MXPA00011178A - 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens - Google Patents

Abstract

The present invention relates to new formulations containing one or more estrogens and 2- phenyl- 1-[4- (2-aminoethoxy)benzyl]-Indole compounds which are useful as estrogenic agents, as well as pharmaceutical compositions and methods of treatment utilizing these compounds, which have general structures (I) or (II).

Description

2-PHENYL-1-T4- (2-AMINOETOXY) -BENCIL] -INDOL IN COMBINATION WITH ESTROGENS DESCRIPTION OF THE INVENTION The present invention relates to the use of novel 2-phenyl-l- [4- (2-aminoethoxy) -benzyl] -indole compounds which are useful as estrogenic agents, together with estrogens, as well as with pharmaceutical compositions and methods of treatment using these compounds.

BACKGROUND OF THE INVENTION The use of replacement hormone therapy to prevent bone loss in postmenopausal women is well-founded. The usual protocol requires estrogen supplementation using formulations containing estrogan, estriol, ethinylestradiol, 17β-estradiol, esterified estrogens or conjugated estrogens isolated from natural sources (eg conjugated estrogens PremarinME from Wyeth-Ayerst) or synthetic estrogens. In some patients the therapy may be contraindicated due to the unopposed estrogen proliferative effects (estrogens that are not supplied in combination with progestins) and that are found on uterine tissue. This proliferation is Ftef: 124346"! - -" • 'nor mii? associated with an increased risk of endometriosis or endometrial cancer, or both. The effects of non-opposite estrogens on breast tissue are less clear, but they are often worrisome. The need for estrogen is evident, which can maintain a bone sparing effect and at the same time minimize the proliferative effects on the uterus and the breasts. It has been shown that certain non-steroidal antiestrogens maintain bone mass in the ovariectomized rat model as well as in human clinical trials. Tamoxifen (sold as the brand of tamoxifen citrate Novadex ™ by Zeneca Pharmaceuticals, Wilmington, Delaware) for example is a useful palliative for the treatment of breast cancer and has been shown to exert an effect similar to estrogen agonist in bone, in humans . However, it is also a partial agonist in the uterus and is the cause of some concern. It has been shown that raloxifene, a benzothiophene antiestrogen stimulates uterine growth in ovariectomized rats to a lesser degree compared to tamoxifen and at the same time maintains the ability to save bone. An adequate review of tissue selective oestrogens is observed in the article "Tissue-Selective Actions of Estrogen Analogs", Bone Vol. 17, No. 4 of October 1995, 181S-190S. The use of Índles as estrogen antagonists has been reported by Von Angerer, Chemical Abstracts, Vol. 99, No. 7, (1983), Extract No. 53886u. See also, J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. 1987, 30, 131-136. See also Gerl Offen., DE 3821148 Al 891228 and WO 96/03375. These compounds of the prior art share structural similarities with the present compounds, but are functionally different. For compounds containing a basic amine, there is no phenyl group that stiffens the side chain. WO A 95 17383 (Karo Bio AB) describes indole antiestrogens with long straight chains. Another related patent, WO A 93 10741 describes 5-hydroxyindoles with a wide range of side chains. WO 93/23374 (Otsuka Pharmaceuticals, Japan) discloses compounds that share structural similarities with those of the present invention, except with the structure referred to as R3 in the present formulas I and II, in the following, the which is defined as thioalkyl and in the reference no such compounds are described with chains from the indole nitrogen having the same structure as those provided by the present invention. In the postmenopausal article Hormone replacement therapy wi th is trogen peri odi cal and s uppl emen ted wi th antiestrogen, Am. J. Obstet. Gynecol. , Vol. 140, No. 7, 1981, pp. 787-792, Kauppila et al. describe their postmenopausal estrogen therapy study of seven estrogen regimens weeks followed by treatments for 10 days with the antiestrogen clomiphene citrate. In addition, in his article Comparison of Megestrol Acétate and Clomiphene Ci treat as Supplemental Medication in Postmenopausal Oestrogen Replacement Therapy, Arch. Gynecol. (1983) 234: 49-58, Kauppila et al. describe combination therapies in postmenopausal women with estrogen and with random supplementation of megestrol acetate or clomiphene citrate. U.S. Patent No. 4,894,373 (Young) describes the use of antiestrogens, including clomiphene and its isomers, citrates and derivatives, in the absence of estrogen to treat menopausal symptoms and treat or prevent osteoporosis. U.S. Patent No. 5,552,401 (Cullinan et al.) Discloses benzothiophene compounds as being useful for the treatment of various medical indications associated with postmenopausal syndrome and uterine fibroid disease, endometriosis and proliferation of smooth muscle cells in the aorta , the compounds are used in pharmaceutical formulations that optionally contain estrogen and progestin. U.S. Patent Nos. 5,646,137 and 5,591,753 (both issued to Black et al.) Describe methods of treating osteoporosis with formulations of arylbenzothiophene compounds of the raloxefin type together with a progestin selected from medroxyprogesterone, norethindrone or norethinodrel, or a pharmaceutically acceptable salt thereof. U.S. Patent No. 5,550,107 (Labrie) claims an invention comprising the treatment of breast or endometrial cancer with an antiestrogen together with at least one compound selected from the group of an androgen, a progestin, at least an inhibitor of the formation of sex steroids, especially 17β-hydroxysteroid dehydrogenase and aromatase activity, at least one inhibitor of prolactin secretion, an inhibitor of growth hormone secretion and an inhibitor of ACTH secretion. U.S. Patent No. 5,672,609 (Bryant et al.) Discloses pyridine compounds useful in treating postmenopausal syndrome and formulations that therefore contain estrogen or progestin. U.S. Patent No. 5,534,527 (Black et al.) Describes the use of aroylbenzothiophenes and oestrogens in the inhibition of bone loss.

DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical formulations and methods for using them, comprising compounds of formulas (I) and (II), in the following, together with estrogens, preferably together with one or more pharmaceutically acceptable carriers or excipients. Among the uses of present formulations are alleviating the symptoms of post-menopausal syndrome in women, which include per-menopausal and post-menopausal symptoms. The present formulations and methods of treatment can be used to mimic undesirable side effects of estrogen treatment or therapy and can be used to minimize the amounts of estrogen needed for a particular regimen. Compounds of the general structure type shown in formulas (I) and (II) are estrogen agonists / antagonists useful for the treatment of diseases associated with estrogen deficiency and are described in EP-A-0802183 published on October 22, 1997, whose content is incorporated herein by reference. The compounds are able to antagonize the effects of 17β-estradiol and at the same time show little uterine stimulation when dosed alone. The present invention includes, together with one or more estrogens, the use of compounds of formulas (I) or (II), in the following: (I) (II) wherein: Rx is selected from H, OH or the esters of Cj-C ^ (straight or branched chain) or C? -C12 alkyl ethers (straight or branched chain or cyclic) thereof, or halogens; or halogenated ethers of Ci-C.1 including trifluoromethyl ether and trichloro ethyl ether. R2, R3, R4, R5 and R6 are independently selected from H, OH or C1-C12 esters (straight or branched chain) or Cj-Cu alkyl ethers (straight or branched chain, or cyclic) of the Halogens, or halogenated ethers of C ^ -C, including trifluoromethyl ether or trichloromethyl ether, cyano, CJ-CJ alkyl (straight or branched chain) or trifluoromethyl, with the proviso that when Rj is H, R2 is not OH .

X is selected from H, C 1 -C 4 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 2 or 3; And it is selected from: a) the portion: R7 and Rβ are independently selected from H, C ^ Cj alkyl or phenyl optionally substituted by CN, C1-C6 alkyl (straight or branched chain), Cj-C6 alkoxy (straight or branched chain), halogen, -OH , -CF3, or -OCF3; or R, and R8 are concatenated together as - (CH2) p-, where p is an integer from 2 to 6, preferably 4 to 6, the ring formed in this way is optionally substituted with 1-3 substituents which are selected of alkyl of Cj-Cj, trifluoromethyl, halogen, hydrogen, phenyl, nitro and -CN; b) a saturated, unsaturated or partially unsaturated five-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (C ^ C alkyl,) -, -N =, and -S (0) -, where m is an integer of 0-2, optionally substituted with 1-3 substituents which are independently selected from hydroxyl, halo, C 1 -C 6 alkyl, trihalomethyl, Ci-C alkoxy, trihalomethoxy, C 1 C acyloxy, C 1 C alkylthio, C 1 C alkylsulfonyl, hydroxyalkyl C ^ C ,, -C02H, -CN-, -CONHRi-, -NH2, Ci-C ,, alkylamino, (C1-C4) dialkylamino, -NHS02R1 # -NHCORj, -N02 and phenyl optionally substituted with 1- 3 alkyl of Cj-C ,,, where ^ is as defined above, or Cj-Cj alkyl, - c) a saturated, unsaturated or partially unsaturated six-membered heterocycle containing up to 2 heteroatoms which are selected of the group consisting of -O-, -NH-, -N (Cj-C alkyl, -N = and -S (0) "-, where m is an integer of 0-2, optionally substituted with 1 -3 substituents which are independently selected from the group consisting of hydrogen, hydroxyl, halo, C 1 -C 4 alkyl, trihalomethyl, C 4 alkoxy, trihalomethoxy, C 1 -C 6 acyloxy, C 1 -C 12 alkylsulfinyl alkylthio C4, alkylsulfonyl of -C ,, hydroxyal of -C, -C02H, -CN-, -CONHRj-, -NH2-, C 1 -C 4 alkylamino, dialkyl (^^ 4) amino, - HSOjRi-, -NHCORj-, -N02, and phenyl optionally substituted with 1-3 alkyl of -C ,; d) a seven-membered, saturated, unsaturated or partially unsaturated heterocycle containing up to two heteroatoms selected from the group consisting of -O-, -NH-, -N (Cj-C- alkyl, -N =, and -S (0) m-, where m is a 0-2 whole number, optionally substituted with 1-3 substituents which are independently selected from the group consisting of hydrogen, hydroxyl, halo, alkyl, trihalomethyl, Cj-C ^ trihalomethoxy alkoxy, C ^ C acyloxy Alkylthio of C ^ Cj, alkylsulfinyl of ^ ^, alkylsulfonyl of CJ-CÍ, hydroxyalkyl of Cj-C ,, -C02H, -CN, -CONHR! -, -NH2, alkylamino of C, - ^ dialkyl (Ci- C amino, -NHSOjR ,, - HCOR !, -N02 and phenyl optionally substituted with 1-3 alkyl of e) a bicyclic heterocycle containing 6-12 carbon atoms either bridging or fused and containing up to two heteroatoms which are selected from the group consisting of -O-, -NH-, -Nalkyl of Cj-) -, and -S (0) m-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents that are independently selected from the group consisting of hydrogen, hydroxyl, halo, Ci-Ca alkyl, trihalomethyl , C 1 -C 4 alkoxy, trihalomethoxy, C 1 -C 6 acyloxy, C 1 -C 4 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 hydroxyalkyl, -C 0 2 H, -CN , -CONHR ,, -NH2, C 1 C, C 1 -C alkyl dialkylamino, -NHS02R1 (-NHCORlf -N02 and phenyl optionally substituted with 1-3 C 1 Cj alkyl, - and pharmaceutically acceptable salts of the same.

The most preferred formulations of this invention are those having, together with one or more pharmaceutical carriers or excipients: a) one or more estrogens; and b) one or more compounds that are selected from general structures I or II, above, in which: R-! is selected from H, OH or the Cx-C12 esters or alkyl ethers thereof, halogen; R2, R3, R1; R5 and R6 are independently selected from H, OH or the C ^ C ^ esters or alkyl ethers thereof, halogen, cyano, Cj-Cj alkyl or trihalomethyl, preferably trifluoromethyl, with the proviso that when R! is H, R2 is not OH; X is selected from H, C1-C6 alkyl, cyano, nitro, trifluoromethyl, halogen; And it's the portion X * ' R7 and Ra are independently selected from H, Cl-C6 alkyl or, combined with - (CH2) p-, where p is an integer from 2 to 6, so as to form a ring, the ring is optionally substituted by up to 3 substituents selected from the group of hydrogen, hydroxyl, halo, C 1 -C 4 alkyl, trihalomethyl, C 1 d alkoxy, trihalomethoxy, C 4 alkylthio, C 1 C 2 alkylsulfinyl, alkylsulfonyl of Ci-C ,, hydroxyalkyl of C ^ C ,, -C02H, -CN, -CONH (alkyl of Cj-Ct), -NH2, alkylamino of Cj-C., dialkylamino of dC. ,, -NHS02 (alkyl) of C ,, -C4), -NHCO (C1-C4 alkyl) and -N02; and the pharmaceutically acceptable salts thereof. The rings formed by concatenated R, and Rβ, mentioned above, may include, but are not limited to aziridine, azetidine, pyrrolidine, piperidine, hexamethylenamine 0 heptamethylene-amine rings. The most preferred compounds of the present formulations are those that have structural formulas 1 or II above, wherein Rx is OH; R2-R6 are as defined above; X is selected from the group of Cl, N02, CN, CF3, or CH3; and Y is the portion »» - «--- -numt ^^. and R7 and R8 are concatenated together as - (CH2) r-, where r is an integer from 4 to 6 to form a ring optionally substituted by up to 3 substituents which are selected from the group of hydrogen, hydroxyl, halo, alkyl, C 1 -C 4, trihalomethyl, C 1 -C 4 alkoxy, trihalomethoxy, C 1 -C 4 alkylthio, C 1 C 4 alkylsulfinyl, C 1 C alkylsulfonyl, C 1 -C 6 hydroxyalkyl, -C 0 2 H, -CN, -CONH (C ^ C alkyl, -NH2, alkylamino of ^ -04, dialkylamino of CJ-CÍ, NHS02 (C ^ C alkyl,), -NHCO (C1-C4 alkyl) and -N02; and pharmaceutically acceptable salts In another embodiment of this invention, when R7 and R8 are concatenated together as - (CH2) p-, where p is an integer from 2 to 6, preferably from 4 to 6, the ring formed in this way optionally it is substituted with 1-3 its isomers which are selected from C1-C2 alkyl, trifluoromethyl, halogen, phenyl, nitro and -CN.The invention includes sulfate, sulfamates and sulfate esters of groups f The sulphates can be prepared easily by the reaction of the free phenolic compounds with sulfur trioxide forming complexes with an amine such as pyridine, trimethylamine, triethylamine, etc. The sulfamates can be prepared by treatment of the free phenolic compound with the desired amino or alkylamino or dialkylaminosulfamyl chloride in the presence of a suitable base such as pyridine.

The sulfate esters can be prepared by reaction of the free phenol with the desired alkanesulfonyl chloride in the presence of a suitable base such as pyridine. Additionally, this invention includes compounds containing the phosphates in the phenol as well as dialkyl phosphates. The phosphates can be prepared by reaction of the phenol with the appropriate chlorophosphate. The dialkyl phosphates can be hydrolyzed to provide the free phosphates. Phosphinates are also claimed wherein the phenol is reacted with desired dialkylphosphonic chloride to provide the desired dialkyl phosphinate of the phenol. The invention includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids. Inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid are useful. , succinic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid. It is known that compounds possessing a basic nitrogen can form complexes with many different acids (both protic and non-protic) and it is usually preferred to administer a compound of this invention in the form of an acid addition salt.

Additionally, this invention includes quaternary ammonium salts of the compounds herein. These can be prepared by reacting nucleophilic amines of the side chain with a suitable reactive alkylating agent such as alkyl halide or benzyl halide. The compounds used in this invention are prepared by a process which comprises one of the following: a) reacting a compound of formula wherein n, R and X are as defined in the above and hal is chloro or bromo, with a compound of the formula: HNR7Rß wherein R7 and R8 are as defined above, to provide a corresponding compound of formula I or II; or b) reacting a compound of the formula: wherein Rj-R ,, and X are as defined in the above, in the presence of a base, for example NaH with a compound of formula wherein n, R5, R6 and Y are as defined above and hal is halogen, for example Cl or Br, to provide a corresponding compound of formula I, if necessary, protect any reactive substituent group during each preceding process and remove it, - and if desired, convert a phenolic group present to a phosphate, sulfate, sulfamate or sulfate ester; and, if desired, converting the compound of formula I or II to a pharmaceutically acceptable salt.

Methods The compounds of this invention can be synthesized in a general sense according to Reaction Scheme 1, below.

Reaction scheme 1 NaH, DMF The initial indole synthesis is carried out by heating an α-bromo-ketone (b) appropriately substituted with the desired aniline (a) in DMF to form the indole (c). The product is then alkylated with benzyl chloride (e) to provide the substituted (f) indole. Benzyl chloride (e) can be easily prepared from 3 not substituted with chlorosulfonyl isocyanate, followed by tetylamine. A compound of the nitro group in position 3 can be prepared by treatment of the mdol with sodium nitrite and acetic acid. One skilled in the art recognizes that these routes are not limiting and that other routes are also available.

Reaction scheme 2 3 - . 3 -Deproteger 1-Protect nitrogen nitrogen 2-Functionalize position 4 -Add chain 3 with -X lateral The synthesis of the selected representative examples are provided in the following schemes: Reaction scheme 3 s- ~ rc? a ^ '^ -'. ^ The synthesis of the analogs with a 3 carbon chain (example No. 166) between the oxygen and the basic amine can be carried out as shown in reaction scheme 4.

Reaction scheme 4 EtOH / THF The synthesis procedure shown in the Reaction Scheme 4 can be used for compounds with two carbon chains analogous to Example No. 97 in Reaction Scheme 3. This is shown in Reaction Scheme 4 for the synthesis of Example No. 127.

Reaction diagram 4th CAS # [20886-03-7] CAS # [51388-20-6] Example No.17 Synthesis of indoles with alternative substituents (CN, Cl) at position 3 of indole use both 3-unsubstituted indole No. 141 for a precursor. Indole is synthesized by the Fisher Method using the hydrazone derived from the condensation of 4-benzyloxyacetophenone CAS No. [54696-05-8] and 4-benzyloxyphenylhydrazine CAS No. [51145-58-5]. Hydrazone No. 140 is then cyclized in acetic acid using zinc chloride to provide the desired indole No. 141. This synthesis can be seen in Reaction Scheme 5.

Reaction scheme 5 Example No. 141 The synthesis of the 3-chloroindole compounds is demonstrated for Example No. 134 and is shown below in Reaction Scheme 6. Indole No. 141 of Reaction Scheme 5 is chlorinated with N-chlorosuccinamide. The 3-chloroindole No. 142 obtained in this way is taken to the final product in a manner analogous to that shown in Reaction Scheme 3.

Reaction scheme 6 Example No. 141 Example No. 142 Same stages as in Reaction Scheme 3 The 3-cyano analogs are synthesized from the indole precursor No. 141 as shown in Reaction Scheme 7.

The reaction of the indole precursor No. 141 with chlorosulfonyl isocyanate followed by the addition of triethylamine provides 3-cyanoindole No. 155. The side chain is produced by conversion of a benzyl alcohol of CAS No. [111728-87-1] to a benzyl bromide No. 156 using thionyl bromide in THF. The indole is alkylated by the side chain in DMF using sodium hydride to provide the intermediate No. 157. This can then be taken for the final product No. 138 in a manner analogous to that shown in Reaction Scheme 4.

Reaction scheme 7 Example No. 141 Example No. 155 2-Et3N [111728-87-1P] Example No. 156 NaH DMF Example No. 138 Compounds 3e formulas (I) and (II) are partial estrogen agonists and show high affinity for the estrogen receptor. However, unlike many estrogens, these compounds do not cause increases in wet uterine weight. These compounds are antiestrogenic in the uterus and can completely antagonize the trophic effects of estrogen agonists in uterine tissue. These compounds are useful for treating or preventing morbid states in mammals or syndromes which are caused or associated with an estrogen deficiency. This tissue selectivity allows its use for desirable estrogenic activity in certain tissues, such as bone, and at the same time limits this activity in others, for example as uterine tissue. Estrogens useful in the formulations of this invention include estrone, estriol, equilin, estradiene, equilenin, eti ni 1 is radiol, 17 β-estr adi ol, 17a-dihydroequilenin, 17β-dihydroequilenin (U.S. Patent No. 2,834,712), 17a-dihydroequilin, 17β-dihydroequilin, menstranol, and conjugated estrogenic hormones such as the products of Premarin "* from Wyeth-Ayerst Laboratories 1. Also, phytoestrogen methods such as equol or enterolactone can be used in the present formulations and a preferred embodiment of this invention. comprises pharmaceutical compositions and methods of treatment using conjugated estrogenic hormones such as those of the products Premarin "" from Wyeth Ayerst Laboratories with 1 or more compounds of formula (I) or (III) included herein. Estergenic esters, such as those sold by "olvay Pharmaceuticals Inc." under the tradename Estratab "" can also be used with the present formulations. Salts of the applicable estrogens are also preferred for the use of the present invention, more preferably sodium salts. Examples of these preferred salts are estrone sodium sulfate, equilin sodium sulfate, sodium alkale dihydroequiline sulfate, sodium 17alpha-estradiol sulfate, delta 8, 9-sodium dehydroestrone sulfate, sodium equilenin sulfate, 17beta dihydroequiline sulfate sodium, 17alpha dihydroequilenine sodium sulfate, 17beta-estradiol sodium sulfate, 17beta-dihydroequilenine sodium sulfate, estrone sodium 3-sulfate, equilin 3 sodium sulfate, 17alpha-dihydroequiline 3-sodium sulfate, 3beta hydroxyster 5 (10 ), 7-dien-17-one-3-sodium sulfate, 5alpha-Pregnan-3beta-20R-diol 20-sodium sulfate, 5alpha-Pregnan-3beta, 16alpha-diol-20-one-3-sodium sulfate, delta (8, 9) -dehydroestrone 3-sodium sulfate, estra-3beta, sodium 17alpha-diol 3 -sulfate, 3beta-hydroxystr-5 (10) -en-17-one-3-sodium sulfate, or 5alpha- Pregnan-3beta, 16alpha, 20R-triol 3-sodium sulfate. Preferred salts of estrone include, but are not limited to, the sodium and piperate salts.

The present compounds of formulas (I) and (II) are tissue-selective compounds and have the ability to behave as estrogen agonists, for example by lowering cholesterol and preventing bone loss., or as estrogen antagonists. Therefore, these compounds in the present formulations are useful for treating many discomforts including osteoporosis, prostatic hypertrophy, infertility, breast cancer, endometrial hyperplasia, endometrial cancer, endometriosis, cystic glandular hyperplasia, uterine hyperplasia, cervical hyperplasia, benign prostatic hyperplasia , cardiovascular disease, contraception, Alzheimer's disease and melanoma. The formulations of this invention can also be used to treat bone loss resulting from secondary osteoporosis, including that categorized as endocrine in nature, including that resulting from glucocorticoid excess, hyperparathyroidism, hyperthyroidism, hypogonadism, hyperprolactinemia and diabetes mellitus. Bone loss can also be induced by medications such as that resulting from heparin treatments, alcohol consumption or the use of tobacco, barbiturates or corticosteroids. Drug-induced bone loss may also be the basis for treatment with gonadotropin-releasing hormone (GnRH or LHRH) or synthetic GnRH antagonists or agonists, such as injectable leuprolide acetate and sold TAP Pharmaceuticals Inc. by LUPRON "", or the goserelin acetate implant sold by Zeneca Pharmaceuticals under the trade name Zoladex "". Such bone loss can also result from the immobilization of chronic individual renal failure, malabsorption syndrome, liver disease, chronic obstructive pulmonary disease, rheumatoid arthritis or sarcoidosis. Additionally, these formulations can be used for hormone replacement therapy in postmenopausal women or in other estrogen deficiency states where estrogen supplementation may be beneficial. The symbiotic activity of the compounds and estrogen or oestrogens of the present methods of treatment are particularly of interest in resolving the undesired consequences of estrogen therapy, such as external bleeding and / or endometrial overstimulation, which can lead to endometrial hyperplasia or endometriosis. Therefore, these formulations can be used in methods to treat or prevent excessive uterine estrogen stimulation in a mammal. The formulations of this invention can also be used in methods of treatment for bone loss, which can result from an imbalance of the individual formation of new bone tissue and the resorption of older tissues, leading to a net loss of bone. Such bone reduction results in a range of individuals, particularly in postmenopausal women, who have experienced hysterectomy / oophorectomy, those who receive or who have received prolonged corticosteroid therapies, those who have experienced adrenal dysgenesis and those who suffer from Cushing's syndrome. Special needs for bone substitution can also be solved by using these formulations in individuals with bone fractures, defective bone structures and those receiving bone-related surgeries and / or prosthetic implantation. In addition to these problems described in the above, these formulations can be used in treatments for osteoarthritis, Paget's disease, osteomalasia, osteoalisteresis, endometrial cancer, multiple myeloma and other forms of cancer that have harmful effects on bone tissues. The methods for treating these diseases included in the above are understood to comprise administering to an individual in need of such treatment a pharmaceutically effective amount of one or more of the compounds of the formulas (I) and (II) or a pharmaceutically acceptable salt of the same, along with a therapeutically desirable amount of an estrogen. This invention also includes pharmaceutical compositions using one or more of the present compounds and / or pharmaceutically acceptable salts thereof, together with one or more carriers, pharmaceutically acceptable excipients, etc. Estrogens regulate many physiological processes. The main target tissues for estrogens include the reproductive tract (ovary, uterus vagina), breast tissue, the skeletal and cardiovascular system as well as the central nervous system (CNS). The reduction in circulating estrogens produces numerous changes. There is a suspension of reproductive function with associated amenorrhea, uterine atrophy and increased vaginal dryness (lack of keratinization). The breast tissue becomes relatively quiescent. There is an increase in the rate of bone loss (2-7%) compared to the normal of 0.5-1.0% / year observed in all individuals over 35. A change in the lipid profile occurs which is increased in low density lipoprotein (LDL) and decreases in commonly measured high density lipoprotein (HDL) and an increased associated risk of a cardiovascular event (heart attack or attack). Changes in the central nervous system include an increase in vasomotor symptoms (flushing) and potential changes in learning and memory. Estrogen replacement therapy (ERT) normalizes some of these changes, particularly those associated with the cardiovascular system (reduced LDL, increased HDL, reduced risk of heart attack), the skeletal system (maintenance of bone mass, reduced risk of fractures). ) and the central nervous system (reduction in the frequency and severity of flushes). Although the reproductive tract He responds, not everything is positive. By the positive side, vaginal dryness is relieved. However, negative uterine responses include hypertrophy and hyperplasia along with some bleeding similar to menstrual bleeding. The breasts are also affected and there are data that correlate exogenous estrogen therapy with an increased risk of breast cancer. Currently, women with intact uteri are generally not prescribed estrogen alone, but estrogen in combination with a progestin to reduce uterine stimulation. Although the risks of endometrial cancer are reduced to treated levels without hormone, the other side effects of progestins reduce compliance in women on hormone replacement. The tissue selective estrogen (TSE) compounds of this invention provide skeletal and cardiovascular positive effects similar to those of estrogens, without the negative effects associated with the uterus and the breasts. The combinations of TSE and estrogen derive the positive effects of estrogen on the CNS, the bone system and the cardiovascular system with the combination that provides complementary or additive effects in the bone and cardiovascular systems. The main variable is the ability of TSEs to block the estrogenic influence in the uterus and breasts, which are the two main negative effects of non-opposite estrogens.

It is understood that the dosage, regimen and mode of administration of these compounds of formulas (I) and (II) will vary according to the discomfort and the individual being treated and will be submitted to the judgment of the practicing physician involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and increase until the desired effects are obtained. Similarly, it will be understood that the dosage or dosages of the estrogen or estrogens used in the present formulations will be selected according to conventional methods. It is further preferred that the dosage will be monitored to obtain the desired result with the minimum of estrogen or estrogen required. The effective administration of these compounds of formulas (I) and (II) can be provided at a dose of about 0.01 mg / day to about 1000 mg / day. Preferably, administration will be from about 1 mg / day to about 600 mg / day in a single dose or in two or more divided doses. More preferably, a daily dose of between about 1 mg / day and about 150 mg / day will be administered. Such doses may be administered in any way useful in directing the active compounds herein to the recipient including the oral, parenteral (including intravenous, intraperitoneal and subcutaneous injections, implants, etc.), intravaginal and transdermal routes.

