MXPA00002700A - Vitronectin receptor antagonists - Google Patents

Abstract

Compounds of formula (I) are disclosed which are vitronectin receptor antagonists and are useful in the treatment of osteoporosis wherein:A is CH2 or O;R1 is H, halo or C1-6alkyl;R2 is H, C1-6alkyl or CH2NR''R'';X is O or CH2;Y is (a), (b), (c), (d), (e), (f) or (g);G is NR'', S or O;R'is H, C1-6alkyl, OC1-6alkyl, SC1-6alkyl, NR''R''or halo;each R''independently is H or C1-6alkyl;and s is 0, 1 or 2;or a pharmaceutically acceptable salt thereof.

Description

VITRONECTIN RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to pharmaceutically active compounds which inhibit the vitronectin receptor and which are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as osteoporosis.

BACKGROUND OF THE INVENTION Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed in a variety of cells. These cell surface adhesion receptors include gpllb / llla (the fibrinogen receptor) and vß3 (the vitronectin receptor). The fibrinogen receptor gpllb / llla is expressed on the surface of platelets, and mediates the aggregation of platelets and the formation of a hemostatic clot at the site of a bleeding wound. Philips et al., Blood, 1998, 71, 831. The vr3 vitronectin receptor is expressed in a number of cells, including endothelial, smooth muscle, osteoclast and tumor cells, and, thus, has a variety of functions. The avß3 receptor expressed on the membrane of osteoclast cells mediates osteoclast damage to the bone matrix, a key step in the bone resorption process. Ross et al., J. Biol. Chem., 1987, 262, 7703. A disease characterized by excessive bone resorption is osteoporosis. The avß3 receptor expressed in human aortic smooth muscle cells mediates its migration into the neointima, a process that can lead to restenosis after percutaneous coronary angioplasty. Brown et al., Cardiovascular Res., 1994, 28, 1815. In addition, Brooks et al., Cell 1994, 79, 1157 has shown that an av3 antagonist is capable of promoting tumor regression by inducing apoptosis of angiogenic blood vessels. In this manner, agents that block the vitronectin receptor would be useful for treating diseases, such as osteoporosis, restenosis and cancer. It is now known that the vitronectin receptor refers to three different integrins, designated avß ?, avß3 and avßs. Horton et al., Int. J. Exp. Pathol., 1990, 71, 741. vß? it binds to fibronectin and vitonectrin. avß3 binds to a wide variety of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand factor, osteopontin, and bone sialoprotein I. avßs binds to vitronectin. The avß5 vitronectin receptor has been shown to be involved in cell adhesion of a variety of cell types, including microvascular endothelial cells, (Davis et al., J. Cell, Biol., 1993, 51, 206), and has been confirmed its role in angiogenesis. Brooks et al., Science, 1994, 264, 569. This integrin is expressed on blood vessels in granulation tissue of human wounds, but not in normal skin. It is known that the vitronectin receptor binds to bone matrix proteins that contain the tri-peptide Arg-gly-Asp (or RGD) motif. Thus, Horton et al., Exp. Cell Res. 1991, 195, 368, disclose that peptides containing RGD and an anti-vitronectin receptor antibody (23C6) inhibit dentin resorption and cell expansion by osteoclasts. In addition, Sato et al., J. Cell Biol. 1990, 111, 1713 discloses that echistatin, a snake venom peptide containing the sequence of RGD, is a potent inhibitor of bone resorption in tissue cultures, and inhibits union of osteoclasts to bone. It has now been discovered that certain compounds are potent inhibitors of avß3 and avßs receptors. In particular, it has been found that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.

BRIEF DESCRIPTION OF THE INVENTION This invention comprises compounds of the formula (I) as described hereinafter, which have pharmacological activity for the inhibition of the vitronectin receptor and are useful in the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as osteoporosis. This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. This invention is also a method for treating diseases that are mediated by the vitronectin receptor. In a particular aspect, the compounds of this invention are useful for treating atherosclerosis, restenosis, inflammation, cancer and diseases in which bone resorption is a factor, such as osteoporosis.

DETAILED DESCRIPTION OF THE INVENTION This invention comprises novel compounds that are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor. The novel compounds comprise a dibenzocydoheptene nucleus in which a nitrogen-containing substituent is present on one of the six-membered aromatic rings of dibenzocydoheptene, and an aliphatic substituent containing an acidic portion is present on the seven-membered ring of dibenzocydoheptene. It is believed that the dibenzocydoheptene ring system orients the substituent side chains on the six- and seven-member rings so that they can interact favorably with the vitronectin receptor. It is preferred that approximately twelve to fourteen intervening covalent bonds via the shortest intramolecular pathway will exist between the acid group on the aliphatic substituent of the seven-membered dibenzocydoheptene ring and the nitrogen of the nitrogen-containing substituent on one of the six aromatic rings. members of the dibenzociceheptene. This invention comprises compounds of the formula (I): wherein: A is CH2 or O; R1 is H, halogen or C? -6 alkyl; R2 is H, C1-6 alkyl or CH2NR "R"; X is O or CH2; And it is G is NR ", S or O, R 'is H, Ci-β alkyl, OC-d-6 alkyl, SC-C-γ-6 alkyl, NR" R "or halogen, each R" is independently H or Ci-β alkyl; and s is 0.1 or 2; or a pharmaceutically acceptable salt thereof. Also included in this invention are the pharmaceutically acceptable acid addition salts and the complexes of the compounds of this invention. In cases where the compounds of this invention may have one or more chiral centers, unless indicated, this invention includes each unique non-racemic compound that could be synthesized and resolved by conventional techniques. In cases where compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and (E) isomers are within the scope of this invention. In cases where the compounds may exist in tautomeric forms, such as keto-enol tautomers, such as, and each tautomeric form is contemplated as being included within this invention whether there is balance or stuck in a form by appropriate substitution with R '. The compounds of the formula (I) inhibit the binding of vitronectin and other peptides containing RGD to the vitronectin receptor. The inhibition of the vitronectin receptor in osteoclasts inhibits the resorption of osteoclastic bone and is useful in the treatment of diseases in which bone resorption is associated with pathology, such as osteoporosis and osteoarthritis. In another aspect, this invention is a method for stimulating bone formation comprising administering a compound that causes an increase in the release of osteocalcin. Increased bone production is a clear benefit in disease states in which there is a deficiency of mineralized bone mass or bone remodeling is desired, such as fracture healing and the prevention of bone fractures. Metabolic diseases and disorders that result in the loss of bone structure would also benefit from such treatment. For example, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or deficiency of sex hormone, Behct's disease, osteomalacia, hyperostosis and osteopetrosis, would benefit from the administration of a compound of this invention. In addition, since the compounds of the present invention inhibit vitronectin receptors in a number of different cell types, said compounds would be useful in the treatment of inflammatory disorders, such as rheumatoid arthritis and psoriasis, and cardiovascular diseases such as atherosclerosis and restenosis The compounds of the formula (I) of the present invention may be useful for the treatment or prevention of other diseases including, but not limited to, thromboembolic disorders, asthma, allergies, adult respiratory distress syndrome, graft-versus-host disease, organ transplant rejection, septic shock, eczema, contact dermatitis, inflammatory bowel disease and other autoimmune diseases. The compounds of the present invention may also be useful for wound healing. The compounds of the present invention are also useful for the treatment, including prevention, of angiogenic disorders. The term "angiogenic disorders" as used herein, includes conditions that involve abnormal neovascularization. When the growth of new blood vessels is the cause of, or contributes to, the pathology associated with a disease, the inhibition of angiogenesis will reduce the harmful effects of the disease. An example of such a white disease is diabetic retinopathy. When the growth of new blood vessels is required to support the growth of a harmful tissue, the inhibition of angiogenesis will reduce the blood supply to the tissue and thus contribute to the reduction in tissue mass based on supply requirements. of blood. Examples include the growth of tumors where neovascularization is a continuous requirement for the tumor to grow, and the establishment of solid tumor metastases. In this way, the compounds of the present invention inhibit angiogenesis of tumor tissues, thereby preventing tumor metastasis and tumor growth. Thus, according to the methods of the present invention, the inhibition of angiogenesis using the compounds of the present invention can decrease the symptoms of the disease, and, in some cases, can cure the disease. Another therapeutic goal for the compounds of the present invention are eye diseases characterized by neovascularization. Such eye diseases include neovascular corneal disorders, such as corneal transplantation, herpetic keratitis, luteal keratitis, pterygia and neovascular cloth associated with the use of contact lenses. Additional eye diseases also include age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity, and neovascular glaucoma. This invention further provides a method for inhibiting tumor growth, comprising administering in step or in physical combination a compound of formula (I) and an antineoplastic agent, such as topotecan and cisplatin. With respect to formula (I): Suitably Y is where R 'is H, C? -4 alquiloalkyl, OC-C dealkyl, SC-C alquilo |alkyl. , NR "R" or Cl and each R "is independently H or C -? - 4 alkyl, Alternatively, Y is wherein each R "is H or C1-4 alkyl, Alternatively, Y is where each R "is independently H or C- alkyl, and s is 1. Alternatively, Y is wherein G is S and each R "is independently H or C? - alkyl Alternatively, Y is where R" is H or C -? - alkyl. Representative novel compounds of this invention are the following: Acid (±) -10,11-dhydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a , d] cycloheptene-10-acetic; (±) -10,11-Dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-3- [3- (4-ethoxypyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (R) -10,11-Dihydro-3- [3- (pyridin-2-ylammon) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-D-Hydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10 acid -acetic; (±) -10,11-Dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-3- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-7-fluoro-3- [3- (pyridin-2-ylammon) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-methyl-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-ethoxypyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; Acid (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-acetic; (S) -10,11-Dihydro-3- [3- [4- (2-propyloxy) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-3- [3- [4- (ethylthio) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10) 11-Dihydro-3- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) 10,11-Dihydro-2-methyl-3- [3-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) 10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -dibenzo [a, f] oxephino-10-acetic acid; (±) 10,11-Dihydro-3- [3- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -dibenzo [a, f] oxefino-10-acetic acid and acid (S) - acid 10,11-dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic; or a pharmaceutically acceptable salt thereof. In case the compounds of this invention can have one or more chiral centers, unless otherwise specified, this invention includes each unique non-racemic compound that can be synthesized and resolved by conventional techniques. In accordance with the present invention, the (S) -configuration of the compounds of the formula (I) is preferred. In case the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and (E) isomers are within the scope of this invention. The meaning of any substituent in any occurrence is independent of its meaning, or the meaning of any other substituent in any other occurrence. The prodrugs of the compounds of this invention are also included in this invention. Prodrugs are any covalently linked vehicles that release the drug of active origin according to formula (I) in vivo. Thus, in another aspect of this invention are the novel prodrugs, which are also intermediates in the preparation of the compounds of the formula (I), of the formula (II): wherein: A is CH2 or O; R1 is H, halogen or C-i ^ alkyl; R2 is H, C1-6 alkyl or CH2NR "R"; X is O or CH2, and is G is NR ", S or O, R 'is H, Ci-β alkyl, OC-C-- -6 alkyl, SC-C?-6 alkyl, NR" R "or halogen; Each R" is independently H or C? -6 alkyl; and s is 0.1 or 2; or a pharmaceutically acceptable salt thereof. In still another aspect of this invention are the novel intermediates of the formula (III): wherein: A is CH2 or O; R1 is H, halogen or C? -6 alkyl; R2 is H, C1-6 alkyl or CH2NR "R"; X is O or CH2, R 'is H, C-? -6 alkyl, OC-Ci-β alkyl, SC-Ci-β alkyl, NR "R" or halogen and each R "is independently H or alkyl of Ci-β, or a pharmaceutically acceptable salt thereof.

The abbreviations and symbols commonly used in the peptide and chemistry techniques are used herein to describe the compounds of this invention. In general, amino acid abbreviations follow the nomenclature of IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem, 158, 9 (1984). C-M alkyl as used herein means an alkyl group optionally substituted by 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Alkyl of C -? - 6 further includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Alkyl of Co-4 and alkyl Co-β further indicates that an alkyl group does not have to be present (for example, that a covalent bond is present). Any C1-4 alkyl or C6-6 alkyl may be optionally substituted with the Rx group, which may be on any carbon atom that results in a stable structure and is available by conventional synthetic techniques. Suitable groups for R x are C 1-4 alkyl, OR ", SR", C 1 alkylsulfonyl, C 1-4 alkylsulfunyloxy, -CN, N (R ") 2> CN 2 N (R") 2, -NO 2, - CF3, -CO2R ", -CON (R") 2, -COR ", -NR" C (O) R ", F, Cl, Br, I or CF3S (O) r-, where r is 0, 1 or 2. Halogen means F, Cl, Br and I. Ar, or aryl, as used herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents, such as those defined above for alkyl, especially C? -4 alkyl, C 1 -4 alkoxy, C al alkoxy, CF 3, NH 2, OH, F, Cl, Br or I. Certain radical groups are abbreviated herein T-Bu refers to the tertiary butyl radical , Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to methyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to C? - alkyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl. Certain reagents are abbreviated in the present. DCC refers to dicyclohexylcarbodumide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethylamine, EDC refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. HOBT refers to 1-h id roxy benzotriazole, THF refers to tetrahydrofuran, DIEA refers to diisopropylethylamine, DEAD refers to diethyl azodicarboxylate, PPh3 refers to triphenylphosphine, DIAD refers to diisopropyl azodicarboxylate, DME refers to dimethoxyethane , DMF refers to dimethylformamide, NBS refers to N-bromosuccinimide, Pd / C refers to a palladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPA refers to diphenylphosphoryl azide, BOP refers to benzotriazole hexafluorophosphate - 1-loxy-tris (dimethylamino) phosphonium, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyridinium chlorochromate.

The compounds of the formula (I) are generally prepared by reacting a compound of the formula (IV) with a compound of the formula (V): wherein R1, R2, Y and A are as defined in formula (I), with any protected reactive functional group, and L1 is OH or halogen; and subsequently removing any protecting group, optionally forming a pharmaceutically acceptable salt. Suitably, certain compounds of the formula (I) are prepared by reacting a compound of the formula (IV) with a compound of the formula (VI): wherein R1, R2, R ', R "and A are as defined in formula (I), with any protected reactive functional group; and subsequently removing any protecting group, and optionally forming a pharmaceutically acceptable salt. Suitably, the reaction of a compound of the formula (IV) with a compound of the formula (VI) is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent. In addition, certain compounds of the formula (I) are prepared by reacting a compound of the formula (IV) with a compound of the formula (VII); wherein R1, R2, R "and A are as defined in formula (I), with any protected reactive functional group, and subsequently removing any protecting group and optionally forming a pharmaceutically acceptable salt. compound of the formula (IV) and a compound of the formula (VII) is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent The compounds of the formula (I) are prepared by the methods described in Bondinell and others, PCT publication No. WO 97/01540 (International Application No. PCT / US96 / 11108, published January 16, 1997, the complete disclosure of which is hereby incorporated by reference.) In addition, the compounds of the formula (I) are prepared by methods analogous to those described in the schemes detailed below.

SCHEME I a) 10% Pd / C, HOAc; b) SOCI2, toluene; c) AICI3, CH2Cl2 Scheme I details the preparation of an intermediate useful in the preparation of the compounds of the formula (I).

SCHEME II a) LiN (TMS) 2, ethyl bromoacetate; Jones reagent, OsO4; c) H2, 10% Pd / C, HOAC; d) C2O2Cl2, DMF; e) AICI3, CH2Cl2, RT; f) H2, 10% Pd / C, HOAC. Scheme II also details the preparation of an intermediate useful in the preparation of compounds of the formula (I).

SCHEME III 15 20 (a) EtOAc / LiHMDS, THF; (b) H2, 10% Pd / C, conc HCl, AcOH; (c) EtSH, AICI3, CH2Cl2; (d) N - oxide of 2 - [(3-hydroxy-1-pl) amino] -4-nitridine, DEAD, (Ph) 3P; (e) NaOEt, EtOH; (f) cyclohexene, 10% Pd / C, EtOH; (g) 1.0 N NaOH, EtOH; (h) HCl. Scheme III details the preparation of a compound of the formula (I). The reaction of 111-1 (which is a compound of scheme I-3) is an aldol-type reaction with the ethyl acetate enolate, which can be generated from ethyl acetate on exposure to a suitable amide base, by example lithium diisoplamide (LDA) or lithium bis (trimethylsilyl) amide (LiHMDS), gives III-2. Frequently, THF is the solvent of choice for an aldol reaction, although THF is commonly used in the presence of various additives, for example HMPA or TMEDA. The reduction of III-2 to give III-3 (which is a compound of scheme II-6) can be achieved by hydrogenolysis on a suitable catalyst, for example palladium metal on activated carbon (Pd / C), in an appiate solvent, such as acetic acid, in the presence of a mineral acid such as HCl. Alternatively, this reduction can be achieved by the treatment of III-2 with triethylsilane in the presence of boron trifluoride etherate by the general method of Orfanopoulos and Smonou (Synth, Commun, 1988, 833). Removal of the methyl ether from III-3 to give III-4 can be achieved with BBr3 in an inert solvent, for example CH2Cl2, or by reaction with ethanethiol and AICI3 in an inert solvent, preferably CH2Cl2. Other useful methods for the renewal of a methyl ether are described in Greene, "Protective Groups in Organic Synthesis" (published by Jonh Wiley and Sons). Compound 4 of scheme 3 (111-4) is reacted with 2 - [(3-hydroxy-1-pl) amino] -4-nitridine N-oxide in a Mitsunobu-type coupling reaction (Organic Reactions 1992 , 42, 335-656; Synthesis 1981, 1-28) to give III-5. The reaction is mediated by the complex formed between diethyl azodicarboxylate and triphenylphosphine, and is carried out in a practical solvent, for example, THF, CH2Cl2 or DMF. Compound III-5 is reacted with an alkali metal salt of a suitable alcohol to give III-6. Suitable alkali metals include lithium, sodium, potassium and cesium, and the alcohol used for the displacement reaction is generally used as the solvent. Methods for forming the alkali metal salts of alcohols are well known to those skilled in the art. The pyridine N-oxide portion of III-6 is reduced to the corresponding pyridine III-7 under transfer hydrogenation conditions using a palladium catalyst, preferably palladium on activated carbon metal, in an inert solvent, for example methanol, ethanol or 2-propanol. Cyclohexene, 1,4-cyclohexadiene, formic acid and formic acid salts, such as potassium formate or ammonium formate, are commonly used as the hydrogen transfer agent in this type of reaction. The ethyl ester of III-7 is hydrolyzed using an aqueous base, for example, LiOH in aqueous THF or NaOH in methanol or aqueous ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for example TFA or HCl, to give the carboxylic acid III-8. Alternatively, the intermediate carboxylate salt can be isolated, if desired, or a carboxylate salt of the carboxylic acid in free form can be prepared by methods well known to those skilled in the art.

SCHEME IV (a) NaH, 2- [N- (3-methansu? fonyloxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine N-oxide, DMSO; (b) TFA, CH2Cl2; (c) see diagram III. Scheme IV describes an alternative method for the preparation of the compounds of the formula (I). The compound IV-1 is reacted with a base, preferably an alkali metal hydride such as sodium hydride or potassium hydride, in a polar aprotic solvent, generally THF, DMF, DMSO or mixtures thereof, to give the corresponding alkali metal phenoxide. Alternatively, an alkali metal amide, for example LDA, or the lithium, sodium or potassium salt of hexamethyldisilazane can be used for deprotonation. The intermediate phenoxide is generally not isolated, but it is reacted in situ with a suitable electrophile, for example 2- [N- (3-methansulfonyloxy-1-propyl) -N- (fer-butoxycarbonyl) -amino] -oxide. ] pyridine, to give the coupled product IV-2. The tert-butoxycarbonyl protecting group in IV-2 is removed under acidic conditions, such as 4M HCl in 1,4-dioxane or TFA in CH 2 Cl 2, to give IV-3. The conditions for the removal of the tert-butoxycarbonyl protecting group are well known to those skilled in the art, and various methods useful in standard reference volumes such as Greene, "Protective Groups in Organic Synthesis" are described. IV-3 is subsequently converted into IV-4 following the procedure explained in Scheme III.

SCHEME V (a) PhOH, Cu, K2CO3; (b) sulfur, morpholine; (c) KOH, H2O, i-PrOH; (d) SOCI2, benzene; (e) AICI3, CH2Cl2; (f) EtOAc, LiN (TMS) 2, TMEDA, THF; (g) Et 3 SiH, BF 3, OEt 2, CH 2 Cl 2; (h) H2, Pd / C, EtOH; (i) BBr3, CH2Cl2. 2-Fluoro-4-methoxyacetophenone commercially available (V-1) reacts with an alcohol, for example phenol, in the presence of copper metal and a suitable base, for example K 2 C 3, to give the diaryl ether V-2. After treatment with sulfur and a suitable primary or secondary amine, preferably morpholine, according to the Harris general method (J. Med. Chem. 1982, 25, 855), V-2 becomes V-3 in a reaction of classic Willgerodt-Kindler. The thioamide thus obtained is hydrolyzed to the corresponding carboxylic acid V-4 by reaction with an alkali metal hydroxide, suitably KOH, in an aqueous alcohol solvent, such as MeOH, EtOH or aqueous i-PrOH. The carboxylic acid V-4 is converted to the corresponding acid chloride by reaction with SOCI2 or oxalyl chloride according to conditions well known to those skilled in the art. Treatment of this acid chloride with a suitable Friedel-Crafts catalyst, such as AICI3 or SnCl4, in an inert solvent, such as CH2Cl2 or CS2, provides the cyclic ketone V-5. Alternatively, the V-4 acid can be converted directly into the V-5 ketone under acidic conditions, for example with polyphosphoric acid. The reaction of V-5 in an aldol-type reaction with the ethyl acetate enolate, which can be generated from ethyl acetate on exposure to a suitable amide base, for example lithium diisopropylamide (LDA) or bis (trimethylsilyl) ) lithium amide (LiHMMDS), gives V-6. Frequently, THF is the solvent of choice for an aldol reaction, although THF is also commonly used in the presence of various additives, for example HMPA or TMEDA. The reduction of V-6 to V-7 can be achieved by treating V-6 with triethylsilane in the presence of boron trifluoride etherate by the general method of Orphanopoulos and Smonu (Synth, Commun., 1988, 833). Any olefinic byproduct resulting from the removal of the alcohol is reduced by hydrogenation over a suitable catalyst, for example palladium metal on activated carbon (Pd / C), in a suitable solvent, such as MeOH or EtOH. Alternatively, the reduction of V-6 to V-7 can be achieved by hydrogenolysis in the presence of a mineral acid such as HCl. Typically, this reaction is catalyzed by Pd / C, and is conducted optimally in acetic acid. The removal of the methyl ether from V-7 to give V-8 can be achieved with BBr3 in an inert solvent, for example CH 2 Cl 2, or by reaction with ethanethiol and AICI 3 in an inert solvent, preferably CH 2 Cl 2. Other useful methods for the removal of a methyl ether are described in Greene, "Protective Groups in Organic Synthesis" (published by John Wiley and Sons). V-8 is subsequently converted to compounds of the formula (I) after the procedure mentioned in scheme III. The acid addition salts of the compounds are prepared in a normal manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic acid. or methanesulfonic. Certain compounds form interior salts or zwitterions that may be acceptable. The cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation, or with a suitable organic amide. Cations such as Li +, Na \ K \ Ca ++, Mg ++ and NH + are specific examples of cations present in pharmaceutically acceptable salts. This invention also provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. Accordingly, the compounds of the formula (I) can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of the formula (I) prepared as described hereinabove can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation can be a regulated, isotonic or aqueous pH solution. Examples of suitable diluents are normal isotonic saline, normal 5% dextrose in water or sodium or ammonium acetate solution of regulated pH. Said formulation is especially suitable for parenteral administration, but can also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds may be encapsulated, tabletted or prepared in an emulsion or syrup for oral administration.

The pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, alba earth, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid vehicles include syrup, peanut oil, olive oil, saline and water. The vehicle may also include a prolonged release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies, but will preferably be between about 20 mg to about 1 g per unit dose. The pharmaceutical preparations are made following conventional pharmacology techniques including spraying, mixing, granulating and compressing, when necessary, for tablet forms; or spraying, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly p.o. or fill in a soft gelatin capsule. For rectal administration, the compounds of this invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The compounds described herein are antagonists of the vitronectin receptor, and are useful for treating diseases in which the underlying pathology is attributable to ligands or cells that interact with the victronectin receptor. For example, these compounds are useful for the treatment of diseases in which the loss of the bone matrix creates a pathology. Thus, the present compounds are useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's disease, hypercalcemin of malignancy, osteolytic lesions caused by bone metastasis, bone loss due to immobilization or deficiency of sex hormone. It is also believed that the compounds of this invention have utility as antitumor, anti-angiogenic, anti-inflammatory and anti-metastatic agents, and are useful in the treatment of atherosclerosis and restenosis. The compound is administered either orally or parenterally to the patient, in such a manner that the concentration of the drug is sufficient to inhibit bone resorption, or other such indication. The pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg / kg in a manner consistent with the patient's condition. Preferably, the oral dose would be from about 0.5 to about 20 mg / kg. For parenteral administration parenteral administration is preferred. An intravenous infusion of the peptide in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is very effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be from about 0.01 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg. The compounds are administered one to four times a day at a level to achieve a total daily dose of about 0.4 to about 400 mg / kg / day. The precise level and method by which the compounds are administered is readily determined by one skilled in the art, by comparing the level of the agent in the blood to the concentration required to have a therapeutic effect. This invention further provides a method for treating osteoporosis or inhibiting bone loss, which comprises administering in step or in physical combination a compound of the formula (I) and other inhibitors of bone resorption, such as bisphosphonates (ie, alendronate). ), hormone replacement therapy, antiestrogen or calcitonin. further, this invention provides a method of treatment using a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, useful in the prevention of bone loss and / or to increase bone mass. In addition, this invention provides a method for inhibiting tumor growth, comprising administering in step or in physical combination a compound of formula (I) and an antineoplastic agent. Compounds of the analogous class of camptothecin, such as topotecan, irinotecan and 9-aminocamptothecin, and platinum coordination complexes, such as cisplatin, ormaplatin and tetraplatin, are well-known groups of antineoplastic agents. Compounds of the analogous class of camoptothecin are described in the U.S. Patents. Nos. 5,004,758, 4,604,463, 4,473,692, 4,545,880, 4,342,776, 4,513,138, 4,399,276, US Patent Application Publication No. 0 418 099 and 0 088 642. Wani et al., J. Med Chem, 1986, 29, 2358, Wani. et al., J. Med. Chem., 1980, 23, 554, Wani et al., J. Med. Chem., 1987, 30, 1774 and Nitta et al., Proc. 14th International Congr. Chemotherapy., 1985, Anticancer Section 1, 28, whose complete descriptions of each are incorporated herein by way of reference. The platinum coordination complex, cisplatin, is available under the tradename Platinol® from Bristol Myers-Squibb Corporation. Useful formulations for cisplatin are described in the U.S. Patents. Nos. 5,562,925 and 4,310,515, the complete description of each of which is hereby incorporated by reference. In the method of inhibiting tumor growth comprising administering stepwise or in physical combination a compound of the formula (I) and an antineoplastic agent, the platinum coordination compound, for example cisplatin, can be administered using a slow intravenous infusion . The preferred vehicle is a dextrose / saline solution containing mannitol. The dosage regimen of the platinum coordination compound may be based on about 1 to about 500 mg per square meter (mg / m2) of body surface area per course of treatment. Infusions of the platinum coordination compound may be given once or twice a week, and weekly treatments may be repeated several times. Using a compound of the analogous class of campothecin in a parenteral administration, the course of therapy generally employed is from about 0.1 to about 300.0 mg / m2 of body surface area per day for approximately five consecutive days. Most preferably, the course of therapy employed for the topotecan is from about 1.0 to about 2.0 mg / m2 of body surface area per day for approximately five consecutive days. Preferably, the course of therapy is repeated at least once at an interval of from about seven days to about twenty-eight days. The pharmaceutical composition can be formulated with both the compound of the formula (I) and the antineoplastic agent in the same container, but different containers are preferred in the formulation. When both agents are provided in solution form, they can be contained in an infusion / injection system for simultaneous administration or in an online arrangement. For convenient administration of the compound of the formula (I) and the antineoplastic agent at the same or different times, a kit is prepared comprising, in a single container such as a box, carton or other container, individual bottles, bags, flasks or other containers each having an effective amount of the compound of the formula (I) for parenteral administration, as described above, and a defective amount of the antineoplastic agent for parenteral administration, as described above. Said equipment may comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized stoppers, as containers of solutions for reconstitution. A variation of this is to include the solution for reconstitution and the lyophilized plug in two single container chambers, which can be mixed before use. With such an arrangement, the antineoplastic agent and the compound of this invention can be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container. When both agents are provided in solution form, they can be contained in an infusion / injection system for simultaneous administration or in an online arrangement. For example, the compound of formula (I) can be an injectable form intravenously, or an infusion bag attached in series, by tube means, to the antineoplastic agent in a second infusion bag. By using said system, a patient may receive an initial bolus injection or infusion of the compound of the formula (I) followed by an infusion of the antineoplastic agent. The compounds can be tested in one of several biological tests to determine the concentration of compound that is required to have a certain pharmacological effect.

Inhibition of binding to vitronectin Binding of [3H] -SK &F-107260 from solid phase to avß3: Human placenta or human platelets vß3 (0.1-0.3 mg / mL) in pH T regulator (containing 2 mM CaCl2 and 1% octylglucoside) was diluted with pH T regulator containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (pH A regulator) and 0.05% NaN3 and then immediately added to 96-well ELISA plates (Corning, New York, NY) at 0.1 mL per well. 0.1-0.2 μg of avß3 was added per well. The plates were incubated overnight at 4 ° C. At the time of the experiment, the cavities were washed once with pH A regulator and incubated with 0.1 mL of 3.5% bovine serum albumin in the same pH regulator for 1 hour at room temperature. After incubation, the cavities were completely aspirated and washed twice with 0.2 mL of pH A regulator. The compounds were dissolved in 100% DMSO to give a 2 mM supply solution, which was diluted with pH regulator. binding (15 mM Tris-HCl (pH 7.4), 100 mM NaCl, 1 mM CaCl 2, 1 mM MnCl 2, 1 mM MgCl 2) to a final compound concentration of 100 μM. This solution was then diluted to the necessary final compound concentration. Various concentrations of unlabeled antagonists (0.001-100 μM) were added to the cavities in triplicate, followed by the addition of 5.0 nM of [3 H] -SK &F-107260 (65-86 Ci / mmol). The plates were incubated for one hour at room temperature. After incubation the cavities were completely aspirated and washed once with 0.2 mL of pH A regulator cooled with ice in cavity-to-cavity form. The receptors were solubilized with 0.1 mL of 1% SDS and the [3H] -SK &F-107260 bound was determined by liquid scintillation counting with the addition of 3 mL of Ready Safe in a LS Beckman liquid scintillation counter, with an efficiency of 40%. The non-specific binding of [3 H] -SK &F-107260 was determined in the presence of 2 μM of SK &F-107260 and was consistently less than 1% of the total radioligand input. IC50 (concentration of the antagonist to inhibit 50% binding of [3H] -SK &; F-107260) was determined by a routine adaptation of the final and non-linear frames curve, which was modified from the LUNDON-2 program. The K i (antagonist dissociation constant) was calculated according to the equation: K, = IC5o / (1 + L / k), where L and Kd were the concentration and dissociation constant of [3H] -SK &; F-107260, respectively. The compounds of the present invention inhibit the binding of vitronectin to SK & F 107260 in the concentration range of about 2.5 to about 0.001 micromolar. The compounds of this invention are also tested for bone resorption in vitro and in vivo in standard tests in the art to evaluate the inhibition of bone formation, such as the gap formation test described in EP 528 587, which also it can be carried out using human osteoclasts instead of rat osteoclasts, and the ovariectomized rat model, described by Wronski et al., Cells and Materials 1991, Suppl. 1, 69-74.

Migration test of vascular smooth muscle cells Rat or human aortic smooth muscle cells were used. Cell migration was monitored in a Transwell cell culture chamber using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with victronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10 6 cells / mL, and pretreated with test compound at various concentrations for 20 minutes at 20 ° C. The solvent was only used as a control. 0.2 mL of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin. Incubation was carried out at 37 ° C in an atmosphere of 95% air / 5% CO2 for 24 hours. After incubation, the cells that did not migrate on the upper surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. The migration was measured either a) by counting the number of cells that had migrated to the lower surface of the filter, or b) extracting the cells stained with 10% acetic acid followed by the determination of the absorbance at 600 nM.

Model of thyroparathyroidectomized rat Each experimental group consists of 5-6 adult male Sprague-Dawley rats (250-400 g of body weight). Rats are thyroparathyroidectomized (by the seller, Taconic Farms) 7 days before use. All rats receive a thyroxine replacement dose every 3 days. After receiving the rats, the levels of circulating ionized calcium are measured in whole blood immediately after it has been extracted by venipuncture of the tail in heparinized tubes. Rats include whether the level of ionized Ca (measured with a Ciba-Corning model 634 pH calcium analyzer) is < 1.2 mM / L. Each rat is equipped with a venous and arterial resident catheter for the supply of the test material and for blood sampling respectively. The rats are then put on a diet of calcium-free food and deionized water. Baseline Ca levels are measured and each rat is given control vehicle or human parathyroid hormone 1-34 peptide (hPTH1-34, dose 1.25 ug / kg / h in saline / 0.1% serum albumin of bovine, Bachem, Ca) or a mixture of hPTH1-34 and test material, by continuous intravenous infusion via the venous catheter using an external syringe pump. The calcemic response of each rat is measured at two-hour intervals during the infusion period of 6-8 hours.

Human osteoclast resorption and adhesion tests Reasorption and gap adhesion tests have been developed and standardized using normal human osteoclasts derived from osteoclastoma tissue. Test 1 was developed for the measurement of osteoclast hole volumes by laser confocal microscopy. Test 2 was developed as a higher emission velocity analysis in which fragments of collagen (released during resorption) are measured by competitive ELISA.

Test 1 (using laser confocal microscopy) • Aliquots of cell suspensions derived from human osteoclastoma are removed from a storage of liquid nitrogen, heated rapidly to 37 ° C and washed x 1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). • The medium is aspirated and replaced with murine anti-HLA-DR antibody and then diluted 1: 3 in RPMI-1640 medium. The suspension is incubated for 30 minutes on ice and mixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000 rpm, 5 minutes at 4 ° C) and the cells are then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells is listed in an improved Neubauer counting chamber. • Sufficient magnetic spheres (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their supply bottle and placed in 5 ml of fresh medium (this delays the preservative of toxic azide). The medium is removed by moving the spheres on a magnet and replaced with fresh media. • The spheres are mixed with the cells and the suspension is incubated for 30 minutes on ice. The suspension is mixed frequently. • The cells coated with spheres are immobilized on a magnet and the remaining cells (fraction rich in osteoclasts) are decanted in a sterile 50 ml centrifuge tube. • Fresh medium is added to the cells coated with spheres to dislodge any entrapped osteoclasts. This washing procedure is repeated x 10. The cells coated with spheres are then discarded. • Viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label living cells. A large hole disposable plastic pasteur pipette is used to add the sample to the chamber • Osteoclasts are pelleted by centrifugation and the density is adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate. • Aliquots of 3 ml of the cell suspension (by compound treatment) are decanted in 15 ml centrifuge tubes. The cells are pelleted by centrifugation. • 3 ml of the appropriate compound treatment (diluted to 50 uM in the EMEM medium) is added to each tube. Also included are suitable vehicle controls, a positive control (murine monoclonal anti-vitronectin receptor antibody [87MEM1] diluted at 100 ug / ml) and an isotype control (IgG2a diluted at 100 ug / ml). The samples are incubated at 37 ° for 30 minutes. • Aliquots of 0.5 ml of the cells are seeded on sterile dentin slides in a 48-well plate and incubated at 37 ° C for 2 hours. Each treatment is analyzed in quadruplicate. • The slides are washed in six changes of warm PBS (10 ml / well in a 6-well plate) and then placed in fresh medium containing the compound treatment or control samples. The samples are incubated at 37 ° C for 48 hours.

Procedure of acid trafarate resistant phosphatase (TRAP) (Selective staining for osteoclast lineage cells) • The bone slides containing the bound osteoclasts are washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes. • Afterwards they are washed in water and incubated for 4 minutes in pH TRAP buffer at 37 ° C (0.5 mg / ml naphthol AS-BI phosphate dissolved in N, N-dimethylformamide and mixed with 0.25 M citrate pH regulator ( pH 4.5), which contains 10 mM of sodium tartrate • After washing in cold water the slides are immersed in cold acetate pH buffer (0.1 M, pH 6.2) containing 1 mg / ml of fast red garnet and incubate at 4 ° C for 4 minutes • Extract the pH regulator and the slides are air dried after washing in water.

• TRAP-positive osteoclasts (red brick / purple precipitate) are enumerated by bright field microscopy and then removed from the surface of the dentin by sonication. The void volumes are determined using the Nikon / Lasertec ILM21W confocal microscope.

Test 2 (using an ELISA reading) Human osteoclasts are enriched and prepared for compound analysis as described in the initial steps of test 1. For clarity, these steps are repeated below. • Aliquots of cell suspensions derived from human osteoclastoma are removed from a storage of liquid nitrogen, heated rapidly to 37 ° C and washed x 1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). "The medium is aspirated and replaced with murine anti-HLA-DR antibody and then diluted 1: 3 in RPMI-1640 medium. The suspension is incubated for 30 minutes on ice and mixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000 rpm, 5 minutes at 4 ° C) and the cells are then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells is listed in an improved Neubauer counting chamber. • Sufficient magnetic spheres (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their supply bottle and placed in 5 ml of fresh medium (this delays the azide preservative toxic). The medium is removed by moving the spheres on a magnet and replaced with fresh media. • The spheres are mixed with the cells and the suspension is incubated for 30 minutes on ice. The suspension is mixed frequently. • The cells coated with spheres are immobilized on a magnet and the remaining cells (fraction rich in osteoclasts) are decanted in a sterile 50 ml centrifuge tube. • Fresh medium is added to the cells coated with spheres to dislodge any entrapped osteoclasts. This washing procedure is repeated x 10. The cells coated with spheres are then discarded. • Viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label living cells. A large hole disposable plastic pasteur pipette is used to add the sample to the chamber • Osteoclasts are pelleted by centrifugation and the density is adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate. Unlike the method described above in test 1, the compounds are analyzed at 4 doses to obtain an IC50, as indicated below: • The osteoclast preparations are pre-incubated for 30 minutes at 37 ° C with the test compound (4 doses ) or controls. • They are then seeded onto bovine cortical bone slides in cavities of a 48-well tissue culture plate and incubated for an additional 2 hours at 37 ° C. • The bone slides are washed in six changes of pH-regulated saline solution with hot phosphate (PBS), to remove non-adherent cells, and then return to the cavities of a 48-well plate containing fresh compound or controls. • The tissue culture plate is then incubated for 48 hours at 37 ° C. • The supernatants of each cavity are aspirated in individual tubes and analyzed in a competitive ELISA that detects the c-telopeptide of type I collagen that is released during the resorption process. This is a commercially available ELISA (Osteometer, Denmark) that contains a rabbit antibody that specifically reacts with a sequence of 8 amino acids (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg) that is present in the carboxy-terminal telopeptide of the a1 chain of type 1 collagen. The results are reported as% inhibition of resorption compared to a vehicle control.

Human osteoclast adhesion test Human osteoclasts are enriched and prepared for compound analysis as described above in the initial 9 steps of test 1. For clarity, these steps are repeated below. • Aliquots of cell suspensions derived from human osteoclastoma are removed from a storage of liquid nitrogen, heated rapidly to 37 ° C and washed x 1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). • The medium is aspirated and replaced with murine anti-HLA-DR antibody and then diluted 1: 3 in RPMI-1640 medium. The suspension is incubated for 30 minutes on ice and mixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000 rpm, 5 minutes at 4 ° C) and the cells are then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells is listed in an improved Neubauer counting chamber. • Sufficient magnetic spheres (5 / mononuclear cell), coated with goat anti-mouse IgG (Dynal, Great Neck, NY) are removed from their supply bottle and placed in 5 ml of fresh medium (this delays the azide preservative toxic). The medium is removed by moving the spheres on a magnet and replaced with fresh media. • The spheres are mixed with the cells and the suspension is incubated for 30 minutes on ice. The suspension is mixed frequently.

• The cells coated with spheres are immobilized on a magnet and the remaining cells (fraction rich in osteoclasts) are decanted in a sterile 50 ml centrifuge tube. • Fresh medium is added to the cells coated with spheres to dislodge any entrapped osteoclasts. This washing procedure is repeated x 10. The cells coated with spheres are then discarded. • Viable osteoclasts are enumerated in a counting chamber, using fluorescein diacetate to label living cells. A large hole disposable plastic pasteur pipette is used to add the sample to the chamber • Osteoclasts are pelleted by centrifugation and the density is adjusted to the appropriate number in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate. • osteoclasts derived from osteoclastoma are pre-incubated with compound (4 doses) or controls at 37 ° C for 30 minutes. • The cells are then seeded on slides coated with osteopontin (human or rat osteopontin, 2.5 ug / ml) and incubated for 2 hours at 37 ° C. • The non-adherent cells are removed by washing the slides vigorously in pH-regulated saline and the cells remaining on the slides are fixed in acetone.

• Osteoclasts are stained for tartrate-resistant phosphatase acid (TRAP), a selective label for cells of this phenotype (see steps 15-17), and are enumerated by light microscopy. The results are expressed as% inhibition of adhesion compared to a vehicle control.

Cell adhesion test Cells and cell culture Human embryonic kidney cells (HEK293) were obtained from ATCC (catalog number CRL 1573). The cells were cultured in Earl's minimal essential medium (EMEM) containing Earl's salts, 10% fetal bovine serum, 1% glutamine and 1% penicillin-esteptomycin.

Constructions and transfections A 3.2 kb EcoRI-Kpnl fragment of the av subunit and a 2.4 kb Xbal-Xhol fragment of the β3 subunit were inserted into the EcoRI-EcoRV cloning sites of the pCDN vector (Aiyar et al., 1994) containing a CMV promoter and a G418 selectable marker by ligation of shaved ends. For stable expression, 80 x 106 HEK 293 cells were electrotransformed with av + ß3 constructs (20 μg of DNA from each subunit) using a Gene Pulser apparatus (Hensley et al., 1994) and placed on 100 mm plates (5 x 105 cells / plate). After 48 hours, the growth medium was supplemented with 450 μg / mL of Geneticin (G418 sulfate, GIBCO-BRL, Bethesda, MD). The cells were kept in selection medium until the colonies were large enough to be tested.

Immunocytochemistry analysis of transfected cells To determine whether the HEK 293 transfectants expressed the vitronectin receptor, the cells were immobilized on glass microscope slides by centrifugation, fixed in acetone for 2 minutes at room temperature and air dried. Specific reactivity with 23C6, a monoclonal antibody specific for the av + ß3 complex was demonstrated using a standard indirect immunofluorescence method.

Cell adhesion studies Corning 96-well ELISA plates were pre-coated overnight at 4 ° C with 0.1 mL human vitronectin (0.2 μg / mL in RPMI medium). At the time of the experiment, the plates were washed once with RPMI medium and blocked with 3.5% BSA in RPMI medium for 1 hour at room temperature. The 293 transfected cells were resuspended in RPMI medium, supplemented with 20 mM Hepes, pH 7.4 and 0.1% BSA at a density of 0.5 x 106 cells / mL. 0.1 mL of cell suspension was added to each well and incubated for 1 hour at 37 ° C, in the presence or absence of several vß3 antagonists. After incubation, 0.025 mL of a 10% formaldehyde solution, pH 7.4, was added and the cells were fixed at room temperature for 10 minutes. The plates were washed 3 times with 0.2 mL of RPMI medium and the adherent cells were stained with 0.1 mL of 0.5% toluidine blue for 20 minutes at room temperature. The excess staining was removed by extensive washing with deionized water. The toluidine blue incorporated into the cells was eluted by the addition of 0.1 mL of 50% ethanol containing 50 mM HCl. Cell adhesion was quantified at an optical density of 600 nm on a microtitre plate reader (Titertek Multiskan MC, Sterling, VA).

Solid phase otyßg binding test: The vitronectrin avß3 receptor was purified from human placenta. The receptor preparation was diluted with 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM CaCl 2, 1 mM MnCl 2, 1 mM MgCl 2 (pH A regulator) and intimately added to ELISA plates. 96 cavities at 0.1 ml per cavity. 0.1-0.2 μg of avß3 was added per well. The plates were incubated overnight at 4 ° C. At the time of the experiment, the cavities were washed once with pH A regulator and incubated with 0.1 ml of 3.5% bovine serum albumin in the same pH regulator for 1 hour at room temperature. After incubation the cavities were completely aspirated and washed twice with 0.2 ml of pH regulator A. In a competition test of [3H] -SK &F-107260, several concentrations of unlabeled antagonists were added (0.001- 100 μM) to the wells, followed by the addition of 5.0 nM of [3H] -SK &F-107260. The plates were incubated for 1 hour at room temperature. After incubation the cavities were completely aspirated and washed once with 0.2 ml of pH A regulator cooled with ice in cavity-to-cavity form. The receptors were solubilized with 0.1 ml of 1% SDS and [3H] -SK &F-107260 bound was determined by liquid scintillation counting with the addition of 3 ml of Ready Safe in a Beckman LS 6800 liquid scintillation counter, with 40% efficiency. The non-specific binding of [3 H] -SK &F-107260 was determined in the presence of 2 μM of SK &F-107260 and was consistently less than 1% of the total radioligand input. The IC5o (concentration of the antagonist to inhibit 50% binding of [3H] -SK &F-107260) was determined by a non-linear final frame curve adaptation routine that was modified from the LUNDON-2 program. The K i (antagonist dissociation constant) was calculated according to the Cheng and Prusoff equation: K, = IC5o / (1 + L / Kd), where L and Kd were the concentration and the dissociation constant of [ 3H] -SK &F-107260, respectively.

Inhibition of GPIIb-Illa binding mediated by RGD Purification of GPIIb-Illa Ten units of washed and expired human platelets (obtained from the Red Cross) were used by gentle agitation in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl 2 at 4 ° C for 2 h. The lysate was centrifuged at 100,000 g for 1 h. The obtained supernatant was applied to a column of lentil lectin Sepharose 4B 5 mL (EY Labs) pre-equilibrated with 20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2, 1% octiglucoside (pH regulator TO). After a 2 hour incubation the column was washed with 50 mL of cold pH A regulator. The GPI Ib-Illa retained in lectin was eluted with pH A regulator containing 10% dextrose. All procedures were carried out at 4 ° C. The GPI Ib-Illa obtained was >95% pure as shown by electrophoresis with SDS polyacrylamide gel.

Incorporation of GPIIb-llla into liposomes A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) was dried on the walls of a glass tube under a stream of nitrogen. Purified GPIIb-llla was diluted to a final concentration of 0.5 mg / mL and mixed with the phospholipids at a protein: phospholipid ratio of 1: 3 (w / w). The mixture was resuspended and sonicated in a bath sonicator for 5 minutes. The mixture was then made overnight using cutting dialysis tubes with a molecular weight of 12,000-14,000 against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl 2 (with 2 changes). The liposomes containing GPIIb-Illa were centrifuged at 12,000 g for 15 minutes and resuspended in the dialysis pH regulator at a final protein concentration of approximately 1 mg / mL. The liposomes were stored at -70 ° C until required.

