AU744153B2 - Bispyrido-cycloheptane compounds useful for inhibition of farnesyl protein transferase - Google Patents

Description

WO 98/57961 PCT/US98/11496 BISPYRIDO-CYCLOHEPTANE COMPOUNDS USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE

BACKGROUND

WO 95/ 10516, published April 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.

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.

SUMMARY OF THE INVENTION This invention provides compounds useful for the inhibtion of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula: R or a pharmaceutically acceptable salt or solvate thereof, wherein: A is alkyl, halo or H; B is methyl, halo or H; the dotted line represents an optional double bond;

R

5

R

6

R

7 and R 8 are independently selected from the group consisting of H, -CF3, -COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with -ORo 10 -SR'O, wherein t is 0, 1 or 2, -NR'oCOOR", -N(R'0) 2

-NO

2

-COR,

-OCOR'o, -OCO 2 -C0 2 Ro or OPO 3 R'O, or R 5 is combined with R 6 to represent =0O or =S and/or R 7 is combined with R 8 to represent =0 or =S;

R'

0 represents H, alkyl, aryl, or aralkyl benzyl); R" represents alkyl or aryl; and R is -C(O)NR'R 2

-S(O)

2 or

-S(O)

2 NRlR2 wherein R' and R 2 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, heterocycloalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted (C3-C6) cycloalkyl, substituted cycloalkylalkyl, 15 substituted heterocycloalkyl, wherein said substituted groups have one or more substituents selected from: C 1

-C

6 alkyl, alkoxy, aralkyl, heteroarylalkyl, -NO 2 alkyloxyalkyl, alkyloxyalkyloxyalkyl, C 3

-C

6 cycloalkyl, aryl, -CN, heteroaryl, heterocycloalkyl, -OH, amino, substituted amino, nitro and halo, with the proviso that R' is not H for or for

-S(O)

2

R

The compounds of this invention: 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 faresyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.

The compounds of this invention inhibit farnesyl protein transferase and the famesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting famesyl protein .transferase, ras faresyl protein transferase) in mammals, S 15 especially humans, by the administration of an effective amount of the 0 tricyclic compounds described above. The administration of the .compounds of this invention to patients, to inhibit faresyl protein transferase, is useful in the treatment of the cancers described below.

9, This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, comprising administering S* an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory :mechanisms loss of contact inhibition). This includes the 2 5 abnormal growth of: tumor cells (tumors) expressing an activated Ras oncogene; tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

This invention also provides a pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of a compound of this invention in combination with a pharmaceutically acceptable carrier.

This invention further provides a method of effecting an antiallergic response in an animal comprising administering to the animal an effective amount of a compound of this invention.

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 a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating 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 or treated include, but are not limited to, lung cancer lung adenocarcinoma), pancreatic cancers pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), .l WO 98/57961 PCT/US98/11496 myeloid leukemias (for example, acute myelogenous leukemia thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.

It is believed that 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 1 0 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 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 neu, src, abl, Ick, and fyn), 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 As used herein, the following terms are used as defined below unless otherwise indicated: MH+-represents the molecular ion plus hydrogen of the 3 5 molecule in the mass spectrum; Bu-represents butyl; Et-represents ethyl; Me-represents methyl; WO 98/57961 PCT/US98/11496 Ph-represents phenyl; benzotriazol-1-yloxy represents

N

N/

0represents

N-N

N S

CH

3 alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms; alkanediyl-represents 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, methylene, ethylene, ethylidene, -CH2CH2CH2-, -CH2CHCH3, -CHCH2CH3, etc.

cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; 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 or

NR

1 0 -(suitable heterocycloalkyl groups including 2- or 3tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 3- or 4piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4dioxanyl, etc.); alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms; WO 98/57961 PCT/US98/11496 alkynyl-represents 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)represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring 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 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, -COOR 1 0 or -NO2; and halo-represents fluoro, chloro, bromo and iodo; and heteroaryl-represents cyclic groups, optionally substituted with R 3 and R 4 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, triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R 3 and R 4 wherein pyridyl N-oxide can be represented as: N N N 0 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 (Et20); ethyl chloroformate (CICO2Et); and 1-(3dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC).

Representative compounds of Formula 1.0 and 2.0 include, but are not limited to: L I i~ i .I I i i I- I; WO 98/57961 PCT/US98/11496 "N 0 0 Br

N

N N O 00 O N N 0 In the compounds of the present invention, A is preferably 1 0 methyl or halo, more preferably Br. B is preferably methyl or halo, more preferably, Br.

R

5

R

6

R

7 and R 8 are preferably selected from the group consisting of H, -CF3, alkyl, aryl, cycloalkyl, and heterocycloalkyl, 1 5 more preferably R 5

R

6

R

7 and R 8 are H.

WO 98/57961 PCT/US98/11496 R is preferably -C(O)RI. Preferably, R 1 is -(CH 2 )nRA, wherein n is an integer from 0 to 6, preferably 1 to 3, most preferably, 1, and wherein RA is selected from aryl, cycloalkyl and heterocycloalkyl. More preferably, R A is selected from S/ o 'CN-C(0)NH 2 and N-C(0)NH 2 ,and The compounds of the present invention may be made according to the reaction schemes described below from compounds having the formula:

A

I-

N

O N-OH These ketones can be prepared according to the methods described in J. Med. Chem. 1984, 27, 20-27 (Kaminski, et.al.), the contents of which are fully incorporated herein by reference.

