RU2200732C2 - Derivatives of triphenylethylene, methods of treatment and prophylaxis of osteoporosis, breast cancer and cardiovascular disease - Google Patents

Abstract

FIELD: organic chemistry, medicine. SUBSTANCE: invention describes derivatives of triphenylethylene of the general formula (I):

where R¹ means

or

; R² and R³ mean H; R⁴ means

; R⁵ and R⁶ mean independently H,

-alkyl; R⁷ means +CN,

-alkyl-OH,

,

-alkyl-NR¹⁰R¹¹,

or oxadiazole substituted with methyl; R⁸ and R¹⁰ mean

-alkyl; R¹⁰ and R¹¹ mean independently methyl or ethyl; R¹², R¹³ mean

-alkyl; X means oxygen atom; n means a whole number taken among 0, 1 or 2; m means a whole number 1 or 2; p means a whole number from 1 to 4 under condition that when R⁴ means

then

Description

Field of Invention
The invention relates to new non-steroidal ligands for estrogen receptors, which have tissue-dependent estrogenic and antiestrogenic activity, as well as to methods for their preparation and their use for the treatment of various painful conditions.

BACKGROUND OF THE INVENTION
Estrogens are an important class of steroid hormones that stimulate the development and maintenance of fundamental sexual characteristics in humans. In the past, estrogens have been found to be useful in treating certain medical conditions and diseases. For example, estradiol, a steroid hormone produced by the ovaries, is useful in the treatment of osteoporosis, cardiovascular disease, premenstrual syndrome, vasomotor symptoms associated with menopause, atrophic vaginitis, Kraurosis vulva, female hypogonadism, primary ovarian failure, excessive hair growth and cancer. Unfortunately, the administration of such steroids has been associated with a number of side effects, including myocardial infarction, thromboembolism, cerebrovascular disease, and endometrial carcinoma.

 For example, hormone replacement therapy (HRT) with estrogen has been found to be a clinically effective treatment for osteoporosis for postmenopausal women, however, less than 15% of patients at this age are currently prescribed HRT, despite clinical trials that have shown a 50% decrease the number of hip fractures and a 30% reduction in cases of cardiovascular disease. The rejection is due to the views of patients and doctors regarding a more than twofold increase in the risk of endometrial cancer observed in HRT cases using only estrogen, as well as the relationship between estrogen therapy and breast cancer. Although this has not been proven in clinics, this perceived risk of breast cancer has led to HRT contraindications in a significant percentage of postmenopausal women. Co-treatment with progestins has been shown to protect the uterus from cancer while preserving the osteoprotective effects of estrogen, however, progestin leads to other side effects, such as cessation of menstruation, chest pain, and mood swings.

 In light of the problems associated with estrogen therapy, a significant number of studies have been conducted to determine the effective non-steroidal estrogenic and antiestrogenic compounds. In general, such compounds can be characterized as both estrogenic and anti-estrogenic, since, although they all bind to estrogen receptors, they can cause both estrogenic and anti-estrogenic effects, depending on the location of the receptor. It was previously postulated that the binding of various estrogenic and antiestrogenic compounds to estrogen receptors is due to the presence of a common pharmacophore (presented further in Scheme A, see the end of the description), which is repeated in the chemical structure of these compounds.

 This pharmacophore later became a structural skeleton, on the basis of which non-steroidal estrogenic and anti-estrogenic compounds were created. Its presence in the structures of various compounds, such as hexestrol, tamoxifen, chroman, triphenylethylene, DES, clomiphene, centchroman, naphoxide, trioxifene, toremifene, zindoxifene, raloxifene, droloxifene, DABP, TAT-59 and other structurally related compounds, was considered by specialists as molecular the key to the specificity of estrogen receptor binding.

 An example of one noteworthy non-steroidal antiestrogen is tamoxifen (TAM), (Z) -1,2-diphenyl-1- [4- [2- (dimethylamino) ethoxy] phenyl] -1-butene, which is a derivative of triphenylethylene. Tamoxifen is an effective antagonist of the growth promoting effects of estrogen in primary target tissues, such as the breast and ovaries.

 Currently, this non-steroidal estrogen, as well as a structurally similar compound known as raloxifene, has been developed for the treatment and / or prevention of osteoporosis, cardiovascular disease and breast cancer in addition to treating and / or preventing various other painful conditions. Both of these compounds have been shown to exhibit an osteoprotective effect on bone mineral density along with a positive effect on plasma cholesterol levels and significantly reduce the incidence of breast and uterine cancer. Unfortunately, both tamoxifen and raloxifene have unacceptable levels of life-threatening side effects, such as endometrial cancer and hepatocellular carcinoma.

 Accordingly, it would be desirable to create a number of non-steroidal compounds that retain favorable characteristics, such as osteoprotective activity, while minimizing undesirable side effects. Although it has now been accepted that the pharmacophore skeleton mentioned above is responsible for the binding specificity of estrogen receptors, it has now been found that, as will be described below, such new estrogen binding ligands that include specific fragments in such pharmacophore compounds can be created, significantly enhancing such beneficial characteristics as osteoprotective function, while minimizing undesirable characteristics such as an increased risk of cancer.

Brief Description of Drawings
FIG. 1 presents data on the uterotrophic activity of the compounds of the present invention in young rats.

 FIG. 2 presents data on changes in bone mineral density in the lumbar spine and in the tibia of rats undergoing ovarectomy.

где R¹-R⁴ имеют указанные далее значения. Кроме того, часть настоящего изобретения составляют фармацевтические композиции, включающие одно или более из соединений формулы (I), а также их использование, способы их получения и промежуточные соединения, участвующие в их синтезе.Summary of invention
The present invention includes a number of compounds represented by formula (I)

where R ¹ -R ⁴ have the following meanings. In addition, part of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula (I), as well as their use, methods for their preparation and intermediates involved in their synthesis.

где R¹ представляет -(CH₂)_nCR⁵=CR⁶R⁷; -(CH₂)_mC(X)NR⁸R⁹ или

R² и R³ независимо представляют H, -СН₃, -ОН, -OCH₃, -ОСН₂СН₃ или -СН₂(СН₃)₂;
R⁴ представляет -CN, -NO₂, -СН₃, -СН₂СН₃, -CH₂CH₂-Y или -Y;
R⁵ и R⁶ независимо представляют Н, -С_1-4алкил, -С_2-4алкенил, -С_2-4алкинил, -Х-С_1-3aлкил, -Х-С_2-4алкенил, -Х-С_2-4алкинил или -Y;
R⁷ представляет -CN, -C_1-4алкил-ОН, -С(О)О(СН₃)₃, -С(O)NR¹⁰R¹¹, -С(O)NR¹²R¹³, -С_1-4алкил-NR¹⁰R¹¹, -C(О)R¹², -С(О)OR¹², -C(O)NR¹²OR¹³, -C(О)NHC(О)R¹², -С(О)NHCH₂R¹², -С(NH₂)(NOR¹²), -S(О)R¹², -S(O)(О)(OR¹²), -S(О)(О)(NHCO₂R¹²), PO₃R¹², -P(О)(NR¹²R¹³)(NR¹²R¹³), -P(O)(NR¹²R¹³)(OR¹⁴),
-C)NR¹²(CH₂)_qOCH₃, -CONR¹²(CH₂)_qNR⁸R⁹ или оксадиазол, замещенный метилом; R⁸ и R⁹ независимо представляют водород, -С_1-7алкил, -С_3-7циклоалкил, -O-С_1-7алкил, -С_1-7алкил-Y или фенил;
R¹⁰ и R¹¹ независимо представляют метил или этил или, взятые вместе, образуют морфолиногруппу, связанную через ее атом азота;
R¹², R¹³ и R¹⁴ независимо представляют H, -С_1-12алкил, -С_2-12алкенил, -С_2-12алкинил, -O-С_1-12алкил, -О-С_2-12алкенил, -О-С_2-12алкинил, -С_3-7циклоалкил, -С_3-7циклоалкенил, линейный и циклический гетероалкил, арил, гетероарил или -Y;
Х представляет кислород или серу;
Y представляет галоген;
n представляет целое число, выбранное из 0, 1 или 2;
m представляет целое число 1 или 2;
р представляет целое число от 1 до 4;
q представляет целое число от 1 до 12.DETAILED DESCRIPTION OF THE INVENTION
The present invention includes a number of compounds represented by formula (I)

where R ¹ represents - (CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; - (CH ₂ ) _m C (X) NR ⁸ R ⁹ or

