International Publication Number WO92/11034, published Jul. 9, 1992, discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is resistant to the antineoplastic agent, by the concurrent administration of the antineoplastic agent and a potentiating agent of the formula: 
wherein the dotted line represents an optional double bond, Xxe2x80x2 is hydrogen or halo, and Yxe2x80x2 is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Yxe2x80x2 can be, amongst others, -COOR wherein Rxe2x80x2 is C1 to C6 alkyl or substituted alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl or -2, -3, or -4 piperidyl or N-substituted piperidyl. Yxe2x80x2 can also be, amongst others, SO2Rxe2x80x2 wherein Rxe2x80x2 is C1 to C6 alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably 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 inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, 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 which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. One compound disclosed in this invention has been demonstrated to have anti-tumor activity in animal models.
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 growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., 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 oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
Compounds useful in the claimed methods are represented by Formula 1.0:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR9 wherein R9 is O31, xe2x80x94CH3 or xe2x80x94(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10 (e.g. xe2x80x94OH), xe2x80x94COR10, xe2x80x94SR10, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, benzotriazol-1-yloxy, CN, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R10;
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 together can represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, R7 and R8 each independently represents H, xe2x80x94CF3, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR10, xe2x80x94SR10, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R11, xe2x80x94CO2R10, OPO3R10or one of R5, R6, R7 and R8 can be taken in combination with R as defined below to represent xe2x80x94(CH2)rxe2x80x94 wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, xe2x80x94CF3 or aryl;
R10 represents H, alkyl, aryl, or aralkyl (preferably benzyl);
R11 represents alkyl or aryl;
R16 and R18 represent H and F respectively, or F and H respectively, when the bond to X is a single bond and X is carbon, preferably R16 is F and R18 is H; or
R16 and R18 each represent H when the bond to X is a single bond;
X represents N or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent xe2x80x94R10, halo, xe2x80x94OR11, xe2x80x94OCO2R11 or xe2x80x94OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR11)2; H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R10, H and xe2x80x94OR10, xe2x95x90O, aryl and H, xe2x95x90NOR10 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein p is 2, 3 or 4;
Z represents O; and
R represents xe2x80x94SR65 wherein R65 is alkyl, aryl, heteroaryl (e.g. pyridyl or pyridyl N-oxide), 2-,3-, or 4-piperidyl or N-substituted piperidyl, wherein the substituent on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl; or
R represents xe2x80x94OR20 wherein R20 is C1 to C12 alkyl, substituted C1 to C12 alkyl, phenyl, substituted phenyl, C7 to C12 phenylalkyl (e.g., benzyl), C7 to C12 phenylalkyl wherein the phenyl moiety is substituted, heteroaryl (e.g., pyridyl or pyridyl N-oxide), or R20 is -2, -3, or -4 piperidyl or N-substituted piperidyl, wherein the substituents on said substituted C1 to C12 alkyl are selected from amino or substituted amino, with the proviso that said amino or said substituted amino for said C1 to C12 alkyl is not on C1, and the substitutents on said substituted amino are selected from C1 to C6 alkyl, the substituents on said substituted phenyl and on said substituted phenyl moiety of the C7 to C12 phenylalkyl are selected from C1 to C6 alkyl and halo, and the substituent on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl (e.g., CH3C(O)xe2x80x94) or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl.
This invention also provides novel compounds of Formula 1.1:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a, b, c, d, A, B, R5, R6, R7, and R8 are as defined for Formula 1.0;
R22 and R24 are the same or different and each independently represents any of the substituents of R1 and R2;
R26 and R28 are the same or different and each independently represents any of the substituents of R3 and R4;
V represents xe2x80x94OR30 or xe2x80x94SR70;
R30 represents aralkyl (e.g., benzyl), aryl (e.g., phenyl or substituted phenylxe2x80x94i.e., phenyl substituted with 1 to 3, preferably 1, group selected from halo, alkyl, haloalkyl or alkoxy), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, or pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), alkyl (e.g., ethyl), or -2, -3, or -4 piperidyl or N-substituted piperidyl, wherein the substituents on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl (e.g., CH3C(O)xe2x80x94) or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl;
R70 represents aryl (e.g., phenyl or substituted phenylxe2x80x94i.e., phenyl substituted with 1 to 3, preferably 1, group selected from halo, alkyl, haloalkyl or alkoxy), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, or pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), or 2-,3-, or 4-piperidyl or N-substituted piperidyl, wherein the substituent on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl; and
the dotted line between carbons 5 and 6 represent an optional double bond (preferably the double bond is absent).
This invention further provides novel compounds of Formula 1.2:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a, b, c, d, A, B, R5, R6, R7, and R8 are as defined for Formula 1.0;
R32 and R34 are the same or different and each independently represents any of the substituents of R1 and R2;
R36 and R38 are the same or different and each independently represents any of the substituents of R3 and R4;
W represents xe2x80x94OR40 or xe2x80x94SR70;
R40 represents alkyl (e.g., ethyl), aryl (e.g., phenyl or substituted phenylxe2x80x94i.e., phenyl substituted with 1 to 3, preferably 1, group selected from halo, alkyl, haloalkyl or alkoxy), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, or pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), or -2, -3, or -4 piperidyl or N-substituted piperidyl, wherein the substituents on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl (e.g., CH3C(O)xe2x80x94) or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl;
R70 is as defined above; and
the dotted line between carbons 5 and 6 represent an optional double bond.