For the purposes of this description, it is understood that transdermal administrations include all administrations through the body surface and the inner linings of the body conduits including epithelial and mucosal tissues. Such administrations can be carried out using the present compounds or pharmaceutically acceptable salts thereof in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal). Oral formulations containing the active compounds of formulas (I) and (II) can comprise any conventionally used oral form including tablets, capsules, buccal forms, troches, lozenges and liquids, suspensions or oral solutions. The capsules may contain mixtures of the active compound or compounds with inert fillers and / or diluents such as pharmaceutically acceptable starches (eg, starch, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses such as crystalline celluloses and microcrystalline, flours, jellies, gums, etc. Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and diluents, binders, lubricants, disintegrants, suspension-improving agents or pharmaceutically acceptable stabilizers can be used.

These include, but are not limited to, magnesium stearate, stearic acid, talcum, sodium laurisulfate, cellulose, mycitric acid, calcium carboxymethylcellulose, polyvinylpyrrolidone, gelatin, arginic acid, acacia gum, xanthan gum, sodium citrate. , complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dried starches and powdered sugar. Oral formulations herein may use standard formulations of delay or release over time to alter the absorption of the active compound or compounds. Suppository formulations can be made from traditional materials including cocoa butter with or without the addition of waxes to alter the melting point of the suppository and glycerin. The bases of water-soluble suppositories such as polyethylene glycols of various molecular weights can also be used. It will be understood that the estrogen of this invention will be administered in the dosages of conventional regimens, according to the tolerance of the recipient and the particular treatment or maintenance protocol that is desired. The compounds of formulas (I) and (II) herein, will be administered in an amount necessary to agonize or antagonize the estrogen or estrogen activity of the formulation to the desired level. When estrogen is used conjugates, USP, the daily dosage is preferred to be 0.1 mg to 5.0 mg, more preferably between about 0.3 mg and about 2.5 mg, and much more preferably between about 0.3 and about 1.25 mg / day. For mestranol or ethinylestradiol, a daily dosage may be from about 1 μg to about 0.15 mg / day, and a dosage of 1 μg to about 0.3 mg / day for ethinylestradiol, preferably between about 0.2 μg to about 0.15 mg / day may be used. of ethinylestradiol. The compounds of this invention can be formulated pure or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and the standard pharmacological practice. The pharmaceutical carrier can be solid or liquid. A solid carrier can include one or more substances which also act as flavoring agents, lubricants, solubilizers, suspension improving agents, fillers, fluidizing agents, compression auxiliaries, binders or tablet disintegrating agents, - it can also be a encapsulating material In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the Compressive properties are necessary in appropriate proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, waxes with low melting point and ion exchange resins. . Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspension improving agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (which partially contains additives as in the above, for example cellulose derivatives, preferably a solution of sodium carboxymethylcellulose), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their derivatives, lecithins and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in compositions in sterile liquid form for parenteral administration. The liquid carrier for pressurized compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds of this invention can also be administered orally either in the form of a liquid or solid composition. The compounds of this invention can be administered rectally or vaginally in the form of a conventional suppository, creams, gels, etc. For administration by intranasal or intrabronchial inhalation or by insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is not toxic to the skin and allows the supply of the agent for systemic absorption into the bloodstream via the skin. The carrier can take many of the forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be a viscous liquid or semi-solid emissions, either oil-in-water or water-in-oil. The pastes consisting of absorbent powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient are also suitable. Various occlusive devices may be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with and without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. Dosage requirements vary with the particular compositions used, the route of administration, the severity of the symptoms presented and the particular subject being treated. The treatment will usually begin with small dosages less than the optimum dose of the compound. Subsequently the dosage will be increased until the optimum effect is reached under the circumstances; the precise dosages for oral, parenteral, transdermal, rectal or vaginal suppository administrations, by nasal or intrabronchial administration and other administrations will be determined by the physician who performs the administration based on the experience with the individual subject treated. Preferably, the pharmaceutical composition is in unit dosage form, for example as tablets or capsules. In such form, the composition is subdivided into a unit dose containing appropriate amounts of the active ingredient; the unit dosage forms may be packaged compositions, for example packaged powders, flasks, ampoules, pre-filled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate amount of any such compositions in package form. The compound or compounds of formula (I) and (II) and the estrogen or oestrogens of the present formulations can be administered in separate dosage units such as separate pills, tablets, powders, etc. or they can be combined in a formulation. When the optimal dosages for the compounds of formulas (I) and (II) and the estrogens of these formulations have been determined, it may be preferable to incorporate both a single formulation for ease of administration. It should also be understood that the formulations herein may or may not include other pharmaceutically active components. The solvents used for the reactions described herein wherein the anhydrous equipment is used Aldrich Sure Seal "E without additional purification The reagents are typically Aldrich and are used without further purification All reactions were carried out under a nitrogen atmosphere Chromatography was carried out using silica gel 230-400 mesh ( Merck Grade 60, Aldrich Chemical Company) Thin-layer thin chromatography was performed with silica gel 60 F2S4 plates from EM Science The 1 H-NMR spectra were obtained on a Bruker AM-400 instrument in DMSO and the chemical shifts are reported in Perkin-Elmer.The melting points are determined in a Thomas-Hoover apparatus and are uncorrected.The IR spectra are recorded in a Perkin-Elmer diffraction apparatus or in Perkin-Elmer 784 spectrophotometers. The mass spectra are recorded in a Kratos MS 50 or Finnigan 8230 equipment as mass spectrometers The elemental analyzes were obtained with a Perki-Elmer 2400 elemental analyzer. The compounds with CHN analysis were reported which are within 0.4% of the theoretical values.

Synthesis of -bromoketones Method a The synthesis of the alphabromoketones is conveniently carried out by simply dissolving the initial phenyl ketone in ethyl ether (0.05-0.10 M) and at room temperature, 1.1 equivalents of bromine are added dropwise. The reaction can be monitored by CCD for consumption of initial materials. The reaction is worked by washing with an aqueous solution of sodium bicarbonate followed by a 10% aqueous solution of sodium sulfite. The ether layer is washed with brine and dried over magnesium sulfate. The concentration of the reaction mixture typically provides the bromoketones in good yield and purity. The bromoketones are taken "as is" (without purification or characterization) for the next step. 3 - . 3 -methylindolea Reaction scheme 8 Table 1 fifteen twenty Method 1 Illustrated for the jmppln or. 7-5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-indole A flask is charged with 4-benzyloxyaniline hydrochloride CAS No. [51145-58-5], (45 g, 0.23 moles), 4'-benzyl loxy-2-bromophenylpropiophenone CAS No. [66414-19-5] ( 21 g, 0.066 moles) and 50 ml of DMF. The reaction is refluxed for 30 minutes and then cooled to rt and then divided between 250 ml EtOAc and 100 ml aqueous 1 N HCl. The EtOAc is Wash with aqueous NaHC03 and extract, then dry over MgSO4. The solution is concentrated and the residue is taken up in CH2C12 and hexanes are added to remove 25 g of the crude solid by precipitation. The solid dissolves ..e? CH2C12 and evaporated on silica gel and chromatographed using CH2Cl2 / hexane (1: 5) to provide 9.2 g of a tan solid (33%): M.p. = 150-152 ° C; XH NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 H), 5.16 (s, 2 H), 5.11 (s, 2H), 2.33 (s, 3 H); IR (KBr), 3470, 2880, 2820, 1620 cm "1; MS m / z 419.

Method 2 (shown in reaction scheme 8) t «p? i -? - ipn illustrated for Example No. 7 The reagents used were the same as in Method 1, except for the additional use of triethylamine in this method. Bromocetone CAS No. [66414-19-5] (50.0 g, in 0.16 moles) in 200 ml of DMF is treated with aniline hydrochloride CAS No. [51145-58-5] (44 g 0.22 moles) and the reaction purge with nitrogen for about 10 minutes. 54.6 ml of triethylamine are added and the reaction is heated at 120 ° C for 2 hours. Analysis by CCD (EtOAc / hexanes) shows that the initial material has disappeared forming a more polar point. The reaction mixture is allowed to cool and an additional 48 g of aniline hydrochloride are added. The reaction is heated at 150 ° C for 2 hours. An additional 5 grams of aniline hydrochloride are added and the reaction is heated at 150 ° C for an additional 30 minutes. The reaction mixture is allowed to cool to room temperature and then poured into approximately 1.5 liters of water and extracted with two liters of ethyl acetate. The solids are dissolved with additional ethyl acetate, as necessary. The ethyl acetate layer is washed with 1 liter of an aqueous solution of 1 N NaOH, 1 liter of water, brine, then dried over magnesium sulfate and filtered. The organic layers are reduced by concentration to give a crude solid which is stirred with 500 ml of methanol and filtered. The solid is then stirred with 500 ml of ethyl ether and filtered. The solid is stirred alternately with methanol and ether until it is whitish in color and has a melting point similar to that described for number 7 in Method 1. The reaction provides 36 grams of product.

Physical data for the characters The following 3-methyl-indols (No. I-No. 20) were synthesized according to the procedure indicated in Reaction Scheme 2 using method 2 and using the appropriately substituted bromoketones (prepared as indicated above) and the anilines (commercially available: Aldrich) as initial materials.

Example No. 1 2-f-enyl-3-methyl-lH-indole P.f. = 90 -94 ° C; a H NMR (DMSO) 11.13 (s, 1 H), 7.68 - 7.64 (m, 2 H), 7.54 - 7.46 (m, 3 H), 7.37 - 7.32 (m, 2 H), 7.12 - 7.06 (m, 1 H), 7.03-6.97 (m, 1 H), 2.40 (s, 3 H); MS at m / z 207 (M +).

Example No. 5-Flouro-2- (4-henyloxy-phenyl) -3-methyl-lH-indole P.f. = 143 - 146 ° C.

Example No. 2 2- (4-benzyloxy-phenyl) -3-methyl-1H-indole P.f. = 118 - 120 ° C; * H NMR (DMSO) 11.03 (s, 1 H), 7.57 (dd.2H, J = 2.0 Hz, 6.6 Hz), 7.48-7.46 (m, 3 H), 7.44 - 7.28 (m, 4 H), 7.18 - 7.11 (m, 2 H), 7.08 - 7.03 (m, 1 H), 7.0 - 6.95 (m, 1 H), 5.16 (s, 2 H), 2.36 (s, 3 H); MS at m / z 313 (M +).

Example No. 3 5-BenzyloxyP.2jjphenyl-3-methyl-lH-indole w P.f. = 141-144 ° C; "H NMR (DMSO) 10.98 (s, 1 H), 7.65-7.61 (m, 2 H), 7.51-7.44 (m, 4 H), 7.42-7.28 (m, 4 H), 7.23 (d, 1 H , J = 8.8Hz), 7.10 (d, 1 H, J = 2.5Hz), 6.80 (d, 1 H, J = 6. 0 Hz), 5.10 (s, 2 H). 2.36 (s, 3 H); EH m / z 313 (M +).

Example No. 4-5-benzyloxy-2- (4-methoxy-phenyl) -3-methyl-1H-indole P.f. = 158 ° C; "H NMR 10.85 (broad S, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d 2 H, J = 8.3 Hz), 7.45 - 7.36 (m, 2 H), 7.34 -7.28 (m, 1 H), 7.21 (d, 1 H, J = 8.6 Hz), 7.09 - 7.04 (m, 3 H), 6.79 (dd, 1 H, J = 8.8 Hz), 5.11 (s, 2 H) 3.80 (s, 3 H), 2.33 (s, 3 H), IR (KBr) 3400, 2900, 1610 cm "1; MS at m / z 343 (M +); CHN calculated for C23H21N02 + 0.25 H20.

Example No. 5 5-methoxy-2- (4-methoxy-phenyl) -3-methyl-lH-indole P.f. = 139 - 142 ° C. JH NMR (DMSO) 10.85 (s, 1 H), 7.57 (d, 2 H, J 8.8 Hz), 7.19 (d, 1 H, J 8.6 Hz), 7.04 (d, 2 H, J = 6.8 Hz), 6.95 (d, 1 H, J = 2.2 Hz) 6.71 (dd, 1 H, J = 8.5 Hz, J = 2. 4 Hz), 3.80 (s, 3 H), 3.76 (s, 3 H), 2.33 (s, 3 H); MS at m / z 267 (M +); CHN calculated for C17H17N02.

Example No. 6 5-benzyloxy-2- (-ethoxy-phenyl) -3-methyl-1H-indole - ST - P.f. = 143-145 ° C; * H NMR MSO) 10.86 (s, 1 H), 7.54 (d, 2 H, J = 8.5 Hz), 7.46 (d, 2 H, J = 7.3 Hz), 7.41-7.37 (m, 2 H), 7.32 -7, .30 (m, 1 H), 7.20 (d, 1 H, J = 8.6 Hz), 7.05 (d, 1 H). 7.03 (d, 2 H, J = 8.8 Hz), 6.79 (dd, 1 H, J = 8.6 Hz, J = 2.4 Hz), 5.10 (s, 2 H), 4.07 (c, 2 H, J = 6.8 Hz ), 2.32 (s, 3 H), 1.34 (t, 3 H, J = 7.0 Hz); MS at m / z 357 (M +).

E n example No. 85-benzyloxy-2- (4-f luoro-phenyl) -3-methyl) -lH-indole P.f. = 132 ° C; H NMR (DMSO) 11.0 (s, 1 H), 7.68-7.64 (m, 2 H), 7.49-7.47 (m, 2 H), 7.41-7.31 (m, 5 H), 7.23 (d, 1 H, J = 8.8 Hz), 7. 1 0 (d, 1 H, J = 2.4 Hz), 6.82 (dd, 1 H, J = 8.8, 2.4 Hz), 5.11 (s, 2 H), 2.34 (s, 3 H); MS The m / z 331; CHN calculated for C22HlßFNO.

Example No. 9 5-benzyloxy-2- (4-henyloxy-3-methoxy-phenyl) -3-methyl-1H-indole P.f. = 155 -158 ° C; ? RMH (DMSO) 10.88 (s, 1H), 7.50 - 7.45 (m, 4 H), 7 41 - 7.35 (m 6H), 7.22 - 7.20 (m, 2 H), 7.14 (s, 2 H), 7.08 ( d, 1 H, J = 2.2Hz), 6.78 (dd, 1 H, J = 8.5 Hz, J = 2.4Hz), 5.13 (s, 2H), 5.11 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H); MS at m / z 449 (M +).

Example No. 102-Benzori, 1dloxol-5-yl-5-benzyloxy-3-methyl-1H-indole P.f. = 142-145 ° C. H NMR (DMSO) 10.86 (s, 1 H), 7.48 (d, 2 H, J = 7.0 Hz), 7.40 7.30 (m, 3 H), 7.20 (, 2 H), 7.10 - 7.05 (m, 3 H ), 6.78 (dd, 1 H, J = 8.8 Hz, J = 2.4Hz), 6.06 (s, 2 H), 5.10 (s, 2 H), 2.31 (s, 3 H); MS at m / z 357 (M +); CHN calculated for C23H19N03.

Example No. 115-benzyloxy-2- (4-isopropoxy-phenyl) -3-methyl) -1H-indole P.f. = 136 - 138 ° C; 'H NMR (DMSO) 10.86 (s, 1 H), 7.55 - 7.51 (m, 2 H), 7.50 7.47 (d, 2 H, J = 7.3 Hz), 7.40 - 7.34 (m 2 H), 7.39 - 7.28 (m, 1 H), 7.20 (d, 1 H, J = 8.7 Hz), 7.06 (d, 1 H, J = 2.2 Hz), 7.02 (d, 2 H, J = 8.8 Hz), 6.77 (dd) 1 H, J = -.4 Hz, 8.8 Hz), 5. 1 0 (2 H), 4.68 - 4.62 (m, 1 H), 2.32 (s, 3 H), 1.28 (d, 6 H) J = 6.0 Hz); MS at m / z 371 (M +).

Example No. 12 5-benzyloxy-2- (4-cyclo-phenyloxy-phenyl) -3-methyl-1H-indole P.f. 161 - 167 ° C; * H NMR (DMSO) 10.85 (s, 1 H), 7.53 (d, 2 H, J = 8.8 Hz), 7.47 (d, H, J = 8.4 Hz), 7.40 - 7.36 (m, 2 H), 7.33 - 7.28 (m, 1 H), 7.20 (d 1 H, J = 8.6 Hz), 7.07 (d, 1 H, J = 2. 4 Hz), 7.01 (d, 1 H, J Hz), 6.78 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 5.10 (S, 2 H), 4.8 8 - 4.84 (m, 1 H), 2.3 2 (s, 3 H), 1.99-1.88 (m, 2 H), 1.78 - 1.69 (m, 4 H). 1.64-1.52 (m, 2 H); IR (KBr) 3400, 2920, 16TJ0 cm "1; MS m / z 397 (M +); CHN calculated for C27H27N02 + 0.25 H20.

Example No. 135-benzyloxy-2- (4-trif luoromethyl-phenyl) -3-methyl-1H-indole * H NMR (DMSO) 1 1.0 (broad s, 1 H), 7.87 - 7.82 (m, 4 H), 7.48 (d, 2 H, J = 8.8 Hz), 7.44 - 7.35 (m, 1 H), 7.34 - 7.26 (m, 2 H), 7.15 (d, 1 H, J = 2.2 Hz), 6.87 (dd 1 H, J = 8.6 Hz, 2.4 Hz), 5.12 (s, 2 H), 2.41 (s, 3 H); CHN calculated for C23H18F3N0.

Example No. 145-benzyloxy-2- (4-methyl-phenyl) -3-methyl-lH-indole P.f. = 144 - 146 ° C; * H NMR (DMSO) 10.91 (s, 1 H), 7.56 - 7.20 (m, 1 0 H), 7.08 (d, 1 H, J = 2.4 Hz), 6.80 (dd, 1 H, J = 2.4 Hz, 8.6 Hz), 5.11 (s, 2 H), 2.34 (s, 3 H), 2.34 (s, 3 H); MS at m / z 327 (M +).

Example No. 15 5-benzyloxy-2- (4-chloro-phenyl) -3-methyl-1H-indole P.f.134-136 ° C; X H NMR (DMSO) 11.04 (s, 1 H), 7.65 (d, 2 H, J = 8.3 Hz), 7.53 (d, H, J = 8.5 Hz), 7.47 (d, 2 H, J = 6.8 Hz), 7. 41 - 7.37 (m, 2 H), 7.31 - 7.28 (m, 1H), 7.25 (d, 1 H, J = 8.5 Hz), 7.11 (d, 1 H, J = 2.4Hz), 6.82 (dd, 1H , J = 8.8 Hz, J = 2.4 Hz), 5.11 (s, 2H), 2.35 (s .3H); IR (KBr) 3380, 1210 cm "1 MS m / z 347 (M +); CHN calculated for C22H18CIN02.

Example No. 16 5-benzyloxy-2- (2,4-dimethoxy-phenyl) -3-methyl-1H-indole Oil; "H NMR (DMSO) 10.58 (s, 1 H), 7.50 - 7.18 (m, 7 H), 7.04 (d, 1 H. J = 2.4 Hz), 6.76 (dd, 1 H, J = 2.3 Hz, 8.6 Hz), 6.69 - 6.62 (m, 2 H), 5.11 (s, 2 H), 3.82 (, s 3 H), 3.78 (s, 3 H), 2.12 (s, 3 H).

Example No. 17 5-benzyloxy-2- (3-benzyloxy-phenyl) -3-methyl-1H-indole P.f. = 83 - 86 ° C Example No. 18 5-Benzyloxy-2- (-benzyloxy-3-luoro-phenyl) -3-methyl-1H-indole P.f. = 135-137"C;" H NMR (DMSO) 10.94 (s, 1 H), 7.50-7.31 (m, 13 H). 7.22 (d, 1 H, J = 8.6 Hz), 7.10 (d, 1 H, J = 2.2 Hz), 6.81 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 5.23 (s, 2 H), 5.11 (s, 2 H), 2.34 (s, 3 H); MS at m / Z 437 (M +); CHN calculated for C29H24FN02.

Example No. 195-benzyloxy ^ 2- (3-methoxy-phenyl) -3-methyl-lH-indole P.f. = 107 - 109 ° C -, 'H NMR (DMSO) 11.00 (s, 1 H), 7.51 - 7.48 (m, 2 H), 7.43 - 7.20 (m, 7 U.), 7.13 - 7.12 (d, 1 H, J = 2.1 Hz), 6.93 - 6.90 (dd, 1 H, J = 2.3 Hz, J = 5.7 Hz), 6.86 - 6.82 (dd, 1 H, J = 2.3 Hz, J = 6.3 Hz), 5.12 (s, 2 H), 3.83 (s, 3 H), 2.38 (s, 3 H), IR (KBr) 3400, 2900, 1600 cm "1; EM at m / z 343 (M +); CHN calculated for C23H21N02 .

Example No. 20 5-benzyloxy-3-methyl-2- (4-trifluoromethoxy-phenyl) -1H-indole P.f. = 127 - 128 ° C, * H NMR (DMSO) 11.07 (s, 1 H), 7.77 - 7.74 (dd, 2 H, J = 1.8 Hz, J = 5.0 Hz), 7.50 - 7 48 (d, 4 H) , J = 8.3 Hz), 7.42 - 7.25 (m, 4 H), 7.14 - 7.13 (d, 1 H, J = 2.2 Hz), 6.87 - 6.83 (dd.1 H, J = 2.3 Hz, J = 6.3 Hz ), 5.13 (s, 2 H), 2.37 (s, 3 H). IR (KBr) 3360, 1600 cm1 MS m / z 396 (M +); CHN calculated for C23H1BF3N02.

Ethyl esters of 3-methylindoleacetic acid Reaction scheme 9 Table 2 15 - 6 - Experimental procedure for ethyl esters of 3-methylated indoleacetic acid Method of synthesis 3 Illustrated for Example No. 26 Ethyl 4- [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy-acetic acid ethyl ester A solution of 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-mdol (indole from Example No. 7) (32 g, 77 mmol) in 0.15 1 of DMF is cooled to 0 ° C. and treated with sodium hydride (2.2 g, 89 mmol). The reaction is stirred for 20 minutes and then benzyl chloride CAS No. 80494-75-3] is added and the reaction is stirred for 18 hours at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate. The ethyl acetate is washed with brine and dried over magnesium sulfate. The ethyl acetate is concentrated and triturated with ether to obtain 21 g of a white solid. The filtrate is concentrated and triturated with ether to provide an additional 7 g of a white solid for a total yield of 28 g: M.p. 129-131 ° C; * H NMR (DMSO) 7.47 (d, 4 H, J = 7.2 Hz), 7.39 (c, 4 H, J = 7.9 Hz), 7.36-7.32 (m, 1 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.19 (d, 1 H, J = 9.0 Hz), 7.13-7.09 (m, 4 H), 6.80 (dd, 1 H, J = 8.8, 2.4 Hz), 6.73 (s, 4 H), 5.16 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 4.66 (s, 2 H), 4.11 (c, 2 H, J = 7.2 Hz), 2.15 (s, 3 H), 1.16 (t, 3 H, J = 7.2 Hz); EM the m / z 612.

Physical data for ethyl esters of indole The following indole alkylation products are prepared according to Reaction Scheme 9 using Method 3 with the appropriately substituted 3-methylindole selected from (No. I-No.16) as the starting material.

Example No. 21 Acid ethyl ester. { (4- [2-phenyl-3-methyl-indol-1-ylmethyl] -phenoxy] -acetic acid Oil; * H NMR (DMSO) 7.57-7.30 (m, 7 H), 7.13-7.02 (m, 2 H), 6.77-6.70 (m, 4 H), 5.22 (s, 2 H). 4.65 (s.2 H), 4.09 (c, 2 H, J = 7.2 Hz), 2.20 (s, 3 H), 1.15 (t, 3 H, J = 7.0 Hz); MS at m / z 399 (M +).

Example No. 22 Ethyl ester of the acid. { 4- [5-benzyloxy-2-phenyl-3-methyl-indol-1-ylmethyl] -phenoxyl-acetic acid Oil; H NMR (DMSO) 7.50 - 7.40 (m, 10 H), 7.22 (d, 1 H, J 8.4 Hz), 7.14 (d, 1 H J = 2.5 Hz), 6.83 (d, 1 H, J = 2.5 Hz) , 6.72 (S, 4 H), 5.18 (S, 2 H), 5 ^ .1 (s, 2 H), 4.65 (s, 2 H), 4.10 (c, 2 H, J = 7.2 Hz), 2.16 (s) , 3 H), 1. 14 (t, 3 H, J = 7.0 Hz); MS at m / z 505 (M +).

Example No. 23 Ethyl ester of the acid. { 4- C5-benzyloxy-2- (4-methoxy-phenyl) -3-methylindol-l-ylmethyl] -phenoxy-acetic acid P.f. = 90 - 96 ° C. "H NMR (DMSO) 7.47 (d, 2 H, J = 6.8 Hz), 7.41 - 7.37 (m, 2 H), 7.33 - 7.27 (m, 3 H), 7.19 (d.1 H, J = 8.8 Hz ), 7.12 (d.1 H, J = 2.4 Hz), 7.03 (d, 2 H, J = 8.8 Hz), 6.80 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 6.74 (s, 4 H) ), 5.16 (s, 2 H), 5.11 (S, 2 H), 4.65 (s, 2 H), 4.11 (c, 2 H, J = 7.0 Hz), 3.79 (s, 3 H), 2.15 (s) , 3 H), 1. 16 (t 3 H, J = 7.0 Hz) -, IR (KBr) 2990, 2900, 1760, 1610 cm1; EM BAR m / z 536 (M + H +).

Example No. 24 Ethyl ester of acid. { 4- [5-methoxy-2- (4-methoxy-phenyl) -3-methyl-indole] -1-ylmethyl] -phenoxy-acetic acid P.f. = 109-113 ° C. * H NMR (DMSO) 7.27 (d, 2 H, J = 8.8 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 7 03 (d, 2 H, J = 8.6 Hz), 6.99 (d, 1 H, J = 2.5 Hz), 6.78-6.70 (m. 5 H), 5.15 (s, 2H), 4.65 (s, 2 H), 4.1 1 (c, 2 H, J = 7.0 Hz), 3.78 (s, 3 H), 3.76 (s, 3 H), 2.15 (s, 3 H), 1. 15 (t, 3 H) , J = 7.1 Hz); MS at m / z 459 (M +).

Example No. 25 (4- r5-Benzyloxy-2- (4-ethoxy-phenyl) -3-methyl-indol-l-ylmethyl] -phenoxyl-acetic acid ethyl ester P.f. = 113-115 ° C; * H NMR (DMSO), 7.45 (d, 2 H, J = 7.3 Hz), 7.40 - 7.25 (m, 5 H), 7.17 (d, 1 E # J = 8.8 Hz), 7.11 (d, 1 H, J = 2.2 Hz), 7.01 (d, 2 H, J = 6.8 Hz), 6.78 (dd, 1 H, J = 8.8 Hz, J = 2.4 Hz), 6.73 (S, 4 H), 5.15 (s, 2 H), 5.10 (s, 2 H), 4.65 (s, 2 H), 4.15 - 4.01, (m, 4 H), 2.14 (s, 3 H), 1.33 (t, 3 H, J = 5.7 Hz), 1.16 (t, 3 H, J = 7.1 Hz); MS at m / z 549 (M +).

Example No. 27 4- [5-Benzyloxy-2- (4-flouro-phenyl) -3-methyl-indole] -1-ylmethyl] -phenoxyl-acetic acid ethyl ester * H NMR (DMSO) 7.50 - 7.15 (m, 16 H), 5.20 (s, 2 H), 5.12 (s, 2 H), 4.62 (s, 2 H), 4.13 (c, 2 H, J = 7.1 Hz), 2.18 (s, 3 H), 1.20 (t, 3 H, J = 7.1 Hz).

Example No. 28 Ethyl ester of the acid. { 4- [5-benzyloxy-2- (3-methoxy-4-benzyloxy) -3-methyl-indol-1-ylmethyl] -phenoxy} -acetic Foam, "H NMR (DMSO) 7.50 - 7.30 (m, 10 H), 7.22 (d, 2H, J = 9.1 Hz), 7.13 (d, 2 H, J = 8.6 Hz), 6.85 - 6.70 (m, 6 H), 5.17 (s 2H), 5.13 (S, 2H), 5.11 (s, 2 H), 4.66 (s, 2 H), 4.14 (m, 2 H), 3.61 (S, 3 H), 2.17 (s, 3 H), 1. 16 (t, 3 H, J = 7.0 Hz).