R ² and R ³ independently represent 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 independently represent H, —C _1-4 alkyl, —C _2-4 alkenyl, —C _2-4 alkynyl, —X — C _1-3 alkyl, —X — C _2-4 alkenyl, —X -C _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 ),
—C) NR ¹² (CH ₂ ) _q OCH ₃ , —CONR ¹² (CH ₂ ) _q NR ⁸ R ⁹ or methyl substituted oxadiazole; R ⁸ and R ⁹ independently represent hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —O — C _1-7 alkyl, —C _1-7 alkyl-Y, or phenyl;
R ¹⁰ and R ¹¹ independently represent methyl or ethyl or, taken together, form a morpholino group linked through its nitrogen atom;
R ¹² , R ¹³ and R ¹⁴ independently represent H, —C _1-12 alkyl, —C _2-12 alkenyl, —C _2-12 alkynyl, —O — C _1-12 alkyl, —O — C _2-12 alkenyl , —O — C _2-12 alkynyl, —C _3-7 cycloalkyl, —C _3-7 cycloalkenyl, linear and cyclic heteroalkyl, aryl, heteroaryl or —Y;
X represents oxygen or sulfur;
Y represents halogen;
n represents an integer selected from 0, 1 or 2;
m represents an integer of 1 or 2;
p represents an integer from 1 to 4;
q represents an integer from 1 to 12.

In this context, the term "alkyl", used alone or in combination, means a branched or unbranched chain of hydrocarbon groups from C ₁ to C ₇ , unless otherwise indicated for the length of the chain. The term “lower alkyl” as used herein refers to C _1-4 alkyl unless otherwise indicated for chain length. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, n-hexyl and the like.

The term “haloalkyl” as used herein means alkyl substituted with one or more halogens. The term “cycloalkyl” as used herein refers to cyclic C ₃ -C ₇ hydrocarbon radicals. Some examples of cycloalkyl radicals include cyclopropyl, cyclobutyl and cyclopentyl.

 The term "aryl", used alone or in combination, here means a monocyclic or polycyclic group, preferably a monocyclic or bicyclic group, i.e. phenyl or naphthyl, which may be unsubstituted or substituted, for example, by one or more, in particular one to three substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Some examples are aryl groups including phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-nitrophenyl, and the like.

 The term “heteroaryl” as used herein means a 5-membered or 6-membered heterocyclic aromatic group which may optionally contain a fused benzene ring and which may be unsubstituted or substituted, for example, by one or more, in particular one to three substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl.

 The term “halogen” as used herein means fluoro, chloro, bromo and iodo.

 The terms “linear and cyclic heteroalkyl” are defined in accordance with the term “alkyl” with the corresponding replacement of carbon atoms by some other atom, such as nitrogen or sulfur, which impart chemical stability to the compound.

In addition, the above functional groups are presented below in brackets "()" surrounding some atoms or groups of atoms, where it is apparently desirable to clarify the molecular structure or binding patterns. In particular, a single atom, such as “O”, or a group of atoms, such as “NH ₂ ”, can be represented in parentheses in the formulas of one of the functional groups presented above [see for example, where R ⁷ is —C (O) R ¹² , —C (O) OR ¹² , —C (O) NR ¹² OR ¹³ , C (NH ₂ ) (NOR ¹² ), etc.]. In such a situation, the brackets are intended to indicate that an atom or group of atoms enclosed in them is bonded to the nearest preceding chemically stable atom that is not enclosed in brackets.

More specifically, for example, —C (O) R ¹² represents a functional group in which oxygen is bonded to carbon, the nearest preceding atom, which is not bracketed and chemically suitable for binding in accordance with the classical theory of binding of electronic orbitals. In another embodiment, —C (NH ₂ ) (NOR ¹² ) represents a functional group in which the nitrogen present in both NH ₂ and NOR ¹² is bound to carbon, the nearest preceding atom, which is not enclosed in parentheses. These examples are illustrated in (a) and (b) below. It should be clear to those skilled in the art that suitable binding schemes (i.e., simple, double bonds, etc.) are obvious in accordance with the rules for linking orbitals.

Кроме того, некоторые из указанных выше функциональных групп представлены в виде "( )" вокруг некоторых атомов или групп атомов, где сразу после скобок следуют буквенные или численные индексы [см., например, где R представляет -CONR¹²(CH₂)_qOCH₃] . В этой ситуации подразумевается, что атом или группы атомов, заключенные в скобки, присутствуют в функциональной группе в количестве, указанном индексом. Например, если q=2, в формуле, где R⁷ представляет -CONR¹²(CH₂)_qOCH₃, тогда R⁷ = -CONR¹²C₂CH₂OCH₃.

In addition, some of the above functional groups are represented as “()” around some atoms or groups of atoms, where alphanumeric indices immediately follow the brackets [see, for example, where R represents —CONR ¹² (CH ₂ ) _q OCH ₃ ]. In this situation, it is understood that an atom or groups of atoms enclosed in brackets are present in the functional group in the amount indicated by the index. For example, if q = 2, in the formula where R ⁷ represents —CONR ¹² (CH ₂ ) _q OCH ₃ , then R ⁷ = —CONR ¹² C ₂ CH ₂ OCH ₃ .

 Those skilled in the art will recognize that there is a stereo center in the compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic mixtures, but also optically active isomers. If the compound of formula (I) is necessary as a separate enantiomer, it can be obtained either by separating the final product, or by stereospecific synthesis, or from an isomerically pure starting material, or from any convenient intermediate. The separation of the final product, intermediate product or starting material can be carried out by any method convenient for those skilled in the art. See, for example, Stereochemistry of Carbon Compounds by E.L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S.H. Wilen. In addition, in cases where tautomers of the compounds of formula (I) are possible, the present invention includes all tautomeric forms of these compounds.

 The following are some specific compounds of formula (I), the synthesis of which is carried out in accordance with the following examples.

 1. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N, N-diethylacrylamide.

 2. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N, N-diethylpropionamide.

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

 4. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N, N-diethyl-2-methylacrylamide.

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

 6. Methyl ester of 3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid.

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

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

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

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

 11. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N- (3-methoxypropyl) acrylamide.

 12. N, N-Dicyclohexyl-3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylamide.

 13. N- (2-Dimethylaminoethyl) -3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N-ethylacrylamide.

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

 15. 3- [4- [1,2-Diphenylbut-1-enyl) phenyl] acrylamide.

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

 17. 1-amino-3- [4- (1,2-diphenylbut-1-enyl) phenyl] prop-2-en-1-one-oxime.

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

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

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

 21. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N, N-diethylthioacrylamide.

 22. 3- [4- (1,2-Diphenylbut-1-enyl) phenyl] -N- (3-hydroxypropyl) acrylamide.

 Typically, compounds of formula (I) can be prepared according to the following synthetic schemes. In all of the following schemes, it is well understood by those skilled in the art that, if necessary, protective groups should be used in accordance with the general principles of chemistry. These protective groups are removed at the final stages of the synthesis under basic, acidic or hydrogenolytic conditions, which are completely obvious to those skilled in the art. Using the appropriate manipulations and protection of any chemical functionalities, it is possible to synthesize any of the following compounds of formula (I) by methods that are similar to the methods presented in Schemes B-G below, as well as the methods described in the Examples section.

 Typically, the synthesis used to prepare the compounds of the present invention is designed to provide access to B-ring analogs with the E configuration of a central tetra-substituted double bond. One method for preparing compounds of formula (I) includes Scheme B presented at the end of the description, wherein a suitable bromide such as bromide (b) [for example, (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1- butene], synthesized in an amount of several grams from acetylene (a) using the Miller method (see Miller RB, Al-Hassan, MI Stereospecific Synthesis of (Z) -Tamoxifen via Carbometalation of Alkylsilanes. J. Org. Chem., 1985, 50, 2121-2123). The combination of bromide (b) with a suitable arylboronic acid, such as (c), is carried out over a palladium catalyst to obtain the desired aldehyde (d) [for example, (Z) -1,2-diphenyl-1- (4-formylphenyl) -1 butene], as an individual isomer. Bromide (b) and aldehyde (d) are universal intermediates for the synthesis of tamoxifen B-ring analogues.

