Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel thiourea and isothiourea derivatives or pharmaceutically acceptable salts thereof which possess excellent activity for inhibiting ras-transformed cell growth, to processes for the preparation thereof, and to a pharmaceutical composition for the inhibition of ras-transformed cell growth comprising the same as an active ingredient.
• a ras protein is farnesylated or geranylgeranylated by famesyltransferases [farnesyl protein transferase (hereinafter referred to as "FPTase”) or geranylgeranyl protein transferase (hereinafter referred to as "GGPTase”), respectively], and then, translocated into an intracelluar membrane, in which the ras protein is activated by GTP or inactivated by GDP.
• the activated, GTP -bound ras protein triggers the stepwise transmission of the outside signal into nucleus, which, in turn, activates translational factors of cells such as myc, jun and fos, thereby leading to cell growth or nucleus division, (see M. Barbacid, Annu. Rev. Biochem., 56, 779, 1987, P J. Casey et al., Natl. Acad. Sci. U.S.A. 86, 8323, 1989).
• a transformed ras protein variant such as H-Ras, N-Ras, K-RasA and K-RasB derived from mutated ras genes
• the mutated ras genes are found in various cancer cases, e.g., colon cancer (about 50%), pancreas cancer (about 90%), lung cancer (about 50%), and thyroid gland cancer (about 30%) (see S. Rodenhuis, Semin. Cancer Biol. 3, 241, 1992).
• a number of researches have attempted to develop inhibitors of ras protein variants, focusing mostly on FPTase inhibitors which inhibit the translocation of ras proteins into an intracellular membrane.
• Cys-Val-Phe-Met a sequence similar to the C-terminal sequence of ras protein(Cys-Al-A2-Met), has been reported (see J. L. Goldstein et al., J. Biol. Chem., 266, 15575, 1991; A. M. Garcia et al., J. Biol. Chem., 268, 18415, 1993; S. L. Graham et al., J. Med. Chem., 37, 725, 1994).
• W09639173 discloses that compounds containing p-cyanobenzyl- imidazolacetate in place of cysteine and N-naphthylmethyl in place of phenylalanine, respectively, in the structure of Cys-Ile-Phe-Met, have FPTase inhibitory activity.
• FPTase inhibitors can not effectively inhibit the geranylgeranylation of the K-ras protein, i.e., the most frequently found ras-protein variant in human cancer. Therefore, FPTase inhibitors fail to inhibit the prenylation of the K-ras protein in cells (see G. L. James et al, J. Biol. Chem. 270, 6221, 1995).
• the present inventors have endeavored to develop ras-transformed cell growth inhibitors which is capable of blocking the prenylation of the K-ras protein more effectively; and have discovered that novel thiourea or isothiourea derivatives exhibit excellent activity for inhibiting K-ras prenylation as well as ras-transformed cell (per se) growth.
• R 1 is C ⁇ -4 alkyl, or benzyl optionally having one or more ring substituents selected from the group consisting of cyano, nitro and methylenedioxy;
• R 2 is C ⁇ -5 alkyl, C 2-5 alkenyl; C 5-7 cycloalkylmethyl; C ⁇ -3 alkylphenyl; a ring containing group selected from the group consisting of benzyl, ⁇
• R 3 is Ci.io alkyl; C 2-5 alkenyl; C 3-8 cycloalkyl; adamantyl; C 1-5 -alkoxy-C 1-5 -alkyl; mono- or di- C 1-5 -alkylamino-C 1-5 -alkyl; C ⁇ -5 alkoxylcarbonyl; phenyl-C 1-5 -alkyl; tetrahydrofuranyl-C ⁇ -5 -alkyl; a nitrogen-containing heterocycle group selected from the group consisting of pyridyl, pyrimidyl, piperidyl, piperazyl, morphorinyl, and morphorinyl-C ⁇ -5 -alkyl, each heterocyclo being optionally substituted with C[.
• R 4 is hydrogen or C[ -4 alkyl
• R 5 is phenyl optionally having one or more substituents selected from the group consisting of halogen, C ⁇ -5 alkyl, C 1 . 5 alkoxy, and trifluoromethyl; benzyl; or pyridyl optionally substituted with hydroxy or methoxy; and
• R 6 is C 1-10 alkyl, C 2-5 alkenyl, or benzyl with one or more optional ring substituents selected from the group consisting of C ⁇ _ 5 alkoxy, cyano and nitro. It is another object of the present invention to provide processes for preparing the compound of formula (I).
• the pharmaceutically acceptable salt of the thiourea or isothiourea derivative of the present invention is a non-toxic salt generated from an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, or an organic acid e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, hydroxymalic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid.
• an inorganic acid e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and
• R 1 is benzyl optionally substituted with cyano, nitro or methylenedioxy
• R 2 is benzyl optionally substituted with halogen, C ⁇ -5 alkyl or trifluoromethyl
• R 3 is C ⁇ -3 alkoxypyridyl
• R 6 is . 10 alkyl.
• the present invention also provides processes for preparing thiourea and isothiourea derivatives of formula(I).
• the compound of formula(I) wherein B is " may be prepared by the process which comprises reacting a compound of formula (XXXII) with a compound of formula (XXXIII) or (XXXIV) :
• R 5 -N . ,S-R° compound of formula(I) wherein B is ⁇ may be prepared by the process which comprises reacting a compound of formula (If) with a compound of formula (XXXV):
• Tr-N Tr-N OMs Tr-N
• Step 1 Amine protection The compound of formula(II) is reacted with N-ethoxycarbonyl phthalimide to give the compound of formula(III) to protect the primary amine group.