Example No. 29 Ethyl ester of acid. { 4- [5-benzyloxy-2- (4-isopropoxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy-acetic acid Oil; ? NMR (DMSO) 7.46 (d, 2H, J = 7.7 Hz), 7.42 - 7.28 (m, 3 H), 7.25 (d, 2 H, J = 8.7 Hz), 7.17 (d, 1 H, J = 8.7 Hz ), 7.11 (d, 1 H, J = 2.4 Hz), 6.99 (d, 2 H, J = 8.6 Hz), 6.79 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.73 (s, 4 H) ), 5.15 (s, 2 H). 5.10 (second 2 H). 4.70 - 4.60 (m, 3 H), 4. 1 0 (c, 2 H, J = 7.0 Hz), 2.15 (s, 3 H). 1.27 (d.6 H, J = 5.9 Hz), 1.16 (t, 3 H. J = 7.1 Hz); MS at m / z 563 (M +).

Example No. 30 Ethyl ester of acid. { 4- [5-benzyloxy-2- (3,4-methylenedioxy-benzyloxy) -3-methyl-indol-1-ylmethyl] -phenoxy} -acetic Oil, 'HEMN (DMSO) 7.45 (d, 2 H, J = 7.0 Hz), 7.37 (m, 2 H), 7.32 (m, 1 H), 7.19 (Id, 1H, J = 8.8 Hz), 7.11 ( d, 1 H, J = 2.2 Hz), 7.00 (d, 1 H. J = 7.9 Hz), 6.90 (d, 1 H. 5.0 Hz), 6.82 -6.75 (m, 6H), 6.07 (s, 2H) , 5.16 (s, 2 H), 5.10 (s, 2H). 4.65 (s, 2 H), 4. 10 (m, 2 H), 2.15 (s, 3 H), 1.15 (t, 3 H, J = 7.0 Hz); MS at m / z 549 (M +).

Example No. 31 Ethyl ester of acid. { 4- f5-benzyloxy-2- (4-cyclopentyloxy-phenyl) -3-methyl-indole-1-ylme <-i 11 -f? T? O? J,.}.

P.f. = 96-98 ° C; * H NMR (d, 1 H, J = 7.2 Hz), 7.40 7.36 (m, 2 H), 7.33 - 7.30 (m, 1 H), 7.1-6 (m 2 H), 7.18 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H. J = 2.4 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 6.79 (dd, 1 H, J = 8.8 Hz, 2.4 Hz) , 6.74 (s, 5 H), 5.15 (S, 2 H), 5.11 (s, 2 H), 4.86 - 4.80 (m, 1 H), 4.66 (s, 2 H), 4.13 (c, 2 H. J = 7.2 Hz), 2.15 (s, 3 H), 1.98 - 1.85 (m, 2 H), 1.79 - 1.65 (m, 4 H), 1.62 - 1.55 (m , 2 H), 1.16 (t, 3 H, J = 7.0 Hz); IR (K-Br) 2950, 2910, 2890, 1760, 1610 cm "1; MS m / z 589 (M +); CHN calculated for C: 77.39 H: 6.67 N: 2.38 Found: C: 76.76 H: 6.63 N : 2.27.

Example No. 32 F4- [5-benzyloxy-3-methyl-2- (4-trifluoromethyl-phenyl) -indol-1-ylmethyl] -phenoxy-acetic acid ethyl ester P.f. = 221 ° C; * H NMR (DMSO) 7.83 (d, 2 H, J = 8.1 Hz), 7.60 (d, 2 H, J = 7.9 Hz), 7.48 (d.2 H, J = 8.4 Hz), 7.40-7.36 (m , 4 H), 7.18 (d, 1 H, J = 2.4 Hz), 6.86 (dd.l H, J = 8.8 Hz, 2.4 Hz), 6.72 (s, 4 H), 5.21 (s, 2 H), 5.12 (s, 2 H), 4.65 (s, 2 H), 4.11 (C, 2 H, J = 7.2 Hz), 2.20 (s, 3 H), 1. 16 (t, 3 H, J = 7. 0 Hz); IR (KBr) 2920, 1730 cm-I; MS at m / z 573 (M +); CHN calculated for C34H30F3N04 + 0. 25 H20.

Example No. 33 (4 - [5-Benzyloxy-2- (4-chlorophenyl) -3-methyl-indol-1-ylmethyl] -phenoxyl-acetic acid ethyl ester P.f. = 99-101 ° C; X H NMR (DMSO '7.52 (d, 2 H, J = 8.6 Hz), 7.46 (d, 2 H, J = 6.8 Hz), 7.42 - 7.38 (m 4 H), 7.36 (m, 1 H), 7.25 (d , 1H, J = 9.0Hz), 7.14 (d, 1H, J = 2.4Hz), 6.83 (dd, 1H, J = 8.8 Hz, J = 2.5 Hz), 6.72 (s, 4H), 5.18 (s, 2H ), 5.11 (s, 2H), 4.65 (S, 2H), 4.11 (c, 2H, J = 7.2 Hz), 2.16 (s, 3H), 1.15 (t, 3H, J = 7.2Hz); / z 539 (M +); CHN calculated for C33H30CINO4 Example No. 34 [4-Benzyloxy-2- (2,4-dimethoxy) -3-methyl-indol-1-ylmethyl] -phenoxy acid ethyl ester. .}. -acetic Oil; * H NMR (DMSO) 7.30 - 6.45 (m, 15 H), 4.95 (s, 2 H), 4.75 - 4.65 (m, 2 H), 4.50 (s 2 H), 3.97 (c, 2 H, J = 7.1 Hz), 3.65 (s, 3 H), 3.51 (s, 3 H), 1.87 (3 H), 1.01 (t, 3 H. J = 7.1 Hz). 3-Methylindole phenylethanoles Reaction scheme 10 68 Table 3 Experimental procedure for the synthesis of 3-methylindol fenetanols Method 4 Illustrated for Example No. 38 2-. { 4- r 5 -benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} ethanol A solution of No. 26 of the previous stage (5.5 g, 8. 8 mmol) in THF is cooled to 0 ° C and a solution of LiAlH, (10 mL, 1 M) in THF is added dropwise. After 30 minutes at 0 ° C, the reaction is carefully suspended with water and partitioned between EtOAc and 1 N HCl. The EtOAc is dried with MgSO 4, concentrated and chromatographed on silica gel EtOAc / hexane (2: 3) to provide 4.0 g of No. 38 as a white foam:? RMH (DMSO) 7.48-7.46 (m, 4 H), 7.42-7.27 (m, 8 H), 7.20 (d, 1H, J = 8.8 Hz), 7.12-7.10 (m, 3 H), 6.80 (dd, 1 H, J = 8.8, 2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2 H), 5.13 (S, 2 H), 5.11 (s, 2 H), 4.80 (t, 1 H, J = 5.5 Hz), 3.86 (t, 2 H, J = 4.8 Hz), 3.63 (c, 2 H, J = 5.3 Hz), 2.15 (s, 3 H).

Physical data for fenetanal indole The following compounds are made according to Reaction Scheme 10 and Method 4 using the appropriately substituted indole ethyl ester selected from No. 21-No. 3. 4.

Example No. 352-Í4- [2-phenyl-3-methyl-indol-l-ylmethyl] -phenoxy} -ethanol Oil: * H NMR (DM? O) 7.57 - 7.32 (m.7 H), 7.13 - 7.02 (m, 2 H), 6.74 (s, 4 H), 5.21 (s 2 H), 4.80 (s, 1 H), 3.86 - 3.83 (m 2 H), 3.62 (s, 2 H), 2.20 (s, 3 H); MS at m / z 357 (M +).

Example No. 36 2-. { 4- t5-methoxy-t- (4-methoxy-phenyl) -3-methyl-indol-1-ylmethyl-phenoxy-ethanol Oil; XH NMR (DMSO) 7.27 (d, 2 H, J = 8.8 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 7.03 (d, 2 HJ = 8.6 Hz), 6.99 (d, 1 HJ = 2.5 Hz), 6.78 - 6.70 (m, 5 H), 5.14 (s, 2 H), 4.80 (broad s, 1H), 3.85 (t, 2 H, J 5.0 Hz), 3.78 (s, 3H), 3.76 ( s, 3 H), 3.63 (t, 2H, J = 5.0 Hz), 2.16 (s, 3H); MS at m / z 417 (M +).

Example No. 37 2 - Í4- [5-benzyloxy-2- (4-ethoxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy-ethanol Foam; X H NMR (DMSO) 7.45 (d, 2 H, J = 7.3 Hz), 7.40 - 7.25 (m, 5 H), 7.17 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H, J = 2.2 Hz), 7.01 (d, 2 H, J = 6.8 Hz), 6.78 (dd, 1 H, J = 8.8 Hz, J = 2.4 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5. 1 0 (s, 2H), 4.80 (s broad, 1 H), 4.06 (c, 2 H, J = 6.8 Hz), 3.85 (t, 2 H, J = 5.0 Hz), 3.63 (t, 2H , J = 4.8Hz), 2.14 (s, 3H), 1.33 (t, 3H, J = 6.9 Hz); MS at m / z 507 (M +).

Example No 39 2 -. { 4- [5-benzyloxy-2 - (4-f ourophenyl) -3-methyl-indol-1-ylmethyl] -phenoxy > - ethanol * H NMR (DMSO) 7.40 - 6.60 (m, 16 H), 5.10 (s, 1 H), 5.07 (s, 2 H), 5.02 (S, 2 H), 3.76 (t, 2 H, J = 4.9 Hz), 3.53 (t, 2 H, J = 5.0 Hz), 2.06 (s, 3 H).

Example No. 40 2- 4- [5-benzyloxy-2- (3,4- [methylenedioxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol Oil; "H NMR (DMSO) 7.45 (d, 2 H, J = 7.0 Hz), 7.37 (m, 2 H), 7.32 (m, 1 H), 7.19 (d, 1H, J = 8.8 Hz), 7.11 (d , 1 H, J = 2.2 Hz), 7.00 (d, 1 H, J = 7.9 Hz), 6.90 (d, 1 H 5.0 Hz), 6.82 -6.75 (m, 6H), 6.07 (s, 2 H), 5.16 (s, 2 H), 5.10 (s, 2 H), 3.86 (t, 2 H, J = 5.0 Hz), 3.63 (t, 2 H, J = 5.0 Hz), 2.15 (s, 3 H): MS at m / z 507 (M +).

Example No. 41 2 - (i- [5-benzyloxy-2- (4-isopropoxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy-ethanol Foam; * H NMR (DMSO) 7.46 (d, 2H, J = 7.7 Hz), 7.42 - 7.28 (m, 3 H), 7.25 (d, 2 H, J = 8.7 Hz), 7.17 (d, 1 H, J = 8.7 Hz), 7.11 (d.1 H, J = 2.4 Hz), 6.99 (d, 2 H, J = 8.6 Hz), 6.79 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.73 (s, 4 H), 5.14 (s, 2 H), 5.10 (s, 2 H), 4.80 (s broad, 1 H), 4.70 - 4.60 (m , 1 H), 3.8 5 (t, 2 H, J = 4.8 Hz), 3.63 (t, 2 H, J = 5.1 Hz), 2.13 (, s, 3 H), 1.30 (d, 6 H, J = 5.9 Hz); MS at m / z 521 (M +). - 7I Example No. 422-. { 4- [5-benzyloxy-2- (4-cydopentyloxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol P.f. = 129-131 ° C; 2 H NMR (DMSO) 7.47 (d, 2 H, J = 7.2 Hz), 7.38 (t, 2 H, J = 7.2 Hz), 7.3 3 - 7.2 8 (m, 1 H), 7.25 (d, 2 H, J = 8. 8 Hz), 7.18 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H, J = 2.4 Hz), 6.98 (d, 2 H, J = 8.8 Hz), 6.79 (dd) , 1 H, J = 8.8 Hz, 2.4 Hz), 6.74 (s, 4H), 5.15 (s, 2 H), 5.11 (s, 2 H), 4.84 - 4.80 (m, 1 H), 4.79 (t, 1 H, J = 5.7 Hz), 3.86 (t, 2 H, J = 4.8 Hz), 3.63 (C, 2 H, J = 5.1 Hz), 2.15 (s, 3 H), 1.96 - 1.87 (m, 2 H), 1.77 - 1.65 (m, 4 H), 1.62 - 1.53 (m, 2 H); IR (KAmplio) 3490 broad, 2920, 1620 cm "1; MS m / Z 547 (M +).

Example No. 43 2-. { 4- [5-benzyloxy-2- (4-trifluoromethyl] -phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy-ethanol Foam; 'H NMR (DMSO) 7.83 (d.2 H, J = 8.1 Hz), 7.59 (d, 2 H, J = 7.9 Hz), 7.47 (d, 2 H, J = 8.3 Hz), 7.42 - 7.36 (m , 2 H), 7.35 - 7.29 (m, 2 H), 7.18 (d, 1 H, J = 2.4 Hz), 6.87 (dd, 1 H, J = 8.1 Hz, 2.4 Hz), 6.77 - 6.68 (m, 4 H), 5.21 (s, 2 H), 5.12 (S, 2 H), 4.81 (broad s, 1 H), 3.85 (t, 2 H, J = 5.1 Hz), 3.63 (t, 2 H. J = 5.1 Hz). 2.19 (s, 3 H); EM at m / z 531.

Example No. 44 2 -. { 4 - [5-Benzyloxy-2- (4-methyl-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol Oil; 'H NMR (DMSO) 7.46 (d, 2 H, J = 7.2 Hz), 7.45 - 7.18 (m, 8 H), 7.12 (d, 1 H, J = 2.4 Hz), 6.81 (dd, 1 H, J = 2.4 Hz, 8.6 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.10 (s, 2 H), 4.80 (s broad, 1 H), 3.85 (t, 2 H. J = 4.8 Hz). 3.63 (t, 2 H, J = 4.9 Hz), 2.34 (s, 3 H), 2.15 (s, 3 H); MS at m / z 477 (M +).

Example No. 45 2-. { 4- [5-benzyloxy-2- (4-chloro-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol P.f. = 110 - 113 ° C. "H NMR (DMSO) 7.52 (d, 2 H, J = 8.6Hz), 7.46 (d, 2 H, J = 6.8Hz), 7.38 (m 4 H), 7.42-7.37 (m.h.), 7.25 (d, 1 H, J = 9.0 Hz), 7.14 (d, 1 H, J = 2.4 Hz), 6.83 (dd, 1 H, J = 8.8 Hz, J = 2.5 Hz), 6.76 - 6.70 (m, 4 H), 5.17 (s, 2 H), 5.1 1 (s 2 H), 3.85 (t, 2 H, J = 5.2 Hz), 3.63 (t, 2 H, J = 5.0 Hz), 2.16 (S, 3 H); MS at m / z 497 (M +).

Example No. 46 2 - (i - [5-benzyloxy-2- (2,4-dimethoxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol Oil; 1 H NMR (DMSO) 7.46 (d, 2 H, J = 7.5 Hz), 7.39 - 7.35 (m, 2 H), 7.31 - 7.28 (m, 1 H), 7.16 - 7.06 (m 3 H), 6.82 - 6.72 (m, 5 H), 6.68 (d, 1 H, J = 2.2 Hz), 6.61 (dd, 1 H, J = 2.4 Hz, 8.3 Hz), 5.0 (s, 1 H), 4.88 (s, 2 H) ), 4.85 (d, 1H, J = 6.3 Hz), 4.69 (d, 1 H, J = 6.3 Hz), 3.63 (t, 2 H, J = 6.9 Hz), 3.58 (s, 3 H), 3.46 iß, 3 H), 3.40 (t, 2 H, J = 6.9 Hz) 1.80 (S, 3 H). Data for 3-methylindol phenylethyl bromides Reaction scheme 11 Table 4 Experimental procedure for the synthesis of 3-methylindolphenethyl bromide Method 5 Illustrated for Example No. 50 B cTTipIn An O -Benzyloxy-2- (4-benzyloxy-phenyl) -1- [4- (2-bromo-ethoxy) -benzyl] -3-methyl-1H-indole To a solution of Example No. 38 (3.3 g, 5.8 mmol) in 50 mL of THF is added CBr, (2.9 g, 8.7 mmol) and PPH3 (2.3 g, 8. 7 mmol). The reaction is stirred at rt for 3 h and then concentrated and chromatographed on silica gel using an elution gradient of EtOAc / hexane (1: 4) to EtOAc to provide 3.2 g of a white solid: M.p. = 131-134-C, 'H NMR (DMSO) 7.64-7.30 (m, 10 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.20 (d, 1 H, J = 8.8 Hz), 7.12-7.09 (m, 3 H), 6.80 (dd, 1 H, J = 8.8, 2.4 Hz), 6.77-6.73 (m, 4 H), 5.16 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 4.20 (t, 2 H, J = 5.3 Hz), 3.73 (t, 2 H, J = 5.5 Hz), 2.15 (s, 3 H); EM BAR 631/633 (M + H1, Br present).

Physical data for phenethylindole bromides The following compounds were made according to Reaction Scheme 11, as described in the Method using the appropriately substituted indole selected from Nos. 35-45.

Example No. 47 1- [4- (2-bromo-efeoxi) -benzyl] -2-phenyl-3-methyl-lH-indole Oil; * H NMR (DMSO) 7.57 - 7.32 (m, 7 H), 7.13 - 7.02 (m, 2 H), 6.74 (s, 4 H), 5.21 (s, 2 H), 4.19 (t, 2 H, J = 5.2 Hz), 3.71 (t, 2 H, J = 5.5 Hz), 2.20 (s, 3 H); MS at m / z 419 (M +): Example No. 48 5-methoxy-2- (4-methoxy-phenyl) -1- [4- (2-bromoethoxy) -benzyl] -3-methyl-1H-indole Oil; X H NMR (DMSO) 7.27 (d, 2 H, J = 8.8 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 7.03 (d, 2 HJ = 8.6 Hz), 6.99 (d, 1 H, J = 2.5 Hz), 6. 80-6.69 (m, 5 H), 5.14 (s, 2H), 4.19 (t, 2H, J = 5.4 Hz), 3. 78 (s, 3 H), 3.76 (s, 3 H), 3.72 (t, 2H, J = 5.5 Hz), 2.16 (s, 3H); MS at m / z 479 (M +).

Example No. 49 5-benzyloxy-2- (4-ethoxy-phenyl) -1- [4- (2-bromo-ethoxy) -benzyl] -3-methyl-1H-indole P.f. = 118-120 ° C; ? NMR (DMSO) 7.45 (d, 2 H, J = 7.3 Hz), 7.41 - 7.26 (m, 5 H), 7.17 (d, 1 H, J = 8.8 Hz), 7.1 1 (d, 1 H, J = 2.2 Hz), 7.01 (d, 2 H, J = 6.8 Hz), 6.78 (dd, 1 H, J = 8.8Hz, J = 2.4 Hz), 6.78 - 6.74 (m, 4 H), 5.15 (s, 2 H), 5.10 (s, 2 H), 4.22 - 4.18 (m, 2 H), 4.04 (c, 2 H, J = 6.8 Hz), 3.72 (t, 2 HJ = 5.5 Hz), 2.14 (s, 3 H), 1.33 (t, 3 H, J = 7.0 Hz); MS at m / z 569 (M +).

Example No. 51 5-Benzyloxy-l- [4- (2-bromo-ethoxy) -benzyl] -2- (4-fluoro-phenyl) -3-methyl-lH-indole P.f. = 114-116 ° C; H NMR (DMSO) 7.47 (m, 2 H), 7.45 - 7.20 (m, 8 H), 7.14 (d, 1 H, J = 2.4 Hz), 6.83 (dd, 1 H, J = 2.7 Hz, 9.0 Hz ), 6.80 - 6.70 (m, 4 H), 5.16 (s, 2 H), 5.1 1 (s, 2 H), 4.19 (t, 2 H, J = 5.27 Hz), 3.72 (t, 2 H, J = 6.4 Hz), 2.15 (s, 3 H); MS at m / z 543 (M +); CHN calculated for C31H27BrFN02.

Example No. 52 2-Benzo [1.3] dioxyl-5-yl-5-benzyloxy-1-T4- (2-bromoethoxy) -benzyl] -3-methyl-1H-indole P.f. = 133-136 ° C; "H NMR (DMSO) 7.45 (d, 2 H, J = 7.0 Hz), 7.41-7.38 (m, 2 H), 7.35-7.30 (m, 1 H), 7.19 (d 1 H, J = 8.8 Hz) , 7.11 (d, 1 H, J = 2.2 Hz), 7.00 (d, 1 H, J = 7.9 Hz), 6.90 (d, 1 H, 1.4 Hz), 6.82 - 6.78 (m, 2 H), 6.77 (s) , 4 H), 6.07 (s, 2 H), 5.16 (S, 2 H), 5.10 (s, 2 H), 4.20 (t 2 H, J = 5.5 Hz), 3.73 (t, 2 H, J = 5.2Hz), 2.15 (s, 3H), MS m / z 569 (M +).

Example No. 52a 5-benzyloxy-l- [4- (2-bromo-ethoxy) -benzyl] -2- (3-methoxy-4-benzyloxy-phenyl) -3-methyl-1H-indole Foam: XH NMR (DMSO) 7.47 - 7.42 (m, 4 H), 7.40 - 7.30 (m, 6 H), 7.20 (d, 1 H, J = 8.8 Hz), 7.12 - 7.10 (m, 2 H), 6.86 -6.84 (m, 2 H), 6.81 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 6.78 (s, 4 H), 5.17 (s, 2 H), 5.11 (s, 2 H), 5.10 (s, 2 H), 4.20 (t, 2 H, J = 5.0 Hz), 3.72 (t, 2 H, J = 5.4 Hz), 3.63 (s, 3 H), 2.17 (s, 3 H); EM BAR m / z 662 (M + H +).

Example No. 53 5-benzyloxy-l- [4- (2-bromoethoxy) -benzyl] -2- (4-isopropoxy-phenyl) -3-methyl-1H-indole P.f. = 125 - 128 ° C. "H NMR (DMSO) 7.46 (d, 2H, J = 7.7 Hz), 7.42 - 7.28 (m, 3 H), 7.25 (d.2H, J = 8.7 Hz), 7.17 (d, 1H, J = 8.7 Hz), 7.11 (d, 1 H, J = 2.4 Hz), 6.99 (d, 2 H, J = 8.6 Hz), 6.79 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.73 (s, 4 H), 5.14 (s, 2 H), 5.10 (s, 2 H), 4.70 - 4.60 (m, 1 H), 4.19 (t, 2 H, J = 5.3 Hz), 3.72 (t, 2 H, J = 4.4 Hz), 2.13 (s, 3 H), 1.30 (d, 6 H. J = 5.9 Hz), EM cl m / z 583 (M +).

Example No. 54 5-benzyloxy-l- [4- (2-bromo-ethoxy) -benzyl] -2- (4-cyclopentyloxy-phenyl) -3-methyl-1H-indole P.f. = 110 - 112"C; 7.47 (d, 2 H, J = 7.0 Hz), 7.38 (t, 2 H, J = 7.0 Hz), 7.35 - 7.28 (m, 1 H), 7.25 (d, 2 H, J = 8.8 Hz), 7.18 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H, J = 2.4 Hz), 6.98 (d, 2 H, J = 8.6 Hz), 6.79 (dd, 1 H, J = 8.6 Hz, 2.4 Hz), 6.78 -6.74 (m, 4 H), 5.16 (s, 2 H), 5.11 (s, 2 H), 4.86 - 4.83 (m, 1 H), 4.20 (t , 2 H. J = 5.3 Hz), 3.73 (t, 2 H, J = 5.5 Hz), 2.15 (s, 3 H), 2.00 - 1.87 (m, 2 H), 1.79 - 1.65 (m, 4 H) , 1.63-1.56 (m, 2 H); IR (KBr) 2950, 2910, 1610 cm "1: MS m / z 609. 611 (M +, Br present).

Example No. 55 5-benzyloxy-l- [4- (2-bromo-ethoxy) -benzyl] -3-methyl-2- (4-trifluoromethyl-phenyl) -lH-indo P.f. = 106 -109 ° C; 1 H NMR (DMSO) 7.83 (d.2H, J = 8.1 Hz), 7.60 (d.2H, J = 7.9 Hz), 7.35-7.29 (m, 2H), 7.48 (d, 2H, J = 8.6 Hz), 7.39 (t, 2 H, J = 7.0 Hz), 7.18 (d, 1 H, J = 2.2 Hz), 6.87 (dd, 1 H, J = 9.0 Hz, 2.6 Hz), 6.77- 6.71 (m, 4 H), 5.22 (s, 2 H), 5.12 (s, 2 H), 4.20 (t, 2 H, J = 5.3 Hz), 3.72 (t, 2 H, J = 5.3 Hz), 2.20 (s, 3 H); IR (KBr) 2910, 2850, 1620 cm "1; MS on M / z 595, 593 (M +) Example No. 56 5-benzyloxy-l- [4- (2-bromo-ethoxy) -benzyl] -3-methyl-2- (4-methyl-phenyl) -lH-indole P.f. = 82-95 ° C; JH NMR (DMSO) 7.46 (d, 2 H, J = 7.2 Hz), 7.45 - 7.18 (m, 8 H), 7.12 (d, 1 H, J 2.4 Hz), 6.81 (dd, 1 H, J = 2.4 Hz, 8.6 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.10 (s, 2 H), 4.19 (t, 2 H, J = 5.3 Hz), 3.72 (t, 2 H, J = 4.4 Hz), 2.34 (s, 3 H), 2.15 (S, 3 H); MS at m / z * 539 (M +).

Example No. 57 5-benzyloxy-l-. { 4- (2-bromo-ethoxy) -benzyl] -3-methyl-2- (4-chloro-phenyl) -lH-indole "H NMR (DMSO) 7.52 (d 2H, J = 8.6Hz), 7.46 (d, 2H, J = 6.8Hz), 7.38 (m 4 H), 7.36 (m, 1H), 7.25 (d 1H, J = 9.0Hz), 7.14 d, 1H, J = 2.4Hz), 6.83 (dd, 1H, J = 8.8Hz, J = 2.5 Hz), 6.72 (m 4H), 5.17 (s, 2H), 5.11 (s 2H) , 4.19 (t, 2H, J = 5.5 Hz), 3.72 (t, 2H, J = 5.5 Hz), 2.16 (s, 3H), MS m / z 559 (M +).

Data for some 3-methyldole-phenylethyl chlorides used as intermediates Reaction scheme 12 Table 5 Experimental procedure for the synthesis of 3-methylindol phenethyl chloride Method 5a Illustrated for Example No. 58 -Benzyloxy-2- (3-benzyloxy-phenyl) -1- [4- (2-chloro-ethoxy) -benzyl] -3-methyl-1H-indole To a solution of 9.7 g (0.0231 mole) of 5-benzyloxy-3-methyl-2- (3-benzyloxyphenyl) -lH-indole (indole Example No. 17) in 80 ml of dry DMF is added 0.85 g of hydride. sodium (60% in mineral oil). After allowing this mixture to stir for 30 minutes (until no further bubbling is indicated) 4.8 g of l-chloromethyl-4- (2-chloroethoxy) -benzene CAS No. [99847-87-7] is added. The reaction mixture is allowed to react at room temperature overnight. 200 ml of ethyl acetate are added to the reaction mixture and then washed with water (3 x 100 ml). The organic solution is collected, washed with saturated brine, stirred, dried over magnesium sulfate, filtered and evaporated to dryness in a rotary evaporator. The product recrystallizes from ethyl acetate.

