Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT).
• FPT farnesyl protein transferase
• a, b, c and d represents N or NO " , and the remaining a, b, c and d groups represent CR 1 or CR 2 ; or each of a, b, c, and d are independently selected from CR 1 or CR 2 ;
• -SCH 2 C 6 H 5 -S(O) t R 16 (wherein t is 0, 1 or 2, e.g., -SOCH 3 and -SO2CH3), -N(R 15 ) 2 , -N0 2 , -OC(O)R 15 , -CO R 15 , -OCO 2 R 16 , -CN, -NR ⁇ COOR 16 , -SR i ⁇ C OJOR 16 (e.g., -SCH 2 CO 2 CH 3 ), -SR 16 N(R 1 ) (provided that R 16 in -SR 16 N(R 1 ) 2 is not -CH 2 -) wherein each R 17 is independently selected from H or -C(O)OR 16 (e.g.,
• R 3 and R 4 are the same or different and each independently represents H, any of the substituents of R 1 and R 2 , or R 3 and R 4 taken together represent a saturated or unsaturated C5-C 7 fused ring to the benzene ring (Ring III);
• R 8 is selected from: H, C 3 to C 4 alkyl (preferably branched chain alkyl, and
• R 9 and R 10 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaiyl, heteroarylalkyl, cycloalkyl or -CON(R 18 ) 2
• R 9 and R 10 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl (i.e., the R 9 and/or R 10 groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R 9 and/or R 10 is H); or
• R 9 and R 10 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring;
• R n and R 12 are independently selected from: H, alkyl, aryl, arylalkyl, heteroaiyl, heteroarylalkyl, cycloalkyl, -CON(R 18 ) 2 -OR 18 or -N(R 18 ) 2 ; wherein R 18 is as defined above; provided that the -OR and -N(R ) 2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom; and wherein said substitutable R" and R 12 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heterarylalkyl; or
• R 11 and R 12 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring;
• R 13 is an imidazolyl ring selected from:
• R' 9 is selected from: (1) H, (2) alkyl, (3) alkyl, (4) aiyl, (5) arylalkyl, (6) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (7) -C(aryl) 3 (e.g., -C(phenyl) 3 , i.e., trityl) or (8) cycloalkyl; said imidazolyl ring 2.0 or 2.1 optionally being substituted with one or two substituents and said imidazole ring 4.0 optionally being substituted with 1-3 substituents and said imidazole ring 4.1 being optionally substituted with one substituent wherein said optional substituents for rings 2.0, 2.1, 4.0 and 4.1 are bound to the carbon atoms of said imidazole rings and said optional substituents are independently selected from: -NHC(O)R 18 ,
• each R 18 is independently selected); R 18 is as defined above; each R 34 is independently selected from H or alkyl (preferably -CH 3 ), preferably H; R 35 is selected from H, -C(O)OR 20 , or -C(O)NHR 20 , and R 20 is as defined below (preferably R 20 is alkyl or cycloalkyl, most preferably cyclopentyl or cyclohexyl); Q represents an aryl ring (e.g., phenyl), a cycloalkyl ring (e.g., cyclopentyl or cyclohexyl) or a heteroaiyl ring (e.g., furanyl, pyrrolyl, thienyl
• R 15 is selected from: H, alkyl, aryl or arylalkyl
• R 18 is selected from: alkyl or aryl
• R 20 is selected from: H, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, heteroaiyl, heteroarylalkyl or heterocycloalkyl, provided that R 20 is not H when R 14 is group 5.0 or 8.0; when R 20 is other than H, then said R 20 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aiyl, -OC(O)R 18 (e.g., -OC(O)CH 3 ), -OR 18 or -N(R 18 ) 2 , wherein each R 18 group is the same or different, and wherein R 18 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
• R 21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, heteroaiyl, heteroarylalkyl or heterocycloalkyl; when R 21 is other than H, then said R 21 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, -OR 18 or -N(R 18 ) 2 , wherein each R 18 group is the same or different, and wherein R 18 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom; n is 0-5; each R 32 and R 33 for each n (i.e., for each -C(R 32 )(R 33 )- group), are independently selected from: H, alkyl, aiyl, arylalkyl, heteroaiyl, heteroarylalkyl, cycloalkyl, -CON(R 18
• R 32 and R 33 together with the carbon atom to which they are bound, form a C 3 to C 6 cycloalkyl ring;
• R 36 is selected from branched alkyl, unbranched alkyl cycloalkyl, heterocycloalkyl, or aryl (e.g., phenyl); and provided that:
• R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N
• R 8 is selected from: C 3 to C 10 alkyl, substituted C 3 to C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl;
• R 14 when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R 11 , R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R 11 and R 12 , are taken together to form a cycloalkyl ring.
