KR20010022861A - Non-Steroidal Ligands for the Estrogen Receptor - Google Patents

Abstract

The present invention relates to novel nonsteroidal ligands for estrogen receptors having tissue dependent-estrogen activity and antiestrogenic activity, methods for their preparation and their use for various diseases.

Description

Non-Steroidal Ligands for the Estrogen Receptor

Estrogen is an important steroid hormone that stimulates the development and maintenance of basic sexual properties in humans. Estrogen has already been found useful in the treatment of certain medical conditions and diseases. For example, estradiol, a steroid hormone produced by the ovary, can be used to treat osteoporosis, cardiovascular disease, premenstrual syndrome, vasomotor symptoms associated with menopause, atrophic vaginitis, gastric atrophy, female sexual dysfunction, major ovarian disease, excessive hair growth and prostate It is useful for the treatment of cancer. However, administration of the steroids has many side effects including myocardial infarction, thromboembolism, cerebral vascular disease and endometrial carcinoma.

For example, hormone replacement therapy (HRT) with estrogen has been shown to be clinically effective in treating osteoporosis in postmenopausal women, despite clinical efforts showing a 50% reduction in hip destruction and a 30% reduction in cardiovascular vaginal disease. Less than 15% of eligible women are currently receiving HRT. There is no response from patients and doctors are concerned about the association between estrogen treatment and breast cancer and the doubled risk of endometrial cancer observed in HRT of estrogen alone. Although not clinically proven, a significant proportion of postmenopausal women have rejected HRT because of the above risk for breast cancer. Concomitant treatment with progestin has been shown to protect the uterus against cancer while maintaining the osteoporogenic effect of estrogen, but progestin causes other side effects such as stop bleeding, breast pain and manic depression.

In view of the problems associated with estrogen treatment, a number of studies have been conducted to identify effective nonsteroidal estrogens and antiestrogenic compounds. In general, all of these compounds bind to estrogen receptors but can be characterized as estrogen and antiestrogenic because they induce estrogen or antiestrogenic effects depending on the position of the receptor. Previously, the incorporation of various nonsteroidal estrogen and antiestrogenic compounds to the estrogen receptor has been claimed to be due to the presence of a common pharmacophore (scheme A) which is identified both in the chemical structure of these compounds.

Scheme A

The drug group forms a structural backbone and nonsteroidal estrogens and antiestrogenic compounds are formed around them. Hexestrol, tamoxifen, chromman, triphenylethylene, DES, clomiphene, centchroman, napoxidene, trioxyphene, toremifene, gindoxifen, raloxifene, droroxifene, DABP, TAT-59 and The presence of such drug groups in various compounds, such as other structurally related compounds, has been accepted in the art as a molecular interpretation of estrogen receptor binding specificity.

Examples of nonsteroidal antiestrogens to be noted are tamoxifen (TAM), (Z) -1,2-diphenyl-1- [4- [2- (dimethylamino) ethoxy] phenyl] -1-butene, which is tri Phenylethylene derivatives. Tamoxifen effectively attenuates the growth-promoting effects of estrogens in major target tissues such as breasts and eggs.

Currently, structurally similar compounds known as nonsteroidal estrogens and raloxifene have been developed for the treatment and / or prevention of osteoporosis, cardiovascular disease and breast cancer as well as for the treatment and / or prevention of many other vaginal diseases. The two compounds, together with the positive effect on plasma cholesterol concentration, exhibited osteoporosis prevention effect on bone mineral density and greatly reduced the incidence of breast and uterine cancer. Tamoxifen and raloxifene, however, have unacceptable side effects that are fatal to life, such as endometriosis and hepatocellular carcinoma.

Therefore, it is desirable to develop a series of nonsteroidal compounds that have beneficial properties such as osteoporosis prevention activity while minimizing undesirable side effects. It is currently accepted that the pharmacokinetic backbone determines estrogen receptor binding specificity, but it has been confirmed that certain novel estrogen binding ligands can be prepared in which a specific moiety is bound to the drug phase compound, thereby increasing the risk of cancer. Maximize beneficial properties such as osteoporosis prevention while minimizing unwanted effects.

The present invention relates to novel nonsteroidal ligands for estrogen receptors having tissue-dependent escrowgen activity and antiestrogenic activity, methods for their preparation and their use for various diseases.

1 is a graph showing the uterotrophic activity of the compounds of the present invention in immature rats;

Figure 2 is a graph showing the change in bone mineral density of lumbar spine and tibia in ovarian loaded rats.

The present invention includes compounds represented by the following general formula (1):

In the above formula, R ¹ -R ⁴ are as follows. The present invention also relates to a pharmaceutical composition comprising one or more of the compounds of Formula 1, uses thereof, preparation methods and intermediates.

The present invention includes compounds represented by the following general formula (1):

Formula 1

In the above formula, R ¹ is-(CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; -(CH ₂ ) _m C (X) NR ⁸ R ⁹ ; or ;

R ² and R ³ are independently H, —CH ₃ , —OH, —OCH ₃ , —OCH ₂ CH ₃ or —CH ₂ (CH ₃ ) ₂ ;

R ⁴ is —CN, —NO ₂ , —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ —Y or —Y;

R ⁵ and R ⁶ are independently H, -C _1-4 alkyl, -C _2-4 alkenyl, -C _2-4 alkynyl, -XC _1-3 alkyl, -XC _2-4 alkenyl, -XC _2-4 alkynyl or -Y;

R ⁷ is —CN, —C _1-4 alkyl-OH, —C (O) O (CH ₃ ) ₃ , —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , -C _{1 -4} alkyl-NR ¹⁰ R ¹¹ , -C (O) R ¹² , -C (O) OR ¹² , -C (O) NR ¹² OR ¹³ , -C (O) NHC (O) R ¹² , -C ( O) NHCH ₂ R ¹² , -C (NH ₂ ) (NOR ¹² ), -S (O) R ¹² , -S (O) (O) (OR ¹² ), -S (O) (O) (NHCO ₂ R ¹² ), PO ₃ R ¹² , -P (O) (NR ¹² R ¹³ ) (NR ¹² R ¹³ ), -P (O) (NR ¹² R ¹³ ) (OR ¹⁴ ), -CONR ¹² (CH ₂ ) _q OCH ₃ , -CONR ¹² (CH ₂ ) _q NR ⁸ R ⁹ or oxadiazole substituted with a methyl group;

R ⁸ and R ⁹ are independently hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —OC _1-7 alkyl, —C _1-7 alkyl-Y or phenyl;

R ¹⁰ and R ¹¹ independently form methyl or ethyl or morpholino groups bonded via a nitrogen atom;

R ¹² , R ¹³ and R ¹⁴ are independently H, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -OC _1-12 alkyl, -OC _2-12 alkenyl , -OC _2-12 alkynyl, -C _3-7 cycloalkyl, -C _3-7 cycloalkenyl, linear or cyclic heteroalkyl, aryl, heteroaryl or -Y;

X is oxygen or sulfur;

Y is halogen;

n is an integer selected from 0, 1 or 2;

m is an integer of 1 or 2;

p is an integer selected from 1 to 4; And

q is an integer selected from 1 to 12.

As used herein, "alkyl" means a straight or pulverized saturated hydrocarbon group from C ₁ to C ₇ , alone or in combination, unless preceded by the length indication of the chain. As used herein, "low cost alkyl" means C ₁ to C ₄ unless the length indication of the chain is preceded. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-hexyl and the like.

As used herein, "haloalkyl" refers to alkyl substituted with one or more halogens. "Cycloalkyl" as used herein includes cyclic hydrocarbon radicals from C ₃ -C ₇ . Exemplary cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclobutyl, and cyclopentyl.

As used herein, "aryl" is a monocyclic or polycyclic group, alone or in combination, preferably a monocyclic or bicyclic group, ie a phenyl group or a naphthyl group, which may be unsubstituted or substituted with one or more substituents. And in particular may be substituted with one to three substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Exemplary aryl groups include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl and the like.