-, P.f. = 125-127 ° C; lH NMR (DMSO) 7.48-7.46 (d, 2 H, J = 6.8 Hz), 7.40 - 7.35 (m, 7 H), 7.33 - 7.28 (m, 2 H), 7.23 - 7.21 (d.1 H, J = 8.8 Hz), 7.13 - 7.12 (d, 1 H. J = 2.2 Hz), 7.07 - 7.04 (m, 1 H), 6.94 - 6.92 (d, 2 H, J = 6.1 Hz), 6.83 6.80 (dd, 1 H, J = 2.5 Hz, J = 6.3 Hz), 6.78 - 6.72 (m, 4 H), 5.14 (s, 2 H), 5.11 (S, 2 H), 5.04 (s, 2 H), 4.13 - 4. 1 0 (t 2 H, J = 5. 1 Hz), 3.86 - 3.84 (t, 2 H. J = 5.1 Hz), 2.14 (s, 3 H); IR 3420. 2900 cm "1; MS m / z, 587 (M +); CHN calculated for C3ßH34CIN03.

Physical data for phenethyl indole chlorides The following compounds were made according to Reaction Scheme 12 as described in Method 5a using the appropriately substituted Inners No. 18, No. 20.

Example No. 59 5-benzyloxy-2- (4-benzyloxy-3-fluoro-phenyl) -1- [4- (2-chloro-ethoxy) -benzyl-3-methyl-1H-indole P.f. = 88-91 ° C; ? NMR (DMSO) 7.49-7.43 (m, 4H), 7.43-7.28 (m, 7H), 7.26-7.21 (m, 2H), 7.13-7.09 (m, 2H), 6.88-6.72 (m, 5H), 5.21 (s, 2H), 5.18 (s, 2H), 5.11 (s, 2H), 4.13 (t, 2H, J = 5.2 Hz), 3.87 (t, 2H, J = 5.2 Hz), 2.16 (s, 3H); MS on M / z 605 (M +); CHN calculated for C3ßH33CIFN03 - $ 8. Example No. 60 5-benzyloxy-l- [4- (2-chloro-ethoxy) -benzyl] -3-methyl-2- (4-trifluoromethoxy-phenyl) -lH-indole P.f. = 108 - 110 ° C; * H NMR (DMSO) 7.49 - 7.48 (m, 6 H), 7.40 -7.25 (m, 4 H), 7.17 - 7.16 (d, 1 H, J = 2.9 Hz), 6.88 - 6.84 (m, 1 H), 6.77 - 6.72 (m, 4 H), 5.20 (s, 2 H), 5.14 - 5.13 (d, 2 H, J = 2.3 Hz), 4.16 - 4.11 (m, 2 H), 3.89 - 3.84 (m, 2 H), 2.19 - 2.17 (m, 3 H) -, IR 3400, 2900, 1600 cm1; EM the m / z 566 (M +); CHN calculated for C32H27CIF3N03 + 0.25 H20.

Aminoethoxy indoles Diagram of reaction 13 Table 6 Experimental procedure for the synthesis of 3-methylaminoethoxyindole Method 6 Illustrated for Example No. 63 Bromide substitution -Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole A solution of Example No. 50 (3.2 g, 5.0 mmol) in 50 mL of THF is treated with piperidine (5.0 mL, 50 mmol) and heated to reflux. After 5 hours, the reaction mixture is concentrated and taken up in EtOAc, washed with saturated NaHCO 3, dried over MgSO 4 and subjected to column chromatography on silica gel using an elution gradient of EtOAc / hexane to EtOAc. An amount of 2.7 g of product is a white solid with a m.p. = 93-95 ° C; 'HRMN (DMSO) 7.48-7.46 (m, 4 H), 7.42-7.38 (m, 4 H), 7.38-7.32 (m, 2 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.19 ( d, 1 H, J = 9.0 Hz), 7.12-7. 1 0 (m, 3 H), 6.80 (dd, 1 H, J = 8.8, 2.4 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.13 (s, 2 H), 5.11 ( s, 2 H), 3.93 (t, 2 HJ = 5.7 Hz), 2.60-2.50 (m, 2 H), 2.41-2.30 (m, 4 H), 2.15 (s, 3 H), 1.47-1.42 (m.4 H), 1.36-1.32 (m, 2 H); EM BAR 637 (M + H *).

Alternative procedure Method 6a Chloride substitution Illustrated synthesis for product No. 76 Example No. 765-benzyloxy-2- (3-benzyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole To a solution of 1.1 g (0.00953 mol) of 5-benzyloxy-2- (3-benzyloxy-phenyl-1- [4- (2-chloro-ethoxy) -benzyl] -3-methyl-1H-indole (Example No 58) in 10 ml of DMF is added 1.1 ml (0.0112 mole) of piperidine and 0.93 g (00561 mole) of potassium iodide.The reaction mixture is heated to "40-50 ° C for 4 hours. The reaction mixture is stirred at room temperature, 150 ml of ethyl acetate are added and the mixture is washed with water (3 x 100 ml) .The organic solution is collected, washed with saturated brine, stirred, dried over sodium sulfate, magnesium, filtered and evaporated to aL-¿, ia¿A provide 1.0 g of product product after purification. P.f. = 125 - 126 ° C: XH NMR (DMSO) 7.48 - 7.45 (d, 2 H, J = 7.2 Hz), 7.41 - 7.35 (m, 7 H). 7.33 - 7.28 (m, 2 H), 7.23 - 7.21 (d, 1 H, J = 9.0 Hz), 7.13 - 7.12 (d, 1 H, J = 2.4 Hz), 7.06 - 7.03 (m, 1 H), 6.95 - 6.91 (m, 2 H), 6.83 - 6.80 (dd, 1 H, J = 2. 4 Hz, J = 6.3 Hz), 6.75 - 6.70 (m, 4 H), 5.13 (s, 2 H), 5.11 (?, 2 H), 5.02 (s, 2 H), 3.93 - 3.90 (t. H, J = 6.0 Hz), 2.56 - 2.53 (t, 2 H, J = 5.9 Hz), 2.49 - 2.48 (m, 4 H), 2.14 (s, 3 H), 1.46 - 1.40 (m, 4 H) , 1.35-1.31 (m, 2 H) -, IR (KBr) 3400, 2900 cm "1; MS m / z 636 (M +); CHN calculated for C43H44N203 + 0.25 H, 0.

Physical data for the substituted amine compounds The following compounds are prepared by Reaction Scheme 13 using Method 6. Except for Examples No. 76 and No. 84, which are prepared using Method 6a.

Example No. 61 5-benzyloxy-2- (4-ethoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 188 - 191 ° C; l NMR (DMSO) 7.45 (d, 2 H, J = 7.3 Hz), 7.40 - 7.25 (m, 5 H), 7.17 (d, 1 H, J = 8.8 Hz), 7.11 (d, 1 H, J = 2.2 Hz), 7.01 (d, 2 H, J = 6. "" 8 Hz), 6.78 (dd, 1 HJ = 8.8Hz, J = 2.4 Hz), 6.73 (S, 4H), 5.15 (s, 2 H) 5.10 (s, 2 H), 4.05 (c, 2 H, J 6.8 Hz), 3.93 (t, 2 H, J = 6.0 Hz), 2.55 (t, 2 H, J = 5.7 Hz), 2.41 - 2.35 (m , 4 H), 2.14 (s, 3 H), 1.46-1.40 (m, 4H), 1.38-1.30 (m, 5 H); MS at m / z 574 (M +).

Ejenrolo No. 62 5-benzyloxy-2-phenyl-3-methyl-1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -lH-indole Oil; a H NMR (DMSO) 7.50-7.43 (m, 4 H), 7.42-7.37 (m, 5 H), 7.33-7.30 (m, 1 H), 7.22 (d, 1 H, J = 8.8 Hz), 7.14 ( d, 1 H, J = 2.4 Hz), 6.81 (d, 1 H, J = 6.6 Hz), 6.72 (s, 4 H), 5.18 (s, 2 H), 5.1 1 (S, 2 H), 3.90 (t, 2 H, J = 6.1 Hz), 2.81-2.75 (m, 2 H), 2.68-2.59 (m, 4 H), 2.16 (s, 3 H), 1.58-1.43 (m, 8 H); MS at m / z 544 (M +).

Example No. 645-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 106 - 107 ° C; JH NMR (DMSO) 7.47 (d, 4 H. J = 8.3 Hz), 7.41 - 7.36 (m, 4 H), 7.36 - 7.30 (m, 2 H), 7.29 (d, 2 H, J = 8. 8 Hz), 7.19 (d, 1 H, J = 8.8 Hz), 7.14 - 7.10 (m, 3 H), 6.80 (dd, 1 H, J = 8.8 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 3.90 (t, 2 H, J = 5.9 Hz), 2.76 (t, 2 H, J = 5.9 Hz), 2.64 2.56 (m, 4 H), 2.15 (s, 3 H), 1.58-1.44 (m, 8 H); EM BAR m / z 651 (M + H +).

Example No. 655-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-diisopropylamino-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 148 - 150 ° C. H NMR (DMSO) 7.47 (d, 4 H, J = 8 3 Hz), 7.41 - 7.36 (m, 4 H), 7.36 - 7.32 (m, 2 H), 7.28 (d, 2 H, J = 8. 8 Hz), 7.19 (d, 1 H, J = 9.0 Hz), 7.13 - 7.08 (m, 3 H), 6.80 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 6.76 - 6.68 (m, 4 H), 5.14 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 3.75 (t, 2 H, J = 7.0 Hz), 2.95 (m, 2 H), 2.67 (t, 2 H, J = 7.0 Hz), 2.15 (s, 3 H), 0.93 (d, 12 H, J = 6.4 Hz); EM BAR m / z 653 (M + H +).

Example No. 66 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [4- (2-butyl-methylamino-1-ylethoxy) -benzyl] -lH-indole P.f. = 101 - 104 ° C; H NMR (DEMO) 7.45 (d, 4 H, J = 7.5 Hz), 7.40 - 7.25 (m, 8 H), 7.19 (d, 1 H J = 8.8 Hz), 7.12-7.08 (m, 3 H), 6.80 (dd 1 H, J = 6.5 Hz, J = 2.4 Hz), 6.72 (s, 4 H), 5.14 (s, 2 H), 5.13 (s, 2 H), 5.10 (s, 2 H), 3.91 (t, 2 H, J = 5.9 Hz), 2.64-2.59 (m, 2H), 2.35-2.29 (m, 2 H), 2.17 (s, 3 H), 2.14 (S, 3 H) ), 1.40-1.31 (m, 2 H), 1.25-1.19 (m 2 H), 0.83 (t, 3 H, 7 2 Hz); MS at m / z 638 (M +).

Example No. 66a 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1-. { 4-dimethylamino) -ethoxy] -benzyl} -lH-indole P.f. = 123-124 ° C Example No. 675-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-l- 4- [2- (2-methyl-piperidin-1-yl) -ethoxyl-benzyl} -lH-indole P.f. = 121 ° C Example No 68 5-Benzyloxy-2 - (4-benzyloxyphenyl) -3-methyl-l- ^ 4 [2- (3-methyl-piperidin-1-yl) -ethoxy] -benzyl} -lH-indole P. f. = 90 ° C Example No. 695-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1-. { 4- [2- (4-methyl-piperidin-1-yl) -ethoxyl-benzyl] -lH-indole P.f. = 98 ° C; 'H NMR (DMSO) 7.46 (d, 4 H, J = 7.2 Hz), 7.42 -7.36 (m, 4 H), 7.36 7.31 (m, 2 H), 7.28 (d, 2 H, J = 8.6 Hz) , 7.19 (d, 1 H, J = 9.0 Hz), 7.12 - 7. 1 0 (m, 3 H), 6.80 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 3.93 (t, 2 H) , J = 5.9 Hz), 2.85 - 2.78 (m, 2 H), 2.62 - 2.56 (m, 2 H), 2.15 (s, 3 H), 1.97 - 1.87 (m, 2 H), 1.55 - 1.47 (m, 2 H), 1.30 - 1.20 (m, 1 H), 1.15 - 1.02 (m, 2 H), 0.85 (d, 3 H, J = 6.6 Hz); MS esl m / z 651 (M + 1) +.

Example No. 70 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1. { 4- [2- ((cis) -2,6-Dimethyl-piperidin-1-yl) -ethoxy] -benzyl} -lH-indole P.f. = 106 - 107 ° C; H NMR (DMSO) 7.46 (d, 4 H, J = 8.1 Hz), 7.42 - 7.36 (m, 4 H), 7.37- 7.31 (m, 2 H), 7.29 (d, 2 H, J = 8.8 Hz) , 7.18 (d, 1 H, J = 8.8 Hz), 7.14 - 7.09 (m, 3 H), 6.80 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 6.72 (s, 4 H), 5.14 ( s, 2 H), 5.13 (S, 2 H), 5.11 (s, 2 H), 3.84 (t, 2 H, J = 7.0 Hz), 2.84 (t, 2 H, J = 6.6 Hz), 2.44 2.37 (m, 2 H), 2.15 (s, 3 H), 1.60 - 1.43 (m, 3 H), 1.32 - 1.18 (m, 1 H), 1.16 - 1.06 (m, 2 H), 1.01 (d, 6) H, J = 6.2 Hz).

Example No. 71 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-4- [2- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -ethoxy] -benzyl} -lH- indole P.f. = 107 ° C; EM ESI m / z 705 (M + l) + Example No. 71a (1S.4R) -5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl. { 4- [2- (2-Aza-bicyclo [2.2.1] hgpt-2-yl) -ethoxy] -benzyl} -IH-indole The (SS, 2R) -2-aza-bicyclo [2.2.l] heptane used to replace the bromide is prepared according to the procedure underlined in Sin. Comm, 26 (3), 577-584 (1996).

P.f. = 95 - 100 ° C; * H NMR (DMSO) 7.32 - 6.55 (m, 21 H), 5.10 -4.90 (m, 6 H), 3.69 (t, 2 H, J = 5.9 Hz), 2.65 - 2.5 (m, 3 H), 2.10 (?, 2 H), 2.0 (S, 3 H), 1.50 - 1.0 (m, 7 H).

Example No. 72 5-benzyloxy-2- (4-flouro-phenyl) -3-methyl- [4- (2-azepan-1-yl-ethoxy) -benzyl-1H-indole Oil; X H NMR (DMSO) 7.50 - 7.43 (m, 2 H), 7.42 - 7.33 (m, 4 H), 7.32 - 7.20 (m, 4 H), 7.13 (d, 1 H, J = 2.4 Hz), 6.83 ( d.1 H, J = 2.4 Hz, 6.7 Hz), 6.71 (s, 4 H), 5.14 (s, 2 H), 5.11 (s, 2 H), 3.89 (t, 2 H, J = 5.9 Hz) , 3.20 (m, 4 H), 2.74 (t, 2 H, J = 6.0 Hz), 2.15 (s, 3 H), 1.60 - 1.40 (m, 8 H); MS at m / z 562 (M +).

Example No. 72a 5-benzyloxy-2- (4-flouro-phenyl) -3-methyl-1- [4- (2-pjperidin-1-yl-ethoxy) -benzyl] -lH-indole Oil, JH NMR (DMSO) 7.32 - 6.53 (m, 16 H), 5.00 (s, 2 H), 4. 96 (S, 2 H), 3.77 (t, 2 H, J = 5.8 Hz), 3.22 - 3.14 (m, 4 H), 2.40 (t, 2 H, J = 5.8 Hz), 2.0 (s, 3 H) ), 1.29-1.17 (m, 6 H).

Example No. 72b 5-benzyloxy-2- (4-chlorophenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole Oil; JH NMR (DMSO) 7.52 (d, 2 H, J = 8.6 Hz), 7.46 (d, 2 H, J = 6.8 Hz), 7.41 7.37 (m, 4 H), 7.35 - 7.29 (m, 1 H), 7.25 (d, 1 H, J = 9.0 Hz), 7.14 (d, 1 H. J = 2.4 Hz), 6.83 (dd, 1 H, J = 8.8 Hz, 2.5 Hz), 6.72 - 6.65 (m, 4 H ), 5.16 (s, 2 H), 5.11 (s, 2 H), 3.90 (t, 2 H, J = 5.9 Hz), 2.55 (t, 2 H, J = 6.0 Hz), 2.41 - 2.26 (m, 4 H), 2.16 (?, 3 H), 1.44 - 1.39 (m, 4 H), 1.38 - 1.29 (m, 2 H); MS at m / z 564 (M +).

Example No. 735-benzyloxy -2- [3,4-methylenedioxy-phenyl] -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole Foam, - ^ NMR (DMSO) 7.45 (d, 2 H, J = 7.0 Hz), 7.41-7.37 (m, 2 H), 7.33-7.29 (m, 1 H), 7.19 (d, 1H, J = 8.8 Hz), 7.11 (d, 1 H, J = 2.2 Hz), 7.00 (d, 1 H, J = 7.9 Hz), 6.90 (d, 1 H, 1.4 Hz), 6.82 - 6.78 (m, 2H), 6.74 (s, 4 H), 6.07 (s, 2 H), 5.16 (s, 2 H), 5.10 (S 2 H), 3.93 (t, 2 H, J = 6.0 Hz), 2.56 (t, 2 H, J = 6.0Hz), 2.41-2.35 (m, 4H), 2.15 (s, 3H), 1.48-1.41 (m, 4H), 1.38-1.28 (m, 2H); MS at m / z 574 (M +).

Example No. 74 5-benzyloxy-2- [4-isopropoxy-phenyl] -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole Foam; JH NMR (DMSO) 7.46 (d, 2H, J = 7.7 Hz), 7.42 - 7.28 (m, 3 H), 7.25 (d, 2 H, J = 8.7 Hz), 7.17 (d, 1 H, J = 8.7 Hz), 7.11 (d, 1 H, J = 2.4 Hz), 6.99 (d, 2 H, J = 8.6 Hz), 6.79 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.73 (s, 4 H), 5.14 (s, 2 H), 5.10 (S, 2 H), 4.70 - 4.60 (m, 1 H), 3.92 (t, 2 H, J = 5.7 Hz), 2.55 (t, 2 H, 5.7 Hz), 2.40 - 2.30 (wide e, 4 H), 2.15 (s, 3 H), 1.50 - 1.40 (m, 4 H), 1.40 1.30 (m, 2 H), 1.28 (d, 6 H, J = 6.2 Hz); MS at m / z 588 (M +).

Example No. 755-benzyloxy-2- [4-methoxy-phenyl] -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole Oil; XH NMR (DMSO) 7.46 (d, 2H, J = 7.2Hz), 7.45-7.18 (m, 8H), 7.12 (d, 1 H, J = 2.4 Hz), 6.81 (dd, 1 H, J = 2.4 Hz , 8.6 Hz), 6.73 (S, 4 H), 5.15 (s, 2 H), 5.10 (s, 2 H), 3.92 (t, 2 H, J = 5.9 Hz), 2.5 5 (t, 2 H, J = 5.9 Hz), 2.45 - 2.30 (m, 7 H), 2. 1 0 (s, 3 H), 1.50 - 1.40 (m, 4 H), 1.48 - 1.35 (m, 2 H); MS at m / z 544 (M +).

Example No. 771- [4- (2-azepan-l-yl-ethoxy) -benzyl] -5-benzyloxy-2 (3-benzyloxy-phenyl) -3-methyl-lH-indole P.f. = 103 - 105 ° C; 'H NMR (DMSO) 7.47 - 7.45 (d, 2 H, J = 8.1 Hz), 7.41 - 7.35 (m, 7 H), 7.32 - 7.29 (t, 2 H, 7.0 Hz), 7.23 - 7.21 (d, 1 H, J = 8.7 Hz), 7.13 - 7.12 (d, 1 H, J = 2.1 Hz), 7. 06 - 7.03 (m, 1 H), 6.95 - 6.91 (m, 2 H), 6.83 - 6.80 (m, 1 H), 6.75 - 6.73 (m, 4 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 5.02 (s 2 H), 3.90 - 3.87 (t 2 H, J = 6.0 Hz ), 2.76 - 2.73 (t, 2) H, J = 6.0 Hz), 2.49 - 2.48 (m, 4 H), 2.13 (S, 3 H), 1.51 (s, 8 H); IR 3400, 2900 cm "1; MS m / z 650 (M +); CHN calculated for C44H46N203.

Example No. 78 5-Benzyloxy-2- (4-benzyloxy-3-luoro-phenyl) -3-methyl- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 125-128 ° C, * H NMR (DMSO) 7.50 - 7.45 (m, 4 H), 7.43 -7.28 (m, 7 H), 7.26 - 7.20 (m, 2 H), 7.14 - 7.09 (m, 2 H), 6.82 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.72 (s, 4 H), 5.21 (s, 2 H), . 16 (S, 2 H), 5.11 (S, 2 H), 3.94 (t, 2 H, J = 5.8 Hz), 2.62 -2 56 (m, 2 H). 2.41 - 2.36 (m, 4 H), 2.15 (S, 3 H), 1.45 -1.40, (m, 4 H), 1.40 - 1.31 (m, 2 H); MS m / Z 654 (M +); CHN calculated for C43H43FN203.

Example No. 79 5-benzyloxy-2- (4-benzyloxy-3-luoro-phenyl) -3-methyl-1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -lH- indole P.f. = 122 - 124 ° C. H NMR (DMSO) 7.50 - 7.28 (m, 10 H), 7.26 - 7.20 (m, 2 H), 7.15 - 7 10 (m, 2 H), 6.88 - 6.76 (m, 2 H), 6.70 (s, 4 H), 5.22 (s, 2 H), 5.16 (s, 2 H), 5.11 (s, 2 H), 3.92 - 3.86 (m, 2 H), 2.82 - 2.65 (m, 2 H), 2.65 - 2.55 (m, 4 H) ), 2.15 (s, 3H), 1.60-1.4 (m, 8H); MS at m / z 668 (M +); CHN calculated for C44H45FN203.

Example No. 80 5-benzyloxy-2- (3-methoxy-phenyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -3-methyl-1H-indole P.f. 86-87 ° C; ? NMR (DMSO) 7.50 - 7.49 (m, 2 H), 7.46 - 7.31 (m, 4 H), 7.24 - 7.21 (d, 1 H, J = 8.8 Hz), 7.15 - 7.14 (d, 1 H, J = 2.3 Hz), 7.00 - 6.93 (m, 2 H), 6.88 - 6.81 (m, 2 H), 6.75 (s, 4 H), 5.18 (s, 2 H), 5.12 (s, 2 H) ), 3.96 - 3.92 (t, 2 H, J = 5.9 Hz). 3.71 (s, 3 H), 2.59 - 2.55 (t, 2 H, J = 5.8 Hz), 2.37 (s, 4 H), 2.18 (s, 3 H), 1.49 - 1.42 (m, 4 H), 1.37 -1.34 (m, 2 H), MS m / z 561 (M +). CHN calculated for C37H40N2O3 + 0.25 H20.

Example No. 81 5-benzyloxy-3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2- (4-trifluoromethoxy-enyl) -lH-indole P.f. = 107 - 108 ° C; "H NMR (DMSO) 7.52 - 7.45 (m, 6 H), 7.41 - 7.26 (m, 4 H), 7.17 - 7.16 (d, 1 H, J = 2.3 Hz), 6.87 - 6.84 (dd, 1 H, J = 2.3 Hz, J = 6.4 Hz), 6.75 - 6.68 (m, 4 H), 5.18 (s, 2 H), 5.13 (s, 2 H), 3.95 - 3.91 (t 2 H. J = 5.9 Hz ), 2.58 2.54 (t 2 H. J = 5.9 Hz), 2.38 - 2.34 (m, 4 H), 2.17 - 2.15 (S, 3 H), 1.49 - 1.42 (m, 4 H), 1.35 - 1.34 ( d.2 H. J = 4.9 Hz), IR 3400. 2900. 1600 cm "1-, EM at m / z 615 (M +); CHN calculated for C37H37F3N203.

Example No. 82 (2-. {4- [5-benzyloxy-f-enyl] -3-methyl-indol-1-ylmethyl] -phenoxy-1-ethyl-cyclohexyl-amino P.f. = 87-90 ° C; aH NMR (DMSO) 7.46 (dd, 4H, J = 6.9Hz, 0.6Hz), 7.42-7.27 (m, 9H), 7.19 (d.1H, J = 9Hz), 7.14-7.08 (m, 3H), 6.80 (dd, 1H, J = 6.4Hz, 2.4Hz), 6.75-6.70 (m, 4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.13 (s, 2H). 3.89 (t, 2H, J = 5.6), 2.84 (m, 2H,), 2.48 (m, 1H), 2.14 (s, 3H), 1.80 (m, 2H), 1.65 (m, 2H), 1.61 (m , 1H), 0.96-1.19 (m, 5H); MS at m / z 650 (M +); CHN calculated for C44H46N204.

Example No. 835-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1-4-methyl-piperazin-1-yl) -ethoxy] -benzyl} -lH- indole P.f. = 88-91 ° C; "H NMR (DMSO) 7.47 (m, 4H), 7.26-7.42 (m, 8H), 7. 19 (d, 1H, J = 8.8), 7.10-1.12 (m, 3H), 6.80 (c, 1H, J = 6.3Hz, 2.4Hz), 6.73 (m, 4H), 5.15 (s.2H), 5.13 (s.2H), 5.11 (s, 2H), 3.94 (t, 2H, J = 5.9Hz), 2.59 (t, 2H), 2.42 (m, 4H), 2.29 (m, 4H). 2.15 (s, 3H), 2.12 (s, 3H); MS at m / Z 652 (M +); CHN calculated for C43H45N303.

Example No. 841- [4- (2-azepan-l-yl-ethoxy) -benzyl] -5-benzyloxy-2- (3-methoxy-phenyl) -3-methyl-lH-indole P.f. = 103 - 105 ° C; * H NMR (DMSO) 7.47-7.45 (d, 2 H, J = 8.1 Hz), 7.41-7.35 (m, 7 H). 7.32 - 7.29 (t, 2 H, 7.0 Hz), 7.23 - 7.21 (d, 1 H, J = 8.7 Hz), 7.13 - 7.12 (d, 1 H, J = 2.1 Hz), 7.06 - 7.03 (m, 1 H), 6.95 - 6.91 (m, 2 H), 6.83 - 6.80 (m, 1 H), 6.75 - 6.73 (m, 4 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 5.02 (s, 2 H), 3.90 - 3.87 (t, 2 H, J = 6.0 Hz), 2.76 - 2.73 (t, 2 H, J = 6.0 Hz), 2.49 - 2.48 (m, 4 H), 2.13 (s) , 3 H), 1.51 (s, 8 H); IR 3400, 2900 cm "1, MS m / z 650 (M +). CHN calculated for C44H46N203.

Data and procedures for compounds of Table 11 (Table of ER receiver data below) of the text Table 7 Hydrogenation of indoles containing benzyl ethers Method 7 Illustrated for Example No. 97 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol A suspension of 10% Pd / C (1.1 g) in EtOH is treated with a solution of No. 63 (2.2 g, 3.4 mmol) in THF / EtOH. Cyclohexadiene (6.0 ml, 63 mmol) is added and the reaction is stirred for 48 hours. The catalyst is filtered through Celite and the reaction mixture is concentrated and chromatographed on silica gel using an elution gradient of MeOH / CH2Cl2 (1:19 to 1:10) to give 0.8 g of the product as a white solid. P.f. = 109-113 ° C; CHN calculated for C39H32N203 + 0.5 H20: * H NMR 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.84 (d, 2 H, J = 8.8 Hz), 6.79 (d, 1 H, J = 2.2 Hz), 6.74 (s, 4 H), 6.56 (dd, 1 H, J = 8.8, 2.4 Hz ), 5.09 (s, 2 H), 3.95-3.93 (m, 2 H), 2.60-2.51 (m, 2 H), 2.39-2.38 (m, 4 H), 2.09 (s, 3 H), 1.46- 1.45 (m, 4 H), 1.35-1.34 (m, 2 H); IR (KBr) 3350 (broad), 2920, 1620, 1510 cm "1, MS (El) m / z 456.

Alternatively, the compounds can be dissolved in a THF / EtOH solution (or other suitable solvent) and hydrogenated with H2 and 10% Pd / C using either a balloon or a Parr hydrogenator. Any procedure is effective. In many of the examples, the compounds are made in acid addition salts. The procedure for the preparation of an HCl salt is given below (Method 8).