Competitive binding to GPIIb-llla Fibrinogen receptor binding (GPIIb-llla) was tested by an indirect competitive binding method using [3H] -SK &F-107260 as a RGD-like ligand. The binding test was carried out in a 96-well filtration plate assembly (Millipore Corporation, Bedford, MA) using hydrophilic Durapore membranes of 0.22 um. The cavities were precoated with 0.2 mL of 10 μg / mL of polylysine (Sigma Chemical Co., San Luis, MO) at room temperature for 1 hour to block non-specific binding. Several concentrations of unlabeled benzazepines were added to the cavities in quadruplicate. [3 H] -SK &F-107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 μg of the liposomes containing purified platelet GPIIb-llla. The mixtures were incubated for 1 hour at room temperature. [3H] -SK &F-107260 bound to GPIIb-llla was separated from unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cooled pH regulator (twice, each 0.2 mL) . The bound radioactivity remaining on the filters was counted in 1.5 mL of Ready Solve (Beckman Instruments, Fullerton, CA) in a Beckman liquid scintillation counter (model LS6800), with a 40% efficiency. The non-specific binding was determined in the presence of SK & F-107260 unlabeled, 2 μM, and was consistently less than 0.14% of the total radioactivity added to the samples. All data points are the average of determinations in quadruplicate. The competition binding data was analyzed by a non-linear final frame curve fitting procedure. This method provides the IC 50 of the antagonists (concentration of the antagonist which inhibits the specific binding of [3 H] -SK &F-107260 by 50% in equilibrium). The IC50 is related to the equilibrium dissociation constant (Ki) of the antagonist based on the Cheng and Prusoff equation: Ki = IC50 / (1 + L / Kd), where L is the concentration of [3H] -SK &; F-107260 used in the competitive binding test (4.5 nM), and Kd is the dissociation constant of [3 H] -SK &F-107260 which is 4.5 nM as determined by the Scatchard analysis. The compounds of this invention that are preferred have an affinity for the vitronectin receptor in relation to the fibrinogen receptor of more than 10: 1. The most preferred compounds have an activity ratio of more than 100: 1. The efficacy of the compounds of the formula (I) alone or in combination with an antineoplastic agent can be determined using several transplantable mouse tumor models. See patents of E.U.A. Nos. 5,004,758 and 5,633,016 for details of these models. The following examples are not designed in any way to limit the scope of this invention, but are provided to illustrate how to make and use the compounds of this invention. Many other modalities will be readily apparent to those skilled in the art.

EXAMPLES General data Nuclear magnetic resonance spectra of protons (1 H NMR) were recorded at 250 or 400 MHz. Chemical shifts are reported in parts per million (d) down of the internal standard tetramethylsilane (TMS). The abbreviations for the NMR data are as follows: s = single band, d = doublet, t = triplet, q = quartet, m = multiple bamda, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimetilsuípóxido and CD3OD is tetradeuteriomethanol. The infrared (IR) spectra were recorded in transmission mode, and the band positions are reported in inverse wave numbers (cm "1) .The mass spectra were obtained using electroaspersion (EA) or FAB ionization techniques. Elemental analyzes were carried out either at home or by Quantitative Technologies Inc., Whitehouse, NJ The melting points were taken on a Thomas-Hoover melting point apparatus and are not corrected.All temperatures are reported in degrees centigrade Thin layer plates Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 were used for thin-layer chromatography, both vaporization and gravity chromatography were carried out on E. Merck Kieselgel 60 silica gel ( 230-400 mesh) Analytical and preparative HPLC were carried out on Rainin or Beckman chromatographs ODS refers to a silica gel chromatographic support derived from octadecylsilyl 5 μ Apex-ODS indicates a drowsiness chromatograph of octadecylsilyl-derived silica gel having a nominal particle size of 5 μ, made by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co., Ltd., Kyoto, Japan. PRP-1® is a polymeric chromatographic support (styrene-divinylbenzene) and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter aid composed of diatomaceous earth washed with acid, and is a registered trademark of Manville Corp., Denver, Colorado. (±) -10,11-Dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate, (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a , d] cyclohepten-10-ethyl acetate and (±) -10,11-dihydro-3- (trifluoromethanesulfonyloxy) -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate were prepared according to WO 9701540- A1. 2- [2- (4-methoxybenzylamino) pyridin-6-yl] ethanol was prepared according to WO 95/32710. 6-methoxy-1-indanone was prepared by the method of House and Hudson (J. Org. Chem. 1970, 35, 647).

Preparation 1 Preparation of 2-r (3-hydroxy-1-propyl) aminolpyridine N-oxide a) N-oxide of 2-r (3-hydroxy-1-propyl) amino-1-pyridine A mixture of 2-chloropyridine N-oxide hydrochloride (16.6 g, 0.1 mol), 3-amino-1 - propanol (15.3 mL, 0.2 mol), NaHCO3 (42 g, 0.5 mol) and ether-amyl alcohol (100 mL). After 21 hours, the reaction was cooled, diluted with CH2Cl2 (300 mL) and filtered by suction to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Chromatography on silica gel (20% MeOH / CHCl3) gave the title compound (15.62 g, 93%) as a yellow solid: CCD (20% MeOH / CHCl3) Rf 0.48; 1 H NMR (250, CDCl 3) d 8.07 (dd, J = 6.6, 1.2 Hz, 1 H), 7.34 (br t, 1 H), 7.10 - 7.30 (m, 1 H), 6.64 (dd, J = 8.5, 1.4 Hz, 1 H), 6.40 - 6.60 (m, 1 H), 4.49 (br s, 1 H), 3.65 - 3.90 (m, 2 H), 3.35 - 3.60 (m, 2 H), 1.75 - 2.00 (m, m, 2 H); MS (EA) m / e 169 (M + H) +.

Preparation 2 Preparation of 2-r (3-hydroxy-1-propyl) amino-1-4-nitropyridine N-oxide a) 2-chloro-4-nitropyridine N-oxide A solution of concentrated H2SO (30 mL) and fuming HNO3 (54 mL) was added dropwise at 0 ° C to a solution of N-oxide hydrochloride of 2-chloropyridine (15.2 g, 91.56 mmol) in concentrated H2SO (30 mL). The reaction mixture was heated at 90 ° C for 1 hour, then cooled to room temperature and poured onto ice (500 g). The reaction mixture was kept at room temperature overnight, then cooled in an ice bath and 50% NaOH was slowly added to give a precipitate. This was collected and dried to give the title compound (5.88 g, 37%) as a light yellow solid: 1 H NMR (400 MHz, CDCl 3) d 8.42 - 8.37 (m, 2 H), 8.06 - 8.04 (m, 1 HOUR). b) 2-f (3-Hydroxy-1-propyl) amino-4-nitropyridine N-oxide According to the procedure of Preparation 1, but substituting the N-oxide hydrochloride of 2- chloropyridine with 2-chloro-4-nitropyridine N-oxide, the title compound was obtained as a yellow powder after chromatography on silica gel (1: 9 MeOH / CH 2 Cl 2). Recrystallization from MeOH / CH 2 Cl 2 / Et 2 O gave the title compound: MS (EA) 214.1 (M + H) +.

Preparation 3 Preparation of 2-r (3-hydroxy-1-propylamine 1-4-methylpyridine N-oxide) a) 2-Chloro-4-methy1pyridine Sodium nitrite (13.88g, 200 mmol) was slowly added at 0 ° C to a solution of 2-amino-4-picoline (15.0 g, 139 mmol) in HCl concentrated (200 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours, then poured onto ice (500 g). The pH was adjusted to 8.0 with concentrated NH 4 OH, and the mixture was extracted with ether (3 x 300 mL). The combined ether layers were washed sequentially with H2O (2 x 200 mL) and brine (200 mL). Drying (MgSO4) and concentration gave the title compound (10.3 g, 58%) as a slightly yellow oil: MS (EA) m / e 127.8 (M + H) +. b) 2-Chloro-4-methylpyridine N-oxide hydrochloride A mixture of 2-chloro-4-methylpyridine (10.0 g, 78.3 mmol) and 34% peracetic acid (76.05 g, 91.0 mmol) in glacial AcOH (10 mL) was heated at 70 ° C for 3 hours. The reaction mixture was cooled, concentrated HCl (35 mL) was added and the mixture was concentrated on the rotavap. Recrystallization of n-butanol followed by trituration with ether gave the title compound (7.16 g, 51%) as a white solid: MS (EA) m / e 143.9 (M + H) +. c) 2-f (3-Hydroxy-1-propyl) amino-4-methylpyridine N-oxide A mixture of 2- N -oxide hydrochloride was refluxed for 19 hours. chloro-4-methylpyridine (7.16 g, 39 mmol), 3-aminopropanol (6.01 g, 80 mmol) and NaHCO3 (16.8 g, 200 mmol) in ter-amyl alcohol (50 mL). The reaction mixture was diluted with CH2Cl2 (200 mL) and filtered, and the filtrate was concentrated on the rotavap. Recrystallization of CH 2 Cl 2 / Et 2 O gave the title compound (5.41 g, 75%) as a yellow solid: CCD (15% MeOH / CH 2 Cl 2) Rf 0.44; 1 H NMR (400, CDCl 3) d 7.92 (d, J = 6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J = 6.6, 2.1 Hz, 1 H ), 3.73 (t, J = 5.7 Hz, 2 H), 3.47 (q, H = 6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82 - 1.88 (m, 2 H); MS (EA) m / e 183 (M + H) +.

Preparation 4 Preparation of 6- (methylamino) -2-pyridylethanol a) 2- (fer-Butoxycarbonylamino) -6-picolin A solution of 2-amino-6-picoline (21.63 g, 200 mmol) and di-fer-butyl dicarbonate (52.38 g, 240 mmol) in CH2Cl2 ( 200 mL) was concentrated on the rotavap at 50 ° C, and the resulting residue was allowed to rotate on the rotavap at 50 ° C under vacuum. After 21.5 hours, the reaction was diluted with hexanes (400 mL) and filtered through silica gel (hexanes followed by 20% EtOAc / hexanes). Concentration left the title compound (41.84 g, quantitative) as a light yellow oil that solidified gradually after standing: 1 H NMR (250 MHz, CDCl 3) d 7.71 (d, J = 8.3 Hz, 1 H), 7.40 - 7.65 (m, 2 H), 6.80 (d, J = 7.5 Hz, 1 H), 2.43 (s, 3 H), 1.50 (s, 9 H); MS (EA) m / e 153 (M + H - C4H8) +. a) 2-f (fer-Butoxycarbonyl) methylamino) -6-picoline NaH (60% in mineral oil, 3.60 g, 90 mmol) was added in portions over several minutes to a solution of 2- (tert-butoxycarbonylamino) -6-picoline (15.62 g, 75 mmol) and iodomethane (9.3 mL, 150 mmol) in anhydrous DMSO (75 mL) at 15 ° C (bath in cold water). The internal temperature rose to 35 ° C. When the gas emanation was stopped, the cold water bath was removed and the reaction allowed to stir at room temperature. After 0.5 hours the dark yellow mixture was poured onto ice / H 2 O (300 mL) and extracted with Et 2 O (3 x 300 mL). The combined organic layers were sequentially washed with H2O (2 x 75 mL) and brine (75 mL). Drying (MgSO) and concentration left a yellow oil which was chromatographed on silica gel (7% EtOAc / hexanes). The title compound (13.01 g, 78%) was obtained as a slightly yellow oil: 1 H NMR (250 MHz, CDCl 3) d 7.51 (app t, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 1 H), 3.38 (s, 3 H), 2.49 (s, 3 H); 2.49 (s, 3 H), 1.50 (s, 9 H); MS (EA) m / e 223 (M + H) +. c) ethyl 6-f (tert-butoxycarboniomethylamino1-2-pyridylacetate LDA was prepared at 0 ° C under argon from diisopropylamine (19.5 ml, 139.14 mmole) and n-BuLi 2.5M in hexanes (46.4 ml, 115.95 mmoles) in dry THF (350 mL) This solution was cooled to -78 ° C and a solution of 2 - [(tert-butoxycarbonyl) methylamino] -6-p-choline (10.31 g, 46.38 mmoles) in dry THF (46 mL), dry THF (2 mL) was also used in the transfer, the orange solution was stirred at -78CC for 15 minutes and then diethyl carbonate (6.2 mL, 51.02 mmoles) was added rapidly. The red solution was stirred at -78 ° C for 15 minutes and then quenched with saturated NH4CI in half (175 mL) .The mixture was warmed to + 5 ° C and extracted with EtOAc (175 mL) then with CH2Cl2. (2 x 100 mL) The combined organic extracts were washed with brine (100 mL), dried (MgSO 4) and concentrated, The cloudy yellow oil was chromatographed on silica gel (15 g). % EtOAc / hexanes) to give the title compound (10.72 g, 79%) as a light yellow oil: 1 H NMR (250 MHz, CDCl 3) d 7.51-7.63 (m, 2 H), 6.91- 7.03 (m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.77 (s, 2 H), 3.38 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.51 (s, 9) H); MS (EA) m / e 295 (M + H) +. d) Ethyl 6- (Methalamine) -2-pyridyl acetate A solution of ethyl 6 - [(fer-butoxycarbonyl) methylamino] -2-pyridylacetate (10.72 g, 36.42 mmol) in Anhydrous dioxane (91 mL) was cooled to the point of partial recrystallization of the solvent, and 4M HCl / dioxane (91 mL, 364.2 mmol) was added. The solution was warmed to room temperature and stirred for 17 hours and then concentrated. The resulting light yellow solid was suspended with CH2Cl2 / toluene and reconcentrated to leave the title compound (8.48 g, quantitative) as a light yellow powder: 1 H NMR (250 MHz, CD3OD) d 7.84 (dd, J = 9.0, 7.2 Hz, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 6.78 (d, J = 7.2 Hz, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 3.93 (s, 2 H), 3.05 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (EA) m / e 195 (M + H) +. e) 6- (Methalamino) -2-pyridylethanol A solution of 1.0 M LiAIH4 in THF (95 mL, 95 mmol) was added dropwise to a mechanically stirred suspension of ethyl 2- (methylamino) -6-pyridylacetate ( 7.34 g, 31.82 mmol) in dry THF (64 mL) at 0 ° C under argon. The addition was made slowly until the gas emanation was stopped and then the remaining solution was added quickly. The addition required 5-7 minutes. The reaction was warmed to room temperature and stirred for 45 minutes, and then heated to reflux. After 10 minutes, the reaction was cooled to 0 ° C and treated by sequential dropwise addition of H 2 O (3.6 mL), 15% NaOH (3.6 mL) and H 2 O (10.8 mL). The mixture was stirred for 15 minutes at 0 ° C and 15 minutes at room temperature, then filtered through a Buchner funnel. The filter pad was washed with enough THF and the filtrate was concentrated. The residue was concentrated from toluene and then chromatographed on silica gel (5% MeOH in 1: 1 EtOAc / CHCl3) to give the title compound (3.23 g, 67%) as a yellow oil which solidified to a Waxy solid: 1 H NMR (250 MHz, CDCl 3) d 7.36 (dd, J = 8.3, 7.3 Hz, 1 H), 6.42 (d, J = 7.3 Hz, 1 H), 6.26 (d, J = 8.3 Hz, 1 H) 4.93 - 5.28 (m, 1 H), 4.38 - 4.60 (m, 1 H), 3.96 (t, J = 5.4 Hz, 2 H), 2.90 (d, J = 5.2 Hz, 3 H), 2.84 ( t, J = 5.4 Hz, 2 H); MS (EA) m / e 153 (M + H) +.

Preparation 5 Preparation of 2- (ethylamino) -4-thiazoletanol a) Ethyl 2-acetylamino-4-thiazoleacetate Ethyl 2-amino-4-thiazoleacetate (3.72 g, 20 mmol) was taken up in acetic acid (4 mL) and acetic anhydride (4 mL), and the resulting suspension was heated reflux for 3 hours. Concentration and flash chromatography on silica gel (5% MeOH / CH 2 Cl 2) gave the title compound (4.1 g, 91%) as a white solid: MS (EA) m / e 229 (M + H) +. b) 2- (Ethylamino) -4-thiazoletanol To a stirred solution of 1.0M LiAIH4 in THF (179 mL, 179 mmoles) was added dropwise a solution of ethyl 2-acetylamino-4-thiazoleacetate (4.4 g, 17.9 mmol) in THF (50 mL). After the addition was complete, the reaction mixture was refluxed for 3 hours, then treated by sequential addition of H 2 O (0.7 mL), 10% NaOH (0.7 mL) and H 2 O (2.1 mL). The resulting mixture was filtered through Celite® and the filtrate was concentrated. Purification by chromatography on silica gel (5% MeOH / CH 2 Cl 2) gave the title compound (1.6 g, 53%) as an amber oil: MS (EA) m / e 173 (M + H) +.

Preparation 6 Preparation of 6-amino-2-pyridylethanol a) 6-Amino-2-pyridylethanol A solution of 2- [2- (4-methoxybenzylamino) pyridin-6-yl] ethanol (0.95 g, 3.7 mmol), prepared according to the procedure of WO 95/32710, in 6N HCl was heated to 60 ° C. After 16 hours, the reaction was concentrated in vacuo and the residue made basic with dry KOH. The resulting mixture was extracted with MeOH, and the MeOH extracts were dried (MgSO) and concentrated. Evaporation chromatography on silica gel (5% MeOH / CH 2 Cl 2) gave the title compound (0.2 g, 40%) as a clear yellow oil: MS (EA) m / e 139 (M + H) +.

Preparation 7 Preparation of 3- (4-nitrobenzyloxycarbonylamino) -1-propanol a) 3- (4-Nitrobenzyloxycarbonylamino) -1-propanol To a stirred suspension under argon at room temperature of 4-nitrobenzyl chloroformate (5 g, 23 mmole) and triethylamine (6.4 mL, 46 mmole) in THF (25 mL) 3-amino-1-propanol (1.9 mL, 26 mmol) was added. The resulting mixture was stirred for 72 hours and then concentrated. The residue was purified by silica gel chromatography (0.5-2% MeOH / CH 2 Cl 2) to give the title compound (2 g, 34%) as a light yellow oil: MS (EA) 255.3 (M + H) +.

Preparation 8 Preparation of 1-F (3-hydroxy-1-propyl) aminolisoquinoline N-oxide a) Chloroisoquinoline N-oxide 1-aminoisoquinoline hydrochloride (Deady, LW Synthetic Communications 1977, 509-514) was converted to 1-chloroisoquinoline N-oxide using potassium nitrite and concentrated HCl according to the general method described in literature (Brown, EVJ Amer. Chem. Soc. 1957, 79, 3565-3566). The title compound was prepared as a light brown solid: MS (EA) m / e 179.9 (M + H) +. b) N - oxide of 1 - [(3-hydroxy-1-propyl) amino-1-tanquinoline In accordance with the procedure of preparation 1 (a), but substituting the N-oxide hydrochloride -chloropyridine by 1-chloroisoquinoline N-oxide, the title compound was prepared as an amber solid: MS (EA) m / e 219.1 (M + H) +.

Preparation 9 Preparation of 2-rN- (3-methanesulfonyloxy-1-propyl) -N- (fer-butoxycarbonyl) D-aminolpyridine N-oxide a) N-oxide of 2-fN- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) -aminolpyridine A solution of N - oxide of 2 - [(3-hydroxy-1-propyl) ) amino] pyridine (8.0 g, 47.6 mmol) in fer-BuOH (80 mL) was treated with di-tert-butyl dicarbonate (11.4 g, 55.3 mmol). After 18 hours the solution was concentrated and the residue was triturated with hexane. The resulting solid was dried under vacuum to give the title compound (12.5 g, 98%) as an off white solid: MS (EA) m / e 269.3 (M + H) +. b) 2-rN- (3-methansulfonyloxy-1-propyl) -N- (fer-butoxycarbonyl) D-aminolpyridine N-oxide. Methanesulfonyl chloride (0.17 mL, 2.20 mmol) was added dropwise to a solution of 2- N-oxide. [N- (3-hydroxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine (0.50 g, 1.86 mmol) and pyridine (0.23 mL, 2.84 mmol) in CHCl3 (5 mL, drying on K2CO3) at 0 ° C. When complete by CCD, the reaction was diluted with CHCl3, washed with ice water, dried (Na2SO4) and concentrated, chromatography on silica gel (10% MeOH / CHCl3) the title compound (0.41 g, 64%) as a colorless oil: 1 H NMR (250 MHz, CDCl 3) d 8.25 (dd, J = 6.0, 1.9 Hz, 1 H), 7.25 (m, 4 H), 4.35 ( t, J = 6.2 Hz, 2 H), 3.75 (t, J = 6.6 Hz, 2 H), 3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). recover N-oxide of 2- [N- (3-hydroxy-1-propyl) -N- (fef-butoxycarbonyl) amino] pyridine unchanged (0.18 g, 36%) of the chromatographic purification.

