MXPA99012080A - Novel aminooxyamide tricyclic inhibitors of farnesylprotein transferase - Google Patents

Abstract

Novel aminooxyamide tricyclic compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel aminooxyamide tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.

Description

INHIBITORS TR1C1CL1COS OF A INOOXIAM1DA OF FARNES1L- PROTE1NA TRANSFERASA NOVEDOSOS BACKGROUND OF THE INVENTION Patent application WO 95/00497 published on January 5, 1995 under the Patent Cooperation Treaty (PCT) describes compounds that inhibit the farnesyl protein transferase (FTase) enzyme and the famesylation of the oncogene Ras protein. Oncogenes often encode the protein components of signal transduction pathways that lead to the simulation of cell growth and mitogenesis. The expression of the oncogene in cultured cells leads to cell transformation, characterized by the ability of cells to grow on soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by untransformed cells. The mutation and / or overexpression of certain oncogenes is frequently associated with human cancer. To acquire the transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a tetrapeptide carboxyl-terminate !. Inhibitors of the enzyme that catalyze this modification, farnesyl protein transferase, have therefore been suggested as anti-carcinogenic agents for tumors where Ras contributes to the transformation. The mutated oncogenic forms of Ras are frequently found in many human cancers, mainly in more than 50% of colon and pancreatic carcinomas (Kohl et al, Science, Vol. 260, 1834 to 1837, 1993). In view of the current interest in the farnesyl protein transferase inhibitors, a contribution to the desirable technique would be the additional compounds useful for the inhibition of farnesyl protein transferase. This invention provides said contribution.

BRIEF DESCRIPTION OF THE INVENTION The inhibition of famesyl protein transferase by means of tricyclic compounds of this invention was not previously reported. Therefore, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention, which: i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; ii) block the phenotypic change induced by a form of transforming Ras that is a famesil receptor but not by means of a form of transforming Ras genetically manipulated to be a geranilgeranil receptor; iii) block the intracellular processing of Ras which is a farnesyl receptor, but do not block Ras genetically manipulated to be a geranylgeranil receptor; and iv) block abnormal cell growth in culture induced by transforming Ras.

This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal growth of: 1) tumor cells (tumors) expressing an activated Ras oncogene; 2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; and 3) benign and malignant cells of other proliferative diseases in which the activation of aberrant Ras occurs. The compounds useful in the claimed methods are represented by the formula 1 .0: or a pharmaceutically acceptable salt or solvate thereof, wherein: A represents N or N-oxide; X represents N, CH, or C, such that when X is N or CH, there is a simple bond to the carbon atom 1 1 as represented by the solid line; or when X is C, there is a double bond to the carbon atom 1 1, as represented by the solid and dashed lines; XI and X2 are independently selected from bromine, iodine or chlorine; X3 and X4 are independently selected from bromine, iodine or chlorine or hydrogen as long as one of X3 or X4 is hydrogen; R5, R6, R7, and R8 each independently represent hydrogen, alkyl, halo, or -CONR40R41 where R40 and R41 independently represent hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkylalkyl , and also where R5 can be combined with R6 to represent = O or = S and / or R7 can be combined with R8 to represent = O or = S; v is 1, 2,3,4, or 6; Z represents -NR19R20 or -N = CR19R20; wherein R19 and R20 are independently selected from hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, -CONR10R12, -COOR10, -COR10, -SO2R10 and -SO2NR10R12, or R19 and R20 together they can form a cycloalkyl or a heterocycloalkyl ring, wherein R10 and R12 are independently selected from hydrogen, alkyl, alkoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalicylic, heterocycloalkylalkyl. Preferably in the compound (1 .0), there is a simple eniace to the carbon atom 11; X is CH; R5, R6, R7, and R8 are hydrogen; X1, X2 and X3 are bromine or chlorine and X4 is hydrogen; v is one or two; and Z is -NR19R20 or -N = CR19R20 wherein R19 and R20 are independently selected from hydrogen, alkyl, aryl, heteroaryl, -COR10 or -COOR10 wherein R10 is hydrogen or alkyl, or R19 and R20 together form a cycloalkyl ring or heterocycloalkyl. When R20 is aryl, an optional substituent on the aryl ring may be alkoxy, hydroxy or halo. When R19 and R20 are considered together, they form a cycloalkyl ring, an optional substituent on the cycloalkyl ring is heterocycloaikyl. Preferred compounds include those of examples 1, 2, 4, 6, 10, 11, 12, 13, 14 and 15. In another embodiment, the present invention is directed toward a pharmaceutical composition for inhibiting the abnormal growth of cells that they comprise an effective amount of the compound (1.0) in combination with a pharmaceutically acceptable carrier. In another embodiment, the present invention is directed toward a method of inhibiting abnormal cell growth, including transformed cells, which comprises administering an effective amount of the compound (1.0) to a mammal (eg, a human) in need. of said treatment. Abnormal cell growth refers to cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal growth of: 1) tumor cells (tumors) expressing an activated Ras oncogene; 2) tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in another gene; 3) benign and malignant cells of other proliferative diseases in which the activation of aberrant Ras occurs, and 4) benign or malignant cells that are activated by mechanisms other than Ras protein. Without being limitative by theory, it is believed that these compounds can function either by inhibiting the function of the G protein, such as ras p21, by blocking the isoprenylation of the G protein, thereby rendering them useful in the treatment of proliferative diseases such as tumor growth and cancer, or by means of the inhibition of ras famesyl-protein transferase, thereby rendering them useful for their antiproliferative activity against ras transformed cells. The cells to be inhibited can be tumor cells expressing an activated ras oncogene. For example, types of cells that can be inhibited include pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, carcinoma tumor in bladder, tumor cells in prostate, tumor cells in breast or tumor cells in colon. further, the inhibition of abnormal growth of cells by treatment with the compound (1.0) may result in inhibiting ras farnesyl protein transferase. The inhibition may be from tumor cells where the Ras protein is activated as a result of the oncogenic mutation in genes different from that of the Ras gene. Alternatively, the compounds (1 .0) can inhibit tumor cells activated by a protein other than the Ras protein. This invention also provides a method for inhibiting tumor growth by administering an effective amount of the compound (1.0) to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, e.g., exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (e.g., acute myelogenous leukemia (AML)), follicular thyroid cancer, myelodysplastic syndrome (MDS) ), bladder carcinoma, prostate carcinoma, breast carcinoma and epidermal carcinoma. It is believed that this invention also provides a method for inhibiting proliferative diseases, both malignant and benign, where Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes, ie, the Ras gene itself is not activated by mutation to an oncogenic form, such inhibition of which has been achieved by the administration of an effective amount of the N-substituted urea compounds (1.0) described herein, to a mammal (e.g., a human) in need of said treatment. For example, benign proliferative neurofibromatosis, or tumors in which Ras is activated due to the mutation or overexpression of tyrosine kinase oncogenes (eg, neu, src, abl, Ick, and fyn), can be inhibited by the compounds of N-substituted urea (1.0). In another embodiment, the present invention is directed toward a method for inhibiting ras farnesyl protein transferase and famesylation of the Ras oncogene protein by administering an effective amount of the compound (1.0) to mammals, especially humans. The compounds of this invention, to inhibit famesyl protein transferase, is useful in the treatment of the cancers described above.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the following terms are used as defined below, unless otherwise indicated: M + represents the molecular ion of the molecule in the mass spectrum; MH + represents the molecular ion plus hydrogen of the molecule in the mass spectrum; Bu represents butyl; Et- represents ethyl, Me- represents methyl, PH- represents phenium; Benzotriazol-1 -iioxy represents 1 - . 1-methyl-tratrazol-5-ylthio represents alkyl- (including the alkyl, alkoxy, alkylamino and dialkylamino moieties) -represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; for example, methyl, propyl, iso-propyl, n-butyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; wherein said alkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O), aryloxy, -OR10, -OCF3, heterocicloalquiio, heteroaryl, -NR10R12, -NHSO2R10, -SO2NHR10 -SO2NH2l, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR 10, wherein R10 and R12 can independently represent hydrogen, alkyl, alkoxy, aryl, araiquyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl; alkenyl represents straight and branched carbon chains having at least one carbon-to-carbon double bond and containing from 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 3 to 6 carbon atoms; wherein said alkenyl group can be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, alkoxy, amino, alkylamino, cyano, -CF3, dialkylamino, hydroxy, oxy, phenoxy, -OCF3, heterocycloalkyl, and -SO2NH2, - NHSO2R10, -SO2NHR10, -SO2R10, -SO2R10, -SRO10, -SR10, -NHSO2, -NO2, - CONR10, -NCOR10 or -COOR 10; alkoxy- an alkyl portion of one to 20 carbon atoms covalently linked to an adjacent structural element by means of an oxygen atom, for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like; wherein said alkoxy group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl , heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, - SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, - OCOR10, -OCO2R10 or -COOR 10 where R10 and R12 are as previously defined herein; Aryl (including the anilic arachidyl moiety) - represents a carboxyl group containing from 6 to 15 carbon atoms and having at least one aromatic ring (for example, aryl is phenyl), where said aryl group can optionally be fused with aryl rings , cycloaikyl, heteroaryl or heterocycloalkyl; and wherein any of the substitutable carbon and nitrogen atoms available in said aryl group and / or said fused ring (s) may be optionally and independently substituted with one, two, three or more of the following: halo , alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, - SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10 , -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, wherein R10 and R12 are as defined hereinabove; aralkyl represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one or more aryl groups; wherein said aralkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl , heteroaryl, -NR10R12, -NHSO2R10 and, - SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, - NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR 10, where R10 and R12 are as defined hereinabove; aryioxy-represents an aryl group, as defined above, wherein said aryl group is covalently linked to an adjacent structural element by means of an oxygen atom, for example phenoxy, wherein said aryl group can optionally be fused with aryl, cycloalkyl, heteroaryl or heterocycloalkyo; and wherein each of the substitutable carbon and nitrogen atoms available in said aryloxy group and / or said fused ring (s) may be optionally and independently substituted with one, two, three, or more of the following : halo, alkyl, aryl, cycloalkio, cyano, -CF3, oxy, (= O), aryioxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, and -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, -SO2R10, - SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, wherein R10 and R12 are as defined hereinbefore; cycloalkyl- represents branched or unbranched saturated carboxylic rings of 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; wherein said cycloaicyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl , heteroaryl, NR10R12, -NHSO2R10, -S02NH2l -S02NHR10, -S02R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, where R10 and R 2 are as defined above in the present; cycloalkylalkyl- represents an alkyl group, as defined above, wherein one or more hydrogen atoms of the alkyl portion have been substituted with one or more cycloalkyl groups; wherein said cycloalkylalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy, (= 0), aryloxy, -OR10, -OCF3, heterocycle, heteroaryl, and -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, where R10 and R12 are as defined above in the present; halo- represents fluoro, chloro, bromo and iodo; heteroalkyl- represents straight and branched carbon chains containing from one to twenty carbon atoms, preferably one to six carbon atoms interrupted by 1 to 3 heteroatoms selected from -O-, -S- and -N-; wherein one of the substitutable carbon and nitrogen atoms available in said heteroalkyl chain may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy (= O) ), aryloxy, -OR10, -OCF3 > heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR, 110u, -SO2R .1? 0 ?, -SORl0u, -SR1U, -NHSO2 > -NO2, NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, wherein R10 and R12 are as defined hereinabove; heteroaryl- represents cyclic groups that have a! minus one heteroatom selected from O, S and N, said heteroatom (s) interrupting a carboxylic ring structure and having a sufficient number of delocalized pi electrons to provide an aromatic character, with aromatic heterocyclic groups containing to 14 carbon atoms, wherein said hetearyl group can optionally be fused with one or more aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings; and wherein one of the substitutable carbon or nitrogen atoms available in said heteroaryl group and / or said fused rings may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyo, cyano, -CF3, oxy, (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, - SO2R10, -SOR10, -SR10, -NHSO2, -NO2, - CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, wherein R10 and R12 are as defined hereinabove. Representative heteroaryl groups may include, for example, furanyl, imidazoium, pyrimidinyl, triazolyl, 2-, 3- or 4-pyridyl N-oxide or 2-, 3- or 4- pyridyl N-oxide where the N- Pyridyl oxide can be represented as: heteroaryl represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heteroaryl groups; wherein said heteroarylalkyl group may be optionally and independently substituted with one, two, three, or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy, (= O), aryioxy, -OR10, -OCF3 , heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OCO2R10 or -COOR10, wherein R10 and R12 are as defined hereinabove: heterocycloalkyl- represents a saturated, branched or unbranched carboxylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, whose carboxylic ring is interrupted by 1 to 3 heteroatoms selected from -O-, -S- and -N-, wherein optionally, said ring may contain one or two unsaturated bonds which do not impart the aromatic character to the ring; and wherein one of the substitutable carbon and nitrogen atoms available in the ring may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy, (= O), aryloxy, -OR10, -OCF3, heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10 , -OCOR10, -OC02R10 or -COOR10, where R 0 and R12 are as defined in the present above. Representative heterocycloalkyl groups may include 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 1-, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 1-, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, wherein R10 is defined hereinbefore and t is 0, 1 or 2. heterocycloalkyl-represents an alkyl group, as defined above, wherein one or more hydrogen atoms have been replaced by one or more heterocycloalkyl groups; where optionally, said ring may contain one or two unsaturated bonds which do not impart the aromatic character to the ring; and wherein said heterocycloalkyalkyl group may be optionally and independently substituted with one, two, three or more of the following: halo, alkyl, aryl, cycloalkyl, cyano, -CF3, oxy, (= O), aryloxy, -OR10, -OCF3 , heterocycloalkyl, heteroaryl, -NR10R12, -NHSO2R10, -SO2NH2, -SO2NHR10, -SO2R10, -SOR10, -SR10, -NHSO2, -NO2, -CONR10R12, -NR12COR10, -COR10, -OCOR10, -OC02R1 ° or -COOR10 , where R10 and R12 are as defined above. The following solvents and reagents are referred to herein with the indicated abbreviations: tetrahydrofuran (THF); ethanol (ETtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N, N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); ethyl chlorformate (CICO2Et); 1- (3-dimethyl aminopropyl) -3-ethylcarbodimide hydrochloride (DEC); and dicyclohexylcarbodimide (DCC).

