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
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • 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

• the present invention relates to Hedgehog pathway antagonists and, more specifically, to novel 1,4-disubstituted phthalazines and therapeutic use thereof.
• the Hedgehog (Hh) signaling pathway plays an important role in embryonic pattern formation and adult tissue maintenance by directing cell differentiation and proliferation.
• the Hedgehog (Hh) protein family which includes Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh) are secreted glycoproteins that undergo post- translational modifications, including autocatalytic cleavage and coupling of cholesterol to the amino-terminal peptide to form the fragment that possesses signaling activity.
• Hh binds to the twelve-pass transmembrane protein Ptch (Ptchl and Ptch2), thereby alleviating Ptch-mediated suppression of Smoothened (Smo).
• Smo activation triggers a series of intracellular events culminating in the stabilization of the GIi transcription factors (GUI, GH2, and GH3) and the expression of Gli-dependent genes that are responsible for cell proliferation, cell survival, angiogenesis and invasion.
• GUI GIi transcription factors
• WO2009002469 discloses certain 1 ,4- disubstituted phthalazine compounds that are asserted to be a treatment option for all tumors driven by inappropriate hedgehog signaling. There still exists a need for potent hedgehog pathway inhibitors, particularly those having desirable toxicology profiles.
• the present invention provides novel 1,4- disubstituted phthalazines that are potent antagonists of this pathway. Particular compounds of the present invention provide desirable drug-drug interaction and related safety profiles with respect to reversible and/or mechanism-based irreversible CYP3A4 inhibition potential.
• X-18698 discloses certain 1 ,4- disubstituted phthalazine compounds that are asserted to be a treatment option for all tumors driven by inappropriate hedgehog signaling.
• potent hedgehog pathway inhibitors particularly those having desirable toxicology profiles.
• the present invention provides novel 1,4- disubstituted phthalazines that are potent antagonists of this pathway.
• Particular compounds of the present invention provide desirable drug
• the present invention provides a compound of Formula I
• R 1 is hydrogen or methyl
• R 2 is hydrogen or methyl
• R 3 ' R 4 , R 5 , R 6 , or R 7 are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that at least three of R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen; or a pharmaceutically acceptable salt thereof.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, carrier or diluent.
• the present invention also provides a method of treating cancer selected from the group consisting of brain cancer, basal cell carcinoma, esophagus cancer, stomach cancer, gastric cancer, pancreatic cancer, biliary tract cancer, prostate cancer, breast cancer, small-cell lung cancer, non-small cell lung cancer, B-cell lymphoma, multiple myeloma, ovarian cancer, colorectal cancer, liver cancer, kidney cancer, melanoma, head and neck cancer, mesothelioma, soft tissue sarcomas, bone sarcomas, leukemia, and testicular cancer in a mammal comprising administering to the mammal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• cancer selected from the group consisting of brain cancer, basal cell carcinoma, esophagus cancer, stomach cancer, gastric cancer, pancreatic cancer, biliary tract cancer, prostate cancer, breast cancer, small-cell lung cancer, non-small cell lung cancer, B-cell lymph
• R 1 is methyl
• R 2 is methyl
• R 3 , R 4 , R 5 , R 6 , or R 7 are independently hydrogen, fluoro, chloro, trifluoromethyl, or methylsulfonyl; (d) R 3 , R 4 , R 5 , R 6 , or R 7 are independently hydrogen, fluoro, or trifluoromethyl;
• R 3 , R 4 , R 5 , R 6 and R 7 are independently fluoro, chloro, trifluoromethyl, or methylsulfonyl, provided that R 3 and R 7 are not simultaneously hydrogen;
• R 4 , R 6 and R 7 are hydrogen
• R 3 and R 5 are independently fluoro, chloro, trifluoromethyl, or methylsulfonyl; and R 4 , R 6 and R 7 are hydrogen;
• R 3 and R 5 are independently fluoro or trifluoromethyl; and R 4 , R 6 and R 7 are hydrogen;
• R 1 is methyl; R 2 is methyl; and R 4 , R 6 and R 7 are hydrogen;
• R 1 is methyl; R 2 is methyl; R 3 and R 5 are independently fluoro, chloro, trifluoromethyl, or methylsulfonyl; and R 4 , R 6 and R 7 are hydrogen; and
• R 1 is methyl; R 2 is methyl; R 3 and R 5 are independently fluoro or trifluoromethyl; and R 4 , R 6 and R 7 are hydrogen.
• a "pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.
• “Pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic salts of compounds of the present invention.
• treatment are meant to include slowing or reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated and even if progression of the disorder or condition is not itself slowed or reversed.
• a methylsulfonyl substituent is equivalent to CH 3 -SO 2 -.