Preparation 10 Preparation of (±) -10.11 -dihydro-3-hydroxy-5H-dibenzora, d1-cycloheptene-10-ethyl acetate a) 6-Methoxy-1-phenylidene A solution of 3.0 M phenylmagnesium bromide in Et2O (680 mL, 2.04 moles) under argon at room temperature was diluted with Et2O (700 mL) with stirring, and a solution of 6-methoxy-1-indanone (277 g, 1.71 mol) in THF (1400 mL) for 1 hour. The reaction mixture was stirred for 2 hours at room temperature and then poured with stirring into saturated NH 4 Cl (2.8 L). H2O (1.4 L) was added, and the organic phase was separated. The aqueous phase was extracted with Et2O (2 x 1 L) and the combined organic extracts were concentrated to give crude 6-methoxy-1-phenyl-1-indanol (445 g) as a brown oil. This oil was dissolved in toluene (2.5 L) and p-toluenesulfonic monohydrate (12.3 g, 0.065 mol) was added. The solution was stirred and refluxed for 16 hours using a Dean-Stark trap with a condenser. The H2O collection was minimal after 2 hours and gave a total of 28 mL. The solution was cooled and extracted sequentially with 5% aqueous Na2CO3 (1 L) and H2O (2 x 1 L). The organic layer was concentrated to give a dark brown oil (400 g). This oil was distilled under vacuum to give the title compound (298.2 g, 79%) as a yellow oil: pe 152-190 ° C / 2.0 Torr.; CCD (10% EtOAc / hexanes) Rf 0.75. b) 2-Benzoyl-4-methoxyphenylacetic acid Acetone (4.2 L) was cooled to 10 ° C and a solution of 6-methoxy-1-phenylidene (271 g, 1.22 mol) in acetone (1.8 L) was added during 1.5 hours concurrently with Jones reagent (1.8 L, prepared from CrO3 (470 g, 4.70 moles), H2O (1 L) and conc H2SO4 (405 mL)). 4% aqueous OsO4 (153 mL) was added to the resulting mixture in two portions, one at the start of the addition and the second at the midpoint of the addition, keeping the temperature of the reaction mixture below 15 ° C. After the addition, the reaction mixture was heated to 22 ° C and stirred for 1.5 hours, during which time a slight exotherm increased the temperature to 28 ° C. The reaction mixture was then cooled to below 20 ° C and isopropanol (1 L) was added, by dripping initially and rapidly after the initial exotherm decreased. Agitation became difficult during this phase. The temperature reached 32 ° C during the addition of isopropanol. H2O (2 L) was added and the mixture transfected into a separatory funnel. Additional H 2 O was added to dissolve the precipitated chromic acid, and the mixture was extracted with CH 2 Cl 2 (2 L). The organic layer (upper) was separated and the aqueous phase was extracted with CH 2 Cl 2 (2 x 1 L). The combined CH2Cl2 extracts were washed sequentially with H2O (2 L) and saturated brine (2 L), and then concentrated to give a wet gray solid (416 g). They were triturated with a mixture of acetone and EtOAc, and filtered and dried to give the title compound (225.4 g, 71%) as an off-white solid: mp 158-159 ° C. c) 2-Benzyl-4-methoxyphenylacetic acid 2-Benzoyl-4-methoxyphenylacetic acid (215.5 g, 0.80 mol) was divided into two equal portions, and each was dissolved in glacial AcOH (1.5 L) in a bottle of water. pressure of 2.5 L. 55 Pd / C (10 g, 0.0048 mol) was added to each, and the mixture was stirred at room temperature under hydrogen in a Parr apparatus. After 2.5 hours, the mixtures were filtered to remove the catalyst, and the filter pads were washed with EtOAc. The combined filtrates were concentrated to give the title compound (215 g, quantitative) as a concentrated yellow solid which was recrystallized after standing: 1 H NMR (250 MHz, CDCl 3) d 7.05-7.35 (m, 6 H), 6.77 (dd, J = 8.3, 2.7 Hz, 1 H), 6.71 (d, J = 2.7 Hz, 1 H), 4.00 (s, 2 H), 3.76 (s, 3 H), 3.54 (s, 2 H) . d) 10.11-Dihydro-3-methoxy-5H-dibenzora, dichlohepten-10-one A solution was 2-benzyl-4-methoxyphenylacetic acid (215 g of crude material containing 204.6 g (0.80 moles) of material pure) in CH 2 Cl 2 (1 L) was stirred under argon at room temperature and DMF (1 mL) was added, followed by oxalyl chloride (400 mL, 4.59 moles). The oxalyl chloride was added for 1 hour, by dripping initially to control the evolution of vigorous gas. The solution was stirred for 16 hours at room temperature and then concentrated to give the crude acid chloride (207.7 g, 0.756 mol, 95%) as a yellow liquid. This liquid was dissolved in CH 2 Cl 2 to a total volume of 500 mL, and the solution and AICI 3 (100.8 g, 0.756 mole) were added concurrently for 1 hour to CH 2 Cl 2 (3.7 L) with stirring under argon at room temperature. The temperature was 28 ° C at the end of the addition. The reaction mixture was stirred for 16 hours at room temperature, during which time a solid precipitated. H2O (1 L) was added, initially by dripping, over a period of 30 minutes. The mixture was then separated and the organic phase was washed sequentially with H2O (1 L) and 5% aqueous NaHCO3 (1 L). The CH2Cl2 solution was then concentrated to give a yellow solid (175.3 g). Recrystallization from EtOAc / hexane gave the title compound (128 g, 71%): mp 107-109 ° C. e) (±) -10,11-Dihydro-10-hydroxy-3-methoxy-5H-d-benzo [a, d-cyclohepten-10-ethyl acetate A 1.0 M solution of bis (trimethylsilyl) Lithium amide in hexanes (1282 mL, 1282 moles) was added to THF (4.0 L) at -70 ° C under argon, then EtOAc (146 mL, 1.49 moles) was added dropwise over 20 minutes. The reaction mixture was allowed to stir for 15 minutes and then N, N, N ', N'-tetramethylethylenediamine (378 mL, 2.5 moles) was added over 20 minutes. The reaction mixture was stirred for 10 minutes, and then a solution of 10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one (119.2 g, 0.50) was added dropwise over 40 minutes. moles) in anhydrous THF (1.26 L). The temperature was kept below -65 ° C during all these additions. The reaction mixture was stirred for 20 minutes at -65 to -70 ° C and then poured into saturated aqueous NH 4 Cl (6.2 L) with vigorous stirring. The organic layer was separated and the aqueous phase was extracted with EtOAc (2 x 1 L). The combined organic extracts were washed with H2O 82 x 1 L) and then concentrated to give a light brown oil (175 g). Thin layer chromatography (20% EtOAc / hexanes) showed higher Rf 0.5 (desired product) and lower Rf 0.7 (recovered ketone). The crude product was chromatographed on silica gel (2 kg, 10% EtOAc / hexanes) to give the title compound (101 g, 61%) as a yellow solid: 1 H NMR (250, CDCl 3) d 7.63 (d, J = 7.7 Hz, 1 H), 7.00 - 7.30 (m, 4 H), 6.80 (d, J = 2.6 Hz, 1 H), 6.69 (dd, J = 8.2, 2.6 Hz, 1 H), 3.95 - 4.35 ( m, 2 H), 4.07 (s, 2 H), 3.76 (s, 3 H), 3.68 (s, 1 H), 3.64 (d, J = 14.2 Hz, 1 H), 3.35 (d, J = 14.2 Hz, 1 H), 2.79 (d, J = 16.0 Hz, 1 H), 2.66 (d, J = 16.0 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 3 H). f) (±) -10.11-Dihydro-3-methoxy-5H-dibenzo [a, d-cycloheptene-10-ethyl acetate (±) -10,11-Dihydro-10-hydroxy-3-methoxy-5H -dibenzo [a, d] cyclohepten-10-ethyl acetate (101 g, 0.31 mol) was dissolved in glacial acetic acid (1.8 L) and 12 N HCl (28.5 mL, 0.34 mol) was added. The mixture was placed in a 2.5 L pressure bottle containing 5% Pd / C (20 g, 0.0094 mole), and the resulting mixture was stirred at 35 ° C under hydrogen in a Parr hydrogenation apparatus equipped with a heater covering. After 18 hours, the reaction was cooled to room temperature and the catalyst was removed by filtration. The filtrate was concentrated to give a light yellow oil (85.1 g). This was chromatographed on silica gel (2 kg, gradient with 5% to 10% EtOAc7hexanes) to give the title compound (69.1 g, 72%) as an oil: 1 H NMR (250 MHz, CDCl 3) d 7.05 - 7.22 (m, 4 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.67 (dd, J = 8.2, 2.7 Hz, 1 H), 4.30 ( d, J = 15.0 Hz, 1 H), 4.11 - 4.25 (m, 2 H), 3.85 (d, J = 15.0 Hz, 1 H), 3.70 - 3.90 (m, 1 H), 3.77 (s, 3 H) ), 3.31 (dd, J = 15.0, 4.1 Hz, 1 H), 2.93 (dd, J = 15.0, 9.2 Hz, 1 H), 2.64 (dd, J = 15.6, 5.0 Hz, 1 H), 2.52 (dd) , J = 15.6, 9.3 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3 H). g) (±) -10,11-Dihydro-3-hydroxy-5H-dibenzora, dichloheptene-10-ethyl acetate A solution of (±) -10,11-dihydro-3-methoxy- 5 H -dibenzo [a, d] cyclohepten-10-ethyl acetate (8.5 g, 0.027 mol) in CH 2 Cl 2 (150 mL) was cooled to -10 ° C with stirring under argon. Ethanethiol (10.7 mL, 0.144 mol) was added, followed by AICI3 (20.6 g, 0.154 mol) in two portions over 15 minutes. An exotherm increased the temperature to 0 ° C after the additions, and the temperature was then increased to 25 ° C using a water bath. The reaction mixture was stirred at 25 to 30 ° C for 2.25 hours, at which point it was poured into ice-H2O. The organic layer was separated, methanol (100 mL) was added and the mixture was extracted with CH2Cl2 (2 x 50 mL). The combined CH2Cl2 extracts were washed with H2O (250 mL) and then concentrated to give a viscous oil (8.6 g). This was taken up in Et2O (150 mL) and the ether was removed by boiling, replacing it with hexane. The desired phenol was first separated as an oil which crystallized upon being stirred at room temperature. Two crops of solid were collected to give the title compound (7.1 g, 89%): mp 110-112 ° C.

Preparation 11 Separation by HPLC of the enantiomers of (±) - 10.11 -dihydro-3-hydroxy-5H-dibenzora.d1cycloheptene-10-ethyl acetate a) (RM +) - 10,11-D, Hydro-3-hydroxy-5H-d, benzora, d1cycloheptene-10-ethyl acetate and (S) - (-) - 10, 11-dihydro-3-hydroxy- 5H-dibenzo [a, d1cycloheptene-10-ethyl acetate (±) -10,11-Dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate was resolved into its enantiomers using the following conditions: Daicel Chiracel OJ® column (21.2 x 250 mm), 20% ethanol in hexane mobile phase, flow rate of 15 mL / min, UV detection at 254 nm, injection of 140 mg; tR for (S) - (-) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohexene-10-ethyl acetate = 10.4 minutes; IR for (R) - (+) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohexene-10-ethyl acetate = 13.1 minutes.

Preparation 12 Preparation of (±) -10,11-dihydro-7-fluoro-3-hydroxy-5H-dibenzophate, d1-cycloheptene-10-ethyl acetate a) 1 - (3-Fluorophenyl) -6-methoxy-1-indanol The title compound was obtained as an amber colored solid according to the procedure of Preparation 10 (a), but substituting phenylmagnesium bromide with bromide of 3-fluorophenylmagnesium: MS (EA) m / e 276.0 (M + H) +. b) 1- (3-Fluorophenyl) -6-methoxylande The title compound was obtained as a colorless oil after chromatography on silica gel (4% EtOAc / hexanes) according to the procedure of preparation 10 ( a), but substituting 6-methoxy-1-phenyl-1-indanol with 1- (3-fluorophenyl) -6-methoxy-1-indanol: MS (EA) m / e 241.1 (M + H) +. c) 2- (3-Fluorobenzoyl) -4-methoxyphenylacetic acid The title compound was obtained as a white solid according to the procedure of preparation 10 (b), but substituting 6-methoxy-1-phenylindene with 2- (3-fluorophenyl) -6-methoxyindene: MS (EA) m / e 289.2 (M + H) +. d) 2- (3-Fluorobenzyl) -4-methoxyphenylacetic acid The title compound was obtained as a colorless oil according to the procedure of preparation 10 (c), but substituting 2-benzoyl-4 acid -methoxyphenylacetic acid with 2- (3-fluorobenzoyl) -4-methoxyphenylacetic acid: MS (EA-) m / e 273.2 (M-H) ". e) 10,11-D yhydro-7-fluoro-3-methoxy-5H-dibenzora, dichloclohepten-10-one The title compound was obtained as a white solid according to the procedure of preparation 10 (d ), but substituting 2-benzyl-4-methoxyphenylacetic acid with 2- (3-fluorobenzyl) -4-methoxyphenylacetic acid: mp 129-130 ° C; MS (EA) m / e 279.2 (M + Na) +. f) (±) -10,11-Dihydro-7-fluoro-10-hydroxy-3-methoxy-5H-dibenzofa.dl-cycloheptene-10-ethyl acetate The title compound was obtained after the chromatography on silica gel (8% EtOAc / hexanes) according to the procedure of preparation 10 (e), but substituting 10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10- ona with 10,11-dihydro-7-fluoro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-one: MS (EA) m / e 362.2 (M + NH4) +. g) (±) -10.11-Dihydro-7-fluoro-3-methoxy-5H-d-benzo [a, d-cycloheptene-10-ethyl acetate The title compound was obtained as a colorless oil after chromatography on silica gel (10% EtOAc / hexanes) according to the procedure of preparation 10 (f), but substituting (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H- dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-7-fluoro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-acetate ethyl acetate: MS (EA) m / e 329.2 (M + H) +. h) (±) -10,11-D yhydro-7-fluoro-3-hydroxy-5H-dibenzora.d1cyclohepten-10-ethyl acetate The title compound was obtained as a white solid after chromatography on silica gel (1% MeOH / CH2Cl2) according to the procedure of preparation 10 (g), but substituting (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene- 10-ethyl acetate with (±) -10,11-dihydro-7-fluoro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 315.0 (M + H)? 332.0 (M + NH4) +.

Preparation 13 Preparation of (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-hydroxy-5H-dibenzora, d1-cycloheptene-10-ethyl acetate a) (±) -10,11-Dihydro-2- (dimethylamino) methy1-7-fluoro-3-hydroxy-5H-dibenzo [a, d1cycloheptene-10-ethyl acetate To a solution of (±) -10,11-dihydro-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.4 g, 1.33 mmol) in 95% ethanol containing 2M dimethylamine in MeOH (1.0 mL) was added aqueous formaldehyde solution (0.5 mL) at room temperature under argon. After 20 hours the reaction was heated to reflux for 5 hours and then concentrated in the rotavap. The residue was partitioned between H2O and Et2O, and the layers separated. The aqueous layer was extracted with Et2O and the combined organic layers were washed with brine, dried (MgSO) and concentrated on the rotavap to give the title compound (330 mg, 67%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3) d 7.20 (m, 1 H), 6.88 (m, 2 H), 6.67 (s, 2 H), 4.25 (d, J = 15.1 Hz, 1 H), 4.18 (q, 2 H), 3.78 (m, 1 H), 3.74 (d, J = 15.1 Hz, 1 H), 3.35 (s, 2 H), 3.20 (dd, 1 H), 2.80 (dd, 1 H), 2.60 (dd, 1 H), 2.53 (dd, 1 H), 2.29 (S, 6 H), 1.27 (t, 3 H) MS (EA) m / e 372.3 (M + H) +.

Preparation 14 Preparation of f ±) -10.11-dihydro-3-hydroxy-2-methyl-5H-dibenzora, d1-cycloheptene-10-ethyl acetate a) (±) -10,11-Dihydro-2-formyl-3-methoxy-5H-d-benzene, ethyl dichloromethane-10-acetate POCI3 (17 mL) was added dropwise to a solution of (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] c -cloheptene-10-ethyl acetate (1.0 g, 3 mmol) in dry DMF (40 mL) at room temperature under argon, and the dark solution was heated at 90 ° C for 48 hours. The reaction was concentrated on the rotavap and the residue was partitioned between H2O and EtOAc. The organic layer was separated, dried (MgSO4) and concentrated on the rotavap. The residue was reconcentrated from xylenes (to remove any remaining DMF) then chromatographed on silica gel (7% EtOAc in hexanes) to give the title compound (230 mg, 21%) as a colorless oil: MS (EA) m / e 339.3 (M + H) +. b) (±) -10,11-Dihydro-3-methoxy-2-methyl-5H-dibenzophate, d1-cyclohepten-10-ethyl acetate A mixture of (±) -10,11-dihydro-2- formyl-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (220 mg, 0.65 mmol), 10% Pd / C (90 mg), glacial HOAc (15 mL) and conc. HCl. (2 mL) was stirred at room temperature under hydrogen (4.22 kg / cm2). After 20 hours, the mixture was filtered through Celite® and the filtrate was concentrated to give the title compound (200 mg, 95%) as a colorless oil: MS (EA) m / e 325.2 (M + H ) + c) (±) -10,11-Dihydro-3-hydroxy-2-methyl-5H-dibenzophate, dichloromethoxy-10-ethyl acetate To dry CH2Cl2 (30 mL) cooled in a ice bath was added diethyl sulfide (0.38 mL, 3.3 mmol) followed by AICI3 (438 mg, 3.3 mmol). To this solution was added dropwise a solution of (±) -10,11-dihydro-3-methoxy-2-methyl-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate (200 mg, 0.6 mmole) in dry CH2Cl2 (6 mL) and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with 1.0 N HCl (10 mL), and the layers were separated. The organic layer was dried (MgSO) and concentrated on the rotavap to give the title compound (100 mg, 56%) as a colorless oil: MS (EA) m / e 311.2 (M + H) +.

Preparation 15 Preparation of (±) -10.11-dihydro-3-hydroxy-6-methyl-5H-dibenzofa.dlcycloheptene-10-ethyl acetate a) 6-Methoxy-1- (2-methylphenyl) -1-indanol The title compound was obtained as an oil according to the procedure of Preparation 10 (a), but substituting phenylmagnesium bromide with 2-bromide. methylphenylmagnesium: MS (EA) m / e 277.0 (M + Na) +. b) 6-Methoxy-1- (2-methylphenyl) indene The title compound was obtained as a colorless oil after chromatography on silica gel (3% EtOAc / hexanes) according to the procedure of the preparation. (a), but substituting 6-methoxy-1-phenyl-1-indanol with 6-methoxy-1- (2-methylphenyl) -1-indanol: MS (EA) m / e 237.2 (M + H) + . c) 4-Methoxy-2- (2-methylbenzoyl) phenylacetic acid The title compound was obtained as a viscous oil according to the procedure of preparation 10 (b), but substituting 6-methoxy-1-phenylindene for 6. -methoxy-1- (2-methylphenyl) indene: MS (EA) m / e 285.3 (M + NH 4) +. d) 4-Methoxy-2- (2-methylbenzyl) D-phenylacetic acid The title compound was obtained as a viscous oil according to the procedure of preparation 10 (c), but substituting 2-benzoyl-4-methoxyphenylacetic acid with 4-methoxy-2- (2-methoxybenzoyl) phenylacetic acid: MS (EA) m / e 288.2 (M + NH4) +. e) 10111-Dihydro-3-methoxy-6-methyl-5H-d-benzoyl, d-cyclohepten-10-one The title compound was obtained as a white solid after chromatography on silica gel (6% EtOAc / hexanes) according to the procedure of preparation 10 (d), but substituting 2-benzyl-4-methoxyphenylacetic acid with 4-methoxy-2- (2-methylbenzyl) phenylacetic acid: MS (EA) m / e 253.0 (M + H) +. f) (±) -10,11 -Dihydro-10-hydroxy-3-methoxy-6-methyl-5H-dibenzora.dlcyclohepten-10-ethyl acetate The title compound was obtained after gel chromatography of silica (8% EtOAc / hexanes) according to the procedure of preparation 10 (e), but substituting 10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one with 10, 11-dihydro-3-methoxy-6-methyl-5H-dibenzo [a, d] cyclohepten-10-one: MS (EA) m / e 358.2 (M + NH4) +. g) (±) -10,11-Dihydro-3-methoxy-6-methyl-5H-d-benzene, d-cyclohepten-10-ethyl acetate The title compound was obtained as a colorless oil after chromatography on silica gel (5% EtOAc / hexanes) according to the procedure of preparation 10 (f), but substituting (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-10-hydroxy-3-methoxy-6-methyl-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS ( EA) m / e 325.3 (M + H) +. h) (±) -10,11-D yhydro-3-hydroxy-6-methy1-5H-dibenzora, d1-cyclohepten-10-ethyl acetate The title compound was obtained as a white solid after trituration with MeOH according to the procedure of preparation 10 (g), but substituting (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with ( ±) -10,11-dihydro-3-methoxy-6-methyl-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 311.2 (M + H) +.

Preparation 16 Preparation of f ±) -10,11 -dihydro-3-r3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzora, d1-cycloheptene-10-ethyl acetate a) (±) -10.11-Dihydro-3-r3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzophate, dichlorohexyl-10-ethyl acetate A solution of 2 - [(3-hydroxy-1-propyl) amino] -4-nitropyridine N-oxide (0.85 g, 4 mmol) and diethyl azodicarboxylate (0.63 mL, 4 mmol) in anhydrous DMF (10 mL) was added dropwise to a solution of (±) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.59 g, 2 mmol) and triphenylphosphine (1.10 g, 4.2 mmol) in anhydrous DMF (10 mL) at room temperature under argon. After 23 the reaction was concentrated and the residue was reconcentrated from xylenes (2 x). Chromatography on silica gel (gradient: 1: 1 EtOAc / hexanes, then EtOAc, then 5% MeOH in 1: 1 EtOAc / CHCl3) gave the crude title compound. (±) -10,11-Dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate unchanged can be recovered from the 1: 1 fractions of EtOAc / hexanes. Rechromatography of the crude title compound (3% MeOH in 1: 1 EtOAc / CHCl3) gave the title compound clean (0.72 g, 73%) as a yellow foam: CCD (10% MeOH in 1: 1 EtOAc / CHCl3) Rf 0.59; 1 H NMR (250 MHz, CDCl 3) d 8.19 (d, J = 7.1 Hz, 1 H), 7.46 (d, J = 2.9 Hz, 1 H), 7.35 (dd, J = 7.1, 2.9 Hz, 1 H), 7.00 - 7.30 (m, 5 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.81 (d, J = 2.6 Hz, 1 H), 6.70 (dd, J = 8.2, 2.6 Hz, 1 H) , 4.29 (d, J = 15.1 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.08 (t, J = 5.5 Hz, 2 H), 3.86 (d, J = 15.1 Hz, 1 H), 3.72 - 3.90 (m, 1 H), 3.59 (q, J = 6.3 Hz, 2 H), 3.30 (dd, J = 15.0, 4.2 Hz, 1 H), 2.93 (dd, J = 15.0, 9.3 Hz, 1 H), 2.64 (dd, J = 15.6, 9.3 Hz, 1 H), 2.10 - 2.30 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (EA) m / e 492 (M + H) +.

Preparation 17 Preparation of (S) -10,11-dihydro-3-r3- (4-nitro-1-oxopyridin-2-ylamino) -1- propyloxy-5H-dibenzora, dl-cycloheptene-10-ethyl acetate a) (S) -10.11 -Dihydro-3-r3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxp-5H-dibenzo [a, d1cycloheptene-10-ethyl acetate] The title compound was prepared according to the procedure of Preparation 16, but substituting (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate with (S) ) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] ccloheptene-10-ethyl acetate: MS (EA) m / e 492 (M + H) +.

Preparation 18 Preparation of 10.11 -dihydro-3-methoxy-5H-dibenzofa, dlcyclohepten-10-one a) 2-Benzyl-4-methoxyphenylacetic acid A solution of 2-benzoyl-4-methoxyphenylacetic acid (13.0 g, 0. 048 moles), prepared by the method of J. Med. Chem. 1981, 24, 998, in glacial acetic acid (600 mL) was treated under argon with 4.3 g of 10% Pd / C and hydrogenated at 3.51 kg / cm2 for 17 hours. The mixture was filtered using Celite® and the filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 14.2 of the title compound: 1 H NMR (400 MHz, CDCl 3) d 3.52 (s, 2 H), 3.75 (s, 3 H), 4.0 ( s, 3H), 6.7 (m, 2H), 7.15 (m, 6H). b) 10,11-Dihydro-3-methoxy-5H-dibenzophate, d1-cyclohepten-10-one A solution of 2-benzyl-4-methoxyphenylacetic acid (14.2 g, 0. 055 m) in benzene (120 mL) and thionyl chloride (28 mL) was brought to reflux for 1 hour and concentrated. The acid chloride was dissolved in dry methylene chloride (40 mL) and the solution was added by dropping under argon to a solution of AICI3 (14.7 gm 0.11 mol) in methylene chloride (600 mL). The reaction was stirred under argon atmosphere for 2.5 hours at room temperature and then quenched with ice-water (200 mL). The layers were separated and the organic phase was washed sequentially with 10% NaOH solution, water and dilute HCl. The resulting solution was diluted with ether (200 mL), dried over MgSO and concentrated. The solid residue was triturated with ether / hexane (1: 1) and 9.35 g of the title compound were collected by filtration: Mp 105-106 ° C; 1 H NMR (400 MHz, CDCl 3) d 3.72 (s, 3 H), 4.71 (s, 2 H), 4.02 (s, 2 H), 6.7 (d, 1 H), 6.82 (s, 1 H), 7.30 (m, 4H), 8.1 (d, 1 H).