The reference to the position of the substituents X, X, X and X4 is based on the numbered ring structure: Certain compounds of the invention can exist in different stereoisomeric forms (i.e., enantiomers, diastereoisomers and atropisomers). The invention contemplates all stereoisomers in both pure form and in mixture, including racemic mixtures. For example, the carbon atom in the C-1 position can be in the S or R stereo configuration. Certain tricyclic compounds will be acidic in nature, ie, those compounds that possess a carboxyl or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptable salts, ie, acid addition salts. For example, pyrido nitrogen atoms can form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for the formation of salts are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methansiphonic and other mineral and carboxylic acids well known to those skilled in the art. The technique. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonium bicarbonate and sodium bicarbonate. The free base forms differ from their respective salt forms in some way in certain physical properties such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention . It is intended that all the acid and base salts mentioned are pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

The compounds of the present invention can be prepared according to the following scheme I: SCHEME I where X, X1, X2, X3, X4, R5, R6, R7, R8, v, Z and the solid and dotted lines are as defined above in the present. Referring to scheme I, the compounds of formula (1.0) can be prepared by reacting the tricyclic amine compounds (5.0, 5.01, 6.0 and 10.9) with the corresponding aminooxy acid of formula (2.6), preferably using a reagent of carbodiimide coupling such as DEC or DCC, in a protic or aprotic solvent such as water, DMF, methanol or ethanol, at temperatures ranging from 0 to 100 ° C, preferably around 25 ° C. The amount of the aminooxy acid (2.6) in the reaction mixture can vary from 1 to 0 moles of tricyclic amine compounds (5.0, 5.01, 6.0 and 10.9), preferably with equimolar amounts of ammonia acid (2.6). About an equimolar amount of coupling agent per mole of aminooxy acid (2.6) can be used. The compounds of the formula (1 .0) can be isolated from the reaction mixture using conventional procedures such as, for example, extraction of the reaction mixture from water with organic solvents, evaporation of the organic solvents, followed by gel chromatography. of silica or other suitable chromatographic medium. Alternatively, the compounds (1.0) can be dissolved in a water-miscible solvent, such as methanol, the methanol solution is added to the water to precipitate the compound, and the precipitate is isolated by filtration or centrifugation. The (+) - Isomers of the compounds of the formulas (5.0.6.0 and 10.9) wherein X is CH can be prepared with high enantioseiectivity by using a process consisting of catalysed transesterification of enzyme. Preferably, a racemic compound of formula (5.0.6.0 and 10.9), wherein X is C, the double bond is present and X3 is not H, is reacted with an enzyme such as Toyobo LIP-300 and an acylating agent such as trifluoroethyl isobutyrate; the resulting (+) - amide is then hydrolyzed, for example by refluxing with an acid such as H2SO, to obtain the corresponding optically enriched (+) isomer where X is CH and R3 is not H. Alternatively, a racemic compound of formula (5.0.6.0 and 10.9), where X is C, the double bond is present and R3 is not H, it is first reduced to the racemic compound of formula (5.0, 6.0 and 10.9) where X is CH and then treated with the enzyme (Toyobo LIP-300) and an acylating agent as described above to obtain the (+) - amide, which is hydrolyzed to obtain the (+) - optically enriched isomer. The compounds of the present invention and the starting materials for their preparation are represented by means of the following examples, which should not be considered as limiting for the scope of the description.