• the compounds of the present invention are capable of reaction, for example, with a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
• pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al, HANDBOOK OF
• PHARMACEUTICAL SALTS PROPERTIES, SELECTION AND USE, (VCHA/Wiley- VCH, 2002); S.M. Berge, et ah, "Pharmaceutical Salts, " Journal of Pharmaceutical Sciences, VoI 66, No. 1, January 1977.
• the compounds of the present invention are preferably formulated as pharmaceutical compositions using a pharmaceutically acceptable carrier, diluent, or excipient and administered by a variety of routes.
• a pharmaceutically acceptable carrier diluent, or excipient
• Such compositions are for oral or intravenous administration.
• Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19 th ed., Mack Publishing Co., 1995).
• REMINGTON THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19 th ed., Mack Publishing Co., 1995).
• X-18698 are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro,
• the compound actually administered will be determined by a physician under the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. Dosages per day normally fall within the range of about 0.1 to about 10 mg/kg of body weight. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed.
• the compounds of Formula I, or salts thereof may be prepared by a variety of procedures known in the art, as well as those described in the Scheme, Preparations, and Examples below.
• the specific synthetic steps for each of the routes described may be combined in different ways to prepare compounds of Formula I, or pharmaceutically acceptable salts thereof.
• Et 2 ⁇ refers to diethyl ether
• DMF dimethylformamide
• DMSO dimethylsulfoxide
• DMAC NN-dimethylacetamide
• NMP N-methylpyrrolidine
• MeOH refers to methanol
• boc or “t-boc” refers to ter?-butoxycarbonyl
• IC50 refers to the concentration of an agent that produces 50% of the maximal inhibitory response possible for that agent.
• a compound of Formula I can be prepared in accordance with reactions as depicted in the Scheme.
• the reaction proceeds in a dipolar aprotic solvent such as DMF, DMAC, or NMP, in the presence of an organic or inorganic base.
• the reaction takes place in NMP, in the presence of potassium carbonate, at a temperature of 50 - 140 0 C.
• a halo piperidyl phthalazine of formula (3) undergoes a Suzuki cross- coupling reaction with a pyrazole boronic ester or acid (4).
• a halo piperidyl phthalazine (3) is combined with 1 -methyl- lH-pyrazole-5 -boronic acid pinacol ester in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium and X-18698
• reaction proceeds in a solvent mixture of toluene/ethanol/water to give the pyrazolyl phthalazine of formula (5).
• Step 3 is a simple boc deprotection accomplished under acidic conditions such as
• Step 4 the aminopiperidinyl phthalazine of formula (6) is acylated to give the piperidinyl amide of Formula I.
• the amine is reacted with an appropriately substituted benzoyl chloride in an inert solvent, such as dichloromethane, in the presence of an organic base such as triethylamine or diisopropylethylamine.
• the amide is formed using an appropriately substituted benzoic acid.
• An active ester is formed using pentafluorophenyl diphenylphosphinate followed by reaction with the amine. The reaction proceeds in a solvent mixture of DMF/DMSO at a temperature of about - 10 to 100 0 C in the presence of an organic base, such as triethylamine or diisopropylethylamine.
• Hedgehog has been implicated as a survival factor for the following cancers: basal cell carcinoma; upper gastro intestinal tract cancers (esophagus, stomach, pancreas, and biliary tract); prostate cancer; breast cancer; small cell lung cancer; non-small cell lung cancer; B-cell lymphoma; multiple myeloma; gastric cancer; ovarian cancer; colorectal cancer; liver cancer; melanoma; head and neck cancer; mesothelioma; soft tissue sarcomas; bone sarcomas; leukemia; testicular cancer; kidney cancer; and brain cancer.
• Daoy cells are grown to confluency in tissue culture T225-flasks in Daoy growth media containing Minimum Essential Medium (MEM) plus 10% Fetal Bovine Serum (FBS) with 0.1 nM non-essential amino acids and 1 mM sodium pyruvate.
• MEM Minimum Essential Medium
• FBS Fetal Bovine Serum
• the cells are removed from the T225 -flasks using trypsin ethylenediaminetetraacetic acid (EDTA), centrifuged, resuspended in media, and then counted.
• EDTA trypsin ethylenediaminetetraacetic acid
• the compounds exemplified herein display an IC50 of ⁇ 40 nM.
• Example Ia The loss of activity for the compound of Example 1 a, ranges from 11 % - 22% and is not concentration dependent. Therefore, values for k inac t and Ki from equation 2 cannot be determined. Based on these data, the compound of Example Ia is not a mechanism based inhibitor of CYP3A4. Compounds, such as Example Ia, that demonstrate low or no mechanism-based irreversible CYP3A4 inhibition potential have a reduced likelihood for negative interactions with other medications that could result in medication dosage changes or a need to stop medication in a patient. Thus, such compounds are desirable and have improved safety profiles.

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• Health & Medical Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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