Scheme 1 shows the preparation of Compound without the optional double bond. Compound is reacted with sodium hydride and allyl bromide in a suitable solvent, DMF, at a temperature of about 0 and stirred at ambient temperature for about 18-24 hours. The product is then recovered by filtration and chromatographed on silica gel to obtain the oxime allylether (compound Compound 3.1 is reacted with a grignard reagent (N-methylpiperidine-4-magnesium chloride, substituted with substituents R5, R6, R7, and R8) in a suitable solvent THF at a temperature of about 0 The grignard reagent may be prepared by methods known in the art. The reaction mixture is added to a saturated ammonium chloride solution which is extracted with ethyl acetate. The ethyl acetate layer is filtered and the filtrate is chromatographed on silica gel to obtain compound Compound is then chlorinated with a chlorinating agent, e.g., thionyl chloride to form comound Compound can be reacted with zinc in glacial actic acid to remove the chlorine subsitutent. The product is recovered by evaporating the acetic WO 98/57961 PCT/US98/11496 acid under high vacuum, dissolving the residue in a suitable solvent, methylene chloride, filtering, and chromatographing the filtrate on silica gel to obtain compound Compound (3.4) can be cyclized to form a tricyclic ring by placing it in a sealed tube, sealed in the presence of air, and heated to 180 oC for about 7 hours to yield a mixed product (a methyl-substituted tricyclic (compound 3.5) and a tricyclic without the methyl substitutent (compound Compounds 3.5 and 3.6 may be separated by chromatographing the mixed product on silica gel. Depending on whether it is desired for the B substituent of compound or to be methyl or H, either compound (3.6 or 3.5) is demethylated by treatment with ethylchloroformate in the presence of a suitable base such as triethyl amine to form compound Compound is then treated with a suitable acid such as hydrochloric acid under reflux conditions for 5-24 hours and the solvent evaporated and the reaction mixture coupled with a suitable carboxylic acid containing the R 1 group using DEC and HOBt coupling conditions known to those skilled in the art to obtain compound If compound is desired, compound can be subjected to the same conditions that compound (3.4) is subjected to and the reaction sequence can proceed as described above.

il- l i' I- I 1~ WO 98/57961 PCT/US98/11496 SCHEME 1 MgCI A A, NaH/atlyl-Br X R 6 N NV R Me -FS,9 O N-OH NO R6 8 0 0NO e R8 Me (3.2) SOCI2

A

A A A A. A Me R= H:Me (85:15)Me (3.5)Me R6 R7 R- 7 s e a l e d tI b e R6^R8 R6 Rs R6 8- R 7 Me Me MeR6 Ra R= H:Me(-85:15)

NI

e HPLC RP-18 A A V A Et OCOCI HCl DEC HOBt N Et3N N N R7 R7 ^R5 R 7

OH

RR

6 RR 8R 6- R M 3 TFA O0 R eo 0 O R' Scheme 2 shows the formation of compound wherein the compound has the double bond. Compound is dehydrated with a suitable base such as DBU at 60 to 150 0 C for 1- 18 hours to obtain compound Compound is then cyclized by sealing in a tube in the presence of air and heated to around 180 oC for 5-30 hours to obtain a mixture of the methyl compound and compound Compound is obtained 1 0 pure by chromatography on silica gel. Compound is then demethylated by treatment with ethylchloroformate in the presence of a suitable base such as triethyl amine to form compound Compound is then treated with a suitable acid such as hydrochloric acid under reflux conditions for 5-24 hours and the 1 5 solvent evaporated and the reaction mixture coupled with a suitable carboxylic acid containing the R 1 group using DEC and HOBt coupling conditions known to those skilled in the art to obtain compound If compound (1.0 is desired with a methyl group, compound can be subjected to the same WO 98/57961 PCT/US98/11496 conditions that compound is subjected to and the reaction sequence can proceed as described above.

SCHEME 2

AW

R6e N' R Me (3.2) (3.2 Base i.e. DBU A A s A RS R 7 R s .S R 7 sealed tube N I I O 180 C 30hrs. RA R6 R 8 R6 Re I Me Me R6" N' R 8 R= H:Me (-85:15) Me HPLC RP-18 EtOCOCI Hl D Et3N R 5

R

7 5 Z RS N R R: 78 RO

R

Me 3TFA0 O R 1 In schemes 1 and 2 above, compounds and are in the form of trifluoroacetic acid salts. The trifluoroacetic acid is removed when treated with the triethyl amine shown in schemes 1 and 2.

Scheme 3 shows the formation of compound wherein A is halogen. Compound with or without the double bond can be nitrated with one equivalent of a suitable nitrating agent such as tetrabutyl ammonium nitrate in the presence of trifluoroacetic anhydride to obtain the nitro compound Compound (5.1) can then be reduced to the amine with a suitable reducing agent such as iron or catalytic hydrogenation in the presence of a palladium catalyst to obtain the amino compound Compound can then be brominated in the presence of a -4 WO 98/57961 PCT/US98/11496 diazotizing agent such as sodium nitrite in the presence of bromine and hydrobomic acid to obtain the brominated compound Compound is then treated with a suitable acid such as hydrochloric acid under reflux conditions for 5-24 hours, the solvent evaporated, and the reaction mixture coupled with a suitable carboxylic acid containing the R 1 group using DEC and HOBt coupling conditions known to those skilled in the art to obtain compound SCHEME 3 02N H2N N N N Fe Fe, CaC12 2 R71)1.Bu4NNO3 5 JR 7 or H2/Pd/C R7