 As shown (at the end of the description) in Scheme C, a combination of bromide (b) and arylboronic acid (e) results in a, b-unsaturated diethylamide (g), which is Compound 1 in the above list, and is illustrated further in Example 2 It should be noted that this method of synthesis of this diethylamide can lead to a low yield, possibly due to the thermal instability of arylboronic acid (e). It was also noted when creating the compounds of the present invention that the identification of diethylamide (g) as a compound of interest (i.e., Compounds 1: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N- diethyl acrylamide) dictates the need for a more efficient method of synthesis to obtain analogues. Accordingly, it was found that as a result of the reaction of Horner-Emmons aldehyde (d) with phosphonate (f), a significantly higher yield of diethylamide (g) is achieved.

In addition, the above scheme C illustrates that a, b-unsaturated diethylamide (g) can be converted into:
(a) thioamide (h) [Compound 21: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylthioacrylamide] using Lawesson's reagent;
(b) saturated amide (i) [Compound 2: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylpropionamide] using hydrogenation, or
(c) cyclopropylamide (j), [Compound 3: 2- [4- (1,2-diphenylbut-1-enyl) phenyl] cyclopropanecarboxylic acid diethylamide] using Corey ylide.

 In accordance with the presented (at the end of the description) Scheme D, diethylamide analogs (g) including a trisubstituted a, b-unsaturated double bond can be synthesized from the corresponding aldehyde such as (d) or a suitable ketone such as (n).

More specifically, the reaction of Hommer-Emmons methylphosphonate (k) with aldehyde (d) can be used to produce a-methylamide (I) [Compound 4: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethyl-2-methylacrylamide] as an individual isomer, and the reaction of phosphonate (f) with ketone (n) can be used to obtain a mixture of E- and Zb-methylamides (o, p) [Compound 5: 3- [4- ( 1,2-diphenylbut-1-enyl) phenyl] -but-2-enoic acid diethylamide, (Z) - and (E) -isomers], which can be separated using flash chromatography, and their relative stereochemistry is determined using ¹ H NMR, NOE follow-up been concerned.

 Scheme E at the end of the description shows how to obtain carboxylic acid (r) [Compound 9: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid] by saponification of methyl ester (q) [Compound 6: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid methyl ester], which, in turn, can be obtained by condensation of the aldehyde (d) with trimethylphosphonoacetate, as shown in Scheme D. Scheme E also illustrates how carboxylic acid (r) can be used as a key intermediate. A synthesis of a number of a, b-neneasyschennyh amides, followed by addition of a series of linear and cyclic alkyl and geteroalkilaminov.

 According to Scheme F at the end of the description, oxadiazole (v) [Compound 18: 3- {2- [4- (1,2-diphenylbut-1-enyl) phenyl] vinyl} -5-methyl- [1, 2,4] -oxadiazole] can be synthesized from nitrile (t) [Compound 7: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylonitrile] by reaction with hydroxylamim to give amidoxime (u) [ Compound 18: 3- {2- [4- (1,2-diphenylbut-1-enyl) phenyl] vinyl} -5-methyl- [1,2,4] -oxadiazole] followed by cyclization with acetic anhydride.

 Scheme G shown at the end of the description shows how alcohol (x) [Compound l9: 3- [4- (1,2-diphenylbut-1-enyl) phenyl] prop-2-en-1-ol] and dimethylamine (y ) [Compound 20: {3 - [- 4- (1,2-diphenylbut-1-enyl) phenyl] allyl} dimethylamine] can be synthesized from tert-butyl ester (w) [Compound 8: 3- [4- ( 1,2-diphenylbut-1-enyl) phenyl] acrylic acid tert-butyl ester] by reduction with hydrogen followed by mesylation and alkylation with dimethylamine.

General procedures
Unless otherwise indicated, all starting materials are obtained from commercial sources and used without further purification. Melting points are determined in capillary tubes on a Mel-Temp instrument and are not corrected. ¹ H NMR and ¹³ C NMR spectra were obtained on a Varian Unity-300 and Varian XRL-300 instrument using TMS as an internal standard in CDC1 ₃ . Chemical shifts are given in ppm (δ); multiplicity is denoted as c (singlet), d (doublet), t (triplet), sq (quartet), m (multiplet), width (expanded). The interaction constants (J) are presented in Hz (Hertz). Microanalysis was performed at Atlantic Microlabs, Inc., and all values differ from theoretical values by ± 0.4%. Mass spectra were obtained on a JEOL JMS-AX505HA mass spectrometer using ionization due to fast atom bombardment. Infrared spectra were recorded on a Perkin-Elmer 1280 infrared spectrophotometer. Analytical thin-layer chromatography was performed on glass plates coated with EM Science silica 60 F254, and visualization was carried out using UV light, iodine, or ammonium molybdate. Flash chromatography was carried out on EM Science 230-400 mesh silica gel, medium-pressure liquid chromatography was performed on a Pharmacia LKB Series system using a Rainin Dynamax UV-C detector and a Merck Lobar SI 60 silica gel column (40-63 mm). HPLC was performed on a Shimadzu LC-6A Series HPLC using either a Rainin Dynamax Ct8 RP column or a Rainin Dynamax Silica column. All solvents were reagent grade and were used without further purification. (E) -1-Bromo-2-phenyl-1- (trimethylsilyl) -1-butene [see (b), Scheme B, above] is prepared according to the Miller method as described above, and 4-formylboronic acid is prepared according to the Noth method (see Feulner N., Linti G., Noth H. Preparation and Structural Characterization of p-Formylbenzeneboronic Acid Chem. Ber., 1990, 123, 1841-1843. Boronic acids [see (e) and (m), Schemes C and D, respectively] were obtained from Glaxo Group Research Ltd., Hertfordshire, UK, from 3- ( 4-bromophenyl) -N, N-diethylacrylamide and 4-bromoacetophenone, respectively, using the Gilman method (see Gilman H., Santucci L., Swayampati DR, Ranck RO Hydroxybenzeneboronic Acids and Anhydrides. J. Am. Chem. Soc., 1957, 79, 3077-3082.

 The following compounds are prepared according to the general synthetic methods set forth above, and examples are provided to better illustrate the methods for preparing the compounds of the present invention. These examples are merely illustrative and in no way limit the scope of the present invention.

Example 1
(Z) -1,2-Diphenyl-1- (4-formylphenyl) -1-butene
A solution of 1.0 g (3.5 mmol) (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene, 625 mg (4.2 mmol, 1.2 equiv.) Of boronic acid [ cm. (c), Scheme B] and 400 mg (0.35 mmol, 0.1 eq) of Pd (PPh ₃ ) ₄ in 10 ml of DME are treated with 2 ml of 2 N. Na ₂ CO ₃ and then boiled under reflux for 6 hours. The solution was cooled to room temperature, poured into NaHCO ₃ (40 ml), extracted with ethyl acetate (2 x 40 ml), dried over magnesium sulfate and the solvent was removed in vacuo. Purification by flash chromatography on silica gel using 20: 1 hexane / ethyl acetate mixture as eluent gave 700 mg (69%) of the title target compound as a yellow solid.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 9.82 (s, 1H), 7.55-7.00 (m, 14H), 2.48 (q, 2H), 0.97 (t, 3H) ) Low resolution mass spectrum m / e 313 (MH ⁺ ) [see, for example, (d), Scheme B].

Example 2
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylacrylamide
Procedure A. Solution 51 mg (0.18 mmol, 1.1 equiv.) (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene, 40 mg (0.16 mmol) arylboronic acid [cm. (e), Scheme C] and 20 mg (16.2 mmol, 0.1 eq.) Pd (PPh ₃ ) ₄ in 5 ml of DME are treated with 0.5 ml of 2 N. Na ₂ CO ₃ and then boiled under reflux for 2 hours. The solution was cooled to room temperature, poured into NaHCO ₃ (20 ml), extracted with ethyl acetate (2 x 20 ml), dried over magnesium sulfate and the solvent was removed in vacuo. Purification by flash chromatography on silica gel using 3: 1 hexane / ethyl acetate as eluent afforded 10 mg (15%) of the title target compound as a white solid. T. pl. 138-140 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.53 (d, 1H, J = 15.4), 7.38-7.11 (m, 12H), 6.86 (d, 2H, J = 8.3), 6.66 (d, 1H, 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 mass spectrum: calculated 410.2483, found 410.2484.