As used herein, "heteroaryl" is a 5- or 5-membered heterocyclic aromatic group, which may optionally be a fused benzene ring, which may be unsubstituted or substituted with one or more substituents, in particular halogen, alkyl It may be substituted with 1 to 3 substituents selected from hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl.

As used herein, "halogen" is meant to include fluorine, chlorine, bromine and iodine.

As used herein, “linear or cyclic heteroalkyl” may be defined according to the “alkyl” definition where the carbon atom is suitably substituted with another atom such as nitrogen or sulfur to make the stable species.

In addition, the functional groups described above have been represented by insertion marks “()” around a particular atom or around a group of atoms, which is preferred for indicating molecular structure or bonding behavior. In particular, the insert can be presented as shown in one of the general formula of the aforementioned functional groups of the same atoms and "O" single atom or "NH _2", such as Yes, R ⁷ is C .....- ( O) R ¹² , -C (O) OR ¹² , -C (O) NR ¹² OR ¹³ , -C (NH ₂ ) (NOR ¹² ), and the like. In this aspect, the inset shows that the atom or group of atoms contained therein is bonded to the closest preceding chemically suitable atom that is not included in the inset.

More specifically, for example, -C (O) R ¹² represents a functional group bonded to a carbon whose oxygen atom is the closest preceding atom that is chemically suitable for bonding according to the traditional orbital electron bonding theory and is not included in the insertion mark. . —C (NH ₂ ) (NOR ¹² ) denotes a functional group bound to carbon, the closest preceding atom whose nitrogen in NH ₂ and NOR ¹² is not included in the insertion indication. The above examples are described in the following (a) and (b). Those skilled in the art recognize that suitable binding aspects (eg, single, double, etc.) are clear from the orbital binding law.

In addition, some of these functional groups have been shown with an insertion mark "()" around a particular atom or around a group of atoms, followed immediately by the insertion mark with a subscript of the alphabet or number [eg, R ⁷ . ...- CONR ¹² (CH ₂ ) _q OCH ₃ ]. In this aspect, the group of atoms or atoms in the inset is present as a multiple of the subscript in the functional group. For example, when q = 2 in —CONR ¹² (CH ₂ ) _q OCH ₃ , R ⁷ is —CONR ¹² CH ₂ CH ₂ OCH ₃ .

Those skilled in the art recognize that there are stereocenters in the compounds of formula (I). Accordingly, the present invention encompasses all possible stereoisomers and geometric isomers of Formula 1 and includes not only racemic compounds but also optically active compounds. If a single enantiomer is required as the compound of formula (1), it can be obtained through stereospecific synthesis from the cleavage of the final product or from isomerically pure starting materials or other convenient intermediates. The cleavage, intermediate or starting material of the final product can be carried out by any suitable method known in the art. Examples include Stereochemistry of Carbon Compounds (Mcgraw Hill, 1962) by E.L.Eliel and Tables of Resoving Agents by S.H.Wilen. Additionally, where tautomers of the compounds of Formula 1 are possible, the present invention includes all tautomers of the compounds of the present invention.

Specific compounds of formula 1 are as follows, and their synthesis was carried out according to the following examples:

Compound number

1. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide.

2. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N, N-diethyl propionamide.

3. 2- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] cyclopropanecarboxylic acid diethylamide.

4. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N, N-diethyl-2-methyl-acrylamide.

5. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -but-2-enoic acid diethylamide.

6. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid methyl ester.

7. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylonitrile.

8. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid tert-butyl ester.

9. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid.

10. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -1-morpholin-4-yl-prop-2-en-1-one.

11. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N- (3-methoxy-propyl) -acrylamide.

12. N, N-dicyclohexyl-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide.

13. N- (2-Dimethylamino-ethyl) -3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide.

14. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N-methyl-N-octyl acrylamide.

15. 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide.

16. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide.

17. 1-Amino-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-one oxime.

18. 3- {2- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -vinyl} -5-methyl- [1,2,4] -oxadiazole.

19. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-ol.

20. {3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -allyl} -dimethylamine.

21. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N, N-diethyl thioacrylamide.

22. 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N- (3-hydroxy-propyl) -acrylamide.

In general, the compounds of Formula 1 may be prepared according to the following synthetic method. In all of the following synthetic methods, it is known in the art that protecting groups should be used where necessary according to the general principles of chemistry. The protecting group is removed at the final stage of the synthesis under process basic, acidic or hydrogenolysis conditions known in the art. By using suitable manipulation or protection of any chemical functionality, compounds of formula (1) not specifically disclosed herein can be synthesized by methods similar to those shown in Schemes 1-6 and described in the Examples.

In general, the synthesis of the compounds of the present invention is designed to access analogs of B-rings having an E-configuration of central tetra-substituted double bonds. One method for preparing a compound having Formula 1 is shown in Scheme 1 below, using the method of Miller, bromide (b) [e.g., (E) -1-bromo-2-phenyl-1- (trimethylsilyl A few grams of a suitable bromide such as) -1-butene] are synthesized from acetylene (a) (Miller, RB; Al-Hassan, MI Stereospecific Synthesis of (Z) -Tamoxifen via Carbometalation of Alkynylsilanes. Org.Chem. 1985, 50, 2121-2123). Under the palladium catalyst, bromide (b) is coupled with a suitable aryl bronic acid such as (c) to form aldehyde (d) as a single isomer [e.g. (Z) -1,2-diphenyl-1- (4-formyl Phenyl) -1-butene]. Bromide (b) and aldehyde (d) are versatile intermediates used in the synthesis of B-ring tamoxifen analogs.

As shown in Scheme 2, a, b-unsaturated diethyl amide (g) is synthesized by coupling bromide (b) with aryl bronic acid (e), which is represented by compound number 1 , Example 2 is illustrated. The synthesis of diethyl amide by the above routes is made in low yield due to the heat instability of aryl bronic acid (e). Of the desired compound as diethyl amide (g) (ie compound no. 1: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide) It has been found during identification of compounds of the present invention that identification requires a more efficient method of synthesis for the preparation of analogs. Thus, diethyl amide g was prepared in significantly improved yield by the Horner-Emmons reaction of aldehyde d with phosphonate f.

In addition, Scheme 2 shows that a, b-unsaturated diethyl amide (g) can be converted as follows:

(a) Thioamide (h), [Compound No. by Lawesson Reagent. 21: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl thioacrylamide];

(b) saturated amide (i), by hydrogenation [Compound No. 2: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl propionamide; or

(c) cyclopropyl amide (j), by Corey Ylide [Compound No. 3: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] cyclopropanecarboxylic acid diethylamide].

In Scheme 3, diethyl amide (g) having a trisubstituted a, b-unsaturated double bond is synthesized from a suitable aldehyde such as (d) or a suitable ketone such as (n). More specifically, a-methyl amide (l) is the sole isomer by Horner-Emmons reaction of aldehyde (d) and methyl phosphonate (k) [Compound No. 4: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl-2-methyl-acrylamide] is synthesized, and ketone (n) and phospho Mixture of E and Zb-methyl amide (o, p) by reaction of nate (f) [Compound No. 5: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -but-2-enoic acid diethylamide-(Z) and (E)] are synthesized, which are Can be separated by flash chromatography according to the relative stereochemistry determined by ¹ H NMR NOE studies.

In Scheme 4, carboxylic acid (r) [compound no. 9: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid] is methyl ester (q) [compound number. 6: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid methyl ester] may be induced by a saponification reaction, which compound is trimethyl phosphono exemplified in Scheme 3. It is synthesized by the condensation reaction of acetate and aldehyde (d). Scheme 4 also shows that carboxylic acid (r) can function as a central intermediate in the synthesis of a series of a, b-unsaturated amides by subsequent coupling reactions with a series of linear and cyclic alkyl and heteroalkyl amines.

All.

In Scheme 5, oxadiazole (v) [Compound No. 18: 3- {2- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -vinyl} -5-methyl- [1,2,4] -oxadiazole] is a nitrile ( t) [Compound No. 7: Amide oxime (u) [Compound No. produced by reaction of 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylonitrile] with hydroxylamine. 18: Acetic of 3- {2- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -vinyl} -5-methyl- [1,2,4] -oxadiazole] It is synthesize | combined by cyclization reaction with anhydride.

