Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention refers to novel compounds based on a substituted aromatic heteroaryl ring system. These novel compounds are useful for the inhibition of protein kinases, particularly of the inhibition of Src family protein kinases. Methods for inhibiting kinases by contacting kinases with these novel compounds are disclosed.
• the present invention refers to pharmaceutical compositions containing these novel compounds' and their use for the preparation of medicaments for treating diseases or disorders associated with unphysiological activity of kinases in the body, particularly for the treatment of cancer, immunosuppression, and osteoporosis.
• kinases are implicated in e.g. cancer, immune system dysfunction and bone remodelling diseases.
• kinases are implicated in e.g. cancer, immune system dysfunction and bone remodelling diseases.
• Kinases phos- phorylate target proteins at particular sites, primarily at tyrosine, threonine or serine residues. By their phosphorylation activity kinases may transduce signals and may be part of a signalling cascade resulting finally in a cellular response to external stimuli.
• the Src protein family belongs to the kinase protein family.
• the Src family consists of the following nine kinases in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk and Yrk. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains: Src homology domain 4 (SH4), a unique domain, SH3 domain, SH2 domain, a catalytic domain (SH1 ), and a C-terminal regulatory region (Tatosyan et al. Biochemistry (Moscow) 65, 49-58 (2000)).
• SH4 Src homology domain 4
• SH3 domain unique domain
• SH2 domain a catalytic domain
• SH1 catalytic domain
• C-terminal regulatory region Tatosyan et al. Biochemistry (Moscow) 65
• Src family kinases are for example involved in cell division (probably through interaction with different growth factor receptors), as well as cell shape changes, adhesion and motility through regulation of integrin signalling and cy- toskeletal architecture (Roche et al., 1995, Science 269, 1567-9; Mao et al., 1997, Oncogene 15, 3083-90; Parsons and Parsons, 1997, Curr. Opin. Cell Biol. 9, 187- 92; Abu-Ghazaleh et al., 2001, Biochem. J. 360, 255-64; Belsches-Jablonski et al., 2001 , Oncogene 20, 1465-75; Alegiyte et al., 2002, Nat. Cell Biol. 4, 632-638; Frame, 2002, BBA 1602, 1 14-30; Kitagawa et al., 2002, J. Biol. Chem. 271, 366- 71 ).
• Colon cancer is a common disease which leads to death in ⁇ 50% of the cases as a consequence of metastasis.
• therapeutic substances are highly desired for more successful treatment strategies of a variety of diseases or disorders, in particular cancer.
• kinase inhibitors that allow to identify and characterise compounds modulating the activity of kinases.
• the compounds of the invention have general formula (I).
• X represents N, O, C or S
• Y represents S, NH, C or O
• L 1 represents a chemical bond; carbonyl; COOH; -(CH 2 ) a - wherein a is 1, 2, 3, 4 or 5; -CH 2 0-; -OCH 2 -; -OCH(CH 3 ) 2 -O- or -S-; -N(R 1 )- wherein R 1 represents H, C alkyl, C 6 .
• L 2 represents a chemical bond; -(CH 2 ) a -; -CH 2 0-; -N(R 1 )-; -NH(CH 2 ) a -; -NCCOR 1 -; or -NHC(0)NH-;
• J represents H; C 1-4 alkyl, wherein C 1-4 may be substituted by at least one halogen; or halogen;
• A is not existent or represents a (hetero)cyclic, aromatic or non- aromatic optionally substituted ring system
• G represents a (hetero)cyclic, aromatic or non-aromatic optionally substituted ring system or L ⁇ A and J form together a cyclic or heterocyclic mono-, bi- or tri- cyclic ring system or a pharmaceutically acceptable salt thereof.
• V, A and J whereby a cyclic or heterocyclic mono-, bi- or tricyclic ring system is formed by L 1 , A and J.
• This ring system may be an aromatic or a non-aromatic ring system fused with the central heteroaryl ring of formula (1).
• the fused ring systems may form a C 9 - C 17 heteroaryl ring, in particular a C 9 , C 13 or C 17 heteroaryl ring, e.g. benzothiazole, benzooxazole, chinoxaline, indole, chi- noline, purin, isochinoline.
• agonist of an enzyme refers to a compound that binds to the enzyme and stimulates the action of the naturally occurring enzyme, or a compound which mimics the activity of the naturally occurring en- zyme.
• antagonist of an enzyme refers to a compound that binds to the enzyme and inhibits the action of the naturally occurring enzyme.
• analog of a compound refers to a compound having a some structural similarity to a particular compound and having essentially the same type of biological activity as the compound.
• derivative of a compound refers to another compound which can be derived, e.g., by chemical synthesis, from the original compound.
• a derivative of a compound has certain structural similarities with the original compound.
• Disease associated with an abnormal activity or level of a kinase refers to diseases in which an abnormal activity or protein level of a kinase is present in certain cells, and in which the abnormal activity or protein level of the kinase is at least partly responsible for the disease.
• a “disease associated with a kinase” refers to a disease that can be treated with a kinase inhibitor, such as the compounds disclosed herein.
• a “kinase” refers to an enzyme having a protein kinase activity.
• Binase activity refers to the activity of an enzyme to phosphorylate a substrate, particularly a protein, whereby a phosphate is covalently coupled to one or more substrate amino acids, particularly threonine, tyrosine or serine.
• a “kinase inhibitor” is a compound which inhibits at least part of the activity of a kinase in a cell.
• the inhibition can be at least about 20%, preferably at least about 40%, even more preferably at least about 50%, 70%, 80%, 90%, 95%, and most preferably at least about 98% of the activity of the kinase.
• a "patient” or “subject” to be treated by the subject method can mean either a human or non-human animal.
• Treating refers to preventing, curing or improving at least one symptom of a disease.
• heteroatom as used herein means an atom of nitrogen, oxygen, or sulfur.
• alkyl refers to the radicals of saturated aliphatic groups, including straight-chain alkyl groups and branched-chain alkyl groups.
• cycloalkyl refers to radicals of cycloalkyl compounds, exam- pies being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
• aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
• alkenyl and alkynyl refer to unsaturated aliphatic groups that contain at least one double or triple bond respectively.
• lower alkyl as used herein means an alkyl group but having from one to six carbons, preferably from one to four carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls.
• aryl as used herein means an aromatic group of 6 to 14 carbon atoms in the ring(s), for example, phenyl and naphthyl. As indicated, the term “aryl” includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic.
• heteroaryl as used herein means an aromatic group which contains at least one heteroatom in at least one ring. Typical examples include 5-, 6- and 7- membered single-ring aromatic groups that may include from one to four heteroatoms. Examples include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, tri- azole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. These aryl groups may also be referred to as “aryl heterocycles" or "heteroaro- matics.”
• ortho, meta and para apply to 1 ,2-, 1 ,3- and 1,4-disubstituted benzenes or other ring systems, respectively.
• 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
• alkoxyl or "alkoxy” as used herein refer to moiety in which an alkyl group is bonded to an oxygen atom, which is in turn bonded to the rest of the molecule. Examples are methoxy, ethoxy, propyloxy, tert-butoxy, etc.
• nitro means -N0 2 ;
• halogen designates -F, -CI, - Br or -I;
• sulfhydryl means -SH;
• hydroxyl means -OH; and
• sulfonyl means -S0 2 -.
• triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoro- methanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
• triflate, tosylate, mesylate, and nonaflate are art- recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfanate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
• Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
• a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry;(i.e., J. Org. Chem. 2002, 67(1), 24A. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
• each expression e.g. alkyl, m, n, etc., when it oc- curs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substi- tuted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• the term "substituted" is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
• Illustrative substituents include, for example, those described herein above.
• the permissible substituents can be one or more and the same or different for appropriate organic com- pounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transforma- tions.
• protecting groups include esters of carboxylic acids, si lyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
• the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P,G.M. Protective Groups in Organic Synthesis, 3'° ed.; Wiley: New York, 1999).
• Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
• Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
• a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, oz by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
• the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl
• diastereomeric salts are formed with an appro- priate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
• Compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
• salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified com- pound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Representative salts include the hydrobro- mide, hydrochloride, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1 - hydroxynaphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as methanesulfonic acid or benzenesulfonic acid.
• salts are sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, gluco- heptonate, lactobionate, and laurylsulphonate salts and the like.
• lactate lactate
• phosphate tosylate
• citrate maleate, fumarate, succinate, tartrate, napthylate, mesylate, gluco- heptonate, lactobionate, and laurylsulphonate salts and the like.
• salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
• such conventional nontoxic salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as formic, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, sali- cyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
• These salts may be prepared from compounds of formula I
• the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
• These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically- acceptable organic primary, secondary or tertiary amine.
• Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like
• Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like, (see, for example, Berge et al., supra).
• Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as kinase inhibitors), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to a soluble or membrane residing kinase.
• the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
• compounds of the present invention have a structure according to formula (I), wherein A and G are independently from each other a mono-, bi- or polycyclic ring system.
• compounds of the present invention have a struc- ture according to formula (I) wherein A and G represent independently from each other a mono- or bicyclic or polycyclic aryl or heteroaryl ring system, e.g. C 7 -C 24 alkaryl, C 4 -C 23 alkheteroaryl or C 6 -C 14 aryl.
• compounds of the present invention have a struc- ture according to formula (I), wherein A and G are independently from each other an aromatic ring system selected from a group consisting of: benzene, pyridine, fu- rane, pyrrole, thiophene, pyrazole, imidazole, thiazole, oxazole, pyridazine, pyrimidine, pyrazine, naphthaline, chinoline, isochinoline, indole, purine, benzofu- rane, phenanthrene, benzooxazole, benzothiophene, benzopyrazole, benzoimida- zole, benzothiazole, carbaxole, chromen.
• a and G are independently from each other an aromatic ring system selected from a group consisting of: benzene, pyridine, fu- rane, pyrrole, thiophene, pyrazole, imidazole, thi
• a and G further may be selected independently from each other from the following specific structures including 2,3dihydrobenzofurane, 1 H-benzo[d] imidazole, in- dene, benzo[d]oxazole-2(3H)-one, dihydro-1 ,2-naphtaline, benzo[1 ,3]disoxole, benzo[1 ,4]oxazine-3-one, 2,3-dihydro-benzo[1,4]dioxine, 3,4-dihydro-2H- benzo[b] [1 ,4]dioxepine.
• B represents NH, C, S or O.
• A represents 3 H-Benzooxazole-2 -one, Benzo(1,3)dioxol-2-one, Benzol(1 ,3)oxathioi-2- one, 3H-Benzofuran-2-one, 1,3-Dihydro-benzoimidazole-2-one, 3H-Benzothiazole- 2-one, 1,3-Dihydro-indole-2-one, 3H-Benzothiazole-2-one, 3H-Benzo(b)thiophen- 2-one or lndan-2-one.
• compounds of the present invention have a structure according to formula (I), wherein A and G are independently from each other C 3 . 10 cycloalkyl, C 3 . 8 heterocycloalkyl, C 5.6 (hetero)cycloalkenyl, C 6 . 12 (het- ero)bicyloalkyI or C 6 . 12 (hetero)bicycloalkenyl.
• compounds of the present invention have a structure according to formula (I), wherein A and G are independently from each other substituted by one or more substituent(s) selected from the group consisting of: .
• substituents may be positioned at any ring atom of the cyclic systems chosen for A and G.
• ring systems A and G of the compounds of the present invention are - independently from each other - substituted at 0, 1 or 2 position(s).
• Substituents of the ring systems A and G may be identical or non-identical.
• a and G may have more than one substituent in ortho-, meta- or para-position. If there is more than one substituent for A or G, these substitutents may again be identical or non-identical at ring system A or G.
• compounds of the present invention have a structure according to formula (I), wherein X represents N and Y represents S, O or NH. It is even more preferred to provide a compound of formula (I), wherein X represents N and Y represents S. Thereby, the central heteroaryl ring system of a compound of the present invention according to formula (I) represents a thiazole.
• compounds of the present invention have a structure according to formula (I), wherein L 2 represents -NH(CH 2 ) a -, -N(R 1 )-, - NHC(0)NH- (urea linkage) or -N(CO)R 1 -. It is particularly preferred to chose a compound of the invention, wherein L 2 represents -NH(CH 2 ) a -. R 1 and a are chosen as indicated above (s. also claim 1). Particularly preferred are compounds, wherein a represents 2 or 3, respectively.
• compounds of the present invention have a structure according to Compound of formula (I), wherein A represents a mono- or bicyclic aryl or heteroaryl ring system, optionally substituted; G represents a poly- or bicyclic (hetero)aryl ring system or imidazole, pyrrole, thiophene, pyridazine, pyrazine, thiazole, or oxazole, optionally substituted; L 2 represents -NH(CH 2 ) a -, -NR 1 -, -NHC(0)NH- or -NH(CO)R 1 - ; L 1 represents a chemical bond, carbonyl or -(CH 2 ) a -.
• substitutions introduced for A and G for these preferred compounds correspond to the substitutions outlined above. It is particularly preferred to provide compounds, wherein L 1 represents a chemical bond and/or L 2 represents -NH(CH 2 ) a - with a representing 1, 2 or 3.
• compounds of the present invention have a structure according to formula (I), wherein G is a poly- or bicyclic (hetero)aryl ring system or a C 3 -C 12 (hetero)cycloalkyl under the provision that L 1 is a chemical bond.
• A represents a bicyclic aryl or heteroaryl ring system, optionally substituted, with the provision that L 1 is carbonyl;
• A represents a bicyclic aryl or heteroaryl ring system, pyrrole, furan, thiophene, pyridine, pyridazine, pyrazine, pyrimidine, pyrazole, thiazole, or oxazole, optionally substituted, or a non-aromatic C 3 .
• L 1 mono- or bicyclic alkyl or heteroalkyl ring, optionally substituted, with the provision that L 1 is -(CH 2 ) a -; or A represents a bicyclic heteroaryl ring system, optionally substituted with the provision that A cannot be benzothiophene, or a substituted bicyclic aryl ring system or pyrrole, pyridazine, pyrazine, pyrimidine, thiazole, pyrazole, or imidazole, optionally substituted, with the provision that L is a chemical bond; G represents a mono- or bicyclic aryl or heteroaryl ring system, op- tionally substituted; and L 2 represents -NH(CH 2 ) a -, -NR 1 -, -NHC(0)NH-, or -NH(CO)R 1 -.
• substitutions introduced for A and G for these preferred compounds correspond to the substitutions outlined above.
• Each of alternatives for the ring systems may be substituted or not substituted.
• Particularly preferred are those compounds according to the invention, wherein A represents a bicyclic het- eroaryl ring system with the provision that A cannot be benzothiophene, or a substituted bicyclic aryl ring system or pyrrole, pyridazine, pyrazine, pyrimidine, thiazole, pyrazole, or imidazole, whereby L 1 is a chemical bond and whereby the A representing these ring systems may be substituted.
• Compounds according to the invention are particularly preferred as kinase inhibitors, particularly as Src family kinase inhibitor.
• Compounds may inhibit kinase activity either by competition with ATP or substrate or by binding to an ailosteric site in the kinase.
• the present invention provides a method of inhibiting a kinase, particularly a kinase of the Src kinase family, e.g., comprising contacting a kinase with a compound of the invention.
• the activity can be inhibited by at least 20%, preferably at least about 50%, more preferably at least about 60%, 70%, 80%, 90%, 95%, and most prefera- bly at least about 98%.
• the invention provides a method for inhibiting a kinase in vitro.
• the kinase is in vivo or ex vivo.
• the invention provides methods for inhibiting a kinase in a cell, comprising contacting the cell with a compound of the invention, such that the activity of the kinase is inhibited.
• the cell may further be contacted with a composi- tion stimulating the uptake of the compound into the cell, e,g., liposomes.
• the invention provides a method for inhibiting a kinase in a cell of a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a formulation comprising a compound of the present invention, such that the kinase is inhibited in a cell of the subject.
• the subject can be one having a disease associated with a kinase, e.g., cancer.
• Preferred types of cancer that can be treated according to the invention include prostate cancer and breast cancer.
• the therapeutic methods of the invention generally comprise administering to a sub- ject in need thereof, a pharmaceutically effective amount of a compound of the in- vention, or a salt, prodrug or composition thereof.
• the compounds of the invention can be administered in an amount effective to inhibit the activity of a kinase.
• the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carri- ers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
• a pharmaceutical composition comprising at least one compound according to the invention and a pharmaceutically acceptable carrier is thereby disclosed herewith.
• Compounds and pharmaceutically acceptable compositions are employed for the preparation of a medicament for the treatment of a disease or a disorder or pathological condition associated with an abnormal activity or level of a kinase, in particular a Src family kinase.
• a variety of diseases has been associated with abnormal activity of a kinase, in particular cancer.
• Compounds according to the invention may be used for the preparation of a medicament for the treatment of solid tumors, e.g. lung, kidney, breast, pancreas, skin, eye, stomach, colon, bone, liver, prostate, ovarian or brain cancer.
• these compounds may also be used for therapeutical purposes for the treatment or the preparation of a medicament for the treatment of non-solid tumor forms, e.g. tumors of the blood forming system.
• Particularly relevant are compounds of the present invention for the treatment of various forms of leukemia and lymphoma, e.g. Hodgkin and Non-Hodgkin lymphoma, particularly for the treatment of childhood cancer.
• compounds according to the invention are useful for polycystic kidney disease, particularly for the inhibition of a tyrosine kinase involved in the etiology of polycystic kidney disease.
• Another disease, which is treatable with compounds of the invention is collagen-induced arthritis, in particular with regard to the inhibition of a p38 kinase.
• compounds of the present invention are administered for the treatment of inflammatory diseases.
• compounds according to the invention may act as inhibitor of e.g. p38 mito- gen-activated protein (MAP) kinase, targeting the treatment of inflammatory diseases.
• MAP mito- gen-activated protein
• the p38 MAP kinase enzyme regulates the production of key proinflammatory cyto- kines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6). Based on their mechanism of action, inhibitors of p38 MAP kinase play a role in the treatment of acute and chronic inflammatory diseases, in- eluding rheumatoid arthritis, osteoarthritis, and Crohn's disease.
• TNF-alpha tumor necrosis factor-alpha
• IL-1 beta interleukin-1 beta
• IL-6 interleukin-6
• PTKs Protein tyrosine kinases
• receptor PTKs receptor PTKs
• cellular, or non-receptor, PTKs cellular, or non-receptor tyrosine kinases.
• 59 receptor tyrosine kinases
• 32 are non-receptor tyrosine kinases.
• kinases in particular tyrosine kinases are also involved in the etiology of inflammatory or obstructive airways diseases
• agents (compounds) of the invention are consequently useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression.
• Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exer- cise-induced asthma, occupational asthma and asthma induced following bacterial infection.
• Kinase inhibitors may be used for the treat- ment of allograft rejection, allergic reactions, immunosuppression (particularly, by inhibition of kinases (e.g. tyrosine kinases), which are involved in the activation of cells of the immune system (e.g. B- or T-Lymphocytes) and for the treatment of osteoporosis and related bone diseases, including osteolytic bone metastases (target: c- Src, a member of the Src kinase family).
• kinases e.g. tyrosine kinases
• B- or T-Lymphocytes e.g. B- or T-Lymphocytes
• osteoporosis and related bone diseases including osteolytic bone metastases (target: c- Src, a member of the Src kinase family).
• Compounds according to the invention for the treatment of osteoporosis are based on (i) their potential as Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties; and (ii) on their potential as ATP-based Src kinase inhibitors incorporating bone-targeting moieties.
• compounds according to the invention may differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts.
• the compounds can be administered orally or parenterally, including the intrave- nous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
• Toxicity and therapeutic efficacy of the compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for deter- mining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
• the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
• Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to de- sign a delivery system that targets such reagents to the site of affected tissue in order to minimize potential damage to normal cells and, thereby, reduce side effects.
• Data obtained from cell culture assays and animal studies can be used in formulat- ing a range of dosage for use in humans.
• the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
• the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
• the therapeutically effective dose can be estimated ini- tially from cell culture assays.
• a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of activity) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
• the compounds of the invention have an IC 50 less than 10 ⁇ M as determined by the biochemical or cellular assay described herein. Some compounds of the invention are effective at concentrations of 10 nM, 100 nM, or 1 ⁇ M. Based on these numbers, it is possible to derive an appropriate dosage for administration to subjects.
• Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound, Such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995)). Commonly used prodrugs of the disclosed compounds can be designed to take advantage of the major drug biotransformation
• Dermal administration includes topical application or transdermal administration.
• Parenteral administration includes intravenous, intraarticular, intramuscular, intraperitoneal, and subcutaneous injections, as well as use of infusion techniques.
• One or more compounds of the invention may be present in association with one or more nontoxic pharmaceutically acceptable ingredients and. optionally, other active anti- pro ⁇ ferative agents, to form the pharmaceutical composition.
• These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Dug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, (1995).
• compositions containing a compound of the invention 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.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents se- lected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically acceptable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents, such as calcium car- bonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, com starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc,
• the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disin- tegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, oz as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypro- pylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin; or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol; or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
• the aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• preservatives for example ethyl or n-propyl p- hydroxybenzoate
• coloring agents for example ethyl or n-propyl p- hydroxybenzoate
• flavoring agents such as sucrose, saccharin or aspartame.
• sweetening agents such as sucrose, saccharin or aspartame.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
• Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
• These compositions may be preserved by the addition of an anti- oxidant such as butylated hydroxyanisol or alpha-tocopherol.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compound of the invention in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent, suspending agent and one or more preservatives are exemplified by those already mentioned above.
• Additional excipients for example sweetening, flavoring and coloring agents, may also be present.
• These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• compositions of the invention may also be in the form of an oil-in- water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial es- ters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening, flavouring agents, preservatives and anti- oxidants.
• Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
• sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
• compositions may be in the form of a sterile injectable aqueous solutions.
• acceptable vehicles and solvents that may be employed are wa- ter, Ringer's solution and isotonic sodium chloride solution.
• Sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the compound of the invention is dissolved in the oily phase.
• the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then introduced into a water and glycerol mixture and processed to form a microemulation.
• the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the active compound.
• a continuous intravenous delivery device may be utilized.
• An example of such a device is the Deltec CADD-PLUS 00 model 5400 intravenous pump.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions of the invention may also be administered in the form of a suppository for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydro- genated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
• creams, ointments, jellies, solutions or suspensions, etc., containing the compound of the invention can be employed.
• topical application shall include mouth washes and gargles.
• the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• the dosage administration will preferably be continuous rather than intermittent throughout the dosage regimen.
• the compounds of the invention may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
• the compounds may be administered simultaneously or sequentially.
• the active compounds may be useful in combination with known anti-cancer and cytotoxic agents.
• the active compounds may be useful in combination with agents that are-effective in the treatment and prevention of osteoporosis, inflammation, neurofibromatosis, restenosis, and viral infections.
• the active compounds may also be useful in combination with inhibitors of other components of signaling pathways of cell surface growth factor receptors.
• Drugs that can be co-administered to a subject being treated with a compound of the invention include antineoplastic agents selected from vinca alkaloids, epipodo- phyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, or amsacrine. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art.
• Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with a compound of the invention to treat a disease, e.g., cancer.
• a disease e.g., cancer.
• the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
• a compound of the invention, materials and/or reagents re- quired for administering the compounds of the invention may be assembled together in a kit.
• the liquid, solution preferably is an aqueous solution, with a sterile aqueous solution being particularly preferred.
• the kit may further comprise one or more other drugs, e.g., a chemo- or radiothera-plastic agent, These normally will be a separate formulation, but may be formulated into a single pharmaceutically acceptable composition.
• the container means may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the formulation may be applied to an in- fected area of the body, such as the lungs, or injected into an animal, or even applied to and mixed with the other components of the kit.
• the compositions of these kits also may be provided in dried or lyophilized forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent.
• kits of the invention may also include an instruction sheet defining administration of the agent.
• Kits may also comprise a compound of the invention, labeled for detecting kinases.
• the kits of the present invention also will typically include a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained. Irrespective of the number or type of containers, the kits of the invention also may comprise, or be packaged with a separate instrument for assisting with the injection/administration or placement of the ultimate complex composition within the body of an animal.
• Such an instrument may be an inhalant, syringe, pipette, forceps, measured spoon, eye dropper or any such medically ap- proved delivery vehicle.
• Other instrumentation includes devices that permit the reading or monitoring of reactions or amounts of compounds or polypeptides.
• the compounds of the present invention may be used as component of a method of treatment of disease associated with a kinase.
• a compound or a composi- tion of the present invention is administered by a method disclosed above to the patient (animal or human). Dosage requirements are dependent e.g. upon the age, the body weight, gender, the method of administration (e.g. orally or parenterally) and the severity of the disease.
• halo ketone III wherein X is CI, Br, I, or other leaving group commonly employed in the art, is treated with thioamide VI in a polar solvent, such as an alcoholic solvent, at a temperature between 40 - 120 °C.
• a polar solvent such as an alcoholic solvent
• the polar solvent is an alcohol such as ethanol, 1-propanol, or 2-propanol.
• Halo ketones III are commercially available or may be prepared using an electrophilic halogen reagent such as bromine, N- chlorosuccinimide, Nl-bromosuccinimide, or phenyltrimethylammonium tribromide using the general methods or as outlined in the specific examples described below or other methods commonly employed in the art. Alternatively, the corresponding alphahydroxy ketone can be converted into III using standard conditions employed in the art to convert an alcohol functionality into a halogen or other leaving group commonly employed in the art. Ketones III are commercially available or are prepared according to methods commonly employed in the art. Thioamide VI can be prepared from nitrile V upon treatment with hydrogen sulphide.
• VI can be prepared from amide IV upon treatment with Lawessons reagent or P S 10 .
• Nitriles V are commercially available or can be prepared according the methods commonly employed in the art.
• Amides are commercially available or they can be prepared by methods commonly employed in the art to prepare amide functionality from carboxylic acid functionality, whereby the requisite carboxylic acid is commercially available or can be prepared by methods commonly employed in the art.
• Amines VII are treated with ammonium thiocyanates or with alkali metal thiocyanates in the presence of acid in an inert organic solvent, such as bromobenzene, chlorobenzene, xylene, toluene, THF, or dioxane at a temperature between 60 - 250 °C.
• an inert organic solvent such as bromobenzene, chlorobenzene, xylene, toluene, THF, or dioxane at a temperature between 60 - 250 °C.
• the required thioureas can be prepared from the amine VII upon treatment with an isothiocyanate bearing a suitable protecting group like ben- zoyl or Fmoc or other protecting group commonly employed in the art followed by deprotection using the general methods described below or other methods commonly employed in the art.
• 6-fluorotryptamine hydrochloride (0.5 g; 2.329 mmol) was dissolved in 15 ml of 1,4-dioxan. After addition of potassium thiocy- anate (0.34 g; 3.494 mmol) the mixture was refluxed 48 h under argon. The precipitated potassium chloride was filtered off and the solution was evaporated in vac- uum. The residue was purified by filtration over silica gel (100 ethyl acetate) to give 0.591 g (quantitative) of a light ocher solid.
• fluo- renylmethyloxycarbonyl chloride (2.60 g; 10 mmol) was dissolved in 10 ml of an- hydrous ethyl acetate. This solution was added drop wise to a suspension of dry potassium thiocyanate (1.07 g; 1 1 mmol) in 10 ml of anhydrous ethyl acetate at 0°C under an argon atmosphere. The solution was allowed to warm to room temperature over several hours, and the reaction was monitored by thin-layer chromatography [silica gel plates; eluant solution, dichloromethane/petroleum ether (Kp.

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