EP0989984A1 - Bispyrido-cycloheptane compounds useful for inhibition of farnesyl protein transferase - Google Patents
Bispyrido-cycloheptane compounds useful for inhibition of farnesyl protein transferaseInfo
- Publication number
- EP0989984A1 EP0989984A1 EP98928887A EP98928887A EP0989984A1 EP 0989984 A1 EP0989984 A1 EP 0989984A1 EP 98928887 A EP98928887 A EP 98928887A EP 98928887 A EP98928887 A EP 98928887A EP 0989984 A1 EP0989984 A1 EP 0989984A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- substituted
- alkyl
- aryl
- halo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
Definitions
- WO 95/ 10516 published April 20, 1995 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
- This invention provides compounds useful for the inhibtion of farnesyl protein transferase (FPT).
- FPT farnesyl protein transferase
- A is alkyl, halo or H
- R5 , R6 , 7 an d R8 are independently selected from the group consisting of H, -CF3 , -COR 10, alkyl or aryl, said alkyl or aryl optionally being substituted with -OR 1 0 , -SR 1 0 , -S(0)tR n , -NR 10 COORl l , -N(RlO)2, -N ⁇ 2, -COR 10 ,
- R 0 represents H, alkyl, aryl, or aralkyl (e.g., benzyl); R 1 1 represents alkyl or aryl;
- R40 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or -D wherein -D represents
- R3 and R4 are independently selected from the group consisting of H, halo, -CF3, -OR 10 (e.g., -OCH3), -COR 10 , -SR 10 (e.g., -SCH3 and -SCH2C6H5), -S(0) t R ⁇ (wherein t is 0, 1 or 2, e.g., -SOCH3 and -SO2CH3), -SCN, -N(R 10 )2, -NR ⁇ R 1 1 , -N ⁇ 2, -OC(0)R 10 , -C02R 10 , -OCO2R 1 1 , -CN, -NHC(O)R 1 0, -NHSO2R 10 , -CONHR 10 , -CONHCH2CH2OH, -NRiOcOOR 11 ,
- -SR 1 1 C(0)OR 1 1 e.g., -SCH2CO2CH3, -SR 1 1 N(R75)2 wherein each R75 i s independently selected from H and -C(0)OR 1 ! (e.g., -S(CH2)2NHC(0)0-t-butyl and -S(CH2)2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol5-ylthio such as l-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, -OR 1 0 or -C ⁇ 2R 1 0 ; and W is O, S or NR 10 wherein Rl ° is as defined above; said R40 cycloalkyl, alken
- R40 represents phenyl substituted with a group selected from -SO2NH2, -NHSO2CH3, -SO2NHCH3, -SO2CH3, -SOCH3, -SCH3, or -NHSO2CF3 , preferably, said group is located in the para (p-) position of the phenyl ring;
- R is -CCC R 1 , -C(0)-OR 1 , -C(0)NR 1 R2, -S(0)2-R 1 , or -S(0)2NR 1 R 2 wherein R and R ⁇ 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, -NO2, alkyloxy alkyl, alkyloxyalkyloxyal
- 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 transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
- 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
- tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene
- 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 inhibiting 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, breast cancer and prostate cancer.
- 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
- 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.
- 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.
- G-protein function such as ras p21
- G-protein isoprenylation thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer.
- these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
- M H + represents the molecular ion plus hydrogen of the molecule in the mass spectrum
- Bu-represents butyl; Et-represents ethyl; Me-represents methyl; Ph-represents phenyl; benzotriazol- 1 -yloxy represents
- EtOH methanol
- MeOH acetic acid
- HO Ac or AcOH ethyl acetate
- DMF N,N-dimethylformamide
- THF trifluoroacetic acid
- TFAA trifluoroacetic anhydride
- HOBT 1-hydroxybenzotriazole
- MCPBA m-chloroperbenzoic acid
- Et3N triethylamine
- Et2 ⁇ diethyl ether
- ethyl chloroformate C1CO2E-
- DEC l-(3- dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride
- Representative compounds of Formula 1.0 and 2.0 include, but are not limited to:
- A is preferably 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, -CF 3 , alkyl, aryl, cycloalkyl, and heterocycloalkyl, more preferably R 5 , R 6 , R 7 and R 8 are H.
- R is preferably -C(0)R 1 .
- R 1 is -(CH 2 ) n R A , wherein n is an integer from 0 to 6, preferably 1 to 3, most preferably, 1 , and wherein R A is selected from aryl, cycloalkyl and heterocycloalkyl. More preferably, R A is selected from
- 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 (1.0) without the optional double bond.
