyl, lower alkanediyl, lower acyl lower alkanediyl, allyloxy , -CF ₃ , -OCF ₃ benzyl, R ₁₄ benzyl, benzyloxy, R _u benzyloxy, phenoxyl, R ₁₄ -phenoxyl, dioxolanyl,

NO _2, -NR ₁₀ R ₁₁ (lower alkyl) -, NR _1X R _1O (lower alkoxy) -,

OH, o-halogen, m-halogen, -NHC (O) OR ₅ , -NHC (O) R ₅ ,

R ₆ O ₂ SNH-, (R ₆ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) O-2 R ₁₀ , tert-butyldimethylsilyloxymethyl, -C (O) R ₁₂

O

hydrogen, and R ₂ and R ₃ together with the adjacent carbon atoms to which they are attached form a dioxolanyl ring.

R _x ', R ₂ ' and R ₃ 'are independently selected from the group consisting of H, lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkandioyl, lower alkyl alkanedioilo, allyloxy, -CF _3, -OCF _3, benzyl, R ₁₄ -benzyl, benzyloxy, R ₁₄ -benzyloxy, phenoxy, R ₁₄ -phenoxy, dioxolanyl, NO _2, -NR _X1 R _{1O, 1O} NR _X1 R (lower alkyl) -, NR 10 _O R _{X 1} (lower alkoxy) -, OH, halogen, -NHC (O) OR ₅ , R ₆ O ₂ SNH-, (R ₆ O ₂ S) ₂ N-, -S (O) ₂ NH _2, S _{(O) 2} R ₁₀ _, tert butildimetilsililoksimetilo, -C (O) R _12,

O

-ch ₂ -n

R13 is

or R _x 'is hydrogen and R ₂ ' and R ₃ 'together with the adjacent carbon atoms to which they are attached form a diosolanyl ring;

wherein n is 0, 1, 2 or 3 indanyl benzofuranyl, benzodioxolyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl or quinolyl;

R ₅ is lower alkyl, phenyl, R ₁₄ -phenyl, benzyl or R ₁₄ -benzyl;

R ₆ is OH, lower alkyl, phenyl, benzyl, R ₁₄ phenyl or R ₁₄ benzyl;

R ₇ is lower alkyl, lower alkoxyl, OH, halogen, -NR ₁₀ R _n , -NHC (O) OR ₅ , -NHC (O) R ₅ , NO ₂ , -CN, -N ₃ , -SH, -S (O) _o _ ₂ - (lower alkyl), -COOR _9, -CONR ₁₀ R _X1, COR _12, phenoxy, benzyloxy, butildimetilsililoksilas and wherein

-OCF ₃ , or tertn is 2 or 3, R-, the groups may be the same or different;

R ₈ is hydrogen, lower alkyl, phenyl lower alkyl, or -C (O) R ₉ ;

R ₉ is H, lower alkyl, phenyl or phenyl lower alkyl;

R ₁₀ and R _{X 1 are} independently selected from H and lower alkyl;

R ₁₂ is H, OH, alkoxyl, phenoxyl, benzyloxy,

-NR ₁₀ R _n , lower alkyl, phenyl or R ₁₄ - phenyl;

R ₁₃ is -O-, -CH ₂ -, -NH- or -N (lower alkyl) -; and

R ₁₄ is 1-3 groups independently selected from the group comprising of lower alkyl, lower alkoxy, -COOH, NO _2, -NR R _{1O U,} OH or halo;

or a pharmaceutically acceptable salt thereof.

Preference is given to compounds of formula I wherein R is H. Another group of good compounds of formula I is that wherein D is B '- (CH ₂ ) _q -, B' - (CH ₂ ) _e -Z- (CH ₂ ) _r -. , B '- (C ₂ -C ₆ allenylene) -, or B' - (CH ₂ ) _f -V-CH ₂ ) _g -, wherein B ', Z, V, q, e, r, f and g are , as defined above. A third group of suitable compounds of formula I is that wherein R ₄ is phenyl, R ₇ substituted phenyl or indolyl. Another group of suitable compounds of formula I is that wherein A is - (CH ₂ ) _p -XB, wherein X, B and p are as defined above. Particular preference is given to compounds of formula I wherein D is: B '- (CH ₂ ) _q -, wherein B' is phenyl, oq is 3 or 4; B '(CH ₂ ) _e -Z- (CH ₂ ) _r - wherein B' is p-fluorophenyl or pmethoxyphenyl, e is zero, Z is -O-, or is 2; B '- (C ₂ -C ₆ alkenylene) - is 3-phenyl-1-propenyl; or B'- (CH ₂ ) _f -V- (CH ₂ ) _g -, wherein B 'is phenyl, f is 1, V is cyclopropylene, og is zero. Also particularly preferred are compounds of formula I wherein A is - (CH ₂ ) _p -XB, wherein p is zero and X is a bond. R _1f R ₂ and R _{3 are} preferably selected from H, OH, -NO ₂ , lower alkoxyl, alkoxyalkoxyl, lower alkyl lower alkanediyl, m-halogen, NR ₁₀ R 11 (lower alkoxy) -, allyloxy, phenoxyl, alkoxycarbonylalkoxyl and -C (O) R ₁₂ . Compounds wherein R _r and R ₃ are each H, and R ₂ is in the para-position are more suitable.

R _{7 is} preferably selected from lower alkyl, lower alkoxyl, halogen, -OCF ₃ , lower alkylthio, -NR ₁₀ R ₁₁ , -CN, OH and -COR ₁₂ . Better are those compounds where n is 1 and R _? is in para-position.

Particularly preferred compounds of the formula I wherein R is hydrogen are listed in Table 1 below.

TABLE 1 D 8th A r ₄ C ₆ H ₅ - (CH ₂ > ₃ - p-CH ₃ OC ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - c ₆ h ₅ - (ch ₂ ) ₄ - p-CH ₃ OC ₆ H ₄ - p-CH ₃ O-CgH ₄ - c ₆ h ₅ - (CH ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - c ₆ h ₅ - C ₆ H ₅ - (CH ₂ ) ₃ - p-OH-C ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂₎ 3 p-CH ₃ OC ₆ H ₄ - p-Cl-C ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) 3- p-CH ₃ CH ₂ -OC ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) 3- p-CH ₃ OC ₆ H ₄ - p-CH ₃ CH ₂ O-CgH ₄ - pFC ₆ H ₄ -O- (CH ₂ ) ₂ - p-CH ₃ OC ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - c ₆ h ₅ - (ch ₂ ) ₃ - p-CH ₃ O-CgH ₄ - pFC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - m-CH ₃ O-CgH ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - p-CF ₃ O-CgH ₄ - C ₆ H ₅ - (CH ₂ ) 3 ^- p-CH ₃ OC ₆ H ₄ - p-CH ₃ -CgH ₄ - c ₆ h ₅ -ch ₂ -ch = ch- p-CH ₃ O-CgH ₄ - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - P- (CH ₃ (CH ₂ ) ₃ ) -OC ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂₎ 3 p-CH ₃ O-CgH ₄ - p-CH ₃ S-CgII ₄ - C ₆ H ₅ - (CH ₂ ) 3- p- (CH ₂ = CH-CH ₂ -O) -c ₆ h ₄ - p-CH ₃ O-CgH ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p- (C ₆ H ₅ -O) -C ₆ H ₄ - p-CH ₃ OC, H ₄ - c, h ₅ - (CH ₂ ) 3- p- (CH ₃ CH ₂ O ₂ C) -C g H ₄ - p-ch ₃ 0-c ₆ h ₄ - c, h ₅ - (ch ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - U u C ₆ H ₅ - (CH ₂ ) ₃ - p- (CH-, CH ₂ CH ₂ -O) -c ₆ h ₄ - p-CH ₃ OC _f , H ₄ - C, H ₅ - (CH ₂ ) ₅ - p-CH ₃ OC ₆ H ₄ - p-CHjO-C, H ₄ - c 'h ₅ - (CH ₂ ) 3- p-CH-, O-CgH ₄ - p- ((CH _{3 CH?) 2} N) -C ₆ H ₄ - C..H ₅ - (CH _? ) ₃ - p- (CH-, CH ₂ O) -C ₆ H ₄ - c ₆ h ₅ -

< ^CH2 1

^^. ch ₂ -ch-ch- p-CH ₃ OC ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂₎ 3 p- ((CH ₃ ) ₂ CH-O) -C ₆ H ₄ - p-CH ₃ OC ₆ H ₄ - pFC ₆ H ₄ O- (CH ₂ ) ₂ - p-CH ₃ OC _e H ₄ - c ₆ h ₅ - C ₆ H ₅ - (CH ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - ifec-®- GgHj - (CH ₂ ) ₃ - p- (CH ₃ O ₂ C) -c ₆ h ₄ - C, H ₅ - C ₆ H ₅ - (CH ₂ ) ₃ - p-ch ₃ 0-c ₆ h ₄ - p- C ₆ H ₅ - (CH ₂ ) ₃ - -Qoch ₃ h ₃ co ^ p-CH, OC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p-CH ₃ OC ₆ H ₄ - p- (H ₃ CC (O)) - C ₆ H ₄ - c ₆ h ₅ - (ch ₂ ) ₃ - and ₃ p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p- (CH ₃ OCH ₂ O) -c ₆ h ₄ - c ₆ h ₅ - p-CH-10-O- (CH ₂ ) ₂ - p-CH ₃ OC ₆ H ₄ - c ₆ h ₅ - C ₆ H ₅ - (CH ₂ ) ₃ - p - (CH-.CHpC (O) CHO) -Cgft, - p-CH ₃ OC ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p- (CH, O-C (O) - (CH ₂ ) ₂ -C (O) O) -C ₆ H ₄ - p-CH ₃ OC ₍ H ₄ - c ₆ h ₅ - (ch ₂ ) ₃ - p ((CH ₃ ) -; N - (CH ₂ ) 3 -) - O -) - p-CHjO-C ₆ H ₄ - C ₆ H ₅ - (CH ₂ ) ₃ - p-HO-C ₆ H ₄ - p-HO-C ₆ H ₄ - She's J p-CH, O-C _fi H ₄ - c ₆ h ₅ -

In the above table, the first compound with (3R, 4S) absolute stereochemistry is preferred.

In another aspect, the invention relates to pharmaceutical compositions comprising novel β-lactam compounds of formula I of the present invention in a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of a cholesterol lowering compound having the structural formula II

R22

R21-E--

II

O R 20 wherein R ₂₀ is phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl and W-substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazole, thiazole, pyrazole, thienyl, oxosolyl and furanyl, and for nitrogen-containing heteroaryls, N-oxides thereof;

R _21, ^R 22 ^i-rr? 3 are independently selected from H or R _20;

W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkanediyl, lower alkyl, lower alkanediyl, allyloxy

-CF ₃ , -OCF ₃ , benzyl, R ₁₄ benzyl, benzyloxy, R ₁₄ benzyloxy, phenoxyl, R ₁₄ -phenoxyl, dioxolanyl, NO ₂ ,

-NR _n R _10, NR ₁₀ R _is (lower alkyl) -, NR R _{1O U} (lower alkoxy) -, OH, halogeno, -NHC (O) OR _5, -NHC (O) R _S,

R ₆ O ₂ SNH-, (R _fi O ₂ S) ₂ N-, -S (O) ₂ NH _2, -S (O) _o _ ₂ R _10, tert butildimetilsililoksimetilo, -C (O) R _12, / - <2 t - "CH2 ~ N R13 and -cN R13

E, F and G independent bonds, C ₃ -C ₆ cycloalkylene; C ₁ -C ₁₀ alkylene; C 1 -C 6 alkyleneyl; C ₁ -C ₁₀ alkynylene; the alkylene-alkynylene or alkynylene chain, as defined, contains one or more substituents selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl, wherein heteroaryl is as defined above; an alkylene, alkenylene or alkynylene chain, as defined, containing one or more groups independently selected from the group consisting of -O-, -S-, -SO-, -SO ₂ -, -NR ₉ , -C (O) - ,

C ₃ -C ₆ cycloalkylene, phenylene, W-substituted phenylene, heteroarylene and W-substituted heteroarylene; or an inserted alkylene, alkylene or alkynylene chain as defined, substituted with one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl; or one of R ₂₁ -E and R ₂₂ -F is selected from the group consisting of halogen, OH, lower alkoxy, -OC (O) R _5, -NR _u R _1O, -SH or -S (lower alkyl);

R ₅ is lower alkyl, phenyl, R ₄ -phenyl, benzyl, or R ₁₄ benzyl;

R ₆ is OH, lower alkyl, phenyl, benzyl, R ₁₄ phenyl or R ₄ benzyl;

R ₈ is H, lower alkyl, phenyl lower alkyl, or -C (O) R ₉ ;

R ₉ is H, lower alkyl, phenyl or phenyl lower alkyl;

R ₁₀ and R _n are independently selected from H and lower alkyl;

R ₁₂ is H / OH 'alkoxyl, phenoxyl, benzyloxy, / - 13

-NR R _{1O U,} lower alkyl, phenyl or R ₁₄ -phenyl;

R ₁₃ is -O-, -CH ₂ -, -NH- or -N (lower alkyl);

R ₁₄ is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxyl, -COOH, -NO ₂ , -NRyoRn, OH or halogen;

provided that when G is a bond, R ₂₃ is not H, and provided that when R ₂₃ is W-substituted phenyl, W is not p-halogen, or a pharmaceutically acceptable salt thereof; in a pharmaceutically acceptable carrier.

Notably, the novel compounds of Formula I are within the confines of Formula II.

Preference is given to compounds of formula II wherein R ₂₁ is H and E is a bond or lower alkylene and those wherein R ₂₁ is phenyl and E is lower alkylene. Also preferred are those compounds of formula II wherein R ₂₂ is H and F is a bond. Another group of more preferred compounds of formula II is where G is a bond and R ₂₃ is phenyl substituted with OH, -NO ₂ , lower alkoxy, alkoxyalkoxyl, m-halogen, lower alkyl, lower alkanediyl, NR ₁₀ R _:: (lower alkoxy) -, allyloxyl, phenoxyl, alkoxycarbonylalkoxy, and -C (O) R ₁₂ - Another group of suitable compounds of formula II is that wherein R ₂₀ is phenyl or phenyl substituted with lower alkyl, lower alkoxyl, halogen, -OC ₃ , lower alkylthio, -NR ₁₀ R ₁₁ , -CN, OH or acetyl.

Some of the compounds outside Formula I but within Formula II are novel. Examples of such compounds are shown in Table 2 below.

TABLE

R ₂ i E r ₂₂ -f- K23 G— K20 Ci ₀ H ₂₁ H C, H _E - 4-CH ₃ OC ₆ H ₄ - c ₁₀ h ₂₁ H C, H _S - 2,4,6-tri-CH ₃ OC ₆ H ₂ - c ₁₀ h ₂₁ - CH ₃ CH _2n - c _s h ₅ - 4-CH ₃ OC ₆ H ₄ - ^ 10 ^ 21 " C ₆ H (CH ₂ ) ₃ - c, h ₅ - 4-CH ₃ OC ₆ H ₄ - ^ 10 ^ 21 " CH ₃ CH ₂ - c, h ₅ - 2,4,6-tri-CH ₃ OC ₆ H ₂ - CioH ₂ i ~ ch ₃ ch ₂ - C, H _S -CH = CH- 4-CH ₃ OC ₆ H ₄ - ^ 10 ^ 21 " ch ₃ - c ₆ h ₅ - 4-CH ₃ OC ₆ H ₄ -

The present invention also relates to the use of compounds of formula I or II as ACAT inhibitors.

The present invention relates to a process for the preparation of β-lactams having hydrogen as well as the stereoselective formula I, wherein R is D and A is a trans relative stereochemistry, from hydroxyamide of formula

CH wherein D, A and R ₄ are as defined above for the cyclization of hydroxyamine, and wherein the hydroxyamine is derived from the carboxylic acid DCH ₂ COOH, the aldehyde A-CHO, and the amino R ₄ NH ₂ , wherein D, A and R ₄ are as as defined above, using a chiral auxiliary oxazolidinone of the formula

wherein R ₁₈ and R ₁₉ are independently selected from the group consisting of: hydrogen, Ο _χ- Ο ₆ alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, and benzyl, wherein the above chiral auxiliary is R - (+) - 4-Benzyl-oxazolidinone.

This process for the preparation of compounds of formula I, named Method D, wherein R is hydrogen and D and A are trans relative stereochemistry, comprises the steps of:

(a) reacting a carboxylic acid of formula D-CH ₂ COOH, wherein D is as defined above, with a chlorinating agent;

(b) deprotonating the chiral oxazolidane as defined above with R- (+) -4-benzyloxazolidinone in the first order with a strong base or a tertiary amino base and treating the resulting anion with the product of step (a).

(c) enolizing the product of step (b) or (I) dialkylboron triflate and a tertiary amine base:

or (ii) TiCl ₄ and tetramethylene diamine (TMEDA) or a mixture of TMEDA and triethylamine.

followed by condensation with an aldehyde of formula A-CHO wherein A is as defined above;

(d) hydrolyzing the product of step (c) with a base and hydrogen peroxide;

(e) condensing the product of step (d) with an amine of formula R ₄ NH ₂ , wherein R ₄ is as defined above, under the action of a dehydrating linking agent, optionally adding an activating agent;

(f) cyclizing the product of step (e), reacting the product of step (e) with:

(i) dialkyl azodicarboxylate and trialkyl phosphine; or (ii) di- or tri-chlorobenzoic chloride, an aqueous base solution and a heterogeneous catalyst, followed by treatment of the resulting di- or tri-chlorobenzoate with an aqueous base solution and a heterogeneous catalyst; or (iii) dialkyl chlorophosphate, an aqueous base solution and a heterogeneous catalyst; or (iv) di- or tri-chlorobenzoyl chloride and metal hydride.

Alternatively, the process of this invention provides the steps of preparing a β-lactam of formula I wherein R is hydrogen and D and A are trans relative stereochemistry from a β-aminoamide derivative of formula

R 'in the cyclization of the β-aminoamide, the carboxylic acids D, A and R ₄ are as used in the reaction of a chiral of the formula wherein the β-aminoamide is derived from DCH ₂ COOH and ACH = NR ₄ imine as defined above with auxazolidinone,

R ¹⁹

wherein R ₁₈ and R ₁₉ are as defined above, and the foregoing chiral auxiliary is R- (+) -4-benzyloxosolidinone in the first order.

This process for the preparation of compounds of Formula I, designated Method F, wherein R is hydrogen and D and A are trans relative stereochemistry, comprises the following steps:

(a) Enolizing the product of Method D (b) with TiCl ₄ and tetramethylethylenodiamine (TMEDA) followed by condensation with an imine of the formula A-CH = NR ₄ wherein A and R ₄ are as defined above;

(b) cyclizing the product of step (a) with a strong non-nucleophilic base, first order bistrimethylsilylamide.

Detailed Description:

The term lower alkyl as used herein refers to straight or branched alkyl chains of 1 to 6 carbon atoms, and lower alkoxy likewise belongs to alkoxy groups having 1 to 6 carbon atoms.

Alkenyl refers to straight or branched carbon chains having one or more conjugated or unconjugated double bonds in the chain, while alkadienyl belongs to chains having two double bonds in the chain. Similarly, alkynyl means straight or branched carbon chains having one or more triple bonds in the chain.

The terms alkenyl, '' alkenylene and alkynylene are used where the alkyl, alkenyl or alkynyl chain joins the other two variables and thereby becomes bivalent.

Cycloalkyl represents a saturated chain ring of 3 to 6 carbon atoms, whereas cycloalkylene belongs to a bivalent ring, respectively, wherein the point of attachment to the other groups includes all positional isomers.

Halogen means radicals of fluorine, chlorine, bromine or iodine.

Heteroaryl includes all positional isomers of the given heteroaryl group as defined above, for example 2-pyridyl, 3-pyridyl and 4-pyridyl. Benzo-fused heteroaryl belongs to the radicals formed by attachment of a benzene radical to adjacent carbon atoms in the heteroaryl ring; examples are indoline, quinolyl, quinazolinyl, quinoxalinyl, benzotriazolyl, indazolyl, benzoxazolyl, benzothienyl and benzofuranyl.

Phenylene means a bivalent phenyl group including ortho, meta and para substitution, while heteroarylene similarly means a bivalent heteroaryl group including all positional isomers.

(Lower alkoxyimino) lower alkyl belongs to the (C 1 -C 8 lower alkoxy) -N = CH- (C-Cc lower alkyl) group.

Lower alkanediyl means of formula

-OC (O) (CH ₂ ) _x . ₄ C (O) OH radical, while lower alkandioyl means radical of formula, while lower alkandioyl means alkyl of formula lower -OC (O) (CH ₂ )! - ₄ C (O) OH alkyl, lower

-OC (OH) (CH ₂ ) ₁ . ₄ C (0) 0 (lower alkyl) radical.

R ₁₄ benzyl and R ₁₄ benzyloxyl belong to the benzyl and benzyloxy radicals substituted on the phenyl ring.

Tertiary amine base means a trialkylamine such as triethylamine or diisopropylethylamine or a nitrogen-containing heterocycle such as pyridine.

Base refers to a metal hydroxide base such as lithium, sodium or potassium hydroxide.

A strong base refers to an anhydrous base such as a metal hydride or alkyl lithium.

Metal hydride refers to a commercially available hydride of a metal such as lithium, sodium or potassium.

Alkylitis refers to an alkylthiol reagent, such as n-butylitis, s-butylitis, t-butylitis or methylitis.

The dehydrating linking agent refers to a carboyimide such as 1- (3'-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DEC) or dicyclohexylcarbodiimide (DCC).

Active agent means an agent used to facilitate the formation of amide linkages such as 1-hydroxybenzotriazole (HOBT) or N-hydroxysuccinimide.

Halide salt means a metal halide salt such as sodium, lithium or potassium bromide.

Carbon chains as defined in E, F optionally substituted with phenyl groups, and G substituted with whether the heteroaryl substitution can have independent different carbon atoms, double substitution to one or two carbon atoms. An experienced person in his or her profession may notice the number of double or triple bond substitution in the chain and the presence of atoms in the chain, the number of substitutions that exist on carbon atoms depends on the length of the chain:

shorter carbon chains cannot accommodate as many double or triple bonds, carbon substitutions, or substitutions as longer carbon chains can. In essence, unsaturated carbon chains have from 1 to 4 double or triple, conjugated or unconjugated bonds. Where carbon atoms are substituted, 1 to 4 substitution groups may be present. Similarly, when the carbon atoms in the chain are replaced, there may be 1 to 4 substituents. Examples of alkyl chains include methyl, ethyl, propyl, butyl and decyl.

Examples of unsaturated groups E, F and G are ethylene and acetylene. E, F and G groups wherein the carbon atoms in the chain are substituted examples of -CH ₂ CH ₂ O-, OCH ₂ CH ₂ -, -CH ₂ O-, -CH ₂ CH ₂ CH ₂ O-, -CH ₂ -O -CH ₂ -, -CH ₂ CH ₂ -O-CH ₂ , -CH ₂ CH ₂ -NH-, -CH ₂ CH ₂ -N (CH ₃ ) -, and -O-CH ₂ -C (O) - NH-.

The compounds of the invention have at least one asymmetric carbon atom and therefore all isomers, including diasteromers and rotational isomers, are intended to be part of the present invention. The invention relates to d and r isomers, whether or not pure, including racemic mixtures. The isomers may be prepared by conventional techniques either by reaction of the enantiomeric starting materials or by separation of the isomers of the compound of formula I or II.

Isomers may have geometric isomers, for example when E, F or G has a double bond. All of these isomers are implicit in the present invention.

Those skilled in the art will readily appreciate that, for some compounds of Formulas I and II, one isomer may have a greater pharmacological activity than the other isomer. The amino compounds of the invention may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation include salt, sulfur, phosphorus, vinegar, citric, oxelic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salt is obtained by contacting the free base form with a sufficient amount of the desired acid to form the salt. The free base form can be recovered by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs in some degree from its corresponding salt form in some physical properties, such as solubility in polar solvents, but on the other hand, for purposes of the invention, the salt is equivalent to its corresponding free base form.