R

6 "N R 8 2)column R 6

R

8 6 4Re 0 0 O o (5.2) Br"' 1) HCI Br NaN02 N N 2PEC/HOBt N r B

R

R *R5 7 Br, 5 R7 OH R6

R

RHBr,6 B

R

R6 O

R

1 R 0O R O0 R 1 1 0 (5.4) Scheme 4 shows the formation of compound wherein A and B are halogen Compound with or without the double bond, can be nitrated with several equivalents of a suitable nitrating agent such as tetrabutyl ammonium nitrate in the presence of trifluoroacetic anhydride to obtain the nitro compound Compound can then be reduced to the amine with a suitable reducing agent such as iron or catalytic hydrogenation in the presence of a palladium catalyst to obtain the amino compound Compound can then be brominated in the presence of a diazotizing agent such as sodium nitrite in the presence of bromine and hydrobomic acid to obtain the dibrominated compound Compound can then be denitrated by treatment with Raney-Nickel in the presence of hydrogen. The de-nitrated compound is then treated with a suitable carboxylic acid containing the RI group using DEC and WO 98/57961 PCT/US98/11496 HOBt coupling conditions known to those skilled in the art to obtain compound SCHEME 4

H

2 N*

NH

2 N2 5 N O 10% Pd/

C

R R71)1. eq.Bu4NNO 3 s 7 H 2 R7 R6- TFAA R 7 I R6-N' R 8 R6 N 8 2) column 6 8 0 OK6 N' 8 NO2 (6.0) N O 2 (6.1) \V 'e Be, r HCI' B' NaNR2 aney-Ni 1

HCI

NaO N N 2 N NT N N 2EC/HOBt R6' N RN R R R

NO

2 H R 0 R Scheme 5 shows the formation of compound starting from compound which may be prepared as shown in Scheme 1, above. Compound is cyclized by sealing in a tube in the presence of air and heated to around 180 °C for 5-30 hours to 1 0 obtain a mixture of the methyl compound (3.8a) and compound Compound is obtained pure by chromatography on silica gel. Compound is then de-methylated by treatment with ethylchloroformate in the presence of a suitable base such as triethyl amine to form compound Compound is then 1 5 treated with a suitable acid such as hydrochloric acid under reflux conditions for 5-24 hours and the solvent evaporated and the reaction mixture coupled with a suitable carboxylic acid containing the R 1 group using DEC and HOBt coupling conditions known to those skilled in the art to obtain compound ,r WO 98/57961 PCT/US98/11496 Scheme

A

A A HO NO N O N0 Rg R sealed tube R R 180 C 30hrs. I I I R6 Re R 6 N 8 R 6 eN R8 Me (32) Me Me (s3.8a) EtOCOCI N Et3N/reflux N 0& N N ONr F EtNreu 5

R

7 6N HCI reflux R 0

R

6 'N Re- R6N R I H o o (3.10) DEC/HOBt N A R7

OH

OJR1 R6-N R8 i 0 When R in Formula or is -C(O)NRIR 2 -S(0)2RI, S(0) 2 NR1R 2 or -C(O)-OR 1 the compounds of the present invention may be made by subjecting compounds 3.7 3.9, 5.3, or 6.3 to treatment with HCI to remove the EtOC(O)- group, thus forming an amine the nitrogen on the piperidine ring is unsubstituted), followed by a conventional reaction to add the desired group. For example, when preparing compounds wherein R is -C(O)-NH-RG, RG 1 0 being an alkyl, cycloalkyl, or heterocycloalkyl group, after treatment with HC1, the resulting amine compound is reacted with an isocyanate of the formula RG-N=C=O, in a suitable solvent such as DMF, THF or CH2C12 using methods well known in the art.

Alternatively, the amine is reacted with phosgene to form a chloroformate intermediate the nitrogen on the piperidine ring is substituted with The chloroformate is generally not isolated and is reacted with an amine of the formula RG-NH 2 wherein RG is as defined above, to form a compound wherein R is

-C(O)-NH-RG.

WO 98/57961 PCTIUS98/11 496 When R is S(0) 2

R

1 the amine can be dissolved in an appropriate solvent such as DMF of THF. A base is added such as triethylamine, and the appropriate alkylsulfonylchloride S(0) 2 C1), prepared by methods known in the art, is added to the reaction mixture at 0°C to ambient temperature with stirring.

After 1-24 hours, the reaction mixture is added to water and the product extracted with a suitable solvent such as ethylacetate.

The crude reaction product can then be chromatographed on a silica gel column.

When R is S(0) 2

NR

1

R

2 the amine can be dissolved in an appropriate solvent such as DMF of THF. A base is added such as triethylamine, and the appropriate alkylaminosulfonyl chloride 2 C1), prepared by methods known in the art, is added to the reaction mixture at 0°C to ambient temperature with stirring. After 1-24 hours, the reaction mixture is added to water and the product extracted with a suitable solvent such as ethylacetate. The crude reaction product can then be chromatographed on a silica gel column.

When R is -C(O)-ORI, compounds 3.7, 3.9, 5.3 or 6.3 are treated with HCI to remove the EtOC(O)- group, followed by reaction with a suitably substituted chlorocarbonate to make the desired compound.

In the above processes, it is sometimes desirable and/or necessary to protect certain R5, R6, R7, R8 groups during the reactions. Conventional protecting groups are operable as described in Greene, T.W, "Protective Groups In Organic Synthesis," John Wiley Sons, New York, 1981. The protecting groups may then be removed by conventional procedures.

Compounds useful in this invention are exemplified by the following examples, which should not be construed to limit the 3 5 scope of the disclosure.

WO 98/57961 PCT/US98/11496 EXAMPLE 1 Preparation of 6,7-dihydro-5H-cyclohepta[b]pyridin-8,9dione-8-oxime-o-allylether 0o

N-

0 o 6,7-dihydro-5H-cyclohepta[b]pyridin-8,9-dione-8-oxime(10 gm, 52.58 mmol) was suspended in 100 ml of dry N,Ndimethylformamide (DMF) under a dry nitrogen atmosphere.