In Scheme 6, alcohol (x) [Compound No. 19: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-ol] and dimethyl amine (y) [compound no. 20: {3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -allyl} -dimethylamine] is obtained by hydrogenation reduction followed by mesylation and alkylation with dimethyl amine. t-butyl ester (w) [compound no. 8: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid tert-butyl ester].

General method

Unless otherwise indicated, all starting materials were purchased commercially and used without further purification. Melting points were measured in capillaries using Mel-Temp apparatus and no correction was made. ¹ NMR and ¹³ C NMR spectra were obtained using Varian-300 and Varian XRL-300 spectrophotometers with TMS as CDCl ₃ internal standard. Chemical shifts are given in ppm (s); Multiplicity is represented by s (singlelet), d (doublet), t (triplet), q (quartet), m (multiplet), br (extended). Coupling constants (J) are expressed in Hz. Microanalysis was performed by Atlantic Microlabs, Inc., and all values were within ± 0.4% of theory. Mass spectra were recorded on a JEOL JMS-AX505HA mass spectrometer by fast atom bombardment ionization. Infrared spectra were recorded using a Perkin-Elmer 1280 infrared spectrometer. Analytical thin layer chromatography was performed on EM Science silica 60 F ₂₅₄ glass coated plates and visualized with ultraviolet, iodine or ammonium molybdate. Flash chromatography was performed on EM Science 230-400 mesh silica gel. MPLC was performed on a Pharmacia LKB series system using a Rainin Dynamax UV-C detector and a Merk Lobar Si60 (40-63 mm) silica gel column. HPLC was performed by Shimadzu LC-6A series HPLC using a Rainin Dynamax C ₁₈ RP column or a Rainin Dynamax silica column. All solvents were reagent grade and used without further purification. (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene [Reference: (b) of Scheme 1] was prepared by the Miller method described above, 4-formylboronic acid was Noth method (Feulner, H .; Linti, G .; Noth, H. Preparation and Structural Characterization of p-Formylbenzeneboronic Acid.Chem. Ber. 1990, 123, 1841-1843). Boronic acid (see (e) and (m) of Schemes 2 and 3, respectively) is described by Gilman method (Gilman, H .; Santucci, L .; Swayampati, DR; Ranck, RO Hydrosybenzeneboronic Acids and Anhydrides. J. Am. Chem. Soc. 1957, 79, 3077-3082) using 3- (4-bromophenyl) -N, N-diethylacrylamide and 4-bromoacetophenone, respectively, in England, Herfordshire, Glaxo Group Research Manufactured by Ltd.

The following compounds were prepared according to the general synthetic methods described above, and the following describes the preparation of various compounds of the present invention in more detail. The following examples are intended to illustrate in more detail, but are not limited by the present invention.

Example 1: (Z) -1,2-diphenyl1- (4-formylphenyl) 1-butene

1.0 g (3.5 mmol) of (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene in 10 ml of DME, bromic acid (see (c) of Scheme 1) 625 mg (4.2) A solution of 400 mg (0.35 mmol, 0.1 equiv) of mmol, 1.2 equiv) and Pd (PPh ₃ ) ₄ was treated with 2 mL 2 N Na ₂ CO ₃ and refluxed for 6 h. The solution was cooled to RT, poured into NaHCO ₃ (40 mL), extracted with ethyl acetate (2 × 40 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. Purification by silica gel flash chromatography using hexanes / ethyl acetate 20/1 as eluent gave 700 mg (69%) of the compound named above as a yellow solid: ¹ H NMR (CDCl ₃ , 300 MHz) s 9.82 (s, 1H), 7.55-7.00 (m, 14H), 2.48 (q, 2H), 0.97 (t, 3H); Low resolution MS m / e 313 (MH ⁺ ). [Reference, Example (d), Scheme 1].

Example 2: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide

Step A

51 mg of (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene in 5 ml of DME (0.18 mmol, 1.1 equiv), aryl bronic acid (see (e) in Scheme 2) A solution of 40 mg (0.16 mmol) and 20 mg (16.2 mmol, 0.1 equiv) of Pd (PPh ₃ ) ₄ was treated with 0.5 ml 2 N Na ₂ CO ₃ and refluxed for 2 hours. The solution was cooled to RT, poured into NaHCO ₃ (20 mL), extracted with ethyl acetate (2 × 20 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. Purification by silica gel flash chromatography using hexane / ethyl acetate 3/1 as eluent gave 10 mg (15%) of the compound named above as a white solid: mp 138-140 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.53 (d, 1 H, J = 15.4), 7.38-7.11 (m, 12 H), 6.86 (d, 2 H, J = 8.3), 6.66 (d, 1 H, J = 15.4), 3.40 (m, 4H), 2.47 (q, 2H, J = 7.3), 1.19 (m, 6H), 0.93 (t, 3H, J = 7.3); High resolution MS Calc. 410.2483, Found 410.2484.

Step B

According to the general procedure of the Horner-Emmons coupling reaction (see Example 7) as described above, diethyl diethylcarbamoylmethylenephosphonate (see Scheme 2 (f)) and aldehyde, (Z) -1,2 -Diphenyl-1- (4-formylphenyl) -1-butene was reacted, purified by silica gel flash chromatography using hexane / ethyl acetate 20/1 to 2/1 as eluent, and named as the white solid. 110 mg (42%) of one compound were obtained: mp 137-138 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.53 (d, 1 H, J = 15.4), 7.36-7.11 (m, 12 H), 6.86 (d, 2 H, J = 8.3), 6.66 (d, 1 H, J = 15.4), 3.42 (m, 4H), 2.47 (q, 2H, J = 7.3), 1.19 (m, 6H), 0.93 (t, 3H, J = 7.3); Anal. (C ₂₉ H ₃₁ NO) C, H, N. See, Example (g), Scheme 2.

Example 3: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl thioacrylamide

3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide (see Example 2) 65 mg (0.16 mmol) and 39 mg (95.2) of Lawesson's reagent mmol, 0.6 equiv) was heated at 85 ° C. for 2 h in 2 ml dry toluene. The solution was cooled to RT and transferred directly onto a silica gel flash chromatography column. Purification with hexane / ethyl acetate 10/1 as eluent gave 54 mg (83%) of thioamide of the compound named above as a yellow foam: mp 43-61 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.85 (d, 0.5 H), 7.75 (d, 0.5 H), 7.65 (d, 0.5 H), 7.40-6.80 (m, 13.5 H), 4.05 (m, 2 H), 3.70 (m, 2H), 2.45 (m, 2H), 1.30 (m, 6H), 0.95 (m, 3H); ¹³ C NMR (CDCl ₃ , 75 MHz) s 193.83, 144.56, 143.96, 143.18, 143.11, 141.92, 138.26, 133.00, 131.22, 130.83, 129.66, 128.28, 128.01, 127.91, 127.86, 127.70, 127.48, 12.126,83. , 124.04, 48.54, 46.40, 29.19, 13.86, 13.67, 13.62, 11.66; IR (CHCl ₃ ) 3050, 1520, 1210, 950, 750; Anal. (C ₂₉ H ₃₁ NS) C, H, N. See, Example (h), Scheme 2.

Example 4: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl propionamide

50 mg (0.12 mmol) of 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide (see Example 2) in 1 ml of dry toluene and A solution of 3 mg of Tris (triphenylphosphine) -rhodium (I) chloride (Wilkinson catalyst) was stirred at 50 ° C. for 16 h on a H ₂ gas atmosphere. The solution was cooled to RT and toluene was removed under vacuum. Purification of the residue by silica gel flash chromatography using hexanes / ethyl acetate 2/1 as eluent gave 48 mg (95%) of the compound named above as a clear, colorless oil: ¹ H NMR (CDCl ₃ , 300). MHz) s 7.37-7.11 (m, 10H), 6.85 (d, 2H, J = 8.3), 6.78 (d, 2H, J = 8.3), 3.31 (q, 2H, J = 7.1), 3.08 (q, 2H, J = 7.3), 2.81 (t, 2H, J = 8.3), 2.44 (m, 4H), 1.03 (m, 6H), 0.91 (t, 3H, J = 7.3) ; Low resolution MS m / e 412 (MH ⁺ ); Anal. (C ₂₉ H ₃₃ NO) C, H, N. See, Example (i), Scheme 2.