Procedure B. Using Diethyl Diethyl Carbamoyl Methylene Phosphonate [see (f) Scheme C], as described in the general procedure for the Horner-Emmons coupling reaction (see Example 7) with an aldehyde, (Z) -1,2-diphenyl-1- (4-formylphenyl) -1-butene is obtained after purification by flash chromatography on silica gel using a hexane / ethyl acetate gradient of 20: 1 -> 2: 1, 110 mg (42%) of the title target compound as a white solid. T. pl. 137-138 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.53 (d, 1H, J = 15.4), 7.36-7.11 (m, 12H), 6.86 (d, 2H, J = 8.3), 6.66 (d, 1H, 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). Analysis: (C ₂₉ H ₃₁ NO) C, H, N [see, for example, (g), Scheme C, above].

Example 3
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylthioacrylamide
A mixture of 65 mg (0.16 mmol) of 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylacrylamide (see Example 2) and 39 mg (95.2 mmol, 0, 6 equiv.) Of Lawesson's reagent is heated in 2 ml of dry toluene at 85 ^{° C.} for 2 hours. The solution was cooled to room temperature and injected directly onto a flash chromatography silica gel column. Purification, eluting with 10: 1 hexane / ethyl acetate, affords 54 mg (83%) of the thioamide of the title target compound as a yellow foam. T. pl. 43-61 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.85 (d, 0.5H), 7.75 (d, 0.5H), 7.65 (d, 0.5H), 7.40-6 80 (m, 13.5H), 4.05 (m, 2H), 3.70 (m, 2H), 2.45 (m, 2H), 1.30 (m, 6H), 0.95 ( m, 3H).

¹³ H NMR (CD1 ₃ , 75 MHz) δ: 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, 127.02, 126.83, 126.45, 124.04, 48.54, 46.40, 29.19, 13.86, 13.67, 13.62, 11.66.

IR (CPC1 ₃ ): 3050, 1520, 1210, 950, 750.

Analysis: (C ₂₉ H ₃₁ NS) C, H, N [see, for example, (h), Scheme C above].

Example 4
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylpropionamide
A solution of 50 mg (0.12 mmol) of 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylacrylamide (see Example 2) and 3 mg of the tris (triphenylphosphine) rhodium complex (I ) chloride (Wilkinson's catalyst) in 1 ml of dry toluene is stirred in an atmosphere of gaseous hydrogen at 50 ^o C for 16 hours. The solution was cooled to room temperature and the toluene was removed in vacuo. Purification of the residue by flash chromatography on silica gel using 2: 1 hexane / ethyl acetate as eluent afforded 48 mg (95%) of the title target compound as a clear, colorless oil.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 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). Mass spectrum of low resolution m / e 412 (MH ⁺ ). Analysis: (C ₂₉ H ₃₃ NO) C, H, N [see, for example, (i), Scheme C, above].

Example 5
2- [4- (1,2-Diphenylbut-1-enyl) phenyl] cyclopropanecarboxylic acid diethylamide
A solution of 12 mg (0.24 mmol, 2.0 equiv.) Of sodium hydride (50% in oil) and 54 mg (0.24 mmol, 2.0 equiv.) Of trimethyloxosulfonium iodide in 2 ml of dry dimethyl sulfoxide is stirred for 30 minutes at room temperature, and by this time gas evolution ceases. Then, a solution of 50 mg (0.12 mmol) of the amide obtained in Example 2 in 0.5 ml of dimethyl sulfoxide is added and the resulting solution is heated at 50 ^{° C.} for 16 hours. The reaction mixture was cooled to room temperature, poured into 20 ml of water, extracted with ethyl acetate (2 x 20 ml). The organic layers were combined, dried over magnesium sulfate and the solvent was removed in vacuo. As a result of purification using medium pressure liquid chromatography on silica gel, using a 4: 1 hexane / ethyl acetate mixture as eluent, 32 mg (62%) of the title target compound are obtained as a white solid. T. pl. 42-44 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.37-7.10 (m, 10H), 6.76 (m, 4H), 3.38 (q, 4H, 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 mass spectrum m / e 424 (MH ⁺ ). Analysis: (C ₃₀ H ₃₃ NO) C, H, N [see, for example, (j), Scheme C, previously].

Example 6
(Methyl) diethyl diethylcarbamoylmethylene phosphonate
A solution of 4.4 ml (2.2 mmol, 1.1 eq.) Of KN (TMS) ₂ (0.5 M in toluene) was added to a cooled (-78 ^° C) solution of 500 mg (2.0 mmol) of diethyl diethylcarbamoylmethylene phosphonate in 5 ml dry THF. The resulting solution was stirred for 10 minutes, then 0.15 mg (2.4 mmol, 1.2 equiv.) Of methyl iodide (without solvent) was added. The resulting solution was allowed to warm to room temperature and stirred for 1 hour, then poured into brine (70 ml) and extracted with ethyl acetate (2 x 60 ml). The organic layers were combined, dried over magnesium sulfate and the solvent was removed in vacuo. Purification of the yellow residue by distillation in Kugelrohr gives 525 mg (100%) of the title target compound as a clear, colorless oil. T. bale. 155 ^o C at 0.15 mm RT. Art.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 4.18 (m, 4H), 3.60 (m, 1H), 3.22 (m, 4H), 1.37 (m, 9H), 1, 18 (m, 6H). [see, for example, (k), Scheme C].

Example 7
General Procedure for the Reaction of Horner-Emmons with (Z) -1,2-diphenyl-1- (4-formylphenyl) -1-butene
A solution of 1.2 eq. KN (TMS) ₂ (0.5M in toluene) was added to a stirred, at 0 ^o C solution of 1.2 eq. the corresponding phosphonate in dry THF. The resulting solution was stirred for 15 minutes at 0 ^° C, then cooled to -78 ^° C and a solution of (Z) -1,2-diphenyl-1- (4-formylphenyl) -1-butene in THF was added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 4 hours, then heated at 50 ^{° C.} for 2 hours to ensure completion of the reaction. The reaction mixture was cooled to room temperature, poured into brine and extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel.

Example 8
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethyl-2-methylacrylamide
Using (methyl) diethyl diethylcarbamoylmethylene phosphonate as previously indicated, after purification by flash chromatography on silica gel using 3: 1 hexane / ethyl acetate mixture, 36 mg (53%) of the title target compound are obtained as a clear, colorless oil.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 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 mass spectrum m / e 424. Analysis: (C ₃₀ H ₃₃ NO) C, H, N [see, for example, (1), Scheme D previously].

Example 9
(Z) - diethylamide and (E) -3- [4- (1,2-diphenylbut-1-enyl) phenyl] -but-2-enoic acid
Using diethyl diethylcarbamoylmethylene phosphonate as used above, purification by flash chromatography on silica gel using 5: 2 hexane / ethyl acetate mixture afforded 95 mg (49%) of the title target (Z) isomer as a solid white and 11 mg (6%) of the (E) -isomer as a colorless oil.

Analytical data for the (Z) -isomer: mp. 109-111 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.39-7.09 (m, 12H), 6.85 (d, 2H, J = 8.3), 6.20 (d, 1H, J = 1.0), 3.44 (q, 2H, 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 mass spectrum m / s 424. Analysis: (C ₃₀ H ₃₃ NO) C, H, N.

 Analytical data for the (E) -isomer.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 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, 2H, 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 mass spectrum m / e 424. Analysis: (C ₃₀ H ₃₃ NO) [see, for example, (o, p), Scheme D previously].

Example 10
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid methyl ester
Using trimethylphosphonoacetate as described above, purification by flash chromatography on silica gel using hexane / ethyl acetate 20: 1 as an eluent gave 2.33 g (100%) of the title target compound as a white solid . T. pl. 133-135 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.53 (d, 1H, J = 16.0), 7.39-7.10 (m, 12H), 6.88 (d, 2H, J = 8.3), 6.27 (d, 1H, J = 16.0), 3.76 (s, 3H), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 369. Analysis: (C ₂₆ H ₂₄ O ₂ ) C, H, N [see, for example, (q), Scheme E previously].