Some of the compounds of the invention are acidic (e.g., those having a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases.

Examples of such salts include sodium, potassium, calcium, aluminum, gold and silver salts. Salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like are also included.

The compounds of formula I and II can be obtained by a number of known methods, and in particular the compounds with trans stereochemistry can be obtained by the new method D disclosed in U.S. Pat. 07/734, 426, filed July 23, 1991, or by a new F method.

Method A:

Compounds of formula Ia and Ib, wherein A, D, R and R ₄ are as defined above, can be obtained by treating an ester of formula V wherein R ₁₅ is lower alkyl such as ethyl or a chiral moiety such as menthyl or 10- (diisopropylsulfonamido) -isobornyl, with a strong base such as lithium diisopropylamine in a suitable solvent such as tetrahydrofuran (THF) at -78 ° C. The co-solvent may optionally be Hexamethylphosphoric triamide (HMPA). The imine of formula IV is introduced into the reaction mixture, warmed to room temperature, and the product is isolated using conventional purification techniques. When a chiral ester of formula V is used, the resulting compound of formula Ia or Ib is not racemic.

Id base alkylating agent acylating agent (R = H) base alkylating agent acylating agent (R = H)

Ia (R * H)

Ib (R * H)

Compounds of formula Ic and Id can be converted to compounds of formula Ia and Ib by treatment with a strong base such as lithium diisopropylamide in a suitable solvent such as THF in the presence or absence of HMPA at -78 ° C with the addition of an alkylating agent RR ₁₇ or acylating agent. agent, such as RC (O) O-alkyl or C (O) C1, where R is as defined above except that R is not hydrogen, and R ₁₇ is a leaving such as a bromo or iodo group.

Method B ':

The trans compounds of formula Id can be converted to the corresponding compounds of formula Ic using Method B above, but using a proton source such as acetic acid in place of the alkylating agent.

Method C:

Trans compounds of formula Id wherein R is hydrogen and A, D and R _x are as defined above can be obtained by treating trans compounds of formula Ic with a strong base such as lithium diisopropylamide or potassium t-butoxide, suitable as THF, in solvent. It will be appreciated by those skilled in the art that, although the reaction conditions of Method C may be similar to those of Method A, there will sometimes be a local conversion to trans under the conditions of Method A.

Method D

COOH chlorinating agent

-D ^^ COCI

XIV

Tier XM

A-CHO

XVII

XVI (alkyl) ₂ BSOgCF ₃ , tertiary amino base or

TiCl ₄ , TMEDA (or TMEDA + Tier D3 Triethylamine)

H ₂ O ₂ / base

XVIII O OH

Tier D4

XIX r ⁴ nh ₂

XX

OH r ⁴ nh coupling agent activating aaent v · Step D5

XXI

XXI (i) P (alkyl) 3 + dialkyl azodicarboxylate;

or (ii) di- or tri-chlorobenzoyl chloride, aqueous base, phase transfer reagent; or (iii) dialkyl chlorophosphate, aqueous base, phase transfer reagent; or iv) di- or tri-chlorobenzoyl chloride + alkali metal hydride

Tier D ₆

In step D of method D to obtain compound XIV, the carboxylic acid XIII is treated with a chlorinating agent, e.g. thionyl chloride or oxalic chloride in a dry atmosphere without being disclosed or in a suitable inert solvent, e.g. toluene at 70 ° C.

In step D2, compound XV is converted to compound XVI by a two-step reaction, the first being deprotonated with a strong base such as alkyl lithium, e.g. n-butyllithium or a metal hydride, e.g. sodium hydride or a tertiary amine base such as triethylamine in a suitable anhydrous organic solvent, e.g. dry THF in a dry, inert atmosphere, e.g. nitrogen, about 0 ° to -85 ° C, preferably about -78 ° C, about 30 to 90 minutes. a second time, preferably about 60 minutes, in a second anion obtained without reacting it with compound XIV in a suitable anhydrous organic solvent, e.g. in dry THF in a dry inert atmosphere, e.g. nitrogen at about -50 ° C to about -85 ° C, preferably about 78 ° C, for about 30 to 60 minutes, preferably about 45 minutes, followed by reaction at about -10 ° C to about 10 ° C preferably about 0 ° C for about 30 to 90 minutes, preferably about 60 minutes, followed by extraction of the product with compound XVI.

In step D3, compound XVI is treated with dialkylboron triflate, e.g. di-n-butylboron triflotas (BH ₂ BSO ₃ CF ₃ ) in a suitable inert organic solvent, e.g. CH ₂ Cl _{2 in a} dry, inert atmosphere such as nitrogen at about -60 ° C to about 10 ° C, preferably about -10 ° C to about 0 ° C for about 10 minutes. Tertiary amine base e.g. diisopropylethylamine is added at about -10 ° C to about 0 ° C, preferably about -6 ° C to -3 ° C, about 20 to 40 minutes, preferably about 30 minutes. The mixture is stirred at about -50 ° C to about -85 ° C, preferably about -78 ° C, about 20-40 minutes, preferably about 30 minutes, and then treated with compound XVII at about -50 ° C to about -50 ° C. 85 ° C, preferably about -78 ° C, for about 20 to 40 minutes, preferably about 30 minutes.

The mixture is stirred at about -10 ° C to about 5 ° C, preferably about 0 ° C, about 30 to 90 minutes, preferably about 60 minutes, then quenched with aqueous pH 7 buffer, e.g. aqueous KH ₂ PO ₄ in both NaOH and methanol and hydrogen peroxide, preferably 30% hydrogen peroxide, at about -5 ° C to 5 ° C, preferably about 0 ° C, for about an hour. The product is isolated by extraction and crystallization from a suitable solvent, e.g. hexane / ethyl acetate to give compound XVIII.

Step D3, alternatively, comprises treating Compound XVI with titanium tetrachloride (TiCl ₄ ) in a suitable inert organic solvent, e.g. CH ₂ Cl ₂ , about -60 ° C to 0 ° C, preferably about -25 ° C to -15 ° C, preferably about -20 ° C, for about a minute. Tetramethylenediamine (TMEDA) or a combination of TMEDA and triethylamine is slowly added over 10 min. over a temperature range of -25 ° C to -10 ° C. The mixture is stirred at a temperature of about -25 ° C to -10 ° C, preferably about 30 to 90 minutes for 60 minutes, and then treated with a compound of formula XVII at a temperature of about -25 ° C ''', preferably about , at -15 ^q C to -10 ° C, the gap, preferably about to

-15 ° C

10 ° C for a period of 30 to 90 minutes,

^U -10 C and preferably min., Then stirred at 30 to 60 minutes, preferably about 40 minutes in a heated approximately from 0 ° C to 10 ° C, preferably about 10 ° C. The mixture is quenched with aqueous tartaric acid, preferably with about 10% tartaric acid and water. The product is then isolated by extraction from a suitable solvent such as ethyl acetate / hexane to give compound XVIII.

In step D4, the compound is treated with hydrogen peroxide, preferably 30% hydrogen peroxide in an inert organic solvent, e.g. THF / water, at about -5 ° C to 5 ° C, preferably about 0 ° C, about 10 7 20 minutes, preferably about 15 minutes, then about 5 ° C to 5 ° C, preferably about 0 ° C, with a base, e.g. lithium hydroxide for about 2 to 4 hours, preferably about 3 hours, until the starting material is removed by thin layer chromatography (TLC). Excess peroxide is removed by adding a solution of sodium sulfide in water to the mixture over a period of about 30 to 90 minutes, preferably about minutes. The solvent is removed in vacuo and the residue is diluted with water. Compound IV is recovered from the mixture by extraction with a suitable solvent, e.g. toluene. The remainder is acidified using a salt in an inert organic aqueous acid solution, to about pH 2-3, preferably about pH 2.4.

The product is isolated by extraction using a suitable inert organic solvent, e.g. ethyl acetate to give compound XIX.

In step D5, compound XIX is reacted with compound XX, a dehydrating coupling agent, e.g. dicyclohexylcarbodiimide (DCC) and an activating agent, e.g. 1-hydroxybenzotriazole (HOBT) in a suitable inert organic solvent, e.g. dimethylformamide or acetonitrile at about 25 ° C to about 50 ° C, preferably about 40 ° C. The reaction is continued for about 4 hours, until the starting material is depleted by TLC. The product is isolated by extraction to give compound XXI. _In step D6, compound XXI is cyclized by treatment with triphenylphosphine or preferably trialkylphosphine, e.g. tri-n-butylphosphine and dialkyl azodicarboxylate, e.g. diethyl azodicarboxylate (DEAD) in a suitable anhydrous organic solvent, e.g. dry THF in a dry, inert atmosphere, e.g. nitrogen at about -50 ° C to about -85 ° C, preferably about -70 ° C, for about 1 to 3 hours, preferably about 2 hours. The reaction is then continued at room temperature for about 12 to 24 hours. The compound of formula I is purified by preparative high performance liquid chromatography (HPLC) to give a trans stereochemistry. The use of tributylphosphine in this step yields a much higher reaction yield than the triphenylphosphine. Step D6 alternatively consists of compound XXI and a suitable heterogeneous catalyst, e.g. of tetra-n-butylammonium hydrosulfate in a suitable solvent such as methylene chloride. The mixture is stirred under cooling at about 20 ° C to about 0 ° C, preferably about 20 ° C to about 10 ° C, and then treated with an aqueous base such as an alkali metal hydroxide, preferably 50% aqueous sodium hydroxide. Di- or tri-chlorobenzoyl chloride, preferably 2,6-dichlorobenzoyl chloride, or trichlorobenzoyl chloride 2,4,6,669 B is slowly added over a period of 60 minutes, preferably about 30 minutes. The mixture is stirred at about 0 ° C to about 25 ° C, preferably about 15 ° C to about 20 ° C, over a period of 2-4 hours, preferably about 3 hours, and then poured into cold water. The organic layer is separated and washed with water to neutral pH. The di- or tri-chlorobenzoate product is isolated by crystallization from methylene chloride / heptane. The di- or tri-chlorobenzoate product is coupled with a suitable heterogeneous catalyst, e.g. benzyltriethylammonium chloride in a suitable solvent such as a mixture of methylene chloride and methyl t-benzyl ether. The mixture is stirred at about 0 ° C to about 20 ° C, preferably about 15 ° C to 20 ° C, and treated with an aqueous base, e.g. alkali metal hydroxide. After 2 to 4 hours, the organic layer was mixed with hydroxide, preferably 50% sodium, for 6 hours with stirring, preferably poured into ice water, washed with water to neutral pH. The product is isolated by removal of the solvent, followed by purification by chromatography and recrystallization from a suitable solvent to give the compound of formula I with trans-stereochemistry.

A third alternative to Step D6 comprises the treatment of Compound XXI in a suitable solvent such as CH ₂ Cl ₂ with a dialkyl chlorophosphate, preferably diethyl chlorophosphate and an aqueous base such as an alkali metal hydroxide, preferably 50% aqueous sodium hydroxide, in the presence of a heterogeneous catalyst such as n-butylammonium hydrosulphate, or benzyltriethylammonium chloride.

Another alternative of step D6 is treatment of compound XXI with di- or trichlorobenzoyl chloride, preferably 2, 6-dichlorobenzoyl chloride or 2, 4, 6-trichlorobenzoyl chloride and a suitable base such as sodium hydride in a suitable solvent such as CH ₂ Cl ₂ , dimethylformamide or a combination thereof. The product is isolated and purified by chromatography followed by crystallization from a suitable solvent, e.g. ether / hexane. All starting materials XIII, XVII and XX are either commercially available or well known and may be obtained by known methods.

Method E: D y * z ( ₊ Ί ( R ^ k L J r Ra IV XII I a Compounds of formula Ia yes pat can to be to receive, affecting the formula IV imin activated carboxylic acid derivative, whose formula XII, at to the base,

such as triethylamine, tributylamine or diethylisopropylamine in an inert solvent such as CH ₂ Cl ₂ , heptane or toluene. Activated carboxylic acid derivatives of formula XII include acid chlorides (L = Cl), mixed anhydrides with phenyl phosphorus dichloridate (L = OP (O) OPh) and N-methylpyridine esters formed with acid and N-methyl-2-chloropyridine iodide (L = 2). -oxy-N-methylpyridine iodide) in the reaction. The starting materials of formulas IV and V are known or can be obtained by well known methods.

Method F:

Tier F2

In step F1, dissolve in chloride, after

Compound XVI (From Method D, Step 2) in a suitable solvent, e.g. methylene is then treated with titanium tetrachloride at about -60 ° C to about 0 ° C, preferably about -25 ° C to -15 ° C in a dry inert atmosphere, preferably nitrogen, for about 5 minutes. TMEDA is added to the mixture and stirred at approximately -60 ° C to -10 ° C, approximately -25 ° C to -20 ° C for one hour. persuasive (A-CH = NR ₄ ) is added slowly over a period of about 20 to 40 minutes, preferably about 30 minutes and about -60 ° C to 0 ° C, -25 ° C to -15 ° C, 20 to 40 minutes, preferably about 30 minutes. The mixture is then warmed to about 0 ° C and the reaction is checked by high performance liquid chromatography (HPLC) until complete. Subsequently, the mixture is poured into a solution of tartaric acid in water, preferably 10% tartaric acid. The product is isolated by extraction with a suitable solvent, e.g. ethyl acetate, followed by purification by crystallization.

the mixture is mixed, preferably, approximately,

In step F2, product F1 is treated with a strong non-nucleophilic base such as sodium or lithium bistrimethylsilylamide in a suitable inert organic solvent, e.g. CH ₂ Cl _{2 at} about -20 ° C to about 10 ° C, preferably about 0 ° C. The mixture is stirred with gradual heating to about 20 ° C v 25 ° C, followed by HPLC until the starting material is complete, typically after a period of 1 to 2 hours. The reaction mixture is poured into aqueous tartaric acid, preferably 10% tartaric acid, and the product is isolated from the organic layer.

The imines of formula A-CH = NR ₄ can be obtained from aldehydes of formula A-CHO and the amines of formula R ₄ -NH _{2 according} to well-known methods. A-CHO aldehydes and amines of formula R ₄ -NH ₂ are commercially available or can be obtained by well known methods.

By the methods of formula II to the compounds.

the compounds may be obtained analogous to those described in formula I

From the examples that follow, it will be apparent to those skilled in the art that the compounds of Formulas I and II can be converted into different compounds of Formulas I and II in well-known ways. For example, a compound of Formula I where A has a double or triple bond or Formula II where G has a double or triple bond can be converted to the corresponding saturated compound under the action of hydrogen gas in the presence of palladium or platinum on carbon.

Reactive groups other than those mentioned above may be protected during the reaction by conventional protecting groups, which may be disclosed after the reaction by standard methods. The following Table 3 shows some typical protecting groups:

Table 3

Group, need making to protect The group to be protected and the protecting group COOH -COOalkyl, -COObenzyl, -COOphenyl \ NH / \\\ NCOalkyl, NCObenzyl, NCOphenyl, / / / \ \ NCH ₂ OCH ₂ CH ₂ Si (CH ₃ ) ₃ , NC (0) OC (CH ₃ ) ₃ . / / \ N-benzyl, / 0 CH ₃ \ \ 1 NSi (CH _{3) 3,} NSi-C (CH) ₃ / / ₃ 1 CH -nh ₂ Ό 0 ch ₃ i -OH -och ₃ , - 1 • OSi (CH ₃ ) ₃ , - OSi-C (CH) ₃ I 1 ch ₃

The compounds of the present invention have been found to lower serum lipids, particularly serum cholesterol. The compounds of the present invention have been found to inhibit cholesterol absorption in the gut and significantly reduce the formation of cholesterol esters in animal models of liver. Some compounds also inhibit ACAT in the tube. Thus, the compounds of the present invention are hypocholesterolemic agents in their ability to inhibit esterification and / or cholesterol absorption in the gut, and are therefore suitable for the prevention and treatment of atherosclerosis in mammals and in particular humans. Therefore, together with the compound aspect, the present invention also relates to a method of lowering serum cholesterol, which comprises administering to a mammal in need of such treatment an effective amount of a hypocholesterol compound of formula I or II. The compound is preferably administered orally in a pharmaceutically acceptable carrier.

The activity of the compounds of formula I or II in the tube and in the body can be determined as follows.

AGAT assay in vitro mg / ml BSA microsomal (sufficient

This assay measures ACAT activity by measuring the transfer of an ACAT-mediated tritium oleic acid from acyl-CoA to cholesterol to form labeled cholesterol oleate. Rat liver microsomes were used as the ACAT source. Assays are performed in round-bottomed microtitre plates using a well incubation volume of 50 μΐ. 10 μΐ of assay buffer (0.5 M KHPO ₄ , 10 μΐ of dithiothretol, pH 7.4), 7.5 μΐ (bovine serum albumin), and 12.5 μιη protein were added to each incubation tank. Add test compound volume to final concentration of 0.1 to 25μ1), reference compound or vehicle control, and make final volume 47 μΐ. The microtitre plate is then placed on the surface of a 37 ° C water bath for 15 minutes. Incubation begins with the addition of 3μ1 of 3HacilCgA (1 Ci / well, final concentration of 10 μΐ of acylCoA). The plate is then placed on the water bath again for 15 minutes. The incubations were completed by placing 15 μΐ separate narrow strips from each incubation on a thin-layer plate (silica gel GF 20X20 cm). The standards are adapted to several strips so that cholesterol can be identified After drying the plates are eluted with ether: diethyl ether: acetic acid. Standards are developed with iodine vapor and strips corresponding to cholesterol esters are scraped into 7 ml scintillation vials. To each jar an ester group. 90: 10: 1 petroleum is added with 4 ml of scintillant and the amount of radioactivity is determined. The background count is determined from the welded controls. Total activity is determined by the activity in the presence of the carrier. Percentage inhibition is calculated by subtracting the background from the control and test samples and the test value is calculated as a percentage of the control. The IC ₅₀ is plotted against dose dependence of the drug on a logarithmic scale and the concentration at which 50% inhibition is obtained.

In vivo trial of hypolipidemic agents using hyperlipidemic hamsters

Hamsters are divided into groups of six and seven days on a controlled cholesterol diet (Purina Chow # 5001 containing 0.5% cholesterol). Dietary intake is controlled to determine dietary cholesterol in the presence of test compounds. The animals are dosed with test compounds once daily starting on the same day as the diet. Dosing is carried out by administering 0.2 ml of pure corn oil (control group) via the tube into the stomach, or a solution (or suspension) of the test compound in corn oil. All animals that die or are in poor physical condition are killed. Seven days later, the animals were anesthetized with SM ketamine injection and dissected. Blood is collected in vacuum tubes containing EDTA for plasma lipid analysis and liver for tissue lipid analysis. The data obtained are plotted as percentage lipid reduction compared to controls.

The latter invention also relates to a pharmaceutical composition comprising a compound of formula I or II of the present invention and a pharmaceutically acceptable carrier. The compounds of Formula I or Formula II may be administered in any conventional oral dosage form such as capsules, tablets, powders or pastes in which the tasteless tablet is hidden, suspensions or solutions. Dosage forms and pharmaceutical compositions may be prepared using conventional pharmaceutically acceptable media and additives, and conventional techniques. Such pharmaceutically acceptable media include non-toxic compatible excipients, binding agents, disintegrating agents, buffers, preservatives, antioxidants, lubricants, flavoring agents, solubilizers, coloring agents, emulsifiers, and the like. The daily dose of a compound of formula I or II is approximately 7 to 30 mg / kg / day. Therefore, for a 70 kg bodyweight of average weight, the dosage level is approximately 500 to 2000 mg of drug per day in single or 2-4 divided doses. However, the actual dose will be determined by the practitioner and will depend upon the efficacy of the compound being administered, the age, weight, condition and response of the patient.

The following are examples of the preparation of compounds of formulas I and II. The recorded stereochemistry is relative stereochemistry except as otherwise noted. The terms eis / trans belong to the relative orientations at the beta-lactam-3- and 4-positions, each mono-substituted (e.g., R = 4).

EXAMPLE

Prepare lithium diisopropyl amide (LDA) by dissolving 23.96 mL (17.39g, 172 mmol) of diisopropylamine in 230 mL of dry THF at -78 ° C under nitrogen. Add 103.9 mL (166 mmol @ 1.6 M in hexane) of n-butyllithium and stir at -78 ° C for one hour. To this cold solution, add 32.58 g (158 mmol) in about one hour

5-Phenyl valeric acid ethyl ester in 195 mL of dry THF while maintaining the reaction temperature below -65 ° C. Stir at -78 ° C for one hour, then add 38.13 g (158 mmol) of 4-methoxybenzylidine anisidine in 350 mL of dry CH ₂ Cl ₂ . Allow the reaction to slowly return to room temperature and the resulting precipitate will begin to dissolve. Stir the reaction mixture for 16 hours at room temperature. Divide the mixture between 1.2 L IN aqueous hydrochloric acid (HCl) and 1 L ether. Wash the ether layer with 300 mL IN HCl. Combine the acid layers and extract with 1 liter of ether. Combine the ether extracts, dry over MgSO _4, and concentrate in vacuo. Crystallize the precipitate with 200 mL of ethyl acetate-hexane (1: 1) to give the racemic compound 32.05 above, very white crystals, mp 90-93 ° C. Compounds listed in Tables 4 and 4A can also be obtained using a similar method.