Example 5: 2- [4- (1,2-diphenyl-but-1-enyl) -phenyl] cyclopropanecarboxylic acid diethylamide

12 mg (0.24 mmol, 2.0 equiv) of sodium hydroxide (50% in oil) and 54 mg (0.24 mmol, 2.0 equiv) of trimethyloxosulfonium iodide in 2 ml of dry dimethyl sulfoxide were stirred at RT for 30 minutes, At this point, gas evolution stopped. A solution of 50 mg (0.12 mmol) of the amide prepared in Example 2 in 0.5 ml of dimethyl sulfoxide was added and then heated at 50 ° C. for 16 hours. The reaction mixture was cooled to RT, poured into 20 mL of H ₂ O and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried (MgSO ₄ ) and then the solvent was removed in vacuo. The residue was purified by silica gel MPLC using hexanes / ethyl acetate 4/1 as eluent to afford 32 mg (62%) of the above named compound as a white solid: mp 42-44 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.37-7.10 (m, 10 H), 6.76 (m, 4 H), 3.38 (q, 4 H, J = 7.1), 2.45 (q, 2H, J = 7.4 ), 2.30 (m, 1H), 1.79 (m, 1H), 1.55 (m, 1H), 1.11 (m, 7H), 0.92 (t, 3H, J = 7.4); Low resolution MS m / e 424 (MH ⁺ ); Anal. (C ₃₀ H ₃₃ NO) C, H, N. See, Example (j), Scheme 2.

Example 6: (methyl) diethyl diethylcarbamoylmethylenephosphonate

A solution of 4.4 mL (2.2 mmol, 1.1 equiv) of KN (TMS) ₂ (0.5 M in toluene) was cooled (500 mL) of 500 mg (2.0 mmol) of diethyl diethylcarbamoylmethylenephosphonate in 5 mL of dry THF. C) was added to the solution. The solution was stirred for 10 minutes and then 0.15 mL (2.4 mmol, 1.2 equiv) of methyl iodide was added. It was then warmed up to RT, stirred for 1 h, poured into brine (70 mL) and extracted with ethyl acetate (2 × 60 mL). The organic layers were combined, dried (MgSO ₄ ) and then the solvent was removed in vacuo. The yellow residue was purified by Kugelrohr distillation to give 525 mg (100%) of the compound named above as a clear, colorless oil: bp 155 ° C. at 0.15 torr; ¹ H NMR (CDCl ₃ , 300 MHz) s 4.18 (m, 4 H), 3.60 (m, 1 H), 3.22 (m, 4 H), 1.37 (m, 9 H), 1.18 (m, 6 H) . [Reference, Example (k), Scheme 2].

Example 7: General method of the Horner-Emmons reaction with (Z) -1,2-diphenyl-1- (4-formylphenyl) -1-butene

A solution of 1.2 equiv of KN (TMS) ₂ (0.5 M in toluene) was added to a stirred 0 ° C. solution of a suitable phosphonate 1.2 equiv in dry THF. The solution was stirred at 0 ° C. for 15 minutes, cooled to −78 ° C., and then dropwise added a solution of (Z) -1,2-diphenyl-1- (4-formylphenyl) -1-butene in THF. Then, the mixture was warmed up to RT, stirred for 4 hours, and heated to 50 ° C for 2 hours to terminate the reaction. The reaction mixture was cooled to RT, poured into brine and extracted twice with ethyl acetate. The organic layers are combined, dried (MgSO ₄ ), the solvent is removed in vacuo and the residue is purified by silica gel flash chromatography.

Example 8: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl-2-methyl-acrylamide

The reaction was carried out using (methyl) diethyl diethylcarbamoylmethylenephosphonate, purified by silica gel flash chromatography using hexane / ethyl acetate 3/1 as eluent, and the title compound was obtained as a clear, colorless oil. (53%) was obtained: ¹ H NMR (CDCl ₃ , 300 MHz) s 7.39-7.11 (m, 10H), 6.97 (d, 2H, J = 8.0), 6.85 (d, 2H, J = 8.3), 6.32 (s, 1H), 3.38 (m, 4H), 2.47 (q, 2H, J = 7.3), 2.00 (s, 3H), 1.14 (t, 6H, J = 7.1) , 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 424; Anal. (C ₃₀ H ₃₃ NO) C, H, N. See, Example (l), Scheme 3.

Example 9: (Z)-and (E) -3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -but-2-enoic acid diethylamide

The reaction was carried out using the diethyl diethyl carbamoyl methylene phosphonate, and purified by silica gel flash chromatography using hexane / ethyl acetate 5/2 as eluent to afford the white solid (Z) -isomer 95. MG (49%) and 11 mg (6%) of the (E) -isomer of a colorless oil were obtained. Analytical data of the (Z) -isomer are as follows: mp 109-111 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.39-7.09 (m, 12H), 6.85 (d, 2H, J = 8.3), 6.20 (d, 1H, J = 1.0), 3.44 (q, 2 H, J = 7.1), 3.33 (q, 2H, J = 7.1), 2.47 (q, 2H, J = 7.5), 2.16 (d, 3H, J = 1.0), 1.13 (m, 6H) , 0.93 (t, 3H, J = 7.6); Low resolution MS m / e 424; Anal. Analytical data for (C ₃₀ H ₃₃ NO) C, H, N. (E) -isomer is as follows: ¹ H NMR (CDCl ₃ , 300 MHz) s 7.36-7.09 (m, 10H), 7.00 (d , 2H, J = 8.3), 6.81 (d, 2H, J = 8.2), 5.80 (d, 1H, J = 1.0), 3.22 (q, 2H, J = 7.2), 2.91 (q, 2 H, J = 7.1), 2.45 (q, 2H, J = 7.6), 2.04 (d, 3H, J = 1.0), 0.89 (m, 6H), 0.74 (t, 3H, J = 7.6); Low resolution MS m / e 424. See, Example (o, p), Scheme 3.

Example 10: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid methyl ester

Reaction with the trimethyl phosphonoacetate and purification by silica gel flash chromatography using hexanes / ethyl acetate 20/1 as eluent gave 2.33 g (100%) of the compound named above as a white solid: mp 133-135 ℃; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.53 (d, 1 H, J = 16.0), 7.39-7.10 (m, 12 H), 6.88 (d, 2 H, J = 8.3), 6.27 (d, 1 H, J = 16.0), 3.76 (s, 3H), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 369; Anal. (C ₂₆ H ₂₄ O ₂ ) C, H, N. See, Example (q), Scheme 4.

Example 11: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylonitrile

The reaction was carried out using the diethyl cyanomethylphosphonate, and the residue was purified by silica gel flash chromatography using hexane / ethyl acetate 10/1 as eluent to obtain 125 mg (93%) of the compound as a clear, colorless oil. Mp 101-102 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.40-7.07 (m, 13 H), 6.90 (d, 2H, J = 8.6), 5.79 (d, 1H, J = 16.6), 2.48 (q, 2 H, J = 7.3), 0.93 (t, 3H, J = 7.3); Anal. (C ₂₅ H ₂₁ N) C, H, N. See, Example (t), Scheme 5.

Example 12 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid tert-butyl ester

The reaction was carried out using the t-butyl diethylphosphonoacetate, purified by silica gel flash chromatography using hexane / ethyl acetate 20/1 as an eluent, and then recrystallized from high temperature hexane to give the white solid compound 52 mg. (95%) was obtained: mp 139-140 ° C; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.44-7.09 (m, 13 H), 6.86 (d, 2 H, J = 8.3), 6.20 (d, 1 H, J = 16.1), 2.47 (q, 2 H, J = 7.4), 1.49 (s, 9H), 0.93 (t, 3H, J = 7.4); Low resolution MS m / e 373, no MH ⁺ : Anal. (C ₂₉ H ₃₀ O ₂ ) C, H. Reference, Example (w), Scheme 6].