Example 11
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylonitrile
Using diethyl cyanomethylphosphonate as described above, purification by flash chromatography on silica gel using 10: 1 hexane / ethyl acetate as eluent gives 125 mg (93%) of the title target compound as a clear, colorless oil, which cures when standing. T. pl. 101-102 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.40-7.07 (m, 13H), 6.90 (d, 2H, J = 8.6), 5.79 (d, 1H, J = 16.6), 2.46 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3). Analysis: (C ₂₅ H ₂₁ N) C, H, N [see, for example, (t), Scheme F previously].

Example 12
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid tert-butyl ester
Using tert-butyl diethylphosphonoacetate as described above, purification by flash chromatography on silica gel using hexane / ethyl acetate 20: 1 as an eluent, after recrystallization from hot hexane, 52 mg (95%) of the title target compound are obtained in as a white solid. T. pl. 139-140 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.44-7.09 (m, 13H), 6.86 (d, 2H, J = 8.3), 6.20 (d, 1H, J = 16.1), 2.47 (q, 2H, J = 7.4), 1.49 (s, 9H), 0.93 (t, 3H, J = 7.4). The low-resolution mass spectrum m / e 373, MH ^{+ is} absent. Analysis: (C ₂₉ H ₃₀ O ₂ ) C, H, N [see, for example, (w), Scheme G previously].

Example 13
1- [4- (1,2-diphenylbut-1-enyl) phenyl] ethanone
Solution 172 mg (0.60 mmol) (E) -1-bromo-2-phenyl-1- (trimethylsilyl) -1-butene [cm (b), Scheme B, previously], 125 mg (0.60 mmol, 1.0 equiv.) Of boronic acid [see (m), Scheme D] and 70 mg (0.06 mmol, 0.1 eq.) Pd (PPh ₃ ) ₄ in 8 ml of DME are treated with 0.4 ml of 2 N. Na ₂ CO ₃ and then refluxed for 18 hours. The solution was cooled to room temperature, drunk in brine (20 ml), extracted with ethyl acetate (2 x 20 ml), dried over magnesium sulfate, and the solvent was removed in vacuo. Purification by flash chromatography on silica gel using 20: 1 hexane / ethyl acetate mixture as eluent afforded 152 mg (78%) of the title target compound as a yellow solid.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.6 (d, 2H), 7.45-7.10 (m, 10H), 6.98 (d, 2H), 2.48 (m, 3H ), 0.94 (t, 3H) [see, for example, (n), Scheme D previously].

Example 14
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid
A solution of 50 ml (16 mmol, 10.0 equiv.) Of 0.2 M KOH was added dropwise over 2 minutes to a solution of 600 mg of the ester obtained by the method of example 10 (1.6 mmol, 1.0 equiv.), in 90 ml of a mixture of methanol / THF 1: 2. The resulting solution was stirred for 18 hours at room temperature and the solvent was removed in vacuo. The residue was dissolved in 30 ml of 1M Hcl and extracted with ethyl acetate (2 x 60 ml). The organic layers were combined, dried over magnesium sulfate and the solvent was removed in vacuo. Purification by flash chromatography on silica gel using a 95: 5 methylene chloride / methanol mixture as eluent gives 370 mg (63%) of the title target compound as a white solid. T. pl. 148-150 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.60 (d, 1H, J = 15.9), 7.39-7.10 (m, 12H), 6.89 (d, 2H, J = 8.1), 6.27 (d, 1H, J = 15.9), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 355. Analysis: (C ₂₅ H ₂₂ 0 ₂ ) C, H, N [see, for example, (r), Scheme E previously].

Example 15
General Procedure for 3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid coupling reactions
To a solution of 1.0 equiv. acids (20) in dry methylene chloride add 1.0 equiv. EDC, 1.3 eq. NOVT and 1.0 equiv. Et ₃ N, and then 1.2 equiv. corresponding amine. The resulting solution was stirred for 18 hours at room temperature, then poured into 20 ml of H ₂ O and extracted twice with ethyl acetate (2 x 60 ml). The organic layers were combined, washed with H ₂ O (1 x 20 ml), dried over magnesium sulfate, the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, liquid chromatography on silica gel or recrystallization.

Example 16
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -1-morpholin-4-yl-prop-2-en-1-one
Using morpholine, as a result of subsequent purification using medium-pressure liquid chromatography on silica gel, using a 2: 1 hexane / ethyl acetate mixture as eluent, after recrystallization from hot hexane, 12 mg (14%) of the title target compound are obtained as a white solid colors. T. pl. 150-154 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.53 (d, 1H, J = 15.4), 7.39-7.10 (m, 12H), 6.87 (d, 2H, J = 8.3), 6.67 (d, 1H, J = 15.4), 3.65 (m, 8H), 2.48 (q, 2H, J = 7.3), 1.26 (br. 8H), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 424. Analysis: (C ₂₉ H ₂₉ NO ₂ ) C, H, N [see, for example, (s), Scheme E previously].

Example 17
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N- (3-methoxypropyl) acrylamide
Using 3-methoxypropylamine, subsequent purification by medium pressure liquid chromatography on silica gel using 2: 1 hexane / ethyl acetate as eluent afforded 20 mg (30%) of the title target compound as a white solid. T. pl. 132-135 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.43 (d, 1H, J = 15.7), 7.36-7.10 (m, 12H), 7.86 (d, 2H, J = 8.3), 6.20 (d, 1H, 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 mass spectrum m / e 426. Analysis: (C ₂₉ H ₃₁ NO ₂ ) C, H, N [see, for example, (s), Scheme E previously].

Example 18
N, N-Dicyclohexyl-3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylamide
Using dicyclohexylamine, subsequent purification by recrystallization from a hot hexane / ethyl acetate 2: 1 mixture gave 29 mg (28%) of the title target compound as a white solid. T. pl. 194-200 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.43-7.11 (m, 13H), 6.86 (d, 2H, J = 8.3), 6.69 (d, 1H, J = 15.4), 3.50 (m, 2H), 2.48 (q, 2H, J = 7.3), 2.25 (m, 2H, 1.77-1.62 (2 m, 12H) , 1.30-1.10 (m, 8H), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 518. Analysis: (C ₃₇ H ₄₃ NO) C, H, N [see, for example (s), Scheme E previously].

Example 19
N- (2-Dimethylaminoethyl) -3- [4- [1,2-diphenylbut-1-enyl) phenyl] -N-ethyl acrylate acid oxalate
Using 2-dimethylaminoethylamine, as a result of subsequent purification by flash chromatography on silica gel, using an eluent of a mixture of methylene chloride / methanol 15: 1, after obtaining a salt of acid oxalate using 1.1 equiv. oxalic acid in Et ₂ O, 58 mg (53%) of the title target compound are obtained as a white solid. T. pl. 145-147 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.51 (d, 1H, J = 15.1), 7.38-7.10 (m, 12H), 6.88 (d, 2H), 6 60 (d, 1H, 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 mass spectrum m / e 453. Analysis: (C ₃₁ H ₃₆ N ₂ O C ₂ H ₂ O ₄ ) C, H, M [see, for example, (s), Scheme E previously].

Example 20
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N- (3-hydroxypropyl) acrylamide
Using 3-hydroxypropylamine, as a result of further purification using medium pressure liquid chromatography on silica gel, using a gradient of a 2: 1 hexane / ethyl acetate mixture to 100% ethyl acetate as eluent, after recrystallization from hot hexane, 14 mg (15%) of the title compound are obtained target compound in the form of a white solid. T. pl. 144-146 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.47 (d, 1H, J = 15.6), 7.36-7.10 (m, 12H), 7.86 (d, 2H, J = 8.3), 6.22 (d, 1H, 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 mass spectrum m / e 412. Analysis: (C ₂₈ H ₂₉ NO ₂ ) C, H, N [see, for example, (s), Scheme E previously].

Example 21
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N-methyl-N-octyl acrylamide
Using N-methyl-N-octylamine, subsequent purification by medium pressure liquid chromatography on silica gel using 3: 1 hexane / ethyl acetate as eluent afforded 56 mg (41%) of the title target compound as a solid white color, T. pl. 150-154 ^o C. 108-109 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.52 (d, 1H, J = 15.4), 7.38-7.14 (m, 12H), 6.86 (d, 2H, J = 7.8), 6.68 (dd, 1H, 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, 6H). Low resolution mass spectrum m / e 480. Analysis: (C ₃₄ H ₄₁ NO) C, H, N [see, for example, (s), Scheme E previously].