EXAMPLE 1 1 (+) - N-, 2-f4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzol-.βl-cycloheptari, 2-b1pyridin-11 (R) -H)) - 1-piperidinip-2-oxoethoxylbenzamide.

Dissolve the (+) isomer of Preparation Example 3, (0.2g, 0.43 mmol) in 3ml of DMF, stir at room temperature and add 0.056g (= .55mmol) of 4-methiimorpholine, 0.106g (0.55mmol) of DEC, 0.75 g (0.55 mmoles) of HOBT and 0.108 g (0.55 mmoles) of N-benzoylaminooxyacetic acid (Salor). Stir the mixture at room temperature for 18 hours, then concentrate in vacuo to a residue and partition between ethyl acetate and water. Wash the organic phase with aqueous sodium bicarbonate solution and then in brine. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo to a residue. Chromatograph the residue on silica gel, eluting with dichloromethane (saturated with ammonia) -methanol (95% -5%) to yield the title compound (0.2 g) as a white solid, m.p. 0 212 ° - 222 ° C, Mass Spectrum: MH + = 647 [a] D 24-6'c = + 44.2 °, c = 0.08, methanol.

EXAMPLE 2 (+) - 4- (3.10-Dibromo-8-chloro-β-11-dihydro-5H-benzor5.61cycloheptan.2- blp? Ridin-11 (R) H? I-1 -f 1T (1 -metilet »Liden) amino1oxS1acetinpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of the preparation example 1 1 is used in place of N-benzoylamooxyacetic acid, to obtain the title compound, mp = 98 ° C.

EXAMPLE 3 (+) - 4- (3.10-Dibromo-8-chloro-6,11-dihydro-5H-benzor5.61cycloheptari .2-lpyridin-11 (R) -yl)) - 1 -UNI- (4-methoxyphenyl) ) etilidenlaminoloxpacetinpiperidina The title compound is prepared following essentially the same procedure as described in Example 1 except that 4-methoxyphenyl-ethylidene-aminooxyacetic acid is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 101-108 ( d) ° C.

EXAMPLE 4 (+? - 4- (3.10-Dibromo-8-chloro-6,11-dihydro-5H-benzor5,6.1cycloheptap, 2-blpiridin-11 (R) -yl) -1 -r3-111 (1 - Methylidelaminoloxyl-1-oxopropyl piperidine, 0.17 hydrate The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 12 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 90-98. ° C.

EXAMPLE 5 (+) - 1.1 -Dimethylethyl-N-.2-r4- (3,10-dibromo-8-chloro-6.11-dihydro-5H-benzof 5, 61ciciohepta [1, 2-pyridin-l 1 (R) -yl) -1-piperidinin-2-oxoethoxylcarbamate, 0.4 hydrate The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 19 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 137-141 ° C.

EXAMPLE 6 N-1 - (+4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzor5.61cycloheptap, 2-b1pyridin-11 (R) -yl) -1- oxide ÍT. (E -4- pyridinimethylene) amino-oxoacetyl, piperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 13 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 128-140. (d) ° C. COS (IC50) = 0.69 μM.

EXAMPLE 7 (+) - 4- (3.10-Dibromo-8-chloro-β, 11 -d »hydro-5H-benzor5.61cyclohepta1, 2- b pyridine-11 (R) -ih-1 -nT (E -2 -hydroxyphenyl-methylenelaminoloxylacetylpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 14 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 124-129 (d) ° C.

EXAMPLE 8 (+) - 1 -1 -.... (E) -1- (4-Chlorophenyl) ethylideneamino1oxpacetip-4- (3,10-dibromo-8-chloro-6,11-dihydro-5H-benzof5, 61cycloheptal1 -2-b1pyridin-11 (R) - Qpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that 4-chlorophenyiiethyideneaminoxy acetic acid is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 120-129 ° C .

EXAMPLE 9 (+, - 4- (3.10-Dibromo-8-chloro-6,11-dihydro-5H-benzof5,61 cycloheptaf 1,2-blpyridin-11 (R) -yl) -1 -flT. (E) - 1 - (2-thienyl) ethylideneaminoloxylacetylpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that 2-thieniiethyideneaminoxy acetic acid is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 12-122 ( d) ° C.

EXAMPLE 10 (+, - 4- (3,10-Dibromo-8-cioro-6,11-dihydro-5H-benzor-5,61-cycloheptap-2-blpyridin-11 (R) -yl) -1 -11 .. (cyclohexiiiidenlaminololloxpacetillpiperidine The title compound is prepared following essentially the same procedure as described in example 1 except that the carboxylic acid of the preparation example 15 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 95-100 (d) ° C.

EXAMPLE 11 (+, -4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzor-5,61-cycloheptaf-1, 2-b-pyridin- (11 (R) -yl) -1 -H .. 1, 4- dioxospiror4.51decan-8-ylidenlaminonoxylacetylpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 16 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 115-121. (d) ° C.

EXAMPLE 12 (+) - 4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzof5.61cycloheptaf 1, 2-b1pyridin- (11 (R) -ylH -rrrrtetrahydro-4H-pyran-4- ilidenlaminonoxylacetylpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of Preparation Example 17 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 19- 128 ° C.

EXAMPLE 13 (+) - 4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzof5,61 cycloheptai1.2-b1pyridin- (11 (R) -yl) -1 -ip..tetrahydro -4H-thiopyran-4-ylidenlaminoloxylacetylpiperidine The title compound is prepared following essentially the same procedure as described in Example 1 except that the carboxylic acid of the preparation example 18 is used in place of N-benzoylaminooxyacetic acid, to obtain the title compound, mp = 17- 123 ° C.

EXAMPLE 14 (+) - N-r2-r4- (3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzor5.61cycloheptap, 2-b1pyridin- (11 (R) -H) -1 - piperidtnill-2-oxoethoxy acetamide Dissolve 0.06g (0.103mmol) of the product of Example 15 in 1.5ml of pyridine and add 0.018g (0.181mmol) of acetic anhydride. After 1 hour, concentrate under vacuum and divide the residue between ethyl acetate and aqueous sodium bicarbonate solution. Dry the organic layer over magnesium sulfate and concentrate under vacuum to obtain the product as a white solid, mp = 108-117 (d) ° C.

EXAMPLE 15 (+) 1-r (Aminooxy) acetin-4 (3,10-dibromo-8-chloro-6,11-dihydro-5 H -benzof 5,61 cycloheptari, 2-blpiridin-d 1 (R) -yl) piperidine Dissolve 0.170g (0.264 mmoles) of the title compound of Example 5 in 10ml of dioxane saturated with HCl gas. After 1 hour, concentrate in vacuo and triturate the residue with ethyl ether to give the hydrochloride salt of the product as a white solid, mp = 178-192 (d) ° C.

PREPARATION OF THE STARTING MATERIALS The starting materials useful for preparing the compounds of the present invention are represented by the following preparation examples, which should not be considered as limiting within the scope of the description. The aminooxy acids of formula (2.6) are known in the art, are commercially available and can be prepared by methods known in the art, such as J. Med. Chem. (1985) 28, 1447; Org.