- Compound (3.0) is reacted with sodium hydride and allyl bromide in a suitable solvent, e.g., DMF, at a temperature of about 0 °C, 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 3.1).
- 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 e.g., THF at a temperature of about 0 °C.
- a grignard reagent N-methylpiperidine-4-magnesium chloride, substituted with substituents R5, R6, R7, and R8
- 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 (3.2).
- Compound (3.2) is then chlorinated with a chlorinating agent, e.g., thionyl chloride to form comound (3.3).
- a chlorinating agent e.g., thionyl chloride
- Compound (3.3) can be reacted with zinc in glacial actic acid to remove the chlorine subsitutent.
- the product is recovered by evaporating the acetic acid under high vacuum, dissolving the residue in a suitable solvent, e.g., methylene chloride, filtering, and chromatographing the filtrate on silica gel to obtain compound (3.4)
- a suitable solvent e.g., methylene chloride
- 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 °C for about 7 hours to yield a mixed product (a methyl-substituted tricyclic (compound 3.5) and a tricyclic without the methyl substitutent (compound 3.6)).
- Compounds 3.5 and 3.6 may be separated by chromatographing the mixed product on silica gel.
- compound (3.7) 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 (1.0).
- compound (3.2) can be subjected to the same conditions that compound (3.4) is subjected to and the reaction sequence can proceed as described above.
- Scheme 2 shows the formation of compound (1.0) wherein the compound has the double bond.
- Compound (3.2) is dehydrated with a suitable base such as DBU at 60 to 150°C for 1 - 18 hours to obtain compound (4.0).
- Compound (4.0) is then cyclized by sealing in a tube in the presence of air and heated to around 180 °C for 5-30 hours to obtain a mixture of the methyl compound (4.2) and compound (4.3).
- Compound (4.3) is obtained pure by chromatography on silica gel.
- Compound (4.3) is then de- methylated by treatment with ethylchloroformate in the presence of a suitable base such as triethyl amine to form compound (4.4).
- Compound (4.4) 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 (1.0). If compound (1.0 ) is desired with a methyl group, compound (4.2) can be subjected to the same conditions that compound (4.3) is subjected to and the reaction sequence can proceed as described above.
- 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 (1.0).
- 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 (
- Scheme 3 shows the formation of compound (1.0) wherein A is halogen.
- Compound (5.0) 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 (5.1).
- 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 (5.2).
- Compound (5.2) 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 brominated compound (5.3).
- Scheme 4 shows the formation of compound (1.0) wherein A and B are halogen .
- Compound (5.0) 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 (6.0).
- Compound (6.0) 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 (6.1).
- Compound (6.1) 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 di- brominated compound (6.2).
- Compound (6.2) can then be de- nitrated by treatment with Raney-Nickel in the presence of hydrogen.
- the de-nitrated compound is then treated 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 (6.4).
- Scheme 5 shows the formation of compound (2.0), starting from compound (3.2), which may be prepared as shown in Scheme 1 , above.
- Compound (3.2) is cyclized by sealing in a tube in the presence of air and heated to around 180 °C for 5-30 hours to obtain a mixture of the methyl compound (3.8a) and compound (3.8).
- Compound (3.8) is obtained pure by chromatography on silica gel.
- Compound (3.8) is then de-methylated by treatment with ethylchloroformate in the presence of a suitable base such as triethyl amine to form compound (3.9).
- the compounds of the present invention may be made by subjecting compounds 3.7 , 3.9, 5.3, or 6.3 to treatment with HCl to remove the EtOC(O)- group, thus forming an amine (i.e., the nitrogen on the piperidine ring is unsubstituted), followed by a conventional reaction to add the desired group.
- R G being an alkyl, cycloalkyl, or heterocycloalkyl group
- the amine is reacted with phosgene to form a chloroformate intermediate (i.e., the nitrogen on the piperidine ring is substituted with -C(O)Cl).
- the chloroformate is generally not isolated and is reacted with an amine of the formula R G -NH2, wherein R G is as defined above, to form a compound wherein R is -C(0)-NH-R G .
- R is S(0) 2 R !
- the amine can be dissolved in an appropriate solvent such as DMF of THF.
- a base is added such as triethylamine, and the appropriate alkylsulfonylchlori.de (R 1 - 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.
- R is S(0) 2 NR R
- 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 (R 1 R 2 N-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.
- R is -C(0)-OR 1
- compounds 3.7, 3.9, 5.3 or 6.3 are treated with HCl to remove the EtOC(O)- group, followed by reaction with a suitably substituted chlorocarbonate to make the desired compound.
- 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+l) 330
- 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 0.035 gm of title product.