Example 22
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylamide
Using a saturated solution of ammonia in CH ₂ Cl ₂ , subsequent purification by medium pressure liquid chromatography on silica gel using 2: 1 hexane / ethyl acetate as eluent gave 39 mg (39%) of the title target compound as a solid white matter. T. pl. 200-202 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.47 (d, 1H, J = 15.6), 7.39-7.10 (m, 12H), 6.87 (d, 2H, J = 8.3), 6.27 (d, 1H, J = 15.6), 2.48 (q, 2H, J = 7.3), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 354. Analysis: (C ₂₅ H ₃₀ NO) C, H, N.

Example 23
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N-ethyl acrylamide
A solution of 0.2 ml (0.4 mmol, 1.2 equiv.) Of oxalyl chloride (2 M in CH ₂ Cl ₂ ) adds 120 mg (0.3 mmol) of the acid obtained by the method of Example 14 to the solution stirred at 0 ^{° C.} in 2 ml of dry methylene chloride. The resulting solution was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was dissolved in 2 ml of ether and then added to a rapidly stirred solution of 23 ml of ethylamine (70 wt.% In H ₂ O) (0.4 mmol, 1.2 equiv.) In 2 ml of 1M NaOH. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate and extracted; the aqueous layer was washed with ethyl acetate (3 x 10 ml). The organic layers were combined, dried over magnesium sulfate, the solvent was removed in vacuo, and the residue was purified by recrystallization from hot ethyl acetate to give 45 mg (35%) of the title target compound as a white solid. T. pl. 192-193 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.45 (d, 1H, J = 15.6), 7.39-7.10 (m, 12H), 6.86 (d, 2H, J = 8.1), 6.20 (d, 1H, J = 15.6), 3.38 (m, 2H, J = 7.3], 2.48 (q, 2H, J = 7.3), 1.17 (t, 3H, J = 7.3), 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 382. Analysis: (C ₂₇ H ₂₇ NO) C , H, N [see, for example, (s), Scheme E previously].

Example 24
1-amino-3- [4- (1,2-diphenylbut-1-enyl) phenyl] prop-2-en-3-one oxime
A solution of 1.16 ml (1.16 mmol, 3.1 equiv.) Of sodium methoxide in methanol (1.0 M) is added to a solution of 78 mg (1.12 mmol, 3.0 equiv.) Of hydroxylamine hydrochloride in 4 ml of dry methanol. The resulting solution was refluxed for 15 minutes, then cooled to room temperature. A solution of 125 mg (0.37 mmol) of the nitrile obtained by the method of Example 11, which was dissolved in 2 ml of a dry methanol / THF 2: 1 mixture, was added, and the reaction mixture was refluxed for 16 hours. The reaction mixture was cooled, poured into 20 ml of brine and extracted with ethyl acetate (2 x 20 ml), dried over magnesium sulfate and the solvents removed in vacuo. Purification by flash chromatography on silica gel gave 61 mg (47%) of the title target compound as a white solid. T. pl. 182-185 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.38-7.07 (m, 12H), 6.85 (d, 2H, J = 8.0), 6.68 (d, 1H, J = 16.7), 6.32 (d, 1H, J = 16.7), 4.60 (s, broad, 2H), 2.47 (q, 2H, J = 7.6), 2.17 ( s, 1H), 0.93 (t, 3H, J = 7.6). Low resolution mass spectrum m / e 369. Analysis: (C ₂₅ H ₂₄ N ₂ O) C, H, N [see, for example, (u), Scheme F previously].

Example 25
3- {2- [4- (1,2-diphenylbut-1-enyl) phenyl] vinyl} -5-methyl- [1,2,4] -oxadiazole
A solution of 60 mg (0.16 mmol) of the amidoxime obtained by the method of example 24, which is located in 5 ml of acetic anhydride, is heated at 80 ^o C for 18 hours, cooled to room temperature, poured into 10 ml of 4 N. NaOH and extracted with ethyl acetate (2 x 20 ml). The organic layers are combined, dried over magnesium sulfate, and the solvent is removed in vacuo. The crude material was purified by flash chromatography on silica gel using a 10: 1 hexane / ethyl acetate mixture as eluent to give 21 mg of a slightly contaminated product, which was recrystallized from a hot methanol / ethyl acetate 10: 1 mixture to obtain 13 mg (20%) of the title in the title of the target compound as a white crystalline solid. T. pl. 158-159 ^o C.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 7.50 (d, 1H, J = 16.4), 7.37-7.12 (m, 13H), 6.87 (m, 2H), 2 58 (s, 3H); 2.47 (q, 2H, J = 7.3); 0.93 (t, 3H, J = 7.3). Low resolution mass spectrum m / e 392. Analysis: (C ₂₇ H ₂₄ N ₂ O) C, H, N (see, for example, (v), Scheme F previously].

Example 26
3- [4- (1,2-diphenylbut-1-enide) 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 solution of the ester obtained by the method of Example 12, which was found in 3, cooled to -78 ^{° C.} ml THF. The resulting solution was stirred for 30 minutes at -78 ^° C, then warmed to room temperature and stirred for 16 hours. Excess DIBAL-H is quenched 1 n. Hcl and the reaction mixture are poured into 20 ml of 1 N. Hcl and extracted with ethyl acetate (2 x 20 ml). The organic layers were combined, dried over magnesium sulfate and the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel using hexane / ethyl acetate 5: 1 as eluent gave 94 mg (60%) of the title target compound as a white solid. T. pl. 80-83 ^o C.

¹ H NMR (CDCl ₃ , 300 MHz) δ: 7.41-7.02 (m, 12H), 6.82 (d, 2H, J = 8.3), 6.45 (d, 1H, J = 15.8), 6.23 (dt, 1H, 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 mass spectrum m / e 340. Analysis: (C ₂₅ H ₂₄ O) C, H [see, for example, (x), Scheme G previously].

Example 27
{3- [4- (1,2-Diphenylbut-1-enyl) phenyl] allyl} dimethylamine
A solution of 90 mg (0.27 mmol) of the alcohol obtained by the method of example 26 and 41 mg (0.32 mmol, 1.2 equiv.) Of diisopropylethylamine in 2 ml of dry dichloromethane is treated with 33 mg (0.29 mmol, 1.1 equiv.) methanesulfonyl chloride and the resulting solution was stirred at room temperature for 3 hours. Then the solution was poured into 10 ml of ethyl acetate and extracted with 10 ml of brine, dried over magnesium sulfate and the solvents were removed in vacuo to give 108 mg (97%) of a thick golden oil. This material is immediately dissolved in 3 ml of dry methanol, and then 1 ml of dimethylamine is added. The resulting solution was stirred for 16 hours at room temperature, then the solvents were removed in vacuo. The residue is dissolved in 10 ml of ethyl acetate and extracted with 1 N. Hcl. The aqueous layer was isolated and basified by adding 3 N. NaOH and then extracted with ethyl acetate (2 x 10 ml). The alkaline extracts are combined, dried over magnesium sulfate and the solvent is removed in vacuo. Purification by medium pressure liquid chromatography on silica gel using a 15: 1 dichloromethane / methanol mixture as eluent gives 37 mg (40%) of the title target compound as a clear, colorless oil.

¹ H NMR (CDC1 ₃ , 300 MHz) δ: 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, 1H, 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 mass spectrum m / e 396. Analysis: (C ₂₉ H ₃₃ N) C, H, N [see, for example, (y), Scheme G previously].

 Compounds of formula (I) that contain acid moieties may form pharmaceutically acceptable salts with suitable cations. Suitable pharmaceutically acceptable cations include cations of alkali metals (e.g., sodium or potassium) and alkaline earth metals (e.g., calcium or magnesium). In light of the foregoing, any references to compounds of the present invention appearing herein include both compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof.

 As indicated previously, the compounds of the present invention are suitable for the treatment and / or prophylaxis of various disorders or conditions, such as cardiovascular disease, breast cancer, osteoporosis and arthritis. Some other examples of disorders or conditions in which the compounds of the present invention are also useful for treatment and / or prophylaxis include premenstrual syndrome, vasomotor symptoms associated with menopause, atrophic vaginitis, Kraurosis vulva, female hypogonadism, primary ovarian failure, excessive hair growth and cancer the prostate.