• This invention also provides compounds of formula 1.0, as described above, wherein when R 14 is group 5.0, and X is N, and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R", R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R 11 and R 12 , are taken together to form a cyloalkyl ring.
• the compounds of this invention (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transfo ⁇ -ning Ras which is a farnesyl acceptor but not by a form of transfoi ⁇ ning Ras engineered to be a geranylgeranyl acceptor; (ill) 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 transfoj-rning Ras.
• 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 farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above.
• farnesyl protein transferase e.g., ras farnesyl protein transferase
• the administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase is useful in the treatment of the cancers described below.
• This invention provides a method for inhibiting or treating 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.
• This invention also provides a method for inhibiting or treating 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.
• this invention provides a method for mhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds.
• tumors which may be inhibited or treated 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, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
• lung cancer e.g., lung adenocarcinoma
• pancreatic cancers e.g., pancreatic carcinoma such as, for example
• this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes— i.e., the Ras gene itself is not activated by mutation to an oncogenic form— with said inhibition or treatment 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.
• a mammal e.g., a human
• the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited or treated by the tricyclic compounds described herein.
• the tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. 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. DETAILED DESCRIPTION OF THE INVENTION
• MH + represents the molecular ion plus hydrogen of the molecule in the mass spectrum
• CH ⁇ L j represents dichlorome thane
• heterocycloalkyl represents a saturated, branched or unbranched carbocylic 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 -O-, -S- or - NR 24 , wherein R 24 represents alkyl, aryl, -C(O)N(R 18 ) 2 wherein R 18 is as above defined (e.g., -C(O)NH 2 ) or acyl- (suitable heterocycloalkyl groups include 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, morpholinyl, etc.).
• the compounds of formula 1.0 include the 2R and 2S isomers shown below (2R is preferred):
• R 8 substituents include: benzyl, -CH 2 C(CH 3 ) 2 , -CH 2 - cyclohexyl, -CH 2 -cyclopropyl, -(CH 2 ) 2 CH 3 ,
• R 9 and R 10 groups examples include H and benzyl
• R 11 and R 12 groups include: H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , benzyl, ethyl, p-chlorophenyl, and -OH.
• Cyclopropyl is an Example of the R 11 and R 12 group being taken together with the carbon atom to which they are bound to form a cycloalkyl ring.
• R 13 moiety examples include: -CH 3 , -CH 2 OH, -CH 2 OC(O)O-cyclohexyl, -CH 2 OC(O)O- cyclopentyl, ethyl, isopropyl, NH 2 , and -NHC(O)CF 3 .
• R 19 examples include: -C(O)NH-cyclohexyl, -C(phenyl) 3 , H, methyl or ethyl.
• R 20 for group 5.0 examples include: t-butyl, ethyl, benzyl, -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , n-butyl, n-hexyl, n-octyl, p- chlorophenyl, cyclohexyl, cyclopentyl,
• R for group 5.0 Another example of R for group 5.0 is
• R 20 and R 21 for 6.0 include: cyclohexyl, t-butyl, H, -CH(CH 3 ) 2> ethyl, -(CH 2 ) 2 CH 3 , phenyl, benzyl, -(CH ⁇ phenyl, and - CH 3 .
• R 20 for 7.0 examples include: 4-pyridylNO, -OCH 3 , -CH(CH 3 ) 2 , -t-butyl, H, propyl, cyclohexyl and
• R 36 for 7.1 examples include: cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl,
• R 20 for 8.0 examples include: methyl, i-propyl and cyclohexylmethyl .
• R 32 and R 33 include: H, phenyl, -OH and benzyl.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R 8 is selected from: C 3 to C 10 alkyl, substituted C 3 to C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R 8 is selected from: C 3 to C 10 alkyl, substituted C 3 to C 10 alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroaryl
• R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R", R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R 11 and R 12 , are taken together to form a cyloalkyl ring.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is group 5.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R", R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R 11 and R 12 , are taken together to form a cyloalkyl ring.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is C or CH (preferably CH), then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is 5.0 and X is C or CH (preferably CH), then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is selected from: group 6.0, 7.0, 7.1 or 8.0, and X is N, then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
• Compounds of this invention include compounds of formula 1.0 wherein when R 14 is 5.0 and X is N, then R 8 is selected from: arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, or substituted cycloalkylalkyl.
• R 14 is the carbamate group 5.0 and the other substituents are as defined for formula 1.0.
• Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is N and the other substituents are as defined for formula 1.0.
• R 14 is the carbamate group 5.0, X is C or CH (preferably CH) and the other substituents are as defined for formula 1.0.
• Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is N, R 8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.
• Another embodiment of this invention is directed to compounds wherein R 14 is the carbamate group 5.0, X is N, R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.
• R 14 is the carbamate group 5.0
• X is N
• R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl) , and the other substituents are as defined for formula 1.0.
• R 14 is the carbamate group 5.0, X is C or CH (preferably CH), R 8 is arylalkyl or substituted arylalkyl (preferably arylalkyl), and the other substituents are as defined for formula 1.0.
• R 14 is the carbamate group 5.0, X is C or CH (preferably CH), R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl), and the other substituents are as defined for formula 1.0.
• R 14 is the carbamate group 5.0
• X is C or CH (preferably CH)
• R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably cycloalkylalkyl), and the other substituents are as defined for formula 1.0.
• Another embodiment of this invention is directed to compounds wherein when R 14 is group 5.0, and X is C or CH (preferably CH), and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the - C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R", R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R" and R 12 , are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.
• Another embodiment of this invention is directed to compounds wherein when R 14 is group 5.0, and X is N, and R 8 is H, then the alkyl chain between R 13 (i.e., imidazole ring 2.0, 4.0 or 4.1) and the amide moiety (i.e., the -C(O)NR 18 group) is substituted, i.e.,: (a) at least one of R 9 , R 10 , R 11 , R 12 , R 32 , or R 33 is other than H, and/or (b) R 9 and R 10 , and/or R 11 and R 12 , are taken together to form a cyloalkyl ring, and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R 8 is arylalkyl. or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably heteroarylalkyl) and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is N, R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from:6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R 8 is arylalkyl or substituted arylalkyl (preferably arylalkyl) and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R 8 is heteroarylalkyl or substituted heteroarylalkyl (preferably, heteroarylalkyl) and the other substituents are as defined for formula 1.0.
• R 14 is a group selected from: 6.0, 7.0, 7.1 or 8.0, X is C or CH (preferably, CH), R 8 is cycloalkylalkyl or substituted cycloalkylalkyl (preferably, cycloalkylalkyl) and the other substituents are as defined for formula 1.0.
• R 1 , R 2 , R 3 , and R 4 are preferably selected from H or halo, and are more preferably selected from H, Br, F, or Cl, and are most preferably selected from H, Br or Cl.
• Representative compounds of formula 1.0 include trihalo, dihalo and monohalo substituted compounds, such as, for example: (1) 3,8, 10-trihalo; (2) 3,7,8- trihalo; (3) 3,8-dihalo; (4) 8-halo; and (5) 10-halo substituted compounds; wherein each halo is independently selected.
• Preferred compounds of formula 1.0 include: (1) 3-Br,8-Cl, 10-Br-substituted compounds; (2) 3-Br,7-Br,8-Cl-substituted compounds; (3) 3-Br,8- Cl-substituted compounds; (4) 8-Cl-substituted compounds; and (5) 10-Cl-substituted compounds.
• the 3,8-dihalo compounds are more preferred and the 8-halo compounds are most preferred.
• 3-Br,8-Cl substituted compounds are more preferred and 8-C1 substituted compounds are most preferred.
• Substituent a is preferably N or NO ' with N being preferred.
• a and B are preferably H 2 , i.e., the optional bond is absent and the C5-C6 bridge is unsubstituted.
• R 5 , R 6 , and R 7 are preferably H.
• X is preferably N or CH (i.e., the optional bond is absent), and more preferably X is N.
• R 8 is preferably selected from: arylalkyl, substituted aryl alkyl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl or substituted cycloal-k-ylalkyl. Most preferably, R 8 is selected from: aryHC. -CJalkyl, substituted aryl- (C. -CJalkyl, heteroaiyl- (C,- CJalkyl, substituted heteroa ⁇ yl-(C r CJalkyl, cycloalkyKC.-CJalkyl, or substituted cycloalkyl-(C.-CJalkyl.
• R 8 is selected from: aryl-CH 2 -, substituted aryl-CH 2 ⁇ , heteroaryl-CH 2 -, substituted heteroaiyl- CH 2 , cycloalkyl-CH 2 - or substituted cycloalkyl-CH 2 -. Even more preferably, R 8 is selected from: benzyl, 3-pyridylmethyl, 4-fluoro-benzyl or cyclopropylmethyl, and still more preferably R 8 is benzyl.
• R 13 is preferably ring 2.0 or 4.0.
• the substituents are generally selected from: -N(R 18 ) 2 , -NHC(O)R 18 , -C(R 34 ) 2 OR 35 , or alkyl, e.g., -CH 3 , -CH 2 OH, -CH 2 OC(O)O-cyclohexyl, -CH 2 OC(O)O- cyclopentyl, ethyl, isopropyl, NH 2 , or -NHC(O)CF 3 .