- FABMS (M+l) 431
- 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.
- 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 incubated for 10-16 days at 37°C under 5% C02 to allow colony outgrowth.
- MTT 3-[4,5-dimethyl- thiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue
- Colonies can be counted and the IC5 ⁇ 's can be determined.
- 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 forms suitable for oral administration.
- 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 water- propylene 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.
- the compound is administered orally.
- the pharmaceutical preparation is in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., 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 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 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.
- 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 from 1 to 1,000 mg/day. The preferred dosage ranges for other animals can readily be determined by using standard testing methods .
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US87774397A | 1997-06-17 | 1997-06-17 | |
PCT/US1998/011496 WO1998057961A1 (en) | 1997-06-17 | 1998-06-15 | Bispyrido-cycloheptane compounds useful for inhibition of farnesyl protein transferase |
US877743 | 2001-06-11 |
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EP0989984A1 true EP0989984A1 (en) | 2000-04-05 |
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EP98928887A Withdrawn EP0989984A1 (en) | 1997-06-17 | 1998-06-15 | Bispyrido-cycloheptane compounds useful for inhibition of farnesyl protein transferase |
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EP (1) | EP0989984A1 (en) |
JP (1) | JP2002504145A (en) |
KR (1) | KR20010013825A (en) |
CN (1) | CN1266432A (en) |
AR (1) | AR015122A1 (en) |
AU (1) | AU744153B2 (en) |
CA (1) | CA2293713C (en) |
CO (1) | CO4940447A1 (en) |
HU (1) | HUP0004274A3 (en) |
IL (1) | IL133388A0 (en) |
NZ (1) | NZ501418A (en) |
WO (1) | WO1998057961A1 (en) |
ZA (1) | ZA985214B (en) |
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CA2764387A1 (en) | 2009-06-05 | 2010-12-09 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
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ATE210652T1 (en) * | 1993-10-15 | 2001-12-15 | Schering Corp | TRICYCLIC CARBAMAT DERIVATIVES FOR INHIBITING G-PROTEIN FUNCTION AND FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
US5719148A (en) * | 1993-10-15 | 1998-02-17 | Schering Corporation | Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases |
IL111235A (en) * | 1993-10-15 | 2001-03-19 | Schering Plough Corp | Pharmaceutical compositions for inhibition of g-protein function and for treatment of proliferative diseases containing tricyclic compounds some such compounds and process for preparing part of them |
CN1326847C (en) * | 1995-12-22 | 2007-07-18 | 先灵公司 | Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative diseases |
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1998
- 1998-06-15 WO PCT/US1998/011496 patent/WO1998057961A1/en not_active Application Discontinuation
- 1998-06-15 CN CN98808118A patent/CN1266432A/en active Pending
- 1998-06-15 NZ NZ501418A patent/NZ501418A/en unknown
- 1998-06-15 IL IL13338898A patent/IL133388A0/en unknown
- 1998-06-15 KR KR1019997011845A patent/KR20010013825A/en not_active Application Discontinuation
- 1998-06-15 AU AU80581/98A patent/AU744153B2/en not_active Ceased
- 1998-06-15 CA CA002293713A patent/CA2293713C/en not_active Expired - Fee Related
- 1998-06-15 EP EP98928887A patent/EP0989984A1/en not_active Withdrawn
- 1998-06-15 HU HU0004274A patent/HUP0004274A3/en unknown
- 1998-06-15 JP JP50449199A patent/JP2002504145A/en not_active Ceased
- 1998-06-15 ZA ZA985214A patent/ZA985214B/en unknown
- 1998-06-16 AR ARP980102863A patent/AR015122A1/en unknown
- 1998-06-16 CO CO98034143A patent/CO4940447A1/en unknown
Non-Patent Citations (1)
Title |
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See references of WO9857961A1 * |
Also Published As
Publication number | Publication date |
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ZA985214B (en) | 1999-01-07 |
HUP0004274A2 (en) | 2001-08-28 |
HUP0004274A3 (en) | 2002-03-28 |
JP2002504145A (en) | 2002-02-05 |
CN1266432A (en) | 2000-09-13 |
CO4940447A1 (en) | 2000-07-24 |
AU8058198A (en) | 1999-01-04 |
CA2293713A1 (en) | 1998-12-23 |
CA2293713C (en) | 2006-12-05 |
IL133388A0 (en) | 2001-04-30 |
KR20010013825A (en) | 2001-02-26 |
WO1998057961A1 (en) | 1998-12-23 |
NZ501418A (en) | 2001-04-27 |
AR015122A1 (en) | 2001-04-18 |
AU744153B2 (en) | 2002-02-14 |
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