Synth ColI.Vol 111, (1955), p172; and Eur.J.Med Chem (1994) 29, p.33. or by methods described hereinafter, such as in schemes IV and V. Similarly, carbadiimide coupling agents such as DEC and DCC are well known and commercially available. The tricyclic compounds which are used as starting materials such as the compound (11.0), inorganic and organic bases, and alcohols which can be prepared using the methods known in the art, such as those taught in J.K. Wong et al., Bioorganic & Medicinal Chemistry Letters, Vol. Lll No. 6, pp.1073-1078, (1993); Patent E.U.A. 5,089,496; 5,151, 423; 4,454,143; 4, 355.036; PCT / E.U.A. 94/1 f 390 (WO95 / 10514; PCT / EUA 94/1 1391, (WO95 / 10515); PCT / EUA 94/1 1392, (WO95 / 10516); Stanley R. Sandler and Wolf Karo, Organic Functionai Group Preparations , 2pd. Edition, Academic Press, Inc., San Diego, Cal. Vol. 1-3 (1983), and in J. March, Advanced Organic Chemistry, Reactions &Mechanisms, and Structure, 3rd Edition, John Wiley & Sons, New York, 1346 pp. (1985) Alternative mechanistic trajectories and analogous structures within the scope of the invention may be apparent to those skilled in the art The starting materials used to prepare the compounds of the present invention they are described in scheme IV: SCHEME IV where for the scheme IV, A, X, X1, X2, X3, Z, R5, R6, R7 and R8, v and the solid and dotted lines are as defined here above and R15 can represent one of the values for R10 and R12 as defined here above. In step A (scheme IV), the compounds of formula (10.0) can be prepared by reacting the compounds of formula (1.1) with a nitrating agent and / or optional protic or aprotic solvent such as those described in the present above. In a first method, the compound (1.0) is reacted with approximately an equimolar amount of a nitrate salt, such as potassium nitrate, and acid, such as sulfuric acid at temperatures ranging from about -20 ° to + 5 ° C. In a second process, the compound (1.0) is reacted with approximately an equimolar amount of nitric acid and acid, such as sulfuric acid at temperatures ranging from about -20 ° to + 5 ° C. In a third procedure, the compound (11.0) is treated with a mixture consisting of about two equivalents of trifluoromethansuiphonic acid and about one equivalent of nitric acid in a solvent such as trifluoromethansuiphonic acid. In a fourth procedure, the compound (1.0) is treated with a mixture consisting of about one equivalent of fuming nitric acid and about ten equivalents of trifluoromethanesulfonic anhydride in a solvent such as nitromethane. In a fifth procedure, the compound (11.0) is treated with a nitronium salt, such as nitronium tetrafluoroborate, in a solvent, such as sulfolane. In a sixth procedure, the compound (11.0) is reacted with fuming nitric acid at temperatures ranging from about -20 ° to + 50 ° C. In step B (scheme IV), compounds of formula (9.0) can be prepared by reacting compounds of formula (10.0) with a reducing agent. In a first method, the compound (10.0) can be reacted with about ten equivalents of a metal, such as iron, in a solvent, such as ethanol, in the presence of a salt, such as calcium chloride, at temperatures that They vary from around 0 ° to + 80 ° C. In a second method, the compound (10.0) can be reacted with about ten equivalents of a metal, such as zinc, in a solvent, such as ethanol, in the presence of an acid, such as acetic acid at temperatures varying from around 0 ° C to + 80 ° C. In a third procedure, the compound (10.0) can be reacted with about five equivalents of stannous chloride hydrated in a solvent, such as ethyl acetate. In a fourth method, the compound (10.0) can be reacted with about ten equivalents of a metal, such as tin, in a solvent, such as ethanol, in the presence of an acid, such as hydrochloric acid. In step C (scheme IV), the compounds of the formula (8.0) can be prepared by reacting compounds of the formula (9.0) with a halogenating agent. In a first method, the compound (9.0) can be reacted with an excess of an elemental halogen, such as bromine, in a suitable solvent, such as acetic acid at temperatures ranging from about 0 ° to + 80 ° C. In a second process, the compound (9.0) can be reacted with an excess of mineral acid, such as hydrogen bromide, in a suitable solvent, such as dimethyl sulfoxide at temperatures ranging from about 20 ° C to about 135 ° C. ° C. In a third process the compound (9.0) can be reacted with a salt, such as pyridinium perbromide, in a solvent such as THF, at temperatures of about 0 ° to + 40 ° C. In a fourth procedure, the compound (9.0) can be reacted with a halogen, such as chloride, in the presence of a Lewis acid, such as iron chloride (III), in a suitable solvent, such as dichloromethane. In step D (scheme IV), the compounds of the formula (7.0) can be prepared by reacting compounds of the formula (8.0) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula (8.0) ) with an oxidizing agent in the presence of a hydrogen atom source. In a first method, the compound (8.0) can be reacted with a diazotizing agent, such as t-butyl nitrite, in a solvent and a hydrogen atom source, such as DMF at temperatures of about 0 ° to +100. ° C. In a second method, the compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid such as hydrochloric acid, and a reducing agent, such as hypophosphoric acid at temperatures of about -15 °. at + 50 ° C. In a third method, the compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite, and an acid, such as aqueous sulfuric acid, followed by treatment with a metal, such as copper. In a fourth procedure, the compound (8.0) can be reacted with a diazotizing agent, such as sodium nitrite and an acid, such as fluoboric acid, followed by treatment with a reducing agent, such as sodium borohydride. In step E (scheme IV), the compounds of the formula (6.0) can be prepared by reacting compounds of the formula (7.0) under hydrolysis conditions. In a first method, the compound (7.0) can be reacted with an acid, such as hydrochloric acid, at temperatures of about 20 ° to + 90 ° C. In a second process, the compound (7.0) can be reacted with a base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at temperatures of about 20 ° to + 90 ° C. In a third method, the compound (7.0) can be reacted with a neuclofile, such as hydrazine hydrate, in a solvent, such as ethanol, with an optional base, such as sodium hydroxide, at temperatures of about 20 °. at + 90 ° C. In a fourth procedure, the compound (7.0) can be reacted with a silyl chloride, such as trimethylsilyl chloride, in a solvent, such as THF or CH2Cl2 at temperatures ranging from about 0 ° C to reflux. In a fifth process, the compound (7.0) can be reacted with an acid, such as trifluoroacetic acid, in an aprotic solvent, such as CH2Cl2.

In step F (scheme IV), the compounds of the formula (5.0) wherein X = CH can be prepared by reacting compounds of the formula (6.0) under reducing conditions. The compound (6.0) can be reacted with a metal alkyl hydride, such as diisobutyl aluminum hydride, in a solvent, such as toluene, at temperatures from 0 ° to + 90 ° C. In step G (scheme IV), the compounds of the formula (1 .0) can be prepared using the methods as described in Scheme I, hereinabove. In step K (scheme IV), the compounds of the formula (6.1) can be prepared by reacting the compound of the formula (5.9) with a nitrating agent and / or optional protic or aprotic solvent according to the procedures described in step A (scheme IV). In step L (scheme IV), the compounds of the formula (6.2) can be prepared by reacting the compound of the formula (6.1) with a reducing agent according to the procedures described in step B (scheme IV). In step M (scheme IV), the compounds of the formula (6.31) can be prepared by reacting the compound of the formula (6.2) with a halogenating agent according to the procedures described in step C (scheme IV). In step N (scheme IV), the compounds of the formula (6.3) can be prepared by reacting the compound of the formula (6.31) with an oxidizing agent followed by a reducing agent, or by reacting compounds of the formula ( 6.31) with an oxidizing agent in the presence of a hydrogen atom source according to the procedures described in step D (scheme IV). In step O (scheme IV), the compounds of the formula (6.5) can be prepared by reacting compounds of the formula (6.3) with sodium borohydride (NaBH) in a solvent such as ethanol / toluene under reflux conditions during 10 minutes or at 25 ° C for 2 hours or more. In step P (scheme IV), the compounds of the formula (6.7) can be prepared by reacting compounds of the formula (6.5) with SOCI2 in a solvent such as CH2Cl2 at a temperature of about 25 ° C for about 4 hours or more. In step Q (scheme IV), the compounds of the formula (5.0) where X = N, can be prepared by reacting compounds (6.7) with an excess amount of the piperazine compound of the formula (6.9) in such a solvent as THF at 25 ° C or reflux for 1 hour or more. Additional starting materials that can be used to prepare the compounds of the present invention are described in Scheme V.

SCHEME V X = N of (6.71, 6.9) In step A (scheme V), the compounds of the formula (10.0) can be prepared from the compound of the formula (1.1) using the procedures described in scheme IV, step A.