• R 19 is preferably H or alkyl, most preferably H, methyl or ethyl, and more preferably methyl.
• R 14 is preferably a carbamate group represented by substituent 5.0 described above.
• R 20 for substituent 5.0 is selected from: alkyl, substituted alkyl, aryl, cycloalkyl, or cycloalkyl substituted with -OH provided that said -OH substituent is not bound to a carbon that is adjacent to an oxygen atom. More preferably R 20 for substituent 5.0 is selected from: C. to C 4 alkyl and C 5 to C 7 cycloalkyl.
• R 20 for substituent 5.0 is selected from: t-butyl, i-propyl and cyclohexyl, with i-propyl and cyclohexyl being more preferred, and with cyclohexyl being even more preferred.
• R 20 in substituent 6.0 is preferably selected from: alkyl or cycloalkyl; most preferably t-butyl, isopropyl or cyclohexyl; and more preferably cyclohexyl.
• R 21 is preferably selected from: H or alkyl; most preferably H, methyl or isopropyl; and more preferably H.
• R 20 in substituent 7.0 is preferably selected from: cycloalkyl or alkyl; most preferably cyclohexyl, cyclopentyl, isopropyl; and more preferably cyclohexyl.
• R 36 in substituent 7.1 is preferably selected from: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and most preferably selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• R 20 in substituent 8.0 is preferably selected from: alkyl or cycloalkylalkyl; most preferably methyl, isopropyl or cyclohexylmethyl; more preferably methyl or isopropyl; and even more preferably methyl.
• R 9 , R 10 , R 11 , and R 12 are preferably selected from: H, C, to C 4 alkyl (e.g., methyl or isopropyl), -CON(R 18 ) 2 (e.g., -CONH , or when R 9 and R 10 , and/or R 11 and R 12 are taken together to form a cycloalkyl ring, said ring is preferably cyclopropyl cyclopentyl or cyclohexyl.
• R 9 , R 10 , R", and R 12 are preferably H when R 14 is the carbamate substituent 5.0 and R 8 is not H.
• R 14 is selected from substituents 6.0, 7.0, 7.1 and 8.0, and at least one of R 9 , R 10 , R u , and R 12 is other than H, then at least one of R 9 , R 10 , R 11 , and R 12 is:
• (I) preferably selected from: (1) C, to C 4 alkyl,
• (II) most preferably selected from: (1) methyl, (2) isopropyl, (3) -CONH 2 or (4) cyclopropyl; and
• R 9 and R 10 being H, and one of R 11 and R 12 being selected from: alkyl (preferably, methyl or isopropyl), and the other being selected from H or alkyl (preferably, methyl); (2) R 9 and R 10 being H, and R 11 and R 12 being taken together to form a cycloalkyl ring (preferably, cyclopropyl); or
• R 11 and R 12 being H, and one of R 9 and R 10 being -CONH 2 , and the other being H.
• n is preferably 0-4, more preferably 0-2, and most preferably 0 or 1.
• each R 32 and R 33 are independently selected from: H, -OR 18 , aryl or arylalkyl (e.g., benzyl); most preferably H, -OH or phenyl; and more preferably H.
• Compounds of formula 1.0, wherein X is N or CH, include, with reference to the C-11 bond, the R- and S- isomers:
• Compounds of formula 1.0 also include compounds having the 2S stereochemistry and the C-11 R- or C-11 S- stereochemistry.
• Compounds of this invention include: - 22
• Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1, 17.0-19.0, 19.1, 20.0, 20.1, 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that the compounds have the 2S stereochemistry.
• Compounds of the invention also include compounds corresponding to 13.0- 15.0, 15.1 , 16.0, 16.1 , 17.0- 19.0, 19.1, 20.0, 20.1 , 21.0-23.0, 23.1 , 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl.
• Compounds of the invention also include compounds corresponding to 13.0-15.0, 15.1, 16.0, 16.1 , 17.0-19.0, 19.1, 20.0, 20.1 , 21.0-23.0, 23.1, 24.0, and 24.1-24.7, except that Ring I is phenyl instead of pyridyl and the compounds have the 2S stereochemistry.
• Preferred compounds of formula 1.0 include compounds of the formula:
• R 14 is the carbamate group 5.0 wherein all substituents are as above defined.
• a preferred compound of formula 25.0 is:
• Compounds of formula 25.0 include:
• Preferred compounds of formulas 28.0 and 29.0 are those wherein the R 1 to R 4 substituents are selected to produce trihalo, dihalo and monohalo substituted compounds, as described above.
• Compounds of formula 29.0 are preferred.