Method 8 1. 0 g of the free base Example No. 97 of the above hydrogenation process in a large test tube is dissolved in 20 ml of MeOH. This is treated with slow addition of 2.6 ml of 1.0 N HCl and then 4.0 ml of deionized water. The tube partially opens to the atmosphere to encourage slow evaporation of solvents. After about 10 minutes the crystals begin to appear and after 4 hours the solution is filtered and the solid crystals are washed with water. The product is presented as 0.42 g in white crystalline plates with a melting point of 184-185 ° C. The mother liquors provide an additional crop of 0.30 g of white solid with a melting point of 177-182 ° C, CHN calculated for C29H32N203 + HCl + 1 H20. Alternatively, the compounds can be made into quaternary ammonium salts. It is provided below an example procedure for the synthesis of Example No. 107 (Method 9).

Method 9 Example No. 107 2- (4-Hydroxy-fo'i 1) -3-Methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol methoiodide Dissolve 0.8 g of Example No. 97 in 18 ml of THF and treat with 2 ml of methyl iodide. The solution is refluxed for 1 hour. The reaction is allowed to come to room temperature and the solids are concentrated to give 0.72 g as a crystalline solid. P.f. = 214 - 217 ° C. CHN calculated for C29H32N203 + CH3I + 0.5 H20.

Example No. 106 2- (4-Hydroxy-phenyl) -3-methyl-l- [4- (2-dimethyl-l-yl-ethoxy) -benzyl] -lH-indole-5-ol methoiodide It is prepared in a manner similar to No. 106, except that No. 100 is used for the starting material: P.f. = 245 - 250 ° C; XR NMR (DMSO) 9.66 (s, 1 H), 8.69 (s, 1 H), 7.16 (d, 2 H, J = 8.4 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.84 (d 1 H, J = 8.6 Hz), 6.81 - 6.75 (m, 6H), 6.56 (dd, 1 H, J = 2.4 Hz, 8.7 Hz), 5.12 (s, 2 H), 4.34 (m, 2 H) , 3.70 (t, 2 H, J = 4.6 Hz), 3.11 (S, 9 H), 2.09 (S, 3 H), - IR (KBr) 3250, 1500, 1250; MS at m / z 416 (M +); CHN calculated for C26H2ßN203 + 1.09 CH3I + 0.8 H20.

Physical data for final deprotected compounds The following compounds are free base, HCl salts or acetate salts. They are prepared according to the procedure indicated in method 7 using the appropriate benzyl ether for precursor. When a compound of table 1 does not contain a free phenolic functionality, then it is unnecessary to de-benzylate and method 7 is not applied. Physical data for these compounds (No. 85, No. 90-No. 91) are presented below.

Example No. 85 4-. { 3 -Methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl]] H-indole} (HCl) P.f.134 - 137 ° C; H NMR (DMSO) 10.33 (s, 1 H), 7.56-7.3 (m, 6 H), 7.32 (d, 1 H, J = 8.1 Hz), 7.14 - 7.0 (m, 2 H), 6.80 (s, 4 H), 5.24 (S, 2 H), 4.28 (t, 2 H, J = 5.0 Hz), 3.50 - 3.40 (m, 4 H), 3.0 -2.95 (m, 2 H), 2. 10 (s, 3 H), 1.80 - 1.60 (m, 5 H), 1. 40 - 1.35 (m, 1 H); IR 3400, 2900, 1510, 1250 cm "1, MS (+) BAR m / z 425 [M + H] ': CHN calculated for C29H32N20 + 1.0 HCl + 1.0 H20.

Example No. 86 Hydrochloride of 4-. { 3-Methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-2-yl > -phenol (HCl) P.f. = 192 - 194 ° C; 'H NMR (DMSO), 10.28 (s, 1 H), 9.75 (s, 1 H), 7.51 - 7.49 (m, 1H), 7.27 (dd, 1 H, J = 7.0 Hz, 0.7 Hz), 7.18 ( d, 2 H, J = 7.6 Hz), 7.09 - 7.02 (m, 2 H), 6.86 (d, 2 H, J = 8.6 Hz), 6.80 (s, 4 H), 5.20 (s, 2 H), 4.28 (t, 2 H, J = 4.9 Hz), 3.50 - 3.35 (m, 4 H), 3.0 - 2.85 (m, 2 H), 2.20 (s, 3 H), 1.80 - 1.60 (m, 5 H) , 1.40-1.30 (m, 1 H); IR 3400, 3100, 2600, 1500, 1225 cm "1 MS m / z 440 (M +); CHN calculated for C29H32N202 + 1 HCl.

Example No. 87 3-Methyl-2-phenyl-1- [4- (2-pjperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 228-230 ° C; H NMR 10.1 (broad s, 1 H), 8.76 (s, 1 H), 7.55-7.45 (m, 5 H), 7. 10 (d, 1 H, J = 8.8 Hz), 6.85 - 6.80 (m, 5 H), 6.61 (d, 1 H, J = 8.8 Hz), 5.15 (S, 2 H), 4.25 (t, 2 H , J = 4.8 Hz), 3.47-3.35 (m, 4 H), 2.96-2.87 (m, 2 H), 2.12 (s, 3 H), 1.75-1.65 (m, 5 H), 1.31-1.28 (m , 1 HOUR); EM the m / z 440 (M +). CHN calculated for C27H32N202 + 1 HCl + .33 H20; IR (KBr) 3200, 2500, 1450, 1200 cm -1.

Example No. 88 4-. { 5-methoxy-3-methyl-l-. { 4- [2- (piperidin-1-yl-ethoxy] -benzyl] -1 H-indol-2-yl} - phenol P.f.t = 87-90 ° C; 'H NMR (DMSO) 9.67 (s, 1 H), 7.16 (d, 2 H, J = 8.6 Hz), 7.16 (1 H embedded), 6.98 (d.1 H, J = 2.4 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 6.73 (s, 4 H), 6.69 (dd, 1 H. J = 8.8, 2.4 Hz), 5.13 (s, 2 H), 3.94 (t, 2 H, J = 5.7 Hz), 3.76 (s, 3 H), 2.63-2.50 (m, 2 H). 2.43-2.31 (m, 4 H), 2.15 (s, 3 H), 1.49-1.40 (m, 4 H), 1.39-1.25 (m, 2 H); IR (KBr) 3400 (broad), 2920.1610.1520 cm "1, MS the M / z 470; CHN calculated for C30H34N203 + 0.1 H20.

Example No. 89 2- (-methoxy-phenyl) -3-methyl-1-. { 4- [2- (piperidin-1-yl) -ethoxy] -benzyl} -lH-indol-5-ol P.f. = 188-189 ° C; H NMR (DMSO) 8.70 (l s, 1 H), 7.27 (d, 2 H, J = 8.6 Hz), 7.06 (d, 1 H, J = 8.6 Hz), 7.02 (d, 2 H, J = 8.8 Hz .), 6.81 (d, 1 H, J = 2.2 Hz), 6.73 (s, 4 H), 6.58 (dd, 1 H, J = 8.8, 2.4 Hz), 5.10 (s 2 H), 3.93 (t , 2 H, J = 5.9 Hz). 3.79 (s, 3 H), 2.56 (t, 2 H, J = 5.9 Hz), 2.41 - 2.32 (m, 4 H), 1.10 (s, 3 H), 1.47-1.41 (m, 4 H), 1.34 -1.31 (m, 2 H); MS at m / z 470; CHN calculated for C30H34N203 + 0.1 H20.

Example No. 90 5-methoxy-2- (4-methoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole (HCl) P.f. = 188-191 ° C; ? NMR (DMSO) 10.35 (broad s, 1 H), 7.27 (d, 2 H, J = 8.8 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 7.03 (d, 2 H J = 8.6 Hz), 6.99 (d, 1 H, J 2.5 Hz), 6.8 2 - 6.7 8 (m, 4 H), 6.71 (dd, 1 H, J = 8.8 Hz), J = 2.5 Hz), 5.17. (s, 2 H), 4.31 4.22 (m, 2 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.43 - 3.36 (m 4 H), 2.97 -2.83 (m, 2 H), 2.16 ( s, 3 H), 1.80 - 1.59 (m 5 H), 1.41 - 1.26 (m, 1H); IR (KBr) 2920 1450 1250 cm -1; MS m / z 484 (M +); CHN calculated for C31H36N203 + 1 HCl.

Example No. 91 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -5-methoxy-2- (4-methoxy-phenyl) -3-methyl-1H-indole (HCl) P.f. = 161-163 ° C; 'H NMR (DMSO) 10.65 (broad s, 1 H), 7.27 (d, 2 H, J = 8.8 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 7.03 (d, 2 HJ = 8.6 Hz), 6.99 (d, 1 H, J = 2.5 Hz), 6.82 - 6.77 ( m, 4 H) 6.71 (dd, 1 H, J = 8.8 Hz, J = 2.5 Hz), 5.17 (s 2 H), 4.27 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H ), 3.44 3.30 (m, 4 H), 3.17 (m, 2H), 2.16 (s, 3H), 1.82 - 1.77 (m, 4 H), 1.63 - 1.48 (m, 4 H) -, EM the m / z 499 (M +); CHN calculated for C32H3sN203 + 1 HCl.

Example No. 92 2- (4-Ethoxyphenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 173-175 ° C; "H NMR (DMSO) 8.69 (s, 1 H), 7.25 (d, 2 H, J = 8.8 Hz), 7.04 (d, 1 H, J = 8.8 Hz) 6.99 (dd, 2 H, J = 6.8 Hz , J = 2.0 Hz), 6.80 (d 1 H, J = Hz), 6.73 (s 4H), 6.59 (dd, 1 H, J = 8.5 J = 2.2), 5.09 (1 s 2H), 4.05 (c, 2 H, J = 7.03 Hz), 3.93 (t, 2 H, J = 6.0 Hz), 2.62 - 2.56 (m, 2H), 2.41 - 2.36 (m 4 H), 2.09 (s, 3H), 1.45 - 1.41 ( m, 4H), 1.38-1.30 (m, 5H); MS m / z 484 (M +), CHN calculated for C31H36N203 + .25H20.

Example No. 93 1- [4- (2-azepan-l-yl-ethoxy) -benzyl] -2- (4-ethoxy-phenyl) -3-methyl-lH-indol-5-ol P.f. = 133-135 ° C; * H NMR (DMSO) 8.69 (s, 1 H), 7.25 (d, 2- H, J = 8.8 Hz), 7.04 (d, 1 H, J = 8.8 Hz). 6.99 (dd 2 H, J = 6.8 Hz, J = 2.0 Hz), 6.80 (d, 1 H, J = 2.2 Hz), 6.73 (s 4 H), 6.59 (dd, 1 H, J = 8.5 Hz, J = 2.2 Hz), 5.09 (s, 2H), 4.05 (c, 2H, J = 7.03 Hz), 3.90 (t, 2H, J = 6.1 Hz), 2.75 (t, 2H, J = 6.0 Hz), 2.62 - 2.58 (m, 4 H), 2.09 (s, 3 H), 1.58-1.44 (m, 8 H), 1.33 (t, 3H, J = 7.0 Hz); IR (KBr) 2930, 1470, 1250 cm "1; MS m / z 498 (M +); CHN calculated for C32H3BN203 Example No. 94 4-f 5-Fluoro-3-methyl-l- [4- (2-Pidperidin-1-yl-ethoxy) benzyl] -lH-indol-2-yl} -phenol (HCl) P.f. = 223-225 ° C; * H NMR (DMSO) 10.30 (broad s, 1 H), 7.27 -7.23 (m, 2 H), 7.17 (d 2 H, J = 8.6 Hz), 6.88 - 6.79 (m, 7H), . 20 (s, 2H), 4.28 (t, 2H J = 5.0 Hz), 3.42 - 3.35 (m, 4 H), 3. 00 - 2.85 (m, 2 H), 2.14 (s, 3 H), 1.78 - 1.70 4 H), 1.67 - 1.59 (m, 1 H). 1.40-1.26 (m, 1 H); MS on M / z 458 (M +).

Example No. 95 1- ^ 4- (2-Azepan-1-yl-ethoxy) -benzyl] -3-methyl-2-phenyl-1H-indol-5-ol (HCl) P.f. = 203-204 ° C; H NMR (DMSO) 10.50 (broad s, 1 H), 8.80 (s, 1 H), 7.50-7.38 (m, 5 H); 7.10 (d, 1 H, J = 8.8 Hz), 6.83 - 6.77 (m, 5 H), 6.60 (d, 1 H, J = 6.6 Hz), 5.15 (s, 2 H), 4.26 (t, 2 H, J = 5.2 Hz), 3.45 - 3.35 (m, 4 H), 3.21-3. 1 0 (m, 2 H), 2.12 (s, 3 H), 1.85-1.75 (m, 4 H), 1.70 - 1.51 (m, 4 H); MS at M / z 454 (M +); CHN calculated for C30H34N202 + 1 HCl.

Example No. 96 2- (4-hydroxy-phenyl) -3-methyl-l- [4- (2-pyrrolidin- -yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 105-110 ° C; CHN calculated for C28H30N203 + 0.4 H20; * H NMR (DMSO) 9.65 (s, 1 H), 8.67 (s, 1 H), 7.15 (d, 2 H, J 8.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.84 (d, 2 H) , J = 2 H), 6.79 (d.

H, J = 2.4 Hz), 6.56 (dd, 1 H, J = 8.6, 2.2 Hz), 6.74 (s, 4 H), 5.09 (s, 2 H), 3.95 (t, 2 H, J = 5.7 Hz ), 3.39-3.23 (m, 4 H), 2.80-2.75 (, 2 H). 2.09 (s, 3 H), 1.67-1.64 (m, 4 H); IR (KBr) 3410 (broad), 1620, 1510 cm 'EM (El) m / z 442 Ejenrolo No. 97 1- [4- (2-Azepan-l-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-lH-indol-5-ol (HCl) P.f. = 168-171 ° C; "HNMR (DMSO) 10.11 (broad s, 1H), 9.70 (s, 1H), 8.71 (?, 1 H), 7.15 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.85 (d, 2 H, J = 8.8 Hz), 6.80 - 6.77 (m, 5 H), 6.56 (dd, 1 H, J = 8.8 Hz, 2.2 Hz), 5.11 (s, 2 H) , 4.26 (t, 2 H, J = 4.6 Hz), 3.48 - 3.30 (m, 4 H), 3.22 - 3.08 (m, 2 H), 2.09 (s, 3 H), 1.83 - 1.76 (m, 4 H) ), 1.67-1.48 (m, 4 H), IR (KBr) 3500 broad, 3250 broad, 2900, 1610, EM BAR mJz 471 (M + H +), CHN calculated for C30H34N2O3 + 2.5 H20 + HCl.

Example No. 98 Acetate salt of Example No. 97 It is prepared by precipitation of the free base No. 97 from acetone and acetic acid. P.f. = 174 - 178 ° C Example No. 99 1- [4- (2-Azocan-l-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-lH-indol-5-ol P.f. = 98-102 ° C; "H NMR (DMSO) 9.63 (s, 1 H), 8.68 (s, 1 H), 7.15 - 7.13 (m, 2 H), 7.05 (d, 1 H, J = 8.5 Hz), 6.83 (dd, 2 H, J = 2.0 Hz, 6.6 Hz), 6.79 (d, 1 H, J = 2.2 Hz), 6.73 (s, 4 H), 6.55 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 5.08 ( s, 2 H), 3.89 (t, 2 H, J = 5.7 Hz), 2.74 (t, 2 H, J = 5.4 Hz), 2.55 (broad s, 4 H), 2.08 (S, 3 H), 1.55 (s, 2 H), 1.46 (s, 8 H), IR 3400, 2900, 1250 cm "1; MS m / z 484 (M +); CHN calculated for C31H36N203 + .30 H20.

Example No. 1002- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-dimethyl-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 95-105 ° C; IR (KBr) 3400 broad, 2900, 1610 cm "1, MS m / z 416 (M +); CHN calculated for C26H2ßN203 + 0.5 H20.

Example No. 1012- (4-hydroxy-phenyl) -3-Methyl-l- [4- (2-diethyl-l-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 100- 107 ° C. CHN calculated for C28H32N20, + 0.25 H20: H NMR (DMSO) 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (d, 2 H, J = 8.6 Hz), 7-.05 (d, 1 H, J = 8.8 Hz), 6.84 (d, 2 H, J = 8.6 Hz), 6.79 (d, 1 H. 2.2 Hz), 6.74 (s, 4 H) , 6.56 (dd, 1 H, J = 8.8. 2. 4 Hz), 5.09 (?, 2 H), 3.95-3.85 (m, 2 H), 2.80-2.60 (m, 2 H), 2.58-2.40 (m, 4 H), 2.09 (s, 3 H). 0.93 (t 6 H. J = 7.0 Hz), IR (KBr) 3410 (broad), 2950, 1610, 1510 cm "1; EM BAR 445 (M + H +).

Example No. 102 1- [4- (2-Dipropylamino-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol P.f. = 83 - 86"C; aH NMR (DMSO) 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (d, 2 H, J = 8.6), 7.04 (d, 1 H, J = 8.6 Hz), 6.83 (d, 2 H, J = 8.6 Hz), 6.78 (d, 1 H, J = 2.2 Hz), 6.72 (m, 4 H), 6.55 (dd, 1 H, J = 2.4 Hz, 8.2 Hz), 5.08 (s, 2 H), 3.88 (t, 2 H, J = 6.0 Hz), 2.80 - 2.63 (m, 2 H), 2.59 - 2.45 (m, 4 H), 2.10 (s, 3 H) ), 1.41-1.30 (m, 4 H), 0.79 (t, 6 H, J = 7.3 Hz), IR 3400, 2900, 1250, EM BAR m / z 473 [M + H +], CHN calculated for C30H36N203 +. 20 H20.

Example No. 103 1- [4- (2-dibutylamino-ethoxy) -benzyl] -2- (4-hvdroxyphenyl) -3-methyl-lH-indol-5-ol Foam; H NMR (DMSO) 9.63 (s, 1H), 8.66 (s, 1 H), 7.15 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8. 8 Hz), 6.8 3 (d, 2 H, J = 8.6 Hz), 6.79 (d, 1 H, J4.2 Hz), 6.78 - 6.71 (m, 4 H), 6.55 (dd, 1 H, J = 8.6 Hz J = 2.4 Hz ), 5.10 (.S, 2 H), 3.8 8 (t, 2 H, J = 5.5 Hz), 2.68 - 2.62 (m, 2H), 2.42-2.34 (m, 4 H), 2.08 (s 3 H), 1.38-1.19 (m, 8H), 0.82 (t 6 H, J 7.2 Hz); IR (KBr) 3400, 1450 cm "1; MS m / z 501 (M +).

Example No. 104 1- [4- (2-Dylsopropylamino-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol P.f. = 96-102 ° C; JH NMR (DMSO) 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (d.2H, 8.6 Hz), 7.04 (d, 1H J = 8.6 Hz), 6.83 (d, 2 H, J = 8.6 Hz), 6.79 (d, 1 H. J = 2.4 Hz), 6.77 - 6.69 (m, 4 H), 6.56 (dd, 1 H, J = 8 6 Hz, 2.2 Hz), 5.08 (s 2 H), 3.75 (t, 2 H, J = 7.0 Hz), 3.01 - 2.92 (m, 2 H), 2.67 (t, 2 H, J = 7.0 Hz), 2.09 (s, 3 H) , 0.93 (d, 12 H, 6.6 Hz); IR (KBr) 3400 broad, 2940, 1620 cm "1; MS BAR m / z 473 (M + H +); CHN calculated for C30H36N203 + 0.5 H20.

Example No. 105 l-. { 4- [2- (Butyl-methyl-amino) -ethoxyl-benzyl} -2- (4-hydroxy-phenyl) -3-methyl-lH-Indol-5-ol P.f. = 102-107 ° C; lH NMR (DMSO) 9.60 (s, 1 H), 8.67 (s, 1 H), 7.14 (d, 2 H, J = 8.4 Hz), 7.04 (d, 'l H, J = 8.6 Hz), 6.82 ( d, 2 H, J = 8.8 Hz), 6.78 (d, 1 H, J = 2.3 Hz), 6.73 (s, 4 H), 6.5 5 (dd, 1 H, J = 8.8 Hz, J = 2.4 Hz) , 5.08 (s, 2 H), 3.92 (t, 2H, J = 6.0 Hz), 2.64-2.59 (m, 2 H), 2.38-2.29 (m, 2 H), 2.20 (broad s, 3 H), 2.08 (s, 3 H), 1.40-1.31 (m, 2 H), 1.25- 1. 19 (m, 2 H), 0.83 (t 3 H, 7.2 Hz); IR (KBr) 3420.1460, 1230 cm "1; MS m / z 638 (M +).

Example No. 108 2- (4-hydroxy-f-enyl) -3-methyl-1-. { 4- 12- (2-methyl-piperidin-1-yl) -ethoxy] -benzyl ^ -lH-indol-5-ol P.f. = 121 - 123 ° C; lH NMR (DMSO) 9.65 (s, 1 H), 8.68 (s, 1 H), 7.14 (d, 2 H, J = 8.6 Hz), 7.04 (d, 1 H, J = 8.8 Hz), 6.84 (d , 2 H, J = 8.6 Hz), 6.79 (d, 1 H, J = 2.0 Hz), 6.74 (s, 4 H), 6.56 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.09 (s) , 2 H), 3.97 - 3.86 (m, 2 H), 2.95 - 2.73 (m, 2 H), 2.62 - 2.53 (m, 1 H), 2.36 2.14 (m, 2 H), 2.09 (s, 3 H ), 1.61 - 1.30 (m, 4 H), 1.28 - 1.09 (m, 2 H), 0.98 (d, 3 H, J = 5.1 Hz); IR (KBr) 3400, 2920, 2850, 1610 cm1; CHN calculated for C30H34N203 + 0.25 H20.

Example No. 109 2- (4-hydroxy-phenyl) -3-methyl-1-} 4- [2- (3-methyl-piperidin-1-yl) -ethoxy] -benzyl-1H-indol-5-ol P.f. = 121 - 123 ° C; "H NMR (DMSO) 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (dd, 2 H, J = 8.3 Hz, 1.4 Hz), 7.04 (dd, 1 H, J = 8.6 Hz, 1.2 Hz), 6.84 (dd, 2 H, J = 8.6 Hz, 1.7 Hz), 6.79 (s, 1 H), 6.79 (s, 4 H), 6.56 (d, 1 H, J = 8.6 Hz), 5.08 (s, 2 H), 3.94 (t, 2 H, J = 5.0 Hz), 2.86 - 2.71 (m, 2 H), 2.63- 2.50 (m, 2 H), 2.48 (s, 3 H), 1.92 - 1.79 (m, 2 H), 1.63 - 1.35 (m, 5 H), 0. 79 (d, 3 H, J = 5.2 Hz); IR (KBr) 3400, 2910, 1625 cm "1; CHN calculated for C30H34N2O3 + 0.25 H20.

Example No. 110 2- (4-hydroxy-phenyl) -3-methyl-l- [4-r2- (4-methyl-piperidin-1-yl) -ethoxy] -benzyl] -lH-Indol-5-ol (HCl) P.f. = 154-162 ° C; X H NMR (DMSO) 10.00 (s broad, 1 H), 9.71 (s, 1 H), 8.71 (s, 1 H), 7.15 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.85 (d, 2 H, J = 8.6 Hz), 6.83 - 6.77 (m, 4 H), 6.57 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 5.11 ( s, 2 H), 4.27 (t, 2 H, J = 1 4.8 Hz), 3.51 - 3.35 (m, 4 H), 3.01 - 2.37 (m, 2 H), 2.09 (s, 3 H), 1.74 (d, 2 H, J = 13.4 Hz), 1.61 - 1.37 (m, 4 H), 0.88 (d, 3 H, J = 6.4 Hz); IR (KBr) 3410, 2910, 1620 cm "1; MS m / z 470 (M + H +); CHN calculated for C30H34N203 + HCl + 2 H20.

Example No. 111 l-. { 4- [2- (3,3 -Dimethyl-piperidin-1-yl) -ethoxy] -benzyl} -2- (4-hydroxy-phenyl) -3-methyl-lH-indol-5-ol P.f. = 100 ° C; H NMR (DMSO) 9.65 (s, 1 H), 8.67 (s, 1 H), 7.15 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.84 (d , 2 H, J = 8.6 Hz), 6.79 (d, 1 H, J = 2.4 Hz), 6.74 (s, 4 H), 6.56 (dd, 1 H, J = 8.8, 2.4 Hz), 5.09 (s, 2 H), 3.93 (t, 2 H, J = 5.7 Hz), 2.60-2.50 (m, 2 H), 2.37-2.25 (m, 2 H), 2.09 (s, 3 H), 2.10-1.99 (m , 2 H), 1.46 (t, 2 H, J = 5.9 Hz), 1.13 (t, 2 H, J = 6.4 Hz), 0.86 (s, 6 H); EM at m / z 484.

Example No. 112 l-. { 4- [2 ((cis) -2,6-dimethyl-piperidin-1-yl) -ethoxy] benzyl} -2- (4-hvdroxy-phenyl) -3-methyl-lH-Indol-5-ol P.f. = 114 - 121"C; H NMR (DMSO) 9.62 (s, 1 H), 8.64 (s, 1 H), 7.11 (d, 2 H, J = 8.6 Hz), 7.01 (d, 1 H, J = 8.6 Hz), 6.81 (d, 2 H, J = 8.8 Hz), 6..76 (d, 1 H, J = 2.2 Hz), 6.72 - 6.66 (m, 4 H), 6.53 (dd, 1 H, J = 8.6 Hz, 2.2 Hz), 5.06 (S, 2 H), 3.86 - 3.72 (m, 2 H), 2.86 - 2.76 (m, 2 H), 2.43 - 2.35 (m, 2 H), 2. 06 (s, 3 H), 1.78 - 1.59 (m, 3 H), 1.29 - 1.17 (m, 1 H), 1.12 - 0.92 (m, 8 H); IR (KBr) 3400 broad, 2920.1630 cm "1; EM BAR m / z 485 (M + H +); CHN calculated for C31H36N203 + 0.1 acetone + 0. 75 H20.

Example No. 113 2- (4-hydroxy-f-enyl) -1- [2- (4-hydroxy-pjperidin-1-yl) -ethoxy] -benzyl'V-3-methyl-lH-Indol-5- ol P.f. = 80 - 90 ° C; JH NMR (DMSO) 9.66 (s, 1 H), 8.68 (s, 1 H), 7.15 (d, 2 H, J = 7.6 Hz), 7.04 (d, 1 H, J = 8.8 Hz), 6.84 (dd) , 2 H, J = 2.0 Hz, 6.6 Hz), 6.78 (d, 1 H, 2.2 Hz), 6.73 (s, 4 H), 6.55 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 5.09 ( s, 2 H), 4.50 (d, 1 H, J = 4.2 Hz), 3.92 (t, 2 H, J = 5.8 Hz), 3.40 (m, 2 H), 2.72 (m, 2H), 2.60 (m , 2 H), 2. 1 0 (s, 3 H), 2.15-2.05 (m, 1 H), 1.75-1.63 (m, 2, H), 1.42-1.28 (m, 2 H); IR (KBr) 3400, 2900, 1250 cm "1; MS m / z 472 (M +); CHN calculated for C29H32N204 + .11 CH2C12.

Example No. 114 (1S.4R) -l-. { 4- [2- (2-aza-bicyclo [2.2.1] hept-2-yl) ethoxy] -benzyl} -2- (4-hydroxy-phenyl) -3-methyl-lH-Indol-5-ol P.f. = 125 - 130 ° C; * H NMR (DMSO) 9.65 (s, 1 H), 8.67 (s, 1 H), 7.13 (d, 2 H, J = 8.6 Hz), 7.04 (d, 1 H, J = 8.5 Hz), 6.83 ( dd, 2 H, J = 2.0 Hz, 6.6 Hz), 6.78 (d, 1 H, J = 2.2 Hz), 6.73 (s, 4 H), 6.55 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 5.08 (s, 2 H), 3.95 -3.8 (m, 2 H), 2.90 - 2.70 (3 H), 2.30 - 2.20 (m, 2 H), 2.10 (s, 3 H), 1.70 - 1.60 (m, 1 H), 1. 60 - 1.30 (m, 4 H), 1.25 - 1.15 (m, 2 H); IR (IBr) 3400, 2950, 1500; EM BAR m / z 469 [M + H] *; CHN calculated for C3OH32N203 + .34 EtOAc.