Data com 120.5-122.0 "C com 120.5-121.5 "C O m • CN <Ti 1 O CN σ » 4- » r-4 u 7th CN m t-4 1 tH m -P r-4 O ? 00 m i "4 1 LD LT) i-4 -P f-1 CI MS: (M + 1) 432 en 116-117 ^W C 1 F · X <£> U i 1 CU X UJ U i 1 CU 1 X KO U i 1 Oops 1 F · X co U i 1 CU 1 IT X co U i 0, 1 -r X kO O i 1 • H M 4J 1 CO M · K CN 'T X KO u i 1 CU Atitin- stuff stereoche- intersection w oh n X * 3 * % X cn X κ cn n cn M * K cn m X M * cn m 4: 1 will go for it trans X T cn m 1 ιΛ X NC U 1 iT> X • X O 1 • j *> X KO O 1 14 *) X co O 1 m X KO O L- · X O 1 X £> O 1 CN 1 CU oh 1 U7 X KO U X X X X X X Q. 1 o u OJ X υ 1 and> X u 1 ΠΊ CM X u Lfl X k £> U l m CN X U 1 Lf> X KO u 1 CM CM X u 1 iZ) X kO U t CM CM X O 1 m X kO u 1 ΓΊ CN X u 1 L; *) X KO u 1 m CN X O 1 iD X KO u N £ < r-4 X i-H u H Q. r-4 w i-1 X r-1 o «—1

CONTINUATION

en 120.5-122.O ^U C FAB MS: (M + 1) 486.2 FAB MS: (M + 1) 486.2 en 119.5-120.5 C com 152.5-155.0 "C o 3 X X f X X • P rH com 90.5-91.0 "C * W> K 33 rH X X X X rH cm m 10 * »*» *. · » 2 2 n 6 r- σι o o m o · r ~ - σ oo oo oo r ~ kO ro rH «3 cn Oh X X X X LJ rH X rH rH CJ v. {g 03 g ^ 0 p g x o cn o CM CM CM X · · «· rH x r * * i * cn item. analysis C = 68.56, H = 5.31, N = 3.08; found: C = 68.32, H = 5.12, N = 2.97 1 .r s kO O i et 1 -T X kO U i 1 • H M P 1 K CM 1 -T 2 kO U i 1 • H M 4- » 1 * 3 · CM 1 X ό U i 1 CU 1 X kO U i 1 et 1 'T X kO CJ i 1 CU 2 kO U i 1 et rH > 1 2 • H M > 1 CU 1 m 1 -r 2 kO U 1 9, 2 O 1 (i.e. 3R, 4R cn cn cn cn oh cn cn cn cn cn cn cn cn cn cn cn * 3 » cn cn n c (d M -P n C (0 M JJ 1 x kO u 1 CM S 1 Λ 1 2 U II 2 U tn 2 kO U 1 1 2 U II 2 U 1 n 2 kO U 1 2 U II 2 U n 2 kO U 1 «T 2 kO U 1 2 O 0. 2 Y 2 U 1 v 2 kO U et 1 > tr X kO CJ 1 Y 2 1 n 1 X kO u i 1 CU 1 'T X • θ ' CJ 1 Y 2 et 2 1 c \; 2 U n 2 U 1 , N X u m X o 2 2 2 2 2 2 t ΡΊ <\ l 32 U tn X kO U 1 m CM X u □ Ί X kO u 1 m CM X u 1 X kO u 1 m CN X u 1 ιΛ X kO U I n CM X cj X kO U 1 n CM X cj 1 m X kO u 1 m cm X CJ 1 L · *) X kO U 1 P, CM X o 1 u *> X kO u 1 Γ2 CN X o U7 X kO CJ 1H Η » rH • o rH 2 rH u rH 2 rH 2 rH t-1 1-i

CONTINUATION

item. analysis C = 73.97, H = 5.96, N = 3.45, found: Cl, 8.73; 073.63, H = 5.92, N = 3.52, Cl = 9.12 item. analysis 081.01, H = 7.06, N = 3.63 found: 080.97, H = 7.06, N = 3.74 item. analysis 080.32, H = 6.31, N = 3.02 found: 080.26, H = 6.27, N = 3.18 en 101.5-102.5 ° C V £> r — 1 in II »—1 έ i H U a 5 m 00 1 v oo 4- » H DC cO U 1 r-l U 1 1 X C £> U 1 ΠΊ DC U 1 <x 1 'T 33 KO O 4 DC U 1 CL 1 33 KO O 1 9th X O 1 n. 1 M · 33 kO U 1 9th DC U 1 a 1 <r 33 kO O 1 9th DC υ 1 Cu will go <n • r | ϋ ra c (C M 4-1 ra c (0 u 4- » n ♦ H Uh 1 'J' 33 KO O i 1 w • H 0 1 v 33 co U $ s i • T 33 KO U 1 9th DC O 1 M * wow 1 CN m DC U • H cn DC m U n cn UA DC U o - o 1 CN n 33 U • H W X U? n U n CN X X u u - o 33 DC 33 33 DC X en CM 33 O In 33 KO O 1 m CM X O 1 1D 33 KO U 33 1 m CK) 33 O 1 tn 33 KO u cn CM 33 O L ~> 33 kO O en CM DC O 1 m 33 CO U 1 n CM 33 O 1 ιΛ 33 kO U s r-H CU C f-1 a: r-1 3 rd M 3 H r-H

CONTINUATION

u 'T o rH 1 n o rl • P f-1 U 3 O «—1 t — 1 1 to 00 o t-1 P i-1 EIMS (M) = 443 U 3 r * σ » 1 σ » P r — i 96-97'C en 91.5-92.5 ° C 86.0-87.0 ° C 130.0-131.0 ° C 1 s KO U 1 9, 35 U 1 a b 1 '<M ® 2 O '' f o 1 m · * » X -4 V s a - 1 * r S KO U i X υ Qk X KO U 1 9, X u 1 a 1 v X k £ l o 1 9, X u 1 a 1 X kO U 1 9, X o 1 a 1 4T X kO U 1 9, X u 1 a 1 v X kD u 1 9, X u a 1 X kO O 1 9, X u a will go w C Ifl P P n • H ϋ n • H O co H ϋ to • H U to Ή □ CO -H U I DC KO υ 1 ω n X O 1 sr en en X o -H co CM CM ^z = < ^s q u en m X U -H CO CM CM X Z = z Ok \ ac υ γ ~ α ° v ° T 1 T X KO υ o 1 X u (N m X u 1 'T » 'T X kO O 1 o 1 CM X O m X u Λ en 8 £ v <n 8th ° o DC X X X X X X X X 1 m CM X u 1 m X kO U 1 en CM X u 1 u ^- »X ^ o m CM X u 1 m X KO U m CM X o 1 ui X M? U 1 en CM X u □ n X kO U 1 en CM X u 1 and X u 1 en CM X u x u en CM X o 1 and X vO O 1 en CM X u 1 and X kO O 1AU % r-4 § t-4 s > < r-1 CS3 r — i < X «—1 CQ X i-1 o X r ^- 4

CONTINUATION

CONTINUATION

mp 50-52 ° C en 71.0-72.5 “C U a (Τι O «—1 1 00 o rd -P r-1 O > m • 00 <N rd 1 tn t ** <N «—1 P rd U a m r * r * 1 o r * r * P »—1 U o r * r-l rd 1 kO r-1 rd P • H 129.5-130.5 ° C mp 170.0-170.5 ° C com 89.5-90.0 "C mp 100-104 ° C RJ · X co U 9, 33 O a 1 -r 33 CO U 4 32 U 1 Cl 1 v X Cl3 u 1 9, s u 1 a 1 X co U 1 9th X o 1 (X 1 • r X c £> U 1 9, X u 1 (X 1 X co U 1 9, X o 1 (X X KO O 1 9, X o 1 (X 1 X KO U 1 9th X u 1 a 1 cn X co U 1 C X CO U 1 9th X o 1 a trans 01 H ϋ 0) • H ϋ 0) • rl 0 n • H ϋ co • H ϋ co • H ϋ CO • H 0 m H 0 CO • H ϋ 1 -r 33 & O 1 O 1 cn CM 32 U m 33 U 1 33 co U 1 ? u- X o 1 1 • T X KO o 1 LT) X co O 1 o 1 CM X o i o II CM X o t X 1% R * U CO Yeah? O 4? V X * ό 1 ΜΓ X co U ? CM X u m X o 1 A ό 32 33 X X X X X X X X 1 m CM X U 1 σι X KO O 1 m iKJ X u 1 U ~ l X KO O t f— cm X u 1 Ι.Ί X Mon · o r-> CM X (J 1 m X kO O 'cn (N X O σ> X co U (n CM X o 1 cn X co u 1 m CM X O 1 uT X kO U 1 m c.M. X o ui X KO u 1 cn CM X U 1 σ> X kO U 'cn CM X O 1 cn X co U 1BQ oh 03 rd w « rd E X rd X X r ^- 4 this rd s X r-1 X X rd ΪΗ X rd t <] X rd

CONTINUATION

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CONTINUATION

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Data com 176.0-177.0 "C en 83.5-84.0 ^u C en 158.5-159.0 ^u C U 3 10th rH 1 CM <0 r-1 -P »—1 com 185.0-186.0 "C Relevant stereochemistry Pi Pi m Pi co m C <d M 4J n • H ϋ Pi Ή K 0 Pi co co ω Pi co oh K Pi co ω ω (O oz _H 1 v X Ό u ί 1 a 1 x kO u i 1 04 1 T X kO O i 1 • H M P I <0 M * K CM 1 T X m.p. u i 1 a 1 X kO 0 1 $ s (1 1 MT X kO U to s 1 04 O m 04 X 1 in X SP U u *> X kO O 1 u) X m.p. 0 I u) X M.p. u 1 U) X kO U 1 in X SP O 1 tM 1 Oops 04 (X 33 33 X 1 m X m.p. u M Pu H 1 ui X kO U 1 w 1 Cs) Pi 1 04 X o o 04 X O O Oops X 0 0 X X * 01 X 0 1 Lfl X kO O N > PU M I ^- 1 E rH D rH > r-H s rH X r ^- 1

com 123.0-124.0 C U r * r-l r — 1 1 m r-l rH P r-H u 3 00 LO 1 * x> m P r— | m 3 n II z K K to t ~~ - 00 Γ- o r-l X 00 <0 II II οχ X • t KO o (0 m ·· ko c · m · ko ko .p ko • r- m r ~ > —I II <0 II (DOMO 3R, 4S ω • H υ n c OJ M -U <n • H υ 1 -r X \ o O i 1 cu 1 Lf) 33 KO U 1 * T 33 KO U i 1 1 v X KV o 1 $ Σ 1 1 m X KO (J 33 KO O $ Σ 1 M ¹ v X II u i 1 X u 1 $ s 1 1 m 33 KO O X 1 '.N u m X u X CN 33 U 1 ΟΊ 33 KO U 1 z 1 X o 1 U) X M? D .N X O > 1 rH * 7) U 1— X U rH o rH

EXAMPLE 2

Step 1: Add 39.1 mL (117.2 mmol) of ethyl magnesium bromide to a solution of 31.00 g (97.6 mmol) of (-) - 10- (diisopropylsulfonamide) -isoborneol (see Oppolzer, et al., Tet. Lett.) ., 25 (1984), p. 5885) 370 mL of dry THF at 0 ° C. Stir the mixture for 0.5 hours at 0 ° C, then for 0.5 hours at room temperature. To this mixture, add 37.74 mL (39.67 g, 117.2 mmol) of 5-phenylvaleric acid anhydride at 0 ° C and stir at room temperature overnight. Pour the mixture into one liter of a partially saturated NaHCO ₃ r extract two 800 ml portions of hexane. Dry the combined hexane layers with Na ₂ SO ₄ and concentrate in vacuo. Chromatograph the residue (57.35 g) in three portions over 800 g SiO ₂ , eluting with 2% ethyl acetate-CH ₂ Cl ₂ to give the desired ester (42.07 g, 92%), FAB MS: (M + 1) 479 .

Step 2: Using a procedure similar to Example 1, treat the first-stage ester by washing the ether layer with 200 mL of IN aqueous HCl, drying over MgSO _4, and concentrating in vacuo. Chromatograph the residue over 1 kg SiO ₂ , eluting with 20% ethyl acetate-hexane, to give 24.19 g (79%) of the alcohol recovered and 25.66 (66%) of the desired enantiomerically saturated β-lactam. This lactam can be further saturated by chromatography on a Chiralcel ™ OD column (Daicel Chemical Industries, Ltd., Fort Lee, NJ), eluting with

10% isopropanol-hexane. Crystallize the resulting enantiometrically pure (3S, 4S) compound from ether-hexane to give a white solid, en, 84-85 ° C [α] ^z D = -98.0 ° (MeOH). In a similar manner, the following enantiometrically pure (3R, 4R) compound (Example 2A) can also be obtained:

(en 84-85 ° C, FAB MS: (M + l) 402.2, [a] D = ^z 9 + 8.0 ° (MeOH)).

EXAMPLE 3

Prepare a lithium isopropylcyclohexyl amide (LICA) solution by dissolving 0.68 mL (0.58 g, 4.11 mmol) of isopropyl cyclohexyl amine in 20 mL of THF at -78 ° C under nitrogen. Add 2.58 mL (4.03 mmol) n-butyl lithium (1.6M from Aldrich, Milwaukee, WI) and stir at -78 ° C for one hour. Add 1.04 g (2.61 mmol) of the Example IK compound in 5 mL of dry THF. After 2 hours at -78 ° C, add 2.8 mL (2.89 g, 16 mmol) of hexamethylphosphoric triamide, followed by

0.33 mL (641 mg, 4.11 mmol) of ethyl iodide at -78 ° C. Stir the mixture at room temperature overnight. Quench the reaction with 40 mL of 1N aqueous HCl and extract with two 50 mL portions of CH ₂ Cl ₂ . Connect

CH ₂ Cl ₂ layers and wash successively with 50 mL of IN aqueous HCl and 50 mL of Na ₂ SO ₄ . Dry over MgSO ₄ and concentrate in vacuo. Chromatograph the residue over 40 g of SiO ₂ , eluting with 20% ethyl acetate-hexane, to give 0.95 g (83%) of the title compound as a colorless oil, FAB MS: (M + 1) 426, 4.

In a similar manner, the following compounds can be obtained as shown in Tables 5 and 5A.

TABLE IN

Data en 103.0-103.5 ^U C FAB MS: (M + 1) 448 Cl MS: (M + 1) 512 en 145.5-147.0 C O 3 m cn ao 1 m C4 00 P r-1 U co t-l 1 OJ CO i-H 4J »-H d 3 σ σι 1 ao σ 4-) r-1 com 100.0-100.5C Ct X co o 1 o d) 2 1 a 1 -r X cO U 1 O d) 2 1 a 1 -r X co u 1 o d) 2 1 a 1 -j * X co u 1 o d) 2 • H M -P 1 co Ν ' K Csl 1 v X CO U 1 O d) 2 1 a 1 -r X CO a 1 o φ 2 1 • H P -P 1 co v CM 1 -r X co d 1 o d) 2 1 a 1 -r X co d 1 O d) 2 1 a Relevant stereochemistry CQ cn n cn N * X m X t cn cn cn n · cn cn cn Ν ' X cn cn n * K X cn cn Ν ' cn cn cn N * K X cn 1 and X CO u 1 LT) X CO U 1 etc. X CO U 1 and X CO u 1 and X CO U 1 and X co U 1 X d II X d 1 cT> X cO O 1 and X co d X 1 (N X u cn X u 1 LT> X co O 1 rsj o rl O 1 cm X u cn X u 1 CM X u cn X o 1 CM X u cn X u 1 CM X d cn X d 1 CM X d cn X d Q. 1 cn CM X d and X CO U 1 cn CM X d 1 10 X CO d 1 cn cm X d 1 and X co U 1 n CM X u cn X cO U cn CM X d 1 m X co U 1 cn Csl X d 1 n X CO d 1 n CM X d 1 and X co d 1 CM CM X d 1 and X CO d For example, < m X X u cn a cn ω cn co d cn X cn

CONTINUATION OF TABLE

en 130-131 C υ 3 σι 00 ι ao 00 4-) r-1 U 3 O t-1 i-1 1 <31 Oh i-4 4-1 ι — I U 3 IO <31 1 m <31 4-1 i-4 FAB MS: (M + 1) 430.4 FAB MS: (M + 1) 516.4 FAB MS: (M + 1) 430.4 O * 1 1 1 5Γ 1 1 'T 1 X X X X X X X 10th 10th 10th 10th 10th 10th 10th U U u u O U O o o o o o o o Φ Φ Φ Φ Φ Φ Φ s s 2 s s 2 2 a a (X ά ά ά O u • H cn cn cn cn cn e cn φ 'T K «K u tk X cn cn cn X (0 cn cn cn cn cn <n hl cn 1 v 1 X 1 V X 10th u II X X 10th U | O I o u o 1 1 <1) a) X X X X 2 X 2 10th 10th 10th 10th 1 10th 1 O o u u £ X O a 1 <n • «—s, CM X 1 1 o 1 CM CM 'k-n' CM X X X 1 1 1 o o o cn Cn m i'n cn X m X X X X X 10th X u υ u u u u u 1 CM m 1 O ¹ 1 T 1 ΓΠ 1 cn 1 m CM CM CM CM CM CM CM X X X X X X X o u o u u u u 1 m 1 m 1 Lfl 1 JI 1 m 1 LO 1 σι X X X X X X X 10th 10th 10th 10th 10th 10th 10th u o U o CJ u o M t> X X 2 X o CO cn cn n cn cn cn

TO 5Α TABLES

Data 0 m 00 ν ' 1 m r ~ Ν ' -P 1 - Vol 0 3 m • co o i-1 1 o co o t-1 AJ 0 3 m σι Ν ' 1 o 00 Ν ' AJ <—1 Cl MS: (M + 1) 512.6 CM 00 Ν ' r — 1 + S cn S u 0 3 00 σ » 1 co σι P i-1 EI MS: (M +) 425 0 3 CO σι 1 co σι AJ i-1 O CM & 1 -r X co O 1 o d) s 1 a 1 X CO O 1 o d) 2 1 a 1 -r X co 0 1 o d) S 1 h 1 -r X co 0 1 o d) S 1 a 1 -r X CO 0 1 O d) 2 1 • H M AJ 1 CO K v CM 1 cr X co 0 1 O d) 2 1 • H P AJ 1 co K M * CM 1 N · X CO 0 1 o d> 2 1 a 1 N X CO 0 1 o d) 2 1 a Relevant stereochemistry cn N * cn ω cn sr K X n oh X co oh oh <n oh sr cn CO X Ν ' X co cn Ν ' cn co ω ω cn 1 o 1 cn (N et 1 ιΌ X CO 0 1 ΙΌ X CO 0 1 ΙΌ X co 0 1 ΙΌ X CO 0 1 ιΌ X CO 0 1 ΙΌ X CO 0 1 X 0 II X 0 1 IT) X MO 0 1 ΙΌ X CO 0 1 t-l 1 CM CM Oops 1 CN X 0 m X u 1 LO X co 0 1 CN X 0 m X 0 1 CO CN X 0 1 ΙΌ X CO 0 1 CN X 0 n X 0 1 CN X 0 m X 0 1 CN X 0 cn X 0 1 m X 0 1 ω 1 cn et 1 r-M CM X o r— ( 0 1 r-1 CM X o 0 1-1 CM K O O 1 CN X o 0 1 CN X o 0 1 CN X o 0 1 CM K O r - t 0 1 CM K O rP 0 N > o <n & <n Eh <n D m > m s m X m > < co

Add 100 mg (0.30 mmol) of Example IV trans β-lactam in 2 mL dry THF to a solution of 1.22 (0.32 mmol) LDA (1.5M from Aldrich, Milwaukee, WI) in 0.5 mL dry

THF at -78 ° C under nitrogen. Stir for 5 minutes at -78 ° C, then stop with 0.3 ml acetic acid at low temperature. Divide the mixture between 30 mL of ethyl acetate and 20 mL of water. Wash the organic layer with 20 mL of 10% aqueous NaHCO ₃ , dry over

MgSO ₄ and concentrate in vacuo to give 98 mg of an oily solid. Chromatograph the residue over SiO ₂ , eluting with 20% ethyl acetate-hexane, to give 26 mg of the ais β-lactam title product as a white solid, mp 141.3-142.3 ° C.

EXAMPLE 5

Dissolve 32.05 g (79.8 mmol) of Racemic Example 1 in 500 mL of THF. Add 1.79 g (16.0 mmol) of potassium t-butoxide and stir at 0 ° C for 1.5 h. Partition the reaction mixture between 600 mL 1N aqueous HCl and 1.2 L ether. Extract the aqueous layer with 400 mL of ether. Combine the ether layers, dry over MgSO _4, and concentrate in vacuo to isolate 32.0 g of eis and trans β-lactams (2.7: 1). Isolate the pure trans β-lactam by HPLC chromatography on silica gel eluting with 10% ethyl acetate-hexane. Crystallize from ethyl acetate-hexane to give white crystals en 96, 5 ° C-97, 5 ° C. Using a method similar to Example 5, the following compounds as shown in Tables 6 and 6A can be obtained:

TABLE

Data FAB MS (M + 1) = 402.2 en 109.5-110.0 ^u C CIMS (M + 1) = 390 item. analysis C = 77.78, H = 6.78, N = 3.49; found: C = 77.75, H = 6.70, N = 3.60 oh 1 -r X mo u 4 x u X \ 0 U 1 9, X u 1 X MO U 1 ffl 1 * r 1 -T X MO O 1 9th X u 1 m Relevant stereochemistry 3S, 4Ratskir enantiomer ω K X ffl OT C (0 M 4-1 m C <0 M 4-> 4 1 -r X 0 O 1 ς, X o 1 v 1 vr X MO U 1 o 0 X u 1 ffl 1 -r X 0 · O 1 9, X o 1 'T 1 ΜΓ X MO o 1 9th X u 1 'T X X X X X Q. 1 0 CM X u 1 m X .0 u 1 m CM X u 1 0 X MO U 1 n CM X u 1 10th X MO u 1 0 CM X u 1 0 X MO U For example, ffl ffl u ffl Q. ffl ffl ffl

CONTINUATION OF TABLE

CIMS (M + 1) = 406 item. analysis C = 78.04, H = 7.04, N = 3.37; found: C = 78.01, H = 7.03, N = 3.47 item. analysis C = 74.79, H = 6.52, N = 3.35; found: C = 74.74, H = 6.44, N = 3.48 item. analysis C = 81.01, H = 7.06, N = 3.63; found: C = 81.25, H = 7.09, N = 3.75 item. analysis C = 80.32, H = 6.31, N = 3.02; found: C = 80.36, H = 6.29, N = 3.16 1 cT X " co u 1 r-1 U 1 v 1 cT X co O 1 ? Ccl X u m X u 1 1 cT X CD a 1 cn m X u 1 'T 1 CT X CO u 1 cn X u 1 N * X CO O 1 ? U-> X \ £> U 1 'T trans « C (0 M 4-J n C nj U 4-1 n C (0 s 4-> m C (0 H 4-1 1 k * X CO u 1 o cn X o 1 T 1 C, X c £> U 1 o m X u 1 'T 1 CT X CD O 1 o m X u 1 1 <T X CD U 1 o cn X o 1 1 CT X cD U 1 o m X o 1 X X X X X 1 cn CN X u 1 m X CD O 1 m CN X u 1 m X CD U 1 cn CN X u 1 m X CD O 1 cn CN X u 1 cn X D O 1 cn CN X u 1 m X CD O o Lf) X m n LO LD X m

CONTINUED TABLES vo

O <0 r- | -7.5 ° Λ Λ a o 3 u u O u m 3 Ή o m o O 3 O O 3 3 O io l .J • • • o _O 0 o i-l r- o (M r- 1-1 o o r- 00 r- 3 1-1 r- 1 3 Lf) m 1 1 1 r- i-l 1 LO o- r * » r ~ LO m m 00 1 m o- | 1 • • 1 i-1 • co 1 o cn m i-1 m o LO f r- [- i— r- 00 r-1 r- <—1 r * 4-4 4-> X> -X 4-> 4- · 4-> 4- » 4- » 4-> rH r-1 r-1 Γ — t r— Γ— r-1 r "1 Γ— r— < 1 1 sr 1 1 * 3 · 1 'T 1 * 3 1 1 'T 33 X X X X X X X «0 0 0 0 0 0 <0 0 u O u U u u o O i i i o i i i 4 1 m 33 1 33 X X 3? X X X X 3? O u u O u u u u 0 0 1 1 1 1 1 1 1 1 O u T 'T -T 'T sr 'T • rd • H (U «5 λ: co X CO co ko 0 CO> co 3 co co co co co co co co C -r4 X C Ή X c C C C C c C C (0 4-1 (0 <d 4-> <d (0 <0 (d (d <d <d <d (d X CLi> X (X > X X X X X X X X 4-> O KO 4-> O > co 4-> 4-> 4-> 4- » 4-> 4-1 4-1 4-> 1 * T 1 X. 1 CO X 8th CO X 8th co X 8th · * X Q. € 1 1 'T '3- (0- 1 ? CM X T CM X o 1 * h ⁹ o- ( 1 -p X ή ά ifS O X U Csl X C) u 1 1D X u II ? LT> 0 O 1 V M 1 m n E X 0 CM E X 0 O co 7th - X u U 1 u 1 U X 1 • 1 u 3? *** ' X u 1 1 1 KO 1 0 1 1 O KT O vr 33 33 33 X X X X X X X "Rt 1 fO | I I I I I I * 73 C ") co (* 1 CO m co CM X X— «» X— ». O CM CM CM CM CM CM CM O 33 X X X X X X X ± 1 U u u u u u u u ΓΪ ) I l l l 1 I 1 1 L 1 lt 10 m and LT) in UI m X_ X 33, 33 33, X 33, X 0 ° U U 0 U u 6th u XI 2 CU O X ω H D > s LT) LT) m IT) LT) LO LO LT) LD m

CONTINUATION OF TABLE

P n CM <—1 1 (N CJ r— * -P to item. analysis C = 78.52, H = 7.50, N = 3.16; found: C = 78.32, H = 7.37, N = 3.25 item. analysis C = 74.42, H = 6.25, N = 3.47; found: C = 74.57, H = 6.29, N = 3.51 item. analysis C = 71.25, H = 5.74, N = 3.32; found: C = 71.34, H = 5.73, N = 3.43 item. analysis C = 78.04, H = 7.03, N = 3.37; found: C = 77.90, H = 6.94, N = 3.51 1 • r X CO υ 1 9, x D 1 1 -r X co O 1 9, K u 1 1 .r K co o 1 9, K u 1 I X CO O i 1 M * 1 <r X CO U s 1 trans m C fl -P m C ra P -P σι C fl P -P tn c <o P 4-) 1 • r X CO U 1 9, X o 1 'T 1 X u 1 o m X u 1 1 ΜΓ K co o 1 9, X u 1 v 1 T X Cp U 1 O m X u 1 'T 1 cr X co U 1 o cn X o 1 sr x X X X X 1 CM CM X U 1 9th in X > £> O 1 co CM X υ 1 cn X cp O 1 9th CM CM X u 1 m X CO O 1 (N i 9th Πξ 9th to 1 1 r \ X u 1 ιΧΊ OC. u X m LD you are m 3 m § LD

TABLE 6Α

Data 0 5 LO i-4 i-i 1 n l 't r-1 II i * 0 p CO Csl i-1 1 CM CM r - l II t O CM Oops V s vp 0 1 o Φ s 1 xr 1 m X c £> 0 Relevant stereochemistry Oops ω co c (fl n 4-> 1 0 1 1 * 1 CM oh 1 ιΛ X CD O 'T X 0 1 o m X 0 1 1 X 1 CM CM oh X X 1 w 1 i-M CM oh 1 X 0 CM 1 * 1 X 0 1 . * 1 X 0 2 CM CM X 0 1 tn X CD 0 N > CU < 10 2 LO

EXAMPLE 6

Dissolve 200 mg (0.47 mmol) of Example 3G β-lactam in 4 mL of EtOAc and add 10 mg of 10% Pd / C. Hydrogenate for 4 hours at 1 atm. Filter the mixture through celite and concentrate. Chromatograph the residue over 40 g of SiO ₂ , eluting with 20% EtOAc-hexane to give 188 mg (94%) of the title β-lactam as a colorless oil, C1 MS: (M + 1) 428, 1.