Sodium hydride (60% oil dispersion, 1.388gm, 57.83 mmol) was added portionwise over 15 minutes to the stirred mixture at 0 oC.

Allylbromide (8.4 ml) was added dropwise over 30 minutes.

After the addition was over the mixture was stirred at ambient temperature for 18 hours. The DMF was concentrated to approximately 25 ml under high vacuum and diluted with 500 ml of methylenechloride. The mixture was washed with water two times, dried over magnesium sulfate, filtered and the solvent evaporated to obtain a gum which was chromatographed on a silica gel column using 25%-50% ethylacetate/hexanes as the eluent to obtain 5.7gm, 47% of the title product. FABMS (M+1)=231 EXAMPLE 2 Preparation of 5,6,7,9-tetrahydro-9-hydroxy-9-(1methyl-4-piperidinyl)-8H-cyclohepta[b]pyridin-8-one 0- (2-propenyl)oxime-o-allyl ether

N

HO N-0

N

Me 6,7-dihydro-5H-cyclohepta[b]pyridin-8,9-dione-8-oxime-oallylether (10.13 gm, 44 mmol) was dissolved in 150 ml of dry THF under nitrogen atmosphere and cooled to 0°C in an ice bath.

3 0 While stirring, 88 ml of a 1 molar THF solution of Nmethylpiperidine-4-magnesiumchloride was added dropwise.

After evidence of reaction completion by TLC 1 hour, the WO 98/57961 PCT/US98/11496 reaction mixture was added to 500 ml of saturated ammonium chloride solution and extracted with 3X500 ml of ethylacetate.

The ethylacetate layer was dried over magnesium chloride, filtered and evaporated to drynes under reduced pressure to obtain a crude oil which was chromatographed on silica gel using 2.5%-5%methanol/methylenechloride as the eluent to obtain 4.82 gm of title product. FABMS (M+1)=330 EXAMPLE 3 Preparation of 5,6,7,9-tetrahydro-9-chloro-9-(1-methyl- 4-piperidinyl)-8H-cyclohepta[b]pyridin-8-one 0-(2propenyl)oxime-o-allyl ether S

N-O

N

Me 5,6,7,9-Tetrahydro-9-hydroxy-9-(1-methyl-4-piperidinyl)-8hcyclohepta[b]pyridin-8-one 0-(2-propenyl)oxime (0.593 gm, 1.8 mmol) was dissolved in 10 ml of dry methylenechloride.

Thionylchloride (0.428gm, 3.6 mmol) was added dropwise and the reaction stirred at ambient temperature for 1 hour. The reaction mixture was carefully neutralized to pH 8-8.5 with saturated sodium bicarbonate solution, and the product extracted with methylenechloride, dried over magnesium sulfate filtered, and evaporated to dryness to obtain a dark brown gum which was used in the next step without purification. FABMS (M+1)=348 EXAMPLE 4 Preparation of 5,6,7,9-tetrahydro-9-(1-methyl-4piperidinyl)-8H-cyclohepta[b]pyridin-8-one 0-(2propenyl)oxime-o-allylether N

N-O

l r- ;-ii .I r- r c WO 98/5796 1PCIS/149 PCT[US98/11496 5,6,7,9-Tetrahydro-9-chloro-9-(I1 -me thylI-4-piperidinyI) -8hcyclohepta[b]pyridin-8-one

O-(

2 -propenyl)oxime (2.36 gin, 6.8 inmol) was dissolved in 50 ml of glacial acetic acid under a dry nitrogen atmosphere. Zinc (1.77gm, 27.2 mmol) was added and the reaction mixture refluxed for 2 hours. The acetic acid was evaporated under high vacuum and the residue dissolved in methylenechioride and filtered. The methylenechloride solution was washed with brine, and evaporated to dryness to obtain agum which was chromatographed on silica gel using 2.5 1 0 methylenechloride as the eluent to obtain 2.03 gmn of title product.

FABMS (M+l)=314 EXAMPLE Preparation of n-methyl- 4-(6,11-dihydro-SH- 1 5 cyclohepta[2,1-b:4,5-b']dipyridin-11-yl)-1.piperidine and n-methyl- 4-(6,11-dihydro-8-mnethyl-5Hcyclohepta[2,1-b:4,5-b']dipyridin-11-yl)-1-piperidine N N N N N N M e Me 5,6,7,9-Tetrahydro-9-(1-methyl-4-piperidinyl)-8Hcyclohepta[b]pyridin-8 -one O-( 2 -propenyl)oxime-o-allylether (2 gin, 6.4 minol) was placed in a pressure tube, sealed in the presence of air, and heated to 180 'C for 7 hours. The reaction mixture was allowed to cool to ambient temperature, and the 2 5 brown residue chromnatographed on silica gel using as the eluent to obtain I gin of N- METHYL- 4-(6,l dhdo5hccoet[21b45b'dprdn 11-yl)-1-piperidine and 0.1 gin of n-methyl- 4-(6,ll-dihydro-8inethyl-5h-cyclohepta[2,l-b:4,5-b']dipyridin-1 l-yl)-lI-piperidine.

3 0 FABMS (M+1)=294 and 308 respectively WO 98/57961 PCT/US98/11496 EXAMPLE 6 Preparation of ethyl 4-(6,11-dihydro-5H-cyclohepta[2,1b:4,5-b']dipyridin-11-yl)-1-piperidinecarboxylate N? N

N

o o n-methyl- 4-(6,11-dihydro-5h-cyclohepta[2,1-b:4,5-b']dipyridin- 11-yl)-l-piperidine (0.5 gm, 0.787 mmol) was suspended in 15 ml of dry toluene under a dry nitrogen atmosphere and heated to reflux. A solution of triethylamine (0.77 ml, 5.5 mmol) and 1 0 ethylchloroformate (0.6 ml, 6.3 mmol) was added and the reaction refluxed for 3 hours. The reaction mixture was cooled to ambient temperature, ethylacetate added, and washed with 50 ml of IN sodium hydroxide solution. The aqueous layer was washed three times with ethylacetate. The organic layers were dried over 1 5 magnesium sulfate, filtered and evaporated to dryness and chromatographed on silica gel using 2.5%-5%methanol/ methylenechloride as the eluent to obtain 0.19 gm of title product.