In step AA (scheme V), the compounds of the formula (10.3) can be prepared by reacting the compound of the formula (10.0) with 1,3-dibromo-5,5-dimethylhydantoin in an acid, such as acid trifluoromethansuiphonic or sulfuric acid for 24 hours or more at 25 ° C. In step BB (scheme V), the compounds of the formula (10.5) can be prepared by treating the compounds of the formula (10.3) with a reducing agent, using the procedures taught in scheme IV, step B. In step CC (Scheme V), the compounds of the formula (10.7) can be prepared by reacting compounds of the formula (10.5) with sodium nitrite (NaNO2) in concentrated aqueous HCl at temperatures ranging from about -10 ° C to 0 ° C for 2 hours or more, then treating the reaction mixture with phosphoric acid (H3PO2) at 0 ° C for 4 hours or more. In step DD (scheme V), the compounds of the formula (10.9) can be prepared by reacting compounds of the formula (10.7) with concentrated aqueous HCl at about 85 ° C for about 18 hours or more. The compound (10.9) can be reacted using the same procedures described in scheme IV to treat a compound (5.0) and (6.0) and subsequent intermediates therein, to obtain the desired compounds of the formula (1 .0). In step EE (Scheme V), the compounds of the formula (10.8) can be prepared by reacting the compound of the formula (10.7) with NalO and RuO2 in acetonitrile and water for about 18 to 24 hours or more at 25 °. C. In step FF (Scheme V), the compounds of the formula (5.01) wherein X = CH can be prepared by reacting compounds of the formula (10.9) under reducing conditions. The compound (10.9) can be reacted with a metal alkyl hydride, such as disobuthyl aluminum hydride, in a solvent, such as toluene, at temperatures of from about 0 ° to + 90 ° C. In step GG (scheme V), the compounds of the formula (1.0) can be prepared using the methods as described in Scheme I, hereinafter in the previous part. In step OO (scheme V), the compounds of the formula (6.51) can be prepared by reacting compounds of the formula (10.8) with sodium borohydride (NaBH) in a solvent such as ethanol / toluene under reflux conditions during 10 minutes or at 25 ° C for two hours or more. In step PP (scheme V), the compounds of the formula (6.71) can be prepared by reacting compounds of the formula (6.51) with SOCI2 in a solvent such as CH2Cl2 at a temperature of about 25 ° C for 4 hours approximately or more. In step QQ (scheme V), compounds of formula (5.01) where X = N, can be prepared by reacting compounds (6.71) with an excess amount of the piperazine compound of formula (6.9) in a solvent such as THF at 25 ° C or reflux for 1 hour or more.

SCHEME VI wherein v, R9 and R10 are as defined here above. In Scheme VI, the aminoxycarboxylic acids of formula (2.61) where Z = NR9R10 can be prepared by reacting a compound of formula (2.1) with an amino alcohol of formula (2.2) in a protic or aprotic solvent such as water or DMF with a base such as sodium hydroxide or carbonate of sodium at a temperature of 25 ° to 100 ° C. Alternatively, the aminooxycarboxylic acids of formula (2.61) can be prepared by reacting a compound of formula (2.63) with the appropriate reagent containing the requisite groups R9 and R10 to give the desired substituents R9 and R10. For example, alkyl substituents can be obtained using alkylating reagents such as an alkyioheiogenide; acyl substituents can be obtained using acylation reagents such as an acyl haiogenide; Sulfonyl substituents can be obtained using sulfonating reagents such as sulfonyl halide. In Scheme VI, compound (2.63) can be prepared by hydrolyzing the oxime compound of formula (2.65) with an inorganic acid, such as hydrochloric, sulfuric, phosphoric acid and the like, or an organic acid such as acetic acid, 25 ° to 100 ° C. In scheme VI, the oxime compound of formula (2.65) wherein Z = N = CR9R10 can be prepared by reacting the brominated carboxy compound of formula (2.1) with the compound oxime (2.3) in a protic or aprotic solvent such as DMF , benzene or water in the presence of a base such as sodium hydroxide or sodium carbonate at a temperature ranging from 0 ° to 100 ° C. Alternatively, the oxime compound (2.65) can be prepared by reacting a vinyl compound of formula (2.4) with the oxime compound (2.3) in an alcohol solvent such as ethanol, at a temperature of 0 ° to 100 ° C. , followed by treatment with base (OH-) such as sodium or potassium hydroxide, at a temperature of 0 ° to 100 ° C. Alternatively, the compound oxime (2.65) can be prepared by treating the compound (2.63) with pyridine or alcoholic solvents such as ethanol using equimolar amounts of the corresponding aldehyde or ketone reagents. The intention of the following preparation examples is to exemplify the selected starting materials for preparing the compounds of the present invention.

Preparation Example 1 Step A: Combine 15 g (38.5 mmoies) of 4-8 ethyl ester (chloro-3-bromo-5,6-dihydro-1 1 H -benzo [5,6] cyclohepta [1,2-b] pyridin-1 1 -ylidene) -1-piperidine-1-carboxylic acid (as taught in the preparation example 47 of PCT / US 94/1 1392) and 150 ml of H2SO4 at -5 ° C, then add 3.89g (38.5 mmoles) of KNO and stir for 4 hours. Stir the mixture in 3L of ice and basify with 50% NaOH (aqueous). Extract with CH2CL2, dry over MgSO, then filter and concentrate in vacuo to obtain a residue. Recrystallize the acetone residue to produce 6.69g of the product.

Step B: Combine 6.69g (13.1 mmoles) of the product from step A and 100ml of 85% EtOH / water, then add 0.66g (5.9 mmoles) of CaCl2 and 6.56g (117.9 mmol) of Fe and heat the mixture to reflux overnight. Filter the hot reaction mixture with Celite® and rinse the filter cake with hot EtOH. Concentrate the filtrate in vacuo to yield 7.72 g of the product.

Step C: Combine 7.70 g of the product from step B and 35 ml of HOAc, then add 45 ml of a Br2 solution in HOAc and stir the mixture at room temperature overnight. Add 300 ml of 1 N NaOH (aqueous), then 75 ml of 50% NaOH (aqueous) and extract with EtOAc. Dry the extract over MgSO4 and concentrate in vacuo to obtain a residue. Chromatograph the residue (silica gel 20% -30% EtOAc / hexane) to yield 3.47 g of the product Qunto with 1.28 g more of the partially purified product).

Step D: Combine 0.557g (5.4 mmol) of t-butylnitrite and 3ml of DMF, and heat the mixture at 60 ° -70 ° C. Slowly add (dropwise) a mixture of 2.00g (3.6 mmoles) of the product from step C and 4mi of DMF, then cool the mixture to room temperature. Add another 0.64ml of t-butylnitrite at 40 ° C and reheat the mixture at 60 ° -70 ° C for 0.5 hours. Cool to room temperature and pour the mixture into 150 ml of water. Extract with CH2Cl2, dry the extract over MgSO4 and concentrate in vacuo to obtain a residue. Chromatograph the residue (silica gel, 10% -20% EtOAc / hexane) to yield 0.74 g of the product.

Step E: Combine 0.70 g (1.4 mmol) of the product from step D and 8 ml of concentrated HCl (aqueous) and heat the mixture to reflux overnight. Add 30ml of 1N NaOH (aqueous), then 5ml of 50% NaOH (aqueous) and extract with CH2Cl2. Dry the extract over MgSO4 and concentrate in vacuo to yield 0.59g of the title compound.

Preparation Example 2 [racemic compound as well as (+) - and - (-) - isomers] Prepare a solution of 8.1 g of the title compound of Preparation Example 7 in toluene and add 17.3 ml of a 1 M solution of DIBAL (aluminum disubethyl hydride) in toluene. Heat the mixture to reflux and slowly add (dropwise) another 21 ml of a 1 M DIBAL / toluene solution over a period of 40 minutes. Cool the reaction mixture to about 0 ° C and add 700ml of 1 M HCl (aqueous). Separate and discard the organic phase. Wash the aqueous phase with CH2Cl2, discard the extract, then basify the aqueous phase by adding 50% NaOH (aqueous). Extract with CH2CI2, dry the extract over MgSO4 and concentrate in vacuo to yield 7.30g of the title compound, which is a racemic mixture of enantiomers.

Preparation Example 3-Separation of Enantiomers The racemic compound of the title of Preparation Example 1 is separated by preparative chiral chromatography (Chiralpack AD, column 5cm x 50cm, using PrOH / hexane 20% + diethylamine 0.2%), to produce the (+) - isomer and the ( -) - isomer of the title compound. Alternatively, the enantiomers can be separated by crystallization with an amino acid such as N-acetylphenialalanine.