Example 13: 1- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -ethanone

(E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene in 8 ml of DME (see (b) of Scheme 1) 172 mg (0.60 mmol), bromic acid (of Scheme 3 (m)) 125 mg (0.60 mmol, 1.0 equiv) and Pd (PPh ₃ ) ₄ 70 mg (0.06 mmol, 0.1 equiv) were treated with 0.4 mL of 2 N Na ₂ CO ₃ and refluxed for 18 h. . The solution was cooled to RT, poured into brine (40 mL), extracted with ethyl acetate (2 × 20 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. Purification by silica gel flash chromatography using hexane / ethyl acetate 20/1 as eluent gave 152 mg (78%) of the compound named above as a yellow solid: ¹ H NMR (CDCl ₃ , 300 MHz) s 7.6 (d, 2H), 7.45-7.10 (m, 10H), 6.98 (d, 2H), 2.48 (m, 3H), 0.94 (t, 3-H). [Reference, Example (n), Scheme 3].

Example 14 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid

50 mL (16 mmol, 10.0 equiv.) Of 0.2 M KOH was added dropwise over 2 minutes to a solution of 600 mg (1.6 mmol, 1.0 equiv.) Of the ester prepared in Example 10 in 90 mL of methanol / THF 1/2. . The solution was then stirred at RT for 18 h and the solvent was removed in vacuo. The residue was dissolved in 30 mL of 1 M HCl and extracted with ethyl acetate (2 × 60 mL). The organic layers were combined, dried (MgSO ₄ ) and then the solvent was removed in vacuo. Purification of the residue by silica gel flash chromatography using methylene chloride / methanol 95/5 as eluent gave 370 mg (63%) of the compound named above as a white solid: mp 148-150 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.60 (d, 1 H, J = 15.9), 7.39-7.10 (m, 12 H), 6.89 (d, 2 H, J = 8.1), 6.27 (d, 1 H, J = 15.9), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 355; Anal. (C ₂₅ H ₂₂ O ₂ ) C, H. Reference, Example (r), scheme 4.

Example 15: General method of coupling reaction with 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid

To a solution of acid (20) 1.0 equiv in dry methylene chloride, EDC 1.0 equiv, HOBT 1.3 equiv and Et ₃ N 1.0 equiv were added, followed by the addition of the appropriate amine 1.2 equiv. The solution was stirred at RT for 18 h, poured into 20 mL of H ₂ O and extracted twice with ethyl acetate (2 × 60 mL). The organic layers were combined, washed with H ₂ O (1 × 20 mL), dried (MgSO ₄ ) and the solvent removed in vacuo, then the residue was purified by silica gel flash chromatography, silica gel MPLC, or recrystallization.

Example 16: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -1-morpholin-4-yl-prop-2-en-1-one

The reaction was carried out using morpholine, purified by silica gel MPLC using hexane / ethyl acetate 2/1 as eluent, and then recrystallized from hot hexane to give 12 mg (14%) of the compound named above as a white solid: mp 150-154 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.53 (d, 1 H, J = 15.4), 7.39-7.10 (m, 12 H), 6.87 (d, 2 H, J = 8.3), 6.67 (d, 1 H, J = 15.4), 3.65 (m, 8H), 2.48 (q, 2H, J = 7.3), 1.26 (broad, 8H), 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 424; Anal. (C ₂₉ H ₂₉ NO ₂ ) C, H, N. Reference, Example (s), Scheme 4].

Example 17: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N- (3-methoxy-propyl) -acrylamide

Reaction was carried out with 3-methoxypropylamine, recrystallized from hot hexane and purified by silica gel MPLC using hexane / ethyl acetate 2/1 as eluent to afford 20 mg (30%) of the compound named above as a white solid. mp 132-135 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.43 (d, 1 H, J = 15.7), 7.36-7.10 (m, 12 H), 7.86 (d, 2 H, J = 8.3), 6.20 (d, 1 H, J = 15.7), 3.46 (m, 4H), 3.34 (s, 1H), 2.48 (q, 2H, J = 7.5), 1.80 (m, 2H), 0.92 (t, 3H, J = 7.5); Low resolution MS m / e 426; Anal. (C ₂₉ H ₃₁ NO ₂ ) C, H, N. See, Example (s), Scheme 4.

Example 18 N, N-dicyclohexyl-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide

Reaction with dicytohexylamine and purification by recrystallization from hot hexane / ethyl acetate 2/1 gave 29 mg (28%) of the compound named above as a white solid: mp 194-200 ° C; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.43-7.11 (m, 13 H), 6.86 (d, 2 H, J = 8.3), 6.69 (d, 1 H, J = 15.4), 3.50 (m, 2 H), 2.48 (q, 2H, J = 7.3), 2.25 (m, 2H), 1.77-1.62 (2m, 12H), 1.30-1.10 (m, 8H), 0.93 (t, 3H , J = 7.3); Low resolution MS m / e 518; Anal. (C ₃₇ H ₄₃ NO) C, H, N. See, Example (s), Scheme 4.

Example 19 N- (2-Dimethylamino-ethyl) -3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide hydrogen oxalate

Reaction was carried out using 2-dimethylaminoethylamine, purified by silica gel flash chromatography using methylene chloride / methanol 15/1 as eluent, and then a hydrogen oxalate salt was produced with 1.1 equiv of oxalic acid in Et ₂ O, 58 mg (53%) of the compound named above were obtained as a white solid: mp 145-147 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.51 (d, 1 H, J = 15.1), 7.38-7.10 (m, 12 H), 6.88 (d, 2 H), 6.60 (d, 1 H, J = 15.1), 6.12 (m, 2H), 3.70 (m, 2H), 3.47 (m, 3H), 3.35 (m, 2H), 2.90 (m, 4H), 2.48 (q, 2H, J = 7.4), 1.20 (m, 2H), 0.93 (t, 3H, J = 7.4); Low resolution MS m / e 453; Anal. (C ₃₁ H ₃₆ N ₂ OC ₂ H ₂ O ₄ ) C, H, N. See, Example (s), Scheme 4.

Example 20: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N- (3-hydroxy-propyl) -acrylamide

Reaction was carried out using 3-hydroxypropylamine, purified by silica gel MPLC using a concentration gradient of hexane / ethyl acetate 2/1 to 100% ethyl acetate as eluent, and then recrystallized from hot hexane to give a white solid. 14 mg (15%) of compound were obtained: mp 144-146 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.47 (d, 1 H, J = 15.6), 7.36-7.10 (m, 12 H), 7.86 (d, 2 H, J = 8.3), 6.22 (d, 1 H, J = 15.6), 3.62 (m, 2H), 3.51 (m, 2H), 3.25 (t, 1H), 2.47 (q, 2H, J = 7.3), 1.71 (m, 2H) , 0.94 (t, 3H, J = 7.3); Low resolution MS m / e 412; Anal. (C ₂₈ H ₂₉ NO ₂ ) C, H, N. See, Example (s), Scheme 4.

Example 21: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N-methyl-N-octyl acrylamide

Reaction with N-methyl-N-octylamine and purification with silica gel MPLC using hexanes / ethyl acetate 3/1 as eluent gave 56 mg (41%) of the above named compound as a white solid: mp 108- 109 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.52 (d, 1 H, J = 15.4), 7.38-7.14 (m, 12 H), 6.86 (d, 2 H, J = 7.8), 6.68 (dd, 1 H, J = 15.4), 3.00 (d, 4H), 2.48 (q, 2H, J = 7.3), 1.26 (m, 8H), 0.93 (t, 3H, J = 7.3), 0.86 (m , 6 H); Low resolution MS m / e 480; Anal. (C ₃₄ H ₄₁ NO) C, H, N. See, Example (s), Scheme 4.