This invention additionally provides compounds of Formula 1.3:
a, b, c, d, A, B, R5, R6, R7, and R8 are as defined for Formula 1.0;
R44 and R46 are the same or different and each independently represents any of the substituents of R1 and R2;
R48 and R50 are the same or different and each independently represents any of the substituents of R3 and R4;
Y represents xe2x80x94OR52 or xe2x80x94SR70;
R52 represents aralkyl (e.g., benzyl), aryl (e.g., phenyl or substituted phenylxe2x80x94i.e., phenyl substituted with 1 to 3, preferably 1, group selected from halo, alkyl, haloalkyl or alkoxy), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, or pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), alkyl (e.g., ethyl), or -2, -3, or -4 piperidyl or N-substituted piperidyl, wherein the substituents on said N-substituted piperidyl is C1 to C4 alkyl, alkylcarbonyl (e.g., CH3C(O)xe2x80x94) or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl;
R70 is as defined above; and
the dotted line between carbons 5 and 6 represent an optional double bond (preferably the double bond is absent); and
with the provisos that: (a) when Y represents xe2x80x94OR52, and when there is a single bond between carbon atoms 5 and 6, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not phenyl; and (b) when Y represents xe2x80x94OR52, and when there is a single bond between carbon atoms 5 and 6, and when both R44 and R46 are hydrogen, and when R48 is Cl at the C-8 position and R50 is H, then R52 is not ethyl.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, 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 the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, bladder carcinoma, and myelodysplastic syndrome (MDS).
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, lyn, fyn), may be inhibited by the tricyclic compounds described herein.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
The tricyclic compounds useful in the methods of this invention inhibit abnormal cellular growth. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
This invention also provides a process for producing 3-nitro substituted compounds. The process comprises reacting one molar equivalent of a compound: 
wherein R1, R2, R3, R4, A, B, a, b, d, and the dotted lines are as defined for Formula 1.0; and R75 represents H or xe2x80x94OR76 wherein R76 represents alkyl (e.g., C1 to C4 alkyl, preferably ethyl); with one molar equivalent of a nitrating reagent, said nitrating reagent being preformed (i.e., prepared first) by mixing, at cold temperature (e.g., at 0xc2x0 C.) equimolar amounts of tetrabutyl ammonium nitrate with trifluoroacetic anhydride; the reaction of the nitrating reagent with the compound of Formula 1.0g taking place in a suitable aprotic solvent (e.g., methylene chloride, chloroform, toluene or THF); said reaction with said nitrating reagent being conducted at a temperature and for a period of time sufficient to allow the reaction to proceed at a reasonable rate to produce the desired final 3-nitro compound of Formula 1.0h (described below)xe2x80x94i.e., the reaction of the compound of Formula 1.0g with said nitrating reagent is conducted at an initial temperature of 0xc2x0 C., and said reaction temperature is thereafter allowed to rise to about 25xc2x0 C. during the reaction time period. The reaction usually proceeds overnight to completion, i.e., the reaction usually proceeds for about 16 hours. The reaction can be conducted within a temperature of 0xc2x0 C. to about 25xc2x0 C. during a time period of about 10 to about 24 hours. Preferably the reaction is initially conducted at 0xc2x0 C. and the temperature is allowed to warm up to 25xc2x0 C. The reaction produces the 3-nitro compound: 
is produced.
The compound of Formula 1.0 h can then be converted to other 3-substituted products by methods well known to those skilled in the art. For example, the 3-nitro compounds can be converted to 3-amino, 3-halo, 3 -cyano, 3-alkyl, 3-aryl, 3-thio, 3-arylalkyl, 3-hydroxyl, and 3-OR77 wherein R77 is alkyl or aryl. The 3-substituted compounds can then be converted to final products by the procedures described herein.
This invention also provides a process for producing 3-nitro compounds of the formula: 
by producing a compound of Formula 1.0h from 1.0g as described above; and then hydrolyzing the compound of Formula 1.0h by dissolving the compound of Formula 1.0h in a sufficient amount of concentrated acid (e.g., concentrated HCl or aqueous sulfuric acid), and heating the resulting mixture to a temperature sufficient to remove (hydrolyze) the xe2x80x94C(O)R75 substituent, for example, heating to reflux or to a temperature of about 100xc2x0 C.