• R 8 is selected from: benzyl, 4- fluorobenzyl, 3-pyridylmethyl or cyclopropylmethyl;
• R 20 is cyclohexyl, i-propyl or t-butyl (more preferred is cyclohexyl), R 1 is Br or H, R 3 is Cl, and R 4 is H.
• R 8 is benzyl
• R 20 is cyclohexyl, i-propyl or t- butyl (even more preferred cyclohexyl)
• R 1 is H
• R 3 is Cl
• R 4 is H or Cl.
• Preferred compounds of this invention include:
• More preferred compounds include the compounds of Examples 58, 199, 225, 226, 229, 232 and 326. Compounds of Examples 58, 199, 225, 229 and 326 are even more preferred. The compound of Example 225 is even still more preferred. Preferably the compound of Examples 225, 229 and 326 are administered orally.
• This invention is also directed to the compounds of Examples 26, 30, 32, 41, 42, 43, 44, 81, 105, 106, 293, and 309.
• the compound of Example 309 is preferred.
• This invention is also directed to the compounds of Examples 31, 34, 35, 36, 37, 38, 39, 40, 67, 68, 69, 70, 73, 75, 263, 282, 283, 284, 287, and 289.
• the compounds of Examples 67, 68, 69, and 70 are preferred.
• This invention is also directed to the compounds of Examples 27, 28, 29, 71, 72, 74, 76, 98, 101, 103, 104, 107, 108, 110, 111, 255, 256, 257, 258, 259, 260, 261, 262, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 285, 286, 286A, 290, 291, 292, 294, 295, 296, 297, 299, 300, 301, 302, and 303.
• Compounds of Examples 101, 103, 71 , 72 Step B, 72 Step C and 259 are preferred
• This invention is also directed to compounds of Examples 33, 279, 280, and 281. Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
• Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers, atropisomers) forms.
• the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
• 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.
• 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.
• 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 NaOH, potassium carbonate, ammonia and sodium bicarbonate.
• a suitable dilute aqueous base solution such as dilute aqueous NaOH, 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.
• the compounds of formula 1.0 can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate.
• solvated forms including hydrated forms, e.g., hemi-hydrate.
• pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
• R 11 and R 12 are preferably methyl when H is bound to the amide nitrogen (i.e., when R 8 in formula 1.0 is H), e.g., 41.0, and are preferably H when the amide nitrogen is substituted (i.e., R 8 in formula 1.0 is other than H), e.g., 41.1.
• acylating agents can be used in place of cyclohexyl isocyanate to obtain compounds having different groups bound to the carbonyl group that is bound to the piperazine nitrogen.
• esters can be used in place of compound 31.0 to obtain compounds having different carbon chains between the imidazole ring and the - C(O)NH-group.
• Y represents C, N or NO " such that there can only be 0-2 Y substituents that are independently selected from N or NO " .
• R A represents the optional substituents in the imidazole ring that are defined for imidazole ring 4.0 above.
• R B represents the optional substituents defined above for the aryl or heteroaiyl groups for R 8 .
• R 12 are methyl, and using compound 42.0 (see Preparative Example 40 in WO 95/ 10516 published April 20, 1995) compound 43.0
• the synthesis of the intermediate amine 51.0 begins with the alkylation of the sodium salt of imidazole (or substituted imidazole) 44.0 with 45.0 at 90°C.
• Standard LAH reduction of the ester 46.0 gives the alcohol 47.0.
• Tosylation of 47.0 and displacement of tosylate with potassium phthalimide 49.0 in DMF at 90°C gives the phthali-mido derivative 50.0 which can be readily converted to the amine 51.0 with hydrazine in refluxing EtOH.
• Compounds wherein R 8 ⁇ H can be prepared as described in Scheme 1.
• R 11 and R 12 are preferably methyl when H is bound to the amide nitrogen (i.e., when R 8 in formula 1.0 is H), and are preferably H when the amide nitrogen is substituted (i.e., R 8 in formula 1.0 is other than H).
• Reaction Step a Isatoic anhydride/methylene chloride
• Reaction Step b sodium nitrite /hydrochloric acid/methanol/ cuprous chloride
• Reaction Step c (i) aq. hydrochloric acid/methanol/reflux (ii) sodium hydroxide /sodium cyanide
• Reaction Step d cone, hydrochloric acid/reflux.
• Reaction Step e di-ter .butyldicarbonate/ -sodium hydroxide / tetrahydrofuran .
• Reactants V and VI are:
• the nitrile may be reduced with DIBAL-H to the aldehyde.
• the aldehyde can then be treated with the appropriate Grignard reagent to give the alcohol.