 It should be clear to those skilled in the art that the treatment references made here apply both to prevention and to the treatment of stable diseases or symptoms. It should also be noted that the amount of the compound of the present invention necessary for use in treatment will vary depending on the nature of the condition to be treated, the age and condition of the patient, and ultimately depends on the decision of the attending physician or veterinarian. However, usually the doses used to treat adults are in the range of 0.001 mg / kg to about 100 mg / kg per day. The desired dose can be either in the form of a single dose, or it can be divided into individual doses taken at appropriate intervals, for example, as two, three, four or more fractions of the dose per day.

 The present invention also provides novel pharmaceutical compositions of the compounds of formula (I). Although it is possible that the compounds of the present invention can be taken for therapeutic purposes simply as a chemical preparation, it is preferred that the active ingredient is in the form of a pharmaceutical composition. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) should be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and should not harm the recipient.

 The compositions of the present invention can be administered by standard methods for the treatment of these diseases, for example, orally, parenterally, sublingually, transdermally, rectally, by the cheek or by inhalation. For oral administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner. For example, tablets or capsules for oral administration may contain conventional excipients, such as binding agents (e.g., syrups, acacia, gelatin, sorbitol, tragacanth, plant starch, or polyvinylpyrrolidone), excipients (e.g., lactose, sugar, microcrystalline cellulose, corn starch , calcium phosphate or sorbitol), lubricants (e.g. magnesium stearate, stearic acid, talc, polyethylene glycol or dioxide, silicon), disintegrants (e.g. potato starch or sodium starch glycolollate) or wetting other agents such as sodium lauryl sulfate. The tablets may be coated in accordance with methods known to those skilled in the art.

 In another embodiment, the compounds of the present invention can be included in liquid preparations for oral administration, such as, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. In addition, compositions containing these compounds may be in the form of dry products intended for dilution with water or other suitable carriers before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lectin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oil esters, propylene glycol or ethyl alcohol, and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.

 Such preparations can also be prepared in the form of suppositories, for example containing conventional suppository bases, such as cocoa butter and other glycerides. Compositions for inhalation can usually be prepared in the form of solutions, suspensions or emulsions, which can be taken in the form of a dry powder or in the form of aerosols using convenient propellants, such as dichlorodifluoromethane or trichlorofluoromethane. Typical transdermal compositions include conventional aqueous or non-aqueous vehicles, such as creams, ointments, lotions, or pastes, or may be in the form of medical plasters, patches, or membranes.

 In addition, the compositions of the present invention can be prepared for parenteral administration by injection or continuous infusion. Compositions for injection may be in such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain pharmaceutically acceptable agents such as suspending, stabilizing and / or disintegrating agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (eg, sterile, pyrogen-free water) before use.

 The compositions of the present invention can also be formulated as sustained release formulations. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the present invention can be prepared together with suitable polymeric or hydrophobic materials (such as, for example, emulsions in a suitable oil), ion exchange resins, or weakly soluble derivatives, such as, for example, slightly soluble salts.

 The biological activity of the compounds of formula (I) is evaluated in accordance with the following schemes, the results of which are given below. In particular, the compounds of formula (I) can be evaluated in relation to their profiles of osteoprotective activity and anti-uterotrophic activity using the methods outlined in the following schemes.

It should be clear to those skilled in the art that some suitable rat estrogen receptor binding assay variants are known and available for initial screening of the compounds of the present invention with respect to their ability to bind the corresponding receptors. Compounds are first evaluated as described further in rat rat estrogen receptor binding assays for their ability to inhibit [ ³ H] -estradiol binding. Compounds that exhibit an IC ₅₀ <10 μM are sent for in vitro functional analysis of estrogenic activity against the human endometrial cell line Ishikava (Ishikava), as set forth below.

Ishikava-Var subconfluent cells are removed from growth-promoting conditions and resuspended in phenol-free red DMEM-F12 containing 5% purified charcoal FBS and 2 mM glutamine at a concentration of 58500 cells / ml. Cells are seeded at a density of 13,000 cells / cm ² and placed in an incubator (37 ^° C, 5% CO ₂ ) for 3 days. Cells are harvested and resuspended in phenol-free red DMEM-F12 containing 1% purified charcoal FBS, 2 mM glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin at a concentration of 83,000 cells / ml. Cells are seeded at a density of 8300 cells / cell in 96-well plates and left to attach overnight. Add appropriate drug treatment in 2 X concentrations in 0.1 ml of medium containing 0.2% DMSO. The plates are incubated for 2 days, the medium is aspirated and the plates washed once with 300 μl of 0.9% sterile brine. The plates are frozen at -70 ^{° C.} and then warmed to room temperature. Attached cells are analyzed for alkaline phosphatase activity by adding 200 μl of 5 mM p-nitrophenyl phosphate in 1 M diethanolamine, pH 10.4, containing 0.1% (w / v) Triton X-100, incubating at 37 ^o C for 30 minutes and measuring absorbance at 405 nm on a Molecular Devices ThermoMax plate reader.

The compounds of the present invention are analyzed, as described above, in order to evaluate their ability to induce the expression of alkaline phosphatase, an in vitro reaction specific for estrogen agonists, which has been shown to correlate with the in vitro uterotrophic reaction of estrogen agonists in rats. In the table below, the results are expressed as the concentration of various representative compounds of the present invention, which causes 50% of their maximum activity of alkaline phosphatase (E _max ), and the maximum activity is expressed as a percentage of the activity of alkaline phosphatase caused by a saturating concentration of estradiol. Additional studies have shown that all compounds in which E _max was <20% act as estradiol antagonists at concentrations that reflect their similarity to receptor binding.

It was found that compound 1 binds to the estrogen receptor with an approximately 10-fold greater affinity than tamoxifen, which shifts it to lower EC ₅₀ in the functional analysis of Ishikawa cells (see table). In addition, compound 1 has a significantly lower agonistic activity (E _max ) than tamoxifen. A number of amide analogs of compound 1 were evaluated in order to establish structural requirements for lowering the EC ₅₀ and minimizing E _max in Ishikawa functional analysis. The results show that a wide range of structural differences (lyophilicity, steric bulk, donors and acceptors of H-bonds) is possible in this range of molecules, and only volumetric compound 12 shows a reduced affinity for the receptor. Compound 1 shows the highest affinity in the receptor binding assay and has the lowest EC ₅₀ in the functional assay, however, when analyzing the results for E _max , compounds 9, 14 and 15 show the lowest residual agonistic activity.

In order to evaluate the compounds presented earlier with respect to their in vivo anti-uterotrophic activity, groups of five 21 day old female SD rats (30-35 g) were weighed and weights were recorded for each treatment group, as shown in FIG. 1. Stock solutions (10X) of triphenylethylene analogs in ethanol are diluted with 0.5% methyl cellulose and animals are forced to administer doses of 10 μmol / kg. Estradiol is dissolved in sesame oil and doses of 100 nmol / kg are administered by subcutaneous injection. The animals are dosed for 3 days, and on day 4 they are killed by strangulation of CO ₂ . The bodies are weighed, the uterus is removed, drained and weighed. Results are expressed as uterine weight / body weight ± standard error. The solid boxes represent the results obtained for animals that were given only a test compound. The empty rectangles represent the results obtained for animals to which test compounds were administered 6 hours before a dose of estradiol. Compounds 9 and 15 show a residual agonistic activity that is less than that of tamoxifen.