Example No. 115 2- (4-hydroxy-phenyl) -3-methyl-1-. { 4- [2- (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) -ethoxyl-benzyl > -lH-indol-5-ol P.f. = 98 - 100 ° C; X H NMR (DMSO) 9.64 (s, 1 H), 8.67 (s, 1 H), 7.14 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.6 Hz), 6.84 (d , 2 H, J = 8.6 Hz), 6.79 (d, 1 H, J = 2.4 Hz), 6.75 - 6.69 (m, 4 H), 6.56 (dd, 1 H, J = 8.6 Hz, 2.4 Hz), 5.08 (s, 2 H) 3.83 (t, 2 H, J = 5.9 Hz), 3.12 - 3.07 (m, 1 H), 2.94 - 2.87 (m, 1 H), 2.85 (d, 1 H, J = 9.2 Hz ), 2.78 - 2.70 (d, 1 H), 2.17 (d, 1 H, J = 9.2 Hz), 2.09 (s, 3 H), 1.55 - 1.42 (m, 2 H), 1.29 (c, 2 H, J = 13.6 Hz), 1. 14 (s, 3 H), 1.11 - 1.02 (m, 2 H), 0.96 (S, 3 H), 0.82 (s, 3 H); IR (KBr) 3400 wide, 2940, 2900, 1630 cm "1; MS ESI m / z 525 (M + H +); CHN calculated for C34H40N203 + 0.5 H20.

Example No. 116 2- (4-Fluoro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 201 - 203 - C - l? Ü NMR (DMSO) 10.22 (s, 1 H), 8.78 (s, 1 H), 7.45 - 7.35 (m, 2 H), 7.34 - 7.25 (m, 2 H), 7.11 (d, 1 H, J = 8.6 Hz), 6.90 - 6.70 (m, 5 H), 6.61 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 5.15 (s, 2 H), 4.27 (t , 2 H, 4.8 Hz), 3.50 - 3.34 (m, 4 H), 3.0 - 2.85 (m, 2 H), 2. 1 0 (s, 3 H), 1.80 (m, 5 H), 1.40 - 1.25 (ra, 1 H); MS at m / z 458 (M +); CHN calculated for C29H31FN 202 + 1 HCl.

Example No. 117 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-fluoro-phenyl) -3-methyl-1H-indol-5-ol P.f. = 181 - 184 ° C; 'H NMR (DMSO) 10.68 (s, 1 H), 8.80 (s, 1 H), 7.50 - 7.36 (m, 2 H), 7.34 - 7.26 (m, 2 H), 7.12 (d, 1 H, J = 8.8 Hz), 6.86 - 6.73 (m, 5 H), 6.63 (dd 1H, J = 2.2 Hz, 8.5 Hz), 5.13 (s, 2H), 4.29 (t, 2 H, J = 5.2 Hz), 3.50 - 3.30 (m, 4 H), 3.20 - 3.08 (m, 2 H), 2.11 (s, 3 H), 1.90 - 1.70 (m, 4 H), 1.68 - 1.45 (m, 4 H); IR (KBr) 3500, 3100, 2910, 1450, 1250 cm "1; MS e / I m / z 472 (M +); CHN calculated for C30H33FN202 + 1 HCl.

Example No. 118 2- (3-methoxy-4-hydroxy-phenyl) -3-methyl-1- [4- (2-pjperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol ( HCl) P.f. = 161-163 ° C; H NMR (DMSO) 10. 12 (broad s, 1H), 9.25 (s, 1 H), 8.71 (S 1 H), 7.05 (d, 1H, J = 8. @), 6.85-6.79 (m, 8 H), 6.57 (dd, 1H, J = 8.5Hz, J = 2.2Hz), 5.13 (s, 2H), 4.27 (t, 2H, J = 5.0Hz), 3.64 (s, 3H), 3.44 - 3.37 ( m, 4 H), 2.93-2.85 (m, 2H), 2.11 (s, 3H), 1.80-1.60 (m, 5 H), 1.40-1.25 (m, 1H); MS at m / z 486 (M +); CHN calculated for C30H34N204 + 1HC1 + 1 H20; IR (KBr) 3190, 1470, 1230 was "1.

Example No. 119 2-Benzo [1.3] dioxol-5-yl-3-methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 122-125 ° C; tB NMR (DMSO) 9.80 (broad s, 1 H), 8.73 (s, 1 H), 7.07 (d, 1 H, J = 8.7 Hz), 7.02 (d, 1 H, J = 8.0 Hz), 6.89 (d, 1 H, J = 1.7 HZ), 6.80 - 6.75 (m, 6 H), 6.5 8 (dd, 1 H, J = 6.4 Hz, J = 2.2Hz), 6.06 (s, 2H), 5.13 (s, 2H), 4.30- 4.19 (, 2 H), 3.51 - 3.30 (m, 4 H), 2.99-2.85 (m, 2 H), 2.10 (s, 3 H), 1.81-1.59 (m, 5 H), 1.41-1.26 (m, 1 H ); MS m / z 484 (M +); CHN calculated for C30H32N2O4 + HCl +.26 H20.

Example No. 120 2- (4-isopropoxy-f-enyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 120-125 ° C; H NMR (DMSO) 10.18 (s, 1 H), 8.73 (s, 1 H), 7.25 (d, 2 H, J = 8.6 Hz), 7.04 (d, 1 H, J = 8.8 Hz), 6.99 ( d, 2 H, J = 8.8 Hz), 6.82 - 6.80 (m, 5 H), 6.59 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 5.12 (s, 2 H), 4.67 - 4.61 (m , 1 H), 4.27 2 H, J = 4.8 Hz), 3.50 - 3.35 (m, '4 H), 3.0 - 2.85 (m, 2 H), 2. 1 0 (S, 3 H), 1.80 1.60 ( m, 5 H), 1.40-1.25 (m, 7 H); IR (KBr) 3400, 3000, 1500, 1250; MS at m / z 498 (M +); CHN calculated for C32H3ßN203 + 1.0 HCl +.70 H20.

Example No. 121 1- [4- (2-azepan-l-yl-ethoxy) -benzyl] -2- (4-isopropoxy-phenyl) -3-methyl-lH-indol-5-ol (HCl) P.f. = 120-125 ° C; H NMR (DMSO) 10.36 (s, 1 H), 8.73 (s, 1 H), 7.26 - 7.23 (m, 2 H), 7.05 (d, 1 H, J = 8.8 Hz), 7.01- 6.98 (m, 2 H), 6.85 - 6.75 (m, 5 H), 6.57 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 5.12 (s, 2 H), 4.67 - 4.61 (m, 1 H), 4.27 ( t, 2 H, J = 4.8 Hz), 3.50 - 3.30 (m, 4 H), 3.20 - 3.10 (m, 2 H), 2.10 (s, 3 H), 1.85 - 1.75 (m, 4 H), 1.65 - 1.50 (m, 4 H), 1.27 (d, 6 H, J = 6.1 Hz); IR (KBr) 3400, 1500, 1250: MS m / z 512 (M +); Calculated for C33H40N203 + 1.0 HCl +.5 H20.

Example No. 122 2- (4-Cyclo-phenyloxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-Indol-5-ol P.f. = 121 - 135 ° C; 'H NMR (DMSO) 9.80 (broad s, 1 H), 8.72 (S, 1 H), 7.24 (d, 2 H, J = 8.8 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6. 98 (d, 2 H, J = 8.8 Hz), 6.83 - 6.78 (m, 5 H), 6.57 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), 5.13 (s, 2 H), 4.86 - 4.82 (m, 1 H), 4.25 (t, 2 H, J = 4.8 Hz), 3.50 - 3.38 (m, 4 H), 2.92 (c, 2 H, J = 8.8 Hz), 2.11 (s, 3 H) , 1.98 - 1.85 (m, 2 H), 1. 8 1 - 1.56 (m, 1 1 H), 1.41 - 1.29 (m, 1 H); IR (KBr) 3400, 2920, 1620 crn "1; MS m / z 524 (M +); CHN calculated for C31H40N203 + 0.5 H20.

Example No. 1233-methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2- (4-trifluoromethyl-phenyl) -lH-indol-5-ol P.f. = 174 ° C; "H NMR (DMSO) 8.8 (s, 1 H), 7.82 (d, 2 H, J = 8.1 Hz), 7.59 (d, 2 H, J = 7.9 Hz), 7.17 (d, 1 H, J = 8.6 Hz), 6.86 (d, 1 H, J = 2.4 Hz), 6.75 - 6.68 (m, 4 H), 6.65 (dd, 1 H, J = 8.8 Hz, 2.4 Hz), S. 16 (s, 2 H) ), 3.93 (t, 2 H, J = 5.7 Hz), 2.62 - 2.56 (m, 2 H), 2.42 - 1.32 (m, 4 H), 2.15 (s, 3 H), 1.48 - 1.40 (m, 4) H), 1.39 1.29 (m, 1 H): IR (KBr) 3410, 2910. 2850, 1620 cm "1; MS at m / z 508 (M +); CHN calculated for C30H31F2N2O2 + 0.25 H, 0.

Example No. 1243-methyl-l- [4- (2-piperidin-l-yl-ethoxy) -benzyl] -2-p-tolyl-lH-indol-5-ol P.f. 162 - 164 ° C; * H NMR (DEMSO) 8.70 (s, 1 H), 7.28 - 7.24 (, 4 H), 7.07 (d, 1 H. J8.4 Hz), 6.81 (d.1 H, J = 2.2 Hz), 6.73 (s, 4 H), 6.58 (dd, 1 H. J = 2.4 Hz, 8.8 Hz), 5.11 (s, 2 H), 3.92 (t, 2 H, J = 5.9 Hz), 2.55 (t, 2 H) , J = 5.9 Hz), 2.45 -2.30 (m, 7 H), 2.10 (s 3 H), 1.50 - 1.40 (m, 4 H), 1.48 - 1.35 (m, 2 H); IR (KBr) 3400, 2900, 1200; MS at m / z 454 (M +); CHN calculated for C30H34N202.

Example No. 1252- (4-chloro-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 161-164 ° C; H NMR (DMSO) 10. 12 (broad s, 1 H), 8.80 (s, 1 H), 7.53 (d, 2H, J = 8.3 Hz). 7.36 (d, 2H, J = 8.8 Hz), 7.12 (d, 1 H, J = 8.8 Hz), 6.85-6.75 (m, 5 H). 6.63 (dd, 1H, J = 8.8 HZ, J = 2.4 Hz), 5.14 (s, 2H), 4.29-4.22 (m, 2H), 3.45-3.36 (m, 4 H), 2.97 - 2.84 (m, 2H) ) 2.11 (s, 3H), 1.83-1.61 (m, 5H), 1.37-1.25 (m, 1H); MS at m / z 475 (M +); CHN calculated for C29H31CIN202 + HC1 +.25 H20.

Example No. 126 2- (2,4-dimethoxyfyl) -3-methyl-l- 4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 85-92 ° C; X H NMR (DMSO) 8.62 (s, 1 H), 7.10 (d, 1 H, J = 8.4 Hz), 7.01 (d, 1 H, J = 8.6 Hz). 6.80 - 6.70 (m, 5 H), 6.69 (d, 1 H, 2.2 Hz), 6.59 (dd, 1 H. J = 2.4 Hz. 8.5 Hz), 6.52 (dd, 1 H, J = 1..4 Hz, 8.8 Hz), 5.02 (d, 1 H, J = 6.5 Hz). 4.83 (d, 1 H, J = 6.3 Hz), 4.0 - 3.90 (m, 2 H), 3.80 (s, 3 H), 3.67 (s, 3 H), 2.65 - 2.50 (m, 2 H), 2.45 - 2.30 (m, 4 H), 2.0 (s, 3 H), 1.55 - 1.40 (m, 4 H), 1.39 - 1.30 (m, 2 H); IR (KBr) 3400, 2900, 1520, 1250; MS m / z 500 (M +); CHN calculated for C31H36N204 + .05 CH2Cl2.

Example No. 1272- (3-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 115 - 118 ° C; X H NMR (DMSO) 9.57 (s, 1 H), 8.71 (s, 1 H), 7.27 - 7.23 (t, 1 H, J = S. 1 Hz), 7.06 - 7.04 (d, 1 H, J = 8.8 Hz). 6.81 - 6.74 (m, 8 H), 6.59 6.56 (dd.1 H, J = 2.3 Hz, J = 6.3 Hz), 5.12 (s, 2 H). 3.94 - 3.91 (t, 2 H. J = 5.9 Hz), 2.57 - 2.54 (t, 2 H, J = 5.8 Hz), 2.36 (s, 4 H), 2.11 (s, 3 H), 1.45 - 1.41 ( m, 4 H), 1.34-1.33 (m, 2 H); IR (KBr) 3400, 2900 cm "1; MS m / z 456 (M +), CHN calculated for C29H32N203 + 1.0 H20.

Example No. 128 1- [4- (2-azepan-l-yl-ethoxy) -benzyl] -2- (3-hydroxyphenyl) -3-methyl-lH-indol-5-ol P.f. = 94-97 ° C, 'H NMR (DMSO) 9.58 (s, 1 H). 8.71 (1 h), 7.27 - 7.23 (t, 1 H, J = 7.9 Hz), 7.07 - 7.04 (d, 1 H, J = 8.7 Hz), 6.81 - 6.74 (m, 8 H), 6.59 - 6.56 (dd, 1 H, J = 2.4 Hz, J = 6.3 Hz), 5.12 (s, 2 H), 3.9 (m, 2 H), 2.80 (s, 2 H), 2.65 (s, 4 H), 2.11 (s, 3 H), 1.54 - 1.50 (m, 8 H); IR 3400, 2900 cm "1; MS m / z 470 (M +); CHN calculated for C30H34N2O3 + 0.75 H20 + 0.23 Ethyl acetate.

Example No. 129 2- (3-f luoro-4-hydroxy-f-enyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole-5- ol P.f. = 11 7-119 ° C; X H NMR (DMSO) 10. 1 (s, 1 H), 8.71 (s, 1 H), 7.10 - 6.95 (m, 4 H), 6.80 (d, 1 H, J = 2.2 Hz), 6.74 (s, 4 H) , 6.59 (dd, 1H, J = 2.2 Hz, 8.5 Hz), 5.1 (s, 2H), 3.93 (t, 2H, J 5.9 Hz), 2.56 (t, 2H, J = 5.8 Hz), 2.44 - 2.30 ( m, 4H), 2. 1 0 (s, 3 H), 1.45 -1.40 (m, 4H), 1.36-1.32 (m, 2H); MS at m / z 475 (M +); CHN calculated for C29H31FN203.

Example No. 130 2- (3-f luoro-4-hydroxy-f-enyl) -3-methyl-1- [4- (azepan-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 88-91 ° C; ? HNMR (DMSO) 10.10 (s, 1H), 8.71 (s, 1H), 7.12-6.94 (m, 4 H), 6.80 (d, 1 H, J 2.2 Hz), 6.74 (s, 4 H), 6.58 (dd, 1 H, J = 2.2 Hz, 8.5 Hz), 5.10 (s, 2 H), 3.9 lt, 2 H, J = 5.9 Hz), 2.76 (t, 2 H, J = 5.9), 2.62 - 2.60 (m, 4H), 2.10 (s, 3 H), 1.70 - 1.40 (m, 8 H); MS at m / Z 488 (M +); CHN calculated for C30H33FN2O3.

Example No. 131 2- (3-methoxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol P.f. = 120 - 123 ° C. "H NMR (DMSO) 8.76 (s.1 H), 7.42-7.46 (t, 1 H. J = 7.9 Hz), 7.12-7.90 (d, 1 H, J = 8.7 Hz), 6.99-6.92 (m, 2 H), 6.86 - 6.83 (m, 2 H), 6.76 (S, 4 H), 6.63 - 6.60 (dd, f H, J = 2.1 Hz, J = 6.5 Hz), 5.14 (s, 2 H), 3.96 - 3.92 (t, 2 H, J, = 5.9 Hz), 3.70 (s, 3 H), 2.59 - 2.55 (t, H. J = 5.9 Hz), 2.37 (s, 4 H), 2.14 (s, 3 H), 1.49-1.44 (m, 4 H), 1.35-1.34 (m, 2 H), IR 3400, 2950, 1600 cm "1; MS at m / z 471 (M +); CHN calculated for C30H34N203.

Example No. 1323-methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -2- (4-trifluoromethoxy-phenyl) -lH-indol-5-ol P.f. = 122 - 125 ° C; H NMR (DMSO) 8.80 (s, 1 H), 7.51 - 7.45 (m, 4 H), 7.17 - 7.14 (d, 1 H, J = 8.7 Hz), 6.85 - 6.84 (d, 1H, J = 2.0 Hz), 6.75 - 6.69 (m, 4 H), 6.66 - 6.62 (m, 1 H), 5.14 (S, 2 H), 3.95 - 3.92 (t, 2 H, J = 5.8 Hz), 2.59 - 2.55 (t, 2 H, J = 5.6Hz), 2.49 - 2.38 (m, 4 H), 2.13 (s, 3 H), 1.47 - 1.44 (m, 4 H), 1.36 - 1.34 (d, 2 H, J = 4.8 Hz); IR 3400, 2900, 1600 cm "1; MS m / z 525 (M +); CHN calculated for C30H31F3N203 + 0.25 H, 0 Synthesis procedures and physical data for compounds substituted with chloro, ethyl or cyano groups in position 3 of indole Table 8 Synthesis of 3-chloro analogs No. 133-No. 136 Diagram of reaction 14 Synthesis of 3-chloroindole Example No 140 - R = H Example No. 140 Example No. 141 - R = H Example No. 142 - R = H Example No. 143 - R = CH3 Example No. 140 Formation of hydrazone 4-Benzyloxyphenylhydrazine CAS No. [51145-58-51 (50.0 g, 233.4 mmol) is mixed with 4-benzyloxy acetophenone CAS No. [54696-05-8] (63.0 g, 280.0 mmol) in 800 ml of pure ethanol . A catalytic amount of acetic acid (5 drops ..) is added. The reaction is heated to reflux for 2.5 h. During the development of the reflux, the condensed product is separated by solidification of the hot solution. The solution is reduced by cooling to rt. The desired product is collected by vacuum filtration as a light yellow solid (85 g, 86%). P.f. = 165-174 ° C; * H NMR (DMSO) 8.91 (s, 1 H), 7.68 (d, 2 H, J = 8.8 Hz), 7.48-7.32 (m, 10 H), 7.12 (d.2 H. J = 9 Hz), 7.00 (d, 2 H, J = 8.8 Hz), 6.88 (d, 2 H, J 9.0 Hz). 5.11 (, S, 2 H), 5.01 (s, 2 H), 2. 17 (s, 3 H); MS mz 422 (M +).

Example No. 141 Formation of indole from hydrazone: 5-benzyloxy-2- (4-benzyloxy-phenyl) -lH-indole A flask is charged with N- (4-benzyloxy-phenyl) -N '- [1- (4-benzyloxy-phenyl) ethylidene] -hydrazine (No. 140) (10.0 g, 23.7 mmol), ZnCl2 (8.06 g, 59.17 immoles) and 70 ml of acetic acid. The reaction flask is heated at 105 ° C for no more than 20 min. During the warm-up period, the reaction is carefully monitored by CCD for the disappearance of the initial material. The progress of the reaction can be demonstrated as the product is separated by solidification of the solution while heating. The reaction is then cooled to rt and more separation of crushed product is observed. The reaction content is poured into a separatory funnel containing 100 ml of ether and 200 ml of H20, which is stirred vigorously. The insoluble residue as the desired product is sedimented in the ether layer which is collected by vacuum filtration. The product is further purified by trituration in ether to give a light gray solid (4.4 g, 46%). P.f. = 202 - 204 ° C; X H NMR (DMSO) 11.24 (s, 1 H), 7.73 (d, 2 H, J = 8.8 Hz), 7.48 - 7.4 1 (m, 4 H), 7.45 - 7.27 (m, 6 H), 7.25 (d, 1 H, J = 8.6 Hz), 7.12 - 7.04 (m, 3 H), 6.77 (dd, 1 H, J = 2.4 Hz, 8.6 Hz), 6.65 (d, 1 H, J = 1.5 Hz) , 5.14 (s, 2 H), 5.08 (s, 2 H); IR 3420, 3000, 1625 cm "1, MS m / z 405 (M +); CHN calculated for C28H23N02 + 0.40 H20.

Example No. 142 Chlorination of indole to obtain 5-benzyloxy-3-chloro-2- (4-benzyloxy-phenyl) -lH-indole A flask is charged with 5-benzyloxy-2- (4-benzyloxy-phenyl) -1H-indole No. 141 (8.0 g, 20.0 mmol) and 50 ml of CH2C12. The reaction is cooled to 0 ° C and N-chlorosuccinimide (2.9 g, 22 mol) is added. The reaction is stirred at 0 ° C for 20 min. The reaction is then washed with a 10% sodium sulfite solution, dried over MgSO4 and concentrated. To the resulting solid coffee, MeOH is added and the mixture is stirred for 15 min. The solid is filtered to provide 6.8 g of a tan solid (78%). P.f. = 157-160 ° C; 41 NMR (DMSO) 11.5 (s, 1 H), 7.80 (d, 2 H, J = 7.0 HZ), 7.42 - 7.28 (m, 1 1 H), 7.17 (d, 2 H, J = 8.7 Hz), 7. 01 (d, 1 H, J = 2.2 Hz), 6.88 (dd, 1 H, J = 8.8 Hz, J = 2.4 Hz), 5.17 (s, 2 H), 5.13 (s, 2 H); MS at m / z 439 (M +).

Example No. 143 5-benzyloxy-3-chloro-2- (2-methyl-4-benzyloxy-phenyl) -lH-indole Indole is synthesized in a manner analogous to indole No. 142 immediately preceding: P.f. H NMR (DMSO) 11.34 (s, l H), 7.48-7.44 (m, 4 H), 7.42 - 7.24 (m, 8 H), 7.02 (dd, 2 H, J = 9.3 Hz, J = 2.4 Hz) , 6.95 (dd, 1 H, J = 8.4 Hz, J = 2.6 Hz), 6.88 (dd, 1 H, J = 8.8 Hz, J = 2.4 Hz), 5.16 (s, 2 H), 5.14 (s, 2 H), 2.23 (s 3 H); MS at m / z 453 (M +).

Example No. 144 Alkylation of indole to provide (4 - [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-chloro-indol-1-ylmethyl] -phenoxyl-acetic acid ethyl ester This procedure is carried out in a manner analogous to that indicated by the synthesis of ethyl esters of 3-methylindol acetic acid indicated in method 3. P.f. = 90-94 ° C; XH NMR (DMSO) 7.45 (d, 4H, J = 7.8 Hz), 7.41 - 7.26 (m, 9 H), 7.14 (d, 2 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 2.4 Hz), 6.91 (dd, 1 H, J = 9.0 Hz, J = 2.5 Hz), 6.80-6.74 (m, 4H), 5.24 (s, 2H), . 15 (S, 2H), 5.14 (s, 2H), 4.66 (s-2 H), 4.12 (c, 2H, J = 7.2 Hz), 1. 16 (t, 3H, J = 7.5 Hz); MS at m / z 631 (M +).

Example No. 145 Reduction of No. 144 to obtain No. 145 2-. { 4- [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-chloro-indol-1-ylmethyl] -phenoxy} -ethanol This reaction is carried out in a manner analogous to that indicated for the synthesis of the 3-methylindoles indicated in method 4. The compound is not purified or characterized, but is used as obtained for the next step.

Example No. 146 Bromination of No. 145 to obtain benzyloxy-2- (-benzyloxy-phenyl) -1- [4- (2-bromo-ethoxy) -benzyl] -3-chloro-1H-indole This reaction is carried out analogously to that indicated for the synthesis of 3-methylindoles indicated in the method 5. P.f. = 155-158 ° C; H NMR (DMSO) 7.45 (d 4 H, J = 7.8 Hz), 7.41 - 7.25 (m, 9H), 7.14 (d, 2 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 2.4 Hz ), 6.91 (dd, 1 H, J = 9.0 Hz, J = 2.5 Hz), 6.74 (s, 4H), 5.24 (s, 2 H), 5.15 (s, 2H), 5.14 (s, 2 H), 4.20 (t, 2. H, J = 5.3 Hz), 3.74 (t, 2 H, J = 5.3 Hz); MS at m / z 651 (M +).

Example No. 147 Substitution of No. 146 with piperidine to obtain 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-chloro-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole This reaction is carried out analogously to that indicated for the synthesis of the 3-methylindoles indicated in method 6, using piperidine to replace the bromide. P.f. 96-98 ° C; H NMR (DMSO) 7.45 (d, 4 H, J = 7.8 Hz), 7.40 -7.30 (m, 9 H), 7.14 (d, 2 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 2.4 Hz), 6.91 (dd, 1 H, J = 9.0Hz, J = 2.5 Hz), 6.74 (s, 4 H), 5.24 (S, 2H), 5.15 (s, 2 H), 5.14 (s, 2 H), 3.93 (t, 2 H, J = 6.0 Hz), 2.56 (t, 2 H, J = 6.0 Hz), 2.41-2.32 (m, 4 H), 1.48-1.39 (m, 4 H), 1.38 -1.31 (m, 2 H).

Example No. 148 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-chloro-l- [4- (2-azepan-1-yl-ethoxy) -benzyl] -lH-indole The reaction is carried out in the same way as above, except that the substituted amine used is hexamethylamine. P.f. = 94-97 ° C; 1 H NMR (DMSO) 7.45 (d, 4H, J = 7.8 Hz), 7.42 -7.30 (m, 9H), 7.14 (d, 2 H, J = 8.7 Hz), 7.04 (d, 1 H, J = 2.4 Hz), 6.91 (dd, l H, J = 9.0 Hz, J = 2.5 Hz), 6.74 (s, 4 H), 5.24 (S, 2H), 5.15 (S. 2H), 5.14 (s, 2H), 3.93 (t, 2 H, J = 6.0 Hz), 2.75 (t, 2H, J = 6.0 Hz), 2.63-2.59 (m, 4 H), 1.58-1.44 (m, 8 H); MS at m / z 671 (M +).

Example No. 149 5-benzyloxy-2- (2-methyl-4-benzyloxy-phenyl) -3-chloro-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole The reactions to elaborate this compound are analogous to those used to elaborate No. 147. Oil; aH NMR (DMSO) 7.50 - 7.29 (m, 11 H), 7.17 (d, 1 H, J = 8.4 Hz), 7.05 (d, 1 H, J = 2.4 Hz), 7.02 (d, 1 H, J = 2.4 Hz), 6.93 - 6.85 (m, 2 H), 6.75 - 6.65 (m, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.07 (m, 2 H), 3.92 (t, 2 H) , J = 5.9Hz), 2.55 (t, 2H, J = 5.9Hz), 2.42 - 2.29 (m, 4 H), 1.94 (s, 3H), 1.44 - 1.40 (m 4 H), 1.38 - 1.34 (m , 2H).

Example No. 133 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-pyrrolidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) It is synthesized as described for example No. 134. P.f. = 233-235 ° C; ^ NMR (DMSO) 10.50 (s, 1 H), 9.88 (s, 1 H), 9.01 (S, 1 H), 7.30 - 7.20 (m, 3 H), 6.90 - 6.80 (m, 7 H), 6.68 (dd, 1 H, J = 2.4, Hz, 8.8 Hz), 5.20 (s, 2 H), 4.22 (t, 2 H, J = 4.8 Hz], 3.47 (t, 2 H, J = 4.8 Hz), 3.10 (broad m, 4 H), 1.90 (s, 4 H), IR (KBr) 3400, 1625, 1475, 825 cm "1; MS m / z 462 (M +); CHN calculated for C27H27CIN203 + 1 HCl +.75 H20.

Example No. 134 Removal of the benzylic ethers to obtain 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole-5 -ol (HCl) The benzyl ethers are removed analogously to the procedure indicated for 3-methylindoles indicated in method 7. This compound is then converted to the hydrochloride salt as previously described in method 8; P.f. = 207-209 ° C; "H NMR (DMSO) 10.10 (broad s, 1 H), 9.86 (s, 1 H), 9.07 (s, 1 H), 7.26 (d, 2 H, J = 8.6 Hz), 7.22 (d, 1 H, J = 8.8 Hz), 6.87 (d, 2 H, J = 8.6 Hz), 6.81 - 6.78 (m 5 H), 6.65 (dd, 1 H, J = 8.8 Hz, J = 2.2 Hz), 5.20 (s) , 2 H), 4.27 (t 2H, J = 5.0Hz), 3.44 - 3.37 (m, 4 H), 3.00 - 2.85 (m, 2 H), 1.81- 1.60 (m, 5H), 1.41 - 1.26 ( m 1 H); IR (KBr) 3350, 1470, 1250 cm "1. MS at m / z 476 (M +); CHN calculated for C28H29C1N203 + HCl + 1.5 H20.