Example 22: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide

Reaction was carried out using a saturated solution of ammonia in CH ₂ Cl ₂ and purified by silica gel MPLC using hexanes / ethyl acetate 2/1 as eluent to afford 39 mg (39%) of the above named compound as a white solid: mp 200 -202 ° C; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.47 (d, 1 H, J = 15.6), 7.39-7.10 (m, 12 H), 6.87 (d, 2 H, J = 8.3), 6.27 (d, 1 H, J = 15.6), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 354; Anal. (C ₂₅ H ₂₃ NO) C, H, N.

Example 23: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide

A solution of 0.2 ml (0.4 mmol, 1.2 equiv.) Of oxaryl chloride (2 M in CH ₂ Cl ₂ ) was prepared in Example 14 and stirred with 120 mg (0.3 mmol) of acid in 2 ml of dry methylene chloride Added to 0 ° C. solution. The solution was then warmed up to RT and stirred overnight. The solvent is removed in vacuo and the residue is dissolved in 2 ml of ether and then in 23 ml of rapidly stirred solution of ethylamine (70 wt% in H ₂ O) (0.4 mmol, 1.2 equiv.) In 2 ml of 1 M NaOH. Added. The solution was stirred for 2 h at RT. The solution was poured into ethyl acetate and then extracted; The aqueous layer was washed with ethyl acetate (3 × 10 mL). The organic layers were combined, dried (MgSO ₄ ) and the solvent removed in vacuo and recrystallized from hot ethyl acetate to purify the residue to give 45 mg (35%) of the compound named above as a white solid: mp 192-193 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.45 (d, 1 H, J = 15.6), 7.39-7.10 (m, 12 H), 6.86 (d, 2 H, J = 8.1), 6.20 (d, 1 H, J = 15.6), 3.38 (m, 2H, J = 7.3), 2.48 (q, 2H, J = 7.3), 1.17 (t, 3H, J = 7.3); Low resolution MS m / e 382; Anal. (C ₂₇ H ₂₇ NO) C, H, N. Reference, Example (s), Scheme 4].

Example 24 1-amino-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-one oxime

A solution of 1.16 mL (1.16 mmol, 3.1 equiv.) Of sodium methoxide in methanol (1.0 M) was added to a solution of 78 mg (1.12 mmol, 3.0 equiv.) Of hydroxyamine hydrochloride in 4 mL of dry methanol. The solution was refluxed for 15 minutes and cooled to RT. A solution of 125 mg (0.37 mmol) of nitrile prepared in Example 11 in 2 ml of dry methanol / THF 2/1 was added and the reaction mixture was refluxed for 16 h. The solution was cooled, poured into 20 mL brine, extracted with ethyl acetate (2 × 20 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. Purification by silica gel flash chromatography yielded 61 mg (47%) of the compound named above as a white solid: mp 182-185 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.38-7.07 (m, 12H), 6.85 (d, 2H, J = 8.0), 6.68 (d, 1H, J = 16.7), 6.32 (d, 1 H, J = 16.7), 4.60 (s, br, 2H), 2.47 (q, 2H, J = 7.6), 2.17 (s, 1H), 0.93 (t, 3H, J = 7.6); Low resolution MS m / e 369; Anal. (C ₂₅ H ₂₄ N ₂ O) C, H, N. See, Example (u), Scheme 5.

Example 25: 3- {2- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -vinyl} -5-methyl- [1,2,4] -oxadiazole

A solution of 60 mg (0.16 mmol) of the amide oxime prepared in Example 24 in 5 ml of acetic anhydride was heated at 80 ° C. for 18 hours, cooled to RT and then poured into 10 ml of 4N NaOH, followed by ethyl acetate Extracted with (2 × 20 mL). The organic layers were then combined, dried (MgSO ₄ ) and the solvent removed in vacuo. The crude material was purified by flash chromatography using hexane / ethyl acetate 10/1 as eluent to afford 21 mg of slightly impure product, which was recrystallized from hot hexane / ethyl acetate 10/1 to give a white crystalline solid. 13 mg (20%) were obtained:

mp 158-59 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.50 (d, 1 H, J = 16.4), 7.37-7.12 (m, 13 H), 6.87 (m, 2 H), 2.58 (s, 3 H), 2.47 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3); Low resolution MS m / e 392; Anal. (C ₂₇ H ₂₄ N ₂ O) C, H, N. See, Example (v), Scheme 5.

Example 26: 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-ol

A solution of 1.35 mL (1.35 mmol, 2.5 equiv) of 1.0 M DIBAL-H in THF was added dropwise to a -78 ° C solution of the ester prepared in Example 12 in 3 mL of THF. The solution was stirred at −78 ° C. for 30 minutes, warmed up to RT and then stirred for 16 hours. Excess DIBAL-H was quenched with 1 N HCl and the reaction mixture was poured into 20 mL of 1 N HCl and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, dried (MgSO ₄ ) and then the solvent was removed in vacuo. Purify the residue by silica gel flash chromatography using hexanes / ethyl acetate 5/1 as eluent to afford 94 mg (60%) of the above named compound as a white solid: mp 80-83 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) s 7.41-7.02 (m, 12H), 6.82 (d, 2H, J = 8.3), 6.45 (d, 1H, J = 15.8), 6.23 (dt, 1 H, J = 5.8, 15.9), 4.24 (m, 2H), 2.47 (q, 2H, J = 7.6), 1.31 (t, 1H, J = 5.9), 0.93 (t, 3H, J = 7.6); Low resolution MS m / e 340; Anal. (C ₂₅ H ₂₄ O) C, H, N. See, Example (x), Scheme 6.

Example 27 {3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -allyl} -dimethylamine

A solution of 90 mg (0.27 mmol) of alcohol prepared in Example 26 and 41 mg (0.32 mmol, 1.2 equiv) of alcohol prepared in Example 26 in 2 ml of dry dichloromethane was obtained with 33 mg (0.29 mmol, 1.1) of methinesulfonyl chloride. equiv) and stirred at RT for 3 h. The solution was then poured into 10 ml of ethyl acetate, extracted with 10 ml of brine, dried (MgSO ₄ ) and the solvent removed in vacuo to give 108 mg (97%) of a thick gold oil. The material was immediately dissolved in 3 ml of dry methanol and 1 ml of dimethylamine was added. The solution was stirred for 16 h at RT and the solvent was removed in vacuo. The residue was dissolved with 10 ml of ethyl acetate and extracted with 1 N HCl. The aqueous layer was separated and made basic by addition of 3 N NaOH and extracted with ethyl acetate (2 × 10 mL). The basic extracts were combined, dried (MgSO ₄ ) and then the solvent was removed in vacuo. Purification of the residue by silica gel MPLC using dichloromethane / methanol 15/1 as eluent gave 37 mg (40%) of the above named compound as a clear, colorless oil: ¹ H NMR (CDCl ₃ , 300 MHz) s 7.37 -7.09 (m, 10H), 7.02 (d, 2H, J = 8.5), 6.81 (d, 2H, J = 8.1), 6.34 (d, 1H, J = 15.9), 6.14 (dt, 1 H, J = 6.6, 15.9), 3.17 (d, 2H, J = 6.6), 2.59-2.42 (m, 6H), 1.01 (t, 6H, J = 7.3), 0.92 (t, 3H, J = 7.4); Low resolution MS m / e 396; Anal. (C ₂₉ H ₃₃ N) C, H, N. See, Example (y), Scheme 6].

Compounds of formula (I) comprising an acidic moiety may form a pharmaceutically acceptable salt with a suitable cation. Suitable pharmaceutically acceptable cations include alkali metal (eg sodium or potassium) and alkaline earth metal (eg calcium or magnesium) cations. In view of the foregoing, reference to a compound herein in the present application is construed to include the compound of Formula 1 as well as pharmaceutically acceptable salts and solvates thereof.

As mentioned above, the compounds of the present invention are useful for the treatment and / or prevention of various diseases or conditions such as cardiovascular disease, breast cancer, osteoporosis and arthritis diseases. Other examples of diseases or conditions in which the compounds of the present invention are useful for the treatment and / or prophylaxis include premenstrual syndrome, vasomotor symptom associated with menopause, atrophic vaginitis, false atrophy, female sexual dysfunction, major ovarian disease, excessive hair growth and prostate Contains cancer.