EXAMPLE 7

Add 4.03 g (0.0205) of 4.33 g (0.205 mol) of N- (4-methoxybenzylidene) -aniline and 7.6 g (0.0410 mol) of tributylamine in 40 ml of heptane under reflux. moles) of 5-phenylvaleryl chloride in 15 mL of heptane solution for approximately four hours under reflux. After evaporating the solvent for two hours, evaporate the solution and dissolve the precipitate in 150 mL of EtOAc.

Wash with IN HCl ( ₂ x 30 mL) saturated with NaHCO ₃ (1 x 30 mL) and brine (1 x 30 mL), then dry over MgSO ₄ and evaporate to give 7.6 g of a semi-solid. Recrystallization from 15% EtOAc in hexane gave 3.08 g of the title compound, m.p. 75-76 ° C. The residue was separated from the crystals by chromatography (silica gel, 5% ethyl acetate in hexane) and recrystallization to give 2.31 g of compound.

By applying a method similar to Example 7, the following compounds as shown in Tables 7 and 7A can be obtained.

TABLE

CONTINUATION OF TABLE

Γ

CONTINUATION OF TABLE r

CONTINUED TABLE r-

7Α TO TABLES

I

o 3 r * · 00 0 3 m CM 0 o io LO T 0 3 to O □ U 0 o t-H m i-1 r4 CM 00 p— m τ-H > 1 | 1 1 σι 00 LD 1 C LD o m 1 1 1 00 00 CM M Γ ~ 00 o o ε r — J rH CM σι r- LD «—T 0 P 4-1 4-1 4-1 4-1 4-> 4-1 4-1 Q. r-1 · —I r— | f— «Ή t-1 1 'T 1 sr 1 'T 1 X X X X LO LO LO LO 0 0 0 0 4 4 4 4 1 1 1 X X X X O X X X o | u 1 u I o | Pi ' ύ 0 0 ¹ sr 'T (0 ε £ φ <3 X a: o c o • H Φ 01 4J P c • H Φ 01 01 01 01 (fl 01 -P -P • H Ή • H • H P • H < 01 u u u o 1 4-1 υ | m 31st 1 | 1 • * r 'T X X x_ O CM X X X ύ 0 a X 0 0 ^f 0 ⁿ 0 ^C 1 4 4 4 o 4 oh, 4 0 X X X <5 X X * X 1 u 0 0 0 0 0 CM 1 1 1 0 1 1 I Oops 1 * ^ r 1 1 CM X 0 1 1 1 I LO tCl m CM X. X X X X X X X ^£ 0 0 0 ¹ · 1 X Z 1 m X u cn X 1 . 2 v 0 0 X o 1 2 1 To the O 1 1 CM m <71 X ui U I o CM X 0 v M CM X 0 1 u * - * O ω 1 1 0, 1 m X 1 tn X 1 m X f-H p 1 m X CM LO LO <o > 1 LO Oops 0 0 0 0 υ 0 N 0 Q. X > H) X X 2 < < < cu r- r * r- r * r- · r- r-

CONTINUATION OF TABLE A

item. analysis C = 76.56, H = 8.80, N = 3.31; found: C = 76.37, H = 8.90, N = 3.46 u co r-4 r — i 1 i-1 rH -P f— item. analysis C = 76.22, H = 5.45, N, 3.29. found: C = 76.00, H = 5.46, N = 3.39 1 v 33 co U 1 9, o 1 v 1 «Γ X KO U 1 9th g 1 1 .T X KO U 1 9, o 1 sT trans n • H υ n H 0 1 v X KO u 1 9, X o 1 1 'T PC vo v 9> X o 1 -T 1 .r X KO u 1 9th X o 1 X 1 in X vC U X 1 X o O 1 CKI X u 1 in X ve u / O \ 7 o < r r- J < [

EXAMPLE 8

Stir 981 mg (3.01 mmol) of 1AK A sample of β-lactam above and 20 mg of 10% palladium on carbon in 10 mL of acetate for 24 hours at 1 atm.

hydrogen gas at room temperature. Filter the mixture through celite and concentrate in vacuo. Chromatograph the residue over 50 g of SiO ₂ , eluting with 40% ethyl acetate-hexane, to give 818 mg (92%) of a yellow solid, m.p. 142.0-142.5 ° C.

In a similar manner, the following compounds of Tables 8 and 8A can be obtained, and by conventional means, the amino groups of 8A and 8B can be protected by a t-butoxycarbonyl (BOC) group to give 8G and 8H, respectively:

TABLE

Data en 138.5-139.5 ^U C FAB MS (M + 1) = 387.1 u 3 00 1 KO -P i-1 en 129.0-131.0 ^u C en 171.0-171.5 ^W C CI MS: (M + 1) = 487 T oh 1 v X MO O 1 9th X a 1 1 -r X 0 o 1 9th X o 1 1 X 0 u 1 CM X 2 1 m 1 ΜΓ X 0 u 1 9th X o 1 'T 1 ΜΓ X 0 u 1 9th X u 1 1 ΜΓ X 0 u 1 9th X u 1 'T The corresponding stereochemistry a M • H u m C <0 M -P m C (0 M 4-> he C <0 M P tn c (0 P 4-1 ω Ή υ 1 ΜΓ X MO O 1 CM X 2 1 1 -T X 0 o 1 CM X 2 1 1 ΜΓ X 0 o 1 o 0 X u 1 T 1 ΜΓ X 0 U 1 9th X o 1 'T 1 -T X 0 o 1 X ? I MP X 0 o 1 X 2 1 O o 1 ? u K * » Ch X u 'T X X X X X X X Q. 1 m CM X o 1 0 X 0 u 1 0 CM X u 1 0 X 0 u 1 0 CM X u 1 0 X MO u 1 0 CM X U 1 X 0 o 1 CM X 2 1 1 0 CM X u 1 0 X 0 u 1 0 CM X u 0 X 0 u N > CU CQ 03 o 00 Q. 00 ω 00 (jp 00 K 00

FOR 8Α TABLES

Data U 3 Γ- η rH 1 KO n <—1 + J r - 4 MS MS (M + 1) = 397 O CM cd 1 K ve U 4 x o 1 Ί ¹ 1 M * X ve U 1 9, X u 1 'T Relevant stereochemistry OS 'T w OO cd cn m 1 o 1 .n CM OS 1 vr X ve O 1 CM X s 1 1 M * X ve O 1 X s 1 o o 1 ? u CO m X o • = r 1 t-l 1 CM CM cd X X 1 ω 1 i-H CM (i.e. 1 CM X o n X u 1 CM X o n X u N > Ol. < 00 o co

EXAMPLE 9

Step 1: Combine 5-phenylvaleric acid (89.9 g, 0.504 mol) and thionyl chloride (89.3 mL, 1.225 mol), heat to 70 ° C, and reflux for one hour. Distil off excess thionyl chloride in vacuo (50-100 mm Hg) and add 200 ml of dry toluene to the precipitate which forms. Distill in vacuo again, then add 188 mL of dry THF to the crude 5-phenylvaleryl chloride and use the resulting solution in the next step.

Step 2. Combine 76 g (0.4289) of R - (+) - 4-benzyl-oxazolidinone and 1.3 L of dry THF under a dry nitrogen atmosphere. Cool the resulting solution to -78 ° C and add 278 L of a 1.6 M solution of n-butyl lithium in hexane over 3040 minutes. Stir for an additional 30 minutes, then add the Tier 1 solution within 45 minutes. Allow the mixture to warm to 0 ° C and stir for one hour. Quench the reaction by adding 673.6 mL of K ₂ CO ₃ (1M aqueous solution and stir for 1 h. Distill the THF under vacuum at 30-35 C. Dilute with 1 L of water and extract with CH ₂ Cl _2. Combine the organic extracts and add 800 mL of water, to 800 ml of brine.

Wash the residue with 3x800 ml

Dry the organic extracts over MgSO ₄ , filter, then concentrate in vacuo to an oil. Dissolve the oil in 200 ml hexane, then distill the hexane in vacuo. Repeat treatment with hexane two more times, then dissolve the oil in 1.7 ml CH ₂ Cl ₂ . used directly in the next step.

The resulting solution

Step 3: Cool the Step 3: 2 solution to -5 C-0 C in a dry nitrogen atmosphere. Maintaining the reaction mixture at -6 ° C to -30 ° C. add 129.8 mL of di-n-butylboron triflate. After the addition, stir the mixture for 10 min, then add 97.12 ml of diisopropylethylamine, again keeping the temperature between -6 ° C and -3 ° C. After the addition, stir the mixture at 0 ° C for 30 min, then cool the mixture to -78 ° C and 30 min. stir. Add 57.4 ml of p-anise aldehyde and stir for 30 min. at -78 ° C, then one hour at 0 ° C. Stop the reaction at 0-5 ° C by adding 688.2 ml of pH 7 buffer solution (68 g KH ₂ PO ₄ , 12 g NaOH and 800 ml water), then add 473 ml 30% H ₂ O ₂ and stir the mixture for one hour at 0 ° C. Extract the mixture with 3x600 ml hexane: ethyl acetate (1: 1), wash the organic extracts with 800 ml saturated NaHCO ₃ 800 ml brine. Organic over Na ₂ SO ₄ , filter and evaporate to oil. Crystallize the oil from hexane / ethyl acetate (1: 1) to give a white solid.

combine and (aqueous), then dry the extracts

Tier 4: Combine Tier 3 product (170g,

0.36 mol), 1595 ml of THF and 400 ml of water, stir and cool to approximately 3 ° C. to the mixture within 15 min. add 226 mL (2.156 mol) of 30% H ₂ O ₂ , then add LiOH solution (36.2 g, 0.862 mol) in 400 mL of water over 30 min. time frame. Stir the reaction mixture at 0 ° C to 5 ° C for 3 hours. While maintaining the temperature <27 ° C, add 272 g of sodium sulfide solution in 850 ml of water within 70 min. Concentrate the solvent in vacuo and add 7 l of water. Extract with 4x1.7 1 toluene. Acidify the aqueous layers with 3N HCl to pH 2.4. Extract with one portion of 2.6 l and two portions of 1.7 l of ethyl acetate. Combine the ethyl acetate extracts, wash with brine, dry over Na ₂ SO ₄ , filter, then evaporate to give a white solid, 112 g.

Step 5: Combine Step 4 product (19.47 g, 62 mmol), 400 mL acetonitrile, 9.49 g (62 mmol) 1-hydroxybenzotriazole (HOBT), 22.91 g (186 mmol) panizidine and 14.05 g (68 , 2 mmol) dicyclohexylcarbodiimide (DCC). Stir the reaction mixture at 40 ° C for four hours and confirm the starting material was consumed with TLC (6: 4 hexane / ethyl acetate). Concentrate the mixture to 1/3 its volume and partition between 300 mL water and 300 mL ethyl acetate. Filter the organic layer, then wash with 200 mL of IN HCl followed by two 100 mL portions of saturated NaHCO ₃ and two 100 mL brine. Dry the organic layer over Na ₂ SO ₄ and concentrate to isolate 24 g of a brown solid.

Step 6: Combine Step 5 product (115 g, 0.2745 mol) and 2.3 L THF in a dry nitrogen atmosphere and refrigerate to -70 ° C. Stir the mixture by adding 137 ml (0.551 mol) of tri-n-butylphosphine in 113 ml of THF and 163 ml (1.03 mol) of diethyl azodicarboxylate (DEAD) over two hours. Allow the mixture to warm to room temperature and stir overnight. Separate the solvent under vacuum. Filter the precipitate through a pad of silica gel using CH ₂ Cl ₂ / hesane / ethyl acetate (70: 24: 6) as the eluent. Evaporate the solvent and purify the residue by preparative HPLC (silica gel, 15% ethyl acetate / hexane) to give 88 g of (3R, 4S) enantiometrically pure title compound, [?] D = -19.3 ° (MeOH).

Example 7AU (0.686 g, 0.0012 mol) was dissolved in 1: 1 ethanol: ethyl acetate, hydrogenated over 0.70 g 10% Pd on carbon at 50 psi for 16 hours.

The resulting product was chromatographed (silica gel, 80:20 hexane: ethyl acetate) to give 0.432 g of the title compound, mp 160-161 ° C. Applying substantially the same process may yield the following compound

Elemental Analysis

Calculated for C ₂₅ H ₂₅ NO ₃ C, 77.49; H, 6.50; N, 3.61;

Found: C, 77.47; H, 6.46; N, 3.74

The flask was charged with Example 7J (27 g, 73.6 mmol) in acetone (0.6 L), water (1.3 mL, 73 mmol) and p-toluenesulfonic acid monohydrate (15.4 g, 81.1 mmol). The solution was stirred for 5.5 h at 22 ° C and the product collected by filtration (341 g). Recrystallization from methanol gave 26.0 g (79% yield) of the title compound, mp 200-202 ° C.

EXAMPLE 12

To a solution of the product of Example 11 (0.60 g, 1.36 mmol), triethylamine (0.14 g, 1.4 mmol) was added phenylacetyl chloride (0.310 g, 2.0 mmol) in 2 mL of CH ₂ Cl ₂ over 5 h. . After 5h, the mixture was concentrated to dryness and the residue was purified by chromatography (silica, 2: 1 hexane: ethyl acetate) to afford 0.27 g (51% yield) of the title compound.

218 ° C. The following compounds can be obtained by essentially the same method:

Example 13

To a biphasic mixture of Example 11 (15 mL) and 30% aqueous (0.80 g, 1.8 mmol), CH ₂ Cl ₂ tetrabutylammonium hydroxide (2.36 mL, 3.64 mmol) was added p-toluenesulfonyl chloride (0.515 g). , 2.7 mmol). After 2h the reaction mixture was washed with 1X1 N HC1 2X layer was dried over MgSO _4th

H ₂ O and Organic Recrystallization from ethyl 0.38 (50% yield) above 204-205 ° C.

acetate gave the compound, lt

Example 14

OCH

To a solution of Example 11 (0.8 g, 1.8 mmol), methanol (20 mL) and triethylamine (0.19 g, 1.8 mmol) was added phenylacetaldehyde (0.44 g, 3.6 mmol). After

0.25h to and ZnCl ₂ (0.174 g, 1.3 mmol). After 3.5h, the reaction was quenched with ammonium chloride, partially concentrated in vacuo and the layer was washed 2X with water, concentrated to a crude reaction with NaBH ₃ CN (0.172 g, 2.7 mmol).

CH ₂ Cl ₂ . Organic dried and obtained. Recrystallization from CH ₂ Cl ₂ gave the product 0.44 g (65% yield) of the title compound, mp 138-139.5 ° C.

In substantially the same manner, the following compounds can be obtained:

To a compound of Example 1AS (5.1 g, 9.8 mmol) in 25 mL of THF was added 49 mL (49 mmol) of 1M tetrabutylamine fluoride in 49 mL, 49 mmol, 1M THF at room temperature. Allow the mixture to stir overnight. TLC (50% EtOAc / hexane) indicates consumption of starting material. Transfer the reaction mixture to a separatory funnel, partition between saturated ammonium chloride and ether, extract with ether. Combine the ethereal extracts, wash with water and brine, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate to a residue. Chromatography (SiO ₂ , 30-40% EtOAc / hexane) gives 3.31 g (84%) of the title compound, mp 91-92 ° C.

The following compounds can be obtained in substantially the same manner:

Example 15A Example 15B

en 112-113 ° C en 170-171 ° C

Example 16

To a solution of the product of Example 15A (0.20 g, 0.5 mmol) in 50 mL of CH ₂ Cl ₂ at room temperature, add MnO ₂ (0.64 g, 7.4 mmol). Allow the mixture to stir all night. TLC (20% EtOAc / hexane) indicates consumption of starting material. Filter the mixture by washing the filtered precipitate and concentrate to give 0.19 g (95%) of the compound, mp 129-130 ° C.

over celite, fine with CH ₂ C1 ₂ . The filtrate for the above

When applied in substantially the same manner, the following compound may be obtained.

Example 17

To a solution of the compound of Example 1AU (0.31 g, 0.74 mmol) in 4 mL of CH ₂ Cl ₂ at room temperature, add m-chloroperbenzoic acid (0.61 g, 0.092 mmol). Control the reaction with TLC (50% EtOAc / Hexane). After consuming the starting material (~ lh), add Ca (OH) ₂ (0.1 g, 1.3 mmol). Stir the mixture for an additional 15 min.

Filter the mixture through celite, filter the precipitate thoroughly with CH ₂ Cl ₂ . Concentrate the filtrate on silica gel using sufficient silica gel until a loose, falling powder is obtained. Load the resulting chromatography columns loaded with 5% MeOH / CH ₂ Cl ₂ . Rinse with 5% powder on silica gel

MeOH / CH ₂ Cl ₂ 0.26 g of the above sulfoxide (Example 17), to obtain the sulfonate:

0.5 for analog

134-135 ° C and

The following compounds can be obtained in substantially the same manner:

Example 18

Heat a mixture of the sample compound (1.72 g, 3.49 mmol), 20 mL of THF, and 3N HCl (20 mL) under reflux overnight. Monitor the reaction with NaHCO _{3 in} TLC at room temperature and combine, (50% EtOAc / hexane). After initial use, cool to room temperature, neutralize with saturated extraction with ethyl acetate. Wash the extracts with water and brine, dry over anhydrous Na ₂ SO ₄ , filter and concentrate to hardness. Recrystallize from CH ₂ Cl ₂ / MeOH to give the title compound, en 190.5-191.5 ° C.

In substantially the same manner, the following compounds may be obtained:

Example 18A

mp 189-191 ° C

Example 19

To a solution of the product of Example 16A (1.0 g, 2.5 mmol) and motfolin (0.44 mL, 5.0 mmol) in THF-e at room temperature add NaBH ₃ CN (0.19 g, 3.0 mmol) and ZnCl ₂ (0.21 g, 1.5 mmol) in methanol. Control the reaction with TLC (505 EtOAc / hexane). After the starting material is reacted, the mixture is diluted with 0.1 N

NaOH (120 mL) and the organic solvent was removed on a rotary evaporator. Extract the resulting solution with ethyl acetate. Combine the extracts, wash with water and brine, dry over anhydrous Na ₂ SO ₄ , filter and concentrate to hardness. Recrystallize from Et ₂ O / hexane to give 0.81 g (69%) of the title compound, mp 100-101 ° C.

The following compounds can be obtained in essentially the same manner:

Heat a solution of 1AR Example compound (1.10 g, 2.95 mmol), 15% H ₂ O ₂ (0.45 mL) in 3 mL acetic acid to 100 ° C for 3.5h under TLC control (5% MeOH / CH). ₂ Cl ₂ ). After reacting the starting material, cool to room temperature, neutralize with saturated N ₂ CO _3, and dilute with ethyl acetate. Filter the mixture and wash the filtrate with water and brine, dry over anhydrous Na ₂ SO ₄ , filter and concentrate to a residue. Chromatograph the residue (silica gel, 10% MeOH / CH ₂ Cl ₂ ) to isolate the title compound, FAB MS (M + 1) = 389.1

Example 21

To a solution of the product of Example 15A (0.46 g, 1, 15 mmol) and methyl iodide (0.21 mL, 3.45 mmol) in dry DMF (5 mL) add freshly prepared AgO (0.40 g, 1.73 mmol). ). Heat the mixture to 40-50 ° C under TLC control (EtOAc / hexane). Add proportional amounts of AgO and methyl iodide until TLC shows the starting materials to room temperature and ethyl acetate, Extract the ethyl acetate extracts, wash with water and brine, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate to a precipitate. Chromatograph the residue (silica gel, 30% EtOAc / hexane) to isolate the title compound, FAB MS (M + 1) = 416.

The following compound can be obtained in the same manner:

consumption. Cool and divide between water with ethyl acetate.

Example 21A

mp 84-85 ° C

Example 22

To a solution of the product of Example 16 (2.76 g, 6.94 mmol) in acetone (80 mL), add the freshly prepared Jone ¹ s reagent (8 mL) while maintaining the temperature of the reaction mixture at 15-20 ° C. Control with TLC (5% MeOH / CH ₂ Cl ₂ ). After the starting material is reacted, quench the reaction with methanol. Concentrate to the precipitate and partition the precipitate between CH ₂ Cl ₂ and water. Extract with CH ₂ Cl ₂ , combine the extracts, wash with water, 10% Na ₂ SO ₄ (vand) and brine, then dry over anhydrous N ₂ SO ₄ . Filter and concentrate to obtain 2.90 g of the title compound, m.p. 64-65 ° C.

The following compound can be obtained in substantially the same manner:

mp 158-159 ° C

Example 23

In the 22 A sample product (0.30,

N-methylmorpholine (0.11 mL, 0.94 mmol), (0.13 mL, 0.42 mmol) and HOBT (0.12 g,

In 8 mL of CH ₂ Cl ₂ solution at room

0.72 mmol), morpholine (0.87 mmol) at 0 ° C, add EDC1 (0.2 G, 1.03 mmol) overnight. Control with TLC starting material, wash with anhydrous sediment. MeOH / CH ₂ Cl ₂ ),

Stir the mixture through (5% MeOH / CH ₂ Cl ₂ ). After dilution CH ₂ C1 ₂ ,

1M HCl, water, dry over

Na ₂ SO ₄ , filter and concentrate to

Chromatograph the residue (SiO ₂ , 3% (86%) for the title compound

0.3 g obtained m.p. 61-62 ° C.

Example 24

To the product of Example 22A (0.30, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.94 mmol), ethanol (0.1 mL, 1.44 mmol) and HOBT (0.12 g, 0.87 mmol) Add 8 mL of CH ₂ Cl ₂ solution at room temperature in EDCI (0.2 g, 1.03 mmol). Stir the mixture all night. Control with TLC (5% MeOH / CH ₂ Cl ₂ ). After reacting the starting material, dilute with CH ₂ Cl ₂ , wash with 1M HCl, water, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate to a residue. Chromatograph the residue (SiO ₂ , 3% MeOH / CH ₂ CL ₂ ), 0.33 g, to give the title compound, mp 76-77 ° C.