• There can be an additional round of oxidation and Grignard addition to give the R 9 , R 10 disubstituted derivatives with either R 9 R 10 or R 9 • R 10 .
• the resulting alcohol may be converted to the amine by the methodology shown in either Schemes 1 or 2.
• Example 5 except use the amine from Preparative Example 2 to obtain the title compound.
• the ketone (starting material) 5,6-dihydro-10-Chloro-l lH- benzo[5,6]cyclohepta[l,2-c]pyridine- l 1-one can be prepared following the procedure described by Villani et al., J. Het. Chem. 8, 73-81 (1971). The product was prepared substituting the 10-Chloro for the 10H tricycle and following the procedure described in Preparative Example 169. 1H NMR (CDC1 3 ⁇ ) 2.97 (m, 2H), 3.55 (m, 1H), 4.03 (m, 1H),
• nBuLi (2.5 mL; 2.5M in hexanes; 2.1 eq.) was added to iPr 2 NH (0.87 mL, 2.1 eq.) in THF (8.0 mL) at 0°C.
• the resulting solution was stirred 45 minutes before adding the nitrile (l.Og, 2.97 mmol) in THF (7.0 mL).
• the reaction mixture was stirred at 0°C for 30 minutes before adding Mel (0.37 mL, 2.0 eq.).
• the resulting solution was warmed to room temperature and stirred one hour.
• the reaction was quenched by the addition of IN HC1 until acidic, diluted with water (40 mL) and extracted with EtOAc (2 X 200 mL).
• Step A Dissolve the product of Step A (0.5 g, 1.23 mmol) in 10 mL of ethanol saturated with ammonia. Add 8.8 mg (0.017 mmol) of H 2 PtCl 6 .6H 2 O, 1 g of Raney Ni in water and hydrogenate at 54 psi on a Parr shaker over night. Filter through Celite and concentrate under vacuum.
• Ethyl 4-pyridyl acetate (4.5g, 27.24mmoles) was placed in a 500mL Parr bottle and dissolved in anhydrous EtOH (70mL). To the bottle was added 10% Palladium on charcoal (l.Og). The bottle was put on a hydrogenator and the contents shaken under 55 psi hydrogen pressure at 25°C for 94h. The mixture was filtered through Celite ® and washed with 4x40mL anhydrous EtOH. The filtrate was rotovapped down and the residue chromatographed on silica gel using 3% (10% cone.
• Ethyl 4-piperidinyl acetate from Preparative Example 31 (500mg; 2.92mmoles) was dissolved in anhydrous CH-CL j (25mL). To the stiiring solution was added trimethylsilyl isocyanate (5.9mL; 43.8mmoles) and the solution was stirred at 25°C for 17h. The solution was worked up in CH 2 Cl 2 -saturated NaHCO 3 and the product chromatographed on silica gel using 2- 3%(conc.
• Isonipecotic acid (lOg, 77.42mmoles) and sodium hydroxide (3.097g, 77.42mmoles) were dissolved in THF-water (1: 1) (230mL) and di-t-butyldicarbonate (18.59mL, 85.17mmoles) was added. The solution was stirred at 25°C for 90h. The inixture was treated with BioRad ® 50W-X4(H + ) ion exchange resin (86.6mL) and the resin was filtered off and washed with THF and then water.
• the anhydride (0.5088g, 1.99mmoles) (prepared as described in Preparative Example 44) and 1- (3 -aminopropyl) -imidazole (0.260mL, 2.18mmoles) were dissolved in anhydrous dichloromethane (lOmL) and the mixture was stirred under argon at 25°C for 5min. The mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The dichloromethane layer was dried (MgSO 4 ), filtered and evaporated to dryness.
• Step A The title compound of Step A (1.3422g) (3.96mmoles) was dissolved in methanol (18ml) and dichloromethane (20ml) and sodium borohydride (0.219g) (5.79mmoles) was added. The mixture was stirred under argon at 0°C for lh and then allowed to warm up to 25°C over a period of lh. The mixture was diluted with dichloromethane (800ml) and washed with IN NaOH (150ml). The aqueous layer was extracted with dichloromethane (2X100ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The product was chromatographed on silica gel using 1% (10% cone.
• Methylamine (1.19mL, 8.52mmoles) were dissolved in anhydrous dichloromethane (8.5mL) and the solution was cooled to 0°C.
• Methanesulfonyl chloride (0.4mL, 5.16mmoles) was added over 30min and the mixture was stirred at 0°C for a total of 1.25h.
• the solution was evaporated to dryness to give the 11-mesyl derivative which was used without further purification.
• the latter was dissolved in anhydrous dichloromethane (40mL) and the solution was stirred at 0°C.