 As an example of the functional profile of these compounds in relation to bone tissue, compound 9 was evaluated for 90 day old estrogen deficient rats after ovarectomy by their ability to inhibit a decrease in bone density. 90 day old SD rats were divided into groups of 6. Three groups were surgically removed from the ovaries. 2 days after ovarectomy, the animals were forcibly injected with either 10 μmol / kg of compound 9 in 0.5% methylcellulose, or the vehicle once a day for 28 days. One group underwent a simulation of the operation and 2 days after the operation, the carrier was administered once a day for 28 days. On days 0, 14, and 28, rats were anesthetized with isoflurane and placed in a supine position, their backs being parallel to the long axis of the densitometric table. The lumbar spine was scanned using the pelvic bones as a mark. To scan the right tibia, the paw was fixed in a position parallel to the long axis of the table and scanned until it joined the thigh. Lumbar spine analyzes were performed by dividing the vertebral and intervertebral spaces using normal analytical programs and including only target vertebrae in the entire area of interest. The right tibia was analyzed using high-resolution subregional programs, focusing 3-5 mm to the periphery of the growth plate, previously identified as the site of accelerated bone loss associated with ovarectomy. Results on days 14 and 28 did not differ significantly. The results obtained on day 28 are presented in figure 2. In FIG. 2, an oral dose of 10 μmol / kg of Compound 9 demonstrates complete agonistic activity, maintaining BMD at levels for the rats undergoing simulated surgery over 28 day studies. The results of biochemical analysis show that the mechanism of action is due to inhibition of bone resorption, which corresponds to their activity as estrogen agonists in bone tissue. BMD is determined using dual energy fluoroscopic absorptiometry using a Hologic QDR-2000 bone densitometer and a regional high-resolution software package with boundary scan length, width, line position and dot resolution of 5.2705, 0.0254 and 0.0127 cm, respectively.

Claims (15)

1. Derivatives of triphenylethylene of the formula (I)

where R ¹ represents - (CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; - (CH ₂ ) _m C (X) NR ⁸ R ⁹ or

R ² and R ³ independently represent H, —CH ₃ , —OH, —OCH ₃ , —OCH ₂ CH _3, or —CH (CH ₃ ) ₂ ;
R ⁴ is —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ —Y or —Y;
R ⁵ and R ⁶ independently represent H, —C _1-4 alkyl, —C _2-4 alkenyl, —C _2-4 alkynyl, —XC _1-3 alkyl, —X — C _2-4 alkenyl, —X — C _2-4 alkynyl or -Y;
R ⁷ is —CN, —C _1-4 alkyl-OH, —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , —C _1-4 alkyl-NR ¹⁰ R ¹¹ , —C ( O) OR ¹² or oxadiazole substituted with methyl;
R ⁸ and R ⁹ independently represent hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —O — C _1-7 alkyl, —C _1-7 alkyl-Y;
R ¹⁰ and R ¹¹ independently represent methyl or ethyl;
R ¹² and R ¹³ independently represent H, —C _1-12 alkyl, —C _2-12 alkenyl, —C _2-12 alkynyl, —O — C _1-12 alkyl, —O — C _2-12 alkenyl, —O —C _2-12 alkynyl, —C _3-7 cycloalkyl, —C _3-7 cycloalkenyl or —Y;
X represents oxygen;
Y represents halogen;
n represents an integer selected from 0, 1 or 2;
m represents an integer of 1 or 2;
p represents an integer from 1 to 4,
with the proviso that when R ⁴ is —CH ₂ CH ₃ , R ² and R ³ are not both hydrogens.  2. The compound of claim 1, wherein X is O. 3. The compound of claim 2, wherein R ¹ is - (CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ . 4. The compound of claim 1, wherein R ² and R ^{3 are} independently selected from H, —OH, or —OCH ₃ . 5. The compound according to claim 4, where R ² and R ³ represent N. 6. The compound of claim 1, wherein R ⁴ is either —CH ₃ , —CH ₂ CH ₃ , or —CH ₂ CH ₂ —Cl. 7. The compound of claim 1, wherein R ⁵ and R ⁶ independently represent H or —C _1-4 alkyl. 8. The compound of claim 1, wherein R ⁸ and R ⁹ independently represent hydrogen, —C _1-7 alkyl, or —C _3-7 cycloalkyl. 9. The compound of claim 1, wherein R ⁷ is —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ^13, or —C (O) OR ¹² . 10. The compound of claim 1, wherein R ¹² and R ¹³ independently represent H, —C _1-12 alkyl, —C _2-12 alkenyl. 11. The compound of claim 1, wherein the compound is selected from one of the following:
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylpropionamide;
2- [4- (1,2-diphenylbut-1-enyl) phenyl] cyclopropanecarboxylic acid diethylamide;
3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diesel-2-methylacrylamide;
3- [4- (1,2-diphenylbut-1-enyl) phenyl] but-2-enoic acid diethylamide;
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid methyl ester;
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylonitrile;
tert-butyl ether
3- [4- (1,2-diphenylbut-1-enyl) phenyl] acrylic acid;
1-amino-3- [4- (1,2-diphenylbut-1-enyl) phenyl] prop-2-en-1-one-oxime;
3- {2- [4- (1,2-diphenylbut-1-enyl) phenyl] vinyl} -5-methyl- [1,2,4] oxadiazole;
3- [4- (1,2-diphenylbut-1-enyl) phenyl] prop-2-en-1-ol;
{3- [4- (1,2-diphenylbut-1-enyl) phenyl] allyl} dimethylamine or 3- [4- (1,2-diphenylbut-1-enyl) phenyl] -N, N-diethylthioacrylamide.  12. A method of treating osteoporosis in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1.  13. A method for preventing osteoporosis in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1. 14. A method of treating breast cancer or cardiovascular disease in a mammal, comprising administering to said mammal an effective amount of a compound of formula I

where R ¹ represents - (CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; - (CH ₂ ) _m C (X) NR ⁸ R ⁹ or

R ² and R ³ independently represent H, —CH ₃ , —OH, —OCH ₃ , —OCH ₂ CH _3, or —CH (CH ₃ ) ₂ ;
R ⁴ is —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ —Y or —Y;
R ⁵ and R ⁶ independently represent H, —C _1-4 alkyl, —C _2-4 alkenyl, —C _2-4 alkynyl, —XC _1-3 alkyl, —X — C _2-4 alkenyl, —X — C _2-4 alkynyl or -Y;
R ⁷ is —CN, —C _1-4 alkyl-OH, —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , —C _1-4 alkyl-NR ¹⁰ R ¹¹ , —C ( O) OR ¹² or oxadiazole substituted with methyl;
R ⁸ and R ⁹ independently represent hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —O — C _1-7 alkyl, —C _1-7 alkyl-Y;
R ¹⁰ and R ¹¹ independently represent methyl or ethyl;
R ¹² and R ¹³ independently represent H, —C _1-12 alkyl, —C _2-12 alkenyl, —C _2-12 alkynyl, —O — C _1-12 alkyl, —O — C _2-12 alkenyl, —O —C _2-12 alkynyl, —C _3-7 cycloalkyl, —C _3-7 cycloalkenyl or —Y;
X represents oxygen;
Y represents halogen;
n represents an integer selected from 0, 1 or 2;
m represents an integer of 1 or 2;
p represents an integer from 1 to 4. 15. A method for the prevention of breast cancer or cardiovascular disease in a mammal, comprising administering to said mammal an effective amount of a compound of formula I

where R ¹ represents - (CH ₂ ) _n CR ⁵ = CR ⁶ R ⁷ ; - (CH ₂ ) _m C (X) NR ⁸ R ⁹ or

R ² and R ³ independently represent H, —CH ₃ , —OH, —OCH ₃ , —OCH ₂ CH _3, or —CH (CH ₃ ) ₂ ;
R ⁴ is —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CH ₂ —Y or —Y;
R ⁵ and R ⁶ independently represent H, —C _1-4 alkyl, —C _2-4 alkenyl, —C _2-4 alkynyl, —XC _1-3 alkyl, —X — C _2-4 alkenyl, —X — C _2-4 alkynyl or -Y;
R ⁷ is —CN, —C _1-4 alkyl-OH, —C (O) NR ¹⁰ R ¹¹ , —C (O) NR ¹² R ¹³ , —C _1-4 alkyl-NR ¹⁰ R ¹¹ , —C ( O) OR ¹² or oxadiazole substituted with methyl;
R ⁸ and R ⁹ independently represent hydrogen, —C _1-7 alkyl, —C _3-7 cycloalkyl, —O — C _1-7 alkyl, —C _1-7 alkyl-Y;
R ¹⁰ and R ¹¹ independently represent methyl or ethyl;
R ¹² and R ¹³ independently represent H, —C _1-12 alkyl, —C _2-12 alkenyl, —C _2-12 alkynyl, —O — C _1-12 alkyl, —O — C _2-12 alkenyl, —O -C _2-12 alkynyl; -C _3-7 cycloalkyl; -C _3-7 cycloalkenyl; or -Y;
X represents oxygen;
Y represents halogen;
n represents an integer selected from 0, 1 or 2;
m represents an integer of 1 or 2;
p represents an integer from 1 to 4.

Images