The following compound can be obtained in substantially the same manner:

An example

To a solution of Example 8B (0.26 g, 0.67 mmol), pyridine (3 drops) in 5 mL of CH ₂ Cl ₂ at 0 ° C, add methanesulfonyl chloride (0.05 mL, 0.67 mmol) . Stir the mixture all night. Control with TLC (50%

EtOAc / hexane). After reacting the starting material, dilute with CH ₂ Cl ₂ , wash with 0.5 M HCl, 5% NaHCO ₃ , water and brine, dry over anhydrous sodium sulfate, filter, and concentrate to a residue. Chromatograph the residue (SiO ₂ , 50% EtOAc / hexane), 0.18 g (58% yield) to afford the title compound, FAB MS (M + 1) = 465. The following compounds can be obtained in substantially the same manner:

Example 26

NHCOCH3

Ph (CH ₂ ) _34k

OCK ₃

To a solution of Example 8C (0.20 g, 0.52 mmol) and triethylamine (0.11 mL, 0.79 mmol) in 3 mL of CH ₂ Cl ₂ at room temperature was added acetyl chloride (0.04 mL, 0.57 mmol). Control with TLC (50% EtOAc / Hexane).

After reacting the starting material (~ 3h), dilute with CH ₂ Cl ₂ , wash with 5% NaHCO ₃ , brine, dry over anhydrous Na ₂ SO ₄ , filter and concentrate to give 0.19 g (85% yield) of the title compound, mp 153-154 ° C.

Example 27

A suspension of the sample product (0.6 g, 1.5 mmol), hydroxylamine hydrochloride (0.4 g, 4.5 mmol), sodium acetate (0.4 g, 4.5 mmol), methanol (12 mL) and water heat to reflux overnight. Control with TLC (50% EtOAc / Hexane). After consumption of the starting material, evaporate to dryness, partition the precipitate between water and ethyl acetate, extract with EtOAc, combine the extracts, wash with water and brine, dry over anhydrous Na ₂ SO ₄ , filter, and concentrate to a residue. Chromatograph the precipitate (silica gel, 20%

EtOAc / hexane) for the title compound, mp 9899 ° C; and Example 27A to obtain:

Example 28

Heat a solution of the sample product (3.2 g, 7.38 mmol) in CH ₂ Cl ₂ (15 mL) in trifluoroacetic anhydride (15 mL) under reflux for 15 min. Control the reaction with

TLC (100% EtOAc). After consuming the starting material, distill most of the solvent, cool to room temperature, evaporate to a residue. Dissolve the precipitate in 50% triethylamine / methanol solution (30 mL) for 15 min. stir, evaporate to dryness on a rotary evaporator. Redissolve CH ₂ Cl ₂ , wash with NH ₂ Cl (saturated), dry over anhydrous Na ₂ SO ₄ , filter, and concentrate on sufficient silica gel (1 g SiO ₂ / mmol substrate) to give a loose, fluffy powder. Chromatograph a powder column filled with silica gel and 30% EtOAc / hexane. Wash with 30-60% EtOAc / hexane to obtain a precipitate of 2.65 g (89%). Recrystallize LT 3369 B from Et ₂ O / CH ₂ Cl _{2 to give} the title compound, en 134-135 ° C.

Example 29

Dissolve the sample product (1.81 g, 4.49 mmol) in 25 mL of THF, cool to 0 ° C. Add 1 N NaOH (5.39 mL, 5.39 mmol) and aqueous ammonia (16.8 mL, 5.39 mmol) followed by chorolox (6.7 mL, 5.39 mmol). Control the reaction with TLC (50% EtOAc / Hexane). After consuming the starting material, dilute with EtOAc, wash with water and brine, dry over anhydrous Na ₂ SO _4, and concentrate to give sulfinamine (1.88 g).

Dissolve the sulfylamine (1.8 g, 4.49 mmol) in CH ₂ Cl ₂ (50 mL), add m-chloroperbenzoic acid (1.70 g, 9.88 mmol). Control the reaction with TLC (50% EtOAc / Hexane). After consuming the starting material, stop with solid Ca (OH) ₂ (1.78 g, 24.0 mmol), stir for 20 minutes, filter, and concentrate on a sufficient amount of silica gel (1 g SiO ₂ / mmol substrate) until loose debris is formed. powder. Apply the powder onto a chromatography column loaded with silica gel and 50% EtOAc / hexane. Wash with 50% EtOAc / hexane, 0.49 g (24%), to afford the title compound, mp 174-176 ° C.

Example 30

To a solution of Example 70 (0.768 g, 2.06 mmol) in 25 mL of CH ₂ Cl ₂ at 0 ° C, add BBr ₃ (5.15 mL, 5.15 mmol, 1M CH ₂ Cl ₂ ). Control the reaction with TLC (30% EtOAc). After consuming the starting material, quench with NaHCO ₃ (saturated) and methanol for 30 min. stir, wash with NaHCO ₃ (sat.) and water, dry over anhydrous NaSO ₄ , filter, and concentrate on sufficient silica gel (1 g

SiO ₂ / mmol of substrate) until a loose, falling powder is formed. Apply the powder onto a chromatography column loaded with silica gel and 100% EtOAc. Wash with 100% EtOAc followed by 5% MeOH / EtOAc to give 0.234 g (32%) of the title compound, Cl MS (M + 1) = 359.

Example 31

Heat a mixture of the sample product (0.23 glycol (0.2 mL, 3.6 mmol) g, 0.6 mmol), ethylene p-toluene sulfonic acid, and toluene (5 mL) under reflux overnight. Control by ^f H NMR and TLC (50% EtOAc / hexane). Cool to room temperature, wash with NaHCO ₃ (sat.), Water and brine, dry over anhydrous Na ₂ SO ₄ and concentrate to give 0.27 g (100%) of the title compound, EI MS (M) = 443. The following compound can be obtained in substantially the same manner.

Example 31A

Example 32

Stir 388 g (1.00 mmol) of the 8F Example compound and 180 mg (1.20 mmol) of chloramine-T NaJ in 4.6 mL of DMF. Add 377 mg (1.2 mmol) and stir

18 hours at room temperature. Partition the reaction between 30 mL of 1N HCl and 30 mL of ethyl acetate. Wash the organic layer with 10% aqueous Na ₂ SO ₃ and dry the organic solution with MgSO ₄ . Concentrate in vacuo and chromatograph the residue (silica gel, 40% ethyl acetate-hexane) to isolate 170 g of the title compound, CI MS (M + 1) = 514, and 41 mg of diiodo analog (Example 32A):

Example 33

Add 400 mg (0.96 mmol) of acid and 5 mL

Example 8E Mix 25 mL of vinegar water at 0 ° C and 133 mg (1.92 mmol) of NaNO _{2 in} 4.7 mL of water. Stir for 20 min at 0 ° C, add 212 mg (3.26 mmol) NaN _{3 in} 9 mL water and stir for 3 h while warming to room temperature. Dilute with ethyl acetate and neutralize with NH ₄ OH. Dry the ethyl acetate layer with MgSO ₄ and concentrate to a precipitate. Recrystallize the precipitate from ether hexane to give the title compound, mp 80-84 ° C.

Example 34

Dissolve 300 mg (0.77 mmol) of 8F in 3 mL of CH ₂ Cl ₂ and add 98 μΐ (120 mg, 0.80 mmol) of 3-carbomethoxypropionyl chloride and 146 μΐ (109 mg,

0.84 mmol) of Hunig's base. Stir for 1.5h at room temperature. Add another full portion of acid chloride and Hunig's base and stir for an additional hour. Partition the reaction between ethyl acetate and 1N HCl. Dry the ethyl acetate layer with MgSO ₄ and concentrate to a precipitate. Chromatograph the residue (SiO ₂ , 40% ethyl acetate-hexane) and filter through a grade I basic Al ₂ O ₃ wash with 50% ethyl acetate / hexane to give 334 mg (86%) of the title compound, EI MS (M +) = 501.25.

Example 35

Benzyl bromide (0.44 g) was added to a solution of the compound of Example 15B (1.0 g) in 15 mL of acetone containing K ₂ CO ₃ (0.715 g). The reaction mixture was refluxed for 26 h. The reaction mixture is then poured into water and the product is extracted with ethyl acetate. The crude product was recrystallized from ethyl acetate / hexane (0.908 g, 74% yield) to give the desired product, mp 115-116 ° C.

The following compounds can be obtained essentially as follows:

Example 35A

Example 35B the same

Elemental Analysis: C ₂₇ H ₂₉ NO ₃ : C, 78.04; H, 7.03; N _3, 37 Found: C, 78.00; H, 7.02; N, 3.55

Example 36

Example ii

Al 20 ° C.

Compound (0.19 g) was cooled in pre-added diethylzinc solution in toluene (4.3 mL, 1.2 M solution) followed by diiodomethane (2.56 g). The reaction mixture was allowed to warm slowly to ambient temperature over 3h. The reaction mixture was then heated to 45 ° C for 5 min. After cooling, the reaction mixture was treated with aqueous NHCl and the product was extracted with diethyl ether. The organic layer was washed with water, brine and concentrated to a residue. The residue was purified by chromatography (SiO ₂ , ethyl acetate / hexane (3: 7)) to give the title compound (0.17 g, 88% yield).

calcd- C, 78.42; H, 6.58; N, 3.39 Found C, 78.32; H, 6.48; N, 3.61.

Example 37

and Tier ₃ (a)

Combine 5-phenylvaleric acid (89.9 g, 0.504 mmol) with SOCl ₂ (89.3 mL, 1.225 mol) in a 500 mL round-bottomed flask with reflux and drying tube.

Heat the flask to 70 ° C and boil for lh. Distill in vacuo (50-100 mm Hg), excess SOCl ₂ and add 200 ml dry toluene to the rest of the mixture. Re-distill in vacuo to remove toluene and remaining SOC1 ₂ . Add 188 mL of dry THF to the crude acid chloride remaining in the reaction vessel and use the resulting solution directly in the next step.

step (b)

Under nitrogen atmosphere, combine 76 g (0.4289 mol) of R - (+) - 4-benzyloxazolidinone and 1.3 L of dry THF. Cool the resulting solution to -78 ° C over a period of 30-40 min, add 278 mL, 1.6 M n-butyl lithium in hexane solution. After the addition, stir the mixture for an additional 30 min. Add the 5-phenylvaleronium chloride solution of step (a) over a 45 minute period. Allow the mixture to warm to 0 ° C and stir for 1h. Stop the reaction by adding 673.6 mL of K ₂ CO ₃ (1 M aqueous solution) and stir for 1 h. Distil the THF under vacuum at 30-35 ° C. Dilute the precipitate with 11 water and extract with three 800 ml portions of CH ₂ Cl ₂ . Combine the organic extracts and wash with 800 ml water, then 800 ml brine. Dry the organic extracts over MgSO ₄ , filter, then concentrate in vacuo to an oil. Dissolve the oil in 200 ml hexane, then distill the hexane in vacuo. Repeat treatment with hexane two more times, then dissolve the oil in 1.7 ml CH ₂ Cl ₂ . The resulting solution is used directly in the next step, step (c)

100

Cool the product solution of step (b) to -5 ° C under a dry nitrogen atmosphere. Add 129.8 ml of di-n-butylboron triflate at a rate such that the reaction mixture is maintained at a temperature of -6 ° C to -3 ° C. After the addition, stir the mixture for 10 min, then add 97.12 ml of diisopropylethylamine at a rate that allows the reaction mixture to be maintained at -6 ° C to -3 ° C. After the addition, stir the mixture for 30 min at 0 ° C, then cool the mixture to -78 ° C and stir for 30 min. Add 57.4 ml of p-anise aldehyde and stir the mixture for 30 min at -78 ° C, then for 1 h at 0 ° C. While maintaining the temperature between 0 ° C and 5 ° C, quench the reaction by adding 688.2 mL of pH 7 buffer (68 g KH ₂ PO ₄ , 12 g NaOH and 800 mL water) followed by 473 mL 30% H ₂ O ₂ and stir the resulting mixture for 1 h at 0 ° C. Extract the mixture with three portions of hexane 600 mL: 1: 1 ethyl acetate. Combine the organic extracts and wash with 800 ml saturated NaHCO ₃ (aqueous) followed by 800 ml brine. Dry the organic extracts over Na ₂ SO ₄ , filter, evaporate to oil. Crystallize the oil from hexane / ethyl acetate (1: 1) to give 176 g of a white solid.

step (d)

101

Combine (c) 1595 mL of THF (170 g, 0.36 mol), step product, and 400 mL of water, stir and cool to about 3 ° C. Add 226 mL (2.156 mol) of 30% H ₂ O ₂ to the mixture over 15 min, followed by a solution of LiOH (36.2 g, 0.862 mol) in 400 mL of water over 30 min. Stir the reaction mixture for 3 h at 0 ° C to 5 ° C. While maintaining the reaction temperature at <27 ° C, add 272 g of Na ₂ SO ₃ in 850 mL of water over 70 min. 10 Distil off the volume of the solvent under vacuum and add 71 water. Extract with four portions of 1,7 l of toluene. Acidify the aqueous layers with 3N HCl to pH 2.4. Extract with one portion of 2.6 L and two portions of 1.7 L of ethyl acetate. Combine the ethyl acetate extracts, wash with brine, dry over Na ₂ SO ₄ , filter, then evaporate to give 112 g of a white solid.

step (e)

102

I

Ph

Combine the product of step (d) (19.47 g, 62 mmol), 400 mL of acetonitrile, 9.49 g (62 mmol) of 1-hydroxybenzotriazole (HOBT), 22.91 g (186 mmol) of p-anisidine and 14.05 g (68.2 mmol) of dicyclohexylcarbodiimide (DCC).

Stir the reaction mixture at 40 ° C for 4 hours and confirm the starting material consumption by TLC (6: 4 hexane / ethyl acetate). Concentrate the mixture to 1/3 its volume and divide between 300 mL water and 300 mL ethyl acetate. Dry the organic layer over Na ₂ SO ₄ and concentrate to give 24 g of a solid.

step (f)

OCH _a

och ₃ och ₃

103

Under dry nitrogen, combine the product of step (e) (115 g, 0.2745 mol) with 2.3 L of THF and cool to 70 ° C. Stir the mixture and add 137 mL (0.551 mol) of tri-n-butylphosphine solution in 113 mL of THF and 163 mL (1.03 mol) of diethyl azodicarboxylate (DEAD) at the same time. Allow the mixture to warm to room temperature and stir overnight. Remove the solvent under vacuum. Filter the precipitate through a pad of silica gel using CH ₂ Cl ₂ / hexane / ethyl acetate (70: 24: 6) as eluent. Evaporate the solvent and purify the residue by preparative HPLC (silica gel, ethyl acetate / hexane) to give the product.

g (80% yield) β-lactam

Example 38

33.7 g (0.1 mol) of Example 37 (b) in 200 ml CH ₂ C1 ₂ Cool the product of Step

Cold TiCl ₄ .

stir for 10 min at -20 ° C, then slowly add 30 mL (2 equiv.) of tetramethylethylenediamine (TMEDA) over a period of 10 min, keeping the temperature below -10 ° C. Stir the mixture for 70 min at -150 ° C to -20 ° C.

stir the solution and add 11 mL (0.1 mol) of the mixture

-10 C after aldehyde.

add 24 ml (2 equiv.) of p-anise

Stir at -15 ° C to -10 ° C for 1h, then allow to warm to 10 ° C with stirring for 1 minute. Stop the reaction by adding 600 mL of 10% aqueous

104 tartaric acid, then add 600 ml ethyl acetate. Stir well, then separate the layers by extracting the aqueous layer with another 200 mL of ethyl acetate. Combine the organic extracts and wash successively with water saturated with NaHCO ₃ (aqueous) and brine. Dry the organic solution over anhydrous Na ₂ SO ₄ , filter, then concentrate to a precipitate. Crystallize the precipitate from 100 mL of ethyl acetate + 210 mL of hexane to give 36.8 g of the title compound, which can be used in Step 37 (d).

Example 39

OCHg Step (a)

OCH- »

OCH?

105

Dissolve 500 g (0.85 mol) of the product of Step (e) of Example 37 in 1700 mL of CH ₂ Cl ₂ , then add 4.0 g (12 mmol) of tera-n-butylammonium hydrogen sulfate. Stir the mixture while cooling to 10 ° C-20 ° C and add 50% aqueous NaOH (200 g). Slowly, over 30 minutes add 60 g (285 mmol) of 2,6-dichlorobenzoyl chloride to the stirred mixture. Continue stirring for 3h at 15 ° to 20 ° C, then pour into 200 ml of cold water. Separate the layers and wash the organic layer with water until a neutral pH is reached. Distil the methylene chloride solution to a volume of 800 ml. Reflux the solution and add 800 ml heptane. For crystallization, cool the warm solution to 0 ° C. Collect the product by filtration to obtain 116 g of dichlorobenzoate.

and ₃

Combine 500 g (0.85 mol) of the product of step (a) with 250 g (1.1 mol) of benzyltriethylammonium chloride, 2000 ml of CH ₂ Cl ₂ and 800 ml of methyl t-butyl ether. Stir the mixture under cooling to 15-20 ° C, then add 1000 ml of 50% aqueous NaOH over a period of 10 minutes. Stir the mixture for 4h, then pour into 5000 ml water and 4 kg ice. Separate the layers and wash the organic layer with water until the pH is neutral. Distil the solvent down to a volume of 2000 ml, then filter. Evaporate the filtrate to a precipitate and purify the residue by chromatography on a crude product

106 silica gel. Crystallize the product from 6 volumes of a 1: 2 mixture of methyl t-butyl ether and heptane at 0 ° C to give 240 g of product.

Example 40

TiCl ₄

TMEDA

107

Dissolve 3.23 g (10 mmol) of nitrogen in step 37 (b). Add 10 mL of the mixture, stir in atmosphere, (10 mmol) of a 1M solution in 50 mL for 30 min followed by 50 mL of CH ₂ Cl ₂ followed by cooling to -20 ° C.

TiCl ₄ solution in CH ₂ Cl ₂ , min, then add 1.5 mL (10 mmol) of TMEDA. Wash the mixture at -25 ° C to -20 ° C for 1 hour, then slowly add 4.8 g (20 mmol) of Schiff's base from aniseed aldehyde and p-anisidine, CH ₂ Cl ₂ , over a period of 30 minutes. . Stir the mixture at -20 ° C and slowly heat to 0 ° C. The reaction was controlled by HPLC (Zorbax * Sil column, 1: 4 ethyl acetate / hexane) with stirring at 0 ° C until completion. Quench the reaction by pouring it into 50 ml of 10% aqueous tartaric acid. Extract with ethyl acetate, then wash the organic layer sequentially with saturated NaHCO ₃ (aqueous) and brine. Dry the organic solution over anhydrous Na ₂ SO ₄ , filter, then concentrate to obtain a crude product. Crystallize from ethyl acetate / hexane to obtain a clear product.

108

Tier (b)

(1.77 mol) in 1M THF. The mixture

A solution of 0.505 g (0.89 mmol) of product of step (a) in 25 mL of CH ₂ Cl _{2 is} stirred at 0 ° C, then treated with 1.77 mL of sodium bistrimethylsilylamide solution while warming to room temperature, then continue stirring until determined with HPLC (typically within 1 to 1 1/2 h) we find the starting material is gone. Stop the reaction in 10% tartaric acid / water. Wash the organic layer successively with saturated NaHCO ₃ (aqueous) and brine, then dry over anhydrous Na ₂ SO ₄ . Filter and concentrate to obtain the title compound.

The following dosage forms show several dosage forms of the present invention. The term active compound means I

109 or a compound of formula II, first order (3R, 4S) -1,4bis- (4-methoxy-phenyl) -3- (3-phenylpropyl) -2-azetidinone. However, this compound may be substituted by an equally effective amount of other compounds of formula I or II.

Example A

Pills

No. The Ingredient mg / tablet mg / tablet 1 Active compound 100 500 1 Lactose USP 122 113 3 Corn starch, food quality standard as 10% paste in purified water 30th 40 4 5 Corn starch, food quality standard Magnesium stearate 45 3 40 7th

A total of 300,700

Method of production

Mix the compounds of No. 1 and 2 in a suitable mixer for 10-15 minutes. Granulate the mixture with a dot

No. 3. Chop the wet granules through a coarse sieve (eg 1/4, 0.63 cm) if necessary. Dry the wet pellets. Sift the dried pellets, if necessary, and mix with the compound of item 4 and stir for 10-15 minutes. Add the compound of item 5 and stir for 1-3 minutes. Use a suitable tablet machine to compress the mixture to the desired size and weight.

110

Example B

Capsules

No. The Ingredient mg / tablet mg / tablet 1 Active compound 100 500 2 Lactose USP 106 123 3 Corn starch, food product standard 40 70 4 Magnesium Stearate NF 4 7th Total 250 700

Method of production

Mix the compounds of Nos. 1, 2 and 3 in a blender for 10-15 minutes. Add item 4 and stir for 13 minutes. Fill the appropriate two-piece hard gelatin capsules with the appropriate capsule machine mix.

Using the assay methods described above, the following data in the tube and in the body were obtained for selected compounds, which are listed in the following table by their respective sample numbers.

For ACAT tube data, a negative percentage of inhibition indicates clear stimulation whereas positive values indicate inhibition. In the case of body results, the data is presented as a percentage change from the control, suggesting that negative values indicate a positive pilid-down effect.