Example No. 135 3-chloro-2- (4-hydroxy-phenyl) -1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -lH-indol-5-ol (HCl) It is synthesized as described for No. 134. P.f. = 196-198 ° C; "H NM 'R (DMSO) 10.10 (broad s, 1 H), 9.86 (s, 1 H), 9.07 (s, 1 H), 7.26 (d 2 H, J = 8.8 Hz), 7.22 (d, 1 H, J = 9.0 Hz), 6.87 (d, 2 H, J = 8.6 Hz), 6.84-6.78 (m, 5 H), 6.65 (dd, 1 H, J = 8.8 Hz, J = 2.2 Hz), 5.20 (s, 2 H), 4.27 (t 2H, J = 5.0Hz), 3.45-3.30 (m, 4 H), 3.21-3.10 (m, 2 H), 1.82-1.76 (m, 4 H), 1.65 - 1.46 (m, 4 H). MS at m / z 491 (M +); CHN calculated for C29H31CIN203 + 1 HCl + .37 H20; IR (KBr) 3400, 3200, 1450, 1125.

Example No. 136 3-chloro-2- (4-hydroxy-2-methyl-phenyl) -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol It is synthesized as described for No. 134 except that the compound does not become a salt. Foam; "H NMR (DMSO) 9.64 (s, 1 H), 9.01 (s, 1 H), 7.25 (d, 1 H, J = 8.8 Hz), 7.03 (d, 1 H, J 8.1 Hz), 6.79 (d , 1 H, J = 2.4 Hz), 6.78 - 6.65 (m, 7 H), 5.06 - 4.92 (m 2 H), 3.94 (t, 2 H, J = 5.9 Hz), 2.62 - 2.57 (m, 2 H ), 2.42 - 2.32 (m, 4 H), 1.90 (s, 3 H), 1.48 - 1.40 (m, 4 H), 1.40 - 1.32 (m, 2 H), MS m / z 490 (M +); IR (KBr) 3430, 2900, 1450 cm "1; CHN calculated for C29H31CIN203 + 1.0 H20.

Synthesis of the 3-ethylindole analog No. 137 This compound is synthesized in exact analogy to the example provided for 3-methylindoles, supra, using methods a and 2-8. The only difference is that the initial material used is 4'-benzyloxy) -butyrophenone CAS No. [26945-71-1] instead of 4 '- (benzyloxy) propiophenone. The data for the intermediaries are as follows.

Example No. 150 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-ethyl-1H-indole P.f. = 101-108 ° C: MS m / z 433 (M +).

Example No. 151 2- (4-Benzyloxy-phenyl) -3-ethyl-indol-1-ylmethyl] -phenoxy acid ethyl ester} -acetic P.f. = 72-75 ° C; MS at m / z 625 (M +).

Example No. 152 2-. { 4- [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-ethyl-indol-1-ylmethyl] -phenoxy} -ethanol P.f. = 105 - 113 ° C; MS at m / z 583 (M +).

Example No. 153 Benzyloxy-2- (4-benzyloxy-phenyl) -1- [4- (2-bromo-ethoxy) -benzyl] -3-ethyl-1H-indole P.f. = 140 ° C (decomp.); MS at m / z 647, 645 (M +, Br present).

Example No. 1545-benzyloxy-2- (4-benzyloxy-phenyl) -3-ethyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 92-96 ° C; H NMR (DMSO) 7.47 (d, 4 H, J = 7.2 Hz), 7.42 - 7.39 (m, 4 H), 7.36 - 7.30 (m, 2 H), 7.27 (d, 2 H, J 8.6 Hz), 7.18 (d, 1 H, J = 8.8 Hz), 7.14 (d, 1 H, J = 2.4 Hz), 7. 1 0 (d, 2 H, J = 8.8 Hz), 6.79 (dd, 1 H, J = 8.8 Hz, 2.2 Hz), 6.73 (s, 4 H), 5.13 (s 2 H), 5.11 (s, 4 H), 3.93 (t, 2 H, J = 5.9 Hz), 2.62 - 2.53 (m , 4 H). 2.40 - 2.33 (m, 4 H), 1.49 - 1.42 (m, 4 H), 1.37 - 1.30 (m, 2 H), 1. 1 0 (t, 3 H, J = 7.2 Hz). MS at m / z 650 (M + H +).

Example No. 137 2- (4-hydroxy-phenyl) -3-ethyl-1- [4- (2-piperidin-1-ylethoxy) -benzyl] -lH-indol-5-ol (HCl) P.f. = 160 - 164 ° C; H NMR (DMSO) 9.78 (broad s, 1 H), 9.69 (S, 1 H), 8.69 (s, 1 H), 7.14 (d.2 H, 8.6), 7.05 (d, 1 H, J = 8.6 Hz), 6.87 - 6.78 (m, 7 H), 6.56 (dd 1 H, J = 8.8 Hz, 2.4 Hz), 5.08 (s, 2 H). 4.25 (t, 2 H, J = 4.4 Hz), 3.45 -3.38 (m, 5 H), 3.00 - 2.86 (m, 2 H), 2.57 - 2.50 (m, 2 H), 1.83 - 1.59 (m, 5 H), 1.41 1.28 (m, 1 H), 1. 10 (t, 2 H, J = 7.5 Hz); IR (KBr) 3400 broad, 3200 broad, 2920, 1610 cm "1. MS m / z 470 (M +); CHN calculated for C30H34N2O3 + HCl + 1.5 H20. jgy Reaction Scheme 15 Synthesis of 3-cyanoindole analogues Example No. 141 Example No. 155 2- Et3N CAS # [111728-87-1] Example No. 156 NaH, DMF Example No. 155 5-benzyloxy-3-cyano-2- (4-benzyloxy-phenyl) -1H-indole Into a reaction flask, 5-benzyloxy-2- (4-benzyloxy-phenyl) -1H-indole No. 141 (5.90 g, 14.6 mmol) is mixed with 90 ml of CH2C12 and cooled to 0 ° C (the initial material). it does not dissolve completely in CH2C12). While stirring vigorously, a solution of chlorosulfonyl isocyanate (2.26 g, 16.0 mmol) in 25 ml of CH2C12 is added dropwise over a period of 45 min. The reaction is carried out at 0 ° C for 2 h while being detected by CCD for the formation of the insoluble N-chlorosulfonylamide intermediate. After this period, Et3N (1.47 g, 14.6 ml) in 25 ml of CH2C12 is added dropwise over 45 min at 0 ° C. The insoluble residue becomes soluble in the reaction solvent as the addition of Et3N approaches its completion. The reaction is allowed to proceed for an additional 1 h at 0 ° C and 2 h at rt. The progress of the reaction is observed by the formation of an insoluble product solid as the reaction time elapses. The solvent is reduced by distillation and the solid residue is purified by trituration with methanol to provide (4.0 g, 63.8%). P.f. = 238-242 ° C; JH NMR (DMSO) 12.31 (s, 1 H), 7.88 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.25 Hz), 7.55 - 7.30 (m, 7 H), 7.23 (d, 2 H, J = 8.8 Hz), 7.14 (d, 1 H, J = 2.4 Hz), 6.97 (dd, 1 H, J = 2.2 Hz, 8.8 Hz), 5.20 (s, 2 H), 5.17 (s, 2 H); MS at m / z 430 (M +).

Example No. 156 4- (2-Chloroethoxy) benzyl bromide To the 4- (2-chloroethoxy) benzyl alcohol (CAS No. [111728-87-1] (6.4 g, 34.31 mmol) in 100 ml of dioxane at 0 ° C is slowly added thionyl bromide (7.13 g, 34.31 mmole) The reaction is carried out at 0 ° C after 5 min.The reaction mixture is diluted with 200 ml of ether and washed with H20 (1 x 30 ml) and then with NaHCO3 (2 x 25 ml) and 30 ml. ml of brine The organic extract is dried over MgSO4 and concentrated The crude product is purified by chromatography on silica gel (15% EtOAc / Hex) to provide 5.0 g (58%) of the desired product. ° C; H NMR (DMSO) 7.37 (d, 2 H, J = 8.8 Hz), 6.93 (d, 2 H. J = 8.8 Hz), 4.68 (s, 2 H), 4.24 (t, 2 H, J = 5.05 Hz), 3.93 (t, 2 H, J = 5.27 Hz), MS m / z 248 (M +).

Example No. 157 benzyloxy-2- (4-benzyloxy-phenyl) -1- f4- (2-chloro-ethoxy) -benzyl] -3-cyano-1 H-indole In a reaction flask the initial material of 3-cyanoindole No. 155 (2.86 g, 6.64 mmol) is dissolved in 25 ml of DMF at 0 ° C and NaH is added slowly (191.2 mg, 8 mmol). The reaction is stirred at 0 ° C for 20 min. In a flask of Separate reaction containing 4- (2-chloroethoxy) -crylide bromide No. 156 (1.81 g, 7.28 mmol) in 15 ml of DMF at 0 ° C, the solution of anhydol anion prepared above is captured by syringe and added slowly. The reaction is stirred at 0 ° C for 20 min and promoted up to rt for 1 h. The reaction is suspended with a few drops of H20. The reaction mixture is partitioned between EtOAc (2 x 100 ml) and 80 ml of H20. The organic extract is washed with 80 ml of brine, dried over MgSO4 and concentrated. The crude product is purified by trituration with ether to give the product as a white solid (2.80 g, 70.4%). P.f. = 160-162 ° C; H NMR (DM? O) 7.53 - 7.28 (m, 13 H), 7.23 (m, 3 H), 6.97 (dd, 1 H, J = 2.4 Hz, 9.0 Hz), 6.86 - 6.78 (m, 4 H) , 5.37 (s, 2 H), 5.18 (s, 4 H) 4.15 (t, 2 H, J = 4.8 Hz), 3.87 (t, 2 H, J = 5.3 Hz); MS at m / z 598 (M +).

Examples No. 158 and 159 Substitution of the chlorine group with pipepdine and hexamethylamine is carried out analogously to the procedure indicated in method 6 using No. 157 as starting material above.

Example No. 158 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-cyano-l- [4-2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole P.f. = 148 - 150 ° C. H NMR (DMSO) 7.54 - 7.30 (m, 13 H), 7.25 - 7.18 (m, 3 H), 6.98 (dd, 1 H, J = 2.4 Hz, 9.0 Hz), 6.84 - 6.74 (m, 4 H) , 5.35 (s, 2 H), 5.17 (s, 4 H), 3.94 (t, 2 H, 5.9 Hz), 2.55 (t, 2 H, 5.7 Hz), 2.35 (s broad, 4 H), 1.50 - 1.40 m, 4 H), 1.38-1.25 (m, 2 H); IR 3400, 2910, 2250, 1250 crn "1; EM BAR 648 [M + H] +.

Example No. 159 5-Benzyloxy-2- (4-benzyloxy-phenyl) -3-cyano-1- [4- (2-azepan-1-yl) -ethoxy) -benzyl] -lH-indole ? NMR (DMSO) 8.60 (broad s, 1 H), 7.60 - 7.28 (m, 12 H), 7.25 - 7.16 (m, 3 H), 6.97 (dd, 1 H, J = 2.4 Hz, 9.0 Hz), 6.88 -6.75 (m, 4 H), 5.35 (s, 2 H), 5.17 (s, 4 H), 3.92 (t, 2 H, J = 6-2 Hz), 3.08-3.00 (m, 2 H), 2.77 (t, 2 H, J = 5.9 Hz), 2.63 (t, 4 H, J = 4.8 Hz), 1.78 - 1.68 (m, 2 H), 1.60 - 1.40 (m, 4 H); MS at m / z 661 (M +).

Examples No. 138 and No. 139 The benzyl ethers are removed by hydrogen transfer using 1,4-cyclohexadiene and Pd 10% / C, as described in method 7. The compounds are converted into their respective hydrochloride salts as described in method 8.

Example No. 138 5 -Hydroxy -2 - (4-hydroxy-phenyl) -1- [4- (2-piperidin-1-yl) ethoxy) -benzyl] -lH-indole-3-carbonitrile (HCl) P.f. = 173 - 175 ° C, H NMR (DMSO) 10.40 (s, 1 H), 10. 12 (s, 1 H), 9.40 (s, 1 H), 7.38 (m, 2 H), 7.30 (d. 1 H, J = 8.8 Hz), 7.02 - 6.90 (m, 3 H), 6.88 (s, 4 H), 6.75 (dd, 1 H, J = 2.4 Hz, 9Hz), 5.33 (?, 2 H), 4.30 (t, 2 H, J = 4.8 Hz), 3.51 - 3.38 (m, 4 H). 2.92 (m, 2 H), 1.85 - 1.73 (m, 4 H), 1.68 - 1.59 (m, 1 H), 1.26 - 1.21 (m, 1 H), IR 3400, 2200, 1250 cm "1; m / z 467 (M +); CHN calculated for C29H29N303 + 1.0 HCl + 1.0 H20.

Example No. 139 1- [4-2-azepan-l-yl-ethoxy-benzyl] - (5-hydroxy-2- (4-hydroxy-phenyl) -lH-indol-3-carbonitrile (HCl) P.f. = 160-163 ° C, "H NMR (DMSO) 10.22 (s, 1 H), 10.08 (s, 1 H), 9.35 (?, 1 H), 7.40- 7.37 (m, 2 H) 7.30 (d , 1 H, 8.8 Hz), 7.0 - 6.90 (m, 3 H), 6.87 (s, 4 H), 6.74 (dd, l H, J = 2.41 Hz, 9 Hz), 5.33 (s, 2 H), 4.27 (t, 2 H, J = 5.0 Hz), 3.50 - 3.30 (m, 4 H), 3.20 (m, 12 H), 1.85 - 1.70 (m, 4 H), 1.65 - 1.50 (m, 4 H); IR 3300, 2200, 1250 cm "1; MS at m / z 481 (.M +); CHN calculated for C30H31N303 + 1 HCl + 1 H20.

Esteres de Índoles Nos. 97 and 98 Table 9 Method 9 Example No. 162 Ester di-pivalate 2- (4-hydroxy-phenyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-5-ol The free base of example No. 97 is used as the starting material for this synthesis. It's number 97 (1.0 g, 2.5 mmol) in 20 ml of CH2C12 with diisopropylethylamine (0.7 g, 6.3 mmol) and catalytic DMAP. The reaction is cooled to 0 ° C and treated with pivaloyl chloride (0.7 ml, 5.6 mmol) and allowed to reach rt and stirred overnight. The reaction is worked up by diluting it with CH2C12 and washing with water and brine. After drying over MgSO4, the solution is concentrated and subjected to chromotography on silica gel (Me0H / CH2Cl2, 1:19) to provide the desired material as an orange foam (1.08 g). This material is then taken up in 15 ml of ethyl acetate and treated with 2.5 ml of a 1M HCl / Et20 solution. Hexane is added until the solution becomes turbid. The product is separated by precipitation as HCl salt. This material is recrystallized from ethyl acetate / hexane to provide 0.42 g of pure compound No. 162. No. 162: P.f. = 182 -185 ° C; CHN calculated for C39H48N205 + HCl + 0.25 H20.

Example No. 160 Dipropionate 1- [4- (2-azepan-1-yl) ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indol-5-ol (HCl) The compound is prepared analogously to Example No. 162, except that the starting material used is from Example No. 98 and the acylating agent used is propionyl chloride: P.f. = 170.5-172 ° C; CHN calculated for C36H42N20s + HCl + 0.75 H20; EM BAR 605 (M + Na) +.

Example No. 161 1- [4- (2-azepan-1-yl-ethoxy-benzyl] -2- (4-hydroxy-phenyl) -3-methyl-lH-indol-5-ol (HCl) dipavalate The compound is prepared analogously to Example No. 162, except that the initial material used is Example No. 98: P.f. = 143-151 ° C; CHN calculated for C40H50N2Os + HCl + 0.75 H20.

Experimental part for example No. 166 Reaction scheme 16 Synthesis of No. 166 Example No. 163a Example No. 163b EXAMPLE No. 166 2- (4-hydroxy-phenyl) -3-methyl-1--. { 4- [3- (piperidin-1-yl) -propoxy] -benzyl] -lH-indol-5-ol The title compound is prepared according to Reaction Scheme 16 the steps given below: Method 11 Example No. 163a 4- (3-Chloropropoxy) -benzyl alcohol A solution of 4-hydroxybenzyl alcohol CAS No. [623-05-2] (10 g, 80.5 mmol) in 70 ml of ethanol is treated with 1,3-bromochloropropane (16.0 g, 100 mmol) and potassium hydroxide (5.0, 89 mmol) and refluxed for 2 hours. The solution is cooled and filtered and then the filtrate is concentrated. The concentrate is taken up in ether and washed with water, brine and dried over magnesium sulfate. The material is chromatographed on silica gel using ethyl acetate / hexanes (3: 7) to provide 11.6 g of the product as a white solid: M.p. = 65-C, lH NMR (DMSO) 7.21 (d, 2 H, J = 8.8 Hz), 6.88 (d, 2 H, J = 8.8 Hz), 5.03 (t, 1 H, J = 5.7 Hz), 4. 40 (d, 2H, J = 5.5 Hz), 4.05 (t, 2 H, J = 6.1 Hz), 3.77 (t, 2 H, J = 6.4 Hz); EM at m / z 200.

Method 12 Example No. 163b 4- (3-Chloropropoxy) benzyl bromide A solution consisting of 4- (3-chloropropoxy) -benzyl alcohol No. 162 (10.6 g, 52.8 mmol) in 0.125 1 dioxane is cooled to 0 ° C and treated with dropwise addition of thionyl bromide (12.0 g) , 58.0 moles) After 10 minutes, the reaction is complete. The dioxane is diluted with diethyl ether and washed with water, brine and then dried over MgSO4. The material is reduced by concentration to provide 15 g of an oil: XH NMR (DMSO) 7.36 (d, 2 H. J = 8.8 Hz), 6.92 (d, 2 H, J = 8.6 Hz), 4.68 (s, 2 H), 4.08 (t, 2 H, J = 5.9 Hz), 3.77 (t, 2 H, J = 6.4 Hz); MS (BAR) 266 (M + H *).

Method 13 Example No. 164 5-Benzyloxy-2- (4-benzyloxy-phenyl) -1- [4- (3-chloro-propoxy) -benzyl] -3-methyl-1H-indole A solution consisting of 5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1H-indole No. 7 (6.5 g 15.5 mmoles) in 60 ml of DMF is cooled to 0 ° C and treated with the addition of sodium hydride (0.68 g, 17.0 moles) and stir for 20 minutes. Then a solution of 4- (3-chloropropoxy) benzyl bromide No. 163 in 10 ml of DMF is slowly added. The reaction is allowed to reach rt and is stirred for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The ethyl acetate is washed with water, brine and dried over magnesium sulfate and concentrated. The concentrate is treated with methanol and 5 g of the desired product precipitate as a white solid with a melting point of 130-132 ° C.

Method 14 Example No. 165 5-Benzyloxy-2- (4-benzyloxy-f-enyl) -1- [4- (3-piperidin-1-yl-propoxy) -benzyl] -3-methyl-lH-indole A solution of 5-benzyloxy-2- (4-benzyloxy-phenyl) -1- [4- (3-chloro-propoxy) benzyl] -3-methyl-1H-indole No. 164 (3 g, . 1 mmol), potassium iodide (2.5 g, 15.3 mmol) and piperidine (3.0 ml, 30.6 mmol) is heated in 30 ml of DMF at 100 ° C for 18 hours. The reaction is worked by pouring it into water and extracting it with ethyl acetate. The organic layer is washed with water, brine and dried over magnesium sulfate. The solution is concentrated to an oil and the product is separated by precipitation when methanol is added. The product is obtained as a white solid. P.f. = 104-106-C. IR NMR (DMSO) 7.47 (d, 4 H, J = 7.5 Hz), 7.38 (c, 4 H, J = 7.9 Hz), 7.36-7.30 (m, 1 H), 7.28 (d, 2 H, J = 8.3 Hz), 7.19 (d, 1 H, J = 8.8 Hz), 7.12-7.10 (m, 4 H), 6.80 (dd, 1 H, J = 8.8, 2.0 Hz), 6.72 (s, 4 H), 5.14 (s, 2 H), 5.13 (s, 2 H), 5. 1 1 (s, 2 H), 3.86 (t 2 H. J = 6.4 Hz), 2.35-2.20 (m, 6 H), 2.14 (s, 3 H), 1.78-1.75 (m, 2 H), 1.47-1.42 (m, 4 H), 1.40-1.31 (m, 2 H); EM at m / z 650.

Method 15 Example No 166 2 - (4-hydroxy-phenyl) -3-methyl-l-. { 4- [3 - (piperidin- - il) -propoxy] -benzyl} -lH-Indol- 5 -ol A solution of 2.35 g of 5-benzyloxy -2 - (4-benzyloxy-phenyl) -1- [4- (3-piperidin-1-yl-propoxy) -benzyl] -3-methyl-1H-indole Do not . 165 in 25 ml of tetrahydrofuran and 25 ml of ethanol is added to 2.3 g of 10% palladium in carbon. 10 ml of cyclohexadiene are added and the reaction is allowed to stir room temperature for 18 hours. The catalyst is filtered through Celite and the reaction mixture is concentrated and chromatographed on silica gel using dichloromethane / methanol (4: 1) to elute 0.8 g of the product as a white foam: P.f. = 125-130-C; H NMR 9.68 (s, 1 H), 8.70 (S, 1 H), 7.15 (d, 2 H, J = 8.6 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.85 (d, 2 H, J = 8.6 Hz). 6.80 (d, 1 H, J = 2.4 Hz), 6.74 (d, 4 H, J = 2.6 Hz), 6.57 (dd, 1 H, J = 8.6, 2.2 Hz), 5.09 (s, 2 H), 3.88 (t, 2 H, J = 6.4 Hz), 3.60-3.15 (m, 2 H), 2.62-2.38 (m, 4 H), 2.09 (s, 3 H), 1.92-1.78 (m, 2 H), 1.55-1.43 (m, 4 H), 1.42-1.30 (m, 2 H); IR (KBr) 3400 (broad), 2900, 1620, 1515 cm-I; EM at m / z 470.

Summary of No. 167 and No. 168 Table 10 Reaction scheme 17 Synthesis scheme for examples Nos. 167 and No. 168 Example No. 169 Example No. 170 Synthesis of example No. 167 2- (4-hydroxy-phenyl) -1- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) -benzyl] -3-methyl-1H-indol-5-ol Example No. 169 4-formyl-2-methoxy-phenoxy acetic acid ethyl ester A flask containing vanillin (20 g, 0.13 mol), ethyl bromoacetate (28.4 g, 0.17 mol) and potassium carbonate (32.7 g, 0.24 mol) and 200 ml of acetone is heated at reflux for 3 hours. The reaction is allowed to proceed to rt. The acetone is distilled off and the residue is partitioned between water and ethyl acetate. The ethyl acetate is washed with brine and dried over magnesium sulfate. The organic layer is concentrated and the solid is triturated with hexanes to provide 28.4 g of example No. 169. P.f. = 56-59 ° C; JH NMR (DMSO) 9.83 (s, 1 H), 7.50 (dd, 1 H, J = 2.0 Hz, 8.3 Hz), 7.42 (d, 1 H, J = 1.7 Hz), 7.07 (d, 1 H, J = 8.4 Hz), 4.91 (s 2 H), 4.16 (c, 2 H, J = 7.2 Hz), 3.84 (s, 3 H), 1.20 (t 3 H, J = 7.1 Hz); MS on M / z 238 (M +); CHN calculated for C12H140s.

Example No. 170 (4-Chloromethyl-2-methoxy-phenoxy) -acetic acid ethyl ester A solution of Example No. 169 (28.8 g, 0.119 mol) in 600 mL of EtOH / THF (1: 1) is treated with sodium borohydride (2.25 g, 0.06 mol) at 0 ° C and stirred for 45 minutes. The solvents are evaporated and the reaction mixture is diluted with ethyl acetate and washed with a solution of IN HCl. The product obtained in this manner (14.2 g, 0.059 mol) as an oil is dissolved in 140 ml of THF and cooled to 0 ° C. This solution which is then treated with dropwise addition of thionyl chloride (7.38 g, 0.062 mol) at ° C. After 1 hour, the reaction is poured into 400 ml of water and extracted with ether. The ether layer is washed with a sodium bicarbonate solution and dried over magnesium sulfate. This is concentrated and subjected to chromatography by chromatography on silica gel using ethyl acetate / hexane (1: 9). The product is obtained as 10.5 g of a white solid. P.f. = 64-66 ° C, 1 H NMR (DMSO) 7.06 (d, 1 H, J = 2.0 Hz), 6.91 (dd, 1 H, J = 2.0 Hz. 2.2 Hz), 6.83 (d, 1 H, 1 = 2.1 Hz), 4.75 (s, 1- H), 4.70 (s, 2 H), 4.13 (c, 2 H, J = 7.2 Hz), 3.77 (s, 3 H), 1. 19 (t, 3 H, J = 7. 1 Hz); MS / z 258 (M +); CHN calculated for C12H15C104.

Example No. 171 2-Methoxy-4- [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy acid ethyl ester} -acetic.

Alkylation of indole No. 7 is performed as previously described in Method No. 3 using example No. 170 as the electrophile. P.f. = 120 - 123 ° C; ? NMR (DMSO) 7.48 - 7.20 (m, 13 H), 7.18 - 7.10 (m, 3 H), 6.80 (dd, 1 H, J = 2.5 Hz, 8.8 Hz), 6.64 (d, 1 H, J = 8.4 Hz), 6.52 (d, 1 H, J = 2.0 Hz), 6.24 (dd, 1 H, J = 1. 9 Hz. 8.1 Hz), 5.13 (s, 4 H), 5.10 (s, 2 H), 4.61 (s, 2 H), 4. 10 (c, 2 H, J = 7.0 Hz), 3.58 (s, 3 H), 2.15 (s, 3 H), 1. 15 (t, 3 H, J = 7.0 Hz.); MS at m / z 641 (M +).

Example No. 172 2-. { 2-methoxy-4- [5-benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-indol-1-ylmethyl] -phenoxy} -ethanol The reduction of ester No. 171 is carried out as previously described in Method 4. P.f. = 86 - 90 ° C; JH NMR (DMSO) 7.48 - 7.20 (m, 13 H), 7.18 - 7.10 (m, 3 H), 6.80 (dd, 1 H, J = 2.5 Hz, 8.8 Hz), 6.64 (d, 1 H, J = 8.4 Hz), 6.52 (d, 1 H. J = 2.0 Hz), 6.24 (dd, 1 H, J = 1.9 Hz, 8.1 Hz), 5.13 (s, 4 H), 5.10 (s, 2 H), 4.76 (t, 1 H, J = 5.5 Hz), 3.83 (t, 2 H, J = 5.1 Hz), 3.63 (c, 2 H. J = 5.3 Hz), 3.56 (s, 3 H), 2.15 (s, 3 H); MS at m / z 599 (M +).

Example No. 1735-benzyloxy-2- (4-benzyloxy-phenyl) -1- [3-methoxy-4- (2-bromo-ethoxy) -benzyl] -3-methyl-1H-indole The conversion of the alcohol of Example No. 172 to the bromide is carried out analogously to that described in method 5. P.f. = 150 - 152 ° C; JH NMR (DMSO) 7.48 - 7.20 (m, 13 H), 7.18 - 7. 1 0 (m, 3 H), 6.80 (dd, 1 H, J = 2.5 Hz, 8.8 Hz), 6.64 (d, 1 H , J = 8.4 Hz), 6.52 (d, 1 H, J = 2.0 Hz), 6.24 (dd, 1 H, J = 1.9 Hz, 8.1 Hz), 5.13 (s, 4 H), 5.10 (s, 2 H ), 4.15 (t, 2 H, J = 5.3 Hz), 3.70 (t, 2 H, J = 5.7 Hz), 3.58 (s, 3 H), 2.15 (s, 3 H), MS the m / z 661 (M +).

Example No. 174 5-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indole The replacement of the bromide with piperidine is carried out as previously described in Method 6. * H NMR (DMSO) 7.48-7.20 (m, 13 H), 7.18-7.1 (m, 3 H), 6.80 (dd, 1 H. J = 2.5 Hz, 8.8 Hz), 6.64 (d, 1 H, J = 8.4 Hz), 6.52 (d.1 H, J = 2.0 Hz), 6.24 (dd.1 H, J = 1.9 Hz, 8.1 Hz), 5.13 (s, 4 H), 5.10 (S, 2 H), 3.90 (t, 2 H, J = 5.7 Hz), 3.55 (s, 3 H), 2.62 - 2.50 (s broad, 2 H ), 2.45 - 2.30 (broad s, 4 H), 2.15 (S, 3 H), 1.50 - 1.40 (m, 4 H), 1.40 - 1.35 (m, 2 H); EM BAR m / z 667 (M + H +).

Example No. 175 5-Benzyloxy-2- (4-benzyloxy-phenyl) -3-methyl-1- [2-methoxy-4- (2-azepan-1-yl-ethoxy) -benzyl] -lH-indole The reaction is performed exactly as for No. 174, except that hexamethyleneamine is used to displace the bromide in place of piperidine. Foam; H NMR (DMSO) 7.48 - 7.20 (m, 13 H), 7.18 - 7.10 (m, 3 H), 6.80 (dd, 1 H, J = 2.5 Hz, 8.8 Hz), 6.64 (d, 1 H, J = 8.4 Hz), 6.52 (d, 1 H, J = 2.0 Hz), 6.24 (dd.1 H, J = 1.9 Hz, 8.1 Hz), 5.13 (s.4 H). 5.10 (s 2 H), 3.90 (t, 2 H, J = 5.7 Hz), 3.55 (S, 3 H), 2.85 - 2.70 (s broad, 2 H), 2.70 - 2.55 (s, 4 H), 2. 1 0 (S, 3 H), 1.60 - 1.15 (m, 8 H); EM BAR m / z 681 (M + H +) Example No. 167 2- (4-hydroxy-phenyl) -1- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) -benzyl] -3-methyl-1H-indol-5-ol Compound No. 173 is hydrogenated by transfer hydrogenation as previously described in Method 7. The compound is isolated as the hydrochloride salt by dissolving the ether and treating with 1.2 equivalents of a 1 N / HC1 ether solution (this is a variation of method 8). P.f. = 123 - 127 ° C; a H NMR (DMSO) 10.20 (broad s, 1 H), 9.72 (s, 1 H), 8.71 (s, 1 H), 7.17 (d, 2 H, J = 8.6 Hz), 7.11 (d, 1 H, J = 8.8 Hz), 6.87 (d, 2 H, J = 8.6 Hz), 6.79 (m, 2 H), _B- ß | Uj- ^ k? 6. 57 (dd, 1 H, J = 2.4 Hz, 8.8 Hz), 6.55 (d, 1 H, J = 1.7 Hz), 6.33 (dd, 1 H, J = 1.7 Hz. 8.1 Hz), 5.11 (s, 2 H), 4.23 (t, 2 H. J = 4.8 Hz), 3.60 (s, 3 H), 3.45 (m, 2 H), 3.35 (m, 2 H), 2.95 (m, 2 H), 2.10 ( s, 3 H), 1.70 (m, 5 H), 1.35 (m, 1 H), IR 3500, 1500, 1275 cm "1; MS (+) BAR m / z 487 (M + H) *; CHN calculated for C30H34N2O4 + 1 HCl + 1.0 H20.

Example No. 1682- (4-hydroxy-phenyl) -1- [3-methoxy-4- (2-azepan-l-yl) -ethoxy) -benzyl] -3-methyl-lH-indol-5-ol It is prepared in the same way as described in Example No. 167. P.f. = 142 - 146 ° C. SH NMR (DMSO) 10.36 (1 H), 9.72 (s, 1 H), 8.71 (s, 1 H), 7.18 (d.2H J = 8.3 Hz), 7.11 (d, 1H, J = 8.6 Hz), 6.87 (d, 2 H, J = 8.3 Hz), 6.82 (dl H, J = 8.1 Hz), 6.79 (d, 1 H, J = 2.2 Hz). 6.57 (dd, 1 H, J = 2.2 Hz, 8.6 Hz), 6.55 (d.1 H, J = 1.8 Hz), 6.33 (dd, 1 H, J = 1.5 Hz, 8.1 Hz), 5.11 (s, 2 H), 4.24 (t, 2 H. J = 4.6 Hz), 3.60 (s, 3 H), 3.40 (m, 4 H), 3.20 (m, 2 H), 2. 1 0 (s, 3 H) , 1.75 (m, 4 H). 1.55 (, 4 H); IR (KBr) 3300, 1500, 1270, 1200 cm "1; MS BAR m / z 501 (M + H) +; CHN calculated for C31H36N204 + 1.0 HCl + 0.12 CH3OH.

Biological data Method 16 Stroke receptor binding test in vitro Preparation of the receiver CHO cells that overexpress the estrogen receptor are grown in 150 mm2 containers in DMEM + 10% dextran-coated activated charcoal, purified fetal bovine serum. The plates are washed twice with PBS and once with mM Tris-HCl, pH 7.4, 1 mM EDTA. The cells are harvested by scraping the surface after the cell suspension is placed on ice. The cells are broken with a portable motorized tissue grinder using two discharges of seconds. The crude preparation is centrifuged at 12,000 g for 20 minutes followed by centrifugation for 60 minutes at 100,000 g to produce a ribosome-free cytosol. The cytosol is then frozen and stored at -80 ° C. The protein concentration of the cytosol is estimated using the BCA assay with the standard reference protein.

Union test conditions The competition test was performed on 96-well plates (polystyrene *) which binds < 2.0% of [3H] -17β-estradiol introduced total, and each data point is recovered in triplicate. Aliquots of 100 μg / 100 μl of the receptor preparation are placed per well. A saturating dose of 2.5 nM [3H] 17ß-estradiol + competitor (or buffer) in a volume of 50 μl is added in the preliminary competition when evaluating competitors of lOOx and 500x, only [3H] 17β-estradiol 0.8 nM is used. . The plate is incubated at room temperature for 2.5 h. At the end of this incubation period, 150 μl of ice-cold dextran coated activated carbon (activated charcoal 5% coated with 69 K 0.05% dextran) are added to each well and the plate is immediately centrifuged at 99 g for 5 minutes at 4 ° C. Then 200 μl of the supernatant solution is removed by scintillation counting. Samples are subjected to 2% or 10 minutes, whichever comes first. Because polystyrene absorbs a small amount of [3 H] 17-estradiol, the wells contain radioactivity and cytosol, but are not processed with activated carbon and are included to quantify the amounts of available isotope. In addition, wells containing radioactivity but without cytosol are processed with activated carbon to estimate the non-removable MPE of [3H] 17β-estradiol. HE They used 96-well plates Corning No. 25880-96, because they have been shown to bind the least amount of estradiol.

Analysis of the results The radioactivity per minute (CPM) counts were automatically converted to decays per minute (DPM) by the Beckman LS 7500 scintillation counter using a set of cooled standards to generate an H No. for each sample. To calculate the% binding of estradiol in the presence of 100 or 500 times of competitor, the following formula was applied: ((Sample DPM-DPM not removed by activated carbon / (DPM of estradiol-DPM not removed by activated carbon)) x 100% =% estradiol binding For the generation of the IC50 curves, the union% versus compound% is plotted. IC50's are generated for compounds that show > 30% competition at a competitor concentration of 500x. For a description of these methods see Hulme, E.C., ed. 1992. Receptor-Ligand Interactions: A Practical Approach. IRL Press, New York, (see especially chapter 8).

Table 11 Estrogen receptor binding Table 12 Estrogen receptor binding • - * --- - • - Table 13 Estrogen receptor binding Table 14 Estrogen receptor binding Table 15 Estrogen receptor binding Method 17 Assay of alkaline phosphatase in Ishikawa cells Maintenance and treatment of cells: Ishikawa cells are maintained in DMEM / F12 (50%: 50%) containing phenol red + 10% fetal bovine serum and the medium is supplemented with 2 mM Glutamax, 1% Pen / Strap and 1 mM sodium pyruvate. Five days before the start of each experiment (cell treatment) the medium is changed to phenol-free of DMEM / F12 + purified serum in activated charcoal coated with 10% dextran. On the day before treatment, cells are harvested using 0.5% trypsin / EDTA and plated at a density of 5 x 10 * cells / well in 96-well tissue culture plates. The test compounds are dosed at 10"s, 10" 7 and 10"8 M in addition to 10" 6 M (compound) + 10"'M 17β-estradiol to assess the ability of the compounds to function as antiestrogens. cells are treated for 48 h before the assay. Each 96-well plate contains a control of 17 β-estradiol. The same population for each dose is n = 8.

Alkaline phosphatase assay: At the end of 48 h, the medium is aspirated into the cells and washed three times with phosphate buffered saline (PBS). 50 μl of lysis buffer is added to each well (0.1 M Tris-HCl, pH 9.8, Triton X-100 0.2%). The plates are placed at -80 ° C for a minimum of 15 minutes. The plates are reheated to 37 ° C followed by the addition of 150 μl of 0.1 M Tris-HCl, pH 9.8, containing 4 mM para-nitrophenylphosphate (pNPP) to each well (final concentration, 3 mM pNPP). Absorbance and dependent calculations are performed using the KineticCalc Application program (Bio-Tek Instruments, Inc., inooski, VT). The results are expressed as the mean +/- S.D. (standard deviation) of the enzyme reaction rate (slope) averaged over the line portion of the reaction kinetic curve (optical density readings every 5 minutes for 30 minutes of absorbance reading). The results for the compounds are summarized as percent of the response relative to 1 nM 17β-estradiol.

Several compounds are assayed for the estrogenic activity by the alkaline phosphatase method and the corresponding DES0 values (95% C.I.) are calculated. The four included in the following are used as reference standards. 17β-estradiol 0.03 nM 17a-estradiol 1.42 nM estriol 0.13 nM estrone 0.36 nM A description of these methods is described by Holinka, C.F., Hata, H., Kuramoto, H. and Gurpide, E. (1986) Effects of steroid hormones and antisteroids on alkaline phosphatase activity in human endometrial cancer cells (Ishikawa Line). Cancer Research, 46: 2771-2774, and by Littlefield, B.A., Gurpide, E., Markiewicz, L., McKinley, B. and Hochberg, R.B. (1990) . A simple and sensitive microtiter pest estrogen bioassay based on stimulation alkaline phosphatase in Ishikawa cells, • Estrogen action of D5 adrenal steroids. Endocrinology, 6: 2757-2762.

Ishikawa alkaline phosphatase assay Compound% activation 17β-estradiol 100% tamoxifen activity 0% activity (45% with 1 nM 17β-estradiol) raloxifene 5% activity (5% with 1 nM 17β-estradiol) Example No. 98 1% activity (1% with 1 nM 17β-estradiol) Method No. 18 2X VIT ERE infection test Maintenance and treatment of cells The Chinese hamster ovary (CHO) cells which have been stably transfected with the human estrogen receptor are maintained in DMEM + 10% fetal bovine serum 10% (FBS9.) At 48 h before treatment, the growth medium is replaces with DMEM that lacks phenol red + 10% FBS purified with 10% dextran-coated activated charcoal (treatment medium) Cells are plated at a density of 5000 cells / well in 96-well plates containing 200 μl of medium / well.

Transfection of calcium phosphate Indicator DNA is combined (Promega pGL2 plasmid containing two battery copies of ERE vitellogenin in the front of the minimal thymidine kinase promoter that activates the luciferase gene) with the B-galactosidase expression plasmid pCHUO (Pharmacia) and carrier DNA (pTZ18U) in the following relationship: μG of indicator DNA 5 μG of pCHUO DNA 5 μG of pTZ18U 20 μG of DNA / l ml of transfection solution The DNA (20 μG) is dissolved in 500 μl of 250 mM of Sterile CaCl2 and dropwise added to 500 μl of 2 X HeBS (0.28 M NaCl, 50 mM HEPES, 1.5 mM Na2HP04, pH 7.05) and incubated at room temperature for 20 minutes. 20 μl of this mixture of cells are added to each well and remain on the cells for 16 h. At the end of this incubation the precipitate is removed, the cells are washed with medium, fresh treatment medium is replaced and the cells are treated either with vehicle, 17μ-estradiol 1μM, 1μM compound or 1μM + 17β-estradiol compound 1 nM (tests for estrogen antagonism). Each treatment condition is performed in 8 wells (n = 8) which are incubated for 24 hours before the luciferase assay.

Luciferase assay After exposure for 24 h to the compounds, the medium is removed and each well is washed 2 X with 125 μl of PBS lacking Mg + * and Ca * +. After removing the PBS, 25 μl of Promega lysis buffer is added to each well and allowed to sit at room temperature for 15 min, followed by 15 min at -80 ° C and 15 min at 37 ° C. 20 μl of lysate is transferred to an opaque 96 well plate for evaluation of luciferase activity and 5 μl of remaining lysate is used for evaluation of B-galactosidase activity (transfection normalization). The luciferan substrate (Promega) is added in 100 μl aliquots to each well automatically by the luminometer and the light produced (relative light units) is read 10 seconds after the addition.

Luciferase infection assay (standards) Composition% activation 17ß-estradiol 100% activity striated! 38% activity tamoxifen 0% activity (10% with 17 n-estradiol 1 nM) raloxifene 0% activity (0% with 17 n-estradiol 1 nM) Β-galactosidase assay To the 5 μl remnants of the lysate, 45 μl of PBS is added. Then 50 μl of the Promega B-galactosidase 2X assay buffer is added, mixed well and incubated at 37 ° C for 1 hour. A plate containing a standard curve (0.1 to 1.5 milliunits in triplicate) is installed for each experimental run. The plates are analyzed in a Molecular Devices spectrophotometric plate reader at 410 nm. The optical densities for the unknown sample are converted to milliunits of activity by mathematical extrapolation from the standard curve.

Analysis of the results The luciferase data are generated as relative light units (RLU) accumulated during a 10 second measurement and are automatically transferred to a JPM file (SAS Inc) where the background RLUs are subtracted. The B-galactosidase values are automatically imported into the file and these values are divided among the RLUs to normalize the data. The mean and standard deviations are determined for n = 8 for every treatment The activity of the compounds is compared to 17β-estradiol for each plate. The percentage of activity compared to 17β-estradiol is calculated using the formula% = ((Estradiol-control) / (value of the compound) X 100. These techniques are described in Tzukerman, MT, Esty, A., Santiso-Mere, D., Danielian, P., Parker, MG, Stein, RB, Pike, JW and McDonnel, DP (1994) .The transactivational capacity of the human estrogen receptor was determined both in the cellular and promoter context and was mediated by two regions. functionally distinct intramolecular (see Molecular Endocrinology, 8: 21-30).

Table 16 Luciferase infection activity fifteen fifteen fifteen - = ^ _ J.S, Method No. 19 Uterotrophic / antiuterotrophic bioensavo in rat The estrogenic and antiestrogenic properties of the compounds were determined in an immature rat uterotrophic assay (4 days) which (as previously described by L.J. Black and R.L. Goode, Life Sciences, 26, 1453 (1980)). They are tested in groups of six immature Sprague-Dawley rats (females, 18 days old). The animals are treated by daily ip injection with 10 μg of compound, 100 μg of compound (100 μg of compound + 1 μg of 17β-estradiol) to verify antiestrogenicity and 1 μg of 17 β-estradiol, with 50% DMSO / solution 50% saline as an injection vehicle. On day 4, the animals are sacrificed by asphyxiation by C02 and their uteri are removed and cut to remove the excess lipid, any fluid is removed and the wet weight is determined. A small section of a horn is sent for histology and the rest is used to isolate total RNA in order to evaluate the complement component of expression 3.

Table 17 Uterine test in immature 3-day old rats Method No. 20 6-week ovariectomized rat model Female CD Sprague-Dawley rats, ovx or false ovx, are obtained 1 day after surgery of Taconic Farm (weight range 240-275 g). 3 or 4 rats / cage are housed in a room in a protocol of 14/10 (light / dark) and are provided with food (feed for rat purine 500) and with water ad libitum. Treatment for all studies begins 1 day after the animals arrive and are dosed 5 or 7 days per week, as indicated for 6 weeks. A matched group in age of rats operated on false does not receive any treatment and serve as a control group full of intact estrogen for each study. All treatments are prepared in 1% Tween 80 in normal saline at defined concentrations so that the volume of treatment is 0.1 ml / 100 g of body weight. 17β-estradiol is dissolved in corn oil (20 μg / ml) and is administered subcutaneously, 0.1 ml / rat. All dosages are adjusted at three-week intervals according to the mean body weight measurements of the group. Five weeks after the start of treatment and one week before the end of the study, each rat is evaluated to determine bone mineral density.

(BMD). The BMDs of the proximal tibia (PT) and the fourth lumbar vertebra (L4) in anesthetized rats are measured using a double-energy X-ray abscessiometer (Eclipse XR-26, Norland Corp. Ft. Atkins, Wl). Double-energy X-ray Absorptiometer (DXA) measurements for each rat are performed as follows: 15 minutes before the DXA measurements, the rats are anesthetized with an intraperitoneal injection of 100 mg / kg of ketamine (Bristol Laboratories, Syracuse , NY) and 0.75 mg / kg acepromazine (Aveco, Ft. Dodge, IA). The rat is placed on an acrylic plate under a DXA scanner perpendicular to its trajectory, the members are extended and fixed with paper tape to a surface of the plate. A preliminary scan is performed at a scanning speed of 50 mm / second with a scan resolution of 1.5 mm X 1.5 mm to determine the region of interest in PT and L4. Programming elements of small subjects are used at a scanning speed of 10 mm / second with a resolution of 0.5 mm X 0.5 mm for the final measurements of BMD. The programming elements allow the operator to define an area of 1.5 cm in width to cover the total length of L4. The BMDs for the respective sites are calculated by the programming elements as a function of the double beam attenuation (46.8 KeV and 80 KeV) of X-rays generated by the source below the subject and the detector moving along the area defined above the subject. The data ^^^^ - 20.8: -for BMD values (expressed in g / cm2) and individual scans are stored for statistical analysis. One week after the evaluation of BMD the rats are sacrificed by suffocation with carbon dioxide and the blood is collected for cholesterol determination. The uteri are removed and weighed. Total cholesterol is determined using the Boehringer-Mannheim Hitachi 911 clinical analyzer using the Cholesterol / HP equipment. The statistics are compared using the one-way analysis of variance with the Dunnet tests.

Table 18 Study of ovariectomized rats of 6 weeks of Example No. 98 Treatment BMD (mg / cm2) * '»Weight Weight Uterine body cholesterol (mg / dl" r (g>' - ° (mg) '' ° Tibia L, proximal Study'1 Wrong 0.211"0.183 * 43" 426.4 '"71.6" (intact) ± 0.003 ± 0.003 ± 6.0 ± 25.0 ± 5.0 Vehicle (Ovx) 0.189 0.169 62.7 118.2 87.2 ± 0.004 ± 0.004 ± 8.2 ± 7.8 ± 3.0 "Mean ± SEM After 5 weeks of treatment e After 6 weeks of treatment d Daily treatment x 7 days / week x6 weeks * p < 0.05 versus corresponding vehicle value ** p < 0.01 versus corresponding vehicle value It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A pharmaceutical composition comprising one or more estrogens and a compound containing the structure: (I) (II) wherein: Rj is selected from H, OH or the esters of C ^ C ^ (straight or branched chain) or alkyl ethers of -C ^ (straight or branched chain or cyclic) of the same, or halogens; or O-halted C1-C4 ethers including trifluoromethyl ether and trichloromethyl ether. R2, R3, R4, R5 and R6 are independently selected from H, OH or the Cx-C12 esters (straight or branched chain) or C1-C12 alkyl ethers (straight or branched chain, or cyclic) of the Halogens, or halogenated ethers of Cj-C, which include trifluoromethyl ether or trichloromethyl ether, cyano, CJ-CJ alkyl (straight or branched chain) or trifluoromethyl, with the proviso that when j is H, R2 is not OH. X is selected from H, C 1 -C 6 alkyl, cyano, nitro, trifluoromethyl, halogen; n is 2 or 3; And it is selected from: a) the portion: Rs where R7 and RB are independently selected from H, C ^ C alkyl, or phenyl optionally substituted by CN, Cj-C3 alkyl (straight or branched chain), Cj-Cg alkoxy (straight or branched chain), halogen, -OH, -CF3, or - OCF3; or R7 and Rβ are concatenated together as - (CH2) p-, where p is an integer from 2 to 6, preferably 4 to 6, the ring formed in this manner is optionally substituted with 1-3 substituents which are selected from CJ-CJ alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro and -CN; b) a saturated, unsaturated or partially unsaturated five-membered heterocycle containing up to 2 heteroatoms which are selected from the group consisting of -0-, -NH-, -N (C ^ C- alkyl, -N =, and - S (0) "-, wherein m is an integer of 0-2, optionally substituted with 1-3 substituents which are independently selected from hydroxyl, halo, C 1 C alkyl, trihalomethyl, C 1 alkoxy, trihalomethoxy, C 1 -C acyloxy, C 1 -C 4 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, -CN-, -CONHR 2 -, -NH 2, C 1 -C 4 alkylamino, dialkyl (C ^ C amino, -NHSO..R !, -NHCORi, -N02 and phenyl optionally substituted with 1-3 C1-C4 alkyl wherein Rx is as defined above, or Cj-C3 alkyl , - c) A bicyclic heterocycle containing from 6 to 12 carbon atoms either bridged or fused and containing up to 2 heteroatoms which are selected from the group consisting of -O-, -NH-, -N (C ^ alkyl) C, and -S (0) m-, where m is an integer of 0-2, optionally substituted with 1-3 substituents which are independently selected from the group consisting of hydroxyl, halo, alkyl, trihalomethyl, C 1 -C 6 alkoxy, trihalomethoxy, C 1 d acyloxy, C 1 C alkylthio, , C1-C4 alkylsulfinyl, alkylsulfonyl of Cj ^ -C ,, C1-C4 hydroxyalkyl, -C02H, -CN-, -CO HR! -, -NH2-, Cj-C alkylamino, (C1-C4) dialkylamino, -NHSOjR! -, -NHCOR! -, -N02 , and phenyl optionally substituted with 1-3 of CC alkyl; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition according to claim 1, characterized in that: Rj is selected from H, OH or the Cx-C4 alkyl esters or ethers thereof, or halogens; R 2, R 3, R 4, Rs and R 6 are independently selected from H, OH or the C 1 -C 4 alkyl esters or ethers thereof, halogen, cyano, C 1 -C 6 alkyl or trifluoromethyl, with the proviso that when R is H, R2 is not OH; X is selected from H, C? -Ce alkyl, cyano, nitro, trifluoromethyl, halogen; And it's the portion: R * s R7 and Rβ are independently selected from H, alkyl of or are combined with - (CH2) p-, where p is an integer from 2 to 6, so as to form a ring, the ring formed in this way is optionally substituted up to 3 substituents selected from hydroxyl, halo, CJ-CI alkyl, trihalomethyl, C1-C4 alkoxy, tphalomethoxy, C 1 C alkylthio, C 3 -C 4 alkylsulfonyl, Ci-C alkylsulfonyl, hydroxyalkyl of C1-C4, -C02H, -CN-, - CONHC alkyl of C ^ C, -NH2-, CX-C4 alkylamino, dialkyl (C ^ C amino, -NHS02C1-C4- alkyl, -NHCO alkyl of -C , and -N02; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

3. The pharmaceutical composition according to claim 1, characterized in that: Rx is OH; R2, R3, R4, R5 and Rs are independently selected from H, OH or the C3-C4 alkyl esters or ethers thereof, halogen, cyano, C ^ Cj alkyl or trifluoromethyl, with the proviso that when RS is H, R2 is not OH; X is selected from H, Cl, N02, CN, CF3 or CH3; And it's the portion: X R * s; R, and Rβ are concatenated together as - (CH2) r-, where r is an integer from 4 to 6, to form a ring optionally substituted by up to 3 substituents that are selected from hydroxyl, halo, Cj-C alkyl , trihalomethyl, C 1 -C 4 alkoxy, trihalomethoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, hydroxy alkyl of C 1 O ,, -C0 2 H, -CN-, -CONH (alkyl) of C1-C4), -NH2-, CJ-CJ alkylamino, dialkylamino of dC, -NHS02 alkyl of C ^ C, -, -NHCO alkyl of Cj-C, and -N02; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 1, characterized in that the compound is 5-benzyloxy-2- (4-ethoxy-enyl) -3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) benzyl] -IH-indole or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 1, characterized in that the compound is 1- [4- (2-azepan-1-yl-ethoxy) benzyl] -2- (4-hydroxyphenyl) -3-methyl-1H-indole 5-ol or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 1, characterized in that the compound is 4-. { 3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) benzyl] -lH-indole} or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 1, characterized in that the compound is 4-. { 5-fluoro-3-methyl-l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -lH-indol-2-yl} -phenol or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, characterized in that the compound is 1- [4- (2-azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxyphenyl) -3-methyl-1H-indole -5-ol or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 1, characterized in that the compound is 2- (4-idroxyphenyl) -3-methyl-l- [4- (2-diethyl-1-yl-ethoxy) benzyl] -1H-indole 5-ol or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 1, characterized in that the compound is 2- (4-hydroxyphenyl) -3-methyl-1- [4- (2-diethyl-1-yl) ethoxy) benzyl] -1H-indole 5-ol or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 1, characterized in that the compound is 2- (4-cyclophenyloxyphenyl) -3-methyl-l- [4- (2-piperidin-1-yl-ethoxy) encyl] -lH-indole 5-ol or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 1, characterized in that the compound is 3-methyl-1- [4- (2-piperidin-1-yl-ethoxy) benzyl] -2- (4-trifluoromethylphenyl) -lH-indole -5-ol or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 1, characterized in that the compound is 2- (4-hydroxyphenyl) -1- [3-methoxy-4- (2-piperidin-1-ylethoxy) benzyl] -3-methyl-1H- Indole-5-ol or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 1, characterized in that the compound is 2- (4- hydroxyphenyl) -1- [3-methoxy-4- (2-azepan-l-yl-e-oxy) -benzyl] -3-methyl-lH-indol-5-ol or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition according to any of claims 1 to 14, characterized in that one or more estrogens are selected from equilin, equilenin, estradiene, ethinyl estradiol, 17β-estradiol, 17alpha-dihydroequilenin, 17β-dihydroequilenin, menstranol, estrogen conjugates, estrone, 17alpha-estradiol sulfate, Delta 8, 9-dehydroestrone, equol or enterolactone or a pharmaceutically acceptable salt or ester thereof.

16. The pharmaceutical composition according to claim 15, characterized in that the pharmaceutically acceptable salt of one or more estrogens is a sodium salt.

17. A method for treating or preventing bone loss in a mammal, the method is characterized in that it comprises administering to the mammal in need thereof an effective amount of an estrogen and an effective amount of a compound according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

18. A method for treating or preventing disease states by syndrome which are caused or associated with an estrogen deficiency in a mammal, the method is characterized in that it comprises administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

19. A method for treating or preventing cardiovascular diseases in a mammal, the method is characterized in that it comprises administering to the mammal in need thereof an effective amount of an estrogen and an effective amount of a compound according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

20. A method for treating or preventing diseases in a mammal, which results from the proliferation or abnormal development, actions or growth of endometrial or endometrial-like tissue, the method is characterized in that it comprises administering to a mammal in need thereof an effective amount of an estrogen and an effective amount of a compound in accordance with any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

21. A method of treatment, according to claim 20, characterized in that the disease is endometriosis.

22. A product, characterized in that it comprises one or more estrogens and a compound having the structure (I) or (II), according to any of claims 1 to 14, combined for preparation for simultaneous, separate or sequential use in the treatment or prevention of cardiovascular diseases or a disease in a mammal which results from the proliferation or abnormal development, actions or growth of endometrial tissue or similar to endometrial, or disease states or syndromes which are caused or associated with an estrogen deficiency.