The compound of Formula 1.0i can then be converted to other 3-substituted compounds as discussed above for the compounds of Formula 1.0h. The compounds of Formula 1.0i can then be converted to compounds of this invention by the methods described herein. This invention also provides a process for producing compounds of the formula: 
by reacting one molar equivalent a compound of formula: 
with one molar equivalent of a nitrating reagent, said nitrating reagent being preformed (i.e., prepared first) by mixing, at cold temperature (e.g., at 0xc2x0 C.) equimolar amounts of tetrabutyl ammonium nitrate with trifluoroacetic anhydride; the reaction of the nitrating reagent with the compound of Formula 1.0k taking place in a suitable aprotic solvent (e.g., methylene chloride, chloroform, toluene or THF); said reaction with said nitrating reagent being conducted at a temperature and for a period of time sufficient to allow the reaction to proceed at a reasonable rate to produce the desired final 3-nitro compound of Formula 1.0jxe2x80x94i.e., the reaction of the compound of Formula 1.0k with said nitrating reagent is conducted at an initial temperature of 0xc2x0 C., and said reaction temperature is thereafter allowed to rise to about 25xc2x0 C. during the reaction time period. The reaction usually proceeds overnight to completion, i.e., the reaction usually proceeds for about 16 hours. The reaction can be conducted within a temperature of 0xc2x0 C. to about 25xc2x0 C. during a time period of about 10 to about 24 hours. Preferably the reaction is initially conducted at 0xc2x0 C. and the temperature is allowed to warm up to 25xc2x0 C. In Formulas 1.0j and 1.0k, R1, R2, R3, R4, A, B, a, b, d, and the dotted lines are as defined for Formula 1.0.
The compounds of Formula 1.0j can be converted to compounds of Formula 1.0h by methods described below. Also, as discussed above for the compounds of Formula 1.0h, the compounds of Formula 1.0j can be converted to other 3-substituted compounds wherein the substituents are those discussed above for Formula 1.0h.
The compounds of Formula 1.0j can be converted to compounds of Formula 1.0m: 
wherein R78 is H or xe2x80x94COORa wherein Ra is a C1 to C3 alkyl group (preferably R78 is H), by reducing a compound of Formula 1.0j with a suitable reducing agent (such as sodium borohydride) in a suitable solvent (such as EtOH or MeOH) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., 0 to about 25xc2x0 C.); reacting the resulting product (Formula 1.0j wherein the xe2x95x90O has been reduced to a xe2x80x94OH) with a chlorinating agent (e.g., thionyl chloride) in an suitable organic solvent (e.g., benzene, toluene or pyridine) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., about xe2x88x9220 to about 20xc2x0 C., preferably at xe2x88x9215xc2x0 C.) to produce a compound of Formula 1.0n: 
and reacting a compound of Formula 1.0n with a compound of the formula: 
wherein R78 is as previously defined, and is preferably H, in a suitable organic solvent (such as THF or toluene) containing a suitable base (such as triethylamine or N-methylmorpholine) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., 25 to about 120xc2x0 C.).
Compounds of Formula 1.0m can be converted to compounds of this invention by the methods disclosed herein. Also, as discussed above for the compounds of Formula 1.0h, the compounds of Formula 1.0m can be converted to other 3-substituted compounds wherein the substituents are those discussed above for Formula 1.0h.
This invention also provides novel compounds (produced in the above described processes as intermediates to the compounds of this invention) having the formulas: 
wherein all substituents are as defined herein.
Preferably, for the intermediate compounds of the processes of this invention, R1 and R2 are H; R3 is halo, most preferably Cl, in the C-8 position; R4 is H; and A and B are H when the double between C-5 and C-6 is present, and A and B are H2 when the bond between C-5 and C-6 is a single bond (most preferably the bond between C-5 and C-6 is a single bond). Those skilled in the art will appreciate that Rings I, II, and/or III can be further substituted, as described herein, to produce the desired compounds of the invention.
Examples of such novel intermediate compounds include: 
As used herein, the following terms are used as defined below unless otherwise indicated:
M+xe2x80x94represents the molecular ion of the molecule in the mass spectrum;
MH+xe2x80x94represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
alkylxe2x80x94(including the alkyl portions of alkoxy, alkylamino and dialkylamino)xe2x80x94represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
alkanediylxe2x80x94represents a divalent, straight or branched hydrocarbon chain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, the two available bonds being from the same or different carbon atoms thereof, e.g., methylene, ethylene, ethylidene, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CHCH3, xe2x80x94CHCH2CH3, etc.
cycloalkylxe2x80x94represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
heterocycloalkylxe2x80x94represents a saturated, branched or unbranched carbocyclic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94or xe2x80x94NR10-(suitable heterocycloalkyl groups including 2- or 3-THFyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, etc.);
alkenylxe2x80x94represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
alkynylxe2x80x94represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
aryl (including the aryl portion of aryloxy and aralkyl)xe2x80x94represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, xe2x80x94COOR10 or xe2x80x94NO2; and
haloxe2x80x94represents fluoro, chloro, bromo and iodo; and
heteroarylxe2x80x94represents cyclic groups, optionally substituted with R3 and R41 having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., 2-, 3- or 4-pyridyl (optionally substituted with R3 and R4) and pyridyl N-oxide: 
xe2x80x83(e.g., 2-, 3- or 4-pyridyl N-oxide, optionally substitued with R3 and R4).
Reference to the positions of the substituents in Rings I and III, for example, is based on the numbered ring structure: 
For example, in Formula 1.0, R1 can be at the C-4 position and R2 can be at the C-2 or C-3 position. Also, for example, R3 can be at the C-8 position and R4 can be at the C-9 position.