111

TABLE

For example, ACAT (tube) % Reduction (in the body) ic ₅₀ (mM) % Inhib. Kone. (mM Serum Cholest. Colest. Esters The dose mg / kg 1 - 38 10th -45 -95 50 -17 -55 10th 0 0 5 1A 7.5 83 25th -10 -26 100 1B 28th 10th 0 0 50 1C - 22nd 10th -6 -15 50 1D - 39 10th 0 0 50 IE - 3 10th - - - 1F - 61 10th 0 20th 50 1G - 21st 10th -11 0 50 1H - 57 10th -21 -51 50 11th 4.5 81 10th - - - 1J 3.0 86 10th - - - IK - -70 10th 0 0 50 1L - 20th 10th -31 -75 50 -22 -34 10th -25 -30 5 1M 7.0 80 10th -11 -31 25th 1P - 9th 10th -19 -54 50 1S - -19 10th 0 -32 85 IT - -11 10th 0 0 50 1U 19th 58 10th 0 0 50 IV - 64 10th - - - 1W - 9th 10th - - - IX - 9th 10th -12 - 50 1Y - 50 10th - - -

112

CONTINUED TABLE

1Z - 15th 10th -15 -39 50 1AA - -36 10th - - - IAB - 17th 10th - - - 1AC 40 10th -16 -33 50 1AD - -5 10th - - - INPP - -7 10th - - - 1AF - 0 10th - - - 1AG - -3 10th -16 -29 50 1AH - 4 10th - - - 1AI - 27th 10th - - - 1AJ - -17 10th 0 0 50 1AK - -33 10th - - - 1AL - -43 10th 0 0 50 1AM - - - -12 -29 50 1AN - - - -34 -85 50 1A0 - - - -33 -78 50 1PM - - - -51 -95 50 1AQ - - - -20 -22 50 1AR - -41 10th -22 -25 50 1AS 1.0 83 10th 0 -19 50 1AT 5.0 70 10th 0 -28 50 1AU - 44 10th 0 -21 50 1AV - 7th 10th 15th 0 50 1AW - 68 10th -14 -16 50 1ΑΧ - - - -16 -52 50 1AY - - - -28 -78 50 1Z - - - -37 -91 50 1BA - - - 0 -0 50 1BB - -16 10th 0 0 50

113

CONTINUED TABLE

1BC - -2 10th 0 0 50 1BD - 17th 10th 0 -25 50 1BE - 30th 10th -10 -21 50 1BF - -17 10th 0 -23 50 1BG - 3 10th 12th 0 50 1BH - 50 10th 0- 0 50 IBI - 59 10th -17 -45 50 1BJ - 56 10th 0 0 50 1BK - 55 10th 0 0 50 1BL - 42 10th -10 0 50 IBM - 38 10th 0-21 50 1BN 7.0 - - -16 0 50 1B0 5.4 79 10th -48 -93 50 IBP 58 10th -9 0 50 1BQ - 35 10th 0 -17 50 1BR - - - -15 -70 50 IBS - - - 0 -43 50 1BT - - - 0 0 50 1BU - - - -39 -95 50 1BV - - - -11 0 50 1BW - - - -9 -29 50 1ΒΧ - - - 0 0 50 IBY - - - -18 -72 50 1BZ - - - -9 0 50 1CA - - - -12 0 50 ICB - 33 10th 0 0 50 ICC - 46th 10th 0 0 50 1CD 7.0 84 10th 0 -23 50 1CE - 15th 10th -19 -17 50

114

CONTINUED TABLE

1CF - 53 10th -23 -47 50 1CG - 8th 10th -30 -61 50 1CH - - - -49 -95 50 -41 -90 10th -24 -80 3 1CI - 26th 10th -8 -23 50 1CJ - - - 0 0 50 1CK - -12 10th 0 -28 50 1CL - 89 10th 0 -18 50 1CM 0 0 50 1CN - -28 10th 0 0 50 2 6.0 82 10th -15 -37 5 -28 -69 10th 2A 25th - - 0 0 50 3 - 56 10th 0 0 50 3A - 33 10th -12 -29 50 3B 6.0 84 10th -11 -16 50 3C - -18 10th - - - 3D 12th 42 10th 0 0 50 3E - -24 10th 0 0 50 3F 1.7 82 10th 0 -31 50 3G 5.0 74 10th 9th 0 50 3H - 66 10th -10 31st 50 31st - 43 10th -9 0 50 3J - 45 10th 0 -16 50 3K - 19th 10th 0 0 50 3L - 53 10th 0 0 25th 3M - 13th 10th 0 0 50 3N - 62 10th 0 0 50

115

CONTINUED TABLE

30th - -28 10th 0 0 50 3Q - 3 10th -6 0 50 3R - -8 10th 0 0 50 3T - -9 10th - - - 3U - 46th 10th 0 0 50 3V 6.5 60 10- 0 0 50 3W - 56 10th 0 0 50 3X - 3 10th - - - 3Y - -33 10th 0 0 50 4 - 16th 10th - - - 5 18th 33 10th -29 -77.5 50 -20 -72 25th -21 -60 10th 5A - -70 10- - - 5C - 21st 10th -17 -24 50 5D - - - -38 -95 50 -41 -94 30th -24 -77 10th 5E - - - -38 -91 50 5F - - - -44 -98 50 -15 -59 30th -13 -25 10th 5G - - - -44 -93 50 5H - - - -57 -96 50 51 - - - -26 -70 50 5J - - - -38 -90 50 5K - - - -28 -49 50 5L - - - -50 -95 10th -39 -84 3

116

CONTINUED TABLE

-54 -64 1 5M - - - -8 -36 10th -12 0 3 -20 -50 50 5N - -23 10th -17 -55 50 5P - 53 10th -11 -33 50 5Q - -36 10th 0 -19 50 5R - 18th 10th -20 -21 50 5S - 28th 10th -52 -98 50 5T - - - -15 -48 50 5U - - - -48 -86 50 5V - - - -37 -77 50 5W - -16 10th ⁰ -19 50 5X - 38 10th 0 -39 50 5Y - - - -29 0 50 5Z - - - -16 0 50 5AA - - - -53 -93 50 5AB - 30th 10th -28 -72 50 6th 5 59 10th 14th 0 50 7th - - - -49 -95 40 -41 -89.5 10th -30 -50 3 7A - - - -22 -54 50 7B - - - -13 -45 50 7C - - - -51 -95 50 7D - - - -35 -74 50 7E - - - -52 -93 50 7F - - - 0 -26 50 7J - - - -21 -27 50

117

CONTINUED TABLE

7K - - - 0 -32 50 7L - - - 0 0 50 7M - - - -38 -94 50 7N - - - -11 0 50 70 - - - -14 -20 50 7P - - - -40 -95 50 7Q - - - -16 0 50 7R - - - -35 -80 50 7S - - - -27 -82 50 7T - - -49 -93 50 7U - - - -2 9 -60 50 7V - - - 0 0 50 7W - - 12th 0 50 7X - - - -26 -78 50 7Y - - -53 -94 50 -27 -79 10th -22 -55 3 7Z - - - -21 -39 50 7AA - - - -10 -42 50 7AC - 31st 10th 0 0 50 7AD - -22 10th -12 50 7 AE - -95 10th -17 -10 50 7AF - 53 10th 23rd -15 50 7AG - - - 0 -15 50 7AH - -5 10th 16th 50 7AI - - - -63 -95 50 -20 -73 10th -11 -46 3 7AJ - - - 0 -18 50

118

CONTINUED TABLE

7AK - - - 12th -28 50 7AL - - - -13 0 50 7 AM - - - -24 -70 50 7AN - - - -12 -42 50 7A0 - - - -41 -90 50 7PM - - - -24 -82 50 7AQ - - - -52 -91 50 7AR - - - -32 -88 50 7AS - - - 0 -20 50 7AT - - - -10 -32 50 8th - -12 10th - - - 8A - -17 10th 0 0 50 8B - -5 10th -9 -35 50 8C - 63 ^{10th 0} 0 50 8E - - 0 -32 50 8F - 8th 10th -16 -48 50 -20 -45 25th 9th 26th 30th 20th -43 -93 10th -21.5 -66 5 -25 -68 3 10A - -37 10th -19 -58 50 11th - - - -8 0 50 12th - - - -12 0 50 12A - - - -14 -39 50 12B - - - 0 -26 50 12C - - - 0 0 50 12D - - - 0 0 50 13th - - - -18 0 50 14th - - - 30th -87 50

TABLE 9 CONTINUATION 14A - - 14B - - 14C - - 15th - -6 15A - 2 15B - -55 16th - 42 16A - 55 17th - 25th 17A - 38 17B - - 18th - - 19th 0 24th 19A - 64 19B - 53 19C - - 19D - - 19E - - 20th - - 21st - - 21A - - 22nd - - 22A - - 23rd - - 24th - - 24A - 25th - - 25A - - 25B - -

31st -78 50 0 0 50 0 0 50 -21 50 0 0 50 0 -18 50 -25 -29 50 -30 -53 50 -17 -52 50 -11 -25 50 0 -39 50 0 0 50 -20 -51 50 -20 -34 50 -26 -31 50 -9 -46 50 -15 -18 50 -19 -30 50 12th 0 50 -27 -56 50 0 -25 50 -17 -33 50 -16 -22 50 -22 -40 50 -17 0 50 -21 -76 50 -8 -34 50 -13 0 50 0 0 50

120

CONTINUED TABLE

25C - - - -8 -46 26th - - - -4 -26 27th - - - -12 -36 27A - - - -15 -42 28th - - - -19 0 29th - - - -22 -24 31st - - - -19 -52 31A - - - 0 0 32 - - - 0 0 32A - - - 0 0 33 - - - 0 0 34 - - - -39 -94 35 - 18th 10th -15 -32 35A - - - -34 -84 35B - 65 10th -53 -99 36 - - - -53 -94

Claims (22)

DEFINITION OF INVENTION 1) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = = R ₄ = p-CH ₃ OC ₆ H ₄ -; 2) D = C ₆ H ₅ (CH ₂ ) ₄ -, A = • R ₄ ⁼ p — CH ₃ OC ₆ H ₄ -; 3) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = - p-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -; 4) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = = p-OH-C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -; 5) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = = p-CH ₃ OC ₆ H ₄ -, R ₄ = p-ClC ₆ H ₄ -; 6) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = = p C ₂ H ₅ OC ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -; 7) D = C ₆ H (CH ₂ ) ₃ -, A = p-CH ₃ OC ₆ H ₄ -, R ₄ = p C ₂ H ₅ OC ₆ H ₄ -; 1) D = C ₅ H ₅ (CH ₂ ) ₃ , conformation; A compound having the structural formula (I): wherein A is -CH = CH-B; - (CH ₂ ) _p -XB wherein p is 0, 1 or 2 and X is a bond, -NH-, or -S (O) _o _ _2; heteroaryl, benzo-fused heteroaryl, W-substituted heteroaryl or W-substituted benzo-fused heteroaryl, wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, thiazolyl, pyrazolyl, thienyl, oxanyl, and their N-oxides, and wherein W is 1-3 substituents on the ring carbon atoms selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkanediyl, lower alkyl, lower alkandioilo, allyloxy, CF _3, -OCF _3, benzyl, R ₁₄ -benzyl, benzyloxy, R ₁₄ -benziloksilo, phenoxy, R ₁₄ -fenoksilo, dioxolanyl, -NO _2, -NR ₁₀ R _n, NR _{I (} , R ₁₃ (lower alkyl) -, NR 4 R 6 (lower alkoxy) -, OH, 122 halogen, -NHC (O) OR ₅ , R ₆ O ₂ SNH-, (R ₆ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ , -S (O) _o _ ₂ R _10, tert-butildimetilsililoksimetilo, -C (O) R ₁₂ and CH ₂ -N, v / ¹ 2,4, 6- (CH ₃ O) ₃ C ₆ H ₂ -, 3R, 4R conformation; = C ₆ H ₅ -, r ₄ ^- C ₈ Hc ^- , R ₄ 115) D = C ₁₀ H ₂₁ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ CH = CH-, R ₄ = 2,4,6- (CH ₃ O) ₃ C ₆ H ₂ -, 3S, 4R-conformation; 114) D = C ₁₀ H ₂₁ -, R = CH ₃ CH ₂ -, A 2,4,6-tri-CH ₃ OC ₆ H ₄ -, 3R, 4S-confluent; 155 100) D = C ₆ H ₅ (CH ₂ ) ₃ -, r = ch ₃ ch ₂ -, a = c ₆ h ₅ ch = ch-, r ₄ = p-CHOC ₆ H ₄ -, s, 4S conformation. a; 101) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, 3 R, 4 S conformation and ; 102) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ -, A p -CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 103) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ -, A p -CH ₃ OC ₆ H ₄ -, S, 4S-conformation; 104) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = CH ₃ -, A p -CH ₃ OC ₆ H ₄ -, 3 S, 4 S -configuration; C ₆ H ₅ -, R ₄ = C ₆ H ₅ -, R ₄ = 105) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 2,4, 6- (CH ₃ O) ₃ C ₆ H ₂ -, 3R, 4R conformation; 81) D = H, R = CH ₃ CH ₂ -, A = C ₆ H ₅ CH = CH-, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 82) D = H, R = CH ₃ CH ₂ -, A = C ₆ H _b CH = CH-, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 83) D = H, R = CH ₃ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₅ -, 3S, 4S-conformation; 84) D = H, R = CH ₃ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; 85) D = H, R = CH ₃ CH ₂ -, A = 4-NO ₂ C _b H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; 86) D = H, R = CH ₃ CH ₂ -, A = 4-NO ₂ C, H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R-conformation; 87) D = H, R = 3S, 4S-conformation; 2,4,6-tri-CH ₃ OC ₆ H ₂ , 3R, 4S conformation; Conformation of 2,4,6-tri-CH ₃ OC ₆ H ₂ -, 3S, 4S; 2, 4, 6-tri-CH ₃ OC ₆ H ₂ -, will go: trans = 4: 1; 2,4,6-tri-CH-, OC ₆ H ₄ -, 3R, 4S conformation; R ₄ = R ₄ = R ₄ = r ₄ = Rl = 134 76) D = C ₆ H ₅ (CH ₂ ) ₃ ~, R = CH ₃ CH ₂ , A = C ₆ H ₅ CH = CH-, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3S, 4S- conformation; 77) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 78) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ - A = C ₆ H ₅ -, r ₄ = p-CH ₃ OC ₆ H ₄ -, 3R, 4S conformation; 79) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ , A = C ₆ H ₅ -, r ₄ = p-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 80) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = CH ₃ , A = C ₆ H ₅ , r ₄ = p-CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 81) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = ch ₃ ch ₂ -, A = c ₆ h ₅ -, r ₄ = p-CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 82) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = R ₄ = p-CH ₃ OC ₆ H ₄ -, 3R, 4S conformation; 83) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = p -CH ₃ OC ₆ H ₄ -, racemate; C ₆ H ₄ (CH ₂ ) ₃ -, a = c ₆ h ₅ ch = ch-, r ₄ = 84) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = R ₄ = p-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 85) D = C ₆ H ₅ (CH ₂ ) ₃ , R = H, A - p ch ₃ oc ₆ h ₄ , r ₄ p-CH ₃ OC ₆ H ₄ -, 3R, 4S-configurative; 86) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; 87) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CH ₃ OC ₆ H ₄ -, R ₄ = 2,4,6-tri-CH ₃ OC ₂ H _fe -, 3S, 4S-conformation in a; 74) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, p-CH ₃ OC ₆ H ₄ -, 3R, 4S conformation; 75) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ , 2) D = C ₆ H ₅ -CH ₂ CO-, conformation; 2. A compound according to claim 1 wherein R is hydrogen. 3-NH ₂ C ₆ H ₄ -, trans conformation; 3,4- (CH ₃ ) ₂ -C ₆ H ₄ -, trans conformation; 155) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₂ CHO) -C ₆ H ₄ -, R ₄ = 3- F-4-CH ₃ OC _b H ₄ -, trans conformation; 154) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4 -CH ₃ OC, H ₄ -, R ₄ = 3- NO ₂ C ₆ H ₄ -, trans conformation; 148) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 3-CH ₃ OC ₆ H ₄ -, trans conformation; 3-pyridyl, trans conformation; 3-NH ₂ C ₆ H ₄ -, trans conformation; 3,4- (CH ₃ ) ₂ -C ₆ H ₄ -, trans conformation; 120) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₂ CHO) -C ₆ H ₄ -, R ₄ = 3-F-4-CH ₃ OC ₆ H ₄ - trans conformation; 119) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 3-CH ₃ OC ₆ H ₄ -, trans conformation; 3-pyridyl, trans conformation; 3) D = C ₆ H ₅ (CH ₂ ) ₃ -, 3R, 4R-conformation; A compound according to claim 1 or 2 wherein B '- (CH ₂ ) _e -Z- (CH ₂ ) _r - is wherein B' - (C ₂ -C ₆ ) is B '- (CH ₂ ). _q -, alkenylene) - or B '- (CH ₂ ) f V - (CH ₂ ) _g - wherein B', Z, V, q, e, r, f and g are as defined in claim 1. 4-C ₂ H ₅ OC ₆ H ₄ -, cis-conformation; 259) D = C ₆ H ₅ -CH ₂ -CH-CH-, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ , \ / CH trans conformation; 260) D = C ₆ H ₃ (CH ₂ ) ₄ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconfactor. 4-CH ₃ OC ₆ H ₄ -, trans conformation; 255) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = OCO (CH ₂ ) ₂ CO ₂ CH ₃ , R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 256) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = ₄ C ₆ H ₅ CH ₂ OC ₆ H ₄ -, cis-conformation; 257) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = O-CH ₂ -CO ₂ C ₂ H ₅ , R ₄ = 4-CH ₃ OC _f , H ₄ -, cis-conformation; 258) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH3OC ₆ H ₄ -, cis-conformation; 247) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, trans conformation; -ch = noch ₃ , r ₄ = 248) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-HS-C ₆ H ₄ -, R ₄ = ₄ CH ₃ OC ₆ H ₄ -, cis-conformation; 249) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-NH ₂ SO ₂ -C ₆ H ₄ -, R ₄ = ₄ CH ₃ OC ₆ H ₄ -, cis-conformation; • N 250) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A cis-conformation; OH, R ₄ = C ₆ H 4-CH ₃ OC ₆ H ₄ -, cis-conformation; R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 239) D = C ₆ H _s (CH ₂ ) ₃ -, R = H, A = 4-C ₂ H ₅ OC (O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , cis-conformation; 240) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-C ₂ H ₅ OCO (O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , trans conformation; 241) D = C ₆ H ₅ (CH _{2) 3} -, R = H, A = 4-CH ₃ SO ₂ NH-C _a H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis conformation; 242) D = CgH ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ SO ₂ ) ₂ NC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans-conf. ormaci and; 168 243) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ SO ₂ ) ₂ NC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ , cis- conformation; 244) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SO ₂ NH-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans- conformation; 245) D - C ₆ H ₃ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OCONH-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 246) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = —CH = NOCH ₃ , R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 237) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-HOOC-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 236) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-HOOC-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 235) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OCH ₂ -C ₆ H ₄ -, R ₄ = 4-CH3OC ₆ H ₄ -, 234) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OCH ₂ -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 233) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A trans conformation; R4 4-CH ₃ OC ₆ H ₄ -NH-CH ₂ -, r ₄ 4LT 3369 B 167 232) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A cis-conformation; 4-CH ₃ SO-C ₆ H ₄ -, trans conformation; 225) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A =, R ₄ = 4 -CH ₃ OC ₆ H ₄ -, '/ cis conformation; n H 226) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; NH 227) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = ^ 0 R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; \ = ^ / v_ / R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 228) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = ~ ^ y- ^CH 2 ^N x 229) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = _Λ ° ^Η 3 ' R ₄ = -CH ₃ OC ₆ H ₄ -, cis-conformation; 230) D = C, H ₅ (CH ₂ ) ₃ -, R = H, A = _ ^ ^{N CH} 3 ' R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 231) D = C _± H ₅ (CH ₂ ) ₃ -, R = A = CH ₃ OC ₆ H ₄ -, cis conformation; = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 224) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ 4-CH ₃ SO ₂ C ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 222) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SO _{2 Cf} H ₄ -, R ₄ = -CH ₃ OC ₆ H ₄ -, cis-conformation; 166 223) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, trans conformation; 221) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH-, SO-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 220) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CHO-C ₆ H ₄ -, R ₄ = 4-HO-C ₆ H ₄ -, cis-conformation; 219) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CHO-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 218) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-HOC ₆ H ₄ -, trans conformation; 205) D = NH ₂ , R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, zinc conformation, p-toluenesulfonic acid salt); 206) D = C ₆ H ₅ CH ₂ CONH-, R = H, A = 4-CH ₃ OC _ft H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 207) D = CH ₃ CH ₂ CONH-, R = H, A = 4-CH ₃ OC, .H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 208) D = C ₆ H ₅ OCH ₂ CONH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 209) D = C ₆ H ₅ CH ₂ OCONH-, R = H, A = 4-CH ₃ OC _ę H ₄ -, R ₄ = ^ 6 ^ 5 ^- t 210) D = C ₆ H ₅ -N (CH ₃ ) -CONH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis conformation; 165 211) D = p-CH ₃ -C ₆ H ₄ -SO ₂ NH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 212) D = C ₆ H ₅ (CH ₂ ) ₂ NH, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 213) D = p -CH ₃ OC ₆ H ₄ CH ₂ NH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ , cis-conformation; 214) D = (C ₆ H ₅ ) ₂ CHCH ₂ NH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis conformation; 215) D = C ₆ H ₅ (CH ₂ ) ₃ NH- _z R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis conformation; 216) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-HO-C ₆ H ₄ -, R ₄ = ₄ CH ₃ OC ₆ H ₄ -, trans conformation; 217) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-HOCH ₂ -C ₆ H ₄ -, R ₄ = 4-HOC ₆ H ₄ -, trans conformation; 204) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans -confactor; 164 199) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4 - ((CH ₃ ) ₃ COC (O) NH) -C ₆ H ₄ -, R ₄ = 4 -CH ₃ OC ₆ H ₄ -, cis-conformation; 200) D = CH ₃ CH ₂ -, R = H, A = 4-NH ₂ C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R-conformation; 201) D = CH ₃ CH ₂ -, R = H, A = 4- ((CH ₃ ) ₃ COC (O) NH) C ₆ H ₄ -, R ₄ = 4-CH ₃ C ₆ H ₄ -, 3S , 4R-conformation; 202) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4conformation; 203) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 197) D = 4-NH ₂ -C ₆ H ₄ - (CH ₂ ) ₃ -, R = = 4-NH ₂ -C ₆ H ₄ -, R ₄ = = 4-NH ₂ -C ₆ H ₄ -, R ₄ = 4-CH, OC _fi H R ₄ = H, A 4-CH ₃ OC ₆ H ₄ -, trans -confactor; 196) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 195) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, R ₄ 162 178) D = R = H, A = 4-CH3OC, ini ₄ -, FU = CgHs-, cis-conformation; 179) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = trans conformation; 180) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC _f> H ₄ ^- , R ₄ = trans conformation; 181) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = trans conformation; 182) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ CH ₂ O) -C ₆ H ₄ -, R ₄ = 4- (C ₆ H ₅ CH ₂₎ C ₆ H ₄ -, trans konformaci it; 183) D = CH ₃ OC (O) CH = C (CH ₃ ) NH-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 184) D = C ₆ H ₅ (CH ₂ ) ₂ N (CH ₃ ) -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 185) D = r> R = H, A = 4-CHjOC ^ -, R ₄ = C ₆ H ₅ -, cis-conformation; CH ₃ CH ₂ OC (O) -, R ₄ 4186) D = CJL, (CH ₂ ) ₃ -, R = H, A = CH ₃ OC ₆ H ₄ -, cis-conformation; 163 186) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = CH ₃ CH ₂ OC (O) -, R ₄ = ₄ CH ₃ OC ₆ H ₄ -, cis conformation; 187) D = R = C ₆ H ₅ -, A - R ₄ = 4-CH ₃ OC ₆ H ₄ -; 188) D = cyclo-C ₆ H ₈ -, R = C ₆ H ₅ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 189) D = C ₆ H ₅ -, R = C ₆ H ₅ CH ₂ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, cisconformation; 190) D = C ₁₀ H ₂₁ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconfactor; 191) D = C ₆ H ₅ CH ₂ -, R = C ₆ H ₅ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, cisconformation; 192) D = β-naphthoxyl; R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 193) D = CH ₃ , R = H, A = 4-H ₂ NC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 194) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-JC ₆ H ₄ -, trans conformation; 169) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH ₂ ) ₃ O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 170) D = C ₆ H ₅ (CH ₂ ) ₂ -O-, R = H, A = R ₄ = 4 -CH ₃ OC ₆ H ₄ -, cisconformation; ¹⁷¹ > ^D trans conformation; R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 172) D = R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 173) D =, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 174) D = C ₆ H ₅ (CH ₂ ) ₅ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconformation; 175) D = 4-O ₂ NC ₆ H ₄ -O- (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation ; 176) D = R = H, A = 4-CH ₃ OC ₆ H ₄ -, R, = C ^ -, trans conformation; 177) D = 4- (CH ₃ O) C ₆ H ₄ O (CH ₂ ) ₂ -, R = C ₆ H ₅ -, trans conformation; H, A 4- CH ₃ OC ₆ H ₄ -, trans conformation; 156) D = Ο ₆ Η ₅ (ΟΗ ₂ ) ₃ -, R = H, A = - ^^ - OCH ₃ , R ₄ = C ₆ H ₅ , trans conformation; 160 157) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH ₂ ) ₂ O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 158) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CH ₃ -4-CH ₃ OC ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 159) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ ) OC (O)) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans- conformation; 160) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-F-4-CH ₃ OC ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans- conformation; 161) D - C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ OCH ₂ O) -C ₆ H ₄ -, R ₄ C ₆ H ₅ , trans conformation; 162) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₂ N) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , trans conformation; 163) D = CAiCHjJa-, trans-conformation; R = H, R4 = 4-CHjOC ₆ H ₄ -, 164) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = -C OCH _3r R ₄ = 4-CH; PC ₆ H ₄ -, cis conformation; 165) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2,4- (CH ₃ O) ₂ -C ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , trans conformation; 166) D = C ,, H ₅ (CH ₂ ) 3 -, R = H, A = 4- (C ₂ H ₅ ) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation; 167) D = 4-O ₂ NC ₆ H ₄ - (CH ₂ ) ₃ -, R - H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 161 168) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = CH ₃ OC ₆ H ₄ -, R ₄ = 4 - ((C ₂ H ₅ ) ₂ N) C ₆ H ₄ -, trans conformation; 149) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-NCC ₆ H ₄ -, trans conformation; 150) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 3,5 -F ₂ C ₆ H ₃ -, trans conformation; 151) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-01 ^ 00 ^ -, R 4 = yOCH-j, \ = x / 7 trans conformation; 152) D = 0 ^ 5 (0 ^) 3-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R 4 = 4-CH ₃ CC ₆ H ₄ -, trans conformation; 153) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4- (C ₂ H ₅ OC (O)) C ₆ H ₄ -, trans conformation; 147) D = C ₆ H _s (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4- (C ₆ H ₅ CH ₂ O) C ₆ H ₄ -, R ₄ 158 134) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₂ = CHCH ₂ O) C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 135) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ O) C ₆ H ₄ -, R ₄ = 4 -CH ₃ OC ₆ H ₄ -, trans -conformation; 136) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 137) D = C ₆ H ₅ O (CH ₂ ) ₂ -, R = H, A = R ₄ = 4 -CH ₃ OC ₆ H ₄ -, trans conformation; 138) D = C ₆ H ₅ (CH ₂ ) ₆ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 139) D = C ₆ H ₅ (CH ₂ ) ₂ O-, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 140) D = 4-FC ₆ H ₄ O (CH ₂ ) ₂ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 141) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconformation; 142) D = (CH ₃ ) ₂ CH-, R = H, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; 143) D = C ₆ H ₅ (CH ₂ ) ₃ N (CH ₃ ) R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation; 144) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = C ₂ H ₅ -, A = C _f , H ₅ CH ₂ CH ₂ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S , 4R conformation; 145) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC, H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation; 159 146) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, trans conformation; 131) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = trans conformation; 132) D = C 1, H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₂ H ₅ O) C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 133) D = C, H ₅ (CH ₂ ) ₃ -, R = H, A = = 4-CH ₃ OC ₆ H ₄ -, R ₄ = = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 127) D = C ₆ H ₅ (CH ₂ ) ₃ H ·, R = H, A = -OCH. *, R, = Cgl, trans-conformation; 128) D = CŲijaijaų * -, R = H, A = · -OCH-j, R, = Cį,, trans conformation; 129) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3, 4- (CH ₃ O) ₂ C ₆ H ₃ -, R ₄ = -CH ₃ OC ₅ H ₄ -, trans -conformation; 130) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ O) C ₆ H ₄ -, trans conformation; 4-CH ₃ C ₆ H ₄ -, trans conformation; 126) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ SC ₆ H ₄ -, trans conformation; 125) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 124) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ 4- (C ₂ H ₅ -O) C ₆ H ₄ -, trans conformation; 4-Cl-C ₆ H ₄ -, trans conformation; 157 123) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, R ₄ = 122) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC _ę H ₄ -, R ₄ = 4-FC ₆ H ₄ -, trans conformation; 121) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A Conformation of 4-CH ₃ OC ₆ H ₄ -, 3R, 4S; 120) D = C ₆ H ₅ (CH ₂ ) ₃ - R = H, A Conformation of 4-CH ₃ OC ₆ H ₄ ~, 3S, 4S; 116) D = C ₁₀ H ₂₁ -, R = CH ₃ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 117) D = C ₆ H ₅ -, R = H, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R-conformation; 118) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4R-conformation; 119) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R-conformation; 113) D = C ₁₀ H ₂₁ -, R = CH ₃ CH ₂ -, A Conformation of 4-CH ₃ OC ₆ H ₄ -, 3S, 4S; 106) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 107) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = ΟςΗ ₄ (CH ₂ ) ₃ -, A = C ₆ H ₅ CH = CH-, R ₄ = 4-CH ₃ OC ₆ H ₄ -, racemate; 108) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 109) D = C ₁₀ H ₂₁ -, R = CH ₃ CH ₂ -, A = C ^ H ₅ -, R ₄ = CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 110) D = C ₁₀ H ₂₁ -, R = C ₆ H ₅ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3 R, 4 S -formation; 111) D = C ₁₀ H ₂₁ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R-conformation; 156 112) D = C ₁₀ H ₂₁ -, R = C ₆ H _{5 -} (CH ₂ ) ₃ -, a = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, CH ₃ CH ₂ -, 154 88) D = (CH ₃ ) ₂ N-, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 89) D = C ₆ H ₅ -, R = CH ₃ CH ₂ -, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 90) D = C _{X 0} H ₂₁ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis conformation; 91) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = C ₂ H ₅ -, A = C ₆ H ₅ CH = CH-, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R -conf ormaci and; 92) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4 - ((CH ₃ ) ₂ N (CH ₂ ) ₃ O) -C ₆ H ₄ -, R ₄ = 4 -CH ₃ OC ₆ H ₄ -, cis-conformation; 93) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ CH = CH-, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R -conf ormaci and; 94) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 95) D = C ₆ H _{5 -} (CH ₂ ) ₃ -, R = C ₆ H ₅ -, A = C ₆ H ₅ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 96) D = _Cf H ₅ (CH ₂ ) ₃ -, R = C ₁₀ H ₂₁ -, A = C ₆ H ₅ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3S, 4R configurat and; 97) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 2,4,6tri-CH ₃ OC ₆ H ₂ -, 3S, 4S conformation; 98) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3R, 4S-configurat and; 99) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 66) D = 0 ^ (0¾) ₃ -, R = H, A =, R ₄ = 4-CH / 5C 6 H, -, cis-conformation; 67) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis-conformation; 68) D = C ₁₀ H ₂₁ -, R = H, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R conformation; 69) D = C ₁₀ H ₂₁ -, R = H, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₅ -, 3S, 4R-conformation; 70) D = C ₁₀ H ₂₁ -, R = H, A = C ₆ H ₅ -, R ₄ = 2.4, 6- (CH ₃ O) ₃ C ₆ H ₂ -, 3R, 4R conformation; 71) D = H, R = A = C _f H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S conformation; 72) D = H, R = C ₃ H ₇ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R conformation; 73) D = C ,, H ₅ CH ₂ -, R = A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 74) D = _Cf H ₅ CH ₂ -, R = A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S conformation; 75) D = CH ₃ CH ₂ -, R = A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3S, 4S conformation; 153 76) D = CH ₃ CH ₂ -, R = A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 77) D = H, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4R-conformation; 78) D = cyclo-C ₁ H ₆ -, R = A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis / trans mixture (8: 5) relative to phenyl; 79) D = H, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 3R, 4S-conformation; 80) D = H, R CH ₃ CH ₂ -, A - C ₆ H ₅ -, R ₄ 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 65) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SCH ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 61) D = 3-cyclohexylpropyl, R = H, A = 4-CH ₃ OCgH ₄ -, R ₄ = 4-CH ₃ OC _fi H ₄ -, cis-conformation; 62) D = 4-FC ₆ H ₄ -O (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis- conformation; 63) D = 4-FC _t , H ₄ -O- (CH ₂ ) ₂ -, R = H, A = 4 -CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis conformation; 152 64) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 60) D = C ₈ H ₅ (CH ₂ ) ₆ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 59) D = C ₆ H ₅ O (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 57) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = (CH ₃ ) ₃ CSi (CH ₃ ) ₂ -O-C ₆ H ₄ -, cis-conformation; 58) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = (4-Methoxyphenyl) -3- (3-phenylpropyl) -azetidinone. 4-CH ₃ OC ₆ H ₄ -, trans -confactor; 153) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4 - ((CH ₃ ) ₃ COC (O) NH) -C ₆ H ₄ -, R ₄ = 4 -CH ₃ OC ₆ H ₄ -, cis-conformation. = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 151) D = 4-NH ₂ -C ₆ H ₄ - (CH ₂ ) ₃ -, R = 4-CH ₃ OC ₆ H ₄ -, trans conformation; H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 141 152) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-OH-C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 150) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, cis conformation; 149) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-NH ₂ -C ₆ H ₄ -, R ₄ = = 4-CH ₃ OC ₆ H-, R ₄ = 143) D = J cis-conformation; , R = H, A = 4-CH 2 O - H, -, R, = -i, 144) D = C6H5 (CH _{2) 3} -, R = H, A = 4-0 ^ 00 ^ -, R 4 = trans conformation; 145) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = trans conformation; 146) D = Ο6Η ₅ (ΟΗ ₂ ) ₃ -, R = H, A = 4-CHpąii, -, FU = DJ trans-conformation; 147) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ CH ₂ O) -C ₆ H ₄ -, R ₄ = 4- (C ₆ H ₅ CH ₂ O) C ₆ H ₄ -, trans conformation; 148) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-NH ₂ -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 139) D = C ₆ H ₅ (CH ₂ ) ₅ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconfactor; 140) D = 4-O ₂ NC ₆ H ₄ -O- (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation a; 141) D =, R = H, A = 4-CHOC 1 -, = C 8 H 3 -, trans conformation; 140 142) 4- (CH ₃ O) C ₆ H ₄ O (CH ₂ ) ₂ -, R = H, A C ₆ H ₅ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, 136) D = trans conformation; 137) D = trans conformation; 138) D = \ (ch ₂ ) ₃ trans conformation; R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -,, R = H, A = R. 4-JC ₆ H ₄ -, trans conformation; 134) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH ₂ ) ₃ O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ ~, trans-conf ormaci and; 135) D = C ₆ H ₅ (CH ₂ ) ₂ -O-, R = H, A = R ₄ cis conformation; 4-CH ₃ OC ₆ H ₄ -, trans conformation; 121) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = <r ^{cH 3} ' R ₄ = CrH, 6 ⁿ 5 ′ trans conformation; 138 122) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH ₂ ) ₂ O) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 123) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CH ₃ -4-CH ₃ OC ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans -conformation; 124) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ OC (O)) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation ; 125) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-F-4-CH ₃ OC ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans- conformation; 126) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ OCH ₂ O) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ -, trans conformation; 127) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₂ N) -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , trans conformation; 128) D = HHsfOįh-, R = H, A = -C # h-OCH ₃ , R 4 = 4-0 ^ 00 ^ -, o ' ^{, ==} / trans-conformation; 129) D = CgHsfCH ;, ^ -, R = H, A = y-OCH ₃ , R ₄ = 4-CH 2 O-C 8 III -, O cis-conformation; 130) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2, 4- (CH ₃ O) ₂ -C ₆ H ₃ -, R ₄ = 4-CH ₃ OC ₆ H ₄ - , trans conformation; 131) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₂ H ₅ O) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ , trans conformation; 132) D = 4-O ₂ NC ₆ H ₄ - (CH ₂ ) ₃ ~, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 139 133) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ CC ₆ H ₄ -, trans conformation; 118) D = C _a H ₅ (CH _{2) 3} -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 136 99) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ -C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 100) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₂ H ₅ O) C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans -conformation; 101) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ CH ₂ O) C ₆ H ₄ -, R ₄ = 4 -CH ₃ OC ₆ H ₄ - , trans conformation and; 102) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₂ = CHCH ₂ O) C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 103) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ O) C ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans -conformac and; 104) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 105) D = C ₆ H ₅ O (CH ₂ ) ₂ -, R = H, A = R ₄ = 4 -CH ₃ OC ₆ H ₄ -, trans conformation; 106) D = C ₆ H ₅ (CH ₂ ) ₆ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 107) D = C ₆ H ₅ (CH ₂ ) ₂ O-, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 108) D = 4-FC, H ₄ O (CH ₂ ) ₂ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, trans conformation; 109) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = H, A = R ₄ = 4-CH ₃ OC ₆ H ₄ -, transconformation; 110) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ , trans conformation; 137 111) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₂ H ₅ OC (0)) C ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, r ₄ = 112) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-NO ₂ C ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, r ₄ = 113) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((C ₂ H ₅ ) ₂ N) C ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ - _z r ₄ = 114) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-NC-C ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, r ₄ = 115) D = C ₆ H ₅ {CH ₂ ) ₃ -, R = H, A = 3,5 -F ₂ -C ₆ H ₃ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, r ₄ = 116) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H _{4 1} -OCH; trans conformation; 117) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = = 4-CH ₃ OC ₆ H ₄ -, R ₄ =) ₃ i «', r = h, a = ~ ° ^{CH 3} ' 95) D = C ₆ H ₅ (trans conformation of CH ₂ ; / = \ 96) D = C ₆ H ₅ (CH ₂ ) ₃ ^ R = H, A = R ₄ = C ₆ H _s , -och ₃ , r ₄ = c ₆ h ₅ , trans-conformation; 97) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3, 4- (CH ₃ O) ₂ C ₆ H ₃ -, R ₄ = ₄ CH ₃ OC ₆ H ₄ -, trans- conformation; 98) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4- (C ₆ H ₅ O) C ₆ H ₄ -, trans conformation; = 4-CH ₃ OC ₆ H ₄ -, R ₄ 94) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ C ₆ H ₄ -, trans conformation; 4-CH ₃ SC ₆ H ₄ -, trans conformation; 93) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 92) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ 4- (C ₂ H ₅ -O) C ₆ H ₄ -, trans conformation; = 4-CH ₃ OC ₆ H ₄ ~, R ₄ = 91) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-Cl-C ₆ H ₄ -, trans conformation; = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 90) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 89) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-FC ₆ H ₄ -, trans conformation; 4-CH ₃ OC ₆ H ₄ -, 3R, 4S-configurator; 135 88) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 4-CH ₃ OC ₆ H ₄ -, trans conformation; 67) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = cis conformation; 68) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4 - ((CH ₃ ) ₂ N - (CH ₂ ) ₃ -O-) C ₆ ] = 4-CH ₃ OC ₆ H ₄ , cis conformation; 69) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ , A = C ₆ H ₅ CH = CH-, R, p -CH ₃ OC ₆ H ₄ -, 3S, 4R-conf. ormaci and; 70) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ , p-CH ₃ OC ₆ H ₄ , 3S, 4S conformation; 71) D = C ₆ H _{5 -} (CH ₂ ) ₃ -, R = C ₆ H ₅ -, A = C ₆ H ₅ -, p -CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 72) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = C ₁₀ H ₂₁ -, A = C ₆ H ₅ -, p-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; 73) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = CH ₃ CH ₂ -, A = C ₆ H ₅ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 66) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SC ₆ H ₄ -, 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 62) D = 3-cyclohexylpropyl, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC _ę H ₄ -, cis-conformation; 63) D = 4-FC ₆ H ₄ -O- (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis -conformation; 64) D = 4-FC ₆ H ₄ -O- (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 35 C ₆ H _? -, cis-conformation; 133 65) D = C ₆ H ₅ (CH ₂ ) ₄ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, 4-CH ₃ OC ₆ H ₄ -, trans conformation; 57) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = - (CH ₃ ) ₃ CSi (CH ₃ ) ₂ -OC ₆ H ₄ -, cis-conformation; 59) D = C ₆ H ₅ (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 129 4) D = C ₆ H ₅ (CH ₂ ) ₃ -, 3 S, 4 R conformation; A compound according to claim 3 wherein D is B '- (CH ₂ ) _q - wherein B' is phenyl, oq is 3 or 4; B '- (CH ₂ ) _e -Z- (CH ₂ ) _r - wherein B' is p-fluorophenyl or p-methoxyphenyl, e is zero, Z is -O-, or is 2; B '- (C ₂ -C ₆ alkenylene) - is 3-phenyl-1-propenyl; or B '- (CH _{2) f} -V- _{(CH?) g} -, wherein B' is phenyl, f is 1, V is cyclopropylene, and g is the 0th 5 represents a chiral auxiliary of formula wherein R ₁₈ and R ₁₉ are independently selected from the group consisting of: hydrogen, C 1 -C 8 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, and benzyl; and b) cyclizing the product of step (a) to a strong non-nucleophilic base. Wherein D, A, R ₄ are as defined in claim 1, wherein the process comprises: (a) reacting a carboxylic acid of formula DCH ₂ -COOH wherein D is as defined above with a chlorinating agent; (b) a chiral oxazolidinone of formula 5) D = C ₆ H ₅ (CH ₂ ) ₂ -, 3S, 4S-conformation; 5. A compound according to claim 1, 2, 3 or 4 wherein A is - (CH ₂ ) _p -XB, wherein X, B and p are as defined in claim 1. 