IL117798A - Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them - Google Patents

Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them

Info

Publication number: IL117798A
Authority: IL; Israel
Prior art keywords: alkyl; formula; group; substituted; compound
Prior art date: 1995-04-07

Application number

IL11779896A

Other languages

English (en)

Hebrew (he)

Other versions

IL117798A0 (en

Original Assignee

Schering Plough Corp

Kenilworth And Pharmacopeia In

Priority date (The priority date 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 date listed.)

1995-04-07

Filing date

1996-04-02

Publication date

2001-11-25

1996-04-02 Application filed by Schering Plough Corp, Kenilworth And Pharmacopeia In filed Critical Schering Plough Corp

1996-08-04 Publication of IL117798A0 publication Critical patent/IL117798A0/xx

2001-11-25 Publication of IL117798A publication Critical patent/IL117798A/en

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 401
230000005764 inhibitory process Effects 0.000 title claims description 18
239000008194 pharmaceutical composition Substances 0.000 title claims description 14
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 6
230000002062 proliferating effect Effects 0.000 title description 6
201000010099 disease Diseases 0.000 title description 5
125000000217 alkyl group Chemical group 0.000 claims abstract description 90
-1 aralkoxy Chemical group 0.000 claims abstract description 80
125000003118 aryl group Chemical group 0.000 claims abstract description 54
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 38
125000001424 substituent group Chemical group 0.000 claims abstract description 38
125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 37
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 30
125000003545 alkoxy group Chemical group 0.000 claims abstract description 29
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 24
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 23
229910052799 carbon Inorganic materials 0.000 claims abstract description 20
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 19
125000005843 halogen group Chemical group 0.000 claims abstract description 19
229910052701 rubidium Inorganic materials 0.000 claims abstract description 18
229910052705 radium Inorganic materials 0.000 claims abstract description 17
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 15
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 13
150000001413 amino acids Chemical class 0.000 claims abstract description 13
125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 13
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 10
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 10
125000004104 aryloxy group Chemical group 0.000 claims abstract description 9
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
150000002019 disulfides Chemical class 0.000 claims abstract description 9
125000005842 heteroatom Chemical group 0.000 claims abstract description 9
125000004076 pyridyl group Chemical group 0.000 claims abstract description 9
125000003386 piperidinyl group Chemical group 0.000 claims abstract description 8
125000003107 substituted aryl group Chemical group 0.000 claims abstract description 8
125000004122 cyclic group Chemical group 0.000 claims abstract description 7
229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
125000004649 C2-C8 alkynyl group Chemical group 0.000 claims abstract description 6
125000005110 aryl thio group Chemical group 0.000 claims abstract description 6
229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
125000006501 nitrophenyl group Chemical group 0.000 claims abstract description 5
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 4
125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 4
108010014186 ras Proteins Proteins 0.000 claims description 21
150000003839 salts Chemical class 0.000 claims description 21
102000016914 ras Proteins Human genes 0.000 claims description 19
102000004357 Transferases Human genes 0.000 claims description 17
108090000992 Transferases Proteins 0.000 claims description 17
210000004881 tumor cell Anatomy 0.000 claims description 17
125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
125000003342 alkenyl group Chemical group 0.000 claims description 14
229910052796 boron Inorganic materials 0.000 claims description 11
210000004027 cell Anatomy 0.000 claims description 11
230000002159 abnormal effect Effects 0.000 claims description 9
229910052794 bromium Inorganic materials 0.000 claims description 9
230000010261 cell growth Effects 0.000 claims description 9
230000002401 inhibitory effect Effects 0.000 claims description 7
108700042226 ras Genes Proteins 0.000 claims description 7
125000000547 substituted alkyl group Chemical group 0.000 claims description 7
230000035772 mutation Effects 0.000 claims description 6
231100000590 oncogenic Toxicity 0.000 claims description 6
230000002246 oncogenic effect Effects 0.000 claims description 6
229910052739 hydrogen Inorganic materials 0.000 claims description 5
206010005003 Bladder cancer Diseases 0.000 claims description 3
201000009030 Carcinoma Diseases 0.000 claims description 3
206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
101150040459 RAS gene Proteins 0.000 claims description 3
201000001531 bladder carcinoma Diseases 0.000 claims description 3
208000029742 colonic neoplasm Diseases 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
230000003325 follicular Effects 0.000 claims description 3
201000005202 lung cancer Diseases 0.000 claims description 3
208000020816 lung neoplasm Diseases 0.000 claims description 3
238000004519 manufacturing process Methods 0.000 claims description 3
208000025113 myeloid leukemia Diseases 0.000 claims description 3
108090000623 proteins and genes Proteins 0.000 claims description 3
210000001685 thyroid gland Anatomy 0.000 claims description 3
208000010570 urinary bladder carcinoma Diseases 0.000 claims description 3
QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 claims description 2
229910014585 C2-Ce Inorganic materials 0.000 claims description 2
210000001072 colon Anatomy 0.000 claims description 2
210000000066 myeloid cell Anatomy 0.000 claims 2
201000002528 pancreatic cancer Diseases 0.000 claims 2
101100112682 Danio rerio ccne1 gene Proteins 0.000 claims 1
239000003814 drug Substances 0.000 claims 1
125000001188 haloalkyl group Chemical group 0.000 abstract description 2
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 abstract description 2
125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 2
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
239000000047 product Substances 0.000 description 102
238000000034 method Methods 0.000 description 90
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
238000006243 chemical reaction Methods 0.000 description 72
239000000203 mixture Substances 0.000 description 67
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
239000012141 concentrate Substances 0.000 description 51
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
239000000243 solution Substances 0.000 description 39
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 38
238000003756 stirring Methods 0.000 description 37
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
239000000741 silica gel Substances 0.000 description 34
229910002027 silica gel Inorganic materials 0.000 description 34
150000001412 amines Chemical class 0.000 description 33
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
235000019439 ethyl acetate Nutrition 0.000 description 28
239000011347 resin Substances 0.000 description 27
229920005989 resin Polymers 0.000 description 27
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 26
230000008569 process Effects 0.000 description 26
239000002904 solvent Substances 0.000 description 26