Those skilled in the art recognize that what is referred to as treatment herein includes the prophylaxis as well as the treatment of the disease or symptom. In addition, those skilled in the art will recognize that the amount of a compound of the present invention required for therapeutic use will vary depending on the nature of the condition of the treatment condition and the age and condition of the patient, and ultimately the judgment of the physician or veterinarian. On the other hand, dosages useful for treating adults are typically from .001 mg / kg to about 100 mg / kg per day. The desired dosage is usually given in one dose or divided into suitable intervals, such as two, three, four or more sub-doses per day.

The present invention provides novel pharmaceutical compositions of the compound of formula (I). The compounds of the present invention may be administered therapeutically as raw chemicals, but are preferably provided as active ingredients in pharmaceutical preparations. Accordingly, the present invention provides a pharmaceutical composition or a pharmaceutically acceptable salt thereof comprising one or more pharmaceutically acceptable carriers and, optionally, other compounds of formula 1 together with other therapeutic and / or prophylactic components. Additionally. The carrier should be "acceptable" in the sense of being compatible with the other ingredients of the composition and not harmful to its recipient.

The compositions of the present invention may be administered in standard dosage forms such as oral, parenteral, sublingual, transdermal, rectal, inhaled or buccal administration used in the treatment of the disease. For buccal administration, the compositions may take the form of tablets or fiducifixes prepared according to conventional methods. For example, tablets and capsules for oral administration include binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth, slime or polyvinylpyrrolidone of starch), fillers (e.g. lactose, sugar, microcrystalline cellulose, Corn = starch, calcium phosphate or sorbitol), lubricants (e.g. magnesium stearate, slearic acid, talc, polyethylene glycol or silica), disintegrants (e.g. potato starch or sodium starch glycolate) or sodium lauryl sulfate Conventional excipients such as wetting agents. Tablets may be coated according to known methods.

In another variation, the compounds of the present invention may be included in oral liquid preparations such as water soluble or oily suspensions, solutions, emulsions, syrups or elixirs. Furthermore, compositions comprising the compounds of the present invention may be prepared in dry form for composition with water or other suitable excipients prior to use. The liquid composition may comprise a suspension such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate or acacia; Water-insoluble excipients such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; And conventional additives such as storage agents such as methyl or propyl p-hydroxybenzoate or sorbic acid.

The composition may also be formulated as a suppository comprising a conventional suppository base such as cocoa butter or other glycerides. Compositions for inhalation may be provided in the form of solutions, suspensions or emulsions that can typically be administered as dry powders or in the form of aerosols using conventional propellants such as dichlorodifluoromethane or trichlorofluoromethane. . Typical transdermal compositions include conventional water-soluble or non-aqueous excipients such as creams, plasters, lotions or pastes, and take the form of a warning, patch or warning, patch or membrane with the drug added.

In addition, the compositions of the present invention may be formulated for parenteral administration by injection or continuous infusion. Compositions for injection may be formulated as suspensions, solutions or emulsions in oily or water soluble excipients, and may include preparations such as suspensions, stabilizers and / or dispersants. As a variant, the active ingredient may be prepared in powder form for composition with a suitable excipient (eg, sterile, pyrogen-free) prior to use.

In addition, the compositions according to the invention may be formulated with a depot. The enteric composition may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds of the present invention may be formulated with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils), rather soluble derivatives such as ion exchange resins or rather soluble salts.

The biological activity of the compound of formula 1 was evaluated according to the following method and showed a suitable result. In particular, the compounds of formula (1) are evaluated in order to prevent osteoporosis activity and anti-uterotropic profile according to the following method.

Those skilled in the art recognize that there are a variety of acceptable rat estrogen receptor binding assays, and that they are useful for the initial screening of compounds of the invention in terms of their ability to bind to suitable receptors. Compounds were initially evaluated for their inhibitory ability of [ ³ H] -estradiol binding as described below in the rat estrogen receptor binding assay. Compounds showing an IC50 <10 μM were subjected to in vitro functional analysis of the estrogen activity in the lshikawa human endometrioma cell line as described below.

Subadhesion Ishikawa-Var I cells were removed under maintenance growth conditions and resuspended at a concentration of 58,500 cells / ml in phenol red-free DMEM-F12 containing 5% charcoal stripped FBS and 2 mM glutamine. Cells were plated at a density of 13,000 cells / cm ₂ and treated for 3 days in a thermostat (37 ° C., 5% CO ₂ ). Cells were collected and resuspended at a concentration of 83,000 cells / ml in phenol red-free DMEM-F12 containing 1% charcoal stripped FBS, 2 mM glutamine, penicillin 100 units / ml and 100 μg / ml streptomycin. Cells were seeded at a density of 8300 cells / ml in 96 well plates and allowed to attach overnight. Suitable medications at 2 × concentration were added to 0.1 ml of medium containing 0.2% DMSO. The plates were incubated for 2 days, the medium was aspirated and the plates washed once with 300 μl of 0.9% sterile saline. The plate was frozen at -70 ° C and warmed up to RT. 200 μl of 5 mM p-nitrophenylphosphate in 1 M diethanolamine at pH 10.4 containing 0.1% (w / v) Triton X-100 was added and incubated at 37 ° C. for 30 minutes, followed by Molecular Devices Alkaline phosphatase activity on attached cells was analyzed by measuring absorbance at 405 nm using a ThermoMax plate reader.

As described above to evaluate the specific in vitro response to the estrogen agonist, which appears to be correlated with the in vivo uterotropic response of the estrogen agonist in rats, to the expression inducing ability of the alkaline phosphatase of the compounds of the present invention. . As can be seen in Table 1, the experimental results are expressed as the concentration of the compound of the present invention that induces 50% of the maximum alkaline phosphatase activity (E _max ), the maximum activity being the alkaline induced by the saturation concentration of estradiol. It is expressed as a percentage of phosphatase activity. In further studies, it was found that all compounds showing E _max <20% function as antagonists of estradiol at concentrations that reflect receptor binding affinity.

Compound number EC ₅₀ (nM) ^b E _max (%) ^c Estradiol 0.01 100 Tamoxifen 33 16.5 ± 0.6 One 2.3 11.9 ± 1.2 3 4.9 15.7 ± 1.8 4 20 18.8 ± 2.3 5 7.3 15.0 ± 3.0 9 58 3.8 ± 0.9 10 6.9 14.8 ± 2.4 11 11 14.0 ± 1.5 12 70 19.4 ± 2.0 13 4.6 16.5 ± 1.7 14 12 6.3 ± 1.2 15 8.6 8.9 ± 1.4 16 18 11.8 ± 1.9 21 6.9 18.8 ± 2.6 22 17 15.3 ± 2.4

Compound No. 1 was shown to bind to the estrogen receptor with about 10-fold affinity than tamoxifen and translated to lower EC ₅₀ in Ishikawa cell functional assays (see Table 1). In addition, compound number 1 showed agonist activity (E _max ) significantly lower than tamoxifen. For the series of amide analogues of compound No. 1, the series of amide analogues of compound No. 1 was analyzed to establish the structural requirements necessary to lower EC ₅₀ and minimize E _max in cell functional assays. Structural diversity (lipophilic, conformational size, H-binding donors and recipients) showed broad resistance at the site of the molecule, with only the huge compound number 12 showing reduced receptor affinity. Compound No. 1 showed the highest affinity in the receptor binding assay and the lowest EC ₅₀ in the functional assay, while Compound No. 9, 14 and 15 showed the lowest residual agonist activity when analyzing the E _max data. It was.