Representative structures of Formula 1.0 include but are not limited to: 
Preferably, for the compounds of Formula 1.0 (including 1.0a to 1.0d):
one of a, b, c and d (most preferably a) represents N or NR9 wherein R9 is Oxe2x80x94or xe2x80x94CH3, and the remaining a, b, c and d groups represent CR1 or CR2; more preferably a represents N and the remaining a, b, c and d groups represent CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, (e.g. Cl or Br) benzotriazol-1yloxy or alkyl (most preferably C1 to C4 alkyl, more preferably methyl); most preferably R1 and R2 are selected from H or halo; and more preferably R1 and R2 are selected from H, Cl or Br;
R3 and R4 are the same or different and each independently represents H, halo or alkyl most preferably R3 is halo and R4 is H; more preferably R3 is Cl and R4 is H; even more preferably R3 is Cl at the C-8 position and R4 is H;
R5, R6, R7 and R8 each independently represents H or alkyl; and most preferably R5, R6, R7 and R8 each represents H;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent H, xe2x80x94R10 or xe2x80x94OR10, and most preferably H, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR10)2, (alkyl and H), (alkyl)2, (xe2x80x94H and xe2x80x94OR10) or xe2x95x90O, and most preferably H2; and
R20 is C1 to C12 alkyl, phenyl, substituted phenyl, C7 to C12 phenylalkyl (e.g., benzyl), C7 to C12 phenylalkyl wherein the phenyl moiety is substituted, 3- or 4-N-substituted piperidyl, or heteroaryl (e.g., pyridyl or pyridyl N-oxide), wherein the substituents on said substituted phenyl and on said substituted phenyl moiety of the C7 to C12 phenylalkyl are selected from C1 to C6 alkyl and halo, and wherein the substituents on said N-substituted piperidyl is C1 to C4 alkyl (most preferably methyl), alkylcarbonyl (e.g., CH3C(O)xe2x80x94) or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl; most preferably R20 is C, to C6 alkyl (more preferably ethyl), phenyl, substituted phenyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, 4-pyridyl N-oxide, or 3- or 4-N-substituted piperidyl wherein the substituent on the nitrogen is C1 to C4 alkyl (more preferaby methyl).
Preferably, for the compounds of Formula 1.0, R represents xe2x80x94OR20, with the remaining substituents being as defined above.
Tricyclic compounds useful in the methods of this invention are described in: (1) U.S. Pat. No. 4,282,233; (2) U.S. Pat. No. 4,826,853; (3) WO 88/03138 published on May 5, 1988 (PCT/US87/02777); and (4) U.S. Pat. No. 4,863,931; the disclosures of each being incorporated herein by reference thereto.
Compounds of Formula 1.1 include compounds of the formulas: 
Preferably for compounds of Formula 1.1:
a represents N, and b, c, and d represent carbon;
A and B each represent H2 when the double bond between C-5 and C-6 is absent, and A and B each represent H when the double bond is present;
R5, R6, R7, and R8 each represent H;
R22 and R24 are each independently selected from H, halo (e.g., Cl or Br), benzotriazol-1yloxy or alkyl (most preferably C1 to C4 alkyl, more preferably methyl); most preferably R22 and R24 are each independently selected from H or halo; more preferably R22 and R24 are each independently selected from H, Cl or Br;
R26 and to R28 are each independently selected from H, halo (e.g, Cl or Br) or alkyl, most preferably R26 is halo and R28 is H, more preferably R26 is Cl and R28 is H, even more preferably R26 is Cl at the C-8 position and R28 is H;
V represents xe2x80x94OR30; and
R30 represents aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, and pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), alkyl (e.g., ethyl), or 3- or 4-N-substituted piperidyl (most preferably the substituent on said N-substituted piperidyl is C1 to C4 alkyl, and more preferaby methyl).
For example, compounds of Formula 1.1 include: 
wherein the substitute are as defined above.
Representative example of compounds of formula 1.2 include: 
Preferably for compounds of Formula 1.2:
a represents N, and b, c, and d represent carbon;
A and B each represent H2 when the double bond between C-5 and C-6 absent, and A and B each represent H when the double bond is present;
R5, R6, and R8 each represent H;
R32 and R34 are each independently selected from H, halo (e.g., Cl or Br ) benzotriazol-1yloxy or alkyl (most preferably C1 to C4 alkyl, more prefereably methyl); most preferably R32 and R34 are each independently selected from H or halo; more preferably R32 and R34 are each independently selected from H, Cl or Br;
R36 and to R38 are each independently selected from H or halo (e.g, Cl or Br), most preferably R36 is halo and R38 is H, more preferably R36 is Cl and R38 is H, even more preferably R36 is Cl at the C-8 position and R38 is H;
W represents xe2x80x94OR40; and
R40 represents heteroaryl (e.g., pyridyl, such as 3- or 4-pyridyl, and pyridyl N-oxide, such as 3- or 4-pyridyl N-oxide), alkyl (e.g., ethyl), or 3- or 4-N-substituted piperidyl (most preferably the substituent on said N-substituted piperidyl is C1 to C4 alkyl, and more preferably methyl).
Compounds of Formula 1.3 include compounds wherein (a) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not phenyl; and (b) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when R48 is Cl at the C-8 position and R50 is H, then R52 is not ethyl.
Compounds of Formula 1.3 also include compounds wherein (a) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not aryl; and (b) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when R48 is Cl at the C-8 position and R50 is H, then R52 is not alkyl.