6 '5' 251) D = C ₆ H ₅ (CH ₂ ) ₃ -, R R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 252) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A trans conformation; H, R ₄ = 4-CH ₃ OC ₆ H ₄ -, 169 253) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = trans conformation; Ή, R ₄ = CH ₃ OC ₆ H ₄ -, 254) H, A R ₄ 6) D = C ₆ H ₅ (CH ₂ ) ₂ -, 3 S, 4 R conformation; , A = R ₄ = p-CH ₃ OC ₆ H ₄ ; 3R, 4S = C ₆ H ₅ , R ₄ = p-CH ₃ OC ₆ H ₄ -, 3R, 4S R = H, A = C ₆ H ₅ , R = H, A = C ₆ H ₅ , R = H, A = C ₆ H ₅ , R = H, A = C ₆ H ₅ , R ₄ - p CH ₃ OC ₆ H ₄ , R ₄ = p-CH ₃ OC _e H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, R ₄ - p CH ₃ OC ₆ H ₄ , 128 6. The compound of claim 5, wherein p is zero and X is a bond. 127 7) D = C ₆ H ₅ (CH ₂ ) ₃ -, r = h, A = C ₆ H ₅ , R ₄ = 7) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = C ₆ H ₅ , R ₄ 2, 4, 6-tri-CH ₃ OC ₆ H ₂ -, cis: trans = 4: 1; 7. A compound according to claim 6, characterized in that R _o R ₂ and R ₃ are selected from the group consisting of H, lower alkoxy, NO _2, alkoxyalkoxy, m-halogeno, lower alkyl lower alkandioilo NR R _{1O U} (lower alkoxyl) -, allyloxyl, phenoxyl, alkoxycarbonylalkoxyl and -C (O) R ₁₂ . 8) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-NO ₂ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, 3S, 4R-conformation; 8) D = pFC ₆ H ₄ -O- (CH ₂ ) ₂ -, A = R ₄ = p -CH ₃ OC ₆ H ₄ -; 8) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-CH ₃ OC ₆ H ₄ -, 3S, 4R conformation; A compound according to claim 1,2,3,4,5 or 6 wherein R ₄ is phenyl, R ₇ substituted phenyl or indanyl. 9) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-NO ₂ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ , 3R, 4R-conformation; 9) D = C ₆ H ₅ (CH _{z) 3} -, A = = p-CH ₃ OC ₆ H ₄ -, R ₄ = pFC ₆ H ₄ -; 10) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p-CH ₃ OC ₆ H ₄ -, R ₄ = m-CH ₃ OC ₆ H ₄ -; 11) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p-CH ₃ OC ₆ H ₄ -, R ₄ = p-CF ₃ OC ₆ H ₄ -; 12) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p-CH, OC ₆ H ₄ -, R ₄ = p-CH ₃ -C ₆ H ₄ -; 9) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-NO ₂ C ₆ H ₄ 3 R, 4 R-conformation; 9. A compound according to claim 8 wherein R _{7 is} selected from the group consisting of lower alkyl, lower alkoxyl, halogen, -OF ₃ , lower alkylthio, -NR ₁₀ R _n , CN, OH and COR ₁₂ . 10) D = C ₆ H ₅ (CH ₂ ) -, R = C ₂ H ₅ , A = C ₆ H ₅ CH = CH-, R ₄ = 55) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-benzofuranyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 56) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-benzofuranyl, R ₄ = 10) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = C ₂ H ₅ , A = 2.4, 6-tri-CH ₃ OC ₆ H ₂ -, 3S, 4S-configur 10. A compound according to claim 1, characterized in that it is selected from the following compounds of the general formula: n (I) 11) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = C ₂ H ₅ , A = C ₆ H ₅ CH = CH, R ₄ = 11. A compound according to claim 1 or claim 10 wherein R is hydrogen and R is hydrogen. 11) D = C ₆ H ₅ (CH ₂ ) ₃ , R = C ₂ H ₅ , A = 2,4,6-tri-CH ₃ OC ₆ H ₂ , 3R, 4S conformation and 12) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = C ₆ H ₅ CH = CH-, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3 S, 4 S and; 12) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-CH ₃ OC ₆ H ₄ -, 3S, 4S-confluent; 13) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p-OHC ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, 3 S, 4 S conformation; 13. A pharmaceutical composition comprising an effective amount of a cholesterol lowering compound having the structure represented by the formula: 144 FR ^R 21 ^_E -G-R O (II) wherein R ₂₀ is phenyl, W-substituted phenyl, naphthyl, W-substituted naphthyl, benzodioxolyl, heteroaryl, W-substituted heteroaryl, benzo-fused heteroaryl, wherein the pyrazinyl is selected from pyridinyl, imidazolyl, heteroaryl, pyrrolyl, triazinyl, pyrazol , thienyl, oxazolyl and furanyl, and for containing heteroaryls, their N-oxides; from the group, pyrimidinyl, thiazolyl, nitrogen R ₂₁ , R ₂₂ and R ₂₃ are independently selected from H or R ₂₀ ; W is 1 to 3 substituents independently selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkanediyl, allyloxy, -CF ₃ , OCF ₃ , benzyl, R ₁₄ -benzyl, benzyloxy, R ₁₄ -beziloksilo, phenoxy, R ₁₄ -fenoksilo, dioxolanyl, N0 _2, NR ₁₀ R _n, R _n NR ₁₀ (lower alkyl) -, NR ₁₀ R _is (lower alkoxy) -, OH, halogeno, -NHC (O) OR _5, -NHC (O) R _S, R _h O ₂ SNH-, (R ₆ O ₂ S) ₂ N-, -S (O) ₂ NH ₂ - S (O) O-2 R ₁₀ , tert -butyldimethylsilyloxymethyl, -C (O) R ₁₂ , -ch ₂ ~ n \ _y and E, F and G are independently a bond; C ₃ -C ₆ cycloalkylene; C ₁ -C ₁₀ alkylene; C ₁ -C ₁₀ alkenylene; Οχ-C ^ o alkynylene; alkylene, alkenylene or alkynylene A 145 chain as defined with one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl, and W-substituted heteroaryl, wherein heteroaryl is as defined above; an alkylene, alkenylene, or alkynylene chain as defined in which one or more groups independently selected from the group consisting of -O, -S-, -SO-, -SO ₂ -, NR ₈ -, are inserted, -C (O) -, C ₃ -C ₆ cycloalkylene, phenylene, W-substituted phenylene, heteroarylene, and W-substituted heteroarylene; or an attached alkylene, alkenylene or alkynylene chain as defined with one or more substituents independently selected from the group consisting of phenyl, W-substituted phenyl, heteroaryl and W-substituted heteroaryl; or one of R ₂₁ -E and R ₂₂ -F is selected from the group consisting of halogen, OH, lower alkoxyl, -OC (O) R _S , -NR ₁₀ R _n , -SH or -S (lower alkyl); R ₅ is lower alkyl, phenyl, R ₁₄ -phenyl, benzyl or R ₁₄ -benzyl; R ₆ is OH, lower alkyl, phenyl, benzyl, R ₁₄ phenyl or R ₁₄ benzyl; R ₀ is H, lower alkyl, phenyl-lower alkyl, or C (O) R ₉ ; R ₉ is H, lower alkyl, phenyl or phenyl-lower alkyl; R ₁₀ and R _n are independently selected from H and lower alkyl; R ₁₂ is H, OH, alkoxyl, phenoxyl, benzyloxy, / R 73 r 146 NR R _{1O U,} lower alkyl, phenyl or R ₁₄ -phenyl; R ₁₃ is -O-, -CH ₂ -, -NH- or -N (lower alkyl) -; R ₁₄ is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO _2, -NR R _{1O U,} OH or halo; with the proviso that when G is a bond, R ₂₃ is not H, and provided that when R ₂₃ is W-substituted phenyl, W is not p-halogen; or a pharmaceutically acceptable carrier thereof. appropriate salts pharmaceutically 14. The composition according to Item 13, bes i s k i - r i a n t i t h e r i s i n g compound, chosen of the following formula (I) compounds, where: 1) D = C ₆ H ₅ (CH ₂ ) ₃ , 3 R, 4 S conformation; R = H, A = R ₄ = p-CH ₃ OC ₆ H ₄ ; 2) D = C ₆ H ₅ -CH ₂ CO-, 3R, 4S-conformation; R = A · = c ₆ h ₅ , R ₄ = p-CH ₃ OC ₃ H ₄ -, 3) D = C ₆ H ₅ (CH ₂ ) ₃ -, 3R, 4R-conformation; R = H, A = c ₆ h ₅ , R ₄ = p-CH ₃ OC ₆ H ₄ -, 4) D = C ₆ H ₅ (CH ₂ ) ₃ -, 3S, 4R-conformation; R = H, A = c ₆ h ₅ , r ₄ = p-CH ₃ OC ₆ H ₄ -, 5) D = C ₆ H ₅ (CH ₂ ) ₃ -, 3 S, 4 S conformation; R = H, A = c ₆ h ₅ , R ₄ - p -CH ₃ OC ₆ H ₄ -f 6) D = C ₅ H ₅ (CH ₂ ) ₃ -, 3 S, 4 R conformation; R = H, A = c ₆ h ₅ , R ₄ ⁼ p — CH ₃ OC ₆ H ₄ -, 147 13) D = C ₆ H ₅ CH ₂ CH = CH-, A = R ₄ = p -CH ₃ OC ₆ H ₄ -; 13) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p -CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; 13 wherein k is 1 or 2; D is B '- (CH ₂ ) _m C (O) - wherein m is 1,2,3,4 or 5; B '- (CH ₂ ) _q -, wherein q is 2,3,4,5 or 6; B '- (CH _{2) e} -Z- (CH ₂₎ r, wherein Z is -0-, -C (O) -, phenylene, -NR ₈ - or -S (O) _o _ ₂ e is 0,1,2,3,4 or 5 and r is 1,2,3,4 or 5, provided that the sum of e and r is 1,2,3,4,5 or 6; B '- (C ₂ -C ₆ alkenylene) -; B '- (C ₄ -C ₆ alkadienylene) -; B '- (CH ₂ ) _t ^- Z ^- (C ₂ -C ₆ alkenyl) -, wherein Z is as defined above and wherein t is 0, 1, 2 or 3 with the proviso that t and the number of carbon atoms the sum of the alkenylene chain is 2,3,4,5 or 6; B ¹ - (CH ₂ ) _f -V- (CH ₂ ) _q - wherein V is C ₃ -C ₆ cycloalkylene, f is 1,2,3,4 or 5 og is 0,1,2,3,4 or 5, provided that the sum of f and g is 1,2,3,4,5 or 6; 123 B '- (CH ₂ ) _t ^-V (C ₂ -C ₆ alkenyl) or B' - (C ₂ -C ₆ alkenylene) V - (CH ₂ ) _t -, wherein V and t are as defined above, with the proviso that the sum of t and the number of carbon atoms in the alkenylene chain is 2,3,4,5 or 6; B '- (CH ₂ ) _a -Z- (CH ₂ ) _b -V- (CH ₂ ) _d ~, wherein Z and V are as defined above, oa, b and d are independently 0,1,2, 3,4,5 or 6, provided that the sum of a, b and d is 0,1,2,3,4,5 or 6; T- (CH ₂ ) _s -, wherein T is cycloalkyl of 3, carbon atoms, os is 1,2,3,4,5 or 6; or naphthylmethyl, heteroarylmethyl or W-substituted heteroarylmethyl wherein heteroaryl and W are as defined above; B is B 'is naphthyl, heteroaryl heteroaryl wherein heteroaryl is as defined above, or whether W-substituted is as * 3 R is hydrogen, fluoro, C ₁ -C ₁₅ alkyl, C ₁ -C ₁₅ alkenyl, alkynyl, or B- (CH ₂ ) _h - wherein h is 0, 1, 2 or 3; 124 R _1z R ₂ and R ₃ are independently selected from the group consisting of H, lower alkyl, hydroxy lower alkyl, lower alkoxy, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkandioyl, lower alkyl lower alkanediyl, allyloxy , -CF ₃ , -OCF ₃ , benzyl, R ₁₄ benzyl, benzyloxy, R ₁₄ benzyloxy, phenoxyl, R ₁₄ -phenoxyl, dioxolanyl, NO ₂ , -NR ₁₀ R 11, NR ₁₀ R _and (lower alkyl) -, NR R _{1O U} (lower alkoxy) -, OH, o-halogeno, m-halogeno, -NHC (O) OR _5, -NHC (O) R _5, R ₆ O ₂ SNH-, (R ₆ O ₂ S) ₂ N-, -S (O) ₂ NH _2, -S (O) _o - R _{10 2,} tretbutildimetilsililoksimetilo, -C (O) R _12, O -CN II and R \ or R _Y _x is hydrogen and R ₂ and R ₃ together with neighboring carbon atoms to which they are attached, form a dioxolanyl ring; R _x ', R ₂ ' and R ₃ 'are independently selected from the group consisting of H, lower alkyl, hydroxy-lower alkyl, lower alkoxyl, alkoxyalkyl, alkoxyalkoxyl, alkoxycarbonylalkoxyl, (lower alkoxyimino) lower alkyl, lower alkandioyl, lower alkyl alkanedioyl, allyloxyl, -CF ₃ , -OCF ₃ , benzyl, R ₁₄ benzyl, benzyloxy, R ₁₄ benzyloxy, phenoxyl, R ₁₄ -phenoxyl, dioxolanyl, NO ₂ , -NR ₁₀ R _11f NR ₁₀ R 11 (lower alkyl) -, NR _1c R _n (lower alkoxyl) -, OH, halogen, -NHC (O) OR ₅ , -NHC (O) R ₅ , R ₈ O ₂ SNH -, (Re ₂ O) ₂ N -, -S (O) ₂ NH _2, -S _{(O) 2} R ₁₀ _, tretbutildimetilsililoksimetilo, -C (O) R ₁₂ , or R! ' is hydrogen 125 R ₂ 'and R ₃ ' together with the adjacent carbon atoms to which they are attached form a dioxolanyl ring; R ₄ is // wherein n is 0,1,2 or 3, indanyl, benzofuranyl, tetrahydronaphthyl, pyridyl, pyrazinyl, pyrimidinyl or quinolyl; R _s is lower alkyl, phenyl, R ₁₄ -phenyl, benzyl or R ₁₄ -benzyl; R ₆ is OH, lower alkyl, phenyl, benzyl, R ₁₄ phenyl or R ₁₄ benzyl; R ₇ is lower alkyl, lower alkoxy, OH, halo, -NR _u R _1O, -NHC (O) OR _5, -NHC (O) R _S, NO _2, -CN, -N _3, -SH, -S (O) _{o- 2} - (lower alkyl), -COOR ₉ , -CONR ₁₀ R _n , COR ₁₂ , phenoxyl, benzyloxy, butyldimethylsilyloxy, and wherein -OCF ₃ , or tertn is 2 or 3, R ₇ groups may be the same or different; R 8 is H, lower alkyl, phenyl-lower alkyl, or -C (O) R ₉ ; R ₉ is H, lower alkyl, phenyl or phenyl-lower alkyl; R ₁₀ and R _n are independently selected from H and lower alkyl; R ₁₂ is H, OH, alkoxyl, phenoxyl, benzyloxy, 126 NR _1Q R _11; lower alkyl, phenyl or R ₁₄ -phenyl; R ₁₃ is -O-, -CH ₂ -, -NH- or -N (lower alkyl) -; and R ₁₄ is 1-3 groups independently selected from the group consisting of lower alkyl, lower alkoxy, -COOH, NO _2, -NR _1X R _1O, OH or halo; or a pharmaceutically acceptable salt thereof. 13 'and wherein the substituents on the substituted nitrogen atoms in the heteroaryl ring, when present, are selected from the group consisting of lower alkyl, lower alkoxyl, -C (O) OR ₅ , -C (O) R ₅ , OH, NR ₁₀ R _1L. (lower alkyl) -, NR ₁₀ R _n (lower alkoxyl) -, -S (O) ₂ NH ₂ and 2- (trimethylsilyl) ethoxymethyl; -C (O) -B; or - ( ^CH 2) _k -N 14) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p -CH ₃ OC ₆ H ₄ CH = CH-, R ₄ = p -CH ₃ OC ₆ H ₄ -, 3S, 4S -conformation; 14) D 14) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p -CH; p-CH ₃ OC ₆ H ₄ -, 3S, 4S-configurative; Deprotonation of a group consisting of: hydrogen, C 1 -C 8 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl and benzyl, with a strong base and treatment of the resultant anion with the product of step (a); 172 (ii) TiCl ₄ and tetramethylethylenediamine (TMEDA) or a mixture of TMEDA and triethylamine; followed by condensation with an aldehyde of the formula A-CHO, wherein A is as defined above; d) hydrolyzing the product of step (c) with a base and hydrogen peroxide; e) condensing the product of step (d) with an amine of formula R ₄ NH ₂ , wherein R ₄ is as defined above, under the action of a dehydrating linking agent and, if necessary, adding an activating agent; and (f) cycling the product of step (e) by: (i) dialkyl azodicarboxylate and trialkyl phosphine; or (ii) di- or tri-chlorobenzoyl chloride, an aqueous base, and an interphase catalyst; or (iii) dialkyl chlorophosphate, an aqueous base and an interphase catalyst; or (iv) di- or tri-chlorobenzoyl chloride and an alkali metal hydride. 15. A process for the preparation of a pharmaceutical composition according to claim 13, wherein 170 described in claim 13 in admixture with a pharmaceutically acceptable carrier. 15) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CH ₃ OC ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, 3 S, 4 S conformation and ; 15) D 15) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3 p -CH ₃ OC ₆ H ₄ -, 3S, 4S-conformation; Use of a compound according to claim 1 for the manufacture of a medicament for lowering serum cholesterol. 16) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p -CH ₃ OC ₆ H ₄ -, R ₄ = 16) D 16) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A =] Use of a compound according to claim 1 for the manufacture of a medicament for the inhibition of the acyl-CoA: cholesterol acyltransferase enzyme. 17) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = p -CH ₃ OC ₆ H ₄ -, R ₄ = p-CF ₃ OC ₆ H ₄ -, trans conformation; 17) D 17) D = C _h H ₅ (CH ₂ ) ₃ -, R = H, A =] p -CF ₃ OC ₆ H ₄ -, trans -confactor; A pharmaceutical composition according to claim 13 for lowering serum cholesterol and inhibiting acyl-Co: cholesterol acyltransferase enzyme. 18) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = p-ClC ₆ H ₄ -; cis-conformation; 148 18) D 18) D = C, H ₅ (CH ₂ ) ₃ -, R = H, A = p-ClC ₆ H ₄ -, cis conformation; p-NO ₂ C ₆ H ₄ -, R ₄ =, R ₄ - p-CH ₃ OCgH ₄ , C ₆ H ₅ CH = CH-, R ₄ = C ₆ H ₅ CH = CH-, R ₄ = C ₆ H ₅ CH = CH-, R ₄ = p-OH-C ₆ H ₄ -, R ₄ =, OC ₆ H ₄ CH = CH-, R ₄ = -CH ₃ OC ₆ H ₄ -, R ₄ = -ch ₃ oc ₆ h ₄ -, r ₄ = -ch ₃ oc ₆ h ₄ -, r ₄ = 19. A process for the preparation of a compound according to claim 1, wherein R is H and D and A are trans-relative stereochemistry, wherein the hydroxyamide of formula D, A and R ₄ is as described in claim 1 is cyclized by : (i) dialkyl azodicarboxylate and trialkyl phosphine; or (ii) di- or tri-chlorobenzoyl chloride, an aqueous base, and an interphase catalyst; the resulting di- or trichlorobenzoate is then treated with an aqueous base and an interphase catalyst; or (iii) dialkyl chlorophosphate, an aqueous base and an interphase catalyst; or 171 (iv) di- or tri-chlorobenzoyl chloride and an alkali metal hydride. 19) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ , R ₄ = p-CH ₃ -C ₆ H ₄ -, cis conformation; 19) D 19) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ , R ₄ = p-CH ₃ -C ₆ H ₄ -, cis conformation; (C) Enolization of the product of step (b): (i) dialkylboron triflate and a tertiary amino base; wherein R ₁₈ and R ₁₉ are independently selected from The compound of claim 1 having the formula // Oh or 20) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = p C ₆ H ₅ OC ₆ H ₄ -, cis conformation; 20) D 20 4-CH ₃ OC ₆ H ₄ -, cis-conformation; 60) D = C ₆ H ₅ O (CH ₂ ) ₂ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 4-CH ₃ OC ₆ H ₄ -, cis conformation; 61) D = C ₆ H ₅ (CH ₂ ) ₆ -, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = 20) D = C ₆ H ₅ (CH ₂ ) ₃ ~, R = H, A = 4-CH ₃ OC ₆ H ₄ -, R ₄ = p C ₆ H ₅ OC ₆ H ₄ -, cis-conformation; 21. A process for the preparation of a compound according to claim 1, wherein R is hydrogen and D and A are trans relative stereochemistry, which comprises: (a) a compound of the formula 173 enolization with TiCl ₄ and tetramethylenediamine (TMEDA) followed by condensation with an imine of formula A-CH = NR ₄ wherein A and R ₄ are as defined above and wherein the group 21) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-pyridyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 22) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = (CH ₃ ) ₃ CSi (CH ₃ ) ₂ -OCH ₂ C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation and; 23) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = (CH ₃ ) ₃ CSi (CH ₃ ) ₂ OCH ₂ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis conformation; 24) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SC ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis-conformation; 25) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = - ^ || N - I CH ₂ O (CK ₂ ) ₂ Si (CH ₃ ) R ₄ = p-CH ₃ OC ₆ H ₄ -, trans conformation; 26) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = | ( N - CH ₂ O (CH ₂ ) ₂ Si (CH ₃ ) ₃ R ₄ = p -CH ₃ OC _fc H ₄ -, cis-conformation; 27) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A .0 · ^ 0 ^ R ₄ - p CH ₃ OC _f , H ₄ ; 149 28) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₃ CHO) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ - , cis-conformation; 29) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH ₂ ) ₂ -O) C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 30) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3, 4- (CH ₃ O) ₂ C ₆ H ₃ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 31) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3, 4- (CHO) ₂ C ₆ H ₃ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis- conformation; 32) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 33) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 34) D = C ₆ H ₅ (CH ₂ ) ₃ -, R - H, A = 3-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 35) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans -conformation; 36) D = C ₉ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CF ₃ -CH ₄ -, R ₄ = - p -CH ₃ OC ₆ H ₄ -, trans -confactor; 37) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CF ₃ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis-conformation; 38) D = C ₈ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 39) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 150 40) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CF ₃ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis -confirm; 41) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CF ₃ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 42) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ -C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis -confirm and ; 43) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ CH ₂ O) C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ - , 44) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = C ₂ H ₅ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis -confirm; 45) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-thienyl, R ₄ = p-CH ₃ OC ₆ H ₄ -, trans -confirmation; 46) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-thienyl, R ₄ = p-CH ₃ OC ₆ H ₄ -, trans -confirmation; 47) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = CH ₃ (CH ₂ ) ₃ -OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis- conformation; 48) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ O) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 49) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ ) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis -conformac and; 50) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₂ = CHCH ₂ O) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ - , cis-conf ormaci and; 51) D = C ₆ H ₅ (CH ₂ ) ₃ -. R = H, A = 3,4,5-trimethoxyphenyl, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis -confirm; 151 52) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3,4,5-trimethoxyphenyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 53) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = quinolinyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 54) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ CH ₂ O) C ₆ H ₄ -, R ₄ = C ₆ H ₅ -, cis conformation; 55) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-benzofuranyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 56) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A - 2-benzofuranyl, R ₄ = 21) D 22) D 23) D 24) C 25) D 26) C 27) C 28) C 142 = C ₆ H ₅ (CH ₂ ) ₃ ~, a = p - (CH ₃ (CH ₂ ) _{3 -} oc ₆ h ₄ = C ₆ H ₅ (CH ₂ ) ₃ -, A = p -CH ₃ OC ₆ H ₄ = R ₄ = CGH ₅ (CH _{2) 3} -, A = p- (CH = CH = CH _{2) 4} -CgH -, = C ₆ H ₅ (CH _{2) 3} -, A = p (C ₆ H ₅ O) -C ₆ H ₄ -, = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - (CH ₃ CH ₂ O ₂ C) -C ₆ H ₄ -, = C ₆ H ₅ (CH ₂ ) ₃ -, A = p-CH ₃ OC ₆ H ₄ -, R ₄ = = C ₈ H ₅ (CH ₂ ) ₃ -, A = p- (CH ₃ CH ₂ CH ₂ -O) -C g H ₄ = C ₆ H ₅ (CH ₂ ) ₅ -, a = r ₄ = p -CH ₃ OC ₆ H ₄ = C ₆ H ₅ (CH ₂ ) ₃ -, a = p -CH ₃ OC ₆ H ₄ -; R ₄ = p = C ₆ H ₅ (CH ₂ ) ₃ -, a = p - (C ₂ H ₅ O) -c ₆ h ₄ -, = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - ((CH ₃₎ ) ₂ CHO) -C ₆ H ₄ -, = pFC ₆ H ₄ -O- (CH ₂ ) ₂ -, A = p-CH ₃ OC, = C ₆ H ₅ (CH ₂ ) ₃ -, A = p- CH ₃ OC ₆ H ₄ -, r ₄ = = C ₆ H ₅ (CH ₂ ) ₃ -, a = p - (CH ₃ O ₂ C) -c ₆ h ₄ , R ₄ - p -CH ₃ OC ₆ H ₄ -; p-CH ₃ SC ₆ H ₄ -; R ₄ = p-CH ₂ Cl ₂ H ₄ -; R ₄ = p-CH ₃ OC ₆ H ₄ -; R ₄ = p-CH ₃ OC ₆ H ₄ -; Oo _r R,; = p ^- CH ₃ OCgH ₄ -; - ((C ₂ H ₅ ) ₂ N) -C ₆ H ₄ -; R ₄ = C ₆ H ₅ -; R ₄ = p-CH ₃ OC ₆ H ₄ -; R 1 ⁼ p-CH ₃ C ₆ H ₄ -; , H ₄ - _r R ₄ ⁼ C ₆ H ₅ -; 29) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p -CH ₃ OC, H ₄ -, R ₄ = 3, 5-F ₂ -C ₆ H ₃ -; 143 30) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = 2, 4-CH ₃ OC ₆ H ₄ -, R ₄ = 3, 5-F ₂ -C ₆ H ₃ -; 31) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p -CH ₃ OC ₆ H ₄ -, R ₄ = p - (H ₃ CC (O)) - C ₆ H ₄ -; 32) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = OCH. R ₄ = p-CH ₃ OC ₆ H ₄ -; 33) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - (CH ₃ OCH ₂ O) -C ₆ H ₄ -, R ₄ = C ₆ H ₅ -; 34) D = p-CH ₃ OC ₆ H ₄ -O- (CH ₂ ) ₂ -, A = p-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ ; 35) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - (C ₂ H ₅ OC (O) CH ₂ O) -C ^ -, R 1 = p -CH ₃ OC ₂ -; 36) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - (CH ₃ OC (O) - (CH ₂ ) ₂ -C (O) -O) -C ₆ H ₄ -, R ₄ ⁼ p-CH ₃ OC ₆ H ₄ -; 37) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = p - ((CH ₃ ) ₂ N - (CH ₂ ) ₃ -O) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -; 38) D = C ₆ H ₅ (CH ₂ ) ₃ -, A = R ₄ = p-HO-C ₆ H ₄ -; 39) pi ⁵ ',, ^D U · A = p-CH ₃ OC ₆ H ₄ -, R ₄ = C ₆ H ₅ . 12th The compound according to Claims 1, 10 or 11, characterized in that: k i r i a n t i s in that it is (3R, 4S) -1,4-bis 21) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-pyridyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 22) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = (CH ₃ ) ₃ CSi (CH ₃ ) ₂ -OCH ₂ C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 23) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = (CH ₃ ) ₃ CSi (CH ₃ ) ₂ OCH ₂ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis conformation; 24) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ SC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -; cis-conformation; / N - 25) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = <I) CH ₂ O (CH ₂ ) ₂ Si (CH ₃ ) ₃ R ₄ = p -CH ₃ OC _f H ₄ -, trans conformation; 26) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A CH ₂ O (CH ₂ ) ₂ Si (CH ₃ ) ₃ R ₄ = p-CH ₃ OC ₆ H ₄ -, cis conformation; 27) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A 130 R ₄ - p-CH ₃ OC ₆ H ₄ - f 28) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- ((CH ₃ ) ₃ CHO) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ - , cis-conformation; 29) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ (CH) ₂ -O) C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 30) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3,4- (CH ₃ O) ₂ C ₆ H ₃ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 31) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3,4- (CH ₃ O) ₂ C ₆ H ₃ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 32) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 33) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 34) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 35) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-furanyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 36) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CF ₃ -C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, trans conformation; 37) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CF ₃ C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis-conformation; 38) D = C ₆ H ₅ (CH ₂ ) ₃ - R = H, A = 2-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 39) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 131 40) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CF ₃ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 41) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-CF ₃ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 42) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-CH ₃ -C ₆ H ₄ -, R ₄ = p-CH ₃ OC ₆ H ₄ -, cis conformation; 43) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ CH ₂ O) C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ ; 44) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = C ₂ H ₅ OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 45) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 46) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 2-thienyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, trans conformation; 47) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = CH ₃ (CH ₂ ) ₃ -OC ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis- conformation; 48) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ O) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis-conformation; 49) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (C ₆ H ₅ ) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis -conformation; 50) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₂ = CHCH ₂ O) -C ₆ H ₄ -, R ₄ = p -CH ₃ OC ₆ H ₄ - , cis-conformation; 51) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3, 4,5-trimethoxyphenyl, R ₄ = p -CH ₃ OC ₆ H ₄ -, cis conformation; 132 52) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 3- (N-methyl) indolyl; R ₄ = p-CH ₃ OC ₆ H ₄ -, cis conformation; 53) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4-quinolinyl, R ₄ = 5 p -CH ₃ OC ₆ H ₄ -, cis conformation; 54) D = C ₆ H ₅ (CH ₂ ) ₃ -, R = H, A = 4- (CH ₃ CH ₂ O) C ₆ H ₄ ~, R ₄ = C ₆ H ₅ -, cis-conformation; Process for the preparation of compounds according to claim 1, characterized in that it comprises: 174 a) Reaction of the ester of formula D-CH (R) -C (O) OR ₁₇ where R ₁₇ is lower alkyl, menthyl or 10- (diisopropylsulfonamido) isobornyl with a strong base followed by imine of formula A-CH = NR ₄ wherein A and R ₄ are as defined in claim 1; or b) preparing a compound of claim 1 wherein R is not hydrogen, treating the compound of claim 1 wherein R is hydrogen with a strong base and an alkylating or acylating agent; or for a receipt in which the relative point 1 will go, where R is stereoR is is trans relative c) hydrogen of the compound according to claim 1, and D and A being the action of a chemical, hydrogen and the stereochemistry of D and A on a strong base in the temperature range -80 to -40 ^uC and thereafter a proton source; or an acid; or d) subjecting the compound of claim 1, wherein R is hydrogen, and D and A are trans relative stereochemistry, to the compound of claim 1, wherein R is hydrogen and D and A are subjected to relative stereochemistry, with alkali metal t-butoxide, followed by stopping that reaction e) CH (R) -C (O) -Z of the carboxylic acid, wherein D is as defined in claim 1, o O II Z is Cl, -OP-OC ₆ H ₅ or I Cl is reacted with an imine of formula A-CH = NR ₄ wherein A and R ₄ are as defined in claim 1 in the presence of a tertiary amino base.