239000000284 extract Substances 0.000 description 25
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
239000002585 base Substances 0.000 description 24
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 24
239000002253 acid Substances 0.000 description 22
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
229920006395 saturated elastomer Polymers 0.000 description 20
229910052943 magnesium sulfate Inorganic materials 0.000 description 19
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
235000011114 ammonium hydroxide Nutrition 0.000 description 18
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
125000004432 carbon atom Chemical group C* 0.000 description 16
239000000706 filtrate Substances 0.000 description 16
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
239000003153 chemical reaction reagent Substances 0.000 description 13
239000003795 chemical substances by application Substances 0.000 description 13
239000007787 solid Substances 0.000 description 13
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
239000012267 brine Substances 0.000 description 12
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
238000010992 reflux Methods 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 12
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
206010028980 Neoplasm Diseases 0.000 description 11
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 11
238000003556 assay Methods 0.000 description 11
125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
150000002576 ketones Chemical class 0.000 description 11
125000006239 protecting group Chemical group 0.000 description 11
229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 10
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
125000000304 alkynyl group Chemical group 0.000 description 10
229940024606 amino acid Drugs 0.000 description 10
235000001014 amino acid Nutrition 0.000 description 10
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
229910052740 iodine Inorganic materials 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
239000007818 Grignard reagent Substances 0.000 description 9
239000000908 ammonium hydroxide Substances 0.000 description 9
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
150000004795 grignard reagents Chemical class 0.000 description 9
239000000543 intermediate Substances 0.000 description 9
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
229910052786 argon Inorganic materials 0.000 description 8
239000003638 chemical reducing agent Substances 0.000 description 8
150000003512 tertiary amines Chemical class 0.000 description 8
229910052721 tungsten Inorganic materials 0.000 description 8
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
239000002246 antineoplastic agent Substances 0.000 description 7
125000000524 functional group Chemical group 0.000 description 7
230000007062 hydrolysis Effects 0.000 description 7
238000006460 hydrolysis reaction Methods 0.000 description 7
125000005647 linker group Chemical group 0.000 description 7
239000007788 liquid Substances 0.000 description 7
239000000843 powder Substances 0.000 description 7
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 7
125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 6
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
239000003054 catalyst Substances 0.000 description 6
125000004663 dialkyl amino group Chemical group 0.000 description 6
230000000694 effects Effects 0.000 description 6
239000010410 layer Substances 0.000 description 6
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
238000010561 standard procedure Methods 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
150000003573 thiols Chemical class 0.000 description 6
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
239000011260 aqueous acid Substances 0.000 description 5
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
125000002837 carbocyclic group Chemical group 0.000 description 5
150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
239000007822 coupling agent Substances 0.000 description 5
238000005859 coupling reaction Methods 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
239000012458 free base Substances 0.000 description 5
239000008187 granular material Substances 0.000 description 5
150000004820 halides Chemical class 0.000 description 5
150000004678 hydrides Chemical class 0.000 description 5
238000011068 loading method Methods 0.000 description 5
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
230000003389 potentiating effect Effects 0.000 description 5
239000011541 reaction mixture Substances 0.000 description 5
230000002829 reductive effect Effects 0.000 description 5
239000000725 suspension Substances 0.000 description 5
QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
WGNUNYPERJMVRM-UHFFFAOYSA-N 3-pyridylacetic acid Chemical compound OC(=O)CC1=CC=CN=C1 WGNUNYPERJMVRM-UHFFFAOYSA-N 0.000 description 4
229960000549 4-dimethylaminophenol Drugs 0.000 description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
239000007821 HATU Substances 0.000 description 4
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
229940034982 antineoplastic agent Drugs 0.000 description 4
239000001110 calcium chloride Substances 0.000 description 4
235000011148 calcium chloride Nutrition 0.000 description 4
229910001628 calcium chloride Inorganic materials 0.000 description 4
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 4
125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
125000001041 indolyl group Chemical group 0.000 description 4
239000012442 inert solvent Substances 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
230000009467 reduction Effects 0.000 description 4
238000002821 scintillation proximity assay Methods 0.000 description 4
235000011149 sulphuric acid Nutrition 0.000 description 4
230000001131 transforming effect Effects 0.000 description 4
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
230000004614 tumor growth Effects 0.000 description 4
BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
102000004190 Enzymes Human genes 0.000 description 3
108090000790 Enzymes Proteins 0.000 description 3
229910004373 HOAc Inorganic materials 0.000 description 3
238000005481 NMR spectroscopy Methods 0.000 description 3
ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 3
125000003277 amino group Chemical group 0.000 description 3
239000012131 assay buffer Substances 0.000 description 3
239000011324 bead Substances 0.000 description 3
WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
239000002775 capsule Substances 0.000 description 3
230000008878 coupling Effects 0.000 description 3
238000010168 coupling process Methods 0.000 description 3
BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 3
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
239000002552 dosage form Substances 0.000 description 3
239000000839 emulsion Substances 0.000 description 3
208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 3
229950007593 homonicotinic acid Drugs 0.000 description 3
125000002883 imidazolyl group Chemical group 0.000 description 3
150000002466 imines Chemical class 0.000 description 3
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
NIZHERJWXFHGGU-UHFFFAOYSA-N isocyanato(trimethyl)silane Chemical compound C[Si](C)(C)N=C=O NIZHERJWXFHGGU-UHFFFAOYSA-N 0.000 description 3
235000019341 magnesium sulphate Nutrition 0.000 description 3
238000004949 mass spectrometry Methods 0.000 description 3
230000004048 modification Effects 0.000 description 3
238000012986 modification Methods 0.000 description 3
125000001624 naphthyl group Chemical group 0.000 description 3
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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
- C07D401/02—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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems

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Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
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Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

IL11779896A 1995-04-07 1996-04-02 Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them IL117798A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US41832395A	1995-04-07	1995-04-07

Publications (2)

Publication Number	Publication Date
IL117798A0 IL117798A0 (en)	1996-08-04
IL117798A true IL117798A (en)	2001-11-25

Family

ID=23657636

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL11779896A IL117798A (en)	1995-04-07	1996-04-02	Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them

Country Status (20)

Country	Link
EP (1)	EP0819121B1 (de)
JP (1)	JP3038017B2 (de)
KR (1)	KR100329877B1 (de)
AR (1)	AR003116A1 (de)
AT (1)	ATE363472T1 (de)
AU (1)	AU719990B2 (de)
BR (1)	BR9604787A (de)
CA (1)	CA2217499C (de)
CZ (1)	CZ316597A3 (de)
DE (1)	DE69637105T2 (de)
ES (1)	ES2288302T3 (de)
HU (1)	HUP9800456A3 (de)
IL (1)	IL117798A (de)
MX (1)	MX9707665A (de)
NO (1)	NO314082B1 (de)
NZ (1)	NZ306665A (de)
PL (1)	PL322689A1 (de)
SK (1)	SK135597A3 (de)
TW (1)	TW462968B (de)
WO (1)	WO1996031478A1 (de)