Preparation 19 Preparation of (±) -10,11 -dhydro-3-methoxy-5H-dibenzophate, d1-cycloheptene-10-ethyl acetate a) (±) -3- (3-Methoxyphenyl) indenoacetate ethyl ester To a cold solution of 3- (3-methoxyphenyl) indene (4 g, 18 mmol), prepared by the method of J. Med. Chem. 1981, 24,998 in THF (15 mL) at 0 ° C was added dropwise a solution of LiN (TMS) 2 (20 mL, 1 M in THF) for 5 minutes. The resulting solution was added dropwise to a solution of ethyl bromoacetate (3.34 g, 20 mmol) in THF (15 mL) at -78 ° C for 30 minutes. After 2.5 hours, the mixture was quenched with saturated ammonium chloride solution and the layers separated. The organic layer was dried over MgSO and concentrated to give the crude product which was purified by column chromatography (SiO2 / 2-4% EtOAc / hexane) to give the title compound (1.1 g): 1 H NMR (400 MHz, CDCl 3) d 1.30 (t, 3H), 2.50 (m, 1 H), 2.85 (m, 1 H), 3.85 (s, 3H), 4.0 (m, 1 H), 4.20 (q, 2H), 6.6 ( s, 1 H), 6.9 (m, 1 H), 7.2 (s, 1 H), 7.35 (m, 6H). b) (±) -3-f (3-Methoxybenzoyl) 1-phenylsuccinate ethyl A solution of ethyl (±) -3- (3-methoxyphenyl) indenoacetate (1.1 g, 3.6 mmol) in acetone (30 mL) was treated with 4% aqueous solution of osmium tetroxide (0.5 mL) followed by a dropwise addition of reagent Jones 1.2 M (5 mL, 6 mmol) according to the literature procedure (J. Org. Chem. 1993, 58, 4745). After stirring overnight at room temperature, the dark reaction mixture was quenched with isopropanol (2.5 mL), followed by sodium bisulfite (0.9 g) and water (30 mL). The product was extracted with ethyl acetate, washed with brine, dried over MgSO and concentrated to give a solid residue. Trituration with 1: 1 ether / hexane gave 0.76 of the title compound. 1 H NMR (400 MHz, CDCl 3) d 1.18 (t, 3 H), 2.90 (m, 1 H), 3.3 (m, 1 H), 3.92 (s, 3 H), 4.1 (q, 2 H), 4.4 (m, 1 H), 4.4 (d, 1 H), 7.25 (m, 2H), 7.5 (m, 6H). c) (±) -3 - [(3-Methoxybenzyl) 1-phenylsuccinate ethyl A mixture of ethyl (±) -3 - [(3-methoxybenzoyl)] phenylsuccinate (0.76 g, 2.1 mmol) and % Pd / C (0.6 g) in glacial acetic acid (35 mL) was hydrogenated at 3.51 kg / cm2 for 17 hours. The mixture was filtered using Celite® and the filter pad was washed with acetic acid. The filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 0.65 of the title compound: 1 H NMR (400 MHz, CDCl 3) d 1.20 (t, 3H), 2.20 (m, 1 H), 3.0 (m, 1 H), 3.74 (s, 3H), 4.1 (q, 2H), 4.18 (q, 2H), 4.4 (d, 1 H), 6.2 (m, 2H), 7.22 (m, 6H). d) (±) -10,11-D yhydro-3-methoxy-11-oxo-5H-dibenzora, d1-cyclohepten-10-ethyl acetate To a magnetically stirred solution of (±) -3 - [(3 -methoxybenzyl)] ethyl phenylsuccinate (0.65 g, 1.9 mmol) in dry methylene chloride (10 mL) was added DMF (0.2 mL) and oxalyl chloride (0.2 mL, 2.28 mmol). After 1.5 hours, the solution was added dropwise to a suspension of aluminum chloride (0.6 g, 4.5 mmol) in dry methylene chloride (15 mL). The mixture was quenched after 2 hours with water and ice, the layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over MgSO and concentrated. The residue was purified by column chromatography (SiO2 / 2-4% EtOAc / hexane) to give the title compound (0.3 g): 1 H NMR (400 MHz, CDCl 3) d 1.28 (t, 3 H), 2.88 ( m, 1 H), 3.55 (m, 1 H), 3.84 (s, 3 H), 3.88 (d, 1 H), 4.18 (q, 2 H), 4.85 (d, 1 H), 4.95 (m, 1 H), 5.8 (m, 2H), 7.22 (m, 4H), 8.1 (s, 1 H). e) (±) -10,11-D yhydro-3-methoxy-5H-dibenzo [a, d1-cycloheptene-10-ethyl acetate A mixture of (±) -10,11-dihydro-3-methoxy -11-oxo-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate (0.3 g, 0.93 mmol) and 10% Pd / C (0.3 g) in glacial acetic acid (25 mL) was hydrogenated at 3.51 kg / cm2 for 18 hours. The mixture was filtered using Celite® and washed with acetic acid. The filtrate was concentrated and reconcentrated from toluene and methylene chloride to give 0.25 of the title compound: 1 H NMR (400 MHz, CDCl 3) d 1.28 (t, 3 H), 2.60 (m, 2 H), 2.90 (m, 1 H), 3.30 (m, 1 H), 3.80 (s, 3H), 3.85 (d, 1 H), 4.18 (q, 2H), 4.30 (d, 1 H), 6.70 (m, 2H), 7.0 ( d, 1 H), 7.22 (m, 4H).

Preparation 20 Preparation of (±) -10.11 -dihydro-3-hydroxy-dibenzorb, floxepin-10-ethyl acetate a) 4-Methoxy-2-phenoxyacetophenone According to the procedure of Harris, T.W. et al. (J. Med. Chem. 1982, 25 (7), 855-858), 2-fluoro-4-methoxyacetophenone (1.00 g, 5.95 mmol) was reacted with phenol to give the title compound (1.27 g) as an oil: 1 H NMR (300 MHz, CDCl 3) d 7.90 (d, J = 8.8 Hz, 1 H), 7.35 (m, 2 H), 7.20 (m, 1 H), 7.05 (m, 2 H), 6.70 ( m, 2H), 6.70 (dd, J = 2.4, 8.8 Hz, 1 H) 6.35 (d, J = 2.4, 1 H), 3.75 (s, 3 H), 2.62 (s, 3 H). b) 2- (4-Methoxy-2-phenoxyphenyl) -1-morpholin-4-ylethan-1-thione According to the procedure of Harris, T.W. et al. (J. Med. Chem. 1982, 25 (7), 855-858), 4-methoxy-2-phenoxyacetophenone (1.69 g, 6.98 mmole), sulfur (0.36 g, 11.2 mmole) and morpholine (0.98 mL, 11.2 mmol) were reacted to give the title compound (1.24 g) as a white solid: MS (EA) m / e 344.0 (M + H) +. c) 2- (4-Methoxy-2-phenoxy-phenyl) -acetic acid To a solution of 2- (4-methoxy-2-phenoxyphenyl) -1-morpholin-4-ylethan-1-thione (0.35 g, 1.02 mmol) in i-PrOH (15 mL) and H2O (15 mL) was added KOH (0.57 g, 10.2 mmol). The reaction was refluxed for 18 hours, then cooled to room temperature, diluted with H2O and washed with Et2O. The aqueous layer was acidified to pH = 4 with concentrated HCl and extracted with CHCl3. The combined extracts were dried over MgSO4 and concentrated to give the title compound (0.22 g) as a white solid. This was used without further purification: MS (EA) m / e 259.0 (M + H) +. d) 3-Methoxyd-benzorb, floxepin-10-one A solution of 2- (4-methoxy-2-phenoxyphenyl) acetic acid (594 mg, 2.3 mmol) in thionyl chloride (10 mL) was heated to reflux for 30 minutes, then concentrated to dryness and the residue was reconcentrated from toluene. The resulting residue was dissolved in dry CH 2 Cl 2 (3 mL) and the solution was added dropwise at room temperature to a suspension of AICI 3 (673 mg, 5.06 mmol) in dry CH 2 Cl 2 (4 mL) in a flame-dried flask under argon. After stirring for 2.5 hours the mixture was diluted with CH2Cl2 (10 mL) and washed sequentially with 1.0 N NaOH and brine. Drying (MgSO), concentration and flash chromatography on silica gel (5% EtOAc / hexanes) gave the title compound (264 mg, 48%) as a light yellow oil: 1 H NMR (300 MHz, CDCl 3) d 3.80 (s, 3 H), 4.02 (s, 2 H), 6.74 - 8.08 (m, 7 H). e) (±) -10,11 -Dihydro-10-hydroxy-3-methoxydibenzorb, f1oxepin-10-ethyl acetate EtOAc (0.94 mL, 9.6 mmol) was added dropwise to a solution of bis (trimethylsilyl) ) lithium amide (1.0 M in THF, 7 mL, 7 mmol) in dry THF (7 mL) in a flame-dried flask at -78 ° C under argon. After 0.5 hours TMEDA (2.4 mL, 16 mmol) was added. After a further 5 minutes a solution of 3-methoxy dibenzo [b, f] oxepin-10one (760 mg, 3.2 mmol) in THF (2 mL) was added over 3 minutes. Additional dry THF (0.4 mL) was used in the transfer. The reaction was stirred at -78 ° C to -40 ° C for 1 hour, then quenched with saturated NH 4 Cl (10 mL). The mixture was warmed to room temperature and extracted with EtOAc. Drying (MgSO4), concentration and chromatography by silica gel (10% EtOAc / hexanes) gave the title compound as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 1.14-1.20 (t, 3 H), 1.21 - 1.30 (m, 1 H), 2.62 - 2.68 (dd, 1 H), 2.94 - 3.02 (dd, 1 H), 3.24 - 3.30 (dd, 1 H), 3.40 - 3.46 (dd, 1 H), 3.40 - 3.46 (dd, 1 H), 3.78 (s, 3 H), 4.08 -4.18 (m, 2 H), 6.60 - 7.26 (m, 6 H), 7.64 - 7.68 (dd, 1 H) . f) (±) -10,11-Dihydro-3-methoxy-d-benzofb, ethyl-1-ethyl-10-acetate Boron trifluoride etherate (0.48 mL, 3.9 mmol) was added to a solution of (±) -10,11-dihydro-10-hydroxy-3-methoxydibenzo [b, f] oxepino-10-ethyl acetate 8690 mg, 1.95 mmol) and triethylsilane (0.62 mL, 3.9 mmol) in dry CH 2 Cl 2 0 ° C under argon. After 20 minutes, the reaction was quenched with 5% NaHC 3 and the mixture was extracted with CH 2 Cl 2. Drying (MgSO4) and concentration gave a yellow oil. This was dissolved in absolute ethanol (20 mL) and 10% Pd / C (413 mg) was added., 0.39 mmole). The mixture was hydrogenated for 3 hours at 3.51 kg / cm2 in a Parr hydrogenation apparatus. The catalyst was removed by filtration through Celite® and the filtrate was concentrated to give the title compound (523 mg, 86%) as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 7.18-6.58 (m, 7). H), 4.18 -4.08 (m, 2 H), 3.80 (s, 3 H), 3.80 - 3.74 (m, 1 H), 3.40 - 3.30 (dd, 1 H), 2.98 -2.84 (dd, 1 H) , 2.74 - 2.62 (dd, 1 H), 2.60 - 2.52 (m, 1 H), 1.32 - 1.20 (t, 3 H). g) (±) -10,11-Dihydro-3-hydroxy-dibenzofb, ethyl-1-ethyl-10-acetate A solution of (±) -10,11-dihydro-3-methoxydibenzo [b, f] Oxepin-10-ethyl acetate (523 mg, 1.68 mmol) in CH 2 Cl 2 (6.8 mL) was added dropwise to a cold solution of BBr 3 in CH 2 Cl 2 (1.0 M, 6.7 mL, 6.7 mmol) at 0 ° C under argon. The reaction was stirred for 20 minutes and then CH3OH (7 mL) was added carefully. The mixture was concentrated and the residue was chromatographed by steaming on silica gel (15-20% EtOAc / hexanes) to give the title compound (407 mg, 89%) as a light yellow oil: MS (EA) m / e 299 (M + H) +.

Preparation 21 Preparation of N-oxide hydrobromide of 2-IT3-bromo-1-propyl) amino '| - 4-methylpyridine a) 2-f (3-Bromo-1-propyl) amino-4-methylpyridine N-oxide hydrobromide A solution of SOBr 2 (5.0 mL, 64.5 mmol) in CH 2 Cl 2 (20 mL) was added dropwise over 15-20 hours minutes to a solution of 2 - [(3-hydroxy-1-propyl) amino] -4-methylpyridine N-oxide (10.0 g, 54.87 mmol) in CH2Cl2 (100 mL) at 0 ° C. The reaction was warmed to room temperature for 2 hours and then Et2O (200 mL) was added slowly. The solvents were decanted from the gummy precipitate, and the precipitate was washed with additional CH 2 Cl 2 / Et 2 O (several times). The resulting brownish-yellow residue solidified under standing in a refrigerator overnight. The solid was collected and washed with Et2O to give the title compound (15.07 g) as a yellow solid. The additional title compound (2.05 g) was obtained as white needles by concentration of the combined organic layers. The total yield of the title compound was 17.89 g (96%): MS (EA) m / e 245 and 247 (M + H) +. The following examples illustrate methods for preparing the biologically active compounds of this invention from intermediates such as those described in the above preparations.

EXAMPLE 1 Preparation of (±) -10,11-dihydro-3-f4- (pyridin-2-ylamino) -1-butyl) l-5H-dibenzole, d1-cycloheptene-10-acetic acid a) 4- (2-Tetrahydropyranyloxy) -1 -tributyltin-1-butine A solution of n-butyllithium in hexanes (1.6 M, 18.8 ml, 30 mmol) was added in a stream for 2 minutes to a solution of 2- (3-Butynyloxy) tetrahydro-2H-pyran (4.7 mL, 30 mmol) in dry THF (60 mL) at 0 ° C under argon. After 0.5 hours tributyltin chloride (8.1 mL, 30 mmol) was added in one shot, and the reaction was warmed to room temperature. After 3 hr, the reaction was diluted with hexanes (300 mL) and washed sequentially with H2O (2 x 60 mL), 10% KF (2 x 30 mL), and saturated brine (60 mL). Drying (Na2SO), concentration and chromatography with silica gel (3% EtOAc / hexanes) gave the title compound (3.58 g, 27%) as an almost colorless oil: CCD (5% EtOAc / hexanes) Rf 0.37; 1 H NMR (400 MHz, CDCl 3) d 4.66 (narrow t, 1 H) 3.75-3.96 (m, 2H), 2.56 (app t, 2H), 1.76-1.91 (m, 1 H), 1.65-1.78 (m, 1 H), 1.42-1.65 (m, 10H), 1.22-1.41 (m, 6H), 0.82-1.08 (m, 15H). b) (±) -10,11-Dihydro-3-f4- (2-tetrahydropyranyloxy) -1-butyne-1 -I1-5H-dibenzof.dl-cycloheptene-10-ethyl acetate A mixture of (±) -10,11-D-Hydro-3- (trifluoromethanesulfonyl) -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (1.34 g, 3.13 mmol), 4- (2-tetrahydropyranxyloxy) -1-tributyltin-1-butine (1.66 g, 3.76 mmol), LiCl (398 mg, 9.39 mmol), bis (trifhenylphosphine) palladium dichloride (110 mg, 0.094 mmol) and anhydrous dioxane (31 mL) was heated to reflux under argon. After 1.5 hours, the reaction was concentrated to remove most of the dioxane, and the residue was taken up in Et2O (100 mL). 10% KF (50 mL) was added and the mixture was stirred vigorously for 0.5 hour. The aqueous layer was removed and the Et2O layer was filtered through a mixture of Celite® and MgSO4. The filtrate was concentrated and the residue was chromatographed on silica gel (10% EtOAc / hexanes) to give the title compound (1.12 g, 83%) as a light yellow oil: CCD (20% EtOAc / hexanes) Rf0. 40; 1 H NMR (400 MHz, CDCl 3) d 7.21 - 7.30 (m, 1 H), 7.06 - 7.20 (m, 5 H), 7.00 (d, J = 7.8 Hz, 1 H), 4.69 (t, J = 3.6 Hz , 1 H), 4.31 (d, J = 15.2 Hz, 1 H), 4.11 - 4.23 (m, 2 H), 3.76 -3.97 (m, 4 H), 3.59 - 3.68 (m, 1 H), 3.48 - 3.57 (m, 1 H), 3.34 (dd, J = 15.2, 4.1 Hz, 1 H), 2.97 (dd, J = 15.2, 9.5 Hz, 1 H), 2.70 (t, J = 7.3 Hz, 2 H) , 2.65 (dd, J = 15.7, 4.8 Hz, 1 H), 2.51 (dd, J = 15.7, 9.5 Hz, 1 H), 1.78 - 1.92 (m, 1 H), 1.68 - 1.78 (m, 1 H) , 1.44 - 1.68 (m, 4 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (EA) m / e 455 (M + Na) +. c) (±) -10.11-Dihydro-3-r4- (2-tetrahydropyranloxy) -1-butyne-5H-dibenzora.dl-cycloheptene-10-ethyl acetate A mixture of (±) -10 , 11-dihydro-3- [4- (2-tetrahydropyranyloxy) -1-butyn-1-yl] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (1.2 g, 2.77 mmol), 10% Pd / C (0.3 g, 0.28 mmol) and EtOAc (28 mL) was stirred at room temperature under hydrogen (3.51 kg / cm2) in a Parr apparatus. After 3 hr, the reaction was filtered through Celite® and the filtrate was concentrated. Chromatography on silica gel (10% EtOAc / hexanes) gave the title compound (1.06 g, 88%) as a colorless oil: CCD (20% EtOAc / hexanes) Rf 0.51; 1 H NMR (400 MHz, CDCl 3) d 7.05 - 7.20 (m, 4 H), 6.92 - 7.03 (m, 3 H), 4.53 - 4.60 (m, 1 H), 4.34 (d, J = 15.1 Hz, 1 H ), 4.12 -4.26 (m, 2 H), 3.80 - 3.90 (m, 3 H), 3.71 - 3.80 (m, 1 H), 3.44 - 3.53 (m, 1 H), 3.35 - 3.44 (m, 1 H) ), 3.33 (dd, J = 15.1, 4.1 Hz, 1 H), 2.95 (dd, J = 15.1, 9.4 Hz, 1 H), 2.65 (dd, J = 15.5, 4.9 Hz, 1 H), 2.49 - 2.61 (m, 3 H), 1.77 - 1.90 (m, 1 H), 1.45 - 1.77 (m, 9 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (EA) m / e 459 (M + Naf. d) (±) -10,11-Dihydro-3- (4-hydroxy-1-butyl) -5H-dibenzora, d1-cycloheptene-10-ethyl acetate A solution of (±) -10, 11-dihydro-3- [4- (2-tetrahydropyranxyloxy) -1-butyl) -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (456.0 mg, 1.04 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmol) in absolute EtOH (10 mL) was stirred at room temperature. After 2 hours the reaction was quenched with 5% NaHCO3 (1 mL) and concentrated to remove the EtOH. The residue was diluted with H2O (2 mL) and extracted with CH2Cl2. Drying (MgSO4), concentration and chromatography on silica gel (1: 1 EtOAc / hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: CCD (1: 1 EtOAc / hexanes) Rf 0.49; 1 H NMR (250 MHz, CDCl 3) d 6.85 - 7.25 (m, 7 H), 4.34 (d, J = 15.1 Hz, 1 H), 4.08 - 4.30 (m, 2 H), 3.75 - 3.95 (m, 2 H ), 3.53 - 3.72 (m, 2 H), 3.33 (dd, J = 15.1, 4.1 Hz, 1 H), 2.95 (dd, J = 15.1, 9.4 Hz, 1 H), 2.40 - 2.75 (m, 4 H) ), 1.45-1.80 (m, 4 H), 1.27 (t, J = 7.1 Hz, 3 H); MS (EA) m / e 353 (M + H) +. e) (±) -10,11-D¡h¡dro-3- [4- (N-phthalimido) -1-butyll-5H-dibenzofa, d1cycloheptene-10-ethyl acetate Diethyl azodicarboxylate (0.2 mL) , 1.26 mmole) was added dropwise to a solution of (+) - 10,11-dihydro-3- (4-hydroxy-1-butyl) -5H-dibenzo [a, d] cyclohepten-10-acetate. ethyl (0.37 g, 1.05 mmol), triphenylphosphine (0.33 g, 1.26 mmol) and phthalimide (0.19 g, 1.26 mmol) in anhydrous THF (10 mL) at room temperature under argon. After 23 hours, the reaction was concentrated on the rotavap. Chromatography on silica gel (30% EtOAc / hexanes) gave the title compound (0.35 g, 70%) as a colorless oil: MS (EA) m / e 504.3 (M + Na) +. f) (±) -10,11-Dihydro-3- (4-amino-1-butyl) -5H-dibenzora, d1-cyclohepten-10-ethyl acetate Hydrazine monohydrate (0.11 g, 2.18 mmol) was added to a solution of (±) -10,11-d¡h¡dro-3- [4- (N-phtalidimido) -1-butl] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate ( 0.35 g, 0.73 mmol) in absolute EtOH (10 mL) and toluene (2 mL) at room temperature. The reaction was stirred at room temperature for 17 hours, then filtered and the filter pad was washed with toluene. Concentration on the rotavap gave the title compound (0.23 g, 90%) as a colorless oil: MS (EA) m / e 352.3 (M + H) +. g) (±) -10,11 -Dihydro-3-r4- (1-oxopyridin-2-ylammon) -1-butyl-dH-dibenzofa, dlcycloheptene-10-ethyl acetate A mixture of hydrochloride N-oxide of 2-chloropyridine (0.31 g, 1.88 mmol), (±) -10,11-dihydro-3- (4-amino-1-butyl) -5H-dibenzo [a, d] cyclohepten-10-acetate of ethyl (0.22 g, 0.63 mmol) and NaHCO3 (0.26 g, 3.13 mmol), in tert -amyl alcohol (6 mL) was heated to reflux for 21 hours. The reaction mixture was diluted with CH2Cl2 (100 mL) and filtered, and the filtrate was concentrated on the rotavap. Chromatography on silica gel (1: 9: 5 MeOH / CH2Cl2 / EtOAc) gave the title compound (82 mg, 30%) as a yellow oil: MS (EA) m / e 445.2 (M + H) +. h) f ±) -10.11-Dihydro-3-r4- (pyridin-2-ylamino) -1-butyn-5H-dibenzole [a, dichlorhexyl-10-ethyl acetate A mixture of (±) -10, 11-Hydro-3- [4- (1-oxopyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.07 g, 0.16 mmol) ), 10% Pd / C (0.08 g, 0.075 mmol), cyclohexene (0.16 ml, 1.6 mmol) and sodium propane (4 mL) was heated to reflux under argon for 14 hours and then the catalyst was removed by filtration through Celite®. The filter pad was washed with sodium propane and MeOH, and the filtrate was concentrated on the rotavap to give the title compound (0.046 g, 69%) as a clear oil: MS (EA) m / e 429.3 (M + H) +. i) Ethyl- (±) -10,11-dihydro-3-r4- (pyridin-2-ylamino) -1-butyl-5H-dibenzole, d1-cycloheptene-10-acetic acid A mixture of ( ±) -10,11-dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzole [a, d] cyclohepten-10-ethyl acetate (46 mg, 0.11 mmol) and 1.0 N LiOH (0.66 mL, 0.66 mmol) in THF (3 mL) and H 2 O (3 mL) was stirred at room temperature. After 24 hours the reaction mixture was concentrated on the rotavap and the residue was diluted with H2O (5 mL). The solution was cooled in an ice bath and 1.0 N AcOH was added slowly to give a white precipitate. Chromatography at C-18 YMC (45% CH3CN / H2O containing 0.1% TFA) gave the title compound (13 mg, 21%) as a white solid: MS (EA) m / e 401.3 (M + H) +. Anal. cale, for C26H28N2O2 • 0.75 H2O • 1.5 CF3CO2H: C, 59.54; H, 5.31; N, 4.72. Found: C, 59.69; H, 5.31; N, 4.72.