Compounds of Formula 1.3 further include compounds wherein (a) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not aryl; and (b) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when R48 is halo at the C-8 position and R50 is H, then R52 is not alkyl.
Compounds of Formula 1.3 still further include compounds wherein (a) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not aryl; and (b) when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when R48 is halo and R50 is H, then R52 is not alkyl.
Compounds of Formula 1.3 even further include compounds wherein when Y represents xe2x80x94OR52, and when both R44 and R46 are hydrogen, and when both R48 and R50 are H, then R52 is not aryl and R52 is not alkyl.
Preferably for compounds of Formula 1.3:
a represents N, and b, c, and d represent carbon;
A and B each represent H2 when the double bond between C-5 and C-6 is absent, and A and B each represent H when the double bond is present;
R5, R6, R7, and R8 each represent H;
R44 and R46 are each independently selected from H, halo (e.g., Cl or Br) benzotriazol-1yloxy or alkyl (most preferably C1 to C4 alkyl, more preferably methyl); most preferably R44 and R46 are each independently selected from H or halo; more preferably R44 and R46 are each independently selected from H, Cl or Br;
R48 and to R50 are each independently selected from H or halo (e.g, Cl or Br), most preferably R48 is halo and R50 is H, more preferably R48 is Cl and R50 is H, even more preferably R48 is Cl at the C-8 position and R50 is H;
R52 represents heteroaryl (most preferably 3- or 4-pyridyl, or 3- or 4-pyridyl N-oxide), aryl (most preferably phenyl or substituted phenyl, e.g., halo substituted phenyl such as p-bromophenyl), or 3- or 4-N-substituted piperidyl (most preferably the substituent on said N-substitued piperidyl is C1 to C4 alkyl, and more preferaby methyl); and
R70 represents phenyl, 3-pyridyl, 4-pyridyl, 3-pyridyl N-oxide, 4-pyridyl N-oxide, 3- or 4-N-substituted piperidyl, wherein the substituent on said N-substituted piperidyl is C, to C4 alkyl (most preferably methyl), alkylcarbonyl or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl, most preferably the substituent on the N-substituted piperidyl group is C1 to C4 alkyl.
Compounds of Formula 1.3 include: 
wherein all substituents are as defined above.
Compounds of Formula 1.0 include compounds Formula 1.4: 
wherein all substituents are as defined for Formula 1.0. In particular, compounds of Formula 1.4 include compounds wherein R is xe2x80x94SR65. Compounds of Formula 1.4 further include compounds wherein R is xe2x80x94SR65 and R10 is H, alkyl or aryl. Compounds wherein R is xe2x80x94SR65 (and R65 is alkyl) and R10 is H, alkyl or aryl are disclosed in U.S. Pat. No. 4,826,853 and WO88/03138, and can be made in accordance with procedures therein.
Compounds of Formula 1.0 also include compounds of Formula 1.5: 
wherein all substituents are as defined in Formula 1.0. In particular, compounds of Formula 1.5 include compounds wherein R3 is H or halo and R20 is as defined for Formula 1.0 except that heteroaryl is excluded; these compounds are disclosed in U.S. Pat. No. 4,282,233 and can be made according to the process disclosed therein.
Also included in Formula 1.0 are compounds of Formula 1.6:
wherein the substituents are as defined for Formula 1.0. In particular, Formula 1.6 includes compounds wherein R1 to R4 are each independently selected from the substituents given for R1 and R2 of Formula 1.0, and R16 and R18 represent H and F respectively, or F and H respectively (preferably R16 is F and R18 is H); these compounds are disclosed in U.S. Pat. No. 4,863,931 and can be made in accordance with the procedures disclosed therein.
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O).
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, EtOH and the like are equivalent to the unsolvated forms for purposes of the invention.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may 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, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may 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 salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. 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 may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat 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.
All such acid and base salts are intended to be 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.
Compounds within the above described formulas include: 
Preferred compounds useful in this invention are represented by Formulas 500.00, 530.00, 550.00, 565.00, 580.00, 595.00, 600.00, 604.00, 608.00, 610.00, 612.00, 618.00, 626.00, 642.00, 644.00, 656.00, 662.00, 676.00, 800.00, 801.00, 802.00, 803.00, 804.00 and 805.00, and the compounds of Examples 32 and 33.
More preferred compounds useful in this invention are represented by Formulas 500.00, 530.00, 565.00, 580.00, 595.00, 600.00, 608.00, 610.00, 612.00, 618.00, 626.00, 642.00, 644.00, 656.00, 662.00, 801.00, 802.00, 803.00, 804.00 and 805.00, and the compounds of Examples 32 and 33.
The following processes may be employed to produce compounds of Formula 400.00:
Those skilled in the art will appreciate that compounds of Formula 1.0, e.g., Formula 1.4, are represented by the compounds of Formula 400.00. Those skilled in the art will also appreciate that the processes described below for producing compounds of Formula 400.00 (Formula 1.4) are also applicable to the compounds of Formulas 1.1, 1.2 and 1.3.
A compound of Formula 405.00 may be reacted with RC(O)L, wherein R is as defined for Formula 1.0. in the presence of a base to produce compounds of Formula 400.00. 