• Ethyl 4-pyridyl acetate (4.5g, 27.24mmoles) was placed in a 500mL Parr bottle and dissolved in anhydrous EtOH (70mL). 10% Palladium on charcoal (l.Og) was added and the contents shaken under 55 psi hydrogen pressure at 25°C for 94h. The mixture was filtered through Celite ® and washed with 4x40mL anhydrous EtOH. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% cone.
• the single tic spot is a mixture of four isomers which are separated after derivatization into the compounds of Examples 77 to 79 and 87 to 97 below.
• N,N-dimethylfo:rmamide 49.6 ml
• thionylchloride 46.7 ml
• the reaction mixture was allowed to stir for 5 min. and the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 30 min.
• reaction mixture was cooled again in an ice bath and a solution of of N,N-di-tert-butoxycarbonyl-2-R- carboxyl-piperazine (Preparative Example 43) (201.6 gm, 0.61 mmol) in 51.7 ml of pyridine and 1.9 L of acetonitrile was cannulated into the reaction mixture.
• the reaction mixture was allowed to warm to ambient temperature to obtain a yellowish turbid solution.
• lN-p-Cyanobenzyl histamine (0.34, 1.5 mmol) (prepared as described in Preparative Example 163) was added to a solution of the Boc-anhydride (Preparative Example 44) (0.38 gm, 1.5 mmol) in 10 ml of dichloromethane and stirred under a nitrogen. After 1 hr, 0.15 gm more of the Boc-anhydride was added and the reaction monitored for completion by normal phase tic using 10% methanol/ dichloromethane as the eluent. After the reaction went to completion (-1 hour), 0.25 ml (2 mmol) of cyclohexyl isocyanate was added to the reaction mixture and stirred for 1 hour.
• N-(2,3-Epoxypropyl)phthalimide (2.3 gm, 11.3 mmol) was dissolved in N,N-dunethylfo_-mamide and imidazole (1.53 gm, 1.5 eq.) was added and the reaction mixture stirred at 90 °C for 5 hours. Brine was added and the product extracted with ethylacetate to obtain the title product (0.67 gm).
• the reaction mixture was poured into brine and extracted with dichloromethane (3X).
• the dichloromethane layers were combined, dried over MgSO 4 , filtered and evaporated to dryness.
• the residue was chromatographed on a flash column of silica gel using 5% methanol/ dichloromethane to obtain 0.487 gm of pure title compound as a solid.
• reaction mixture was then evaporated to dryness (to get rid of the dioxane for extraction).
• the residue was dissolved in 180 mL of dist. water and the pH adjusted slowly to 4.0 with IN HCl.
• the aqueous solution was washed with 3X180 mL of ethyl acetate (The ethyl acetate was dried over MgSO 4 , filtered, and evaporated to obtain N,N-di-CBZ-2- carboxy-piperazine and saved).
• the pH of the aqueous layer which contains the desired product, was adjusted to 10.5 to 11.0 with 50% NaOH and solid di-tert-butyl-dicarbonate (7.86 gm, 36 mmol) was added and the mixture was stirred while keeping the pH at 10.5 to 11.0 with 50% NaOH. After 1 hr. the pH stabilized.
• the reaction mixture was washed with 2X180 mL of Et-O.
• the aqueous layer was cooled in an ice bath and adjusted pH to 2.0 with IN HCl (slowly). Extract the product with 3X200 mL of ethyl acetate. Dry over MgSO 4 , filter and evaporate to obtain 9.68 gm (88%) of pure product as a white solid.
• the filtrate was evaporated to -1/3 the volume (to get rid of the EtOH) and 200 mL of distilled water was added.
• the aqueous layer was extracted with ethyl acetate three times (the ethyl acetate layer contained pure N,N-Di-Boc-2-carboxy-piperazine which was saved).
• the water layer was evporated to dryness and evaporated from methanol two times to obtain 3.98 (17.37gm, mmol) of pure product.
• reaction mixture was added to brine and the product extracted with ethyl acetate 3 times to obtain a crude oil, after the solvent was evaporated under reduced pressure, which was purified by chromatography on a silica gel column 20%-50% ethyl acetate/hexanes as the eluent.
• the product conta-lning fractions were pooled to obtain 0.67 gm (60%) of pure title compound.
• 2-Ammo--midazole (8 g, 60 mmol) was dissolved in 200 ml of DMF and cooled in an ice bath.
• Sodium hydride 60% oil dispersion (2.4 g, 60 mmol) was added portionwise and the reaction mixture stirred for 1 hour.
• N-(3-Bromopropyl)-phtha----mide (16g, 74 mmol) was added and the reaction mixture stirred for 1/2 hour at 0°C, 1 hour at ambient temperature, and then 1 hour at 85°C.