• the organic solvent may be selected from dichloromethane, dimethylformamide, acetonitrile, methanol, ethyl acetate or a mixture thereof. To facilitate the reaction, the reaction mixture can be heated.
• the compounds of formula(IX) and (XX) are each reacted with hydrogen in the presence of a catalyst(e.g.: palladium and rhodium) to give the compounds of formula(X) and (XXI), respectively.
• a catalyst e.g.: palladium and rhodium
• the preferred solvent for this reaction is dimethylformamide, ethanol or ethyl acetate.
• the compound of formula(XII) is reacted with methanesulfonyl chloride in the presence of an organic bases, to give the compound of formula(XIII).
• the compound of formula(XIII) is reacted with sodium azide in dimethylformamide or hexamethylphosphoramide to give the compound of formula(XIV).
• a compound of formula(XV) is reacted with an aldehyde capable of providing R 2 moiety in the presence of triphenylphosphine and sodium borohydride or other conventional reducing agent to give the compound of formula(XVI).
• the compound of formula(XVIII) or a compound of formula(XXVII) is reacted with pyridine-sulfur trioxide complex or other conventional oxidizing agent to give the compound of formula(XIX) or a compound of formula(XXVIII), respectively.
• Step 14 Olefination The compound of formula(XIX) is reacted with a ylide prepared from the reaction of 3-halophthalimide with triphenylphosphine in the presence of a base such as potassium t-butoxide, to give the compound of form ⁇ la(XX).
• Step 16 Hydrolysis A compound of formula(XXVI) is hydrolyzed in water, or in a mixture of tetrahydrofuran and water in the presence of an alkali or acid condition to give a compound of formula(XXVII).
• Step 17 Amide formation A compound of formula(XXX) is reacted with an amine R 2 -NH 2 in the presence of an appropriate coupling agent to give a compound of formula(XXXI).
• the coupling agent may be hydroxybenzotriazole or dialkylcarbodiimidate.
• a suitable solvent may be dimethylformamide, dichloromethane or a mixture thereof.
• a suitable solvents for this reaction is dimethylformamide, dimethylsulfoxide or hexamethylphosphoamide.
• a compound of formula(If) may be reacted with R 6 -X (X is halogen) in dichloromethane, methanol, ethanol, acetonitrile, acetone or dimethylformamide, optionally in the presence of a base such as sodium hydroxide, potassium carbonate or triethylamine, to give a compound of formula(Ig).
• non-toxic pharmaceutically acceptable salts of the compound(I) may be prepared according to conventional methods known per se in the art, by reacting the compound in an appropriate solvent with a stoichiometric or excess amount of an inorganic or organic acid.
• the present invention also includes within its scope a pharmaceutical composition for the inhibition of ras-transformed cell growth comprising a therapeutically effective amount of the novel compounds of formula(I), as defined above, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
• composition of the present invention may include additives such as lactose or com starch, lubricant such as magnesium stearate, or conventional emulsifier, suspending agent, stabilizer, isotonic agent. If necessary, sweetener and/or flavoring agent may be added.
• additives such as lactose or com starch, lubricant such as magnesium stearate, or conventional emulsifier, suspending agent, stabilizer, isotonic agent. If necessary, sweetener and/or flavoring agent may be added.
• composition of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions.
• carriers such as lactose, com starch, and lubricating agents, e.g. magnesium stearate, are commonly added.
• lactose and/or dried com starch can be used as a diluent.
• the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweeteners and/or flavoring agents may be added.
• composition of the present invention may be in the form of aqueous solution containing pharmaceutically acceptable carriers, e.g., saline, at a pH level of 7.4.
• pharmaceutically acceptable carriers e.g., saline
• the compounds of the present invention may be administered in an effective amount ranging from about 0.1 mg/kg to about 20mg/kg, preferably from about 0.5mg/kg to about lOmg/kg, per day into a subject patient suffered from various cancers, e.g., colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
• the dosage may be changed according to patient's age, weight, susceptibility, or symptom.
• Example 130-131 N- ⁇ 2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] ⁇ ethyl-( 1 -methyl- 1 H-indol -3 -yl)methy lamine prepared from Preparation Example 13 was reacted with the corresponding isothiocyanates under the same condition as described in Example 129 to give the title compounds.

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• Chemical & Material Sciences (AREA)
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Citations (2)

• 1999
  • 1999-07-30 KR KR1019990031188A patent/KR20010011698A/ko unknown
• 2000
  • 2000-07-31 CA CA002380371A patent/CA2380371A1/en not_active Abandoned
  • 2000-07-31 AU AU61867/00A patent/AU765433B2/en not_active Ceased
  • 2000-07-31 EP EP00948382A patent/EP1200430A4/de not_active Withdrawn
  • 2000-07-31 WO PCT/KR2000/000832 patent/WO2001009128A1/en active IP Right Grant
  • 2000-07-31 JP JP2001514331A patent/JP2003506372A/ja active Pending
  • 2000-07-31 KR KR1020027001065A patent/KR100683418B1/ko not_active IP Right Cessation
  • 2000-07-31 CN CN00813419A patent/CN1376155A/zh active Pending

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