Preparation Example 6 Combine 40.Og (0.124 moles) of the starting ketone (as taught in Preparation Example 20 of PCT / EUA 1 1392) and 200 ml of H2SO4 and cool to 0 ° C. Slowly add 13.78g (0.136 moles) of KNO3 for a period of 1.5hrs., Then bring to room temperature and stir all night. Work the reaction using substantially the same procedure as that described for preparation example 4, step A. Undergo chromatography (silica gel, 20%, 30%, 40%, 50% EtOAc / hexane, then 100% EtOAc) to produce 28g of the 9-nitro product, together with a minor amount of the 7-nitro product and 19g of a mixture of the 7-nitro and 9-nitro compounds. MH + (9-nitro) = 367.

Step B: React 28g (76.2mmol) of the 9-nitro product from Step A, 400 ml of 85% EtOH / water, 3.8 g (34.3 mmoles) of CaCl2 and 38.28 g (0.685 mmol) of Fe at 50 ° C. Heat the mixture to reflux overnight, filter by means of Celite® and wash the filter cake with 2 X 200ml of hot EtOH. Combine the filtrate and the washings, and concentrate in vacuo to obtain a residue. Extract the residue with 600 ml of CH2Cl2, wash with 300 ml of water and dry over MgSO4. Filter and concentrate in vacuo to obtain a residue, then chromatograph (on silica gel, 30% EtOAc / CH2Cl2) to yield 24g of the product.

Step C: Combine 13g (38.5mmoies) of the product from Step B, 140ml of HOAc and slowly add a 2.95ml solution (57.8mmol) of Br2 in 10mi of HOAc for a period of 20 minutes. Stir the reaction mixture at room temperature, then concentrate in vacuo to obtain a residue. Add CH2CI2 and water, then adjust to a pH = 8-9 with 50% NaOH (aqueous). Wash the organic phase with water, then in brine and dry over Na2SO. Concentrate in vacuo to produce 1 1 .3g of the product.

Step D: Cool 100 ml of concentrated HCl (aqueous) at 0 ° C, then add 5.61 g (81.4 mmol) of NaNO2 and stir for 10 minutes. Slowly add (in portions) 1 1 .3g (27.1 mmoles) of the product from step C and stir the mixture at 0 ° - 3 ° C for 2.25 hrs. Slowly add (drop by drop) 180ml of H3PO2 (aqueous) at 50% and allow the mixture to stand at 0 ° C overnight. Slowly add (dropwise) 150ml of 50% NaOH for 30 min, to adjust to pH = 9, then extract with CH2Cl2. Wash the extract with water, then in brine and dry over Na2SO4. Concentrate in vacuo to obtain a residue and chromatography (silica gel, 2% E.OAC / CH2CI2) to yield 8.6 g of the product Step E: Combine 8.6g (21 .4 mmol) of the product from step D and 300mi of MeOH and cool to 0 ° C. Add 1.21 g (32.1 mmol) of NaBH4 and stir the mixture at -0 ° C for 1 hour. Add another 0.121g (3.21 mmoles) of NaBH4, stir for 2 hr. at 0 ° C, then let stand overnight at 0 ° C. Concentrate in vacuo to obtain a residue and then divide the residue between CH2Cl2 and water. Separate the organic phase and concentrate in vacuo (50 ° C) to yield 8.2g of the product.

Step F: Combine 8.2g (20.3 mmoles) of the product from step E and 160ml of CH2CI2, cool to 0 ° C, then add slowly (dropwise) 14.8ml (203 mmoles) of SOCI2 for 30 min. Let the mixture reach room temperature and stir for 4.5 hrs., Then concentrate in vacuo to obtain a residue, add CH2Cl2 and wash with 1 N NaOH (aqueous) then in brine and dry over Na2SO4. Concentrate in vacuo to obtain a residue, then add dry THF and 8.7g (101 mmol) of piperazine and stir at room temperature overnight. Concentrate in vacuo to obtain a residue, add CH2Cl2, and wash with 0.25 N NaOH (aqueous), water, then in brine. Dry over Na 2 SO 4 and concentrate in vacuo to yield 9.46 g of the crude product. Chromatograph (silica gel, 5% MeOH / CH 2 Cl 2 + NH 3) to yield 3.5 g of the title compound, as a racemate.

Step G-Separation of enantiomers: The racemic compound of the title of step F (5.7g) is subjected to preparative chiral chromatography (Chiraipack AD, column 5cm x 50cm, flow rate 100ml / min) using 30% PrOH / hexane + 0.2% diethylamine, to yield 2.88. g of the R - (+) - enantiomer and 2.77g of the S - (-) - enantiomer of the title compound.

EXAMPLE OF PREPARATION 7 Combine 25.86 g (55.9 mmol) of 4- (8-chloro-3-bromo-5,6-dihydro-1 1 H-benzo [5,6] cyclohepta [1,2-b] pyridinyl) ethyl ester. 1 1 -ylidene) -1-piperidine-1-carboxylic acid and 250mi of concentrated H2SO4 at -5 ° C, then add 4.8g (56.4 mmoles) of NaN 3 and stir for 2 hours. Pour the mixture into 600g of ice and basify with concentrated NH4OH (aqueous). Filter the mixture, wash with 300 ml of water, then extract with 500 ml of CH2CI2. Wash the extract with 300 ml of water, dry over MgSO4, then filter and concentrate in vacuo to obtain a residue. Chromatograph the residue (in silica gel, 10% E.OAC / CH2CL2) to yield 24.4 g (86% yield) of the product, mp = 165-167 ° C.

Step B: Combine 20g (40.5 mmoles) of the product from step A and 200mi of concentrated H2SO4 at 20 ° C, then cool the mixture to 0 ° C. Add 7. 12g (24.89 mmoles) of 1,3-dibromo-5,5-dimethylhydantoin to the mixture and stir for 3 hours at 20 ° C. Cool to 0 ° C, add an additional 1.0 μg (3.5 mmol) of dibromohydantoin and stir at 20 ° C for 2 hours. Pour the mixture into 400g of ice, basify with concentrated NH4OH (aqueous) at 0 ° C and collect the resulting solid by filtration. Wash the solid with 300 ml of water, suspend in 200 ml of acetone and filter to yield 19.79 g (yield 85.6%) of the product.

Step C: Combine 25g (447mmol) of Fe fillers, 10g (90mmol) of CaCl and a suspension of 20g (34.19mmol) of product from step B in 700ml of 90:10 EtOH / water at 50 ° C. Heat the mixture to reflux overnight, filter through Celite® and wash the filter cake with 2 x 200 ml of hot EtOH. Combine the filtrate and the washings, and concentrate in vacuo to obtain a residue. Extract the residue with 600 ml of CH2Cl2, wash with 300 ml of water and dry over MgSO4. Filter and concentrate in vacuo to obtain a residue, then chromatograph (silica gel, 30% EtOAc / CH 2 Cl 2) to yield 1 1 .4g (yield 60%) of the product. Step D: Slowly add (in portions) 20g (35.9 mmoles) of the product from Step C to a solution of 8g (1 16 mmoles) of NaNO2ml in 120ml of HCl (aqueous) concentrated at -10 ° C. Stir the resulting mixture at 0 ° C for 2 hours, then slowly add (dropwise) 150ml (1.44 mmoles) of 50% H3PO2 at 0 ° C for a period of 1 hour. Stir at 0 ° C for 3 hours, then pour into 600g of ice and basify with concentrated NH4OH (aqueous). Extract with 2 X 300ml of CH2CI2, dry the extracts over MgSO4, then filter and concentrate in vacuo to obtain a residue. Chromatograph the residue (silica gel, 25% EtOAc / hexanes) to yield 13.67 g (70% yield) of the product.

Step E: Combine 6.8g (12.59 mmoles) of the product from step D and 100ml of concentrated HCl (aqueous) and stir at 85 ° C overnight. Cool the mixture, pour in 300g of ice and basify with concentrated NH4OH (aqueous). Extract with 2 x 300 ml of CH2Cl2, then dry the extracts over MgSO. Filter, concentrate in vacuo to obtain a residue, then chromatograph (silica gel, 10% MeOH / EtOAc + 2% NH 4 OH (aqueous) to yield 5.4 g (92% yield) of the title compound.