• the reaction mixture was then cooled to ambient temperature and added to brine and extracted with ethyl acetate to obtain the crude product which was purified by column chromatography using 2% methanol/methylene chloride to obtain 4.88 gm of title compound.
• the diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 99.8% MeOH +0.2% diethylamine) to give 1.62g of the 11S.2R diastereomer A and 1.97 g of the 11R,2R diastereomer B.
• the diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 30% IPA +70% Hexane +0.2% diethylamine) to give 0.72 g of the 11S,2R diastereomer A and 0.57 g of the 11R,2R diastereomer B.
• the pH was lowered to 9.5 using 10% HCl (aq) and cyclohexyl chloroformate (4.0 g, 24.6 mmol) was added dropwise while maintaining the pH at 9.5 with a slow addition of 50% NaOH (aq) with st-xiing at 25°C for an additional 12 h.
• the mixture was extracted with Et 2 ⁇ and the aqueous phase was acidified to pH 3 with 6M HCl (aq) .
• the diastereomers were separated by preparative chiral chromatography (Chiralpack AD, 5 cm X 50 cm column, flow rate 80 mL/min., 60% IPA + 40% hexane +0.2% diethylamine) to give 0.11 g of diastereomer A and 0.23 g of diastereomer B.
• N-Carbethoxyphthalimide (62.8 g, 0.275 mol, 1.1 eq.) was added portionwise over a period of 30 minutes to a stirred solution of histamine dihydrochloride (46.7 g, 0.250 mol, 1.0 eq.) and sodium carbonate (54.3 g, 0.513 mol, 2.05 eq.) in distilled water (1250 ml) at room temperature. The resulting snow-white suspension was stirred vigorously at room temperature for 90 minutes. The solid was filtered off and thoroughly washed with ice- cold distilled water (4 x 50 ml). The solid was collected and dried under vacuum over P 2 O 5 at 60°C for 12h to give the title compound
• Step D To the title compound from Step B above (0.31 g, 1.2 mmol) was added 4M HCl in dioxane (5 mL) and the mixture was stirred at 25°C for 12 h. Concentration in vacuo afforded a residue which was used directly in Step D.
• Tricyclic chloride (5.04g, 1.1 eq.) was added to a solution of the title compound from Preparative Example 50 (4.0g, 17.3 mmol) and TEA (12.05 mL, 5 eq.) in DMF (60 mL). The resulting solution was stirred at room temperature 72 hours at which time the reaction mixture was concentrated under reduced pressure. The residue was diluted with 3M NaOH and extracted with EtOAc. The aqueous layer was neutralized with 50% citric acid and extracted with EtOAc. The combine organics were dried over Na ⁇ O ⁇ filtered, and concentrated in vacuo.
• the crude product was purified by flash chromatography using a 12% (10% NH 4 OH in MeOH) solution in CK-CL ; as eluent to give the C-11 (S)-isomer (2.13g, 54%) as the first eluting isomer and the C-11 (R)-isomer (2.4g, 61%) as the second eluting isomer.
• the ketone (starting material) 5,6-dihydro- l lH- benzo[5,6]cyclohepta[l,2-c]pyridine-l 1-one may be prepared by following the methods described in U.S. 3,419,565.
• Acetonitrile (5ml) was added to a mixture of the 10-Chloro tricycle (0.5g, 1.90mmol) (Preparative Example 9.1) and the substituted piperazine (0.78g, 1.90mmol).Triethyla-mine (1ml,
• Triethylamine (18 mL, 126.65 mmol, 5.0 eq.) was added dropwise to a stirred solution of 5 (previously described in the art; 9.38 g, 25.33 mmol, 1.0 eq.) in anhydrous dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. The solution was stirred at room temperature for 30 minutes and was cooled to 0 °C. A solution of 4 (8.52 g, 30.39 mmol, 1.2 eq.) in anhydrous dichloromethane (50 mL) was added dropwise over a period of 25 minutes. The mixture was slowly (3h) warmed to room temperature and stirred for another 12h.
• the isomers were separated by column chromatography (silica) using 3% MeOH/CH 2 Cl 2 .
• R 14 is as defined in Table 6 below, were obtained.
• the 11R,2R or 11S,2R isomers can be obtained by using the 11R.2R or 11S.2R isomer, respectively, title compounds from Preparative Example 8.
• R 14 is as defined in Table 8, were obtained.
• Step C Dissolve 4.9 g of the product from Step A in 30 mL of methylene chloride and add 13 mL of trifluoroacetic acid. Stir overnight under nitrogen then concentrate in vacuo. The residue was triturated with ether then dried in vacuo giving the product as a clear oil.

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