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1996
- 1996-04-02 IL IL11779896A patent/IL117798A/en not_active IP Right Cessation
- 1996-04-03 BR BR9604787A patent/BR9604787A/pt not_active Application Discontinuation
- 1996-04-03 NZ NZ306665A patent/NZ306665A/xx unknown
- 1996-04-03 PL PL96322689A patent/PL322689A1/xx unknown
- 1996-04-03 CZ CZ973165A patent/CZ316597A3/cs unknown
- 1996-04-03 AU AU55279/96A patent/AU719990B2/en not_active Ceased
- 1996-04-03 EP EP96912469A patent/EP0819121B1/de not_active Expired - Lifetime
- 1996-04-03 CA CA002217499A patent/CA2217499C/en not_active Expired - Fee Related
- 1996-04-03 HU HU9800456A patent/HUP9800456A3/hu unknown
- 1996-04-03 DE DE69637105T patent/DE69637105T2/de not_active Expired - Lifetime
- 1996-04-03 KR KR1019970707063A patent/KR100329877B1/ko not_active Expired - Fee Related
- 1996-04-03 ES ES96912469T patent/ES2288302T3/es not_active Expired - Lifetime
- 1996-04-03 JP JP08530364A patent/JP3038017B2/ja not_active Expired - Fee Related
- 1996-04-03 AT AT96912469T patent/ATE363472T1/de not_active IP Right Cessation
- 1996-04-03 AR ARP960102084A patent/AR003116A1/es not_active Application Discontinuation
- 1996-04-03 MX MX9707665A patent/MX9707665A/es not_active IP Right Cessation
- 1996-04-03 SK SK1355-97A patent/SK135597A3/sk unknown
- 1996-04-03 WO PCT/US1996/004172 patent/WO1996031478A1/en not_active Ceased
- 1996-04-05 TW TW085103970A patent/TW462968B/zh not_active IP Right Cessation
1997
- 1997-10-06 NO NO19974610A patent/NO314082B1/no not_active IP Right Cessation

Also Published As

Publication number	Publication date
ES2288302T3 (es)	2008-01-01
AR003116A1 (es)	1998-07-08
JPH10511981A (ja)	1998-11-17
HUP9800456A2 (hu)	1999-06-28
DE69637105D1 (de)	2007-07-12
BR9604787A (pt)	1998-07-07
NO974610L (no)	1997-12-08
CZ316597A3 (cs)	1998-03-18
DE69637105T2 (de)	2008-04-24
NZ306665A (en)	2000-01-28
NO314082B1 (no)	2003-01-27
EP0819121A1 (de)	1998-01-21
ATE363472T1 (de)	2007-06-15
WO1996031478A1 (en)	1996-10-10
CA2217499C (en)	2004-03-30
HUP9800456A3 (en)	2000-04-28
AU719990B2 (en)	2000-05-18
NO974610D0 (no)	1997-10-06
JP3038017B2 (ja)	2000-05-08
KR100329877B1 (ko)	2002-08-28
MX9707665A (es)	1997-11-29
CA2217499A1 (en)	1996-10-10
AU5527996A (en)	1996-10-23
IL117798A0 (en)	1996-08-04
EP0819121B1 (de)	2007-05-30
TW462968B (en)	2001-11-11
SK135597A3 (en)	1998-07-08
PL322689A1 (en)	1998-02-16

Legal Events

Date	Code	Title	Description
2002-05-23	KB	Patent renewed
2006-12-27	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
IL117798A (en)	2001-11-25	Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them
US6214827B1 (en)	2001-04-10	Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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US5880128A (en)	1999-03-09	Carbonyl piperazinyl and piperidinyl compounds
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WO1996031505A1 (en)	1996-10-10	Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
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EP0989978A1 (de)	2000-04-05	Trizyklische keto amid derivative als farnesyl protein transferase inhibitoren
JP2002533336A (ja)	2002-10-08	三環式ファルネシルタンパク質トランスフェラーゼインヒビター
HK1002865A1 (en)	1998-09-25	Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
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WO1998057964A1 (en)	1998-12-23	Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
EP0989981A1 (de)	2000-04-05	Phenyl-substituierte trizyklische inhibitoren der farnesyl-protein transferase
MXPA97007232A (en)	1998-07-03	Triciaclic compounds of amida and urea, useful for inhibition of the function of protein g and for the treatment of proliferati diseases