FABMS (M+1)=352 EXAMPLE 7 Preparation of ethyl 4-(6,11-dihydro-5H-cyclohepta[2,1b:4,5-b']dipyridin-11-yl)-l-piperidine N N

N

Ethyl 4-(6,11-dihydro-5H-cyclohepta[2, 1-b:4,5-b']dipyridin-11yl)-l-piperidinecarboxylate 0.16 gm, 0.45 mmol) was dissolved in 10 ml of concentrated hydrochloric acid and refluxed for 18 hours. The reaction mixture was evaporated to obtain the title product as the hydrochloride salt. FABMS (M+1)=280 n :L WO 98/5796 1PCUS/149 PCT/US98/11496 EXAMPLE 8 Preparation of 4 -(6,11-dihydro-5H-cyclohepta[2,1.b:4,5.

b']dipyridin-11-yl)-1-(4-pyridinylacetyl) ni-oxide piperidine N N N 0 1 1-Dihydro-5H-cyclohepta[2, 1-b:4,5-b']dipyridin-1 l-yl)- 1piperidine (0.117 gin, 0.3 mmol) was dissolved in 10 ml of dry DMF. 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide 1 0 hydrochloride (DEC) (0.086 gin, 0.45 mmol), 1hydroxybenzotriazole (HOBt) (0.06 1 gin, 0.45 mmol), Nmethylmorpholine 0.33 ml, 3 mmol), and pyridylacetic acid-Noxide (0.069 gin, 0.45 mmol) were added and the reaction mixture stirred at ambient temperature for 24 hours. The reaction 1 5 mixture was added to brine and the product extracted with ethylacetate. The ethylacetate layers were dried over magnesium sulfate and evaporated under vacuo The crude product was chromatographed on a silica column using 20% methanol-2M ainmonia/methylenechloride to obtain 0.085 gm of title product.

FABMS (M+1)=429 EXAMPLE 9 Preparation of 4-(6,11-dihydro-5H-cyclohepta[2,1-b:4,5b -3,8-dinitro-dipyridin. il-yI)- 1-nitropiperidine 0 N N 0

N

N0 2 Ethyl 11 -dihydro-5H-cyclohepta[2,l -b:4,5-b'Ildipyridin- 11yl)-l-piperidinecarboxylate (0.562 gmn, 1.6 minol) was dissolved WO 98/57961' PCT/US98/11496 in dichloromethane and cooled to 0 C in an ice bath. Tetrabutylammonium nitrate (2.43 gm, 8.0 mmol) was added and trifluoroacetic anhydride (1.13 ml, 8.0 mmol) was added dropwise and the reaction mixture stirred fro 2 hours and then at ambient temperature for 18 hours. The reaction mixture was basified to pH 10-11 with 10% sodium hydroxide and the product extracted with dichloromethane three times. The dichloromethane layers were combined and dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using 25%-75% ethylacetate/hexanes as the eluent to obtain 0.41 gm of the title product as a brown solid. FABMS (M+1)=416 EXAMPLE Preparation of 4-(6,11-dihydro-5H-cyclohepta[2,1-b:4,5b']-3,8-diamino-dipyridin-ll-yl)-l-nitropiperidine

H

2 N

NH

2 N N

N

NO

2 4-(6,11-Dihydro-5H-cyclohepta[2,1-b:4,5-b']-3,8-dinitrodipyridin-ll-yl)-l-nitropiperidine 0.4 gm 0.97 mmol) was dissolved in 50 ml of 200 proof ethanol. 0.1 gm of 10% palladium on carbon was added and the mixture hydrogenated at 50 psi for 18 hours. The catalyst was filtered and the ethanol evaporated to obtain a brown gum. The crude product was chromatographed on silica gel using 2.5 methanol/dichloromethane as eluent to obtain 0.113 gm of title product. FABMS (M+1)=356 C -1 ;T .i "L i i;Li;- 1 WO 98/57961 PCT/US98/11496 EXAMPLE 11 Preparation of 4-(6,11-dihydro-5H-cyclohepta[2,1-b:4,5b']-3,8-dibromo-dipyridin-11-yl)-l-nitropiperidine Br Br N N

N

NO

2 11-Dihydro-5H-cyclohepta[2,1-b:4,5-b']-3,8-diaminodipyridin-ll-yl)-l-nitropiperidine 0.099 gm, 0.28 mmol) was dissolved in 16 ml of 48% hydrobromic acid. The reaction mixture was cooled to 0°C in an ice bath and bromine (0.16ml, 3.08 mmol) 1 0 was added dropwise. The reaction mixture was stirred for minutes and a solution of sodium nitrite 0.116 gm, 1.68 mmol) in 2 ml of water was added dropwise and the mixture stirred for 4 hours. The reaction mixture was then basified to pH 10-11 with sodium hydroxide and the product extracted into dichloromethane, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was chromatographed on silica gel using 25% ethylacetate/hexanes as the eluent to obtain 0.04 gm of the title product. FABMS (M+l)=482 EXAMPLE 12 Preparation of 4-(6,11-dihydro-5H-cyclohepta[2,1-b:4,5b']-3,8-dibromo-dipyridin-ll-yl)-piperidine Br Br N N