Representative examples of appropriate bases are pyridineand triethylamine. L designates a suitable leaving group (e.g., Cl or Br).
Compounds of Formula 405.00 may be prepared by cleaving the group COORa from the corresponding carbamates 415.00, for example, via acid hydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH): 
wherein Ra is a group which does not prevent the cleavage reaction, e.g., Ra is an optionally substituted alkyl such as ethyl.
Alternatively, depending upon the nature of Ra, as determined by one skilled in the art, Compound 415.00 may be treated with an organometallic reagent (e.g., CH3Li), a reductive reagent (e.g., Zn in acid), etc., to form compounds of Formula 405.00.
Compound 415.00 may be prepared from the N-alkyl compound shown as Formula 420.00 below, in the manner disclosed in U.S. Pat. Nos. 4,282,233 and 4,335,036.
It also will be apparent to one skilled in the art that there are other methods for converting Compound 420.00 to Compound 405.00. For example, treatment of Compound 420.00 with BrCN via von Braun reaction conditions would provide nitrile 420.00a. Subsequent hydrolysis of the nitrile under either aqueous basic or acidic conditions would produce Compound 405.00. This method is preferable when there is substitution on the piperidine or piperazine ring. 
C. The compounds of Formula 400.00 wherein Z is O may be made by an alternative process using direct conversion of the N-alkyl compound 420.00 with an appropriate compound of Formula 410.00 such as a chloroformate (such as phenylchloroformate). An appropriate base, may be added, and heating may be required. Typically, a temperature ranging from 50-150xc2x0 C. is utilized. Other compounds of the invention can be made by reacting a compound of Formula 400.00, wherein R is phenoxy, with the sodium salt of the appropriate alcohol. 
Compound 420.00 is prepared as described in part B above.
Compounds of Formula 400.00, wherein X is carbon and the bond to carbon 11 (C-11) is a single bond, can be prepared by reducing compounds of Formula 405.00, wherein X is carbon and the bond to C-11 is a double bond, with lithium aluminum hydride in THF. Conversion to final products can be done following the process described above for conversion of compounds of Formula 405.00 to compounds of Formula 400.00.
Compounds of Formula 400.00, wherein X is a carbon atom having an exocyclic double bond to carbon 11, may be prepared from compound 420.00 as described above. Compounds of Formula 420.00 may be produced by the methods disclosed generally in U.S. Pat. No. 3,326,924 or alternatively may. be prepared by a ring closure reaction, wherein the desired cycloheptene ring is formed by treating compound 425.00 with a super acid. Suitable super acids for this purpose include, for example, HF/BF3, CF3SO3H (triflic acid), CH3SO3H/BF3, etc. The reaction can be performed in the absence of, or with, an inert co-solvent such as CH2Cl2. The temperature and time of the reaction vary with the acid employed. For example, with HF/BF3 as the super acid system the temperature may be controlled so as to minimize side reactions, such as HF addition to the exocyclic double bond. For this purpose, the temperature is generally in the range of from about +5xc2x0 C. to xe2x88x9250xc2x0 C. With CF3SO3H as the super acid system, the reaction may be run at elevated temperatures, e.g., from about 25xc2x0 C. to about 150xc2x0 C. and at lower temperatures but the reaction then takes longer to complete.
Generally the super acid is employed in excess, preferably in amounts of from about 1.5 to about 30 equivalents. 
A detone compound of Formula 425.00 may be formed by hydrolysis of 430.00 e.g., such as by reacting a Grignard intermediate of Formula 430.00 with an aqueous acid (e.g., aqueous HCl). Ia in Formula 430.00 represents chloro, bromo or iodo. 
The Grignard intermediate 430.00 is formed by the reaction of the cyano compound 435.00 with an appropriate Grignard reagent 440.00 prepared from 1-alkyl-4halopiperidine. The reaction is generally performed in an inert solvent, such as ether, toluene, or THF, under general Grignard conditions e.g., temperature of from about 0xc2x0 C. to about 75xc2x0 C. Alternatively, other organometallic derivatives of the 1alkyl-4-halo piperidine can be employed. 
The cyano compound of Formula 435.00 is produced by converting the tertiary butyl amide of Formula 445.00 with a suitable dehydrating agent, such as POCl3, SOCl2, P2O5, toluene sulfonyl chloride in pyridine, oxalyl chloride in pyridine, etc. This reaction can be performed in the absence of or with a co-solvent, such as xylene.
The dehydrating agent such as POCl3 is employed in equivalent amounts or greater and preferably in amounts of from about 2 to about 15 equivalents. Any suitable temperature and time can be employed for performing the reaction, but generally heat is added to accelerate the reaction. Preferably the reaction is performed at or near reflux. 
The tert-butylamide of Formula 445.00 may be produced by reaction of a compound of Formula 450.00a and 450.00b, in the presence of base, wherein G is chloro, bromo or iodo. 