In order to assess the in vivo anti-tetrotropic activity of the compounds of the present invention as described above, the body weights of the group of magnetic SD rats (30-35 g) at 21 days of age were measured and the average body weight was determined in FIG. As recorded for each treatment group. Stock solution of triphenylethylene analog in ethanol (10 ×) was diluted with 0.5% methyl cellulose and administered to animals via feeding in an amount of 10 μmol / kg. Estradiol was dissolved in sesame oil and administered by subcutaneous injection in an amount of 100 nmol / kg. Body weights were removed, uterus removed, blotted, and weighed. Data is expressed as uterine weight / weight ± standard deviation. Black bars are data from animals administered test compound alone. White bars are data obtained from animals administered the test compound 6 hours prior to administration of estradiol. Compounds 9 and 15 showed lower residual agonist activity than tamoxifen.

As a functional profile in the bones of the compounds of the present invention, compounds No. 9 were tested in estrogen deficient ovarian rats aged 90 days to ascertain the ability to inhibit a decrease in bone mineral density. SD rats, 90 days old, were divided into six groups. Group 3 was ovarianly loaded. Two days after ovarian administration, 10 μmol / kg or excipient of compound No. 9 in 0.5% methyl cellulose was fed to the animals once a day for 28 days. One group of animals was false-acting, ovarian loaded for 28 days, and excipients were administered once daily, 2 days later. On days 0, 14 and 28, rats were anesthetized with isoflurane and the spine of the rats were positioned so that they were lying flat and parallel to the constriction of the densitometer table. Lumbar spine was scanned using lumbar bone as a landmark. In order to scan the right tibia, the legs were fixed parallel to the long axis of the table and scanned up to the abutment of the femur. The analysis of lumbar spine was performed by dividing the vertebral and intervertebral space with general analysis software and including only the target vertebrae within the desired bulbous area. The right tibia was analyzed by subsite high resolution software and focused on the area 3-5 mm away from the growth plate previously identified as the site where bone loss was accelerated by ovarian loading.

As can be seen in FIG. 2, oral administration of 10 μmol / kg of compound number 9 showed complete agonist activity and maintained BMD to the extent of false-acting rats for 28 days. Biochemical data show that mechanism of action is achieved through inhibition of bone resorption consistent with activity as estrogen agonists in bone. BMD is measured with a dual-energy X-ray absorber using a Hologic QDR-2000 bone densitometer and a high resolution software package with default scan length, width, line space and point resolution of 2, 0.75, 0.01 and 0.005, respectively. It was.

Claims (19)

Compound of Formula 1 Formula 1 In the above formula, R ¹ is-(CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; -(CH ₂ ) _m C (X) NR ⁸ R ⁹ ; or ; R ² and R ³ are independently H, —CH ₃ , —OH, —OCH ₃ , —OCH ₂ CH ₃ or —CH ₂ (CH ₃ ) ₂ ; R ⁴ is —CN, —NO ₂ , —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ —Y or —Y; R ⁵ and R ⁶ are independently H, -C _1-4 alkyl, -C _2-4 alkenyl, -C _2-4 alkynyl, -XC _1-3 alkyl, -XC _2-4 alkenyl, -XC _2-4 alkynyl or -Y; R ⁷ is —CN, —C _1-4 alkyl-OH, —C (O) O (CH ₃ ) ₃ , —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , -C _{1 -4} alkyl-NR ¹⁰ R ¹¹ , -C (O) R ¹² , -C (O) OR ¹² , -C (O) NR ¹² OR ¹³ , -C (O) NHC (O) R ¹² , -C ( O) NHCH ₂ R ¹² , -C (NH ₂ ) (NOR ¹² ), -S (O) R ¹² , -S (O) (O) (OR ¹² ), -S (O) (O) (NHCO ₂ R ¹² ), PO ₃ R ¹² , -P (O) (NR ¹² R ¹³ ) (NR ¹² R ¹³ ), -P (O) (NR ¹² R ¹³ ) (OR ¹⁴ ), -CONR ¹² (CH ₂ ) _q OCH ₃ , -CONR ¹² (CH ₂ ) _q NR ⁸ R ⁹ or oxadiazole substituted with a methyl group; R ⁸ and R ⁹ are independently hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —OC _1-7 alkyl, —C _1-7 alkyl-Y or phenyl; R ¹⁰ and R ¹¹ independently form methyl or ethyl or morpholino groups bonded via a nitrogen atom; R ¹² , R ¹³ and R ¹⁴ are independently H, -C _1-12 alkyl, -C _2-12 alkenyl, -C _2-12 alkynyl, -OC _1-12 alkyl, -OC _2-12 alkenyl , -OC _2-12 alkynyl, -C _3-7 cycloalkyl, -C _3-7 cycloalkenyl, linear or cyclic heteroalkyl, aryl, heteroaryl or -Y; X is oxygen or sulfur; Y is halogen; n is an integer selected from 0, 1 or 2; m is an integer of 1 or 2; p is an integer selected from 1 to 4; And q is an integer selected from 1 to 12. The compound of formula 1 according to claim 1, wherein X is O. The compound of formula 1 according to claim 2, wherein R ¹ is-(CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ . The compound of formula 1 according to claim 1, wherein R ² and R ³ are independently selected from H, -OH, or -OCH ₃ . The compound of formula 1 according to claim 4, wherein R ² and R ³ are H. The compound of formula 1 according to claim 1, wherein R ⁴ is -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ -Cl. The compound of formula 1 according to claim 1, wherein R ⁵ and R ⁶ are independently H or -C _1-4 alkyl. The compound of formula 1 according to claim 1, wherein R ⁸ and R ⁹ are independently hydrogen, -C _1-7 alkyl, or -C _3-7 cycloalkyl. The method of claim 3, wherein R ⁷ is —C (O) O (CH ₃ ) ₃ , —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , —C (O) OR ¹² , -C (O) NHC (O) R ¹² , -C (NH ₂ ) (NOR ¹² ), -S (O) (O) (NHCO ₂ R ¹² ), PO ₃ R ¹² , -P (O) (NR ¹² R ¹³ ) (NR ¹² R ¹³ ) or —P (O) (NR ¹² R ¹³ ) (OR ¹⁴ ). The compound of formula 1 according to claim 1, wherein R ¹² , R ¹³ and R ¹⁴ are independently H, -C _1-12 alkyl, or -C _2-12 alkenyl. The compound of formula 1 according to claim 1, wherein the compound is selected from the following compounds: 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl acrylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl propionamide; 2- [4- (1,2-diphenyl-but-1-enyl) -phenyl] cyclopropanecarboxylic acid diethylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl-2-methyl-acrylamide; 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -but-2-enoic acid diethylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid methyl ester; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylonitrile; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -acrylic acid tert-butyl ester; 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -acrylic acid; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -1-morpholin-4-yl-prop-2-en-1-one; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N- (3-methoxy-propyl) -acrylamide; N, N-dicyclohexyl-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide; N- (2-dimethylamino-ethyl) -3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N-methyl-N-octyl acrylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] acrylamide; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N-ethyl acrylamide; 1-amino-3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-one oxime; 3- {2- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -vinyl} -5-methyl- [1,2,4] -oxadiazole; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -prop-2-en-1-ol; {3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -allyl} -dimethylamine; 3- [4- (1,2-diphenyl-but-1-enyl) -phenyl] -N, N-diethyl thioacrylamide; or 3- [4- (1,2-Diphenyl-but-1-enyl) -phenyl] -N- (3-hydroxy-propyl) -acrylamide. A method for treating osteoporosis in a mammal comprising administering to the mammal an effective amount of the compound of claim 1. A method of treating arthritis disease in a mammal comprising administering to said mammal an effective amount of the compound of claim 1. A method of treating breast cancer in a mammal comprising administering to the mammal an effective amount of the compound of claim 1. A method for treating cardiovascular disease in a mammal, comprising administering to the mammal an effective amount of the compound of claim 1. A method for preventing osteoporosis in a mammal comprising administering to the mammal an effective amount of the compound of claim 1. A method for preventing arthritis disease in a mammal comprising administering to the mammal an effective amount of the compound of claim 1. A method for preventing breast cancer in a mammal comprising administering to the mammal an effective amount of the compound of claim 1. A method for preventing cardiovascular disease in a mammal, comprising administering to the mammal an effective amount of the compound of claim 1.