N

1 -Dihydro-5H-cyclohepta[2,1-b:4,5-b']-3,8-dibromodipyridin-ll-yl)-l-nitropiperidine (0.035 gm, 0.073mmol) was dissolved in absolute ethanol and 20 mg of Raney-Ni was added and the mixture hydrogenated at 50 psi of hydrogen. After 8 hours, the Raney-Ni was filtered and the solvent evaporated to obtain the title compound. FABMS (M+1)=437 23 :Ll;~r :r WO 98/57961 WO 9857961PCTIUS98/1 1496 EXAMPLE 13 Preparation of 4-(3,8-dibromo-6,i1-dihydro-5Hc y cioh epta [2,1 -b :4,5 -b Idip yrid in-il -y (4pyridinylacetyl) ni-oxide piperidine Br Br N

N

N 0 4-(3,8-Dlbromo-6,l1 I-dihydro-5H-cyclohepta[2, I -b:4,5-b t dipyridin-l l-yl)-l-(4-pyridinylacetyl) ni-oxide piperidine was prepared as in procedure 8 utilizing 11 cyclohepta[2, l-b:4,5-b']-3,8-dibromo-dipyridin-l l-yl)-piperidine 1 0 as the starting material. FABMS (M+l)=586 EXAMPLE 14 Preparation of ethyl 4-(3-nitro-6,il-dihydro-5Hcyclohepta[2,i-b :4,5-b']dipyridin-il-yl)-i 1 5 piperidinecarboxylate 0 2 N 7

N

N

0 Ethyl 4-(6,1 1-dihydro-5H-cyclohepta[2, 1-b:4,5-b']dipyridin- 11yl)-1-piperidinecarboxylate (0.512 gin, 1.46 mmol) was dissolved in 20 ml of dry dichloromethane at 0 0 C. Tetrabutylammoniumnitrate (0.489 gin, 1.6 mmol) was added and trifluoroacetic anhydride 0.227m1, 1.6 minol) was added dropwise. The reaction mixture was stirred for 2 hours and then allowed to warm to ambient temperature and stirred for 18 hours.

The reaction mixture was basified to pH 10 with IN sodium 2 5 hydroxide, and the product extracted with 3XI00 ml of dichloromethane and dried over magnesium sulfate and filtered.

The dichioromethane was evaporated and the residue chromatographed on silica gel using 25% to 75% ethylacetate/ WO 98/57961 PCT/US98/11496 hexanes as the eluent to obtain 0.16 gm of title product. FABMS (M+1)=397 EXAMPLE Preparation of ethyl 4-( 3 -amino-6,11-dihydro-5Hcyclohepta[2,1-b:4,5-b']dipyridin-11-yl)-1piperidinecarboxylate

H

2

N

N N Ethyl 4-(3-nitro-6,1 1-dihydro-5H-cyclohepta[2,l-b:4,5b']dipyridin-ll-yl)-l-piperidinecarboxylate 0.14gm, 0.367 mmol) was dissolved in 15 ml of ethanol. Palladium/carbon mg) was added and the reaction mixture hydrogenated at psi of hydrogen for 2 hours. The palladium was filtered and the ethanol evaporated to give 0.12 gm of the title product. FABMS (M+1)=367 EXAMPLE 16 Preparation of ethyl 4-(3-bromo-6,11-dihydro-5Hcyclohepta[2,1-b:4,5-b']dipyridin-ll-yl)-lpiperidinecarboxylate N N Ethyl 4-(3-amino-6,11-dihydro-5H-cyclohepta[2,1-b:4,5b']dipyridin-ll-yl)-1-piperidinecarboxylate 0.05 gm, 0.136 mmol) was dissolved in 4 ml of 48% hydrobromic acid. The reaction mixture was cooled to 0°C and bromine 0.038 ml, 0.738mmol) was added dropwise and stirred for 15 minutes.

Sodium nitrite 0.028 gm, 0.408 mmol) was added, as a solution in 0.5 ml of water, dropwise over 15 minutes. The reaction was r~ :1 WO 98/57961 WO 9857961PCT/US98/1 1496 stirred at 0 0 C for 3-4 hours. The reaction mixture was basified to pH 10 with 10% sodium hydroxide and the produt extracted into ethylacetate. The ethylacetate layer was dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was chromatographed on silica gel using 10-20% methanol! dichoromethane as the eluent to obtain 0.03 5 gm of title product.

FABMS (M+1)=431 EXAMPLE 17 1 0 Preparation of 4-(3-bromo-6,11-dihydro-5H-cyclohepta [2,1-b:4,5-b']dipyridin-11-yl)-1-(4-pyridinylacetyl) nioxide piperidine Br N N

N

0 4-(3-Bromo-6, 1l-dihydro-5H-cyclohepta[2, 1-b:4,5-b'Ijdipyridin- 1 5 11 -yl)-l1-(4-pyridinylacetyl) n 1-oxide piperidine was prepared utilizing procedures 7-8 starting with ethyl 4-(3-bromo-6,11dihydro-5H-cyclohepta[2, 1-b:4,5-b']dipyridin-1 1 1piperidinecarboxylate. FABMS 1)=507 EXAMPLE 18 Preparation of 4-(3-methyl-6,11-dihydro-5H-cyclohepta [2,1-b:4,5-b']dipyridin-11-yl)-1-(4-pyridinylacetyl) nioxide piperidine N N 0