The compound of Formula 450.00a may be formed by hydrolysis of the corresponding nitrile wherein the appropriate cyanomethyl pyridine, such as 2-cyano-3-pyridine, is reacted with a tertiary butyl compound in acid, such as concentrated H2SO4 or concentrated H2SO4 in glacial acetic acid. Suitable tertiary butyl compounds include, but are not limited to, t-butyl alcohol, t-butyl chloride, t-butyl bromide, t-butyl iodide, isobutylene or any other compound which under hydrolytic conditions forms t-butyl carboxamides with cyano compounds. The temperature of the reaction will vary depending upon the reactants, but generally the reaction is conducted in the range of from about 50xc2x0 C. to about 100xc2x0 C. with t-butyl alcohol. The reaction may be performed with inert solvents, but is usually run neat.
An alternative process for the formation of compounds of Formula 400.00a may involve direct cyclization of Compound 455.00 as shown below. 
Cyclization to form the cycloheptene ring may be accomplished with a strong acid (e.g., triflic, polyphosphoric, HF/BF3), and may be performed in an inert solvent, such as ether, toluene or THF. The temperature and time may vary with the acid employed, as described in process A above.
Compounds of Formula 455.00 wherein Zxe2x95x90O may be prepared by treating a compound of Formula 425.00 with an appropriate chloroformate (e.g. ethyl chloroformate) of formula 410.00 in the appropriate solvent, such as toluene, dioxane or xylene, and at a temperature ranging from 50-150xc2x0 C., preferably 100-120xc2x0 C. 
A second method of preparing compounds of Formula 455.00 involves reacting an unsubstituted piperidylidene compound of Formula 460.00 with the appropriate chloroformate (e.g., ethyl chloroformate) of Formula 410.00 in the presence of base, such as pyridine or Et3N. 
Compounds of Formula 460.00 may be produced from the corresponding carbamates of Formula 465.00, via acid hydrolysis, using for example, aqueous HCl, or base hydrolysis using for example, KOH. Alternatively, some compounds can be prepared by treating the carbamate, Formula 465.00, with an organometallic reagent, such as methyl lithium or a reductive reagent, such as Zn in acid, etc., depending upon the nature of the Ra group. For example, if Ra is a simple alkyl group, CO2Ra may be cleaved by alkaline hydrolysis at 100xc2x0 C. 
The carbamate compounds of Formula 465.00 may be prepared from the appropriate alkyl compound of Formula 425.00 by treatment with a chloroformate, preferably in an inert solvent, such as toluene, with warming to approximately 80xc2x0 C. Other alternative methods are available for the conversion of 425.00 to 455.00 as previously described (e.g. Von Braun reaction conditions). Compounds of Formula 425.00 may be prepared as described above.
Various methods can be used as described in WO 88/03138 to provide compounds which are substituted on the pyridine ring, i.e., in positions 2-, 3- and or 4-positions of the tricyclic ring system. For example, the cyclization methods described on pages 20-30 of WO 88/03138 can already have the appropriate substituents on the pyridine ring in place. A variety of substituted pyridines are known in the literature and can be employed in these syntheses. Alternatively, the azaketone of Formula XIX (from page 27 of WO 88/03138) 
wherein R1 and R2 are both H can be converted to the appropriately substituted azaketone wherein R1 and R2 are non-H substitutents. If both R1 and R2 are desired to be non-H substitutents the procedure would be repeated.
The azaketone is thus reacted with an oxidizing agent such as MCPBA or H2O2 to produce the corresponding compound in which the nitrogen of the pyridine ring is an N-oxide: 
wherein one of axe2x80x2, bxe2x80x2, cxe2x80x2 or dxe2x80x2 is Nxe2x86x92O and the others are CH or CR1 or CR2. This reaction is normally run at temperatures from xe2x88x9215xc2x0 C. to reflux, more typically at about 0xc2x0 C. The reaction is preferably conducted in an inert solvent such as CH2Cl2 for MCPBA or acetic acid for hydrogen peroxide.
The azaketone N-oxide of Formula 470.00a can then be reacted with a chlorinating agent such as SO2Cl2 or SOCl2 to form a compound of Formula 470.00b Typically, this reaction results in monosubstitution of Cl in the ortho or para-position relative to the N atom of the ring. 
To provide the disubstituted products, steps 1 and 2 above are repeated. 
Typically, the resulting disubstituted compounds have Cl ortho and para relative to the N atom of the pyridine ring.
The mono or disubstituted compounds of Formulas 470.00b and 470.00c above can be reacted with various nucleophiles such as alkoxides, amines, thiols, etc. This will result in compounds where one or both of the Cl substituents are replaced by the nucleophile to provide a compound of Formula 470.00d or a compound easily converted to Formula 470.00d. 
The substituted ketone of Formula 470.00 can then be converted to the desired compound by the methods described above.
Formula 405.00, wherein R1 or R2 are chlorine, can be made by the following alternate process. 
The N-oxide of Formula 415.00 can be treated with POCl3 to form a compound of Formula 415.01. Typically, this reaction results in mono-substitution of Cl in the ortho or para position relative to the N atom of the ring. The N-oxide of Formula 415.00 can be formed by oxidizing Formula 415.00 with a peroxyacid such as 4-chloroperoxybenzoic acid.
