SK4082000A3 - COMPOUND CONTAINING DIBENZOCYCLOHEPTENE NUCLEUS, PROCESS FOR THEì (54) PRODUCTION THEREOF, PHARMACEUTICAL COMPOSITION CONTA - 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; R<1> is H, halo or C1-6alkyl; R<2> 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

Compound containing a dibenzocycloheptene core, process for its preparation, pharmaceutical compositions containing it, its use and intermediates

Technical field

The invention relates to pharmaceutical active substances that inhibit the vitronectin receptor and 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 family of cellular adhesion receptors by which transmembrane glycoproteins are expressed by various cells. These cell surface adhesion receptors include gpIIb / IIIa (fibrinogen receptor) and α _ν β ₃ (vitronectin receptor). The fibrinogen receptor gpIIb / IIIa is expressed on the platelet surface and mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding injury. Philips et al., Blood, 1988, 71, 831. Vitaminectin receptor α _ν β ₃ is expressed by many cells, including endothelial, smooth muscle, osteoclasts and tumor cells, and thus has different effects. The α _ν β ₃ receptor expressed by the osteoclast cell membrane mediates the adhesion of osteoclasts to the bone matrix, a key step in the bone resorption process. Ross et al., J. Biol. Chem., 1987, 262, 7703. The disease characterized by excessive bone resorption is osteoporosis. The α _ν β ₃ receptor expressed by human aortic smooth muscle cells mediates their migration to the neointima, a process that can lead to restenosis following percutaneous coronary angioplasty. Brown et al., Cardiovascular Res., 1994, 28, 1815. In addition, Brooks et al., Cell, 1994, 79, 1157 found that α _ν β ₃ antagonists are capable of promoting tumor regression by inducing apoptosis of angiogenic blood vessels. Thus, agents that block the vitronectin receptor would be useful for

- Treatment of diseases such as osteoporosis, restenosis and cancer.

The vitronectin receptor is now known to correspond to three different integrins, termed οςβ. α _ν β ₃ and α _ν β ₅ . Horton et al., Int. J. Exp. Pathol., 1990, 71, 741. α _ν β, binds fibronectin and vitronectin. α _ν β ₃ binds a large number of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand factor, osteopontin and bone sialoprotein I. α β ₅ binds vitronectin. The vitronectin α _ν β ₅ receptor has been shown to be involved in the cellular adhesion of various cell types, including microvascular endothelial cells (Davis et al., J. Cell. Biol., 1993, 51, 206), and its role in angiogenesis has been confirmed. , Brooks et al., Science, 1994, 264, 569. This integrin is expressed by blood vessels in human injured granulation tissue, but not in normal skin.

The vitronectin receptor is known to bind to bone matrix proteins that contain the three-peptide Arg-Gly-Asp (or RGD) motif. Horton et al., Exp. Cell Res. 1991, 195, 368, therefore, found that RGD-containing peptides and antireceptor vitronect new antibodies (23C6) inhibited dentin resorption and osteoclast spreading of cells. In addition, Sato et al., J. Cell Biol. 1990, 111, 1713 found that echistatin, a snake venom peptide that contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture and inhibits the attachment of osteoclasts to bone.

It has now been found that certain substances are potent inhibitors of α _ν β ₃ and α _ν β ₅ receptors. In particular, they have been found to be a more potent inhibitor of the vitronectin receptor than the fibrinogen receptor.

SUMMARY OF THE INVENTION

The present invention provides compounds having a dibenzocycloheptene core of Formula I

A (D

-3kde

A is _CH2 or O;

R ¹ is H, halogen or C 1-4 alkyl;

R ² is H, C 1-4 alkyl or CH ₂ NR "R ^" ; X is O or CH ₂ ;

Y is or

G is NR, S, or O;

R 'is H, alkyl, O-alkyl, SC _M alkyl, NRR, or halogen;

each R is independently H or C 1-4 alkyl; and s is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof, having pharmacological activity for inhibiting the vitro-nectin receptor and useful for treating inflammation, cancer and cardiovascular disorders such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as osteoporosis.

The invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutical carrier.

The invention also provides the use of compounds of formula I for the treatment of diseases that are mediated by the vitronectin receptor. In a particular case, the compounds of the invention are useful for the treatment of atherosclerosis, restenosis, inflammation, cancer and diseases in which bone resorption is a factor, such as osteoporosis.

The invention includes novel substances that are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor. The novel compounds include a dibenzocycloheptene nucleus in which a nitrogen-containing substituent is present on one of the aromatic six-membered dibenzocycloheptene rings and an aliphatic substituent containing an acid group is present on the seven-membered dibenzocycloheptene ring. It is believed that the dibenzocycloheptene ring system directs the side chain substituents to six and seven membered rings so that they can interact preferentially with the vitronectin receptor. Preferably, there are about twelve to fourteen inserted covalent bonds through the shortest intramolecular pathway between the acid group on the aliphatic substituent of the seven-membered dibenzocycloheptene ring and the nitrogen-containing substituent on one of the aromatic six-membered dibenzocycloheptene rings.

Also included in the invention are pharmaceutically acceptable addition salts and complexes of the compounds of this invention. In cases where the compounds of the invention may have one or more chiral centers, if not specified, the present invention includes each individual non-racemic substance that can be synthesized and resolved into optical isomers by conventional procedures. In cases where substances have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of the invention. In cases where the substances may exist in tautomeric forms such as keto-enol tautomers such as

O OR * and each tautomeric form is considered to be included in this invention, whether it exists in equilibrium or is blocked in one form by the appropriate substitution with R '.

The compounds of formula I inhibit the binding of vitronectin and other RGD-5 containing peptides to the vitronectin receptor. Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone resorption and is useful in the treatment of diseases in which bone resorption is associated with pathology, such as osteoporosis and osteoarthritis.

Further, the invention provides a method for stimulating bone formation, comprising administering a substance that causes an increase in osteocalcin release. Increased bone formation is a clear benefit in disease states in which there is a lack of mineralized bone mass or when bone remodeling is desired, such as treatment of fractures and prevention of bone fractures. Diseases and metabolic disorders that result in bone loss may also benefit from such treatment. For example, the administration of the compounds of the invention may be beneficial in hyperparathyroidism, Paget's disease, malignant hypercalcemia, osteolytic lesions caused by bone metastases, loss of bone due to immobilization or lack of sex hormone, Behcet's disease, osteometry, hyperostosis and osteopathosis.

In addition, since the compounds of the invention inhibit vitronectin receptors on a number of different cell types, they may be useful in the treatment of inflammatory diseases, such as rheumatoid arthritis and psoriasis, and cardiovascular diseases, such as atherosclerosis and restenosis. The compounds of the invention may be useful in the treatment or prevention of other diseases, including, but not limited to, thromboembolic disorders, asthma, allergies, adult respiratory distress syndrome, transplant versus host disease, organ transplant rejection, septic shock, eczema, contact dermatitis, inflammatory bowel disease, and other autoimmune diseases. The compounds of the invention may also be useful in wound healing.

The compounds of the invention are also useful in the treatment, including prevention, of angiogenic disorders. The term angiogenic disorders as used herein includes conditions in which abnormal neovascularization is involved. Where the growth of new blood vessels is the cause or contributes to the pathology associated with the disease, inhibition of angiogenesis will reduce the malignant effects of the disease. An example of such a targeted disease is diabetic retinopathy. Where it is needed

The growth of new blood vessels to promote malignant tissue growth, inhibition of angiogenesis will reduce blood supply to the tissue and thereby contribute to reducing tissue mass based on blood supply requirements. Examples include tumor growth where neovascularization is a continual requirement for tumor growth and for the formation of solid tumor metastases. Thus, the compounds of the invention inhibit tumor tissue angiogenesis, thereby preventing tumor metastasis and tumor growth.

Thus, according to the methods of the invention, inhibition of angiogenesis using the compounds of the invention can ameliorate the symptoms of the disease and in some cases can treat the disease.

Other therapeutic targets for the compounds of the invention are ocular diseases characterized by neovascularization. Such ophthalmic diseases include corneal neovascular diseases such as corneal transplantation, herpes keratitis, luetic keratitis, palatium, and neovascular panus associated with the use of contact lenses. Other ocular diseases also include age-related macular degenerations, presumed ocular histoplasmosis, retinopathy of premature infants, and neovascular glaucoma.

The present invention further provides a method of inhibiting tumor growth, which comprises sequential or physically related administration, a compound of the invention and an antineoplastic agent such as topotecan and cisplatin.

In relation to the general formula I:

Y is preferably .hL -NRR wherein R ¹ is H, C _1-4 alkyl, OC _M alkyl, SC _{first 4} alkyl, NRR, or Cl, each R is independently H or _{first 4} alkyl.

Y is alternatively

R'RN

-7 wherein each R is H or C 1-4 alkyl. Y is alternatively

O _S \ / ^DB wherein each R 'is independently H or a C _M alkyl, and the first

Y is alternatively

wherein G is S and each R is independently H or C _1-4 alkyl. Y is alternatively

wherein R is H or C _1-4 alkyl.

Representative novel compounds of the present invention are: (±) -10,11-dihydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cyclo heptene 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) -5 H -dibenzo [a, d] cycloheptene-10-acetic acid;

-8 (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetic acid;

(±) -10,11-Dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 1 O-acetic acid;

(±) -1,11-Dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5 H -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] -5A-dibenzo [a, d] cycloheptene-10-acetic acid;

(S) -10 11 _l-dihydro-3- [3- (4-methylpyridin-2-ylannino) -1-propyloxy] -5 / - / - dibenzo [a, d] cycloheptene-10-acetic acid;

(S) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-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] -5 H -dibenzo [a, d] cycloheptene 10-acetic acid;

(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] -5,7-dibenzo [a, d] cycloheptene-10-acetic acid;

(S) -10,11-Dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] 5,7-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-chloro-pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetic acid;

(±) -10,11-Dihydro-2-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid;

-9 (S) -10,11-Dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetic acid;

(±) -10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy) dibenzo [b, f] oxepine-10-acetic acid;

(±) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid; and (±) -10,11-Dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid;

or a pharmaceutically acceptable salt thereof.

In cases where the compounds of the invention may have one or more chiral centers, unless otherwise specified, the invention encompasses any individual non-racemic substance that can be synthesized and resolved by conventional techniques. According to the invention, the (S) configuration of Formula I of the substance is preferred.

In cases where the substances have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are included within the scope of the invention. The meaning of any substituent at any occurrence is independent of the meaning of any other meanings of the substituents at any other occurrence.

Also included in the invention are prodrugs of the compounds of the invention. Precursors are all covalently bonded carriers that release the active parent drug of formula I in vivo. Thus, the invention further provides precursors which are also intermediates of formula II in the preparation of compounds of formula I:

(II)

CO ₂ C ,. ₆ alkyl

-10kde

A is _CH2 or O;

R ¹ is H, halogen or C _1-4 alkyl;

^R2 is H, alkyl or CH ₂ NRR; X is O or CH _2;

Y means

or

G is NR 11, S or O;

R 'is H, C 1-4 alkyl, OC 1-4 alkyl, C 1-4 alkyl, NR "R" or halogen; each R is independently H or C 1-4 alkyl; and s is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

The invention further provides novel intermediates of formula III:

(NI)

-11 where

A is _CH2 or O;

R ¹ is H, halogen or C ₁₄ alkyl;

R ² is H, C 1-4 alkyl or CH ₂ NR 11 R 11;

X is O or CH _2;

R 'is H, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, NR 11 R or halogen; and each R is independently H or C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof.

Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature document presented in Eur. J. Biochem., 158, 9 (1984).

C _1-4 alkyl, as used herein, means an optionally substituted C 1 -C 4 alkyl group and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. C 1-4 alkyl also includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and their simple aliphatic isomers. C ₀ . ₄ alkyl, and C _{0th 6} alkyl also means that it need not be present, no alkyl group (e.g., that a covalent bond is present).

Any C 1-4 alkyl or C 1-4 alkyl may be optionally substituted with a group R ^x , which may be on any carbon atom, resulting in a stable structure and is available using conventional synthesis techniques. Suitable groups for R ^x are C _1-4 alkyl, OR, SR, C _1-4 alkylsulfonyl, C _1-4 . ₄ alkylsulfoxyl, -CN, N (R ") ₂ , CH ₂ N (R") ₂ , -NO ₂ , -CF ₃ -CO ₂ R ", -CON (R) ₂ , -COR, -NRC (O) R, F, Cl, Br, I, or CF ₃ S (O) _r , wherein r is 0, 1 or 2.

Halogen means F, Cl, Br, and I.

Ar or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three substituents such as the substituents defined above for alkyl, especially C _M alkyl, C _M alkoxy, C ,, "alkylthio, CF ₃ , NH ₂ , OH, F, Cl, Br or I.

Some radical groups are abbreviated herein. t-Bu corresponds to the tertiary butyl radical, Boe corresponds to the tert-butyloxy-12carbonyl radical, Fmoc corresponds to the fluorenylmethoxycarbonyl radical, Ph corresponds to the phenyl radical, Cbz corresponds to the benzyloxycarbonyl radical, Bn corresponds to the ethyl radical, corresponds to the _C-alkyl, Nph corresponding

1- or 2-naphthyl and cHex corresponds to cyclohexyl. Tet corresponds to 5-tetrazolyl.

Some reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA is diisopropylethyl amine, EDC hydrochloride / V-ethyl- / ^V - (dimethylaminopropyl) carbodiimide. HOBt stands for 1-hydroxybenzotriazole, THF stands for tetrahydrofuran, DIEA stands for diisopropylethylamine, DEAD stands for diethyl azodicarboxylate, PPh ₃ stands for triphenylphosphine, DIAD stands for diisopropyl azodicarboxylate, DME stands for dimethoxyethane, DMF stands for dimethylformamide, NBS stands for on carbon, PPA is polyphosphoric acid, DPPA is diphenylphosphoryl azide, BOP is benzotriazole-1-oxytris (dimethylamino) phosphonium hexafluorophosphate, HF is hydrofluoric acid, TEA is triethylamine, TFA is trifluoroacetic acid, PCC is pyridinium.

Compounds of formula I are generally prepared by treating a compound of formula IV with a compound of formula V:

wherein R ¹ , R ² , Y and A are as defined for formula I, with protected reactive functional groups, and L ¹ is OH or halogen;

and then removing the protecting group, and optionally forming a pharmaceutically acceptable salt.

13 Some substances of formula I are preferably prepared by treating a compound of formula IV with a compound of formula VI:

ABOUT-

R '(VI) wherein R ¹ , R ² , R', R and A are as defined for formula I, with protected reactive functional groups;

and then removing the protecting group, and optionally forming a pharmaceutically acceptable salt.

The reaction between the compound of formula IV and the compound of formula VI is preferably carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent.

In addition, some compounds of Formula I are prepared by treating a compound of Formula IV with a compound of Formula VII;

wherein R ¹ , R ² , R and A are as defined for formula I, with protected reactive functional groups;

and then removing the protecting group, and optionally forming a pharmaceutically acceptable salt.

The reaction between IV and VII is preferably carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent.

The compounds of formula I are prepared using the methods described in Bondinell et al. WO 97/01540 (International Application No. PCT / US96 / 11108), published Jan. 16, 1997, the entire disclosure of which is incorporated herein by reference.

In addition, the compounds of formula I are prepared by methods analogous to those described in the schemes detailed below.

Scheme I

a) 10% Pd / C, HOAc; b) SOCl ₂ , toluene; (c) AlCl ₃ CH ₂ Cl ₂

Scheme I provides details of the preparation of an intermediate useful in the preparation of a compound of Formula I.

Scheme II

θ ’) (Ό

-15 Scheme II - continued

a) LiN (TMS) ₂ , ethyl bromoacetate; b) Jones reagent, OsO ₄ ; c) _H2, 10% Pd / C, HOAc;

d) C ₂ O ₂ Cl ₂ , DMF; (e) AlCl ₃ , CH ₂ Cl ₂ , room temperature; f) H ₂ , 10% Pd / C, HOAc

Scheme II also provides details of the preparation of an intermediate useful in the preparation of a compound of Formula I.

Scheme III

cn (2)

(3)

(5)

16Scheme III - continued

(a) EtOAc / LiHMDS, THF; (b) H ₂ 10% Pd / C, equ. HCl, AcOH; (c) EtSH, AlCl ₃ . CH ₂ Cl ₂ ; (d) 2 - [(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide, DEAD, (Ph) ₃ P; (e) NaOEt, EtOH; (f) cyclohexene, 10% Pd / C, EtOH; (g) 1.0 M NaOH, EtOH; (h) HCl.

Scheme III gives details of the preparation of the compound of formula I. Reaction of 111-1 (which is Scheme I-3) in an aldol type reaction with ethyl acetate enolate, which can be generated from ethyl acetate by exposure to the appropriate amide base such as lithium dilzopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LiHMDS), yields III-2. THF is often chosen as the solvent for the aldol reaction, although THF is often used in the presence of various additions, for example HMPA or TMEDA. The reduction of III-2 to give III-3 (which is "Scheme II-6") can be accomplished by hydrogenolysis on an appropriate catalyst, for example, palladium on activated carbon (Pd / C), in an appropriate solvent, such as acetic acid, in the presence of a mineral acid such as HCl. Alternatively, this reduction may be performed

By the treatment of III-2 with triethylsilane in the presence of boron trifluoride etherate according to the general method of Orfanopoulos and Smon (Synth. Commun. 1988, 833). Removal of the methyl ether from III-3 to give ill-4 can be accomplished with BBr ₃ in an inert solvent, for example CH ₂ Cl ₂ , or by reaction with ethanethiol and AlCl ₃ in an inert solvent, preferably CH ₂ Cl ₂ . Other useful methods for removing methyl ether are described in Greene, Protective Groups in Organic Synthesis (published by John Wiley and Sons). Compound 4 of Scheme 3 (ill-4) reacts with 2 - [(3-hydroxy-1-propyl) amino] -4-nitropyridine-N -oxide in a Mitsunobu-type coupling reaction (Organic Reactions 1992, 42, 335-656) Synthesis 1981, 1-28) to provide III-5. The reaction is mediated by a complex formed between diethyl azodicarboxylate and triphenylphosphine and is carried out in an aprotic solvent such as THF, CH ₂ Cl ₂ , or DMF. III-5 reacts with an alkali metal salt with the appropriate alcohol to give ill-6. Suitable alkali metals include lithium, sodium, potassium and cesium, and alcohol is generally used as the solvent for the replacement reaction. Methods for forming alkali metal salts with alcohols are well known to those skilled in the art. The pyridine-A / oxide group of ill-6 is reduced to the corresponding pyridine III-7 under transfer hydrogenation conditions using a palladium catalyst, preferably palladium metal on activated carbon, in an inert solvent such as 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 in this type of reaction as a hydrogen transfer agent. The ethyl ester of III-7 is hydrolyzed using an aqueous solution of a base such as LiOH in aqueous THF or NaOH in aqueous methanol or ethanol and the intermediate carboxylate salt is acidified with a suitable acid such as TFA or HCl to give the carboxylic acid III-8. Alternatively, if desired, the intermediate carboxylate salt may be isolated, or the carboxylate salt of the free carboxylic acid may be prepared by methods well known to those skilled in the art.

18Scheme IV

(a) NaH, 2 - [N - (3-methanesulfonyloxy-1-propyl) - N - (tert -butoxycarbonyl) amino] pyridine N -oxide, DMSO; (b) TFA, CH ₂ Cl _2; (c) See Scheme III.

Scheme IV describes an alternative method of preparing a compound of formula

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 such as LDA or the lithium, sodium or potassium salt of hexamethyldisilazane may be used for deprotonation. The intermediate phenoxide is generally not isolated but reacted in situ with the appropriate electrophile, for example 2 - [N - (3-methanesulfonyloxy-1-propyl) - N - (tert-butoxycarbonyl) amino) pyridine N -oxide to give the coupled Product IV-2. The tert-butoxycarbonyl protecting group in IV-2 is removed under acidic conditions such as 4 mol / L HCl in 1,4-dioxane or TFA in CH ₂ Cl ₂ to remove

-19 provides IV-3. The conditions for removal of the tert-butoxycarbonyl protecting group are well known to those skilled in the art, and several useful methods are described in standard guides such as Greene's Protective Groups in Organic Synthesis IV-3 is subsequently converted to IV-4 according to the procedure outlined in on Scheme III.

Scheme V

(a) PhOH, Cu, K ₂ CO ₃ ; (b) sulfur, morpholine; (c) KOH, H ₂ O, / -PrOH; (d) SOCl ₂ , benzene;

(e) AlCl ₃ , CH ₂ Cl ₂ ; (C) EtOAc, LiN (TMS) ₂ , TMEDA, THF; (g) Et ₃ SiH, BF ₃ .EEt ₂ . CH ₂ Cl ₂ ; (h) H ₂ , Pd / C, EtOH; (i) BBr ₃ , CH ₂ Cl ₂ .

Commercially available 2-fluoro-4-methoxyacetophenone (V-1) is reacted with an alcohol such as phenol in the presence of metallic copper and a suitable base such as K ₂ CO ₃ ,

-20 to give the diaryl ether V-2. By treatment with sulfur and the corresponding primary or secondary amine, preferably morpholine, according to the general method of Harris (J. Med. Chem. 1982, 25, 855), V-2 is converted to V-3 in the classical Willgerodt-Kindler reaction. The thioamide thus obtained is hydrolyzed to the corresponding carboxylic acid V-4 by reaction with an alkali metal hydroxide, preferably KOH, in an aqueous solution of an alcoholic solvent such as an aqueous solution of MeOH, EtOH, or i-PrOH. The carboxylic acid V-4 is converted to the corresponding acid chloride either by reaction with SOCl ₂ or oxalyl chloride under conditions well known to those skilled in the art. Treatment of this acid chloride with an appropriate Friedel-Crafts catalyst, such as AlCl ₃ or SnCl ₄ , in an inert solvent such as CH ₂ Cl ₂ or CS ₂ provides the cyclic ketone V-5. Alternatively, the V-4 acid can be converted directly to the ketone V-5 under acidic conditions, for example with polyphosphoric acid. Reaction of V-5 in the aldol type reaction with ethyl acetate enolate, which can be generated from ethyl acetate by exposure to an appropriate amide base, such as lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LiHMDS), provides V-6. For the aldol reaction, THF is often selected as a solvent, although THF is often used in the presence of various additions, for example HMPA or TMEDA. Reduction of V-6 to give V-7 can be accomplished by treatment of V-6 with triethylsilane in the presence of boron trifluoride etherate according to the general method of Orphanopoulos and Smonu (Synth. Commun. 1988, 833). Any olefinic by-products resulting from alcohol elimination are reduced by hydrogenation on an appropriate catalyst, for example, palladium on activated carbon (Pd / C), in an appropriate solvent such as MeOH or EtOH. Alternatively, the reduction of V-6 to give V-7 can be accomplished by hydrogenolysis in the presence of a mineral acid such as HCl. Typically, this reaction is catalyzed by Pd / C, and is optionally carried out in acetic acid. Removal of the methyl ether from V-7 to give V-5 can be accomplished with BBr ₃ in an inert solvent such as CH ₂ Cl ₂ , or by reaction with ethanethiol and AlCl ₃ in an inert solvent, preferably CH ₂ Cl ₂ . Other useful methods for removing methyl ether are described in U.S. Pat

-21 Greene, Protective Groups in Organic Synthesis (published by John Wiley and Sons). Substance V-5 is then converted to the compound of formula I according to the procedure outlined in Scheme III.

The acid addition salts of the compounds are prepared in standard 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 or methanesulfonic acid. Some of these form internal salts or zwitterions, which may be acceptable. The cationic salts are prepared by treating the parent substance with an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide containing the appropriate cation; or with an appropriate organic amine. Cations such as Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺⁺ Mg ^++, and NH ₄ ⁺ are particular examples of cations present in pharmaceutically acceptable salts.

The present invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. Accordingly, the compounds of formula I can be used for the manufacture of medicaments. The pharmaceutical compositions of the compounds of formula I prepared as hereinbefore described may be formulated as solutions or as lyophilized powders for parenteral administration. The powders may be reconstituted prior to use by addition of a suitable diluent or other pharmaceutically acceptable carrier. Liquid formulations may be formulated as buffered isotonic aqueous solutions. Examples of suitable diluents are normal isotonic saline, 5% dextrose standard solution in water or buffered sodium or ammonium acetate solution. Such formulations are particularly suitable for parenteral administration, but may also be used for oral administration or, if included in a metered dose inhaler or nebulizer, for insufflation. It may be desirable to add vehicles such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

Alternatively, these may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or

-22 to facilitate preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, gypsum, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, brine and water. The carrier may also include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies, but preferably will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are manufactured according to conventional pharmacy techniques, including grinding, mixing, granulating and compressing, if necessary, into tablet forms; or milling, mixing and filling into hard gelatin capsules. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such liquid preparations may be administered directly p.o. or filled into a soft gelatin capsule.

For rectal administration, the compounds of the invention may also be combined with such vehicles as cocoa butter, glycerin, gelatin or polyethylene glycols and formed into suppositories.

The compounds described herein are vitronectin receptor antagonists and are useful for treating diseases in which the underlying pathology is attributable to a ligand or cell that interacts with the vitronectin receptor. For example, these agents are useful in the treatment of diseases in which the pathology is caused by bone loss. Thus, these agents are useful for the treatment of ostoeporosis, hyperparathyroidism, Paget's disease, hypercalcaemia of malignancy, osteolytic lesions formed by bone metastases, bone loss due to immobility or sex hormone deficiency. The compounds of the invention are also believed to have utility as antitumor, anti-angiogenic, anti-inflammatory and anti-metastasis agents and are useful for the treatment of atherosclerosis and restenosis.

These agents are administered either orally or parenterally to the patient in such a way that the concentration of the drug is sufficient to inhibit bone resorption, or other such indication. The pharmaceutical composition comprising the agent is administered at an oral dose of between about 0.1 to about 50 mg / kg in a manner consistent with the condition of the patient. Preferably, oral doses would be about 0.5 to about 20 mg / kg. For acute therapy

Parenteral administration is preferred. Intravenous infusion of the peptide in a solution of 5% by weight of dextrose in water or normal saline, or a similar formulation with suitable vehicles, is most effective, although intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg / kg; preferably between 0.1 and 20 mg / kg. These agents are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg / kg / day. The exact level and manner in which these agents are administered is readily determined by those skilled in the art by comparing the blood level of the agent with the concentration required to have a therapeutic effect.

The present invention further provides a method of treating osteoporosis or inhibiting bone loss, comprising sequentially administering or physically combining a compound of the invention and other bone resorption inhibitors such as bisphosphonates (i.e. alendronate), hormone therapy, anti-estrogens, or calcitonin. In addition, the invention provides a method of treatment using a compound of the invention and an anabolic agent such as bone morphogenic protein, iproflavone, useful for preventing bone loss and / or increasing bone mass.

In addition, the present invention provides a method of inhibiting tumor growth, comprising administering sequentially or physically combining a compound of Formula I and an antineoplastic agent. Substances of the class of camptothecin analogs such as topotecan, irinotecan and 9-aminocamptothecin, and platinum coordination complexes such as cisplatin, ormaplatin and tetraplatin are well known class of antineoplastic agents. Substances of the class of camptothecies of new analogs are described in U.S. Pat. U.S. Pat. 5,004,758, 4,604,463, 4,473,692, 4,545,880 4,342,776, 4,513,138, 4,399,276, in EP patent applications no. No. 0418099 and 0088 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, the entire disclosure of which is incorporated herein by reference. The platinum coordination complex, cisplatin, is available under the name Platinol® from Bristol Myers-Squibb Corporation. Useful formulations of cisplatin are described in U.S. Pat.

-24patents no. 5,562,925 and 4,310,515, the entire disclosure of which is incorporated herein by reference.

In a method of inhibiting tumor growth which comprises administering sequentially or physically in conjunction with a compound of the invention and an antineoplastic agent, a platinum coordinating agent, such as cisplatin, may be administered using a slow intravenous infusion. The preferred carrier is a dextrose / saline solution containing mannitol. The dosage schedule of the platinum coordinating agent may be based on from about 1 to about 500 mg per square meter (mg / m ² ) of body surface area for the course of treatment. Platinum coordination agent infusions may be given one to two times a week, and weekly treatments may be repeated several times. Using a camptothecin analog class of substance for parenteral administration, the generally used course of therapy is from about 0.1 to about 300.0 mg / m ² body surface area per day for about five consecutive days. Most preferably, a running course of topotecan of from about 1.0 to about 2.0 mg / m ² body surface area per day for about five consecutive days is used. Preferably, the course of treatment is repeated at least once after about a seven day to about twenty day interval.

The pharmaceutical composition may be formulated so that both the compound of formula I and the antineoplastic agent are in the same container, but preparations with different containers are preferred. When both agents are provided in solution form, they may be contained in an infusion / injection system for simultaneous administration or in a tandem arrangement.

For convenient administration of a compound of formula I and an antineoplastic agent at the same or different times, a kit is prepared comprising, in one container such as a box, carton or other container, individual bottles, sachets, vials or other containers, each having effective an amount of a compound of formula I for parenteral administration as described above, and an effective amount of an antineoplastic agent for parenteral administration as described above. Such a kit may contain, for example, both pharmaceutical agents in separate containers or in the same container, optionally as a lyophilized tablet, and containers of reconstitution solutions. The variation is to include the reconstitution solution and the lyophilized tablet in two chambers of a single container, whereby

They can be brought to mixing before use. In such an arrangement, the antineoplastic agent and the substance of the invention may 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 may be contained in an infusion / injection system for simultaneous administration or in a tandem arrangement. For example, the compound of Formula I may be in i.v. injectable form, or in an infusion bag connected in series using a tubing with an antineoplastic agent in a second infusion bag. Using such a system, the patient may receive an initial bolus-type injection or infusion of a compound of Formula I, followed by an infusion of an antineoplastic agent.

Substances may be tested in one of several bioassays to determine the concentration of the substance required to have a given pharmacological effect.

Inhibition of Vitronectin Binding

Solid-phase binding [ ³ H] -SK & F-107260 to α _ν β ₃ ; α _υ β _{3 of} human placenta or human platelets (0.1 - 0.3 mg / ml) in buffer T (containing 2 mmol / l CaCl ₂ and 1% by weight octylglucoside) was diluted with buffer T containing 1 mmol / l CaCl _2.1 mmol / L MnCl ₂ , 1 mmol / L MgCl ₂ (buffer A) and 0.05% NaN ₃ , and then immediately added to 96-well ELISA plates (Corning, New York, NY) with 0, 1 ml per cup. 0.1 to 0.2 µg α _ν β _{3 was added} per cup. Plates were incubated overnight at 4 ° C. At the time of the experiment, the wells were washed once with buffer A and incubated with 0.1 ml of 3.5% bovine serum albumin in the same buffer for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed twice with 0.2 ml of Buffer A.

The substances were dissolved in 100% DMSO to give a 2 mmol / l stock solution which was diluted with binding buffer (15 mmol / l Tris-HCl (pH 7.4), 100 mmol / l NaCl, 1 mmol / l CaCl ₂ 1 1 mmol / l MnCl ₂ 11 mmol / l MgCl ₂ ) to a final concentration of 100 pmol / l. This solution was then diluted to the desired final compound

-26koncentráciu. To the wells were added various concentrations of unlabeled antagonists (0.001 to 100 pmol / l) in triplicate, the addition of 5.0 nmol / L ^[3 H] -SK & F-107260 (2.40 .10 ¹² to ¹² Bq 3,18.10 / mmol (65 to 86 Ci / mmol)).

Plates were incubated for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed once with 0.2 ml of ice-cold buffer A in the well-cup configuration. Receptors were solubilized with 0.1 ml 1% SDS and bound [ ³ H] -SK & F-107260 was determined by liquid scintillation detection with the addition of 3 ml Ready Safe solution in a Beckman LS liquid scintillation detector with 40% efficiency. Non-specific binding of [ ³ H] -SK & F-107260 was determined in the presence of 2 pmol / l SK & F-107260 and was consistently less than 1% of the total input radioligand. The IC 50 value (concentration of antagonist to inhibit 50% binding of [ ³ H] -SK & F-107260) was determined using a non-linear least-squares curve fitting program modified from the LUNDON-2 program. Kf values (dissociation constant of antagonist) were calculated according to the equation: K i = IC ₅₀ (1 + L / K _d ), where L and K _d were the concentration and dissociation constant [ ³ H] -SK & F-107260.

The compounds of the invention inhibit the binding of vitronectin to SK & F-107260 in a concentration range of about 2.5 to about 0.001 micromol / L.

The compounds of the invention have also been tested for in vitro and in vivo bone resorption in a standard assay in this field to evaluate bone formation inhibition, such as the well formation assay described in EP 528587, which can also be performed using human osteoclasts instead of rat osteoclasts. and the ovariectomized rat model described by Wronski et al., Cell and Materials 1991, Sup. 1.69 to 74.

Migration assay 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 an 8 µm polycarbonate membrane (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine

-27 serum albumin at a concentration of 2.5 to 5.0x10 ⁶ cells / ml, and were pre-treated with the test substance at various concentrations for 20 minutes at 20 ° C. The solvent alone was used for control. 0.2 ml of 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 performed at 37 ° C in an atmosphere of 95% air / 5% CO ₂ for 24 hours. After incubation, non-migrated cells on the top surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa dye. Migration was measured either by a) counting the number of cells that migrated to the bottom surface of the filter or b) extracting the stained cells with a 10% acetic acid solution, followed by determining the absorbance at 600 nm.

Model of thyroparathyroidectomized rats

Each experimental group consists of 5 to 6 adult males

Sprague-Dawley rats (250-400 g body weight). Rats were tyroparathyroidectomized (by the vendor, Taconic Farms) 7 days prior to use. All rats received replacement doses of thyroxine every 3 days. Upon receipt of rats, circulating ionized calcium levels in the blood were measured immediately after being collected in heparinized tubes by tail vein puncture. Rats are included in the experiment if the level of ionized Ca (measured with a Ciba-Corning model 634 calcium pH analyzer) is <1.2 mmol / L. Each rat is equipped with a permanently present venous and arterial catheter to deliver test material and blood samples. The rats are then placed on a calcium-free diet and deionized water. Baseline Ca levels were measured and either rat vehicle or human parathyroid hormone 1-34 peptide (hPTH1-34, dose) was administered to each rat.

1.25 μg / kg / hr. in a saline / 1% bovine serum albumin mixture, Bachem, Ca) or a mixture of hPTH1-34 and test material, by continuous intravenous infusion through a venous catheter using an external piston pump. The calcemic response of the rats was measured at two-hour intervals during the infusion for 6 to 8 hours.

-28 Human osteoclast resorption and adhesion assay

A well resorption and adhesion assay was developed and standardized using normal human osteoclasts derived from osteoclastoma tissue. Assay 1 was developed to measure osteoclast well volumes by laser confocal microscopy. Test 2 was developed as a more powerful control method in which collagen fragments (released during resorption) were measured using a competitive ELISA method.

Assay 1 (using laser confocal microscopy) • Aliquots of human osteoclastoma cell suspension were removed from storage in liquid nitrogen, heated rapidly to 37 ° C and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C).

The medium was aspirated and replaced with a mouse anti-HLA-DR antibody, then diluted 1: 3 with RPML-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently.

Cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber.

• Enough magnetic beads (5 L of mononuclear cells) coated with goat anti-mouse IgG (Dynal, Great Neck, NY) were removed from their stock bottle and placed in 5 ml of fresh medium (these were washed from the toxic azide preservative) . The medium was removed by immobilizing the beads on the magnet and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was often stirred.

The cell-coated beads were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube.

Fresh cell release medium was added to the cell-coated beads

-29 captured osteoclasts. This washing process was repeated x10. Cell-coated beads were discarded.

Viable osteoclasts were counted in a counting chamber, using fluorescein diacetate to label live cells. A plastic Pasteur pipette with a large drain hole was used to add the sample to the chamber.

Osteoclasts were pelleted by centrifugation and the density was set to the appropriate number in EMEM medium (osteoclast number varies from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter sodium bicarbonate.

• 3 ml aliquots of cell suspension (per test substance) are decanted into 15 ml centrifuge tubes. Cells were pelleted by centrifugation.

• 3 ml of the respective test substance (diluted to 50 μιτιο! / Ι in EMEM medium) was added to each tube. Appropriate vehicle controls, positive control (mouse monoclonal antibody [87MEM1] for anti-vitronectin receptor diluted to 100 µg / ml) and isotype control (IgG2a diluted to 100 µg / ml) were also included. Samples were incubated at 37 ° C for 30 minutes.

0.5 ml aliquots of cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37 ° C for 2 hours. Each treatment was monitored in quadruplicate.

The slides were washed with six changes of warm PBS (10 ml / well in a 6-well plate) and then placed in fresh medium containing a sample of the test substance or a control sample. Samples were incubated at 37 ° C for 48 hours.

Method of tartrate-resistant acid phosphatase (TRAP) (selective staining for cells of osteoclast origin) • Bone slices containing bound osteoclasts were washed in phosphate buffered saline and fixed in a 2% glutaraldehyde solution (in 0.2 mol / l sodium cacodylate) for 5 minutes.

They were then washed with water and incubated for 4 minutes in TRAP buffer at 37 ° C

-30 ° C (0.5 mg / ml naphthol AS-BI phosphate dissolved in N, N-dimethylformamide and mixed with 0.25 mol / l citrate buffer (pH 4.5) containing 10 mmol / l sodium tartrate .

After washing with cold water, the slices were immersed in cold acetate buffer (0.1 mol / l, pH 6.2) containing 1 mg / ml fast red garnet and incubated at 4 ° C for 4 minutes.

The excess buffer was aspirated and the slices were air dried after washing in water.

TRAP positive osteoclasts (brick red / purple precipitate) were quantified by sharp field light microscopy and then removed from the dentine surface by ultrasonic treatment.

Well volumes were determined using a Niko / Lasertec ILM21W confocal microscope.

Test 2 (using ELISA subtraction)

Human osteoclasts were enriched and prepared for tracing as described in the initial 9 steps of Test 1. These steps are repeated below for clarity.

Aliquots of cell suspensions derived from human osteoclasts were taken from storage in liquid nitrogen, heated rapidly to 37 ° C, and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C).

The medium was aspirated and replaced with a mouse anti-HLA-DR antibody, then diluted 1: 3 with RPML-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently.

Cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber.

• Enough magnetic beads (5 L of mononuclear cells) coated with goat anti-mouse IgG (Dynal, Great Neck, NY) were removed from their stock bottle and placed in 5 ml of fresh medium (these were washed from the toxic azide preservative) . The medium was removed by immobilizing the beads on the

-31 magnete and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was often stirred.

The cell-coated beads were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube.

Fresh medium was added to the cell-coated beads to release trapped osteoclasts. This washing process was repeated x10. Cell-coated beads were discarded.

Viable osteoclasts were counted in a counting chamber, using fluorescein diacetate to label live cells. A plastic Pasteur pipette with a large drain hole was used to add the sample to the chamber.

Osteoclasts were pelleted by centrifugation and the density was set to the appropriate number in EMEM medium (osteoclast number varies from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter sodium bicarbonate.

In contrast to the method described in Test 1 above, the substances were monitored at 4 doses to obtain IC ₅₀ as shown below:

Osteoclast preparations were preincubated for 30 minutes at 37 ° C with test substance (4 doses) or controls.

They were then seeded into bovine cortical bone slices in 48-well tissue culture plates and incubated for an additional 2 hours at 37 ° C.

The bone slices were washed with six changes of warm phosphate buffered saline (PBS) to remove non-captured cells, and then returned to 48 well plates containing fresh test substance or controls.

The tissue culture plates were then incubated for 48 hours at 37 ° C. Supernatants from individual wells were aspirated into individual tubes and monitored in a competitive ELISA assay that detects the c-telopeptide of type I collagen released during the resorption process. This is a commercially available ELISA (Osteometer, Denmark) which contains rabbit antibodies that specifically

-32 react with the 8-membered amino acid sequence (Glu-Eys-Ala-His-Asp-Gly-GlyArg) that is present on the carboxy-terminal telopeptide and collagen type I 1-chain. Results are expressed as% inhibition of resorption compared to vehicle control.

Human osteoclast adhesion assay

Human osteoclasts were enriched and prepared for tracing as described in the initial 9 steps of Test 1. For clarity, these steps are repeated below.

Aliquots of cell suspensions derived from human osteoclasts were taken from storage in liquid nitrogen, heated rapidly to 37 ° C, and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C).

The medium was aspirated and replaced with a mouse anti-HLA-DR antibody, then diluted 1: 3 with RPML-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently.

Cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber.

• Enough magnetic beads (5 / mononuclear cell) coated with goat anti-mouse IgG (Dynal, Great Neck, NY) were removed from their stock bottle and placed in 5 ml of fresh medium (these were washed from toxic azide preservative) . The medium was removed by immobilizing the beads on the magnet and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was often stirred.

The cell-coated beads were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube.

Fresh cell release medium was added to the cell-coated beads

-33 captured osteoclasts. This washing process was repeated x10. Cell-coated beads were discarded.

Viable osteoclasts were counted in a counting chamber, using fluorescein diacetate to label live cells. A plastic Pasteur pipette with a large drain hole was used to add the sample to the chamber.

Osteoclasts were pelleted by centrifugation and the density was set to the appropriate number in EMEM medium (osteoclast number varies from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter sodium bicarbonate.

Osteoclastoma-derived osteoclasts were preincubated for 30 minutes at 37 ° C with the test substance (4 doses) or controls.

Cells were then seeded onto osteopontin-coated slides (human or rat osteopontin, 2.5 µg / ml) and incubated for 2 hours at 37 ° C.

Uncaptured cells were removed by vigorously washing the plates in phosphate buffered saline and the cells remaining on the plates were fixed in acetone.

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

Cell adhesion assay

Cells and cell cultures

Human embryonic kidney cells (HEK293 cells) were obtained from ATCC (Catalog No. CRL 1573). Cells were grown in Earl's Minimum Essential Medium (EMEM) medium containing Earl's salts, 10% fetal bovine serum, 1% glutamine and 1% penicillin-streptomycin mixture.

Constructs and transfections

The 3.2 kb EcoRI-Kpn1 fragment and _the α subunit and the 2.4 kb XbaI-Xhol fragment of the β ₃ subunit were inserted into the EcoRI-EcoRV cloning sites of the pCDN vector (Aiyar and

(1994), which contains the CMV promoter and the G418 selectable marker by blunting and ligation. For stable expression, 80x10 ⁶ HEK293 cells were electrotransformed with α _ν + β ₃ constructors (20 µg DNA of each subunit) using a Gen Pulser (Hensley et al., 1994) and plated on 100 mm plates (5x10 ⁵ cells per plate). . After 48 hours, the growth medium was supplemented with 450 µg / ml Geneticin (G418 sulfate, GIBCO-BRL, Bethesda, MD). Cells were grown in selection medium until colonies were large enough for assay.

Immunocytochemical analysis of transfected cells

To determine whether HEK293 transfectants expressed the vitronectin receptor, cells were immobilized on microscope slides by centrifugation, fixed in acetone for 2 minutes at room temperature, and air dried. Specific reactivity with 23C6 monoclonal antibodies specific for the α _υ β ₃ complex was demonstrated using a standard indirect immunofluorescence method.

Study of cell adhesion

Corning 96-well ELISA plates were pre-coated overnight at 4 ° C with 0.1 ml of 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. Transfected 293 cells were resuspended in RPMI medium supplemented with 20 mM Hepes, pH 7.4 and 0.1% BSA at a density of 0.5x10 ⁶ 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 various α _ν β ₃ 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. Plates were washed 3 times with 0.2 ml RPMI medium and the captured cells were stained with 0.1 ml of a 0.5% toluidine blue solution for 20 minutes at room temperature. Excess dye was removed by extensive washing with deionized water. Toluidine blue incorporated into the cells is

-35 gel by adding 0.1 ml of a 50% ethanol solution containing 50 mmol / l HCl. Cell adhesion was quantified by optical density at 600 nm on a microplate reader (Titertek Multiskan MC, Sterling, VA).

Solid-phase binding assay α _ν β ₅

The vitronectin receptor α _ν β ₆ was purified from human placenta. The receptor preparation was diluted with 50 mmol / l Tris-HCl, pH 7.5, 100 mmol / l NaCl, 1 mmol / l CaCl ₂ , 1 mmol / l, MnCl ₂ , 1 mmol / l MgCl ₂ (buffer A) and was immediately added to 96-well ELISA plates at 0.1 ml per well. 0.1 to 0.2 µg α _ν β _{3 was added} per cup. Plates were incubated overnight at 4 ° C. At the time of the experiment, the wells were washed once with buffer A and incubated with 0.1 ml of 3.5% bovine serum albumin in the same buffer for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed twice with 0.2 ml of Buffer A.

In the [ ³ H] -SK & F-107260 competition assay, different concentrations of unlabeled antagonist (0.001 to 100 pmol / L) were added to the wells, followed by the addition of 5.0 nmol / L [ ³ H] -SK & F-107260. Plates were incubated for 1 hour at room temperature. After incubation, the wells were aspirated completely and washed once with 0.2 ml ice-cold buffer A in a cup-by-cup configuration. Receptors were solubilized with 0.1 ml 1% SDS and bound [ ³ H] -SK & F-107260 was determined by liquid scintillation detection with the addition of 3 ml Ready Safe solution in a Beckman LS liquid scintillation detector with 40% efficiency. Non-specific binding of [ ³ H] -SK & F-107260 was determined in the presence of 2 pmol / l SK & F-107260 and was consistently less than 1% of the total input radioligand. The IC 50 (concentration of antagonist to inhibit 50% binding of [ ³ H] -SK & F107260) was determined using a non-linear least-squares curve fitting program modified from the LUNDON-2 program. K i values (dissociation constant of antagonist) were calculated according to the Cheng and Prusoff equation: K i = IC 50 (1 + L / 1 · 4), where L and K _d were the concentration and dissociation constant [ ³ H] -SK & F-107260.

-36Inhibition of RGD-mediated GPIIb-IIIa binding

Purification of GPIIb-IIIa

Ten units of washed old blood platelets (obtained from Red Cross) were lysed by gentle agitation in a solution of 3% by weight octyl glucoside, 20 mmol / l Tris-HCl, pH 7.4, 140 mmol / l NaCl, 2 mmol / l CaCl ₂ at 4 ° C for 2 hours. The lysate was centrifuged at 100,000g for 1 hour. The supernatant obtained was applied to a 5 ml lectin-sepharose 4B granule column (EY Labs) in equilibrium with 20 mM Tris-HCl, pH 7.4, 100 mM NaCl 2 mM CaCl ₂ , 1% octyl glucoside (Buffer A). After 2 hours of incubation, the column was washed with 50 ml of cold buffer A. The lectin retained by GPIIb-IIIa was eluted with buffer A containing 10% by weight dextrose. All procedures were performed at 4 ° C. The GPIIb-IIIa obtained was> 95% pure, as seen from SDS polyacrylamide gel electrophoresis.

Incorporation of GPIIb-IIIa into liposomes

A mixture of phosphatidylserine (70% by weight) and phosphatidylcholine (30% by weight) (Avanti Polar Lipids) was dried on the glass tube walls under a stream of nitrogen, purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg / ml and mixed with phospholipids in protein phospholipid ratio of 1: 3 (w / w). The mixture was resuspended and sonicated in an ultrasonic bath for 5 minutes. The mixture was then dialyzed overnight using dialysis tubes to cut a molecular weight of 12000 to 14000 against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl ₂ (with 2 exchanges). Liposomes containing GPIIb-IIIa were centrifuged at 12000g for 15 minutes and resuspended in dialysis buffer to a final protein concentration of about 1 mg / ml. Liposomes were stored at -70 ° C until needed.

Competitive binding to GPIIb-IIIa

Binding to the fibrinogen receptor (GPIIb-IIIa) was tested using the indirect competitive binding method using [ ³ H] -SK & F-107260 as an RGD-type ligand. The binding assay was performed in a 96-well filter

A 37-well apparatus (Millipore Corporation, Bedford, MA) using 0.22 µm hydrophilic durapor membranes. The wells were pre-coated with 0.2 mL of 10 gg / mL polylysine (Sigma Chemical Co., St. Louis, MO.) At room temperature for 1 hour to block non-specific binding. Different concentrations of unlabeled benzazepines were added to the wells in four replicates. [ ³ H] -SK & F107260 was applied to each well at a final concentration of 4.5 nmol / L, followed by addition of 1 gg of purified GPIIb-IIIa-containing liposome plates. The mixtures were incubated for 1 hour at room temperature. GPIIb-IIIa bound [ ³ H] -SK & F-107260 was separated from unbound by filtration using a Millipore filtration apparatus, followed by washing with ice-cold buffer (2 times, 0.2 mL each). Bound radioactivity remaining on the filters was measured in 1.5 ml Ready Solve (Beckman Instruments, Fullerton, CA) in a Beckman Liquid Scintillation Counter (Model LS6800) with a 40% efficiency. Non-specific binding was determined in the presence of 2 pmol / L of unlabeled SK & F-107260 and was consistently less than 0.14% of the total radioactivity added to the samples. All data points are the average of four replicate determinations.

Competitive binding data was analyzed using a non-linear least-squares curve fitting program. This method provides IC ₅₀ values of antagonists (concentration of antagonist that inhibits specific binding of [ ³ H] -SK & F-107260 to 50% at equilibrium). The IC 50 value is relative to the equilibrium dissociation constant (K i) of the antagonist based on the Cheng and Ptusoff equation: K i = IC 50 (1 + L / K d), where L is the [ ³ H] -SK & F-107260 concentration used in the competitive assay binding (4.5 nmol / L) and Kd is the [ ³ H] -SK & F-107260 dissociation constant, which is 4.5 nmol / L, as determined by Scatchard analysis.

Preferred compounds of the invention have an affinity for the vitronectin receptor relative to the fibrinogen receptor of greater than 10: 1, most preferably the compounds have an activity ratio greater than 100.Ί.

The efficacy of the compound of the invention alone or in combination with

The -38 antineoplastic agent can be determined using multiple transplantable mouse tumor models. See U.S. Pat. No. 5,004,758 and 5,633,016 for details of these models.

The examples that follow are not intended to limit the scope of the invention in any way, but are provided to illustrate how to make and use the compounds of the invention. Many other embodiments of the invention will be readily apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

Generally

Proton nuclear magnetic resonance ( ¹ H NMR) spectra were recorded using either 250 or 400 MHz. Chemical shifts are reported in ppm (parts per million) (δ) relative to the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J denotes the NMR coupling constant measured in Hertz. CDCl 3, is deuterated chloroform, DMSO-d ₆ is hexadeuterated dimethylsulfoxide, and CD ₃ OD is tetradeuterated methanol. Infrared (IR) spectra were measured in transmission mode and the band positions are given in wavelengths (cm ^-1 ). Mass spectra were obtained using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyzes were performed at the workplace or at Quantitative Technologies Inc., Whitehouse, NJ. Melting points were measured on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are in degrees Celsius. Thin-layer chromatography was performed using Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin-layer plates. Both flash and gravity chromatography were performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were performed on Rainin or Beckman chromatographs. The ODS corresponds to an octadecylsilylderivatized silica gel chromatography support. 5 μ Apex-ODS

-39 designates an octadecylsilyl-derivatized silica gel chromatography carrier having a nominal particle size of 5 µm, manufactured by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ® is an ODS chromatography support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric (styrenedivinylbenzene) chromatographic support and is a registered trademark of Hamilton Co., Reno, Nevada. Celite® is a filter medium composed of acid washed diatomic silica and is a registered trademark of Manville Corp., Denver, Colorado.

Ethyl 1- (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate, ethyl (±) -10,11-dihydro-3-hydroxy-5H- N-dibenzo- [a, d] cycloheptene-10-acetate and ethyl (±) 10,11-dihydro-3- (trifluoromethanesulfonyloxy) -5 H -dibenzo- [a, d] cycloheptene-10-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 according to the method of House and Hudson (J. Org. Chem. 1970, 35, 647).

Preparation 1

Preparation of 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide

a) 2 - [(3-Hydroxy-1-propyl) amino] pyridine-1 H -oxide

A mixture of 2-chloropyridine-N -oxide hydrochloride (16.6 g, 0.1 mol), 3-amino-1-propanol (15.3 mL, 0.2 mol), NaHCO ₃ (42 g, 0.5 mol) and tert-amyl alcohol (100 mL) was heated to reflux. After 21 hours, the reaction mixture was cooled, diluted with CH ₂ Cl ₂ (300 mL) and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to give a yellow oil. Chromatography on silica gel (20% MeOH / CHCl ₃ ) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20% MeOH / CHCl ₃ ) R f 0.48; ¹ H NMR (250, CDCl ₃ ) δ 8.07 (dd, J = 6.6, 1.2 Hz, 1H), 7.34 (broad t, 1H), 7.10-7.30 (m, 1H), 6.64 (dd, J = 8.5, 1.4 Hz, 1H), 6.40-6.60 (m, 1H), 4.49 (broad s, 1H), 3.65- 3.90 (m, 2H), 3.35-3.60 (m, 2H), 1.75-2.00 (m, 2H): MS (ES) M / e 169 (M + H) ) ⁺ .

-40Preparation 2

Preparation of 2 - [(3-hydroxy-1-propyl) amino] -4-nitropyridine N-oxide

a) 2-Chloro-4-nitropyridine - N -oxide

A solution of concentrated H ₂ SO ₄ (30 mL) and fuming HNO ₃ (54 mL) was added dropwise at 0 ° C to a solution of 2-chloropyridine N-oxide hydrochloride (15.2 g, 91.56 mmol) in a horse. . H ₂ SO ₄ (30 mL). The reaction mixture was heated at 90 ° C for 1 hour, then cooled to room temperature and poured into ice (500 g). The reaction mixture was kept at room temperature overnight, then cooled in an ice bath, and a solution of 50 wt% NaOH was slowly added to give a precipitate. This was separated and dried to give the title compound (5.88 g, 37%) as a pale yellow solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42-8.37 (m, 2 H), 8.06-8.04 (m, 1H).

b) 2 - [(3-Hydroxy-1-propyl) amino] -4-nitropyridine - N - oxide

Following the procedure of Preparation 1, except substituting 2-chloro-4-nitropyridine / N -oxide for 2-chloropyridine-N -oxide hydrochloride, the title compound was obtained as a yellow powder, followed by silica gel chromatography (1: 9). MeOH / CH ₂ Cl ₂ ). Recrystallization from MeOH / CH ₂ Cl ₂ / Et ₂ O gave the title compound: MS (ES) 214.1 (M + H) ⁺ .

Preparation

Preparation of 2 - [(3-hydroxy-1-propyl) amino] -4-methylpyridine-1 H -oxide

a) 2-Chloro-4-methylpyridine

Sodium nitrite (13.88 g, 200 mmol) was added slowly at 0 ° C to a solution of 2 amino-4-picoline (15.0 g, 139 mmol) in the horse. HCl (200 mL). The reaction mixture was allowed to warm to room temperature and stirred for 36 hours, then poured into ice (500 g). The pH was adjusted to 8.0 with horses. NH ₄ OH, and the mixture was extracted with ether (3 x 300 mL). The combined ether layers were washed sequentially with H ₂ O (2 x 200 mL) and brine (200 mL). Drying (MgSO ₄ ) and concentration

-41 gave the title compound (10.3 g, 58%) as a pale yellow oil; MS (ES) mlz 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. hours. The reaction mixture was cooled, horses were added. HCl (35 mL) and the mixture was concentrated on a rotary evaporator. Recrystallization from n-butanol, followed by trituration with ether gave the title compound (7.16 g, 51%) as a white solid; MS (ES) mlz 143.9 (M + H) ⁺ .

c) 2 - [(3-Hydroxy-1-propyl) amino] -4-methylpyridine - N -oxide

A mixture of 2-chloro-4-methylpyridine-N-oxide hydrochloride (7.16 g, 39 mmol), 3-aminopropanol (6.01 g, 80 mmol), and NaHCO ₃ (16.8 g, 200 mmol) in tert- amylalcohol (50 mL) was heated under reflux for 19 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (200 mL) and filtered, and the filtrate was concentrated on a rotary evaporator. Recrystallization from CH ₂ Cl ₂ / Et ₂ O gave the title compound (5.41 g, 75%) as a yellow solid; TLC (15% MeOH / CH ₂ Cl ₂ ) R _f 0.44; ¹ H NMR (400, CDCl ₃ ) 37.92 (d, J = 6.7, 1H), 7.28 (broad t, 1H). 6.43 (s, 1H), 6.33 (dd, J = 6.6, 2.1 Hz, 1H), 3.73 (t, J = 5.7 Hz, 2H), 3.47 (q H = 6.3 Hz, 2H), 2.29 (s, 3H), 1.82-1.88 (m, 2H); MS (ES) mlz 183 (M + H) ⁺ .

Preparation 4

Preparation of 6- (methylamino) -2-pyridylethanol

a) 2- (tert-Butoxycarbonylamino) -6-picoline

A solution of 2-amino-6-picoline (21.63 g, 200 mmol) and di-tert-butyl dicarbonate (52.38 g, 240 mmol) in CH ₂ Cl ₂ (200 mL) was concentrated on a rotary evaporator at 50 ° C , and the resulting residue was rotated on a rotary evaporator at 50 ° C under vacuum. After 21.5 hours, the reaction mixture was diluted with hexanes (400 mL) and filtered through silica gel (hexanes followed by 20% w / w mixture).

-42EtOAc / hexanes). Concentration left the title compound (41.84 g, quantitative) as a pale yellow oil which solidified on standing: ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.71 (d, J = 8.3 Hz, 1H), 7.40-7.65 (m, 2H), 6.80 (d, J = 7.5Hz, 1H), 2.43 (s, 3H), 1.50 (s, 9H); MS (ES) m / e 153 (M + H - C ₄ H ₈ ) ⁺ .

b) 2 - [(tert -Butoxycarbonyl) methylamino] -6-picoline

NaH (60% in mineral oil, 3.60 g, 90 mmol) was added portionwise over several minutes to a solution of 2- (tert-butoxycarbonylamino) -6-picoline (15.62 g, 75 mmol) and iodomethane (9 mL). , 3 mL, 150 mmol) in anhydrous DMSO (75 mL) at 15 ° C (cold water bath). The internal temperature rose to 35 ° C. When gas evolution had subsided, the cold water bath was removed and the reaction mixture was allowed to stir at room temperature. After 0.5 h, the dark yellow mixture was poured into ice / H ₂ O (300 mL) and extracted with Et ₂ O (3 x 300 mL). The combined organic layers were washed successively with H ₂ O (2 x 75 mL) and brine (75 mL). Drying (MgSO ₄ ) 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 pale yellow oil: ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.51 (app. T. 1H), 7.37 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 3.38 (s, 3H), 2.49 (s, 3H), 1.50 (s, 9H) ; MS (ES) mlz 223 (M + H) ⁺

c) Ethyl-6 - [(tert-butoxycarbonyl) methylamino) -2-pyridylacetate

LDA was prepared at 0 ° C under argon from diisopropylamine (19.5 mL, 139.14 mmol) and 2.5 M n-BuLi in hexanes (46.4 mL, 115.95 mmol) in dry THF ( 350 ml). This solution was cooled to -78 ° C and a solution of 2 - [(tert-butoxycarbonyl) methylamino] -6-picoline (10.31 g, 46.38 mmol) in dry THF (46 mL) was added dropwise over 10 minutes. . Additional dry THF (2 mL) was used for transfer. The orange solution was stirred at -78 ° C for 15 minutes, then diethyl carbonate (6.2 mL, 51.02 mmol) was quickly added. The red solution was stirred at -78 ° C for 15 minutes, then quenched with half-saturated NH ₄ Cl (175 mL). The mixture was warmed to + 5 ° C and extracted with EtOAc (175 mL) then CH ₂ Cl ₂

-43 (2 x 100 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO ₄ ) and concentrated. The dark yellow oil was chromatographed on silica gel (15% EtOAc / hexanes) to give the title compound (10.72 g, 79%) as a pale yellow oil: ¹ H NMR (250 MHz, CDCl ₃ ) δ 7, 51-7.63 (m, 2H), 6.91 7.03 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3, 38 (s, 3H), 1.27 (t, J = 7.1Hz, 3H) 1.51 (s, 9H); MS (ES) m / e 295 (M + H +)

d) Ethyl-6- (methylamino) -2-pyridylacetate

A solution of ethyl 6 - [(tert-butoxycarbonyl) methylamino) -2-pyridylacetate (10.72 g, 36.42 mmol) in anhydrous dioxane (91 mL) was cooled to a partial crystallization point of the solvent, and a 4 mol / L solution was added. 1 HCl / dioxane (91 mL, 364.2 mmol). The solution was warmed to room temperature and stirred for 17 hours then concentrated. The resulting pale yellow solid was slurried with CH ₂ Cl ₂ / toluene and concentrated to give the title compound (8.48 g, quantitative) as a pale yellow powder; ¹ H NMR (250 MHz, CD ₃ OD) δ 7.84 (dd, J = 9.0, 7.2 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6 78 (d, J = 7.2Hz, 1H). 4.22 (q, J = 7.1Hz, 2H), 3.93 (s, 2H), 3.05 (s, 3H), 1.27 (t, J = 7.1Hz, 3H); MS (ES) mlz 195 (M + H) ⁺ .

e) 6- (Methylamino) -2-pyridylethanol

A solution of 1.0 M LiAlH ₄ in THF (95 mL, 95 mmol) was added dropwise to a mechanically stirred suspension of ethyl 6- (methylamino) -2-pyridylacetate (7.34 g 31.82 mmol) in dry THF ( 64 mL) at 0 ° C under argon. The addition was made slowly until gas evolution had subsided, then the remaining solution was added quickly. Addition required 5 to 7 minutes. The reaction mixture was warmed to room temperature and stirred for 45 minutes, then heated to reflux. After 10 minutes, the reaction mixture was cooled to 0 ° C and treated successively dropwise by adding 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. Layer on the filter with

It was washed with a large amount of THF and the filtrate was concentrated. The residue was reconcentrated from toluene then chromatographed on silica gel (5% MeOH in 1: 1 EtOAc / CHCl ₃ ) to give the title compound (3.23 g, 67%) as a yellow oil which solidified to give a yellow oil. a waxy solid; ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.36 (dd, J = 8.3, 7.3 Hz, 1H), 6.42 (d, J = 7.3 Hz, 1H), 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, 2H)

2.90 (d, J = 5.2 Hz, 3H); 2.84 (t, J = 5.4 Hz, 2H); MS (ES) mlz 153 (M + H) ⁺

Preparation

Preparation of 2- (ethylamino) -4-thiazoletanol

a) Ethyl 2-acetylamino-4-thiazoleacetate

Ethyl 2-amino-4-thiazoleacetate (3.72 g, 20 mmol) was dissolved in acetic acid (4 mL) and acetic anhydride (4 mL), and the resulting suspension was heated under reflux for 3 hours. Concentration and flash chromatography on silica gel (5% MeOH / CH ₂ H ₂ ) gave the title compound (4.1 g, 91%) as a white solid: MS (ES) m / e 229 (M + H) ⁺ .

b) 2- (Ethylamino) -4-thiazoletanol

To a stirred solution of 1.0 M LiAlH ₄ in THF (179 mL, 179 mmol) was added dropwise a solution of ethyl 2-acetylamino-4-thiazoleacetate (4.4 g, 17.9 mmol) in THF (50 mL). . After complete addition, the reaction mixture was heated to reflux 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 flash chromatography on silica gel (5% MeOH / CH ₂ H ₂ ) gave the title compound (1.6 g 53%) as an amber oil: MS (ES) m / e 173 (M + H) ⁺ .

Preparation 6

Preparation of 6-amino-2-pyridylethanol

(45a) 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 6 mol / L HCl was heated at 60 ° C. After 16 hours, the reaction mixture was concentrated in vacuo and the residue was made alkaline with dry KOH. The resulting mixture was extracted with MeOH and the MeOH extracts were dried (MgSO ₄ ) and concentrated. Flash chromatography on silica gel (5% MeOH / CH ₂ H ₂ ) gave the title compound (0.2 g, 40%) as a pale yellow oil: MS (ES) m / e 139 (M + H) ⁺

Preparation 7

Preparation of 3- (4-nitrobenzyloxycarbonylamino) -1-propanol

a) 3- (4-Nitrobenzyloxycarbonyl) amino-1-propanol

To a suspension of stirred under argon at room temperature 4-nitrobenzyl chloroformate (5 g, 23 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (25 mL) was added 3-amino-1-propanol (1.9 mL). , 26 mmol). The resulting mixture was stirred for 72 hours, 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 pale yellow oil; MS (ES) 255.3 (M + H) &lt; ^{+ &gt};.

Preparation

Preparation of 1 - [(3-hydroxy-1-propyl) amino] isoquinoline N-oxide

a) 1-Chloroisoquinoline N-oxide

1-Aminoisoquinoline N-oxide 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 the literature (Brown, FVJ Amer) Chem. Soc., 1957, 79, 3565-3566). The title compound was prepared as a light brown solid; MS (ES) mlz 179.9 (M + H) ⁺ .

-46b) 1 - [(3-Hydroxy-1-propyl) amino] -isoquinoline-N-oxide

Following the procedure of Preparation 1 (a), except for substituting 1-chloroisoquinoline N-oxide for 2-chloropyridine-N -oxide hydrochloride, the title compound was prepared as an amber solid; MS (ES) mlz 219.1 (M + H) ⁺ .

Preparation 9

Preparation of 2- [N - (3-methanesulfonyloxy-1-propyl) - N - (tert -butoxycarbonyl) amino] pyridine N -oxide

(a) 2 - [N- (3-Hydroxy-1-propyl) - N - (tert -butoxycarbonyl) amino] pyridine - N - oxide

A solution of 2 - [(3-hydroxy-1-propyl) amino-pyridine-1 H -oxide (8.0 g, 47.6 mmol) in tert -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 (ES) m / e 269.3 (M + H) ⁺ .

b) 2- [N- (3-Methanesulfonyloxy-1-propyl) - N - (tert -butoxycarbonyl) amino] pyridine N-oxide

Methanesulfonyl chloride (0.17 mL, 2.20 mmol) was added dropwise to the solution

2- (N - (3-hydroxy-1-propyl) - N - (tert -butoxycarbonyl) amino] pyridine - N - oxide (0.50 g, 1.86 mmol) and pyridine (0, 23 mL, 2.84 mmol) in CHCl ₃ (5 mL, dried over K ₂ CO ₃ ) at 0 ° C. When the reaction was complete by TLC, the reaction mixture was diluted with CHCl ₃ , washed with ice water, dried ( Na ₂ SO _4), and concentrated. silica gel chromatography (10% MeOH / CHCl ₃₎ gave the title compound (0.41 g, 64%) as a colorless oil: ¹ H NMR (250 MHz, _CDCl3 ) δ 8.25 (dd, J = 6.0, 1.9 Hz, 1H), 7.25 (m, 4H), 4.35 (t, J = 6.2 Hz, 2H), 3, 75 (t, J = 6.6 Hz, 2H), 3.00 (s, 3H), 2.00 (m, 2H), 1.40 (s, 9H) unchanged 2- [Λ / - (3hydroxy) -1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine N-oxide (0.18 g, 36%) could also be obtained by chromatographic purification.

-47Preparing 10

Preparation of ethyl (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate

a) 6-Methoxy-1-phenylindene

A solution of 3.0 mol / L phenyl magnesium bromide in Et ₂ O (680 mL, 2.04 mol) under argon at ambient temperature was diluted with Et ₂ O (700 mL) with stirring, and added dropwise over 1 hour solution of 6-methoxy-1-indanone (277 g, 1.71 mol) in THF (1400 mL). The reaction mixture was stirred for 2 hours at ambient temperature and then poured under stirring into saturated NH ₄ Cl (2.8 L). H ₂ O (1.4 L) was added and the organic phase was separated. The aqueous phase was extracted with Et ₂ O (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 acid monohydrate (12.3 g, 0.065 mol) was added. The solution was stirred and heated under reflux for 16 hours using a Dean-Stark cap with a condenser. The capture of H ₂ O was at least 2 hours and was a total of 28 ml. The solution was cooled and extracted successively with an aqueous solution of 5% Na ₂ CO ₃ (1 L) and H ₂ O (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: mp 152-190 ° C / 0.267 kPa (2.0 Torr); TLC (10% EtOAc / hexanes) R _f 0.75.

b) 2-Benzoyl-4-methoxyphenylacetic acid

Acetone (4.2 L) was cooled to 10 ° C, and a solution of 6-methoxy-1-phenylindene (271 g, 1.22 mol) in acetone (1.8 L) was added over 1.5 hours simultaneously with Jones reagent ( 1.8 L, prepared from CrO ₃ (470 g, 4.70 mol), H ₂ O (1 L) and H ₂ SO ₄ (405 mL)). To the resulting mixture was added a 4% aqueous solution of OsO ₄ (153 mL) in two portions, one at the start of the addition and the other in the middle of the addition, keeping the temperature of the reaction mixture below 15 ° C. After the addition, the reaction mixture was warmed to 22 ° C and stirred for 1.5 hours during which time a slight exotherm raised the temperature to 28 ° C. The reaction mixture was then cooled to below 20 ° C

Isopropanol (1 L) was added dropwise initially and rapidly after the initial exothermic effect diminished. Stirring became difficult at this stage. The temperature reached 32 ° C during the isopropanol addition. H ₂ O (2 L) was added and the mixture was transferred to 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 (upper) layer was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 1 L). The combined CH ₂ Cl ₂ extracts were washed successively with H ₂ O (2 L) and saturated brine (2 L), and then concentrated to give a wet gray solid (416 g). This was 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 2.5 L pressure bottle. 5% Pd / C (10 g, 0.0048 mol) was added to each portion, and the mixtures were shaken at ambient temperature under a hydrogen atmosphere in a Parr apparatus. After 2.5 hours, the mixtures were filtered to remove the catalyst and the filter pad was washed with EtOAc. The combined filtrates were concentrated to give the title compound (215 g, quantitative) as a heavy yellow oil which crystallized on standing: ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.05-7.35 (m, 6 H), 6.77 (dd, J = 8.3, 2.7 Hz, 1H), 6.71 (d, J = 2.7 Hz, 1H), 4.00 (5, 2H), 3 76 (s, 3H); 3.54 (s, 2H).

d) 10,11-Dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one

A solution of 2-benzyl-4-methoxyphenylacetic acid (215 g of crude material containing 204.6 g (0.80 mol) of pure material) in CH ₂ Cl ₂ (1 L) was stirred under argon at ambient temperature, added DMF (1 mL), followed by oxalyl chloride (400 mL, 4.59 mol). Oxalyl chloride was added dropwise over 1 hour initially to control the vigorous gas evolution. The solution was stirred for 16 hours at ambient temperature and then concentrated to give 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 AlCl ₃ solution (100.8 g,

-490.756 mol) to CH ₂ Cl ₂ (3.7 L) with stirring under argon at ambient temperature. Upon completion of the addition, the temperature was 28 ° C. The reaction mixture was stirred for 16 hours at ambient temperature during which time a solid precipitated. H ₂ O (1 L) was added, initially dropwise, over a period of 30 minutes. The mixture was then separated and the organic phase was washed sequentially with H ₂ O (1 L) and 5% aqueous NaHCO ₃ (1 L). The CH ₂ Cl ₂ 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) Ethyl (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

A 1.0 mol / L solution of lithium bis (trimethylsilyl) amide in hexanes (1282 mL, 1.282 mol) was added to THF (4.0 L) at -70 ° C under an argon atmosphere, then added dropwise over 20 minutes with EtOAc (146 mL, 1.49 mol). The reaction mixture was allowed to stir for 15 minutes, then Ν, Ν, Ν ', Ν -tetramethylethylenediamine (378 mL, 2.5 mol) was added over 20 minutes. The reaction mixture was stirred for 10 minutes, then a solution of 10,11-dihydo-3-methoxy-5 H -dibenzo [a, d] cyclohepten-10-one (119.2 g, 0.50) was added dropwise over 40 minutes. mol) 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 H ₂ O (2 x II) and then concentrated to give a light brown oil (175 g). Thin layer chromatography (20% EtOAc / hexanes) showed _Rf 0.5 major (desired product) and R, a minor component of 0.7 (obtained by re-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 oil: ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.63 (d, J = 7.7Hz, 1H), 7.00-7.30 (m, 4H), 6.80 (d, J = 2.6Hz, 1H), 6.69 (dd, J = 8.2, 2.6 Hz, 1H), 3.95-4.35 (m, 2H), 4.07 (s, 2H), 3.76 (s, 3H), 3.68 (s, 1H) ), 3.64 (d, J = 14.2 Hz, 1H), 3.35 (d, J = 14.2

Ηζ50Ηζ, 1Η), 2.79 (d, J = 16.0 Hz, 1H). 2.66 (d, J = 16.0 Hz, 1 H). 1.22 (t, J = 7.2Hz, 3H).

f) Ethyl (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

Ethyl (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cycloheptene 10-acetate (101 g, 0.31 mol) was dissolved in glacial acetic acid (1.8 I) and 12 M HCl (28.5 mL, 0.34 mol) was added. The mixture was placed in a 2.5 L pressure flask containing 5% Pd / C (20 g, 0.0094 mol), and the resulting mixture was shaken at 35 ° C under a hydrogen atmosphere in a Parr hydrogenation apparatus equipped with jacketed heating. After 18 hours, the reaction mixture was cooled to ambient 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, step gradient with 5% to 10% EtOAc / hexanes) to give the title compound (69.1 g, 72%) as an oil: ¹ H NMR (250 MHz, CDCl 3) ₃ ) δ 7.05 7.22 (m, 4H), 7.01 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.2, 2.7 Hz, 1H), 4.30 (d, J = 15.0 Hz, 1H). 4.11 - 4.25 (m, 2H), 3.85 (d, J = 15.0 Hz, 1H), 3.70 - 3.90 (m, 1H). 3.77 (s, 3H), 3.31 (dd, J = 15.0, 4.1 Hz, 1H), 2.93 (dd, J = 15.0,

9.2 Hz, 1H), 2.64 (dd, J = 15.6, 5.0 Hz, 1H), 2.52 (dd, J = 15.6, 9.3 Hz, 1H), 1, 27 (t, J = 7.1Hz, 3H).

g) Ethyl (±) -10,11-dihydro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate

A solution of ethyl (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate (8.5 g, 0.027 mol) in CH ₂ Cl ₂ (150 mL) was cooled to - 10 ° C under stirring under argon. Ethanethiol (10.7 mL, 0.144 mol) was added, followed by AlCl ₃ (20.6 g, 0.154 mol) in two portions over 15 minutes. Following these additions, the exothermic reaction raised the temperature to 0 ° C and the temperature was then raised to 25 ° C using a water bath. The reaction mixture was stirred at 25-30 ° C for

2.25 hours when poured into ice-H ₂ O. The organic layer was separated, methanol (100 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (2 x 50 mL). The combined CH ₂ Cl ₂ extracts were washed with H ₂ O (250 mL) and then concentrated to give a viscous oil (8.6 g). This was dissolved in Et ₂ O (150 mL) and the ether removed by boiling

-51 replacing hexane. The desired phenol was first separated as an oil which crystallized with stirring at ambient temperature. Two yields of solid were collected to give the title compound (7.1 g, 89%): m.p. Mp 110-112 ° C.

Preparation 11

HPLC separation of enantiomers of ethyl (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate

(a) Ethyl (R) - (+) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate and ethyl (S) - (-) - 10, 11-Dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate

Ethyl (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate was resolved into its enantiomers using the following conditions: Daicel Chiralcel OJ® column (21.2 x 250 minutes), 20% ethanol in hexane mobile phase, 15 mL / min flow rate, uv detection at 254 nm, 140 mg injected; t _R for ethyl (S) - (-) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohexene-10-acetate =

10.4 minutes .; t _R for ethyl ( _R ) - (+) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cyclohexene-10-acetate = 13.1 minutes.

Preparation 12

Preparation of ethyl (±) -10,11-dihydro-7-fluoro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate

a) 1- (3- [Fluorophenyl) -6-methoxy-1-indanol

Following the procedure of Preparation 10 (a), except for substituting 3- [fluorophenylmagnesium bromide for phenylmagnesium bromide, the title compound was obtained as an amber oil: MS (ES) m / e 276.0 (M + H) ⁺ .

b) 1- (3- [Fluorophenyl) -6-methoxyindene

Following the procedure of Preparation 10 (a), except for substituting 1- (3- [fluorophenyl) -6-methoxy-1-indanol for 6-methoxy-1-phenyl-1-indanol, the title compound was obtained as a colorless oil, followed by silica gel chromatography (4%

-52 mass EtOAc / hexanes): MS (ES) m / e 241.1 (M + H) ⁺ .

c) 2- (3- [Fluorobenzoyl) -4-methoxyphenylacetic acid

Following the procedure of Preparation 10 (b), except for substituting 2- (3- [fluorophenyl) -6-methoxyindene for 6-methoxy-1-phenylindene, the title compound was obtained as a white solid; MS (ES) mlz 289.2 (M + H) ⁺ .

d) 2- (3- [Fluorobenzyl) -4-methoxyphenylacetic acid

Following the procedure of Preparation 10 (c), except for substituting 2- (3 [fluorobenzoyl) -4-methoxyphenylacetic acid for 2-benzoyl-4-methoxyphenylacetic acid, the title compound was obtained as a colorless oil; MS (ES &lt; - &gt;) m / e 273.2 ([delta]).

e) 10,11-Dihydro-7-fluoro-3-methoxy-5,7-dibenzo [a, d] cyclohepten-10-one

Following the procedure of Preparation 10 (d), with the exception of substituting 2- (3 [fluorobenzyl) -4-methoxyphenylacetic acid for 2-benzyl-4-methoxyphenylacetic acid, the title compound was obtained as a white solid; mp 129-130 ° C; MS (ES) m / e 279.2 (M + Na) ^&lt; ^{+ &gt};.

f) Ethyl (±) -10,11-dihydro-7-fluoro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (e), except for the replacement of 10,11-dihydro-7-fluoro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one with 10,11-dihydro-3-methoxy-5H-dibenzo [ a, d] cyclohepten-10-one, the title compound was obtained after chromatography on silica gel (8% EtOAc / hexanes): MS (ES) m / e 362.2 (M + NH ₄ ) ⁺ .

g) Ethyl (±) -10,11-dihydro-7-fluoro-3-methoxy-5,7-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (f), except for the substitution of ethyl (±) -10,11-dihydro-7-fluoro-10-hydroxy-3-methoxy-5 H -dibenzo [a, d] cycloheptene-10- acetate with ethyl 1- (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate,

The title compound was obtained as a colorless oil after silica gel chromatography (10% EtOAc / hexanes): MS (ES) m / e 329.2 (M + H) ⁺ .

h) Ethyl (±) -10,11-dihydro-7-fluoro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (g), except substituting ethyl (±) -10,11-dihydro-7-fluoro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl (±) -10,11-dihydro-3-methoxy-5 H -dibenzo [a, d] cycloheptene-10-acetate, the title compound was obtained as a white solid after silica gel chromatography (1% MeOH / CH ₂₎ Cl ₂ ): MS (ES) m / e 315.0 (M + H) ⁺ , 332.0 (M + NH 4 ⁺⁾ .

Preparation 13

Preparation of ethyl (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate

a) Ethyl (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate

To a solution of ethyl (±) -10,11-dihydro-7-fluoro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate (0.4 g, 1.33 mmol) in 95% ethanol containing 2 mol / L dimethylamine in MeOH (1.0 mL) was added an aqueous solution of 37% formaldehyde (0.5 mL) at room temperature under an argon atmosphere. After 20 hours, the reaction mixture was heated to reflux for 5 hours, then concentrated on a rotary evaporator. The residue was partitioned between H ₂ O and Et ₂ O and the layers were separated. The aqueous layer was extracted with Et ₂ O and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated on a rotary evaporator to give the title compound (330 mg, 67%) as a colorless oil: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (m, 1H), 6.88 (m, 2H), 6.67 (s, 2H), 4.25 (d, J = 15.1 Hz, 1H 4.18 (q, 2H), 3.78 (m, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.55 (s, 2H), 3.20 (dd) 1 H, 2.80 (dd, 1 H). 2.60 (dd, 1H), 2.53 (dd, 1H), 2.29 (s, 6H), 1.27 (t, 3H); MS (ES) mlz 372.3 (M + H) ⁺ .

-54Preparation 14

Preparation of ethyl (±) -10,11-dihydro-3-hydroxy-2-methyl-5 H -dibenzo [a, d] cycloheptene-10-acetate

a) Ethyl (±) -10,11-dihydro-2-formyl-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

POCl ₃ (17 mL) was added dropwise to a solution of ethyl (±) -10,11-dihydro-3-methoxy-5 H -dibenzo [a, d] cycloheptene-10-acetate (1.0 g, 3 mmol) in dry DMF (40 mL) at room temperature under an argon atmosphere, and the dark solution was heated at 90 ° C for 48 hours. The reaction mixture was concentrated on a rotary evaporator and the residue was partitioned between H ₂ O and EtOAc. The organic layer was separated, dried (MgSO 4 and concentrated on a rotary evaporator. The residue was reconcentrated from xylenes (to remove residual DMF) then chromatographed on silica gel (7% EtOAc in hexanes) to give the title compound (230 mg). , 21%) as a colorless oil: MS (ES) m / e 339.3 (M + H) ⁺ .

b) Ethyl (±) -10,11-dihydro-3-methoxy-2-methyl-5 H -dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl 1- (±) -10,11-dihydro-2-formyl-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate (220 mg, 0.65 mmol), 10% Pd / C (90 mg), glacial HOAc (15 mL), and concentrated HCl (2 mL) were shaken at room temperature under a hydrogen atmosphere (60 psi). 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 (ES) m / e 325.2 (M + H) ⁺ .

c) Ethyl (±) -10,11-dihydro-3-hydroxy-2-methyl-5,7-dibenzo [a, d] cycloheptene-10-acetate

To dry CH ₂ Cl ₂ (30 mL) cooled in an ice bath was added diethylsulfide (0.38 mL, 3.3 mmol), followed by AlCl ₃ (438 mg, 3.3 mmol). To this solution was added dropwise a solution of ethyl (±) -10,11-dihydro-3-methoxy-2-methyl-5 H -dibenzo [a, d] cycloheptene-10-acetate (200 mg, 0, 6 mmol) in dry CH ₂ Cl ₂ (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

-55 (MgSO 4) and concentrated on a rotary evaporator to give the title compound (100 mg, 56%) as a colorless oil: MS (ES) m / e 311.2 (M + H) ⁺ .

Preparation 15

Preparation of ethyl (±) -10,11-dihydro-3-hydroxy-6-methyl-5 H -dibenzo [a, d] cycloheptene-10-acetate

a) 6-Methoxy-1- (2-methylphenyl) -1-indanol

Following the procedure of Preparation 10 (a), except for the substitution of 2-methylphenylmagnesium bromide for phenylmagnesium bromide, the title compound was obtained as an oil: MS (ES) m / e 277.0 (M + Na) ⁺ .

b) 6-Methoxy-1- (2-methylphenyl) indene

Following the procedure of Preparation 10 (a), except for replacing 6-methoxy-1- (2-methylphenyl) -1-indanol with 6-methoxy-1-phenyl-1-indanol, the title compound was obtained as a colorless oil after chromatography on silica gel (3% EtOAc / hexanes): MS (ES) m / e 237.2 (M + H) ⁺ .

c) 4-Methoxy-2- (2-methylbenzoyl) phenylacetic acid

Following the procedure of Preparation 10 (b), with the exception of replacing 6-methoxy-1- (2-methylphenyl) indene with 6-methoxy-1-phenylindene, the title compound was obtained as a viscous oil; MS (ES) m / e 285.3 (M + NH ₄₎ ^+.

d) 4-Methoxy-2- (2-methylbenzyl) phenylacetic acid

Following the procedure of Preparation 10 (a), with the exception of substituting 4-methoxy-2- (2-methylbenzoyl) phenylacetic acid for 2-benzoyl-4-methoxyphenylacetic acid, the title compound was obtained as a viscous oil: MS (ES) m / e 288.2 (M + NH ₄ ) ⁺ .

e) 10,11-Dihydro-3-methoxy-6-methyl-5 H -dibenzo [a, d] cyclohepten-10-one

Following the procedure of Preparation 10 (d), except for substituting 4-methoxy-562- (2-methylbenzyl) phenylacetic acid for 2-benzyl-4-methoxyphenylacetic acid, the title compound was obtained as a white solid after silica gel chromatography (6% EtOAc / hexanes): MS (ES) m / e 253.0 (M + H) ⁺ .

f) Ethyl (±) -10,11-dihydro-10-hydroxy-3-methoxy-6-methyl-5B-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (e), except for the replacement of 10,11-dihydro-3-methoxy-6-methyl-5H-dibenzo [a, d] cyclohepten-10-one by 10,11-dihydro-3- methoxy5H-dibenzo [a, d] -cyclohepten-10-one, the title compound was obtained after silica gel chromatography (8% EtOAc / hexanes): MS (ES) m / e 358.2 (M + NH ₄ ) ⁺ .

g) Ethyl (±) -10,11-dihydro-3-methoxy-6-methyl-5 H -dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (f), except substituting ethyl (±) -10,11-dihydro-10-hydroxy-3-methoxy-6-methyl-5 H -dibenzo [a, d] cycloheptene-10- ethyl acetate with ethyl 1- (±) -10,11-dihydro-10-hydroxy-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate gave the title compound as a colorless oil after chromatography on silica gel (5% EtOAc / hexanes); MS (ES) m / e 325.3 (M + H +).

h) Ethyl (±) -10,11-dihydro-3-hydroxy-6-methyl-5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Preparation 10 (g), except substituting ethyl (±) -10,11-dihydro-3-methoxy-6-methyl-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl 1- (±) 10,11-Dihydro-3-methoxy-5H-dibenzo [a, d] cyclohexene-10-acetate gave the title compound as a white solid after trituration with MeOH: MS (ES) m / e 311 2 (M + H) &lt; ^{+ &gt};.

Preparation 16

Preparation of ethyl (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

-57a) Ethyl- (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-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 ethyl (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-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 h, the reaction mixture was concentrated and the residue was reconcentrated from xylenes (2 x). Silica gel chromatography (gradient: 1: 1 EtOAc / hexanes, then EtOAc, then 5% MeOH in 1: 1 EtOAc / CHCl ₃ ) gave the crude title compound. Unchanged (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate was recovered from the 1: 1 EtOAc / hexanes fractions. Re-chromatography of the crude title compound (3% MeOH in 1: 1 EtOAc / CHCl ₃ ) gave the pure title compound (0.72 g, 73%) as a yellow foam: TLC (10% MeOH in 1 : 1 EtOAc / CHCl ₃ ) R _f 0.59; ¹ H NMR (250 MHz, CDCl ₃ ) δ 8.19 (d, J = 7.1 Hz, 1H), 7.46 (d, J = 2.9 Hz, 1H), 7.35 (dd, J) = 7.1, 2.9 Hz, 1H), 7.00 7.30 (m, 5H), 7.00 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.6 Hz, 1H), 6.70 (dd, J = 8.2, 2.6 Hz, 1H), 4.29 (d, J = 15.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.08 (t, J = 5.5 Hz, 2H), 3.86 (d, J = 15.1 Hz, 1H), 3.72-3.90 ( m, 1H), 3.59 (q, J = 6.3 Hz, 2H), 3.30 (dd, J = 15.0, 4.2 Hz, 1H), 2.93 (dd, J = 15 0. 9.3 Hz (1H), 2.64 (dd, J = 15.6, 5.1 Hz, 1H), 2.51 (dd, J = 15.6, 9.3 Hz, 1H) 2.10-2.30 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) m / e 492 (M + H) &lt; - &gt;

Preparation 17

Preparation of ethyl (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] 5H-dibenzo [a, d] cycloheptene-10-acetate

a) Ethyl (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10 acetate

Following the procedure of Preparation 16, except substituting ethyl (S) -10,11-di-58hydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl (±) -10, 11-Dihydro-3-hydroxy-5H-dibenzo [a, d] -cycloheptene-10-acetate, the title compound was prepared: MS (ES) m / e 492 (M + H) ⁺ .

Preparation 18

Preparation of 10,11-Dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one

(a) 2-Benzyl-4-methoxyphenylacetic acid

A solution of 2-benzoyl-4-methoxyphenylacetic acid (13.0 g, 0.048 mol), prepared according to Method 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 50 psi for 17 hours. The mixture was filtered using Celite® and the filtrate was concentrated and reconcentrated from toluene and dichloromethane to give

14.2 g of the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.52 (s, 2H), 3.75 (s, 3H), 4.0 (s, 3H). 6.7 (m, 2H); 7.15 (m, 6H).

b) 10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cyclohepten-10-one

A solution of 2-benzyl-4-methoxyphenylacetic acid (14.2 g, 0.055 mol) in benzene (120 mL) and thionyl chloride (28 mL) was refluxed for 1 hour and concentrated. The acid chloride was dissolved in dry dichloromethane (40 mL) and the solution was added dropwise under argon to a solution of AlCl ₃ (14.7 g, 0.11 mol) in dichloromethane (600 mL). The reaction mixture was stirred under an argon atmosphere for 2.5 hours at room temperature, then quenched with an ice-water mixture (200 mL). The layers were separated and the organic phase was washed successively with 10% NaOH solution, water and dilute HCl. The resulting solution was diluted with ether (200 mL), dried over MgSO _4, and concentrated. The solid residue was triturated with ether / hexane (1: 1) and 9.35 g of the title compound was collected by filtration: mp 105-106 ° C; ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.72 (s, 3H), 4.1 (s, 2H), 4.2 (s, 2H), 6.7 (d, 1H), 6.82 (s, 1H); 7.30 (m, 4H); 8.1 (d, 1H).

-59Preparation 19

Preparation of ethyl (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

a) Ethyl (±) -3- (3-methoxyphenyl) indene acetate

To a cold solution of 3- (3-methoxyphenyl) indene (4 g, 18 mmol), prepared according to Method 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) over 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 over 30 minutes. After 2.5 hours, the reaction was quenched with saturated ammonium chloride solution and the layers were separated. The organic layer was dried over MgSO ₄ and concentrated to give a crude product which was purified by column chromatography (SiO ₂ / 2-4% EtOAc / hexane) to give the title compound (1.1 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.30 (t, 3H), 2.50 (m, 1H), 2.85 (m, 1H), 3.85 (s, 3H), 4 0 (m, 1H), 4.20 (9, 2H), 6.6 (s, 1H),

6.9 (m, 1H); 7.2 (s, 1H); 7.35 (m, 6H).

b) Ethyl (±) -3 - [(3-methoxybenzoyl)] phenylsuccinate

A solution of ethyl (±) -3- (3-methoxyphenyl) indeneacetate (1.1 g, 3.6 mmol) in acetone (30 mL) was treated with an aqueous solution of 4% w / w osmium tetroxide (0.5 mL), followed by addition of 1.2 M Jones reagent (5 mL, 6 mmol) dropwise according to the literature procedure (J. Org. Chem. 1993, 58, 4745). After stirring overnight at room temperature, the dark 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 ₄ , and concentrated to give a solid residue. Trituration with 1: 1 ether / hexane gave 0.76 g of the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18 (t, 3H), 2.90 (m, 1H), 3 3 (m, 1H), 3.92 (s, 3H), 4.1 (q, 2H), 4.4 (m, 1H), 4.4 (d, 1H), 7.25 (m, 2H), 7.5 (m, 6H).

c) Ethyl (±) -3 - [(3-methoxybenzyl)] phenylsuccinate

-60Mixes of ethyl (±) -3 - [(3-methoxybenzoyl)] phenyl succinate (0.76 g, 2.1 mmol) and 10% Pd / C (0.6 g) in glacial acetic acid (35 mL) were added. hydrogenated at 50 psi 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 dichloromethane to give 0.65 g of the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.20 (t, 3H), 2.20 (m, 1H ), 3.0 (m, 1H), 3.74 (s, 3H), 4.1 (q, 2H), 4.18 (q, 2H), 4.4 (d, 1H), 6.2 (m, 2H), 7.22 (m, 6H).

d) Ethyl (±) -10,11-dihydro-3-methoxy-11-oxo-5H-dibenzo [a, d] cycloheptene-10-acetate

To a magnetically stirred solution of ethyl (±) -3 - [(3-methoxybenzyl)] - phenylsuccinate (0.65 g, 1.9 mmol) in dry dichloromethane (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 dichloromethane (15 mL). The reaction mixture was quenched after 2 hours with ice water, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (SiO _z / 2-4% EtOAc / hexane) to give the title compound (0.3 g): ¹ H NMR (400 MHz, _CDCl3) δ 1.28 ( t, 3H), 2.88 (m, 1H), 3.55 (m, 1H), 3.84 (s, 3H), 3.88 (d, 1H), 4.18 (q, 2H), 4.85 (d, 1H), 4.95 (m, 1H), 5.8 (m, 2H), 7.22 (m, 4H), 8.1 (s, 1H).

e) Ethyl (±) -10,11-dihydro-3-methoxy-5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3-methoxy-11-oxo-5/7-dibenzo [a, d] cycloheptene-10-acetate (0.3 g, 0.93 mmol) and 10% Pd / C (0.3 g) in glacial acetic acid (25 mL) was hydrogenated at 50 psi for 18 hours. The mixture was filtered using Celite® and washed with acetic acid. The filtrate was concentrated and reconcentrated from toluene and dichloromethane to give 0.25 g of the title compound: ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.28 (t, 3H), 2.60 (m, 2H 1.90 (m, 1H), 3.30 (m, 1H), 3.80 (s, 3H), 3.85 (d, 1H), 4.18 (q, 2H), 4.30 (d, 1H), 6.70 (m, 2H), 7.0 (d, 1H), 7.22 (m, 4H).

-61 Preparation 20

Preparation of ethyl (±) -10,11-dihydro-3-hydroxy-dibenzo [b, f] oxepine-10-acetate

a) 4-Methoxy-2-phenoxyacetophenone

Following the procedure of Harris, TW 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 ) δ

7.90 (d, J = 8.8 Hz, 1H), 7.35 (m, 2H), 7.20 (m, 1H), 7.05 (m, 2H), 6.70 (dd, J = 2A, 8.8 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H). 3.75 (s, 3H); 2.61 (s, 3H).

b) 2- (4-Methoxy-2-phenoxyphenyl) -1-morpholin-4-ylethan-1-thione

Following the procedure of Harris, TW, et al. (J. Med. Chem. 1982, 25 (7), 855-858) were treated with 4-methoxy-2-phenoxyacetophenone (1.69 g, 6.98 mmol), sulfur (0.36 g, 11.2 mmol), and morpholine (0.98 mL, 11.2 mmol) to give the title compound (1.24 g) as a white solid: MS (ES) m / e 344.0 (M + H) ⁺ .

c) 2- (4-Methoxy-2-phenoxyphenyl) 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 H ₂ O (15 mL) was added KOH (0.57 g, 10.2 mmol). The reaction mixture was heated to reflux for 18 hours, then cooled to room temperature, diluted with H ₂ O and washed with Et ₂ O. The aqueous layer was acidified to pH = 4 with horses. HCl and extracted with CHCl ₃ . The combined extracts were dried over MgSO ₄ and concentrated to give the title compound (0.22 g) as a white solid. This was used without further purification: MS (ES) m / e 259.0 (M + H) ⁺ .

d) 3-Methoxydibenzo [b, f] oxepin-10-one

A solution of 2- (4-methoxy-2-phenoxyphenyl) acetic acid (594 mg, 2.3 mmol) in thionyl chloride (10 mL) was heated under 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.

- 62 ° C to a suspension of AlCl ₃ (673 mg, 5.06 mmol) in dry CH ₂ Cl ₂ (4 mL) in a flame-dried flask under an argon atmosphere. After stirring for 2.5 hours, the mixture was diluted with CH ₂ Cl ₂ (10 mL) and washed sequentially with 1.0 M NaOH and brine. Drying (MgSO ₄ ), concentration and flash chromatography on silica gel (5% EtOAc / hexanes) gave the title compound (264 mg, 48%) as a pale yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 3 80 (s, 3H), 4.02 (s, 2H), 6.74 - 8.08 (m, 7H).

e) Ethyl 1 - (+) - 10,11-dihydro-10-hydroxy-3-methoxydibenzo [b, f] oxepine-10-acetate

Anhydrous EtOAc (0.94 mL, 9.6 mmol) was added dropwise to a solution of lithium bis (trimethylsilyl) amide (1.0 M in THF, 7 mL, 7 mmol) in dry THF (7 mL) in flame dried at -78 ° C under an argon atmosphere. After 0.5 h, TMEDA (2.4 mL, 16 mmol) was added. After an additional 5 minutes, a solution of 3-methoxydibenzo [b, f] oxepin-10-one (760 mg, 3.2 mmol) in THF (2 mL) was added dropwise over 3 minutes. Additional dry THF (0.4 mL) was used for transfer. The reaction mixture was stirred at -78 ° C to -40 ° C for 1 hour, then quenched with saturated NH ₄ Cl solution (10 mL). The mixture was warmed to room temperature and extracted with EtOAc. Drying (MgSO ₄ ), concentration and flash chromatography on silica gel (10% EtOAc / hexanes) gave the title compound as a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.14-1.20 ( t, 3H), 1.21-1.30 (m, 1H), 2.62-2.68 (dd, 1H), 2.94-3.02 (dd, 1H), 3.24-3, 30 (dd, 1H), 3.40-3.46 (dd, 1H), 3.40-3.46 (dd, 1H), 3.78 (s, 3H), 4.08-4.18 ( m, 2H), 6.60-7.26 (m, 6H), 7.64-7.68 (dd, 1H).

f) Ethyl (±) -10,11-dihydro-3-methoxydibenzo [b, f] oxepine-10-acetate

Boron trifluoride etherate (0.48 mL, 3.9 mmol) was added to a solution of ethyl (±) 10,11-dihydro-10-hydroxy-3-methoxydibenzo [b, f] oxepine-10-acetate (690 mg, 1.95 mmol) and triethylsilane (0.62 mL, 3.9 mmol) in dry CH ₂ Cl ₂ at 0 ° C under argon. After 20 minutes, the reaction was quenched with 5% NaHCO ₃ solution and extracted with CH ₂ Cl ₂ . Drying (MgSO ₄ ) and concentration

-63 provided yellow oil. This was dissolved in absolute ethanol (20 mL) and 10% added.

Pd / C (413 mg, 0.39 mmol). The mixture was hydrogenated for 3 hours at 50 psi in a Parr hydrogenator. 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; Ή NMR (300 MHz, CDCl ₃ ) δ 7.18 - 6.58 (m, 7H), 4.18

4.08 (m, 2H), 3.80 (s, 3H), 3.80-3.74 (m, 1H), 3.40-3.30 (dd, 1H), 2.98-2 84 (dd, 1H), 2.74-2.62 (dd, 1H), 2.60-2.52 (m, 1H), 1.32-1.20 (t, 3H).

g) Ethyl (±) -10,11-dihydro-3-hydroxydibenzo [b, f] oxepine-10-acetate

A solution of ethyl (±) -10,11-dihydro-3-methoxydibenzo [b, f] oxepine-10-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 mixture was stirred for 20 minutes, then CH ₃ OH (7 mL) was carefully added. The mixture was concentrated and the residue was subjected to flash chromatography on silica gel (15

20% EtOAc / hexanes) to give the title compound (407 mg, 89%) as a pale yellow oil: MS (ES) m / e 299 (M + H +).

Preparation 21

Preparation of 2 - [(3-bromo-1-propyl) amino] -4-methylpyridine N-oxide hydrobromide

a) 2 - [(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 minutes to a solution of 2 - [(3-hydroxy-1-propyl) amino] -4 -methylpyridine-N-oxide (10.0 g, 54.87 mmol) in CH ₂ Cl ₂ (100 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours, then Et ₂ O (200 mL) was added slowly. 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 while standing in the refrigerator overnight. The solid was collected and washed with Et ₂ O to give the title compound (15.07 g) as a yellow solid. Additional title compound (2.05 g) was obtained as white needles by concentration

-64connected organic layers. The total yield of the title compound was

17.89 g (96%): MS (ES) m / e 245 and 247 (M + H) &lt; ^{+ &gt};.

The following compounds illustrate methods for preparing the biologically active compounds of this invention from intermediate compounds, such as those described in the previous Preparations.

Example 1

Preparation of (±) -10,11-Dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) 4- (2-Tetrahydropyranyloxy) -1-tributylstannyl-1-butyne

A solution of n-butyllithium in hexanes (1.6 M, 18.8 mL, 30 mmol) was added over a period of 2 minutes to a solution of 2- (3-butinyloxy) tetrahydro-2? 7 -pyran (4.7 mL, 30 mmol). ) in dry THF (60 mL) at 0 ° C under an argon atmosphere. After 0.5 h, tributyltin chloride (8.1 mL, 30 mmol) was added all at once, and the reaction mixture was warmed to room temperature. After 3 hours, the reaction mixture was diluted with hexanes (300 mL) and washed sequentially with H ₂ O (2 x 60 mL), 10% KF (2 x 30 mL), and saturated brine (60 mL). Drying (Na ₂ SO ₄ ), concentration and chromatography on silica gel (3% EtOAc / hexanes) gave the title compound (3.58 g, 27%) as an almost colorless oil: TLC (5% EtOAc / hexanes) R f 0.37: ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.66 (narrow t, 1H), 3.75-3.96 (m, 2H), 3.49-3.62 (m, 2H), 2.56 (apparent t, 2H), 1.76-1.91 (m, 1H), 1.65 1.78 (m, 1H), 1.42 -1.65 (m, 10H) 1.22 - 1.41 (m, 6H), 0.82 - 1.08 (m, 15H).

b) Ethyl (±) -10,11-dihydro-3- [4- (2-tetrahydropyranyloxy) -1-butan-1-yl] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- (trifluoromethanesulfonyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate (1.34 g, 3.13 mmol), 4- (2-tetrahydropyranyloxy) ) -1-tributylstannyl-1-butine (1.66 g, 3.76 mmol), LiCl (398 mg, 9.39 mmol), bis (triphenylphosphine) palladium chloride (110 mg, 0.094 mmol), and anhydrous dioxane ( 31 ml)

Was heated under reflux under an argon atmosphere. After 1.5 h, the reaction mixture was concentrated to remove most of the dioxane, and the residue was dissolved in Et ₂ O (100 mL); A solution of 10% KF (50 mL) was added and the mixture was stirred vigorously for 0.5 hour. The aqueous layer was removed and the Et ₂ O layer was filtered through a mixture of Celite ® and MgSO ₄ . The filtrate was concentrated and the residue chromatographed on silica gel (10% EtOAc / hexanes) to give the title compound (1.12 g, 83%) as a pale yellow oil: TLC (20% EtOAc / hexanes) R _f 0.40; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21-7.30 (m, 1H), 7.06-7.20 (m, 5H), 7.00 (d, J = 7.8 Hz) 1 H, 4.69 (t, J = 3.6 Hz, 1H), 4.31 (d, J = 15.2 Hz, 1H), 4.11 -4.23 (m, 2H), 3 76-3.97 (m, 4H), 3.59-3.68 (m, 1H), 3.48 3.57 (m, 1H), 3.34 (dd, J = 15.2, 4.3 Hz, 1H), 2.97 (dd, J = 15.2, 9.5 Hz, 1H), 2.70 (t, J = 7.3 Hz, 2H), 2.65 (dd, J = 15.7, 4.8 Hz, 1H), 2.51 (dd, J = 15.7, 9.5 Hz, 1H), 1.78 -1.92 (m, 1H) 1.38 (m, 1H), 1.44 -1.68 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) mle 455 (M + Na) ⁺ .

c) Ethyl (±) -10,11-dihydro-3- [4- (2-tetrahydropyranyloxy) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- [4- (2-tetrahydropyranyloxy) -1-butan-1-yl] -5,7-dibenzo [a, d] cycloheptene-10-acetate (1) , 2 g, 2.77 mmol), 10% Pd / C (0.3 g, 0.28 mmol) and EtOAc (28 mL) were shaken at room temperature under a hydrogen atmosphere (50 psi) in Parr device. After 3 hours, the reaction mixture 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: TLC (20% EtOAc / hexanes) R _f 0.51; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.05-7.20 (m, 4H), 6.92-7.03 (m, 3H), 4.53-4.60 (m, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.12-4.26 (m, 2H), 3.80-3.90 (m, 3H), 3.71-3.80 ( m, 1H), 3.44 3.53 (m, 1H), 3.35-3.44 (m, 1H), 3.33 (dd, J = 15.1, 4.1 Hz, 1H) 2.95 (dd, J = 15.1,

9.4 Hz, 1H), 1.65 (dd, J = 15.5, 4.9 Hz, 1H), 2.49-2.61 (m, 3H), 1.77-1.90 ( m, 1H), 1.45 - 1.77 (m, 9H), 1.27 (t, J = 7.1 Hz, 3H); MS (ES) m / e 459 (M + Na +).

-66d) Ethyl (±) -10,11-dihydro-3- (4-hydroxy-1-butyl) -5 H -dibenzo [a, d] cycloheptene-10-acetate

A solution of ethyl 1- (±) -10,11-dihydro-3- [4- (2-tetrahydropyranyloxy) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetate (456.0 mg, 1 , 04 mmol) and p-toluenesulfonic acid monohydrate (60 mg, 0.31 mmol) in absolute EtOH (10 mL) were stirred at room temperature. After 2 hours, the reaction was quenched with 5% NaHCO ₃ (1 mL) and concentrated to remove EtOH. The residue was diluted with H ₂ O (2 mL) and extracted with CH ₂ Cl ₂ . Drying (MgSO 4, concentration and silica gel chromatography (1: 1 EtOAc / hexanes) gave the title compound (342.4 mg, 93%) as a colorless oil: TLC (1: 1 EtOAc / hexanes) R _f 0.49 ¹ H NMR (250 MHz, CDCl ₃ ) δ 6.85-7.25 (m, 7H), 4.34 (d, J = 15.1 Hz, 1H), 4.08-4.30 ( m, 2H), 3.75-3.95 (m, 2H), 3.53-3.72 (m, 2H), 3.33 (dd, J = 15.1, 4.1 Hz, 1H) 2.95 (dd, J = 15.1, 9.4 Hz, 1H), 2.40-2.75 (m, 4H), 1.45-1.80 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H) MS (ES) m / e 353 (M + H) &lt; ^{+ &gt};.

e) Ethyl (±) -10,11-dihydro-3- [4- (N-phthalidimido) -1-butyl] -5 H -dibenzo [a, d] cycloheptene 10-acetate

Diethyl azodicarboxylate (0.2 mL, 1.26 mmol) was added dropwise to a solution of ethyl 1- (±) -10,11-dihydro-3- (4-hydroxy-1-butyl) -5- 7-dibenzo [a, d] cycloheptene n-10-acetate (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 an argon atmosphere. After 23 hours, the reaction mixture was concentrated on a rotary evaporator. Chromatography on silica gel (30% EtOAc / hexanes) gave the title compound (0.35 g, 70%) as a colorless oil: MS (ES) m / e 504.3 (M + Na) ⁺ .

f) Ethyl (±) -10,11-dihydro-3- (4-amino-1-butyl) -5H-dibenzo (a, d] cycloheptene-10-acetate

Hydrazine monohydrate (0.11 g, 2.18 mmol) was added to a solution of ethyl- (±) 10,11-dihydro-3- [4- (N -phthalimidoyl) -1-butyl] -5- - / - dibenzo [a, d] cycloheptene-10-acetate (0.35 g, 0.73 mmol) in absolute EtOH (10 mL) and toluene (2 mL) at room temperature

-67teplote. The reaction mixture was stirred at room temperature for 17 hours, then filtered and the filter pad was washed with toluene. Concentration on a rotary evaporator gave the title compound (0.23 g, 90%) as a colorless solid: MS (ES) m / e 352.3 (M + H +).

g) Ethyl (±) -10,11-dihydro-3- [4- (1-oxopyridin-2-ylamino) -1-butyl) -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of 2-chloropyridine N-oxide hydrochloride (0.31 g 1.88 mmol), ethyl (±) 10,11-dihydro-3- (4-amino-1-butyl) -5H-dibenzo [a, d] -cycloheptene-10-acetate (0.22 g, 0.63 mmol) and NaHCO ₃ (0.26 g, 3.13 mmol) in tert-amylalcohol (6 mL) was heated under reflux for 21 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and filtered, and the filtrate was concentrated on a rotary evaporator. Silica gel chromatography (1: 9: 5 MeOH / CH ₂ Cl ₂ / EtOAc) gave the title compound (82 mg, 30%) as a yellow oil: MS (ES) m / e 445.2 (M + H) ⁺ .

h) Ethyl (±) -10,11-dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- [4- (1-oxopyridin-2-ylamino) -1-butyl] -5 H -dibenzo [a, d] cycloheptene-10-acetate ( 0.07 g (0.16 mmol), 10% Pd / C (0.08 g, 0.075 mmol), cyclohexene (0.16 mL, 1.6 mmol) and isopropanol (4 mL) were heated under reflux under an argon atmosphere for 14 hours, then the catalyst was removed by filtration through Celite®. The filter pad was washed with isopropanol and MeOH and the filtrate was concentrated on a rotary evaporator to give the title compound (0.046 g, 69%) as a clear oil: MS (ES) m / e 429.3 (M + H +)

I) Ethyl (±) -10,11-dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Ethyl 1- (±) -10,11-dihydro-3- [4- (pyridin-2-ylamino) -1-butyl] -5H-dibenzo [a, d] cycloheptene-10-acetate mixture ( 46 mg, 0.11 mmol) and 1.0 M LiOH (0.66 mL, 0.66 mmol) in THF (3 mL) and H ₂ O (3 mL) were stirred at room temperature. After 24 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was concentrated

-68 diluted with H ₂ O (5 mL). The solution was cooled in an ice bath and 1.0 M AcOH was slowly added to give a white precipitate. Chromatography on C-18 YMC (45% CH ₃ CN / H ₂ O containing 0.1% TFA) gave the title compound (13 mg, 21%) as a white solid; MS (ES) m / e 401.3 (M + H +) Elemental analysis: Calculated for C ₂₆ H ₂₈ N ₂ O ₂ .0.75H ₂ O.1.5 CF ₃ CO ₂ H: C, 59.54; H N, 4.72. Found: C, 59.69; H, 5.31; N, 4.72.

Example 2

Preparation of (±) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Ethyl 1- (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10 acetate (0.67 g, 1.36 mmol), 3.0 M NaOEt in ethanol (6.8 mL, 6.8 mmol) and absolute ethanol (6.8 mL) were combined and the mixture was heated in oil bath set at 70 ° C. A dark solution was formed, which was heated for 10 minutes, then the oil bath was removed and the solution was allowed to stir for a further 5-7 minutes without external heating. The resulting solution was cooled in ice and the mixture 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 half-saturated 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 (MgSO ₄ ) and concentrated, and the residue was reconcentrated from toluene to give a reddish-orange oil. Chromatography on silica gel (5% MeOH / CHCl ₃ ) gave the title compound (601.1 mg, 90%) as a yellow oil: TLC (5% MeOH / CHCl ₃ ) R f 0.36; ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.95 (d, J = 7.1 Hz, 1H), 6.88 7.30 (m, 6 H), 6.77 (d, J = 2, 6 Hz, 1H), 6.67 (dd, J = 8.2, 2.6 Hz, 1H), 5.95-6.20 (m, 2H), 4.28 (d, J = 15, 0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.04 (t, J = 5.6 Hz, 2H), 3.65-4.00 (m, 4H) 3.46 (q, J = 6.5Hz, 2H), 3.30 (dd, J = 15.0, 4.2Hz, 1H), 2.93

-69 (dd, J = 15.0, 9.2 Hz, 1H), 2.65 (dd, J = 15.6, 5.0 Hz, 1H), 2.52 (dd, J = 15.6 9.4 Hz, 1H), 1.95-2.25 (m, 2H), 1.10-1.45 (m, 6H); MS (ES) mle 491 (M + H) ⁺ .

b) Ethyl (±) -10,11-dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-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) were heated to reflux. under an argon atmosphere. After 23.5 hours, the reaction mixture was hot filtered through Celite® and the filter pad was washed with ethanol. The filtrate was concentrated and the residue was reconcentrated from toluene. Chromatography on silica gel (5% MeOH in 1: 1 EtOAc / CHCl ₃ ) gave the title compound (528.1 mg, 90%) as a pale yellow oil; TLC (10% MeOH in EtOAc / CHCl ₃ ) R _f 0.67; 1 H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, J 5.8 Hz, 1H), 7.05-7.18 (m, 4H), 6.99 (d, J = 8.2) Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.66 (dd, J = 8.2, 2.6 Hz, 1H), 6.17 (dd, J = 5) Δ, 2.1 Hz, 1H), 5.86 (d, J =

2.1 Hz, 1H), 4.73 (broad t, 1H), 4.28 (d, J = 14.9 Hz, 1H), 4.11 - 4.25 (m, 2H), 4.04 ( t, J = 5.9 Hz, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 14.9 Hz, 1H), 3.76-3, 85 (m, 1H), 3.43 (q, J = 6.4 Hz, 2H), 3.30 (dd, J = 15.0, 4.1 Hz, 1H), 2.93 (dd, J) = 15.0,

9.2 Hz, 1H), 2.64 (dd, J = 15.6, 4.8 Hz, 1H), 2.52 (dd, J = 15.6, 9.5 Hz, 1H), 2.01 2 11 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); MS (ES) mlz 475 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

1.0 M NaOH (1.7 mL, 1.7 mmol) was added dropwise to a solution of ethyl (±) -10,11-dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) - 1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate (528.1 mg, 1.11 mmol) in absolute ethanol (11 mL) at room temperature and the solution was heated in an oil bath set at 45 ° C. After 20 hours, the reaction mixture was concentrated and the residue was reconcentrated from

70h ₂ O. The resulting residue was dissolved in H ₂ O (10 mL) and the solution filtered. The pH was adjusted to 7 with 1.0 M HCl and the mixture was vigorously stirred to convert the initially formed gummy precipitate to a solid. Spreading with a glass rod and spatula has helped in this transformation. The pH of the resulting mixture was re-adjusted to 7 and the solid was collected and washed with plenty of H ₂ O. The filtrate was concentrated and the residue was dissolved in H _Z O by means of a small amount of 1.0 mol / L NaOH. The pH was adjusted to 7 to give a small second yield. The yields 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% CH ₃ CN) (H ₂ O containing 0.1% TFA) k '= 1.32; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (d, J = 6.6 Hz, 1H), 7.35-7.65 (m, 1H), 7.02-7.22 ( m, 4H), 6.97 (d, J = 8.3Hz, 1H), 6.82 (d, J =

2.4 Hz, 1H), 6.68 (dd, J = 8.3, 2.4 Hz, 1H), 6.29 (dd, 1H), 6.15 (narrow d, 1H), 4.20 (d, J = 14.6 Hz, 1H), 3.93-4.12 (m, 4H), 3.89 (d, J = 14.6 Hz, 1H), 3.60-3.71 ( m, 1H)

3.30-3.50 (m, 2H), 3.20 (dd, J = 15.1, 4.1 Hz, 1H), 2.83 (dd, J = 15.1, 10.1 Hz, 1H), 2.60 (dd, J = 16.0, 5.3 Hz, 1H), 2.48 (dd, J = 16.0, 8.9 Hz, 1H, partially concealed by solvent residue signal), 1 90-2.05 (m, 2H); 1.30 (t, J = 6.9 Hz, 3H); MS (ES) mle 447 (M + H) ⁺ . Elemental: Calculated for C ₂₇ H ₃₀ N ₂ O ₄ .1,5HCI: C, 64.70; H, 6.33; N, 5.59. Found: C, 64.53; 14,6,14; N, 5.31.

Example 3

Preparation of (±) -10,11-dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5 H -dibenzo [a, d] cycloheptene-10- acetate

a) Ethyl 1- (±) -10,11-dihydro-3- [2- [2- (ethylamino) thiazol-4-yl] -1-ethoxy] -5H-dibenzo [a] , d] cycloheptene-10-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 the solution. ethyl (±) -10,11-dihydro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate (296.4 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in

-71 anhydrous DMF (5 mL) at room temperature. The reaction mixture was kept cold in a water bath at room temperature during the addition. After 16 hours, the reaction mixture 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: TLC (1: 1 EtOAc / hexanes) R f 0.60; ¹ H NMR (250 MHz, CDCl ₃ ) δ 7.00-7.30 (m, 4H), 6.98 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 2, 6 Hz, 1H), 6.68 (dd, J = 8.2, 2.6 Hz, 1H), 6.21 (s, 1H), 5.00-5.25 (m, 1H), 4, 04 - 4.38 (m, 5H), 3.81 (d, J = 15.1 Hz, 1H), 3.70 - 3.90 (m, 1H), 3.13 - 3.40 (m, 3H), 2.99 (t, J = 6.7 Hz, 2H), 2.92 (dd, J = 14.9, 9.3 Hz, 1H), 2.64 (dd, J = 15.6) 5.0 Hz, 1H), 2.51 (dd, J = 15.6, 9.3 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H); MS (ES) mle 451 (M + H) ⁺ .

(b) (±) -10,11-Dihydro-3- [2- [2- (ethylamino) -thiazol-4-yl] -1-ethoxy] -5,7-dibenzo [a, d] cycloheptene-10- acid

1.0 M LiOH (0.32 mL, 0.32 mmol) was added dropwise to a solution of ethyl (±) -10,11-dihydro-3- [2- [2- (ethylamino) thiazole-4-] yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (145.0 mg, 0.32 mmol) in THF (2.4 mL) and H ₂ O (0.48 mL) at 0 ° C. The resulting pinkish-orange biphasic mixture was stirred at 0 ° C for 10 minutes, during which time the color turned orange-yellow, then warmed to room temperature. After 1.5 hours, a little H ₂ O (5 drops) was added and the reaction mixture was stirred for 42 hours, then cooled to 0 ° C and neutralized with TFA (0.025 mL). THF was removed on a rotary evaporator and the resulting oily residue was diluted with 0.1% TFA / CH ₃ CN to give a homogeneous solution. ODS chromatography (gradient: 40% CH ₃ CN / H ₂ O containing 0.1% TFA, then 45% CH ₃ CN / H ₂ O containing 0.1% TFA) gave fractions containing the title compound . These were combined and the CH ₃ CN was removed on a rotary evaporator. The resulting aqueous mixture was basified at 0 ° C to give a homogeneous solution. Careful acidification to pH 4-5 with 1.0 M HCl gave a solid precipitate which was collected, washed with a large amount of H ₂ O, and dried to give the title compound.

-72this paragraph (80.9 mg, 51%) as an off-white solid: HPLC (Hamilton PRP1®, 45% CH ₃ CN / H ₂ O containing 0.1% TFA) k '= 0.89; ¹ H NMR (400 MHz, CD ₃ OD) δ 7.02-7.18 (m, 4H), 7.00 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2) 6 Hz, 1H), 6.68 (dd, J = 8.3, 2.6 Hz, 1H), 6.45 (s, 1H), 4.26 (d, J =

14.9 Hz, 1H), 4.20 (t, J = 6.4 Hz, 2H), 3.87 (d, J = 14.9 Hz, 1H), 3.68-3.80 (m, 1H), 3.34 (q, J = 7.3 Hz, 2H, partially concealed by solvent residue signal), 3.30 (dd, 1H, concealed by solvent residue signal), 2.99 (t, J = 6, 4 Hz, 2H), 2.92 (dd, J = 15.0, 9.4 Hz, 1H), 2.62 (dd, J = 15.9, 5.0 Hz, 1H), 2.47 ( dd, J = 15.9, 9.3 Hz, 1H), 1.27 (t, J = 7.3 Hz, 3H); MS (ES) mlz 423 (M + H) ⁺ . Elemental analysis: Calculated for C ₂₄ H ₂₆ N ₂ O ₃ S.0.67 CF ₃ CO ₂ H: C, 61.03; 14, 5.39; N, 5.62. Found: C, 61.21; H, 5.36; N, 5.60.

Example 4

Preparation of (S) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate

To a stirred solution of ethyl (S) -10,11-dihydro-3-hydroxy-5,7-dibenzo [a, d] cycloheptene-10-acetate (35 g, 118 mmol) in dry THF (1.1 L) and dry DMF (600 mL) was added under argon atmosphere 2 - [(3-hydroxy-1-propyl) amino] pyridine / N -oxide (29.4 g, 175 mmol) and triphenylphosphine (45.9 g, 175 mmol) ). When all solids had completely dissolved (about 1 hour), the reaction mixture was cooled to 0 ° C in an ice bath and diisopropyl azodicarboxylate (36.4 mL, 95%, 175 mmol) was added via syringe. The reaction mixture was allowed to warm slowly to room temperature and stirred for 18 hours. Concentration and flash chromatography on silica gel (95: 5 CHCl / MeOH), followed by the second purification by flash silica gel chromatography (80: 20: 5 CHCl ₃ / EtOAc / EtOH) gave the title compound (37.66 g , 71%) as a pale yellow solid foam: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (dd, J = 6.3, 1.1 Hz, 1H), 7.29 (t, 1H 7.19-7.06 (m, 5H), 6.97 (d,

-73 J = 8.3 Hz, 1H), 6.84 (d, J = 2.5, 1H), 6.79 (dd, J = 8.5, 1.6 Hz, 1H), 6.69 ( dd, J = 8.3, 2.6 Hz, 1H), 6.57 (m, 1H), 4.17 (d, J = 14.7 Hz, 1H), 4.13-4.07 (m) (2H), 4.00 (t, 2H), 3.91 (d, J = 14.7 Hz, 1H), 3.66 (m, 1H), 3.39 (t, 2H), 3.19 (dd, J = 15.1, 4.5 Hz, 1H), 2.85 (dd, J = 15.1, 10.0 Hz, 1H) 2.65 (dd, J = 15.8, 5, 4 Hz, 1H), 1.99 (m, 2H), 1.18 (t, 3H); MS (ES) mlz 447.3 (M + H) ⁺

b) Ethyl (S) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate

To a stirred solution of ethyl (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) was added 10% palladium on charcoal (18 g, 16.9 mmol, carefully pre-wet in isopropanol under argon) and cyclohexene (85 mL, 839 mmol). The reaction mixture was then heated under reflux under an argon atmosphere in an oil bath set at 90 ° C. After 6 hours, an additional amount of 10% palladium on charcoal (18 g, 84 mmol, carefully pre-wet in isopropanol under argon) and cyclohexene (85 mL, 839 mmol) were added. After an additional 18 hours, the reaction mixture was filtered hot through Celite® and the filter pad was washed with 1: 1 MeOH / CHCl ₃ (600 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (95: 5 CHCl ₃ / MeOH) to give the title compound (29.2 g, 81%) as a pale yellow oil: Ή NMR (400 MHz, _DMSO-d6) δ 7.94 (dd, J = 5.4, 1.9 Hz, 1H), 7.35 to 7.31 (m, 1H), 7.18 (d, J = 7 2 Hz, 1H), 7.14-7.06 (m, 3H), 6.97 (d, J = 8.3 Hz, 1H), 6.83 (d, J = 2.6, 1H) 6.68 (dd, J = 8.3, 2.6 Hz, 1H), 6.54 (t, 1H), 6.44 (m, 2H), 4.17 (d, J = 14.6) Hz, 1H), 4.13-4.02 (m, 2H), 4.00 (t, 2H), 3.91 (d, J = 14.7 Hz, 1H), 3.66 (m, 1H) ), 3.35 (m, 2H), 3.19 (dd, J = 15.1, 4.4 Hz, 1H), 2.86 (dd, J = 15.1, 10.1 Hz, 1H) 2.65 (dd, J = 15.8, 5.4 Hz, 1H), 2.55 (dd, J = 15.8, 8.7 Hz, 1H), 1.93 (m, 2H), 1.18 (t, 3 H); MS (ES) mlz 431.4 (M + H) ⁺ .

(c) (S) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

To a stirred solution of ethyl (S) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -7,4-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate (29 , 20 g, 68 mmol) in dioxane (350 mL) was added aqueous 1.0 M NaOH (110 mL, 110 mmol). The cloudy reaction mixture was stirred at 50 ° C in an oil bath for 24 hours, then the resulting homogeneous solution was neutralized with an aqueous 1.0 M HCl solution (110 mL, 110 mmol). The solution was concentrated to near dryness using a rotary evaporator to precipitate the product. The supernatant was decanted off and the remaining gummy solid was dried under vacuum and redissolved in 1: 1 methanol / CHCl ₃ . The clear solution was then concentrated using a rotary evaporator and thoroughly dried under vacuum. The remaining solid was triturated with a small volume of water, filtered and dried under vacuum to give the title compound (26.85 g, 94%) as an off-white powder: HPLC (Hamilton PRP-1®, 35% CH ₃₎ CN / H ₂ O containing 0.1% TFA) k '= 2.88; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.94 (dd, J = 4.7, 1.6 Hz, 1H), 7.38 (m, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 3.9 Hz, 2H), 7.08 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6 83 (d, J = 8.6 Hz, 1H), 6.78 (broad s, 1H), 6.68 (dd, J = 8.3, 2.6 Hz, 1H), 6.50 (d , J =

8.3 Hz, 1H), 6.47 (dd, 1H), 4.20 (d, J = 14.6 Hz, 1H), 4.00 (t, 2H), 3.88 (d, J = 14.6 Hz, 1H), 3.67 (m, 1H), 3.37 (m, 1H), 3.20 (dd, J = 15.2, 4.4 Hz, 1H), 2.83 (dd, J = 15.2, 10.1 Hz, 1H), 2.60 (dd, J = 15.9, 5.3 Hz, 1H), 2.50 (dd, 1H), 1.95 ( m, 2H); MS (ES) mlz 403.3 (M + H) ⁺ . Elemental analysis: Calculated for C ₂₅ H ₆ N ₂ O ₃ · H 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- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A 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 ethyl (±). -10,11-dihydro-3-hydroxy-5 H -dibenzo [a, d] -cycloheptene-10-acetate and

- 75-triphenylphosphine (0.48 g, 1.82 mmol) in anhydrous DMF (5 mL) at room temperature. After 1 hour, the reaction mixture 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 (ES) mle 417 (M + H) ⁺ .

(b) (±) -10,11-Dihydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

A solution of ethyl (±) -10,11-dihydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (0.030 g, 0.072 mmol) and 1.0 N NaOH (0.14 mL, 0.14 mmol) in MeOH (2 mL) was stirred at room temperature overnight, then concentrated. The residue was dissolved in H ₂ O and the pH of the solution was adjusted to 7 with 1.0 M HCl. Concentration and column chromatography on C-18 Bond Elute (10: 9: 1 CH ₃ CN / H ₂ O / TFA) gave the title compound (0.013 g): MS (ES) m / e 389 (M + H) ⁺ .

Example 6

Preparation of (R) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate

A solution of 2 - [(3-hydroxy-1-propyl) amino) pyridine N -oxide (0.70 g, 4 mmol) and diethyl azodicarboxylate (0.65 mL, 4 mmol) in anhydrous DMF (20 mL) was added. dropwise over 10 minutes into a solution of ethyl (R) - 10,11-dihydro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate (0.45 g, 2 mmol) and triphenylphosphine (1.2 g, 4 mmol) in anhydrous DMF (8 mL) at room temperature under an argon atmosphere. After 23.5 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was reconcentrated from xylenes to remove the DMF residue. Silica gel chromatography (1 to 4% CH ₃ OH / CH ₂ Cl ₂ ) gave the title compound (0.50 g 74%) as a yellow oil: MS (ES) m / e 447 (M + H) ⁺

-76b) Ethyl (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl 10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (0.5 g, 1 mmol) 10% Pd / C (0.25 g, 0.2 mmol), cyclohexene (2 mL, 20 mmol) and isopropanol (10 mL) were heated under reflux for 18 hours, then the catalyst was removed by filtration through Celite®. Silica gel chromatography (0.5-2% CH ₃ OH / CH ₂ Cl ₂ ) gave the title compound (0.4 g, 83%) as a pale yellow oil: MS (ES) m / e 431 (M + H) ⁺ .

(c) (R) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

A mixture of ethyl (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-di-benzo [a, d] cycloheptene-10-acetate (0, 4 g, 93 mmol) and 1.0 M 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 mixture was concentrated on a rotary evaporator and the residue was dissolved in H ₂ O. The aqueous solution was adjusted to pH 4 with 3 mol / L HCl and the solid precipitate was collected and washed with H ₂ O. The material was dried in a high vacuum. 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 (ES) mlz 403 (M + H) ⁺ . Elemental: Calculated for C ₂₆ H _{2 S 2} O ₃ N ₂ O .0,5H: 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- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -1-5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -5 H -dibenzo [a, d] cycloheptene- 10-acetate

Following the procedure of Example 6 (a), except for substituting 6- (methylamino) -2-pyridyl-ethanol for 2 - [(3-hydroxy-1-propyl) amino] pyridine - N -oxide, and ethyl (S) -10 11dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihyd-77ro-3-hydroxy-5H-dibenzo [a, d] cycloheptene- 10-acetate, the title compound was obtained as a colorless oil after chromatography on silica gel (0.2 to 2% MeOH / CH ₂ Cl ₂ ): MS (ES) 431.2 (M + H +).

(b) (S) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -5 H -dibenzo [a, d] cycloheptene-10 acetic acid

Ethyl 1- (S) -10,11-dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate ( 80 mg, 0.18 mmol) was dissolved in THF (4 mL) and a solution of LiOH.H ₂ O (35 mg, 0.84 mmol) in H ₂ O (4 mL) was added. The solution was stirred at room temperature for 72 hours then diluted with ether (10 mL). The supernatant was decanted and the solid was suspended in H ₂ O. Careful acidification to pH 4 with 3 mol / L HCl gave the title compound as a white solid: MS (ES) 403 (M + H) ⁺ . Elemental: Calculated for C ₂₅ H ₂₆ N ₂ O ₃ .0,75H ₂ O: 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- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [3- (4-nitrobenzyloxycarbonyl) amino-1-propyloxy] -5F / d ibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (a), except for the substitution of 3- (4-nitro-benzyloxycarbonylamino) -1-propanol for 2 - [(3-hydroxy-1-propyl) amino] pyridine- N -oxide and ethyl- (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl (R) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate, the title compound was obtained as an amber oil: MS (ES) 533.3 (M + H) ⁺ .

b) Ethyl (±) -10,11-dihydro-3- (3-amino-1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- [3- (4-nitrobenzyloxycarbonylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (1.6 g, 3 mmol) ), 10% palladium on carbon

-78 (0.8 g, 1 mmol) and ethanol (50 mL) were shaken under H ₂ (48 psi) for 3 hours, 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 (ES) 348.2 (M + H) ⁺ .

c) Ethyl (±) -10,11-dihydro-3- [3- (pyrimidin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- (3-amino-1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10-acetate (0.4 g, 1 mmol) 1), sodium bicarbonate (0.5 g, 6 mmol), 2-bromopyrimidine (0.34 g, 2 mmol), and ethanol (10 mL) were heated under reflux under argon for 18 hours. The solution was then decanted and concentrated. The residue was purified by silica gel chromatography (0.2 to 2% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.17 g 34%) as a pale yellow oil: MS (ES) 432, 3 (M + H) &lt; ^{+ &gt};.

d) Ethyl- (±) -10,11-dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzofa, d] cycloheptene-10 acetate

A mixture of ethyl (±) -10,11-dihydro-3- [3- (pyrimidin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate (0, 17 g, 0.38 mmol), 10% palladium on carbon (0.085 g, 0.08 mmol), 4 mol / L HCl in dioxane (0.1 mL, 0.4 mmol) and ethanol (5 mL) were shaken. under H ₂ (48 psi) for 6 hours, 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 (ES) 436.3 (M + H) ⁺ .

(e) (±) -10,11-Dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] - cycloheptene-10-acetic acid

Ethyl (±) -10,11-dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10 solution acetate (0.17 g, 0.36 mmol), lithium hydroxide monohydrate (0.042 g, 1 mmol), THF (3 mL), and water (10 mL) were stirred at room temperature for 20 hours, then concentrated. The rest

-79 dissolved in water and the solution was adjusted to pH 4 with 3 mol / L HCl. The resulting solution was kept in the refrigerator overnight, 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 brown solid: MS (ES) 408.3 (M + H) ⁺ . Elemental: Calculated for C ₂₄ H ₂₉ N ₃ O ₃ .1,3HCI: 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- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5H-ibenzo [a] dicycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [3- (1-oxoisoquinolin-1-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (a), except for substituting 1 - [(3-hydroxy-1-propyl) amino] -isoquinoline-1 H -oxide for 2 - [(3-hydroxy-1-propyl) amino] pyridine-]. N -oxide, and replacing ethyl (±) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3 hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate, the title compound was prepared as a pale yellow oil: MS (ES) m / e 497.2 (M + H) ⁺ .

b) Ethyl (±) -10,11-dihydro-3- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (b), except substituting ethyl (±) -10,11-dihydro-3- [3- (1-oxoisoquinolin-1-ylamino) -1-propyloxy] -5,7-dibenzo [a, dicycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate was prepared the title compound as a clear oil: MS (ES) m / e 481.3 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-3- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

According to the procedure of Example 6 (c), except for the replacement of ethyl (±) -10,11-dihydro-3- [3- (isoquinolin-1-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate, was prepared the title compound as an amber solid: MS (ES) m / e 453.2 (M + H) ⁺ . Elemental: Calculated for C ₂₉ H ₂₈ N ₂ O _3, 1,3TFA.0,25H ₂ O: 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- [3- [4- (ethylthio) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-acetate

a) Ethyl- (±) -10,11-dihydro-3- [3- [4- (ethylthio) -1-oxopyridin-2-ylamino] -1-propyloxy] -5 H -benzo [a, d] cycloheptene 10-acetate

Ethyl 1- (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene solution Of 10-acetate (300 mg, 0.61 mmol) and sodium triethylate (145 mg, 1.22 mmol) in DMF (5 mL) was heated at 70 ° C for 3 hours. The solvent was removed on a rotary evaporator and the residue was purified by silica gel chromatography (2 to 6% CH ₃ OH / CH ₂ Cl ₂ ) to give the title compound (90 mg) as an orange oil; MS (ES) m / e

507.3 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11-dihydro-3- [3- [4- (ethylthio) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Ethyl 1- (±) -10,11-dihydro-3- [3 - [- (ethylthio) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a] d] cycloheptene-10-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 H ₂ O and EtOAc and the pH was adjusted to 7-8 with solid Na ₂ CO ₃ . The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H ₂ O, dried (MgSO 4,

-81 and concentrated to give the title compound (60 mg, as a yellow oil: MS (ES) m / e 491.3 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-3- (3- [4- (ethylthio) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10- acid

Following the procedure of Example 6 (c), with the exception of substituting ethyl (±) -10,11-dihydro-3- [3- [4- (ethylthio) pyridin-2-ylamino) -1-propyloxy] -5 H- dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- (3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-acetate, yellow title compound was prepared; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77-7.76 (d, 1H), 7.17-7.15 (d, 1H), 7.13-7.12 (d, 2H), 7.08-7.07 (m, 1H), 6.96-6.94 (d, 1H), 6.81-6.80 (d) s, 1H), 6.68

6.67 (d, 1H), 6.52 (s, 1H), 6.35-6.33 (d, 2H), 6.30 (s, 1H), 4.20-4.16 (d) 1H, 3.99-3.96 (t, 2H), 3.89-3.85 (d, 1H), 3.65-3.63 (m, 1H), 3.36-3.32 (m, 2H), 3.22

3.15 (m, 1H); 2.96-2.90 (m, 2H); 2.85-2.78 (m, 1H), 2.62-2.56 (m, 2H), 1.94 1.90 (m, 2H), 1.26 -1.22 (t, 3H) ; MS (ES) mlz 463.4 (M + H) ⁺ .

Example 11

Preparation of (±) -10,11-Dihydro-2-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] 5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-2-methyl-3- [3 - [N - (tert -butoxycarbonyl) - N - (1-oxopyridin-2-yl) amino] -1-propyloxy] 5H-dibenzo [a, d] cycloheptene-10-acetate

NaH (60% dispersion in mineral oil (0.14 g, 0.37 mmol) was added to a solution of ethyl 1- (±) -10,11-dihydro-3-hydroxy-2-methyl-5H-dibenzo [a, d] cycloheptene-10-acetate (100 mg, 0.32 mmol) in DMSO (2 mL) under an argon atmosphere and the reaction mixture was stirred at room temperature for 0.5 h, then a solution of 2 - [- V - ( 3-methanesulfonyloxy-1-propyl) - N - (tert -butoxycarbonyl) amino] -pyridine N -oxide (160 mg, 0.4 mmol) in DMSO (1 mL) The reaction mixture was stirred at room temperature under argon atmosphere for 18 hours, then quenched with water (20 mL) and extracted with EtOAc.

-82 (MgSO ₄ ), concentration and silica gel chromatography (1% MeOH / CH ₂ Cl ₂ ) gave the title compound (85 mg, 42%) as a colorless oil: MS (ES) m / e 561.3 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11-dihydro-2-methyl-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-ibenzo [a] cycloheptene-10-acetate

TFA (0.16 g, 1.4 mmol) was added dropwise to a solution of ethyl 1- (+) - 10,11-dihydro-2-methyl-3- [3 - [N - (tert -butoxycarbonyl) - N]. - (1-oxopyridin-2-yl) amino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (80 mg, 0.14 mmol) in dry CH ₂ Cl ₂ (3 mL) . The reaction mixture was stirred for 5 hours then concentrated on a rotary evaporator to give the title compound (60 mg, 43%) as a colorless oil: MS (ES) m / e 461.1 (M + H) +

c) Ethyl (±) -10,11-dihydro-2-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (b), except substituting ethyl (±) -10,11-dihydro-2-methyl-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [ a, d] cycloheptene-10-acetate with ethyl (ph) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate, the title compound was prepared as an off-white solid: MS (ES) m / e 417.3 (M + H) ⁺ .

d) (±) -10,11-Dihydro-2-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Following the procedure of Example 6 (c), except substituting ethyl (±) -10,11-dihydro-2-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, dicycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate, the title compound was obtained as an off-white solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (d, 1H), 7.65 (t, 1H), 7.15 (m, 3H), 7.05 (m, 1H), 6.83 (s, 1H), 6.7 (d, 1H), 6.65 (m, 1H), 6.60 (s, 1H), 4.25 (d J = 15.1 Hz, 1H), 4.05 (t, 2H), 3.80 (m, 1H), 3.75 (d, J = 15.1 Hz, 1H), 3.50 (t , 2H).

-833.25 (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, 3H); MS (ES) mlz 417.3 (M + H) ⁺ .

Example 12

Preparation of (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] - cycloheptene-10-acetate

a) Ethyl 1- (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] - 5W-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (a), except substituting ethyl (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl (R) - 10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate gave the title compound after silica gel chromatography (gradient: 1: 1 EtOAc) : hexanes, then EtOAc, then 20% MeOH / CH ₂ Cl ₂ , then 30% MeOH / CH ₂ Cl ₂ ): MS (ES) m / e 522.3 (M + H) ⁺ .

b) Ethyl- (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (b), except substituting ethyl (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (1-oxopyridin-2-ylamino) -1] -propyloxy] 5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] - 5H-dibenzo [a, d] cycloheptene-10-acetate, the title compound was obtained after silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ): MS (ES) m / e 506.2 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Saponification was performed according to the procedure of Example 6 (c), except substituting ethyl (±) -10,11-dihydro-2- (dimethylamino) methyl-7-fluoro-3- [3- (pyridin-2-ylamino)]. -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-di-84hydro-3- [3- (pyridine-2-) ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate. The reaction mixture was acidified with glacial HOAc and the crude product was desalted by chromatography on an XAD-2 ion exchanger to give the title compound as a white solid: MS (ES) m / e 478.3 (M + H +). Calcd for C ₃₀ H ₃₆ FN ₃ O ₅ .1.25H ₂ O: C, 64.32; H, 6.92; N, 7.50. Found: C, 63.87; H, 6.47; N, 7.96.

Example 13

Preparation of (S) -10,11-Dihydro-3- (3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a] d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A solution of 2 - [(3-hydroxy-1-propyl) amino) -4-methylpyridine-1 H -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 ethyl (S) -10,11-dihydro-3-hydroxy-5Hd ibenzoyl, dicycloheptene-10-acetate (1.4 g, 4.72) mmol) and triphenylphosphine (2.60 g, 9.92 mmol) in anhydrous DMF (50 mL) at room temperature under an argon atmosphere. After 19 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was reconcentrated from xylenes to remove residual DMF. Chromatography on silica gel (gradient: 30% EtOAc / hexanes (0.5 L) then EtOAc (1 L) then 5% MeOH / CHCl ₃ ) gave the title compound (1.31 g, 60%) as a yellow oil: MS (ES) m / e 461.3 (M + H) ⁺ .

b) Ethyl (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (S) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-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) were heated under at reflux under argon for 19 hours, then the catalyst was removed by filtration through Celite®. Silica gel chromatography

-85 (1: 9: 10 MeOH / CH ₂ Cl ₂ / EtOAc) gave the title compound (0.65 g, 78%) as a clear oil: MS (ES) m / e 445.2 (M + H) ) ⁺ .

(c) (S) -10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetic acid

A mixture of ethyl (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy) 5 H -dibenzo [a, d] cycloheptene-10-acetate (2) , 08 g, 4.69 mmol) and 1.0 N NaOH (7.0 mL, 7.0 mmol) in absolute EtOH (45 mL) was heated in an oil bath set at 45 ° C. After 18 hours, the reaction mixture was concentrated on a rotary evaporator and the pH was adjusted to 7 with 1.0 M HCl. The solid precipitate was collected and washed with H ₂ O. Overnight drying afforded the title compound (1.61 g, 82%) as an almost colorless solid: MS (ES) m / e 417.4 (M + H). ) ⁺ . Elemental: Calculated for C ₂₆ H ₂₈ N ₂ O ₃ .1,0H ₂ O: 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- [3- [4- (2-propyloxy) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10- acetate

a) Isopropyl- (S) -10,11-dihydro-3- [3- [4- (2-propyloxy) -1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate (0.2 g 0.4 mmol) and sodium isopropoxide (0.067 g, 0.8 mmol) in isopropanol (5 mL) was heated to 80 ° C for

3.5 hours, then additional sodium isopropoxide (0.05 g, 0.6 mmol) was added and the reaction mixture was stirred at room temperature overnight. Concentration and chromatography on silica gel (gradient: 5% to 15% MeOH / CH ₂ Cl ₂ ) gave the title compound (0.106 g, 52%) as a light brown oil: MS (ES) 519.3 (M + H) ) ⁺ .

-86b) Isopropyl- (S) -10,11-dihydro-3- [3- [4- (2-propyloxy) pyridin-2-ylamino) -1-propyloxy] -5H-d ibenzo [a, d] cycloheptene 10-acetate

Following the procedure of Example 13 (b), except for the replacement of isopropyl- (S) 10,11 -dihydro-3- [3- [4- (2-propyloxy) -1-oxopyridin-2-ylamino] -1-propyloxy] -5B-dibenzo [a, d] cycloheptene-10-acetate with ethyl (S) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H -dibenzo [a, d] cycloheptene-10-acetate gave the title compound as a pale yellow oil after chromatography on silica gel (5% MeOH / CH ₂ Cl ₂ ): MS (ES) 503.4 (M + H) ⁺ .

(c) (S) -10,11-Dihydro-3- [3- [4- (2-propyloxy) pyridin-2-ylamino] -1-propyloxy] 5 H -dibenzo [a, d] cycloheptene-10- acid

Following the procedure of Example 13 (c), except for the replacement of isopropyl- (S) 10,11-dihydro-3- [3- [4- (2-propyloxy) pyridin-2-ylamino] -1-propyloxy) -5AY- dibenzo [a, d] cycloheptene-10-acetate with ethyl (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate, the title compound was obtained as a white powder: MS (ES) 461.3 (M + H) ⁺ . Elemental: Calculated for C ₂₈ H ₃₂ N ₂ O4 0.96HCI: 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- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A solution of ethyl (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-acetate (0.47 g, 0.96 mmol) in acetyl chloride (7 mL, 98 mmol) was heated under reflux for 1 hour. The reaction mixture was poured into ice (50 g) and the pH was adjusted to 8.0 using saturated NaHCO ₃ solution (caution: fizzing!). The mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL) and the combined organic layers were washed sequentially with H ₂ O (50 mL) and brine (50 mL).

-87 Drying (MgSO 4 and concentration gave the title compound: MS (ES) 481.2 (M + H) ⁺ .

b) Ethyl (S) -10,11-dihydro-3- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Ethyl (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate (0.13 g, 0.27 mmol) and 2.0 M PCl ₃ in CH ₂ Cl ₂ (8 mL, 16 mmol) was heated under reflux for 22 hours. The reaction mixture was cooled and poured into ice (200 g) and the pH was adjusted to 12 using 40% NaOH. CH ₂ Cl ₂ (2 x 100 mL) extraction, drying (MgSO 4, concentration and chromatography on silica gel (4% MeOH / CH ₂ Cl ₂ ) gave the title compound (93 mg, 74%) as a pale yellow oil: MS (ES) 465.3 (M + H) &lt; ^{+ &gt};.

(c) (S) -10,11-Dihydro-3- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

Following the procedure of Example 13 (c), except substituting ethyl (S) -10,11-dihydro-3- [3- (4-chloropyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] of cycloheptene-10-acetate with ethyl (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] 5 H -dibenzo [a, d] cycloheptene-10- acetate, the title compound was obtained as an off-white powder: MS (ES) 437.2 (M + H +) Elemental analysis: Calculated for C ₂₅ H ₂₅ N ₂ O ₃ · 1.0HCl: C, 63.43; N, 5.92. Found: C, 63.11; H, 5.82; N, 5.62.

Example 16

Preparation of (S) -10,11-Dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene- 10-acetate

Ethyl (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate solution (0.47 g, 0.96 mmol) in acetyl chloride (7

(88 ml, 98 mmol) was heated under reflux for 1 hour. The reaction mixture was poured into ice (50 g) and the pH was adjusted to 8.0 using saturated NaHCO ₃ solution (caution: fizzing!). The mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL) and the combined organic layers were washed sequentially with H ₂ O (50 mL) and brine (50 mL). Drying (MgSO 4) and concentration gave the crude title compound, which was used without further purification. MS (ES) 481.3 (M + H) &lt; ^{+ &gt};.

b) Ethyl 1 - (- S) -10,11-dihydro-3- [3- [4- (dimethylamino) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A mixture of ethyl (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetate (0.96 mmol) and 2.0 M dimethylamine in MeOH (3 mL, 6 mmol) was refluxed for 16 h. Concentration and chromatography on silica gel (7% MeOH / CH ₂ Cl ₂ ) gave the title compound (0.049 g, 10%) as a light brown powder: MS (ES) 490.3 (M + H) ⁺ . Unchanged ethyl (S) -10,11-dihydro-3- [3- (4-chloro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate also obtained from chromatographic purification.

c) Ethyl (S) -10,11-dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10 acetate

Following the procedure of Example 13 (b), except substituting ethyl (S) -10,11-dihydro-3- [3- [4- (dimethylamino) -1-oxopyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (S) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a] d) cycloheptene-10-acetate, the title compound was obtained as a white powder after silica gel chromatography (8% MeOH / CH ₂ Cl ₂ ); MS (ES) 474.3 (M + H) &lt; ^{+ &gt};.

(d) (S) -10,11-Dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Following the procedure of Example 13 (c), except substituting ethyl (S) -10,11-dihydro-3- [3- [4- (dimethylamino) pyridin-2-ylamino] -1-propyloxy] -5H-dibenzo [a] , d] -cycl-89loheptene-10-acetate with ethyl (S) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a] , d] cycloheptene-10-acetate, the title compound was obtained as a white powder: MS (ES) 446.2 (M + H +).

Calcd for C 27 H ₃₁ N ₃ O ₃ .0,5H2O.1,0HCI: 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- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] 5 H -dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (S) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, b] cycloheptene-10-acetate

Following the procedure of Example 2 (a), except substituting ethyl (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5A7-dibenzo [ a, d] cycloheptene-10-acetate (496.9 mg, 1.01 mmol) with ethyl (±) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-Propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate using 0.53 mol / L NaOEt (4.0 mL, 2.12 mmol) and absolute ethanol (10 mL) in the replacement reaction , the title compound (456.2 mg, 92%) was prepared: MS (ES) m / e 491 (M + H + +).

b) Ethyl (S) -10,11-dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 2 (b), except substituting ethyl (S) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy] -5/7- dibenzo [a, d] cycloheptene-10-acetate (456.2 mg, 0.93 mmol) with ethyl (±) -10,11-dihydro-3- [3- (4-ethoxy-1-oxopyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10-acetate, the title compound (475.2 mg, quantitative) was prepared: MS (ES) m / e 475 (M +) Hf.

(90c) (S) -10,11-Dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

1.0 M NaOH (2.0 mL, 2.0 mmol) was added to a solution of ethyl (S) -10,11-dihydro-3- [3- (4-ethoxy-pyridin-2-ylamino) -1-propyloxy ] -5 / 7-dibenzo [a, d] cycloheptene-10-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 mixture was concentrated and the aqueous residue was cooled to 0 ° C in an ice bath. 1.0 M aqueous HCl (2.0 mL, 2.0 mmol) was added slowly with stirring. An opaque solid residue precipitated and was separated using a fritted filter funnel. Drying in a vacuum desiccator overnight provided the title compound (452.6 mg, 83%): MS (ES) m / e 447 (M + H) ⁺ . Elemental: Calculated for C ₂₇ H ₃₀ N ₂ O ₄ 0.20H ₂ 0.1,75HCI: 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- [3- (pyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl- (±) -10,11-dihydro-7-fluoro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5,7-dibenzo [a, d] cycloheptene-10- acetate

Following the procedure of Example 6 (a), except substituting ethyl (±) -10,11-dihydro-7-fluoro-3-hydroxy-5H-dibenzo [a, d] cycloheptene-10-acetate for ethyl - (R) -10,11 dihydro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate gave the title compound as a colorless oil after silica gel chromatography (gradient: 1: 1 EtOAc / hexanes) then EtOAc, then 4% MeOH / CH ₂ Cl ₂ ): MS (ES) m / e

465.3 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11-dihydro-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10 acetate

Following the procedure of Example 6 (b), except substituting ethyl- (±) -10,11-dihydro-7-fluoro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5 H- -dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyl-91 oxy] -5H- dibenzo [a, dicycloheptene-10-acetate, the title compound was obtained: MS (ES) m / e 449.2 (M + H) ⁺

(c) (±) -10,11-Dihydro-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Following the procedure of Example 6 (c), except substituting ethyl (±) -10,11-dihydro-7-fluoro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate, the title substance is obtained; MS (ES) mlz 421.1 (M + H) ⁺ . Elemental analysis: Calculated for C ₂₅ H ₂₅ FN ₂ O ₃ · 0.5H ₂ O: 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- [3- (pyridin-2-ylamino) -1-propyloxy] 5H-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl (±) -10,11-dihydro-6-methyl-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzofa, dicycloheptene-10-acetate

Following the procedure of Example 6 (a), except replacing ethyl (±) -10.11 dihydro-3-hydroxy-6-methyl-5H-dibenzo [a, d] cycloheptene-10-acetate with ethyl (R) 10,11-dihydro-3-hydroxy-5 H -dibenzo [a, d] cycloheptene-10-acetate gave the title compound as a colorless oil after silica gel chromatography (gradient: 1: 1 EtOAc / hexanes then EtOAc, then 4% MeOH / CH ₂ Cl ₂ ): MS (ES) m / e

461.3 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11-dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

Following the procedure of Example 6 (b), except substituting ethyl (±) -10,11-dihydro-6-methyl-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [ α, d] -cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- [3- (1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [ and, d] cycloheptene-10-acetate, the title compound was obtained

-92 after silica gel chromatography (1% MeOH / CH ₂ Cl ₂ ): MS (ES) m / e 445.3 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid

Following the procedure of Example 6 (c), except substituting ethyl (±) -10,11-dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [ a, d] cycloheptene-10-acetate with ethyl (R) -10,11-dihydro-3- (3- (pyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene -10-acetate, the title compound was obtained as a white solid: MS (ES) m / e 417.3 (M + H) + Elemental analysis: Calculated for C ₂₆ H ₂₈ N ₂ O ₃ .1.25H ₂ O: 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- [3- (4-aminopyridin-2-ylamino) -1-propyloxy] 5,7-dibenzo [a, d] cycloheptene-10-acetic acid

a) Ethyl- (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10- acetate

A solution of diisopropyl azodicarboxylate (1.7 mL, 8 mmol) in THF (30 mL) was added dropwise to a solution of ethyl (S) -10,11-dihydro-3-hydroxy-5H-dibenzo [a, d] cycloheptene -10-acetate (426.5 mg, 1.5 mmol), 2 - [(3-hydroxy-1-propyl) amino] -4-nitropyridine-N-oxide (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, then warmed to room temperature. After 23 hours, the reaction mixture was concentrated. Chromatography on silica gel (gradient; 30% to 100% EtOAc / hexanes) gave the title compound (2.7 g, 81%) as an orange foam: MS (ES) m / e 491.8 (M + H) ⁺ .

b) Ethyl (S) -10,11-dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cyclobeptene-10-acetate

-93Mix ethyl- (S) -10,11-dihydro-3- [3- (4-nitro-1-oxopyridin-2-ylamino) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10- acetate (2.7 g, 6 mmol), cyclohexene (6 mL, 60 mmol), 10% Pd / C (1.2 g 1.10 mmol) and isopropanol (30 mL) were heated under reflux under argon for 20 min. 5 hours, then hot filtered through Celite®. The filter layer was washed with hot EtOAc and the combined filtrates were concentrated. The residue was chromatographed on silica gel (5% MeOH / CHCl 3) to give the title compound (2.4 g, 98%) as a colorless foam; MS (ES) mlz 445.9 (M + H) ⁺ .

(c) (S) -10,11-Dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy) -5H-dibenzo [a, d] cycloheptene-10-acetic acid

A mixture of ethyl (S) -10,11-dihydro-3- [3- (4-aminopyridin-2-ylamino) -1-propyloxy) 5α-dibenzo [a, d] cycloheptene-10-acetate (2.4 g) , 5 mmol), LiOH H ₂ O (0.3 g, 7 mmol), THF (30 mL) and H ₂ O (10 mL) were stirred at room temperature for 48 h then concentrated. The residue was diluted with H ₂ O and extracted with Et ₂ O. The Et ₂ O layers were discarded. The aqueous layer was stirred with gentle heating under vacuum to remove residual organic solvents, then filtered. The resulting aqueous solution was stirred at room temperature while adjusting the pH slowly and carefully to 5.5-6.0 with 1.0 M HCl. The mixture was stirred for 0.5 h, then the solid was collected by suction filtration and washed with a large amount of H ₂ O. Drying under high vacuum at 60 ° C gave the title compound (1.0 g, 42%). as a glassy solid: MS (ES) m / e 417.7 (M + H) ⁺ . Elemental analysis: Calculated for C ₂₅ H ₂₇ N ₃ O ₃ .1.4HCl (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- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepine-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepine-10-acetate

-94Mixes of ethyl (±) -10,11-dihydro-3-hydroxydibenzo [b, f] oxepine-10-acetate (257 mg, 0.86 mmol) 2 - [(3-bromo-1-propyl) hydrobromide amino] -4-methylpyridine-N-oxide (308 mg, 0.94 mmol), NaOH pellets (110 mg, 2.75 mmol) and CH ₃ CN (4 mL) were stirred at room temperature under argon for night. The mixture was filtered and the solids were washed with CH ₃ CN. The filtrate was concentrated and the residue was flash chromatographed 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 (ES) m / e 462.6 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11 -dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepine-10-acetate

A mixture of ethyl (±) -10,11-dihydro-3- [3- (4-methyl-1-oxopyridin-2-ylamino) -1-propyloxy] dibenzo [b, f] oxepine-10-acetate (183 mg) , 0.4 mmol), 10% Pd / C (85 mg, 0.08 mmol), cyclohexene (810 mg, 8 mmol) and isopropanol (4 mL) were heated at 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 (ES) m / e 446.9 (M + H) ⁺ .

c) (±) -10,11-Dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy) dibenzo [b, f] oxepine-10-acetic acid

A mixture of ethyl (±) -10,11-dihydro-3- [3- (4-methylpyridin-2-ylamino) -1-propyloxy) dibenzo [b, f] oxepine-10-acetate (119 mg, 0, 27 mmol) and 0.991 N NaOH (0.545 mL, 0.54 mmol) in absolute EtOH (2 mL) was heated in an oil bath set at 45 ° C. After 20 hours, the reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in H ₂ O (1.5 mL). The solution was filtered to remove insoluble material and the filtrate was carefully neutralized by dropwise addition of 1.0 M HCl (0.54 mL, 0.54 mmol). The precipitate was collected and dried under high vacuum to give the title compound (68 mg, 58%) as a white solid: MS (ES) m / e 418.9 (M + H) ⁺ . Elemental analysis: Calculated for C ₂₅ H ₂₆ N ₂ O ₄ · 0.45HCl: C, 69.05; H, 6.13; N, 6.44. Found: C, 69.25; H, 6.27; N, 6.16.

Example 95

Preparation of (±) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid

a) Ethyl (±) -10,11-dihydro-3- [2-6- [N-tert-butoxycarbonyl] -N-methylamino] pyridin-2-yl] 1-ethoxy] dibenzo [b, f ] oxepin-10-acetate

A solution of 6 - [N- (tert-butoxycarbonyl) - N -methylamino] -2-pyridylethanol (397 mg, 1.58 mmol) and diisopropyl azodicarboxylate (0.31 mL, 1.58 mmol) in anhydrous CH ₂ Cl ₂ (8 mL) was added dropwise over 10 minutes to a solution of ethyl (±) -10,11-dihydro-3-hydroxy-dibenzo [b, f] oxepine-10-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 h, the reaction mixture was concentrated on a rotary evaporator and the residue was flash chromatographed on silica gel (2-13% EtOAc / hexanes) to give the title compound (146 mg, 44%) as a clear oil: MS ( ESI) m / e 533.0 (M + H) &lt; ^{+ &gt};.

b) Ethyl (±) -10,11-dihydro-3- (2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid 1 L HCl in dioxane (1.3 mL, 5.2 mmol) was added dropwise to a solution of Ethyl 1 - (+) - 10,11 -dihydro-3- [2-6 - [N-tert-butoxycarbonyl] N-methylamino] pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetate (140 mg, 0.26 mmol) in CH ₂ Cl ₂ (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 (ES) m / e 432.9 (M + H) ⁺ .

(c) (±) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid

Ethyl (±) -10,11-dihydro-3- [2- [6- (methylamino) pyridin-2-yl) -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid (0, 26 mmol) and 0.991 mol / L NaOH (0.525 mL, 0.52 mmol) in absolute EtOH (2 mL) was heated in an oil bath set at 50 ° C. After 20 hours, the reaction mixture was concentrated to rotary

The evaporator was dissolved in H ₂ O (1.5 mL). The solution was filtered to remove insoluble material and the filtrate was carefully neutralized by dropwise addition of 1.0 M HCl. The precipitate was collected and dried under high vacuum to give the title compound (72 mg, 30% for 2 steps) as an off-white solid: MS (ES) m / e 405.0 (M + H) ⁺ . Elemental: Calculated for C ₂₄ H ₂₄ N ₂ O ₄ .1,25HCI.0,25H ₂ O: C, 63.42; H, 5.7 L; N, 6.16. Found: C, 63.35; H, 5.9; N, 6.16.

Example 23

Preparation of (S) -10,11-Dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-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 according to WO94 / 14776 in THF (10 mL)) was added over 45 minutes to lithium aluminum hydride (12 mL). (12 mmol, 1 mol / L in THF) at 0 [deg.] C. The ice bath was removed and the reaction mixture was allowed to stir at room temperature for 4.5 hours, cooled to 0 [deg.] C., diluted with toluene (22 mL). and the reaction was 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 another 10% solution. MeOH in CHCl _3. the combined filtrate was concentrated under reduced pressure. Flash chromatography (10% MeOH / CHCl _3, silica gel) gave 0.25 g of the desired material as a clear oil: MS (ES +) m / z 152.7 [m + H) \

b) Ethyl (S) -10,11-dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetate

A solution of Example 1 (a) (0.23 g, 1.51 mmol) and di-isopropyl azadicarboxylate (0.29 mL, 1.50 mmol) in CH ₂ Cl ₂ (7.5 mL) was added dropwise to the solution. 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 removed and the reaction mixture was allowed to warm to room temperature. After 18 hours, the solvent was removed under reduced pressure. Flash chromatography (50% EtOAc / hexanes to 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 g of the desired material: MS (ES +) m / e

430.9 [M + H] +.

(c) (S) -10,11-Dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid

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 mixture at 50 ° C for 18 hours, the solvent was removed under reduced pressure. The residue was dissolved in H ₂ O (4 mL) and filtered. The filtrate was acidified with 30% TFA in H ₂ O and the resulting precipitate was collected. Preparative HPLC (Hamilton PRP-1 ®, 3% CH ₃ CN / H ₂ O-0.1% TFA) gave 10 mg of the desired material as a hygroscopic solid: MS (ES +) m / z 402.6 [M + H) ⁺ .

Example 24

Parenteral unit dose composition

A formulation containing 20 mg of the compound of Example 1 as a sterile dry powder was prepared as follows: 20 mg of the compound was dissolved in 15 mL of distilled water. The solution was filtered under sterile conditions into a 25 ml multidose vial and lyophilized. The powder is reconstituted by adding 20 ml of a 5% dextrose in water (D5W) solution for intravenous or intramuscular injection. Thus, the dose is determined by the volume of injection. Subsequent dilution may be made by adding a metered volume of this dosage unit to an additional volume of D5W for injection, or the metered dose may be added to another drug delivery mechanism, such as a IV drip bottle or bag or other injection-infusion system.

Example 98

Oral unit dose composition

Capsules for oral administration were prepared 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 was sorted and filled into a hard gelatin capsule.

Example 26

Oral unit dose composition

A tablet for oral administration was prepared 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 solution of 10% by weight of gelatin. The wet granules were sorted, dried, mixed with 10 mg of starch, 5 mg of talc and 3 mg of stearic acid; and pressed into a tablet.

The above description fully describes how to make and use the present invention. However, the invention is not limited to the specific embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. Various references to magazines, patents and other publications cited herein include prior art and are incorporated herein by reference in order to be fully incorporated by reference.

Claims (33)

PATENT CLAIMS A compound comprising a dibenzocycloheptene core of formula I wherein A is _CH2 or O; R ¹ is H, halogen or C 1-4 alkyl; ^R2 is H, alkyl or CH ₂ NRR; X is O or CH _2; Y is or G is NR, S, or O; -100R 'is H, C _1-4 alkyl, OC 1-4 alkyl, S 1-4 alkyl, NRR or halogen; each R is independently H or C 1-4 alkyl; and s is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein Y is K -NR R 'wherein R' is H, C _1-4 alkyl, OC _ML alkyl, SC _M alkyl, NR R or Cl and each R is independently H or C _1-4 alkyl. The compound of claim 1, wherein Y is wherein each R is H or C ₁ . ₄ alkyl, The compound of claim 1, wherein Y is N NR "NR wherein each R is independently H or C _{first 4} alkyl, and the first -101 The compound of claim 1, wherein Y is wherein G is S and each R 1 is independently H or C ₁₄ alkyl. The compound of claim 1, wherein Y is wherein R is H or C 1-4 alkyl. A compound according to claim 1 which is selected from: (±) -10,11-dihydro-3- [2- (6-aminopyridin-2-yl) -1-ethoxy] -5H-dibenzo [a, djcykloheptén-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] -5,7-dibenzo [a, d] cycloheptene-10-acetic acid; (R) -10,11-Dihydro-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5 H -dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-3- [3- (3,4,5,6-tetrahydropyrimidin-2-ylamino) -1-propyloxy] -5 H -benzo [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; -102 (±) -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] -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-ethoxy-pyridin-2-ylamino) -1-propyloxy) -5 H -dibenzo [a, d] cycloheptene-10-acetic acid; (±) -10,11-Dihydro-6-methyl-3- [3- (pyridin-2-ylamino) -1-propyloxy] -5,7-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- 10-acetic acid; (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 [b, f] oxepine-10-acetic acid; (±) -10,11-Dihydro-3- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] dibenzo [b, f] oxepine-10-acetic acid; or -103 (S) -10,11-Dihydro-3- [3- (2-aminopyridin-4-yl) -1-propyloxy] -5H-dibenzo [a, d] cycloheptene-10-acetic acid; or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula (I) according to claim 1, comprising treating a compound of formula (IV) with a compound of formula (V) wherein R ¹ , R ² , Y and A are for formula I with protected reactive functionalities. groups, and L ¹ is OH or halogen; and then deprotecting, and optionally forming a pharmaceutically acceptable salt. 9. A process for the preparation of a compound of formula (I) according to claim 1 which comprises treating a compound of formula (VI) with a compound of formula (IV). R '(VI) wherein R ¹ , R ² , R', R and A are as defined for formula I, with protected reactive functional groups; and then deprotecting and optionally forming a pharmaceutically acceptable salt. -104 10. Preparation of the compound of formula I according to claim 1, characterized uj account whether in that it comprises reacting a compound of formula VII to a compound of formula IV wherein R ^1, R ^2, R and A are as defined in formula I, protected reactive functional groups; and then deprotecting and optionally forming a pharmaceutically acceptable salt. 11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition comprising a compound of claim 1, an antineoplastic agent, and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 12, wherein the antineoplastic agent is topotecan. 14. The pharmaceutical composition of claim 12, wherein the antineoplastic agent is cisplatin. 15. The compound of claim 1 for use in treating a disease state in which antagonism is indicated receptor _α ν β _third -105 16. The compound of claim 1 for use in treating a disease state in which antagonism is indicated receptor _α ν β _fifth The compound of claim 1 for use in the treatment of osteoporosis. The compound of claim 1 for use in inhibiting angiogenesis. The compound of claim 1 for use in inhibiting tumor growth or tumor metastasis. The compound of claim 1 for use in the treatment of atherosclerosis or restenosis. A compound according to claim 1 for use in the treatment of inflammation. A compound according to any one of claims 1 to 7 for use as a medicament. 23. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which antagonism is indicated _α ν β ₃ receptor. 24. The use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of diseases in which antagonism is indicated _α ν β ₅ receptor. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of osteoporosis. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for inhibiting angiogenesis. -10627. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for inhibiting tumor growth and tumor metastasis. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of atherosclerosis or restenosis. Use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of inflammation. Use of a compound of formula I according to claim 1 and an antineoplastic agent for the manufacture of a medicament for inhibiting tumor growth in physical combination or sequential administration. Use according to claim 30, characterized in that the antineoplastic agent is topotecan. Use according to claim 30, characterized in that the antineoplastic agent is cisplatin. Use of a compound of formula I according to claim 1 and a bone resorption inhibitor for the manufacture of a medicament for the treatment of osteoporosis in physical combination or sequential administration. An intermediate of formula II wherein Y- (CH _{2) second 3} —X F CO ₂ C ,. ₆ alkyl (II) -107 A is CH ₂ or O; R ¹ is H, halogen or C 1-4 alkyl; R ² is H, CMalkyl or CH ₂ NRR; X is O or CH ₂ ; Y is or G is NR 11, S or O; R 'is H, C 1-4 alkyl, OC 1-4 alkyl, SC _1-4 alkyl, NR 11 R or halogen; each R is independently H or C 1-4 alkyl; and S is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, for the preparation of a compound of formula I according to claim 1. -108 where A is CH ₂ or O; R ¹ is H, halogen or C 1-4 alkyl; R ² is H, C 1-4 alkyl or CH ₂ NR 11 R 11; X is O or CH ₂ ; R 1 is H, C _1-4 alkyl, OC 1-4 alkyl, C 1-4 alkyl, NR 11 R or halogen; and each R is independently H or C 1-4 alkyl; or a pharmaceutically acceptable salt thereof, for the preparation of a compound of formula I according to claim 1.