N

0 4-(3-Methyl-6,1 1 -dihydro- 5h-cyclohepta [2,l1-b:4,5 dipyri din- 11 -yl)-l1-(4-pyridinylacetyl) ni-oxide piperidine was prepared utilizing procedure 6-8 above starting with n-methyl- 11 WO 98/57961 WO 9857961PCTIUS98/1 1496 dihydro-8-methylI-5H-cyclohepta[2, 1 -b:4,5-b'jldipyridin-1 1 -yI) -Ipiperidine. FABMS (M+1)=443 EXAMPLE 19 Preparation of n-methyl- 4-(6,11-hydroxy-5Hcyclohepta[2,1 ]dipyridin-1 1-yl)-1-piperidine and n-methyl- 4-(6,11-hydroxy-8-methyl-5Hc y cioh epta b: 4,5- b' Idip yr i di n-11- y -i-pi p erid i ne

OH

Me Me Follow procedure as in Example 5 substituting 5,6,7,9-Tetrahydro- 9-hydroxy-9-(l1-methyl-4-piperidinyl)-8H-cyclohepta[b]pyridin- 8-one 0-(2-propenyl)oxime-o-allylether for 5,6,7,9-Tetrahydro-9- (1 -methyl1-4-piperidinyl)- 8H- cy clohepta[b] pyridin- 8-one 0-(2- 1 5 propenyl)oxime-o-allylether to obtain the title compound in 11% yield. FABMS (M+1)=310 and 324 respectively.

EXAMPLE Preparation of 'ethyl 4-(6,1 1-hydroxy-5H-cycloheptall2,ib:4,5-b']dipyridin-11-yl)-1-piperidine

OH

Follow procedure as in Examples 6 and 7 using n-methyl. 4-(6,1 1hydroxy-5H-cyclohepta[2,l -b:4,5-b']dipyridin-l11-yl)-1-piperidine to obtain the title compound which was utitlized directly in the next step.

WO 98/57961 PCT/US98/11496 EXAMPLE 21 Preparation of 4-(6,11-hydroxy-5H-cyclohepta[2,1-b:4,5b']dipyridin-11-yl)-l-(4-pyridinylacetyl) nl-oxide piperidine N N

OH

N

Follow procedure as in Example 8 using ethyl 4-(6,11-hydroxy- 5H-cyclohepta[2,1-b:4,5-b']dipyridin-11ll-yl)-l -piperidine to obtain the title compound in 13 yield. FABMS (M+1)=431

ASSAYS

FPT IC50 (inhibition of farnesyl protein transferase, in vitro enzyme assay) and COS Cell IC50 (Cell-Based Assay) were determined following the assay procedures described in WO 95/10516, published April 20, 1995. GGPT IC50 (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), Cell Mat Assay, and anti-tumor activity (in vivo anti-tumor studies) could be determined by the assay procedures described in WO 95/10516. The disclosure of WO 95/10516 is incorporated herein by reference thereto.

Additional assays can be carried out by following essentially the same procedure as described above, but with substitution of alternative indicator tumor cell lines in place of the T24-BAG cells.

The assays can be conducted using either DLD-1-BAG human colon carcinoma cells expressing an activated K-ras gene or SW620-BAG human colon carcinoma cells expressing an activated K-ras gene.

Using other tumor cell lines known in the art, the activity of the compounds of this invention against other types of cancer cells could be demonstrated.

i -r I .i u lir-i i. I WO 98/57961 PCT/US98/11496 Soft Agar Assay: Anchorage-independent growth is a characteristic of tumorigenic cell lines. Human tumor cells are suspended in growth medium containing 0.3% agarose and an indicated concentration of a farnesyl transferase inhibitor. The solution is overlayed onto growth medium solidified with 0.6% agarose containing the same concentration of farnesyl transferase inhibitor as the top layer. After the top layer is solidified, plates are 1 0 incubated for 10-16 days at 37 0 C under 5% C02 to allow colony outgrowth. After incubation, the colonies are stained by overlaying the agar with a solution of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/mL in PBS). Colonies can be counted and the IC50's can be 1 5 determined.

The results are given in the table below represents micromolar).

Compound of FPT IC50 COS Cell Example No. (uM) (uM) 6 >17.0 8 25%@>1.4 13 0.028 0.125 17 0.29 18 0.16 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g.

magnesium carbonate, magnesium stearate, talc, sugar, lactose.

Tablets, powders, cachets and capsules can be used as solid dosage 3 0 forms suitable for oral administration.

WO 98/57961 PCT/US98/I 1496 For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or waterpropylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, more preferably from about 1 mg. to 300 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by WO 98/57961 PCT/US98/11496 small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being 1 0 treated. A typical recommended dosage regimen is oral administration of from 10 mg to 2000 mg/day preferably 10 to 1000 mg/day, in two to four divided doses to block tumor growth.

The compounds are non-toxic when administered within this dosage range.

The compounds of the present invention are also useful as antihistamines. They act as anti-allergic agents in the treatment of conditions such as perennial and seasonal allergic rhinitis and chronic urticaria. Thus, an effective amount of a compound of the present invention may be administered to an animal to effect an anti-allergic response. Although the required dosage for an antiallergic response will be determined by such factors as the patient's age, sex, weight, and the severity of the allergic reaction to be treated, the preferred human dosage range is preferably 2 5 from 1 to 1,000 mg/day. The preferred dosage ranges for other animals can readily be determined by using standard testing methods.

The following are examples of pharmaceutical dosage forms 3 0 which contain a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not to be limited by the examples provided.

WO 98/57961 PCT/US98/11496 Pharmaceutical Dosage Form Examples EXAMPLE A Tablets

L

No. Ingredients mg/tablet mg/tablet 1. Active compound 100 500 2. Lactose USP 122 113 3. Corn Starch, Food Grade, 30 as a 10% paste in Purified Water 4. Corn Starch, Food Grade 45 Magnesium Stearate 3 7 Total 300 700 Method of Manufacture Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes.

Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix 1 0 with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B Capsules No. Ingredient mg/capsule mg/capsule 1. Active compound 100 500 2. Lactose USP 106 123 3. Corn Starch, Food Grade 4 0 7 0 4. Magnesium Stearate NF 7 7 Total 253 700 Method of Manufacture Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a Suitable encapsulating machine.

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof wifl be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprising" is used in the sense of"including", i.e. the features specified may be o associated with further features in various embodiments of the invention.

2A reference herein to a prior art document is not an admission that the document forms part of the common general knowledge in the art in Australia.

S:

Claims (22)

1. A compound having the formula: B N N N oB N N R o R R5, R6, R and R8 are independently selected from the I group consisting of H, -CF3, -COR"o, alkyl or aryl, said alkyl or aryl Sor a pharmaceutically being subsacceptable salt or solvate thereof, wherein t is 0, 1 or 2, -NR'OCOOR", -N(RIO)2, -NO2, -CORio :-OCOR, -OCOR, -C2R r O R, r R is combined .with R6 to represent =O or =S and/or R7 is combined with R8 to represent =0 or =S; 2R0 B is methyl, halkyl, aryl, or aralkyl; the dotted line represents alkyl or aryln optional double bond; R is -C(0)NR'R2, and -S(0)2NRR2 wherein R and R are independently selected from the group consisting of H, -CFlkyl, -CORyl, arylalkyl or aryl, said alkyl or aryl optionally being substituted with -OR 1 -SR 10 -S(O)tR I 1 wherein t is 25 0, 1 or 2, -NRI°CoORll, -N(RI°) 2 -NO 2 -COR 1 0 -OCOR 0 -OCO 2 R l l -CO 2 R l 0 or OPO 3 R I0 or R 5 is combined with R 6 to represent =0 or =S and/or R 7 is combined with R 8 to represent =0 or =S; represents H, alkyl, aryl, or aralkyl; R II represents alkyl or aryl; and R is -C(O)R 1 -C(O)NR'R 2 -S(O) 2 -R 1 and -S(O) 2 NRIR 2 wherein R' and R 2 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, heterocycloalkyl, substituted alkyl, substituted aryl, substituted arylalkyl, substituted heteroaryl, substituted heteroarylalkyl, substituted (C3-C6) cycloalkyl, substituted cycloalkylalkyl, substituted heterocycloalkyl, wherein said substituted groups have one or more substituents selected from: C1-C6 alkyl, alkoxy, aralkyl, heteroarylalkyl, -N02, alkyloxyalkyl, alkyloxyalkyloxyalkyl, C3-C6 cycloalkyl, aryl, -CN, heteroaryl, heterocycloalkyl, -OH, amino, substituted amino, nitro and 1 0 halo, with the proviso that R 1 is not H for -C(O)-ORI or for -S(O) 2 R 1

2. The compound of claim 1 wherein A and B are independently selected from methyl or halo. 0

3. The compound of claim 1, wherein A is halo, and B is Br.

4. The compound of claim 1, wherein A and B are selected from halo. The compound of claim 1 wherein R 5 R 6 R 7 and R 8 are independently selected from the group consisting of H, -CF 3 alkyl, aryl, cycloalkyl and heterocycloalkyl.

6. The compound of claim 5, wherein R 5 R 6 R 7 and R 8 are H.

7. The compound of claim 5, wherein R is -C(O)R 1

8. The compound of claim 7, wherein R 1 is -(CH 2 )nRA, wherein n is an integer from 0 to 6, and wherein R A is selected from aryl, cycloalkyl and heterocycloalkyl.

9. The compound of claim 8, wherein A and B are independently selected from halo. The compound of claim 9, wherein the halo is Br.

11. The compound of claim 8, wherein R A is selected from 0 N -C(O)NH 2 C N-C(O)NH2 and

12. The compound of claim 5, wherein A and B are independently selected from halo.

13. The compound of claim 1, wherein the compound is selected from the group consisting of q e 0/ O 0N O o r ,and

14. A method for inhibiting the abnormal growth of cells, comprising administering an effective amount of a compound of any one of claims 1 to 4.

15. A method for inhibiting the abnormal growth of cells, comprising administering an effective amount of a compound of any one of claims 5 to 7.

16. A method for inhibiting the abnormal growth of cells, comprising administering an effective amount of a compound of any one of claims 8 to 11.

17. A method for inhibiting the abnormal growth of cells, comprising administering an effective amount of a compound of claim 12 or 13.

18. A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of a compound of any one of claims 1 to 7 in combination with a pharmaceutically acceptable carrier.

19. A pharmaceutical composition for inhibiting the abnormal growth of cells comprising an effective amount of a compound of any one of claims 8 to 13 in combination with a pharmaceutically acceptable carrier.

20. A method of effecting an anti-allergic response in an animal comprising administering to the animal an effective amount of a compound of any one of claims 1 to 13.

21. Use of a compound of any one of claims 1 to 13 for inhibiting the abnormal growth of cells. S22. Use of a compound of any one of claims 1 to 13 for effecting an anti-allergic response in an animal.

23. Use of a compound of any one of claims 1 to 13 for the manufacture of a medicament for inhibiting the abnormal growth of cells.

24. Use of a compound of any one of claims 1 to 13 for the manufacture of a medicament for effecting an anti-allergic response in an animal. (O ORA t LU 37 A compound of claim 1 substantially as herein described with reference to the Examples.

26. A pharmaceutical composition of claim 18 or 19 substantially as herein described with reference to Pharmaceutical Dosage Form Example A or Pharmaceutical Dosage Form Example B. Dated this 27th day of November 2001 SCHERING CORPORATION By their Patent Attorneys GRIFFITH HACK 38