Preparation Example 8 [racemic compound as well as (+) - and (-) enantiome. _, Step A: Combine 16.6g (0.03 mmol) of the product from Preparation Example 7, Step D, with a 3: 1 solution of CH3CN and water (212.65ml CH3CN and 70.8ml of water) and stir the resulting suspension overnight at room temperature . Add 32.833g (0.153 moles) of NalO4 and then 0.31 g (2.30 mmol) of RuO2 and stir at room temperature (the addition of RuO2 is accompanied by an exothermic reaction and the temperature scale from 20 ° to 30 ° C). Stir the mixture for 1 .3 hours (the temperature returned to 25 ° C after approximately 30 minutes), then filter to remove the solids and wash the solids with CH2Cl2. Concentrate the filtrate in vacuo to obtain a residue and dissolve the residue in CH2Cl2. Filter to remove insoluble solids and wash the solids with CH2CI2. Wash the filtrate with water, concentrate to a volume of around 200ml and wash with chlorine, then with water. Extract with 6 N HCl (aqueous). Cool the aqueous extract to 0 ° C and slowly add 50% NaOH (aqueous) to adjust to a pH = 4 while maintaining the temperature < 30 ° C. Extract twice with CH2Cl2, dry over MgSO4 and concentrate in vacuo to obtain a residue. Suspend the residue in 20ml of EtOH and cool to 0 ° C. Collect the resulting solids by filtration and dry the solids under vacuum to produce 7.95g of the product.

Step B: Combine 21.58g (53.75 mmoles) of the product of step A and 500 ml of anhydrous, mix 1: 1 EtOH and toluene, add 1.43g (37.8 mmoles) of NaBH4 and heat the mixture to reflux for 10 minutes. Cool the mixture to 0 ° C, add 100ml of water, then adjust to a pH ~ 4-5 with 1 M HCl (aqueous) while maintaining the temperature at < 10 ° C. Add 250ml EtOAc and separate the layers. Wash the organic layer with brine (3 x 50ml) then dry over Na 2 SO 4. Concentrate in vacuo to obtain a residue (24.01 g) and chromatograph the residue (silica gel, 30% hexane / CH 2 Cl 2) to give the product. The impure fractions were purified by rechromatography. A total of 18.57g of the product is obtained.

Step C: Combine 18.57g (46.02 mmoles) of the product from step B and 500ml of CHC, then add 6.70ml (91.2 mmoles) of SOCI2, and stir the mixture at room temperature for 4 hours. Add a solution of 35.6 g (0.413 mol) of piperazine in 800 ml of THF over a period of 5 minutes and stir the mixture for 1 hour at room temperature. Heat the mixture to reflux overnight, then cool to room temperature and dilute the mixture with 1 L of CH2Cl2. Wash with water (5 x 200ml) and extract the aqueous wash with CHCl3 (3 x 100ml). Combine all organic solutions, wash with brine (3 x 200ml) and dry over MgSO4. Concentrate in vacuo to obtain a residue and chromatograph (silica gel, gradient of 5%, 7.5%, 10% MeOH / CH 2 Cl 2 + NH 4 OH) to give 18.49 g of the title compound as a racemic mixture.

Step D - Separation of Enantiomers: The racemic title compound from step C is separated by preparative chiral chromatography (Chiraipack AD, column 5cm x 50cm flow rate 100ml / min., PrOH 20% / hexane + diethylamine 0.2%), to give 9.14g of ( -t -) - enantiomer and 9.30g of the (-) - enantiomer.

Preparation Example 9: [racemic compound as well as (+) - and (-) - enantiomers] Step A: Combine 13g (33.3 mmol) of the title compound of Preparation Example 7, and 300ml of toluene at 20 ° C, then add 32.5ml (32.5mmol) of a 1M solution of DIBAL in toluene. Heat the mixture at reflux for 1 hour, cool to 20 ° C, add an additional 32.5 ml of 1 M DIBAL solution and heat at reflux for 1 hour. Cool the mixture to 20 ° C and pour into a mixture of 400g of ice, 500ml of EtOAc and 300ml of 10% NaOH (aqueous). Extract the aqueous layer with CH2Cl2 (3 x 200ml), dry the organic layers over MgSO, then concentrate in vacuo to obtain a residue. Chromatograph (silica gel, 12% MeOH / CH 2 Cl 2 + 4% NH 4 OH) to yield 10.4g of the title compound as a racemate.

Step B-Separation of Enantiomers: The racemic title compound from step A is separated by preparative chiral chromatography (Chiraipack AD, 5 cm x 50 cm column, using 5% iPrOH / hexane + 0.2% diethylamine), to give the (+) - enantiomer and the (- ) -enantiomer of the title compound.

Preparation Example 10 Combine 15 g (38.5 mmol) of 4- (8-cioro-3-bromo-5,6-dihydro-1 1 H -benzo [5,6] cyclohepta [1,2-b] pyridin-1 ethyl ester) -ylidene) -1-piperidine-1-carboxylic acid and 150 ml of concentrated H2SO4 at -5 ° C, then add 3.89g (38.5 mmoles) of KNO3 and stir for 4 hours. Pour the mixture into 3L of ice and basify with 50% NaOH (aqueous). Extract with CH2CL2, dry over MgSO4, then filter and concentrate in vacuo to obtain a residue. Recrystallize the residue from acetone to give 6.69% of the product.

Step B: Combine 6.69g (13.1mmol) of the product from step A and 100ml of 85% EtOH / water, then add 0.66g (5.9mmol) of CaCl2 and 6.56g (1 17.9mmol) of Fe and heat the mixture to reflux throughout the night. Filter the reaction mixture through Celite® and rinse the filter cake with hot EtOH. Concentrate the filtrate in vacuo to give 7.72 g of the product.

Step C: Dissolve 9.90 g (18.9 mmol) of the product from step B in 150 ml of CH2CI2 and 200 ml of CH3CN and heat to 60 ° C. Add 2.77 g (20.8 mmol) of N-chlorosuccinimide and heat at reflux for 3 hours; Sift the reaction with TCL (30% EtOAc / H2O). Add an additional 2.35 g (10.4 mmole) of N-chlorosuccinimide and further reflux 45 minutes. Cool the reaction mixture to room temperature and extract with 1 N NaOH and CH 2 Cl 2. Dry the CH2CI2 layer over MgSO4, filter and purify by flash chromatography (1200 ml normal phase silica gel, eluting with 30% EtOAc / H2O) to obtain 6.24 g of the desired product. P.f. 193-195.4 ° C.

Step D: To 160 ml of concentrated HCl at -10 ° C add 20.7 g (30.1 mmoles) of NaNO and stir for 10 minutes. Add 5.18 g (10.1 mmoies) of the product from step A and bring the reaction mixture from -10 ° C to 0 ° C for 2 hours. Cool the reaction to -10 ° C, add 100 ml of H3PO2 and let stand overnight. To extract the reaction mixture, pour over crushed ice and basify with 50% NaOH / CH2CI2. Dry the organic layer over MgSO 4, filter and concentrate to dryness. Purify by flash chromatography (600 ml normal phase silica gel, eluting with 20% EtOAc / hexane) to obtain 3.98 g of the product.

Step E: Dissolve 3.9 g of the product from step D in 100 ml of concentrated HCl and reflux overnight. Cool the mixture, basify with 50% w / w NaOH and extract the resulting mixture with CH2Cl2. Dry the layer CH2CI2 over MgS? 4, evaporate the solvent and dry under vacuum to obtain 3. 09 g of the desired product.

Step F: Using a procedure similar to that described in Preparation Example 8, until obtaining 1.73 g of the desired product, m.p. 169.6-170.1 ° C; [a] 25D = + 48.2 ° (c = 1, MeOH) MH + = 425.

Preparation Example 11 Follow the procedure outlined in Collect, Czech, Chem, Comm. (1990) 55,2086. Dissolve 0.2 g (0.915 mmoles) of aminooxyacetic acid hemydrochloride (Aldrich) and 0.2 g (3 mmoies) of acetone in 2 ml of pyridine and allow it to sit for 18 hours. Concentrate under vacuum and partition the residue between ethyl acetate and 1 N HCl. Dry the organic layer over magnesium sulfate and concentrate under vacuum to give a white solid mp = 77.3-78 ° C.

Preparation Example 12 Follow the procedure of Preparation Example 1 1 but use 2-aminooxipropionic acid hemihydrochloride (Aldrich) instead of aminooxyacetic acid to obtain the product as a colorless oil.

Preparation Example 13 Follow the procedure of the preparation example 1 1 but use 4-pyridinecarboxaldehyde N-oxide (Aldrich) instead of acetone to obtain the product that was recrystallized from the water to give a white solid mp = 227-228 ° C.