EXAMPLE 2 Preparation of (±) -10.11-dihydro-3-r3- (4-ethoxypyridin-2-ylamino) -1-propyloxyl-5H-dibenzole.d1-cycloheptene-10-acetic acid a) (±) -10,11 -Dihydro-3-r3- (4- (ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzole.d1c-cycloheptene-10-acetate ethyl (±) -10,11-Dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzole [a, d] cyclohepten-10-acetate was combined of ethyl (0.67 g, 1.36 mmol), 1.0 M NaOEt in ethanol (6.8 mL, 6.8 mmol) and absolute ethanol (6.8 mL), and the mixture was heated in a pre-set oil bath at 70 [deg.] C. A solution was produced After the oil bath was stirred and the solution was allowed to stir for an additional 5-7 minutes without external heating, the resulting solution was cooled in ice and the reaction was quenched with glacial acetic acid ( 0.47 mL, 8.2 mmol) The mixture was concentrated and the residue was partitioned between CH 2 Cl 2 (10 mL) and saturated in half with NH 4 Cl (10 mL) .The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x. 10 mL) The combined organic layers were dried (MgSO4) and concentrated The residue was reconcentrated from toluene to leave a reddish-orange oil. Chromatography with silica gel (5% MeOH / CHCl3) gave the title compound (601.1 mg, 90%) as a yellow oil: CCD (5% MeOH / CHCl3) Rf 0.36; 1 H NMR (250 MHz, CDCl 3) d 7.95 (d, J = 7.1 Hz, 1 H), 6.88-7.30 (m, 6 H), 6.77 (d, J = 2.6 Hz, 1 H), 6.67 (dd, J = 8.2, 2.6 Hz, 1 H), 5.95 - 6.20 (m, 2 H), 4.28 (d, J = 15.0 Hz, 1 H), 4.18 (q, J = 7.2 Hz), 4.04 (t, J = 5.6 Hz, 2 H), 3.65 - 4.00 (m, 4 H), 3.46 (q, J = 6.5 Hz, 2 H), 3.30 (dd, J = 15.0, 4.2 Hz, 1 H), 2.93 (dd, J = 15.0, 9.2 Hz, 1 H), 2.65 (dd, J = 15.6, 5.0 Hz, 1 H), 2.52 (dd, J = 15.6, 9.4 Hz, 1 H), 1.95 - 2.25 (m, 2 H), 1.10 -1.45 (m, 6 H); MS (EA) m / e 491 (M + H) +. b) (±) -10,11-Dihydro-3-r 3 - (4- (ethoxypyridin-2-ylamino) -1-propyloxy-5H-d, benzoy, dichlorheptene-10- ethyl acetate A mixture of (±) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino-1-propyloxy] -5H-dibenzole [a, d] Cyclohepten-10-ethyl acetate (601.1 mg, 1.23 mmol), cyclohexene (1.2 mL, 12.3 mmol), 10% Pd / C (130 mg, 0.012 mmol) and absolute ethanol (12.3 mL) was heated to reflux under argon. After 23.5 hours the reaction was filtered hot through Celite® and the filter pad was washed with ethanol, the filtrate was concentrated and the residue reconcentrated from toluene, chromatography on silica gel (5% MeOH). in 1: 1 EtOAc / CHCl3) gave the title compound (528.1 mg, 90%) as a light yellow oil: CCD (10% MeOH in EtOAc / CHCl3) Rf 0.67; 1 H NMR (400 MHz, CDCl 3) d 7.89 (d, J = 5.8 Hz, 1 H), 7.05 - 7.18 (m, 4 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.77 (d, J = 2.6 Hz, 1 H), 6.66 (dd, J = 8.2, 2.6 Hz, 1 H), 6.17 (d, J = 5.8, 2.1 Hz, 1 H), 5.86 (d, J = 2.1 Hz, 1 H) , 4.73 (bit, 1 H), 4.28 (d, J = 14.9 Hz, 1 H), 4.11 - 4.25 (m, 2 H), 4.04 (t, J = 5.9 Hz, 2 H), 3.98 (q, J) = 7.0 Hz, 2 H), 3.83 (d, J = 14.9 Hz, 1 H), 3.76 -3.85 (m, 1 H), 3.43 (q, J = 6.9 Hz, 2 H), 3.30 (dd, J = 15.0, 4.1 Hz, 1 H), 2.93 (dd, J = 15.0, 9.2 Hz, 1 H), 2.64 (dd, J = 15.6, 4.8 Hz, 1 H), 2.52 (dd, J = 15.6, 9.5 Hz, 1 H), 2.01 - 2.11 (m, 2 H), 1.37 (t, J = 7.0 Hz, 3 H), 1.27 (t, J = 7.0 Hz, 3 H); MS (EA) m / e 475 (M + H) +. c) Acid (±) -10.11-dihydro-3-r3- (4-ethoxy-pyridin-2-ylamino) -1-propylloxy-5H-dibenzole, d-cycloheptene-10-acetic acid by dripping 1.0 N NaOH (1.7 mL, 1.7 mmol) to a solution of (±) -10,11-d-Hydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] - 5H-dibenzole [a, d] cyclohepten-10-ethyl acetate (528.1 mg, 1.11 mmol) in absolute ethanol (11 mL) at room temperature, and the solution was heated in a pre-set oil bath at 45 ° C. After 20 hours the reaction was concentrated and the residue was reconcentrated from H2O. The resulting residue was dissolved in H2O (10 mL) and the solution was filtered. The pH was adjusted to 7 with 1.0 N HCl and the mixture was stirred vigorously to convert the gummy precipitate initially formed into a solid. Crushing with a glass rod and a spatula helped this transformation. The pH of the resulting mixture was readjusted to 7, and the solid was collected and washed with enough H2O. The filtrate was concentrated and the residue was dissolved in H2O with the aid of a little 1.0 N NaOH. The pH was adjusted to 7 to give a second small crop. The crops were combined and dried under vacuum (40-50 ° C) to give the title compound (453.7 mg, 82%) as an off-white solid: HPLC (Hamilton PRP-1®, 45% CH3CN / H2O containing 0.1 % TFA) k '= 1.32; 1 H NMR (400 MHz, DMSO-d 6) d 7.78 (d, J = 6.6 Hz, 1 H), 7.35 - 7.65 (m, 1 H), 7.02 - 7.22 (m, 4 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 2.4 Hz, 1 H), 6.68 (dd, J = 8.3, 2.4 Hz, 1 H), 6.29 (dd, 1 H), 6.15 (narrow d, 1 H ), 4.20 (d, J = 14.6 Hz, 1 H), 3.93 - 4.12 (m, 4 H), 3.89 (d, J = 14.6 Hz, 1 H), 3.60 - 3.71 (m, 1 H), 3.30 - 3.50 (m, 2 H), 3.20 (dd, J = 15.1, 4.1 Hz, 1 H), 2.83 (dd, J = 15.1, 10.1 Hz, 1 H), 2.60 (dd, J = 16.0, 5.3 Hz, 1 H), 2.48 (dd, J = 16.0, 8.9 Hz, 1 H, 1.90 - 2.05 (m, 2 H) 1.30 (t, J = 6.9 Hz, 3 H), MS (EA) m / e 447 (M + H) + Anal, cale, for C27H30N2O4-1.5 HCl: C, 64.70; H, 6.33; N, 5.59, Found C, 64.53; H, 6.14; N, 5.31.

EXAMPLE 3 Preparation of (±) -10,11-dihydro-3-r2-r2- (ethylamino) thiazole-4-p-1-ethoxy-1-5H-dibenzora.d1-cycloheptene-10-acetic acid a) (±) -10,11-D yhydro-3-r 2 -r 2 - (ethylamino) thiazole-4-ill-1-ethoxy-5H-dibenzofa, d-cycloheptene-10-ethyl acetate A solution of 2 - (ethylamino) -4-thiazoletanol (0.33 g, 1.9 mmol) and diethyl azodicarboxylate (0.30 mL, 1.9 mmol) in anhydrous DMF (5 mL) was added dropwise over 5 minutes to a solution of (±) -10, 11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (296.4 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in anhydrous DMF (5 mL) at room temperature. The reaction was kept cold in a water bath at room temperature during the addition. After 16 hours the reaction was concentrated and the residue was reconcentrated from xylenes (2 x). Chromatography on silica gel (20% EtOAc / hexanes) gave the title compound (145.0 mg, 32%) as a yellow oil: CCD (1: 1 EtOAc / hexanes) Rf 0.60; 1 H NMR (250 MHz, CDCl 3) d 7.00-7.30 (m, 4 H), 6.98 (d, J = 8.2 Hz, 1 H), 6.77 (d, J = 2.6 Hz, 1 H), 6.68 (dd, J = 8.2, 2.6 Hz, 1 H), 6.21 (s, 1 H), 5.00 - 5.25 (m, 1 H), 4.04 -4.38 (m, 5 H), 3.81 (d, J = 15.1 Hz, 1 H) , 3.70 - 3.90 (m, 1 H), 3.13 - 3.40 (m, 3 H), 2.99 (t, J = 6.7 Hz, 2 H), 2.92 (dd, J = 14.9, 9.3 Hz, 1 H), 2.64 (dd, J = 15.6, 5.0 Hz, 1 H), 2.51 (dd, J = 15.6, 9.3 Hz, 1 H), 1.27 (t, J = 7.2 Hz, 3 H); MS (EA) m / e 451 (M + H) +. b) Acid (±) -10, 11-dihydro-3-r2-f2- (ethylamino) thiazol-4-yn-1-ethoxyl-5H-dibenzora, d1-cycloheptene-10-acetic 1.0 N was added by drip LiOH (0.32 mL, 0.32 mmol) to a solution of (±) -10,11-dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5H-dibenzo [a , d] cyclohepten-10-ethyl acetate (145.0 mg, 0.32 mmol) in THF (2.4 mL) and H2O (0.48 mL) at 0 ° C. The resulting two-phase pinkish-orange mixture was stirred at 0 ° C for 10 minutes, after which time the color faded to an orange-yellow tone and then warmed to room temperature. After 1.5 hours a little more H2O was added (5 drops), and the reaction was stirred for 42 hours, then cooled to 0 ° C and neutralized with TFA (0.025 mL). The THF was removed in the rotavap, and the resulting oily residue was diluted with 0.1% TFA / CH3CN to give a homogeneous solution, ODS chromatography (gradient: 40% CH3CN / H2O containing 0.1% TFA, then 45% CH3CN / H2O containing 0.1% TFA) gave fractions containing the title compound. These were grouped and the CH3CN was removed in the rotavap. The resulting aqueous mixture was made basic at 0 ° C to give a homogeneous solution. Careful acidification at pH 4-5 with 1.0 N HCl gave a solid precipitate, which was collected, washed with enough H2O and dried to give the title compound (80.9 mg, 51%) as an off-white solid: HPLC ( Hamilton PRP-1®, 45% CH3CN / H2O containing 0.1% TFA) k '= 0.89; 1 H NMR (400 MHz, CD 3 OD) d 7.02 - 7.18 (m, 4 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.79 (d, J = 2.6 Hz, 1 H), 6.68 (dd, J = 8.3, 2.6 Hz, 1 H), 6.45 (s, 1 H), 4.26 (d, J = 14.9 Hz, 1 H), 4.20 (t, J = 6.4 Hz, 2 H), 3.87 (d, J = 14.9 Hz, 1 H), 3.68 - 3.80 (m, 1 H), 3.34 (q, J = 7.3 Hz, 2 H, partially obscured by residual solvent signal) 3.30 (dd, 1 H, darkened by residual solvent signal ), 2.99 (t, J = 6.4 Hz, 2 H), 2.92 (dd, J = 15.0, 9.4 Hz, 1 H), 2.62 (dd, J = 15.9, 5.0 Hz, 1 H), 2.47 (dd, J = 15.9, 9.3 Hz, 1 H), 1.27 (t, J = 7.3 Hz, 3 H); MS (EA) m / e 423 (M + H) +. Anal. cale, for C 24 H 26 N 2 O 3 S 0.67 CF 3 CO 2 H: C, 61.03; H, 5.39; N, 5.62. Found: C, 61.21; H, 5.36; N, 5.60.

EXAMPLE 4 Preparation of (S) -10,11-dihydro-3-f3- (pyridin-2-ylamino) -1- propyloxy-1-5H-dibenzora.d1-cycloheptene-10-acetic acid a) (S) -10,11-d, hr-3-r3- (1-oxopyridin-2-ylamino) -1-propyloxp-5H-dibenzoic.dl-cycloheptene-10-ethyl acetate To a stirred solution of (S) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate (35 g, 118 mmol) in dry THF (1.1 L) and DMF dry (600 mL) under argon, 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide (29.4 g, 175 mmol) and triphenylphosphine (45.9 g, 175 mmol) was added. After all the solids had completely dissolved (~ 1 h), the reaction was cooled to 0 ° C in an ice bath and diisopropyl azodicarboxylate (36.4 mL, 95%, 175 mmol) was added with a syringe. The reaction was allowed to slowly warm to room temperature and was stirred for 18 hours. Concentration and chromatography by evaporation on silica gel (95: 5 CHCl 3 / MeOH) followed by a second purification by silica gel chromatography (80: 20: 5 CHCIs / EtOAc / EtOH) gave the title compound ( 37.66 g, 71%) as a light yellow solid foam: 1 H NMR (400 MHz, DMSO-d 6) d 8.08 (dd, J = 6.3, 1.1 Hz, 1 H), 7.29 (t, 1 H), 7.19 - 7.06 (m, 5 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.84 (d, J = 2.5, 1 H), 6.79 (dd, J = 8.5, 1.6 Hz, 1 H), 6.69 (dd) , J = 8.3, 2.6 Hz, 1 H), 6.57 (m, 1 H), 4.17 (d, J = 14.7 Hz, 1 H), 4.13 - 4.07 (m, 2 H), 4.00 (t, 2 H) , 3.91 (d, J = 14.7 Hz, 1 H), 3.66 (m, 1 H), 3.39 (t, 2 H), 3.19 (dd, J = 15.1, 4.5 Hz, 1 H), 2.85 (dd, J = 15.1, 4.5 Hz, 1 H), 2.85 (dd, J = 15.1, 10.0 Hz, 1 H), 2.65 (dd, J = 15.8, 5.4 Hz, 1 H), 1.99 (m, 2 H), 1.18 ( t, 3 H); MS (EA) m / e 447.3 (M + H) +. b) (S) -10,11-Dihydro-3-f3- (pyridin-2-ylammon) -1-propyloxy-1-5H-dibenzora.dl-cycloheptene-10-ethyl acetate To one solution stirring of (S) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (37.66 g , 84 mmol) in isopropanol (700 mL) of ethyl was added 10% palladium on activated carbon (18 g, 16.9 mmol, carefully pre-soaked in isopropanol under argon) and cyclohexene (85 mL, 839 mmol). The reaction was then heated to reflux under argon in an oil bath set at 90 ° C. After 6 hours an additional amount of 10% palladium on activated charcoal (18 g, 84 mmol, carefully pre-soaped in isopropanol under argon) and cyclohexene (85 mL, 839 mmol) was added. After an additional 18 hours the reaction was filtered hot through Celite®, and the filter pad was washed with 1: 1 MeOH / CHCl3 (600 mL). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (95: 5 CHCl3 / MeOH) to give the title compound (29.2 g, 81%) as a light yellow oil: 1 H NMR ( 400 MHz, DMSO-d6) d 7.94 (dd, J = 5.4, 1.9 Hz, 1 H), 7.35 - 7.31 (m, 1 H), 7.18 (d, J = 7.2 Hz, 1 H), 7.14 - 7.06 ( m, 3 H), 6.97 (d, J = 8.3 Hz, 1 H), 6.83 (d, J = 2.6, 1 H), 6.68 (dd, J = 8.3, 2.6 Hz, 1 H), 6.54 (t, 1 H), 6.44 (m, 2 H), 4.17 (d, J = 14.6 Hz, 1 H), 4.13 - 4.02 (m, 2 H), 4.00 (t, 2 H), 3.91 (d, J = 14.7 Hz, 1 H), 3.66 (m, 1 H), 3.35 (m, 2 H), 3.19 (dd, J = 15.1, 4.4 Hz, 1 H), 2.86 (dd, J = 15.1, 10.1 Hz, 1 H ), 2.65 (dd, J = 15.8, 5.4 Hz, 1 H), 2.55 (dd, J = 15.8, 8.7 Hz, 1 H), 1.93 (m, 2 H), 1.18 (t, 3 H); MS (EA) m / e 431.4 (M + H) +. c) (S) -10,11-Dihydro-3-f3- (pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d-cycloheptene-10-acetic acid To a stirred solution of (S) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (29.20 g, 68 mmol) ) in dioxane (350 mL) was added 1.0 N aqueous NaOH (110 mL, 110 mmol). The turbid reaction was stirred at 50 ° C in an oil bath for 24 hours and then the resulting homogeneous solution was neutralized with 1.0 N aqueous HCl (110 mL, 110 mmol). The solution was concentrated to near dryness by rotary evaporation to precipitate the product. The supernatant was decanted and the remaining gummy solid was dried under vacuum and redissolved in 1: 1 methanol / CHCl3. The clear solution was then reconcentrated by rotary evaporation and carefully dried under vacuum. The remaining solid was triturated with a small volume of water, filtered and dried in vacuo to give the title compound (26.85 g, 94%) as an off-white powder: CLAR (Hamilton PRP-1®, 35% CH3CN / H2O that contained 0.1% TFA) k '= 2.88; 1 H NMR (400 MHz, DMSO-d 6) d 7.94 (dd, J = 4.7, 1.6 Hz, 1 H), 7.38 (m, 1 H), 7.18 (d, J = 7.3 Hz, 1 H), 7.14 (d , J = 3.9 Hz, 2 H), 7.08 (m, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.78 (br s, 1 H), 6.68 (dd, J = 8.3, 2.6 Hz, 1 H), 6.50 (d, J = 8.3 Hz, 1 H), 6.47 (dd, 1 H), 4.20 (d, J = 14.6 Hz, 1 H ), 3.67 (m, 1 H), 3.37 (m, 1 H), 3.20 (dd, J = 15.2, 4.4 Hz, 1 H), 2.83 (dd, J = 15.2, 10.1 Hz, 1 H), 2.60 ( dd, J = 15.9, 5.3 Hz, 1 H), 2.50 (dd, 1 H), 1.95 (m, 2 H); MS (EA) m / e 403.3 (M + H) +. Anal. cale, for C 25 H 26 N 2 O 3 2 2 O: C, 71.41; H, 6.71; N, 6.66. Found: C, 71.21; H, 6.53; N, 6.54.

EXAMPLE 5 Preparation of (±) -10,11-dihydro-3-r2- (6-aminopyridin-2-yl) -1-ethoxy-1H-dibenzophate, d-cycloheptene-10-acetic acid a) (±) -10,11-D1h¡dro-3-r2- (6-aminopyridin-2-yl) -1-ethoxy-1-5H-dibenzofa, dichlocloheptene-10-ethyl acetate Solution of 6-amino-2-pyridylethanol (0.23 g, 1.68 mmol) and diethyl azodicarboxylate (0.26 mL, 1.68 mmol) in anhydrous DMF (5 mL) was added dropwise to a solution of (±) -10.11- dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate and triphenylphosphine (0.48 g, 1.82 mmol) in anhydrous DMF (5 mL) at room temperature. After 1 hour the reaction was concentrated and the residue was purified by flash chromatography on silica gel (1: 1 EtOAc / hexanes) to give the title compound (0.030 g): MS (EA) m / e 417 (M + H) +. b) Acid (±) -10.11-dihydro-3-r2- (6-aminopyridin-2-yl) -1-ethoxy-5H-dibenzofa.dl-cycloheptene-10-acetic acid A solution of ( ±) -10,11-D-Hydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.030 g, 0.072 mmole) and 1.0 N NaOH (0.14 mL, 0.14 mmole) in MeOH (2 mL) was stirred at room temperature overnight and then concentrated. The residue was dissolved in H2O and the pH of the solution was adjusted to 7 with 1.0 N HCl. The concentration and chromatography on a C-18 Bond Elute column (10: 9: 1 CH3CN / H2O / TFA) gave the compound of title (0.013 g): MS (EA) m / e 389 (M + H) +.

EXAMPLE 6 Preparation of (R) -10,11-dihydro-3-f3- (pyridin-2-ylamino) -1- propyloxy-1-5H-dibenzole, d1-cycloheptene-10-acetic acid a) (R) -10,11 -Dihydro-3-r3- (1-oxopyridin-2-ylammon) -1-propyloxy-1-5H-dibenzora, d1-cycloheptene-10-ethyl acetate A solution of N - oxide of 2 - [(3-hydroxy-1-propyl) amino] pyridine (0.70 g, 4 mmol) and diethyl azodicarboxylate (0.65 mL, 4 mmol) in anhydrous DMF (20 mL) was added dropwise over 10 minutes to a solution of (R) -10,11-dihydro-3-hydroxy 5H-d.benzo [a, d] ccloheptene-10-ethyl acetate (0.45 g, 2 mmol) and triphenylphosphine (1.2 g, 4 mmol) in anhydrous DMF (8 mL) at room temperature under argon. After 23.5 hours the reaction was concentrated on the rotavap, and the residue was reconcentrated from xylenes to remove the residual DMF. Chromatography on silica gel (1-4% CH 3 OH / CH 2 Cl 2) gave the title compound (0.50 g, 74%) as a yellow oil: MS (EA) m / e 447 (M + H) +. b) (R) -10, 11-Hydro-3-r3- (pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofa, dl-cycloheptene-10-ethyl acetate A mixture of (R) - 10,11-D-Hydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.5 g, 1 mmol) , 10% Pd / C (0.25 g, 0.2 mmol), cyclohexene (2 mL, 20 mmol) and isopropanol (10 mL) was heated to reflux for 18 hours, then the catalyst was removed by filtration through Celite®. Chromatography on silica gel (0.5-2% CH 3 OH / CH 2 Cl 2) gave the title compound (0.4 g, 83%) as a light yellow oil EM (EA) m / e 431 (M + H) +. c) Acid (R) -10.11-d-Hydro-3-r3- (pyridn-2-ylamino) -1-propyloxy-1-5H-dibenzof.dl-cycloheptene-10-acetic acid A mixture of (R) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.4 g, 0.93 mmol) and 1.0 N NaOH (1.1 mL, 1.1 mmol) in absolute EtOH (10 mL) was heated in an oil bath set at 50 ° C. After 18 hours, the reaction was concentrated on the rotavap and the residue was dissolved in H2O. The aqueous solution was adjusted to pH 4 with 3 N HCl, and the solid precipitate was collected and washed with H2O. The material was dried in high vacuum at 40 ° C to give the title compound (0.36 g, 96%) as an almost colorless solid: [α] D + 50.8 ° (c = 0.12, CH 3 OH); MS (EA) m / e 403 (M + H) +. Anal. cale, for C25H26N2O3 .5 H2O: C, 72.97; H, 6.61; N, 6.80. Found: C, 73.09; H, 6.38; N, 6.58.

EXAMPLE 7 Preparation of (S) -10,11-dihydro-3-r2-r6-methylamino) pyridin-2-ill-1-ethoxyl-5H-dibenzole, dl-cycloheptene-10-acetic acid a) (S) -10,11-Dihydro-3-r 2 -f 6 - (methylamino) pyridin-2-yl-1-ethoxy-1-5H-dibenzofa.dl-cycloheptene-10-ethyl acetate According to a process Example 6 (a), but substituting 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide with 6- (methylamino) -2-pyridylethanol, and (R) ) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11-dihydro-3-hydroxy-5H-dibenzo [ a, d] cyclohepten-10-ethyl acetate, the title compound was prepared as a colorless oil after chromatography on silica gel (0.2-2% MeOH / CH2Cl2): MS (EA) 431.2 (M + H) +. (b) (S) -10,11-d-Hydro-3-r2-r6- (methylamine) pyridin-2-n-1-ethoxyfl-5H-d-benzop, d1-cycloheptene -10-acetic acid (S) -10,11-dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -5H-dibenzo [a, d] Cycloheptene-10-ethyl acetate (80 mg, 0.18 mmol) was dissolved in THF (4 mL), and a solution of LiOH • H2O (35 mg, 0.84 mmol) in H2O (4 mL) was added. The solution was stirred at room temperature for 72 hours and then diluted with ether (10 mL). The supernatant was decanted and the solid was suspended in H2O. Careful acidification at pH 4 with 3 N HCl gave the title compound as a white solid: MS (EA) 403 (M + H) +. Anal. cale for C25H26N2? 3 • 0.75 H2O: C, 72.18; H, 6.66; N, 6.73. Found: C, 72.44; H, 6.52; N, 6.71.

EXAMPLE 8 Preparation of (±) -10,11-dihydro-3-r3- (3,4,5,6-tetrahydropyrimidin-2-ylaminoH-propyloxy-5H-dibenzole, dl-cycloheptene-10-acetic acid a) (±) -10,11-Dhydro-3-f3- (4-nitrobenzyloxycarbonyl) amino-1-propyloxy-5H-dibenzo [a, d1cycloheptene-10-ethyl acetate The title compound was obtained as an amber oil according to the procedure of Example 6 (a), but substituting the 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide with 3- (4-Nitrobenzyloxycarbonylamino) -1-propanol and (R) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11 -dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) 533.3 (M + H) +. b) (±) -10,11 -Dihydro-3- (3-amino-1-propyloxy) -5H-dibenzora.dlcycloheptene-10-ethyl acetate A mixture of (±) -10,11-dihydro-3- [3- (4-Nitrobenzyloxycarbonylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (1.6 g, 3 mmol), 10% palladium on carbon (0.8 g, 1 mmol) and ethanol (50 mL) was stirred under H 2 (3.37 kg / cm 2) for 3 hours and then the catalyst was removed by filtration through Celite®. The filtrate was concentrated to give the title compound (1.2 g, 100%) as a yellow oil: MS (EA) 348.2 (M + H) +. c) (±) -10,11-D yhydro-3- [3- (pyrimidin-2-ylamino) -1-propyloxy-5H-d-benzene, d] cycloheptene-10-ethyl acetate mixture of (±) -10,11-dihydro-3- (3-amino-1-propyloxy) -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.4 g, 1 mmol), sodium bicarbonate (0.5 g, 6 mmol), 2-bromopyrimidine (0.34 g, 2 mmol) and ethanol (10 mL) was heated to reflux under argon for 18 hours. The solution was decanted and concentrated afterwards. The residue was purified by chromatography on silica gel (0.2-2% MeOH / CH2Cl2) to give the title compound (0.17 g, 34%) as a light yellow oil: MS (EA) 432.3 (M + H) +. d) (±) -10,11-Dihydro-3-r 3-r 3,4,5,6-tetrahydro-rimid-2-ylamino) -1-propyloxp-5 H -dibenzo [ a, ethylcycloheptene-10-ethyl acetate A mixture of (±) -10,11-dihydro-3- [3- (pyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate (0.17 g, 0.38 mmol), 10% palladium on carbon (0.085 g, 0.08 mmol), 4M HCl in dioxane (0.1 mL, 0.4 mmol) and ethanol (45 mL) was stirred under H2 (3.37 kg / cm2) for 6 hours and then the catalyst was removed by filtration through Celite®. The filtrate was concentrated to give the title compound (0.19 g) as a yellow oil: MS (EA) 436.3 (M + H) +. e) Acid (±) -10,11-d, hr-3-r3- (3,4,5,6-tetrahydrodipyrid-2-ylamino) -1-propoxy-5H-dibenzo [a , d1cycloheptene-10-acetic acid A solution of (±) -10,11-dihydro-3- [3- (3,4,5,6-tetrahydropyrimid-2-ylamino) -1-propyloxy] -5H-dibenzo [a , d] cyclohepten-10-ethyl acetate (0.17 g, 0.36 mmol), lithium hydroxide monohydrate (0.042 g, 1 mmol), THF (3 mL) and water (10 mL) was stirred at room temperature for 20 hours and then he concentrated. The residue was dissolved in water and the solution was brought to pH 4 with 3N HCl. The resulting solution was kept in the refrigerator overnight, and then the supernatant was decanted from the solid. The solid was dried under vacuum to give the title compound (0.145 g, 91%) as a tan solid: MS (EA) 408.3 (M + H) +. Anal. cale, for C 24 H 29 N 3 3 3 • 1.3 HCl: C, 63.37; H, 6.71; N, 9.23. Found: C.63.67; H, 6.84; N, 9.46.

EXAMPLE 9 Preparation of (±) -10,11-dihydro-3-r3- (isoquinolin-1-ylamino) -1- propyloxy-5H-dibenzole, dl-cycloheptene-10-acetic acid a) (±) -10,11 -Dihydro-3-f3- (1-oxoisoquinolin-1 -lamino) -1-propyloxy-5H-d-benzene, dichlocycloheptene-10-ethyl acetate The title compound it was prepared as a light yellow oil according to the procedure of example 6 (a), but substituting the N - oxide of 2 - [(3-hydroxy-1-propyl) amino] pyridine with N-oxide of 1 - [( 3-hydroxy-1-propyl) amino] -isoquinoline, and the (R) -10,11-dihydro-3-hydroxy-5H-d-benzo [a, d] c-chlorheptene-10-ethyl acetate with ( ±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 497.2 (M + H) +. b) (±) -10,11 -Dihydro-3- [3- (1-acetyl-1-amino) -1-propyloxy-5H-d-benzo [a, d-cycloheptene-10-ethyl acetate] The title compound was prepared as a clear oil according to the procedure of Example 6 (b), but substituting (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) - 1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-3- [3- [1-oxoisoquinolin-1-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: MS (EA) m / e 481.3 (M + H) +. c) Acid (±) -10,11-dithy-3-f3- (soquinolin-1-amylane) -1-propyloxy-5H-dibenzora, dichlorheptene-10-acetic acid The title compound was prepared as an amber oil according to the procedure of Example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-3- [3- [isoquinolin-1-ylamino) -1-propyloxy ] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 453.2 (M + H) +. Anal. cale, for C29H28N2? 3 • 1.3 TFA • 0.25 H2O: C, 62.71; H, 4.96; N, 4.63. Found: C, 62.45; H, 4.92; N, 4.41.

EXAMPLE 10 Preparation of (±) -10.11-dihydro-3-F3-r4- (ethylthio) pyrimidin-2-ylamino-1-propyloxy-1-5H-dibenzole, d1-cycloheptene-10-acetic acid a) (±) -10.11-D yhydro-3-r3-r4- (ethylthio) -1-oxopyridin-2-ylamino) -1-propylloxy-5H-dibenzophate, d1cycloheptene- 10-ethyl acetate A solution of (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] Cycloheptene-10-ethyl acetate (300 mg, 0.61 mmol) and sodium trioethylate (145 mg, 1.22 mmol) in DMF (5 mL) was heated at 70 ° C for 3 hours. The solvent was removed on the rotavap and the residue was purified by chromatography on silica gel (2-6% CH3OH / CH2Cl2) to give the title compound (90 mg) as an orange oil: MS (EA) m / e 507.3 (M + H) +. b) (±) -10,11-Dh-3-r3-r4- (etlthio) pyridin-2-ylammonol-1-propyloxy-1H-dibenzole, d-cycloheptene-10 ethyl acetate A mixture of (±) -10,11-dihydro-3- [3- [4- (ethylthio) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] ] cyclohepten-10-ethyl acetate (60 mg, 0.119 mmol), Fe powder (70 mg) and glacial acetic acid (2 mL) was heated at 100 ° C for 1.5 hours. The mixture was cooled to room temperature and diluted with H2O and EtOAc, and the pH adjusted to 7-8 with Na2CO3. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, dried (MgSO), and concentrated to give the title compound (60 mg) as a yellow oil: MS (EA) m / e 491.3 (M + H) +. c) Acid (±) -10,11-dithy-3-r3-r4- (ethyltio) pyridin-2-ylammonol-1-propyloxy-1-5H-dibenzofa, d1-cycloheptene-10- The title compound was prepared as a yellow oil according to the procedure of Example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridine-2 ilamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dhydro-3- [3- [4- (ethylthio) pyridine-2 -ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: 1 H NMR (400 MHz, DMSO-de) d 7.77-7.76 (d, 1 H), 7.17 - 7.15 ( d, 1 H), 7.13 - 7.12 (d, 2 H), 7.08 - 707 (m, 1 H), 6.96 - 6.94 (d, 1 H), 6.81 - 6.80 (s, 1 H), 6.68 - 6.67 (d. d, 1 H), 6.52 (s, 1 H), 6.35 - 6.33 (d, 2 H), 6.30 (s, 1 H), 4.20 - 4.16 (d, 1 H), 3.99 - 3.96 (t, 2 H) ), 3.89 - 3.85 (d, 1 H), 3.65 - 3.63 (m, 1 H), 3.36 - 3.32 (m, 2 H), 3.22 -3.15 (m, 1 H), 2.96 - 2.90 (m, 2 H) ); 2.85 - 2.78 (m, 1 H), 2.62 - 2.56 (m, 2 H), 1.94 - 1.90 (m, 2 H), 1.26 - 1.22 (t, 3 H); MS (EA) m / e 463.4 (M + H) +.

EXAMPLE 11 Preparation of (±) -10,11-dihydro-2-methyl-3-f3- (pyridin-2-ylamino) -1- propyloxy-1-5H-dibenzofac acid, d1-cycloheptene-10-acetic acid a) (±) -10.11-Dihydro-2-methyl-3-r3-rN- (tert-butoxycarbonyl) -N- (1-oxopyridin-2-yl) amino-1-propyloxy-1-5H -dibenzole, ethylhexyl-10-ethyl acetate-NaH (60% dispersion in mineral oil, 0.14 g, 0.37 mmol) was added to a solution of (±) -10,11-dihydro-3-hydroxy-2- methyl-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (100 mg, 0.32 mmol) in DMSO (2 mL) under argon, and the reaction was stirred at room temperature for 0.5 hour. Then a solution of 2- [N- (3-methanesulfonyl-1-propyl) -N- (fer-butoxycarbonyl) amino] pyridine N-oxide (160 mg, 0.4 mmol) in DMSO was added dropwise. (1 mL). The reaction was stirred at room temperature under argon for 18 hours, then quenched with water (20 mL) and extracted with EtOAc. Drying (MgSO), concentration and chromatography on silica gel (1% MeOH / CH2Cl2) gave the title compound (85 mg, 42%) as a colorless oil: MS (EA) m / e 561.3 (M + H) +. b) (±) -10,11-D yhydro-2-methyl-3-r3- (1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofa, d1-cycloheptene-10-acetate ethyl ether TFA (0.16 g, 1.4 mmol) was added dropwise to a solution of (±) -10,11-dihydro-2-methyl-3- [3- [N- (tert-butoxycarbonyl) -N- (1 -oxopyridin-2-yl) amino] -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (80 mg, 0.14 mmol) in dry CH 2 Cl 2 (3 mL). The reaction was stirred for 5 hours and then concentrated on the rotavap to give the title compound (60 mg, 43%) as a colorless oil: MS (EA) m / e 461.1 (M + H) +. c) (±) -10.11-Dihydro-2-methy1-3-r3- (pyridin-2-ylamino) -1-propyloxy-5H-dibenzophate, d1-cycloheptene-10-ethyl acetate The title compound was obtained as an off-white solid according to the procedure of Example 6 (b), but substituting (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino ) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-2-methyl-3- [3- [1-oxopyridin-2-ylamino ) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: MS (EA) m / e 417.3 (M + H) +. d) Acid (±) -10,11-dithy-2-methyl-3-r3- (pyridin-2-ylamino) -1-propyloxp-5H-dibenzo [a, d1-cycloheptene-10-acetic acid The title compound was obtained as an off-white solid according to the procedure of example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy ] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate with (±) -10,11-dihydro-2-methyl-3- [3- [pyridin-2-ylam No) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: 1 H NMR (400 MHz, CDCl 3) d 7.75 (d, 1 H), 7.65 (t, 1 H), 7.15 (m, 3 H), 7.05 (m, 1 H), 6.83 (s, 1 H), 6.7 (d, 1 H), 6.65 (m, 1 H), 6.60 (s, 1 H), 4.25 ( d, J = 15.1 Hz, 1 H), 4.05 (t, 2 H), 3.80 (m, 1 H), 3.75 (d, J = 15.1 Hz, 1 H), 3.50 (t, 2 H), 3.25 ( dd, 1 H), 2.85 (dd, 1 H), 2.68 (dd, 1 H), 2.60 (dd, 1 H), 2.15 (t, 2 H), 2.10 (s, 3 H); MS (EA) m / e 417.2 (M + H) +.

EXAMPLE 12 Preparation of (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-3- (pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofac acid, dl-cycloheptene-10- acetic a) (±) -10.11-Dihydro-2- (dimethylamine) methyl-7-fluoro-3-f3- (1-oxopyridin-2-yl) amino-1-propyloxp-5H-dibenzo [a, ethyl dichloromethane-10-acetate The title compound was obtained after chromatography on silica gel (gradient: 1: 1 EtOAc / hexanes, then EtOAc, then 20% MeOH / CH2Cl2, then 30% MeOH / CH2Cl2) according to the procedure of example 6 (a), but substituting (R) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate with (± ) -10,11 -dihydro-2- (dimethylamino) methyl-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: MS (EA) m / e 522.3 (M + H) +. b) (±) -10,11-D¡h¡dro-2- (dimethylamine) methyl-7-fluoro-3-f3- (pyridin-2-ylamino) -1 -prop Lox1-5H-dibenzo [a, d1cycloheptene-10-ethyl acetate] The title compound was obtained after chromatography on silica gel (10% MeOH / CH2Cl2) according to the procedure of Example 6 (b) , but substituting (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-Dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] ] cyclohepten-10-ethyl acetate: MS (EA) m / e 506.2 (M + H) +. c) Acid (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-f3- (pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzole , d1cyclohepten-10-acetic acid Saponification was carried out according to the procedure of example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino ) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 506.2 (M + H) +. The reaction was made acidic with glacial HOAc, and the crude product was desalted by chromatography on XAD-2 resin to give the title compound as a white solid: MS (EA) m / e 478.3 (M + H) +. Anal. cale, for C3oH36FN3O5. 1.25 H2O: C, 64.32; H, 6.92; N, 7.50. Found: C, 63.87; H, 6.47; N, 7.96.

EXAMPLE 13 Preparation of acid S) -10.11-dihydro-3-r3- (4-methylpyridin-2-ylamino) -1- propyloxy-1-5H-dibenzole, d1-cycloheptene-10-acetic acid a) (S) -10,11 -Dihydro-3-r3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzophate, dichlorhexyl-10-acetate ethyl A solution of 2 - [(3-hydroxy-1-propyl) amino] -4-methylpyridine N-oxide (1.72 g, 9.45 mmol) and diethyl azodicarboxylate (1.49 mL, 9.45 mmol) in anhydrous DMF (50 mL ) was added dropwise over 10 minutes to a solution of (S) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate (1.4 g, 4.72 mmol) and triphenylphosphine (2.60 g, 9.92 mmol) in anhydrous DMF (50 mL) at room temperature under argon. After 19 hours, the reaction was concentrated on the rotavap and the residue reconcentrated from xylenes to remove the residual DMF. Chromatography on silica gel (gradient: 30% EtOAc / hexanes (0.5 L), then EtOAc (1 L), then 5% MeOH / CHCL3) gave the title compound (1.31 g, 60%) as a yellow oil: MS (EA) m / e 461.3 (M + H) +. b) (S) -10,11-Dihydro-3-r3- (4-methyl-pyridin-2-ylamino) -1-propyloxy-5H-dibenzo [a, d-cycloheptene-10-ethyl acetate A mixture of ( S) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] c -cloheptene-10-ethyl acetate (0.86 g, 1.87 mmol), 10% Pd / C (0.86 g, 0.81 mmol), cyclohexene (1.89 mL, 18.7 mmol) and isopropanol (20 mL) was heated to reflux under argon for 19 hours and then the catalyst was removed by filtration through Celite®. Chromatography on silica gel (1: 9: 10 MeOH / CH2CL2 / EtOAc) gave the title compound (0.65 g, 78%) as a clear oil: MS (EA) m / e 445.2 (M + H) +. c) Acid (S) -10,11-d, hr-3-r3- (4-methy1pyridin-2-ylamino) -1-propyloxy-5H-dibenzo, d-cycloheptene-10-acetic mixture of (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (2.08 g , 4.69 mmoles) and 1.0 N NaOH (7.0 mL, 7.0 mmoles) in absolute EtOH (45 mL) was heated in an oil bath set at 45 ° C. After 18 hours the reaction was concentrated on the rotavap and the pH was adjusted to 7 with 1.0 N HCl. The solid precipitate was collected and washed with H2O. Drying overnight afforded the title compound (1.62 g, 82%) as an almost colorless solid: MS (EA) m / e 417.4 (M + H) +. Anal. cale, for C26H28N2O3. 1.0 H2O: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.63; H, 6.96; N, 6.30.

EXAMPLE 14 Preparation of (S) -10,11-dihydro-3-r3-r4- (2-propyloxy) pyridin-2-ylaminol-1-propyloxy-1-5H-d-benzo [a, dichlocloheptene-] 10-acetic a) (S) -10,11-D yhydro-3-f3-r4-2-propyloxy) -1-oxopyridin-2-ylamino-1-propyloxy-1-5H-dibenzole, d1cycloheptene-10-isopropyl acetate A mixture of (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d) cyclohepten-10-ethyl acetate (0.2 g, 0.4 mmol) and sodium isopropoxide (0.067 g, 0.8 mmol) in isopropanol (5 mL) was heated at 80 ° C for 3.5 hours, then more sodium isopropoxide was added (0.05 g, 0.6 mmol) and the reaction was stirred at room temperature overnight. Concentration and chromatography on silica gel (gradient: 5% -15% MeOH / CH 2 Cl 2) gave the title compound (0.106 g, 52%) as a light brown oil: MS (EA) m / e 519.3 (M + H) +. b) (S) -10.11-D1H-dr-3-f3-r4- (2-propyloxy) pyridin-2-ylaminol-1-propyloxy-1-5H-dibenzophate, dichlorheptene-10-isopropyl acetate obtained the title compound as a slightly yellow oil after chromatography on silica gel (5% MeOH / CH 2 Cl 2) according to the procedure of example 13 (b), but substituting (S) -10,11 -dihydro- 3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11- dihydro-3- [3- [4- (2-propyloxy) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-isopropyl acetate: MS (EA) m / e 503.4 (M + H) +. c) (S) -10,11-Dihydro-3-f3-r4- (2-propyloxy) pyridin-2-ylamino-1-propyloxy-5-H-d-benzo [a, d-cycloheptene- 10-acetic The title compound was obtained as a white powder according to the procedure of example 13 (c), but substituting (S) -10,11-dihydro-3- [3- (4-methylpyridin- 2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11-dihydro-3- [3- [4- (2-propyloxy ) pyridin-2-alamide] -1-propyloxy] -5H-dibenzo [a, d] c -cloheptene-10-isopropyl acetate: MS (EA) m / e 461.3 (M + H) + . Anal. cale, for C28H32N2O4. 0.96 HCl: C, 67.86; H, 6.70; N, 5.65. Found: C, 68.26; H, 6.86; N, 5.25.

EXAMPLE 15 Preparation of (S) -10.11-dihydro-3-r3- (4-chloropyridin-2-ylamino-1-1-propyloxy-1-5H-dibenzole, d-cycloheptene-10-acetic acid a) (S) -10,11 -Dihydro-3-r 3 - (4-chloro-1 -oxopyridin-2-ylammon) -1-propyloxp-5H-dibenzofa, d1-cycloheptene-10- ethyl acetate A solution of (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-ethyl acetate (0.47 g, 0.96 mmol) in acetyl chloride (7 mL, 98 mmol) was heated to reflux for 1 hour. The reaction mixture was poured onto ice (50 g), and the pH was adjusted to 8.0 using saturated NaHCO3 (caution: bubbles violently!). The mixture was extracted with CH2Cl2 (2 x 100 mL) and the combined organic layers were washed sequentially with H2O (50 mL) and brine (50 mL). Drying (MgSO) and concentration gave the title compound: MS (EA) m / e 481.2 (M + H) +. b) (S) -10,11-Dihydro-3-r3- (4-chloropyridin-2-ylamine) -1-propyloxy-5H-dibenzo [a, d-cycloheptene-10 ethyl acetate A mixture of (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] ] cyclohepten-10-ethyl acetate (0.13 g, 0.27 mmol) and 2.0 M PCI3 in CH2Cl2 (8 mL, 16 mmol) was heated to reflux for 22 hours. The reaction mixture was cooled and poured onto ice (200 g), and the pH was adjusted to 12 using 40% NaOH. Extraction with CH 2 Cl 2 (2 x 100 mL), drying (MgSO 4), concentration and chromatography on silica gel (4% MeOH / CH 2 Cl 2) gave the title compound (93 mg, 74%) as a light yellow oil. : MS (EA) m / e 465.3 (M + H) +. c) (S) -10,11-d-Hydro-3-r3- (4-chloropyridin-2-amylamino) -1-propyloxy-5-H-dibenzofa, d1-cycloheptene-10- The title compound was obtained as an off-white powder according to the procedure of Example 13 (c), but substituting (S) -10,11-dihydro-3- [3- (4-methylpyridine- 2-ylammon) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11-dihydro-3- [3- [4- chloropyridin-2- ilamino] -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 437.2 (M + H) +. Anal. cale, for C25H25N2O3. 1.0 HCl: C, 63.43; H, 5.54; N, 5.92. Found: C, 63.11; H, 5.82; N, 5.62.

EXAMPLE 16 Preparation of (S) -10,11-dihydro-3-y3-y4- (dimethylamino) pyridin-2-ylaminol-1-propyloxp-5H-dibenzop.dl-cycloheptene-10-acetic acid a) (S) -10.11-Hydro-3-f3- (4-chloro-1-oxopyridin-2-ylammon) -1-propyloxy-1-5H-dibenzo [a, d1cycloheptene-10-ethyl acetate A solution of (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.47 g, 0.96 mmol) in acetyl chloride (7 mL, 98 mmol) was heated to reflux for 1 hour. The reaction mixture was poured onto ice (50 g) and the pH was adjusted to 8.0 using saturated NaHC 3 (caution: violently bubbled!). The mixture was extracted with CH2Cl2 (2 x 100 mL) and the combined organic layers were washed sequentially with H2O (50 mL) and brine (50 mL). Drying (MgSO4) and concentration gave the crude title compound which was used subsequently without further purification: MS (EA) m / e 481.3 (M + H) +. b) (S) -10,11 -Dihydro-3-r3- (4-chloro-1-oxopyridin-2-ylaminol-l-propyloxp-5H-dibenzora, dl-cycloheptene-10-ethyl acetate A mixture of (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (0.96 mmol) and 2.0 M dimethylamine in MeOH (3 mL, 6 mmol) was refluxed for 16 hours.The concentration and chromatography on silica gel (7% MeOH / CH2Cl2) gave the title compound (0.049 mg, 10%) as a light brown powder: MS (EA) m / e 465.3 (M + H) + Also recovered from the chromatographic purification (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin -2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate unchanged. c) (S) -10.11-Dihydro-3-y3-r4- (dimethylamino) pyridin-2-ylamino) -1-propyloxy-5H-dibenzora, d1-cycloheptene-10-ethyl acetate obtained the title compound as a white powder after chromatography on silica gel (8% MeOH / CH 2 Cl 2) according to the procedure of example 13 (b), but substituting (S) -10,11-dihydro-3 - [3- (4-Methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11-dihydro-3 - [3- [4- (dimethylamino) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: MS (EA) m / e 474.3 (M + H) +. d) (S) -10,11-Dihydro-3-f3-f4- (dimethylamino) pyridin-2-ylamino) -1-propyloxy-5H-d-benzoate, dl-cycloheptene-10-acetic acid The title compound was obtained as a white powder according to the procedure of Example 13 (c), but substituting (S) -10,11-dihydro-3- [3- (4-methyl-pyridin-2-ylamino ) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (S) -10,11-dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino ) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 446.2 (M + H) +. Anal. cale, for C27H3iN3? 3. 0.5 H2O, 1.0 HCl: C, 66.04; H, 6.77; N, 8.56. Found: C, 65.96; H, 6.60; N, 8.26.