Alternatively, the Cl substituted azaketones of formula 470.00b or 470.00c above can be converted to the corresponding derivatives of Formula 405.00 above wherein R1 and/or R2 is Cl by methods analogous to those described above. At this point the Cl substituent(s) can be displaced by an appropriate nucleophile to provide the desired substituent. Suitable nucleophiles include alkoxide, amines, thiols, etc. This reaction usually requires higher temperatures (e.g., from about 100xc2x0 to about 200xc2x0 C.) than the displacement reaction to produce ketone 470.00d above. It is also usually conducted in a sealed vessel in an inert solvent. The compound of Formula 405.00 is then converted to a compound of Formula 400.00 as described above.
Compounds of formula 400.00 with a double bond between C-5 and C-6 can be prepared by heating a compound of Formula 470.00h in acetic acid with SeO2 to produce a compound of Formula 470.00i. Compounds of Formula 470.00i can be converted to final products according to methods already described. 
Compounds having a piperazine ring bound to the C-11 of the tricyclic nucleus, i.e., Formula 1.0 wherein X is N, are best prepared via alkylation of the appropriately substituted piperazine compound of Formula 700.00 with a compound of Formula 705.00. Compounds of Formula 705.00 contain the appropriately substituted halide (such as Cl, Br, or I) or other similar leaving group (e.g., tosyloxy or mesyloxy). The reaction is usually conducted in an inert solvent, such as THF or toluene, optionally with a base such as Et3N or K2CO3, and typically at a temperature range of ambient to reflux to produce a compound of Formula 710.00.
In this reaction Rg is H or CO2Ra (wherein Ra is a C1 to C4 alkyl group). The preparation of compound 705.00 wherein L is Cl is analogous to the procedure described in U.S. Pat. No. 3,409,621. By methods known in the art compounds of Formula 710.00, wherein Rg is CO2Ra, can be converted to Formula 710.00 wherein Rg is H, by acid or base hydrolysis as described in U.S. Pat. No. 4,826,853. Compounds of formula 710.00, wherein Rg is H, can be converted to compounds of Formula 400.00 by the process used to convert Formula 405.00 to Formula 400.00. Compounds of 410.00, wherein R is 3-pyridyloxy, can be prepared by reacting 3-hydroxy-pyridine with an excess of phosgene in toluene/CH2Cl2 at 0xc2x0 C. in the presence of a base such as pyridine.
An alternate route for generating the compound of Formula 710.00 is by reductive amination of the aza ketone 715.00 with the piperazine 700.00. 
The reaction is typically carried out in a polar solvent, such as MeOH or EtOH, optionally in the presence or a dehydrating agent, such as 3 xc3x85 molecular sieves. The intermediate Schiff base can be reduced agents, such as NaCNBH3, or catalytic hydrogenation, for example, hydrogen over Pd/C.
When Rg is C(Z)R, these are the compounds of the invention.
An alternative process for introducing substituents at the C-1 position of pyridine Ring I of Formula 1.0, involves nitrating a compound of Formula 415.00 (except wherein X is nitrogen) or a compound of Formula 470.00d with tetrbutylammonium nitratexe2x80x94TFAA in CH2Cl2 at a temperature of 0xc2x0 C. to room temperature (about 25xc2x0 C.). The nitro group may then be reduced to the corresponding amine using iron filings in ethanol, or powdered Zn-HOAc in aqueous THF. By methods known to those skilled in the art, the amine group can be converted to a variety of substituents, such as, halo, cyano, thio, hydroxyl, alkyl, alkenyl, alkynyl and haloalkyl.
Compounds of Formulas 1.2 and 1.3, wherein R30, R40, R52 and R70 represent a pyridyl N-oxide, can be produced by reacting compounds of Formulas 1.2, and 1.3, wherein R30, R40, R52 and R70 represent pyridyl, with one molar equivalent of an oxidizing agent (such as oxone).
Compounds of Formula 1.1, wherein R30 or R70 represent a pyridyl N-oxide, can be produced by reacting a compound of the formula (XI) 
with phosgene in the presence of a suitable base, such as pyridine, to form a compound of the formula (XII), which is then reacted with the approriate hydroxypyridine N-oxide or mercaptopyridine N-oxide.
Alternatively, compounds of Formula 1.1, wherein R30 or R70 represent a pyridyl N-oxide, can be produced by reacting a compound of the formula (XI) with carbonyldiimidazole to form a compound of the formula (XIII) which is reacted with the approriate hydroxypyridine N-oxide (or mercaptopyridine N-oxide) in the presence of either ZnBr2 or NaH.
Various electrophilic species can also be added to the pyridine ring from the corresponding halo-substituted pyridine (Formula 405.00 wherein R1 is halo, preferably bromo or iodo). Transmetallation of the halo derivative using an alkyl lithium (e.g. n-BuLi) provides the lithio derivative, which can then be quenched with the appropriate electrophile (e.g. R1L, etc.).
Also, the halogens can be displaced with nucleophiles, such as HOBT, to give compounds with substituents in the pyridine ring.
In the above processes, it is sometimes desirable and/or necessary to protect certain R1, R2, R3 and R4 etc., groups during the reactions. Conventional protecting groups are operable as described in Greene, T. W., xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d John Wiley and Sons, New York, 1981. For example, the groups listed in column 1 of Table 1 may be protected as indicated in column 2 of the table:
Other protecting groups well known in the art also may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures.
USPTO Backgrounds
USPTO Backgrounds