Preparation Example 14 Follow the procedure of the preparation example 1 1 but use 2-hydroxybenzaldehyde (Aldrich) instead of acetone to obtain the product as a white solid mp = 152-153.5 ° C.

Preparation Example 15 Follow the procedure of Preparation Example 1 1 but use ciciohexanone (Aldrich) instead of acetone to obtain the product as a white solid mp = 97-98 ° C.

Preparation Example 16 Follow the procedure of the preparation example 11 but use mono-ethylene ketal of 1,4-cyclohexanedione (Aldrich) instead of acetone to obtain the product as a white solid mp = 132-133 ° C.

Preparation Example 17 } Follow the procedure of Preparation Example 11 but use tetrahydro-4H-pyran-4-one (Aldrich) instead of acetone to obtain the product as a white solid mp = 107-108 ° C.

Preparation Example 18 Follow the procedure of the preparation example 11 but use tetrahydro-4H-thiopyran-4-one (Aldrich) instead of acetone to obtain the product as a white solid mp = 141-143 ° C.

Preparation Example 19 Dissolve 0.2 g (0.915 mmoles) of aminooxyacetic acid hemihydrochloride (Aldrich) in 2 ml of 1 N aqueous sodium hydroxide. Add a solution of 0.2 g (0.915 mmoles) of di-tert-butyldicarbonate (Aldrich) in 2 ml of methanol and stir for 24 hours. Cool to 0 ° C and adjust to a pH of 5-6 with 1 N HCl. Extract with 4 portions of 20 ml of ethyl acetate. Dry the combined organic layers over magnesium sulfate and concentrate in vacuo to give 0.17 g of the product as a colorless oil which crystallized on standing, mp = 1 16-1 19 ° C.

TESTS 1. - In vitro enzyme tests: FPTiC50 (farnesyl protein transferase inhibition, in vitro enzyme test) are determined by the methods described in WO / 10515 or WO 95/10516. The data demonstrate that the compounds of the invention are farnesyl-protein transferase (FPT) inhibitors of partially purified rat brain-Ras-CVLS farnesylation. The data also show that there are compounds of the invention which can be considered as potent (Ras5CV) farnesylation inhibitors (IC5o <10 μM) of Ras-CVLS by partially purified rat brain FPT. 2. - Cell-based test IC 50 COS values refer to the inhibition of COS cell activity of Ras processing, are determined by means of the methods described in WO / 10515 or WO 95/10516.

To prepare pharmaceutical compositions from the compounds described by this invention, the pharmaceutically acceptable, inert carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, lozenges and suppositories. The powders and tablets may comprise from about 5 to about 70% of the active ingredient. Suitable solid carriers are known in the art, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, pills and capsules can be used as solid dosage forms suitable for oral administration. For the preparation of suppositories, low melting wax is first melted, such as a mixture of fatty acid glycerides or cocoa butter, the active ingredient dispersed homogeneously therein by stirring. The molten homogeneous mixture is poured into molds of suitable size, allowed to cool and subsequently solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example, water, or water-propylene glycol solutions for parenteral injection may be mentioned. The liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier., such as an inert compressed gas. Also included are solid preparation forms, which are designed to be converted, just before use, into liquid form preparations for either oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be administered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and / or emulsions, and can be included in a transdermal patch matrix or receptacle, which are conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component, for example, an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation can be varied or adjusted from about 0.1 mg to 1000 mg, most preferably about 1 mg to 300 mg, according to the particular application. The current dose used may vary depending on the requirements of the patient and the severity of the condition to be treated. The determination of the appropriate dosage for a particular situation is within the abilities of a person skilled in the art. Generally, treatment starts with smaller doses that are less than the optimal dose of the compound. Subsequently, the dose is increased by means of small increments until the optimal effect is reached according to the circumstances. For reasons of convenience, the total daily dose may be divided and administered in portions during the day if desired. The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending physician, considering factors such as the age, condition and constitution of the patient, as well as the severity of the symptoms that are being treated. A typical dosage regimen that is recommended is oral administration or from 10 mg to 2000 mg / day, preferably 10 to 1000 mg / day, in two to four divided doses to block tumor growth. The compounds are non-toxic when administered within this dosage regimen. The following are examples of pharmaceutical dosage forms containing the compound of the invention. The scope of the invention in this aspect of pharmaceutical composition should not be limited by the examples that have been provided.

EXAMPLES OF PHARMACEUTICAL DOSE FORM EXAMPLE A-Tablets Manufacturing Method Ingredients 1 and 2 are mixed in a suitable mixer for 10-15 minutes. The mixture is granulated with ingredient 3. The wet granules are milled through a coarse screen (e.g., 0.63 cm) if necessary. The wet granules are dried. Dry granules are sieved if necessary and mixed with ingredient 4 and mixed for 10-15 minutes. Ingredient 5 is added and mixed for 1 -3 minutes. The mixture is compressed to a suitable size and weighed on a suitable tablet machine.

EXAMPLE B-Capsules Manufacturing method Ingredients 1, 2 and 3 are mixed in a suitable mixer for 10-15 minutes. Ingredient 4 is added and mixed for 1-3 minutes. The mixture is filled into suitable two-piece hard gelatin capsules in a suitable encapsulating machine. Although the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. It is intended that said alternatives, modifications and variations fall within the spirit and scope of the present invention.

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1 .- A compound of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: A represents N or N-oxide; X represents N, CH or C, so that when X is N or CH, there is a single bond to a carbon atom 11 as represented by the solid line; or when X is C, there is a double bond to carbon atom 11, as represented by dashed and solid lines; X1 and X2 are independently selected from bromine, iodine or chlorine; X3 and X4 are independently selected from bromine, iodine, chlorine or hydrogen as long as one of X3 or X4 is hydrogen; R5, R6, R7 and R8 independently represent hydrogen, alkyl, aryl, or -CONR40R41 wherein R40 and R41 independently represent hydrogen, alkyl, akoxy, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkio, heterocycloalkyl and heterocyanoalkylalkyl, and subsequently where R5 can be combined with R6 to represent = O or = S and / or R7 can be combined with R8 to represent = 0 or = S; v is 1, 2,3,4,5 or 6; and Z represents -NR19R20 or -N = CR19R20; wherein R19 and R20 are independently selected from hydrogen, alkyl, akoxy, ary, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylaicyl, heterocycloalkyl, heterocycloalkylalkyl, -CONR10R12, -COOR10, -COR10, -SO2R10 and -SO2NR10R12, or R19 and R20 together they can form a cycloalkyl or heterocycloalkyl ring, wherein R10 and R12 are independently selected from hydrogen, alkyl, akoxy, aryl, aralkyl, heteroaryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heterocycloalkylalkyl.

2. The compound according to claim 1 further characterized in that there is a single bond to a carbon atom 1 1, X is CH and R5, R6, R7 and R8 are hydrogen.

3. The compound according to claim 2 wherein X1, X2, and X3 are bromine or chlorine and X4 is hydrogen.

4. The compound according to claim 3, wherein v is one or two; and Z is -NR 9R20 or -N = CRÍ9R20 wherein R19 and R20 are independently selected from hydrogen, alkyl, aryl, heteroaryl, -COR10 or -COOR10 wherein R10 is hydrogen or alkyl, or R19 and R20 together form a cycloalkyl ring or a heterocycloalkyl.

5. - The compound according to claim 4 wherein R20 is aryl and the ring is substituted with alkoxy, hydroxy or halo.

6. The compound according to claim 4 further characterized in that R19 and R20 together form a cycloalkyl ring and the cycloalkyl ring is substituted with heterocycloalkyl.

7. The compound of claim 1 selected from any of the title compounds of examples 1-15.

8. The compound according to claim 1 selected from the title compounds of examples 1, 3,4,5,6,9, 10,1 1, 13, 14 and 15.

9.- A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable carrier.

10. The use of a compound of claim 1 for the manufacture of a medicament for inhibiting the abnormal growth of cells.

11. The use according to claim 10 wherein the inhibited cells are tumor cells expressing an activated ras oncogene.

12. The use according to claim 10 wherein the inhibited cells are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodiplasic tumor cells, tumor cells. of epidermal carcinoma, bladder carcinoma tumor cells or prostate tumor cells, breast tumor cells or colon tumor cells.

13. The use according to claim 10, wherein the inhibition of abnormal cell growth occurs by the inhibition of ras farnesyl protein transferase.

14. The use according to claim 10 wherein the inhibition is of tumor cells wherein the ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene.