Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed 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
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to novel pyrrolotriazine compounds that are useful as anti-cancer agents. This invention also relates to a method of using the compounds in the treatment of proliferative diseases and to pharmaceutical compositions containing the compounds.
• Tropomysosin Related Kinases are a family of receptor tyrosine kinases composed of three family members, TrkA, TrkB and TrkC. The Trks bind with high affinity to, and mediate the signal transduction induced by the Neurotrophin family of ligands whose prototype members are Nerve Growth Factor (NGF), Brain- Derived Neurotrophic Factor (BDNF) and Neurotrophin-3, -4 and -5 (NT-3, NT-4 and NT-5).
• NGF Nerve Growth Factor
• BDNF Brain- Derived Neurotrophic Factor
• NT-3, NT-4 and NT-5 Neurotrophin-3, -4 and -5
• TrkA-NGF interaction was shown as a requirement for the survival of certain peripheral neuron populations involved in mediating pain signaling.
• Trk signaling the subversion of this receptor and its signaling pathway in certain malignancies has also been documented.
• TrkA receptor kinase are implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adrenocarcinoma and activating chromosomal rearrangements of Trks in acute myelogenous leukemia (AML), thyroid and breast cancers and receptor point mutations predicted to be constitutively activating in colon tumors.
• AML acute myelogenous leukemia
• Trk receptor and ligand have also been reported in a variety of tumor types including multiple myeloma, melanoma, neuroblastoma, ovarian and pancreatic carcinoma.
• the neurotrophins and their corresponding Trk receptor subtypes have been shown to exert a variety of pleiotropic responses on malignant cells, including enhanced tumor invasiveness and chemotaxis, activation of apoptosis, stimulation of clonal growth, and altered cell morphology. These effects have been observed in carcinomas of the prostate, breast, thyroid, colon, malignant melanomas, lung ⁇ carcinomas, glioblastomas, pancreatic carcinoids and a wide variety of pediatric and neuroectodermal-derived tumors including WiIm' s tumor, neuroblastomas and medulloblastomas.
• Trks Receptor tyrosine kinases
• transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain.
• RTKs are activated by ligand-induced oligomerization and tyrosine autophosphorylation of specific intracellular substrates such as PLCj ⁇ PD kinase, ras, and raf./MEK/Erkl .
• Tyrosine kinase activity is an absolute requirement for signal transduction through this class of receptor.
• Trk family of RTKs is frequently expressed in lung, breast, pancreatic and prostate cancers as well as in certain type of acute myelogenous leukemia and congenital fibrosarcoma.
• the tyrosine kinase activity of Trk is believed to promote the unregulated activation of cell proliferation machinery.
• TrkA, TrkB, or TrkC kinases individually or in combination, have utility against some of the most common cancers such as brain, melanoma, multiple myeloma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung, renal, ovarian, gynecological, thyroid cancer, and certain type of hematological malignancies.
• Y is C3-C8 cycloalkyl, C 6 -C 1O aryl, a 5 to 13 membered heteroaromatic ring, C3-C 8 alkyl or a 4 to 8 membered heteroalkyl ring, each of said Y groups optionally substituted with 1 to 3 groups selected from the group consisting of halogen, -OH, alkyl, substituted alkyl, -CN, -NH 2 , -CONHR 3 , -OCONHR ⁇ -CONHSOaR 3 , -NHCONHR 3 .
• substituted alkyl -CN, -NHR 7 , -CONHR 7 , -OCONHR 7 , -CONHSO 2 R 7 , -NHCONHR 7 , -CH 2 OR 7 , -CH 2 CH 2 OH, alkoxy, substituted alkoxy, aryl, substituted aryl,
• R 7 is hydrogen or C 1 -C4 alkyl; C 3 -Cg cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, aryloxy, substituted aryloxy, -CF 3 and -OCF 3 ,two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable;
• R 8 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl. an optionally substituted aryl or heteroaryl group; said substituents on the substituted aryl or substituted heteroaryl group are selected from the group consisting of one or more hydrogen, halogen, alkyl, substituted alkyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy and substituted aryloxy;
• R 9 is hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 6 alkoxy; or
• R 8 and R 9 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt or stereoisomer thereof.
• the invention comprises a compound of formula II wherein wherein
• W is -CR 9 - or -N-;
• R 1 is H, Ci-C 6 alkyl, arylalkyl, C 3 -C 8 cycloalkyl, C 9 -C 14 bicycloalkyl,
• R 7 is hydrogen or Cj -C 4 alkyl; C 3 -C 6 cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, aryloxy, substituted aryloxy, -CF 3 and -OCF 31 TWO of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable;
• R 8 is Cj-C 6 alkyl, C 3 -C 6 cycloalkyl, an optionally substituted aryl or heteroaryl group; said substituents on the substituted aryl or substituted heteroaryl group are selected from the group consisting of one or more hydrogen, halogen, alkyl, substituted alkyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy and substituted aryloxy; R 9 is hydrogen, halogen, Cj-Ce alkyl, C 3 -C6 cycloalkyl or Ci-C 6 alkoxy; or R 8 and R 9 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt or stereoisomer thereof.
• the invention comprises a compound of formula m
• R 7 is hydrogen or C1-C4 alkyl; C 3 -C 6 cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, aryloxy, substituted aryloxy, -CF 3 and -OCF 3 , two of which may be attached to the same ring carbon atom provided that the resultant compound is chemically stable; or a pharmaceutically acceptable salt or stereoisomer thereof.
• Preferred compounds of the invention include the following l-(5- ⁇ [4-amino-7-(l-methylethyl)pyrrolo[2,l-fJ[l,2,4]tria2in-5-yl]carbonyl ⁇ -3- pyridinyl)-3-(2,4-dichlorophenyl)urea; 1 -(3- ⁇ [4-amino-7-( 1 -methylethyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-5- yl]carbonyl ⁇ phenyl)-3-[3-(l,l-dimethylethyl)-l-methyl-lH-pyrazol-5-yl]urea; lK5- ⁇ [4-ammo-7-(l-methylethyl)pyiTolo[2,l-fl[l 5 2,4]tria2;in-5-yl]carbonyl ⁇ -3- pyridinyl)-3-(
• alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
• lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
• substituted alkyl refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylsulfon
• halogen refers to fluorine, chlorine, bromine and iodine.
• aryl refers to monocyclic or b ⁇ cyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
• arylalkyl refers to an aryl or a substituted aryl group bonded directly through an alkyl group, such as benzyl.
• aryloxy refers to an aryl or a substituted aryl group bonded directly through an alkoxy group, such as methoxy or ethoxy.
• substituted aryl refers to an aryl group substituted by, for example, one to four substituents such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carb
• the substituent may be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or arylalkyl.
• heteroaryl refers to an optionally substituted, aromatic group for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom and at least one carbon atom-containing ring, for example, pyridine, tetrazole, indazole.
• alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
• substituted alkenyl refers to an alkenyl group substituted by, for example, one to two substituents, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, ⁇ ndolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
• alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably
• substituted alkynyl refers to an alkynyl group substituted by, for example, a substituent, such as, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl. sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclyl, e.g.
• cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 -C 7 carbocylic ring.
• Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl.
• Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
• heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
• the heterocyclic group may be attached at any heteroatom or carbon atom.
• Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl.
• Exemplary bicyclic heterocyclic groups include 2,3-dihydro-2-oxo-lH- indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyfj or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3.4-di
• phthalazinyl piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
• substituents include one or more alkyl or arylalkyl groups as described above or one or more groups described above as alkyl substituents.
• smaller heterocyclyls such as, epoxides and aziridines.
• carbocyclic ring or “carbocyclyl” refers to stable, saturated, partially saturated or unsaturated, mono or bicyclic hydrocarbon rings that contain 3- 12 atoms. Particularly, this includes a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
• Suitable values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dihydroindenyl and tetrahydronaphthyl.
• the term "optionally substituted” as it refers to "carbocyclic ring" or “carbocyclyl” herein indicates that the carbocyclic ring may be substituted at one or more substitutable ring positions by one or more groups independently selected from alkyl (preferably lower alkyl), alkoxy (preferably lower alkoxy), nitro, monoalkylamino (preferably a lower alkylamino), dialkylamino (preferably a di[lower]alkylamino), cyano, halo, haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido (preferably lower alkyl amido), al
• heteroatoms shall include oxygen, sulfur and nitrogen.
• the compounds of formula I may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention.
• the compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be formed as known to those skilled in the art.
• the compounds for formula I may form salts with a variety of organic and inorganic acids.
• Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like).
• Such salts can be formed as known to those skilled in the art.
• zwitterions in addition, zwitterions (“inner salts”) may be formed.
• All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
• the definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity.
• the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
• the individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
• Compounds of formula I may also have prodrug forms.
• prodrug any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug within the scope and spirit of the invention.
• Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 112, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krosgaard- Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H.
• solvates e.g., hydrates
• Methods of solvation are generally known in the art.
• the invention is based on the discovery that certain pyrrolotriazines are inhibitors of protein kinases. More specifically, pyrrolotriazines such as those described in this invention inhibit the protein tyrosine kinase activity of members of the TRK family of receptors. These inhibitors will be useful in the treatment of proliferative diseases that are dependent on signaling by one or more of these receptors. Such diseases include solid tumors of the pancreatic, prostate, lung, head and neck, breast, colon, ovary, as well as other tumor types including multiple myeloma, melanoma, neuroblastoma, gliobalstoma and acute myelogenous leukemia.
• the invention relates to a pharmaceutical composition of compound of formula I 5 or pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier in the treatment of hyperproliferative disorder in mammal.
• said pharmaceutical composition is expected to inhibit the growth and/or metastasis of those primary and recurrent solid tumors which are associated with TrkA, TrkB, TrkC, Flt-3 (Fms-like kinase-3) and Tie-2, especially those tumors which are significantly dependent on TrkA, TrkB, TrkC, Flt-3, Tie-2 for their growth and spread, including for example, cancers of the thyroid, breast, colon, pancreas, or a variety of tumor types including multiple myeloma, melanoma, neuroblastoma and glioblastoma.
• a compound of the formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an antiproliferative effect in a warm-blooded animal such as a human being.
• a method for producing an antiproliferative effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined herein before.
• TrkA, TrkB, Trk C 5 Flt-3 and Tie-2 kinases By virtue of their ability to inhibit TrkA, TrkB, Trk C 5 Flt-3 and Tie-2 kinases, compounds of the invention can be used for the treatment of proliferative diseases, including cancer.
• the TrkA, TrkB and TrkC receptor kinases have been shown to be expressed and activated in tumors including thyroid, breast, colon, and elevated Trk receptors and corresponding ligands have also been reported in a variety of tumor types including multiple myeloma, melanoma, pancreatic carcinoma, neuroblastoma and glioblastoma.
• TrkA, TrkB and TrkC kinases will have efficacy in the treatment of tumors that depend on signaling from either or both of the two receptors. These compounds are expected to have efficacy either as single agent or in combination (simultaneous or sequentially) with other chemotherapeutic agents such as Taxol ® , adriamycin, and cisplatin.
• chemotherapeutic agents such as Taxol ® , adriamycin, and cisplatin.
• the antiproliferative treatment defined herein before may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
• the compounds of this invention may also be useful in combination with known anti-cancer and cytotoxic agents and treatments, including radiation. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within its approved dosage range. Compounds of formula I may be used sequentially with known anticancer or cytotoxic agents and treatment, including radiation when a combination formulation is inappropriate.
• anti-cancer agent includes any known agent that is useful for the treatment of cancer including the following: 17 ⁇ -ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesteroneacetate, leuprolide, flutamide, toremifene, Zoladex; matrix metalloproteinase inhibitors; VEGF inhibitors, such as anti-VEGF antibodies (Avastin ) and small molecules such as ZD6474 and SU6668; Vatalanib, BAY-43-9006, SUl 1248, CP-547632, and CEP-7055; HER
• Gleevec and Sprycel (dasatinib); Casodex ® (bicalutamide, Astra Zeneca), Tamoxifen; MEK-I kinase inhibitors, MAPK kinase inhibitors, PI3 kinase inhibitors; PDGF inhibitors, such as imatinib; anti-angiogenic and antivascular agents which, by interrupting blood flow to solid tumors, render cancer cells quiescent by depriving them of nutrition; castration, which renders androgen dependent carcinomas nonproliferative; inhibitors of non-receptor and receptor tyrosine kinases; inhibitors of integrin signaling; tubulin acting agents such as vinblastine, vincristine, vinorelbine, vinflunine, paclitaxel , docetaxel, 7-O-methylthiomethylpaclitaxel, 4-desacetyl-4- methylcarbonatepaclitaxel, 3'-?err-butyl-3'-N-ter
• 6- thioguanine and 6-mercaptopurine glutamine antagonists, e.g. DON (AT-125; d-oxo- norleucine); ribonucleotide reductase inhibitors; mTOR inhibitors; and haematopoietic growth factors.
• Additional cytotoxic agents include, cyclophosphamide, doxorubicin, daunorubicin, mitoxanthrone, melphalan, hexamethyl melamine, thiotepa, cytarabin. idatrexate, trimetrexate, dacarbazine, L-asparaginase, bicalutamide, leuprolide, pyridobenzoindole derivatives, interferons, and interleukins. [0045] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer.
• the other component(s) of such treatment in addition to the antiproliferative treatment defined herein before may be surgery, radiotherapy or chemotherapy.
• chemotherapy may cover three main categories of therapeutic agent: (i) antiangiogenic agents that work by different mechanisms from those defined hereinbefore (for example, linomide, inhibitors of integrin ⁇ v ⁇ 3 function, angiostatin, razoxane);
• cytostatic agents such as antiestrogens (for example, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), progestogens (for example, megestrol acetate), aromatase inhibitors (for example, anastrozole, letrozole, borazole, exemestane), antihormones, antiprogestogens, antiandrogens (for example, flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example, gosereline acetate, leuprolide), inhibitors of testosterone 5 ⁇ -dihydroreductase (for example, finasteride), farnesyltransferase inhibitors, anti-invasion agents (for example, metalloproteinase inhibitors such as marimastat and inhibitors of urokinase
• antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as antimetabolites (for example, antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); Intercalating antitumour antibiotics (for example, anthracyclines such as doxorubicin, daunomycin, epirubicin and idarabicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example, cisplatin, carboplatin); alkylating agents (for example, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide nitrosoureas, ttiiotepa; antimitotic agents (for example, vinca alkaloids like vincristine, vinorel
• antimetabolites
• the formula I compounds of the invention are of interest for their antiproliferative effects. Such compounds of the invention are expected to be useful in a wide range of disease states including cancer, psoriasis, and rheumatoid arthritis.
• the compounds of formula I are useful in the treatment of a variety of cancers, including (but not limited to) the following: — carcinoma, including that of the prostate, pancreatic ductal adreno- carcinoma, breast, colon, lung, ovary, pancreas, and thyroid; — tumors of the central and peripheral nervous system, including neuroblastoma, glioblastoma, and medullobalstomaf and
• tumors including melanoma and multiple myeloma.
• inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation and inflammatory bowel disease
• the compounds of formula I are especially useful in treatment of tumors having a high incidence of tyrosine kinase activity, such as prostate, colon, brain, thyroid and pancreatic tumors.
• tumors having a high incidence of tyrosine kinase activity such as prostate, colon, brain, thyroid and pancreatic tumors.
• Compounds of formula I may also be useful in the treatment of other cancerous diseases (such as acute myelogenous leukemia) that may be associated with signal transduction pathways operating through kinases such as Flt-3 (Fme-like kinase-3, including wild type or any mutant types such as Flt-3 (ITD)), Tie-2, CDK2, VEGFR, FGFR and IGFR kinases.
• kinases such as Flt-3 (Fme-like kinase-3, including wild type or any mutant types such as Flt-3 (ITD)
• Tie-2 CDK2
• VEGFR VEGFR
• FGFR FGFR
• IGFR kinases IGFR
• compositions of the present invention containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• the pharmaceutical compositions may be in the form of sterile injectable aqueous solutions.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
• the combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent or treatment within its approved dosage range.
• Compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of formula I may be administered either prior to or after administration of the known anticancer or cytotoxic agent(s).
• the compounds may be administered in a dosage range of about 0.05 to 200 mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2 to 4 divided doses.
• BIOLOGICAL ASSAYS TrkA The ability of compounds of the invention to inhibit tyrosine kinase activity of TrkA may be measured using a recombinant enzyme in an assay that measures the ability of compounds to inhibit the phosphorylation of the exogenous substrate, polyGluTyr (PGT 5 4:1).
• PTT 5 4:1 polyGluTyr
• the kinase domain of the human TrkA receptor is expressed in Sf9 insect cells as a histidine (His)-fusion protein using a baculovirus expression system.
• His histidine
• the protein is purified from the lysates of these cells using an Ni- NTA affinity column. After the recombinant enzyme is purified, it is activated by incubation with cold ATP.
• the enzyme assay is performed in a 96-well plate.
• Test compounds are first dissolved in dimethylsulfoxide (DMSO) and then serially-diluted in a 96-well plate.
• DMSO dimethylsulfoxide
• the serially-diluted compounds are transferred to the 96-well assay plate so that the final concentration of DMSO in the enzyme assay is 1.64%.
• All assay components are diluted in phosphorylation buffer (20mm MOPS, 1OmM MgCl 2 , ImM EDTA, 0.015% Brij-35, 0.1mg/ml BSA, 0.0025% Beta-Mercaptoethanol).
• the recombinant enzyme is added to the assay plate containing test compound and the reaction is initiated with a substrate solution containing a final concentration of 0.1 mg/ml PGT 5 3OuM ATP 3 and 0.008mCi/ml 33 P-gammaATP (3000Ci/mmol). After a 1 hour incubation at 30 0 C, the reaction is terminated with 10% TCA and incubated at 4 0 C for 1 hour. The reaction is filtered onto a Unifilter ® GF/CTM filter plate that has been presoaked with 0.1M NaPyrophosphate.
• Microscint-20 is then added to the dried filter plate and the captured 33 P-phosphorylated PGT is quantitated on a microscintillation plate counter (TopCount-NXTTM). Inhibition of the kinase enzymatic activity by the test compound is detected by a reduction in scintillation, and the concentration of compound that is required to inhibit the signal by 50% is reported as the TC 50 value for the test compound.
• the ability of compounds of the invention to inhibit tyrosine kinase activity of TrkB may be measured using a recombinant enzyme in an assay that measures the ability of compounds to inhibit the phosphorylation of the exogenous substrate, polyGluTyr (PGT, 4: 1).
• PTT polyGluTyr
• the kinase domain of the human TrkB receptor (amino acids 526-838) is expressed in insect cells as a histidine (His)-fusion protein and is commercially available from Invitrogen .
• the enzyme assay is performed in a 96-well plate. Test compounds are first dissolved in dimethylsulfoxide (DMSO) and then serially-diluted in a 96-well plate.
• DMSO dimethylsulfoxide
• serially-diluted compounds are transferred to the 96-well assay plate so that the final concentration of DMSO in the enzyme assay is 1.64%.
• AU assay components are diluted in phosphorylation buffer (20mm MOPS 5 1OmM MgCl 2 , ImM EDTA, 0.015% Brij-35, O.lmg/ml BSA- 0.0025% Beta-Mercaptoethanol).
• the recombinant enzyme is added to the assay plate containing test compound and the reaction is initiated with a substrate solution containing a final concentration of O.lmg/ml PGT 5 3OuM ATP 5 and 0.008mCi/ml 33 P- gammaATP (3000Ci/mmol)(Perkin ElmerTM) After a 1 hour incubation at 30 0 C 5 the reaction is terminated with 10% TCA and incubated at 4 0 C for 1 hour. The reaction is filtered onto a Unifilter ® GF/CTM filter plate that has been presoaked with 0.1 M NaPyrophosphate.
• Microscint-20 is then added to the dried filter plate and the captured 33 P-phosphorylated PGT is quantitated on a microscintillation plate counter (TopCount-NXTTM). Inhibition of the kinase enzymatic activity by the test compound is detected by a reduction in scintillation, and the concentration of compound that is required to inhibit the signal by 50% is reported as the IC 50 value for the test compound.
• TopCount-NXTTM microscintillation plate counter
• the instant compounds inhibit TrkA and TrkB with IC50 values between 0.001 to 10 ⁇ M.
• Preferred compounds have IC50 values between 0.001 - 2.5 ⁇ M. More preferred compounds have ICs 0 values between 0.001 - 0.5 ⁇ M. Most preferred compounds have IC50 values between 0.001 — 0.1 ⁇ M. Representative compounds are listed in following table.
• Compound ii was prepared from commercially available Compound i according to known literature procedure (Step 1, Ref.: US 2004/0220186Al). Treatment of Compound ii with ethyl isocyanoacetate in the presence of catalytic amount of rhodium carbonyl complex, Rh 4 (CO) ⁇ , yielded Compound iii (Step 2, Ref.: Shun-Ichi Murahashi et al., Org. Lett., 2001, 3 (3), 421-424). Conversion of Compound iii to Compound iv was accomplished by reacting Compound iii with chloroamine in the presence of a base, such as NaH (Step 3).
• a base such as NaH
• Reaction of Compound iv with foramidine afforded Compound v (Step 4).
• Compound vii was reacted with N-methyl-N-methoxyamine to give Compound viii (Step 7), which, upon treatment with ammonia, yielded Compound ix (Step 8).
• Reaction of Compound ix with an anion of a protected aniline, followed by deprotection provided Compound x (Step 9).
• Compound I can be prepared according to Scheme 2.
• Compounds xi and xii can be prepared according to known procedure (Step 1, USSN 09/573829). Conversion of Compound xii to Compound x ⁇ i can be achieved by treatment of Compound xii with NBS in the presence of a radical initiator, such as ADBN, or BzO 2 , followed by aq. NaHCO 3 or water (Step 2). Oxidation of Compound xiii to Compound xiv can be achieved by using sodium chlorite (Step 3). Transformations of Compound xiv to Compound xv can be achieved by treatment of xiv with diazomethathane (Step 4).
• Conversion of Compound xv to xvi is achieved by treatment with ammonia (Step 5). Sequence of Step 4 and Step 5 can be exchanged for optimal yield. Conversion of Compound xvi to xvii is similar to Step 9 in Scheme 1. Conversion of Compound xvii to xv ⁇ i can be achieved by coupling with acetylene in the presence of a palladium catalyst, or by coupling with substituted boronic acid in the presence of a palladium catalyst (Step 7). Finally, Compound xviii can be further transformed to Compound I according to similar sequences illustrated in Scheme 1.
• HPLC Ret Time is the HPLC retention time that was obtained under the following conditions: column type and length, gradient time [unless otherwise indicated, all gradients started with 100% solvent A (10% MeOH, 90% H 2 O 5 0.1% TFA) and ended with 100% solvent B (90% MeOH 5 10% H 2 O, 0.1% TFAJ], flow rate (mL/min). UV detection was either conducted at 220 nM or at 254.
• Examples 2 to 63 were prepared from Compound IH and corresponding aryl isocyanates utilizing procedure analogous to the one for Compound II described above. The final products were purified by trituration, or recrystallization, or preparative HPLC (C 18 reverse-phase, YMC ODS S5, 5 ⁇ m, 20x100 mm, using H2O- MeOH-0.1%TFA as eluents).
• Method A Chromolith SpeedROD 4.6 x 50 mm, 5 5 ⁇ m column
• Method B Phenomenex Luna Cl 8 (2), 4.6 x 50 mm, 5 5 ⁇ m column
• Method C Waters SunFire Cl 8, 4.6 x 50 mm, 5 ⁇ m column.
• Compound 65A was prepared from Compound IH (30 mg, 0.0733 mmol) and 2,2,2-trifluoro-l-(4-isocyanatopiperidin-l-yl)ethanone (16.3 mg, 0.0733 mmol) utilizing procedure analogous to the one for Compound II described above.
• Examples 69 to 82 were prepared from Compound 68B and corresponding aryl isocyanates utilizing procedure analogous to the one for Compound 68 described above. The final products were purified by trituration, or recrystallization, or preparative HPLC (Cl 8 reverse-phase, YMC ODS S5, 5 ⁇ m, 20x100 mm, using H2O- MeOH-0.1%TFA as eluents).
• Examples 84 to 92 were prepared from Compound IH and the corresponding amino-pyrazoles utilizing procedure analogous to the one for Compound 83 described above. The final products were purified by trituration, or recrystallization, or preparative HPLC (Cl 8 reverse-phase, YMC ODS S5, 5 ⁇ m, 20x100 mm, using H2O-MeOH-0.1 %TFA as eluents).
• Method A Chromolith SpeedROD 4.6 x 50 mm, 5 ⁇ m column;
• Examples 93 and 94 were prepared from Compound 68B and the corresponding amino-pyrazoles utilizing procedure analogous to the one for Compound 83 described above. The final products were purified by trituration, or recrystallization, or preparative HPLC (C 18 reverse-phase, YMC ODS S5, Sum, 20x100 mm, using H2O-MeOH-0.1%TFA as eluents).
• Method A Chromolith SpeedROD 4.6 x 50 mm, 5 ⁇ m column;
• Example 96 was prepared in a manner analogous to Example 95 using morpholine in the place of piperidine.
• HPLC X R 3.07 min (Chromolith SpeedROD 4.6 x 50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 254 nm).
• [M+H+] 564.22.
• Example 98 was prepared from 97C and 2-methoxyisocyante in a manner analogous to Example 97.
• HPLC t ⁇ 2.43 (YMC S5 Combisereen ODS 4.6 x 50 mm, 10-90% aqueous methanol containing 0.2% HsPO 4 , 4 min gradient, monitored at 254 nm)
• M+H+] 485.24.
• Example 100 was prepared from 97C (23 mg, 0.07 mmol) and 3- cyclopropyl-1 -methyl- lH-pyrazol-5-amine (13 mg, 0.097 mmol) in a manner analogous to Example 99.
• the solution was purified by flash chromatography (SiC « 2 , 0% to 10% MeOH/CH 2 Cl 2 ) to afford desired compound (9.3 mg).
• reaction mixture was concentrated and the residue was purified by preparative reversed phase HPLC (YMC S5 ODS 20 x 100 mm, 10-90% aqueous methanol over 10 minutes containing 0.1% TFA 5 20 ml/min, monitoring at 220 nm).
• the desired fractions were passed through an SCX cartridge and concentrated to afford the desired compound (1.8 mg).
• reaction was concentrated and purified by reversed-phase preparative HPLC (YMC ODS-A 20 x 100 mm, 10-90% aqueous methanol containing 0.1% TFA, 20 min gradient, monitored at 220 nm) to give l-(5- (4-amino-7-isopropylpyrrolo[l ,2-fj [1 ,2,4]triazine-5-carbonyl)pyridin-3-yl)-3-(4- morpholino-2-(2-morpholinoethoxy)phenyl)urea (2 mg, 20%).
• Example 110 l-(3- ⁇ [4-amino-7-(l-methylethyI)pyrrolo[2,l-f][l,2,4]triazm-5- yI]carbonyl ⁇ phenyl)-3-(2- ⁇ [2-(l-piperazinyl)ethyl]oxy ⁇ phenyl)urea

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