EXAMPLE 17 Preparation of (S) -10.11-dihydro-3-r3- (4-ethoxypyridin-2-ylamino-1-propyloxy-5H-dibenzop, d-cycloheptene-10-acetic acid a) (S) -10,11 -Dihydro-3-r3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofa, dichloroheptene-10-ethyl acetate The title compound (456.2 mg, 92%) was prepared according to the procedure of Example 2 (a), but substituting (±) -10,11-dihydro-3- [3- (4-nitro-1- oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate with (S) -10,11-dihydro-3- [3- (4-nitride- 1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (496.9 mg, 1.01 mmol) and using 0.53 M NaOEt (4.0 mL, 2.12 mmol) and ethanol absolute (10 mL) in the displacement reaction: MS (EA) m / e 491 (M + H) +. b) (S) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzole, d-cycloheptene-10-ethyl acetate. the title compound (475.2 mg, quantitative) according to the procedure of example 2 (b), but substituting (±) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2 -ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-ethyl acetate with (S) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2 -lamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (456.2 mg, 0.93 mmole): MS (EA) m / e 491 (M + H) +. c) Acid (S) -10,11-dithy-3-r3- (4-ethoxypyridin-2-ylamino) -1-propyloxy-5H-dibenzole, dichloheptene-10-acetic acid 1.0 N NaOH (2.0 mL, 2.0 mmol) to a solution of (S) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (475.2 mg, 1.0 mmol) in absolute ethanol (10 mL), and the solution was heated to 50 ° C in an oil bath. After 20 hours the reaction was concentrated and the aqueous residue was cooled to 0 ° C in an ice bath. 1.0 N aqueous HCl (2.0 mL, 2.0 mmol) was added slowly and with stirring. An opaque solid residue was precipitated and collected in a sintered glass funnel. Drying in a vacuum desiccator overnight gave the title compound (452.6 mg, 83%): MS (EA) m / e 447 (M + H) +. Anal. cale, for C27H30N2O4. 0.20 H2O, 1.75 HCl: C, 63.10; H, 6.30; N, 5.45. Found: C, 63.10; H, 5.98; N, 5.38.

EXAMPLE 18 Preparation of (±) -10,11-dihydro-7-fluoro-3-r3- (pyridin-2-ylamino) -1- propyloxy-1-5H-dibenzole, dichlocycloheptene-10-acetic acid a) (±) -10,11 -Dihydro-7-fluoro-3-f3- (1-oxopyridin-2-ylamino) -1-propyloxfl-5H-dibenzole "a, d1c¡cloheptene-10-acetate ethyl acetate The title compound was obtained as a colorless oil after chromatography on silica gel (gradient: 1: 1 EtOAc / hexanes, then EtOAc, then 4% MeOH / CH2Cl2) according to the procedure of Example 6 (a ), but substituting (R) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptane-10-ethyl acetate with (±) -10,11-dihydro-7-fluoro-3 -hydroxy-5H-dibenzo [a, d] cycloheptene-10-ethyl acetate: MS (EA) m / e 465.3 (M + H) +. b) (±) -10,11-D yhydro-7-fluoro-3-f3- (pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofa, d1-cycloheptene-10-ethyl acetate The compound of the title according to the procedure of example 6 (b), but substituting (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H- dibenzo [a, d] cycloheptane-10-ethyl acetate with (±) -10,11-dihydro-7-fluoro-3- [3- (1-oxopyridin-2-ylammon) -1-prop Loxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 449.2 (M + H) +. c) Acid (±) -10,11-dihydro-7-fluoro-3-r3- (pyridin-2-amylamino) -1-propyloxp-5H-dibenzo [a, d1cycloheptene- 10-acetic The title compound was obtained according to the procedure of Example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1- propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-7-fluoro-3- [3- (pyridin-2-ylamino) -propyloxy] -5H-dibenzo [a, d] cycloheptane-10-ethyl acetate: MS (EA) m / e 421.1 (M + H) +. Anal. cale, for C25H25FN2O3 0.5 H2O: C, 69.99; H, 6.10; N, 6.52. Found: C, 69.86; H, 5.90; N, 6.35.

EXAMPLE 19 Preparation of (±) -10.11-dihydro-6-methyl-3-f3- (pyridin-2-ylamino) -1-propyloxp-5H-dibenzora, d1-cycloheptene-10-acetic acid a) (±) -10,11 -Dihydro-6-methyl-3-r 3 - (1 -oxopyridin-2-ylamino) -1-propyloxy-1-5H-d-benzof, d-cycloheptene-10 ethyl acetate The title compound was obtained as a colorless oil after chromatography on silica gel (gradient: 1: 1 EtOAc / hexanes, then EtOAc, then 4% MeOH / CH 2 Cl 2) according to the procedure of Example 6 (a), but substituting (R) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptane-10-ethyl acetate with (±) -10,11-dihydro-6-methyl -3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 461.3 (M + H) +. b) (±) -10,11-D-Hydro-6-methyl-3-f3- (pyridin-2-ylamino) -1-propyloxy-5H-dibenzo [a, d] Ethyl cyclohepten-10-acetate The title compound was obtained after chromatography on silica gel (1% MeOH / CH 2 Cl 2) according to the procedure of Example 6 (b), but substituting the (R) -10 , 11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro -6-methyl-3- [3- (1-oxopyridin-2-ylammon) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 445.3 (M + H) +. c) Acid (±) -10,11-dihydro-6-methyl-3-r3- (pyridin-2-ylamino) -1-propyloxy-1-5H-dibenzora, d1-cycloheptene-10-acetic obtained the title compound as a white solid according to the procedure of Example 6 (c), but substituting (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1 -propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate with (±) -10,11-dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -propyloxy ] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate: MS (EA) m / e 417.3 (M + H) +. Anal. cale, for C26H28N2O3. 1.25 H2O: C, 71.13; H, 7.02; N, 6.38. Found: C, 71.33; H, 6.67; N, 6.01.

EXAMPLE 20 Preparation of (S) -10.11-dihydro-3-r3- (4-aminopyridin-2-ylamino) -1- propyloxy-1-5H-dibenzop.d1-cycloheptene-10-acetic acid a) (S) -10,11-Dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzo [a, d-cycloheptene-10-ethyl acetate] A solution of diisopropyl azodicarboxylate (1.7 mL, 8 mmol) in THF (10 mL) was added dropwise to a solution of (S) -10., 11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (426.5 mg, 1.5 mmol), 2 - [(3-hydroxy-1-propyl) N-oxide] amino] -4-nitropyridine (1.7 g, 8 mmol) and triphenylphosphine (2.5 g, 8 mmol) in anhydrous DMF (20 mL) at 0 ° C under argon. The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 23 hours the reaction was concentrated. Chromatography on silica gel (gradient: 30% -100% EtOAc / hexanes) gave the title compound (2.7 g, 81%) as an orange foam: MS (EA) m / e 491.8 (M + H) +. b) (S) -10,11-Dihydro-3-r3- (4-aminopyridin-2-ylammon) -1-propyloxy-1-5H-dibenzo [a, d-cycloheptene-10- ethyl acetate A mixture of (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-ethyl acetate (2.7 g, 6 mmol), cyclohexene (6 mL, 60 mmol), 10% Pd / C (1.2 g, 1.10 mmol) and isopropanol (30 mL) was heated to reflux under argon for 20.5 hours and then it was filtered hot through Celite®. The filter pad was washed with hot EtOAc and the combined filtrate materials were concentrated. The residue was chromatographed on silica gel (5% MeOH / CHCl) to give the title compound (2.4 g, 98%) as a colorless foam: MS (EA) m / e 445.9 (M + H) +. c) (S) -10,11-D-Hydro-3-f3- (4-aminopyridin-2-ylamino) -1-propyloxy-1-5H-dibenzofa, dl-cycloheptene-10-acetic acid A mixture of (S) -10,11-dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-ethyl acetate (2.4 g, 5 mmol ), LiOH • H 2 O (0.3 g, 7 mmol), THF (30 mL) and H 2 O (10 mL) was stirred at room temperature for 48 hours and then concentrated. The residue was diluted with H2O and extracted with Et2O. The Et2O layers were discarded. The aqueous layer was stirred with gentle heating under vacuum to remove residual organic solvents and then filtered. The resulting aqueous solution was stirred at room temperature while the pH was slowly and carefully adjusted to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for 0.5 hours, then the solid was collected by suction filtration and washed with a lot of H2O. Drying in high vacuum at 60 ° C gave the title compound (1.0 g, 42%) as a glassy solid: MS (EA) m / e 417.7 (M + H) +. Anal. cale, for C25H27N3O3. 1.4 HCl (468.554): C, 64.08; H, 6.11; N, 8.97. Found: C, 64.16; H, 6.20; N, 8.71.

EXAMPLE 21 Preparation of (±) -10,11-dihydro-3-r3- (4-methylpyridin-2-ylamino) -1- propyloxyldibenzorb.floxepin-10-acetic acid a) (±) -10,11 -Dihydro-3-r 3 - (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy-1-dibenzo [b, f 1 oxepin-10-ethyl acetate A mixture of (± ) -10,11-dihydro-3-hydroxydibenzo [b, f] oxepin-10-ethyl acetate (257 mg, 0.86 mmol), 2 - [(3-bromo-1-propyl) amino N-oxide hydrobromide] ] -4-Methylpyridine (308 mg, 0.94 mmol) NaOH pellets (110 mg, 2.75 mmol) and CH3CN (4 mL) was stirred at room temperature under argon overnight. The mixture was filtered and the solids were washed with CH3CN. The filtrate was concentrated and the residue was chromatographed by evaporation on silica gel (1 - 2.5% CH 3 OH / CH 2 Cl 2) to give the title compound (190 mg, 48%) as a white foam: MS (SE) m / e 462.6 (M + H) +. b) (±) -10,11-Dh-3-r3- (4-methylpyridin-2-ylamino) -1-propyloxy-dibenzo [b, f-oxepin-10-ethyl acetate A mixture of (±) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepin-10- ethyl acetate (183 mg, 0.4 mmol), 10% Pd / C (85 mg, 0.08 mmol), cyclohexene (810 mg, 8 mmol) and Sodium propane (4 mL) was heated to reflux overnight. The catalyst was removed by filtration through celite® and the filter cake was washed with ether. The filtrate was concentrated to give the title compound (122 mg, 68%) as a clear oil: MS (SE) m / e 446.9 (M + H) +. c) Acid (±) -10,11 -dihydro-3-f3- (4-methylpyridin-2-amyl) -1-propyloxy-dibenzofb, f1oxepin-10- acetic A mixture of (±) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepin-10-ethyl acetate ( 119 mg, 0.27 mmole) and 0.991 N NaOH (0.545 mL, 0.54 mmole) in absolute EtOH (2 mL) was heated in an oil bath set at 45 ° C. After 20 hours the reaction was concentrated on the rotavap, and the residue was dissolved in H2O (1.5 mL). The solution was filtered to remove insoluble materials, and the filtrate was carefully neutralized by the dropwise addition of 1.0 N HCl (0.54 mL, 0.54 mmole). The precipitate was collected and dried under high vacuum to give the title compound (68 mg, 58%) as a white solid: MS (SE) m / e 418.9 (M + H) +. Anal. cale, for C25H26N2O4. 0.45 HCl: C, 69.05; H, 6.13; N, 6.44. Found: C, 69.25; H, 6.27; N, 6.16.

EXAMPLE 22 Preparation of (±) -10.11-dihydro-3-r2-r- (methylamino) pyridin-2-yl-1-ethoxy-1-dibenzorb acid, floxepin-10-acetic acid a) (±) -10.11-D1h¡dro-3-r2-r6rN-.er-butoxycarbonyl) -N-methylamino-1-pyridin-2-yl-1-ethoxyfld-benzo [b, f1oxepi n-10-ethyl acetate A solution of 6- [N- (fer-butoxycarbonyl) -N-methylamino] -2-pyridylethanol (397 mg, 1.58 mmole) and diisopropyl azodicarboxylate (0.31 mL, 1.58 mmole) in anhydrous CH2CI2 (8 mL) was added dropwise over 10 minutes to a solution of (±) -10,11-dihydro-3-hydroxydibenzo [b, f] oxepin-10-ethyl acetate (186 mg, 0.63 mmol) and triphenylphosphine ( 413 mg, 1.58 mmol) in anhydrous CH 2 Cl 2 (3.2 mL) at room temperature under argon. After 22 hours the reaction was concentrated on the rotavap and the residue was chromatographed by steaming on silica gel (2-13% EtOAc / hexanes) to give the title compound (146 mg, 44%) as a clear oil: MS (EA) m / e 533.0 (M + H) +. b) Acid (±) -10.11-dihydro-3-r2-r6- (methalamine) pyridin-2-yl-1-ethoxy-pd-benzo [b, f] oxepin-10 -acetic 4 N HCl in dioxane (1.3 mL, 5.2 mmol) was added dropwise to a solution of (±) -10,11-dihydro-3- [2- [6- [N-fer-butoxycarbonyl] -N- methylamino] pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepin-10-ethyl acetate (140 mg, 0.26 mmol) in CH2Cl2 (1.3 mL). After 12 hours the mixture was concentrated and the residue was triturated with ether to give the title compound as a white solid: MS (EA) m / e 432.9 (M + H) +. c) Acid (±) -10,11-dhydro-3-r2-r6- (methalamine) pyridin-2-n-1-ethoxy-1-dibenzo [b, f-oxepin-10-ace] A mixture of (±) -10,11-dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepin-10-acetic acid ( 0.26 mmole) and 0.991 N NaOH (0.525 mL, 0.52 mmole) in absolute EtOH (2 mL) was heated in an oil bath set at 50 ° C. After 20 hours the reaction was concentrated on the rotavap and the residue was dissolved in H2O (1.5 mL). The solution was filtered to remove insoluble materials and the filtrate was carefully neutralized by the dropwise addition of 1.0 N HCl. The precipitate was collected and dried under high vacuum to give the title compound (72 mg, 30% for two steps ) as a whitish solid: MS (EA) m / e 405.0 (M + H) +. Anal. cale, for C24H24N2O4. 1.25 HCl. 0.25 H2O: C, 63.42; H, 5.71; N, 6.16. Found: C, 63.35; H, 5.9; N, 6.16.

EXAMPLE 23 Preparation of (S) -10,11-dihydro-3-r3- (2-aminopyridin-4-yl) -1- propyloxl-SH-dibenzora.dlcic-Iheheptene-IO-acetic acid a) 3- (2-Aminopyridin-4-yl) propan-1-ol A suspension of 3- (2-aminopyridin-4-yl) propanoic acid hydrochloride (0.73 g, 3.60 mmol, prepared from According to WO 94/14776 in THF (10 mL), lithium aluminum hydride (12 mL, 12 mmol, 1 M in THF) was added at 0 [deg.] C. for 45 minutes, the ice bath was stirred and the reaction was left stirring at room temperature for 4.5 hours The reaction was cooled to 0 ° C, diluted with toluene (22 mL) and quenched by the sequential addition of H 2 O (0.86 mL) and NaF (1.54 g) .The resulting suspension was stirred at 0 ° C for 45 minutes The reaction mixture was filtered and the precipitate was washed with 10% MeOH in additional CHCl 3 The combined filtrates were concentrated under reduced pressure, the chromatography by evaporation (10% MeOH / CHC, silica) gave 0.25 g of the desired material as a clear oil: MS (EA) m / e 152.7 (M + H) +. b) (S) -10,11-Dihydro-3-r3- (2-aminopyridin-4-yl) -1-propylloxy-5H-d- benzo | "a, d1c cloheptene-10-ethyl acetate A solution of the compound of Example 1 (a) (0.23 g, 1.51 mmol) and diisopropyl azadicarboxylate (0.29 mL, 1.50 mmol) in CH2Cl2 (7.5 mL) was added dropwise to a solution of triphenylphosphine (0.39 g, 1.50 mmol) and ethyl 2 - [(10S) -3-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-yl] acetate (0.30 g, 1.00 mmol) in CH 2 Cl 2 (5 mL) at 0 ° C. The ice bath was stirred and the reaction was allowed to warm to room temperature After 18 hours the solvent was removed under reduced pressure.Vitaminization chromatography (50% EtOAc / hexanes a 100% EtOAc, silica gel) gave 0.32 g of material containing the desired product.A second purification by flash chromatography (75% to 90% EtOAc / hexanes, silica gel) gave 0.23 of the desired material: MS (EA) m / e 430.9 (M + H) +. c) Acid (S) -10,11-dithy-3-r3- (2-aminopyridin-4-iD-1-propyloxy-5H-dibenzo [a, dichloheptene-10- acetic The compound of example 1 (b) (0.22 g, 0.50 mmol) was dissolved in 1 N NaOH (0.77 mL, 0.77 mmol), EtOH (3 mL) and THF (3 mL), after heating the reaction to 50 °. C for 18 hours the solvent was removed under reduced pressure, the residue was dissolved in H2O (4 mL) and filtered.The filtrate was acidified with 30% TFA in H2O and the resulting precipitate was collected.Preparative HPLC (Hamilton PRP -1®, 3% CH3CN / H2O-0.1% TFA) gave 10 mg of the desired material as a hygroscopic solid: MS (EA) m / e 402.6 (M + H) +.

EXAMPLE 24 Composition for parenteral dosage unit A preparation containing 20 mg of the compound of Example 1 is made as a sterile dry powder as follows: 20 mg of the compound are dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions in a 25 mL multiple dose ampule and lyophilized. The powder is reconstituted by the addition of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is then determined by the injection volume. A subsequent dilution can be made by adding a measured volume of this dosage unit to another volume of D5W for injection, or a metered dose can be added to another mechanism for delivering the drug, such as a bottle or bag for drip infusion. intravenous or other injection-infusion system.

EXAMPLE 25 Composition for oral dose unit A capsule is prepared for oral administration by mixing and grinding 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.

EXAMPLE 26 Composition for oral dose unit A tablet is prepared for oral administration by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of example 1 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg of starch, 5 mg of talc and 3 mg of stearic acid and compressed to form a tablet. The above description completely details how to make and use the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof which are within the scope of the following claims. The various references to bulletins, patents and other publications cited herein comprise the state of the art and are incorporated herein by reference as if they were fully described.

Claims (27)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound according to formula (I):

wherein: A is CH2 or O; R1 is H, halogen or C? -6 alkyl; R2 is H, C1-6 alkyl or CH2NR "R"; X is O or CH2; And it is

G is NR ", S or O; R 'is μ, C? -6 alkyl, OC-C1-6 alkyl, SC-alkyl of d6, NR" R "or halogen; each R" is independently μ or Ci-β alkyl; and s is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein Y is

wherein R 'is μ, C? -4 -4 alkyl, OC OC alquiloC C1-4 alquilo alkyl, SC-alquiloC alquilo - alkyl, NR "R" or Cl and each R "is independently H or C alquilo? alquilo alkyl.

4. A compound according to claim 1, wherein Y is

wherein each R "is H or C? -4 alkyl. 4. A compound according to claim 1, wherein Y is

wherein each R "is independently H or C? - alkyl, and s is 1.

5. A compound according to claim 1, wherein Y is where G is S and each R" is independently μ or alkyl of C -? - 4.

6. A compound according to claim 1, wherein Y is

wherein R "is μ or C alquilo-alkyl.

7. A compound according to claim 1, which is: (±) -10,11-dihydro-3- [2- (6-aminopyridin- 2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid (±) -10,11-dihydro-3- [4- (pyridin-2-ylamino) -1 -butyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid (±) -10,11-dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1 - propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid (S) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [ a, d] cycloheptene-10-acetic acid (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] c-chlorheptene -10-acetic acid (±) -10,11-dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid (±) -10,11-dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5H-dibenzo [a, d] cycloheptene- 10-acetic acid (±) -10,11-dihydro-3- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid (± ) -10,11- dihydro-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5μ-dibenzo [a, d] cycloheptene-10-acetic; (S) -10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5μ-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-ethoxypyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- acid 10-acetic; (S) -10,11-Dihydro-3- [3- [4- (2-propyloxy) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] c-chlorheptene-10- acid acetic; (S) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-dihydro-3- [3- [4- (ethylthio) pyridin-2-ylammon] -1-propyloxy] -5H-dibenzo [a, d] cyclohepten-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) 10,11-dihydro-2-methyl-3- [3-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (S) -10,11-Dihydro-3- [3- (4-amino-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; (±) 10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -dibenzo [a, f] oxephino-10-acetic acid; (±) 10,11-dihydro-3- [3- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -dibenzo [a, f] oxefino-10-acetic acid acid (S) -10,11-dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic; or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a compound according to claim 1, an antineoplastic agent and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to claim 9, further characterized in that the antineoplastic agent is topotecan.

11. A pharmaceutical composition according to claim 9, further characterized in that the antineoplastic agent is cisplatin.

12. A compound according to formula (II):

wherein: A is CH2 or O; R1 is H, halogen or C-i-β alkyl; R2 is H, C? -6 alkyl or CH2NR "R"; X is O or CH2; Y is G is NR ", S or O; R 'is H, C? -6 alkyl, OC-C? -6 alkyl, SC-alkyl of d.6, NR" R "or halogen; is independently H or Ci-β alkyl; and s is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

13. A compound according to formula (III):

wherein: A is CH2 or O; R1 is H, halogen or C-i-β alkyl; R2 is H, C? -6 alkyl or CH2NR "R"; X is O or CH2; R 'is H, C1-6 alkyl, OC-C1-6 alkyl) SC-C-? -6 alkyl, NR "R" or halogen and each R "is independently H or C-? -6 alkyl or a pharmaceutically acceptable salt thereof.

14. - A process for preparing a compound of the formula (I) as defined in claim 1, which comprises reacting a compound of the formula (IV) with a compound of the formula (V):

wherein R1, R2, Y and A are as defined in formula (I), with any protected reactive functional group, and L1 is OH or halogen; and subsequently removing any protecting group and optionally forming a pharmaceutically acceptable salt.

15. A process for preparing a compound of the formula (I) as defined in claim 1, which comprises reacting a compound of the formula (IV) with a compound of the formula (VI):

wherein R1, R2, R ', R "and A are as defined in formula (I), with any protected reactive functional group, and subsequently removing any protecting group and optionally forming a pharmaceutically acceptable salt.

16. - A process for preparing a compound of the formula (I) as defined in claim 1, which comprises reacting a compound of the formula (IV) with a compound of the formula (VII):

wherein R1, R2, R "and A are as defined in formula (I), with any protected reactive functional group, and subsequently removing any protecting group and optionally forming a pharmaceutically acceptable salt. of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of diseases in which antagonism of the av.sub.3 receptor is indicated

18. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of diseases in which antagonism of the av5 receptor is indicated

19. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of osteoporosis.

20. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the inhibition of angiogenesis.

21. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the inhibition of tumor growth or tumor metastasis.

22. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of atherosclerosis or resenosis.

23. The use of a compound of the formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of inflammation.

24. The use of a compound of the formula (I) as claimed in claim 1 and of an antineoplastic agent, in the manufacture of a medicament for the inhibition of tumor growth in physical combination or for administration by steps .

25. The use as claimed in claim 24, wherein the antineoplastic agent is topotecan.

26. The use as claimed in claim 24, wherein the antineoplastic agent is cisplatin.

27. The use of a compound of the formula (I) as claimed in claim 1 and of a bone resorption inhibitor, in the manufacture of a medicament for the treatment of osteoporosis in physical combination or for administration by steps.