ZA200604075B - 6-Alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(ADP-ribose) polymerase inhibitors - Google Patents
6-Alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(ADP-ribose) polymerase inhibitors Download PDFInfo
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- ZA200604075B ZA200604075B ZA200604075A ZA200604075A ZA200604075B ZA 200604075 B ZA200604075 B ZA 200604075B ZA 200604075 A ZA200604075 A ZA 200604075A ZA 200604075 A ZA200604075 A ZA 200604075A ZA 200604075 B ZA200604075 B ZA 200604075B
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- alkyl
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- 229940127397 Poly(ADP-Ribose) Polymerase Inhibitors Drugs 0.000 title description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 title 1
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical class C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 title 1
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Description
6-ALKENYL. AND 6-PHENYLALKYL SUBSTITUNED 2-QUINOLINONES AMD 2-QUINOXALINONES AS POLY(ADP-RIBOSE) POLYMERASE INHIBITORS
Field of the inwention
The present invention relates to inhibitors of PARP andl provides compounds and compositions containing the disclosed compounds. Moreover, the present inventions provides methods of using the disclosed PARP inhibitomys for instance as a medicine—
The nuclear erazyme poly(ADP-ribose) polymerase-1 (MPARP-1) is a member of the
PARP enzyme: family consisting of PARP-1 and severaml recently identified novel poly(ADP-ribosylating) enzymes. PARP is also referrexd to as poly(adenosine 5'- diphospho-ribose) polymerase or PARS (poly(ADP-ribwose) synthetase).
PARP-1 is a major nuclear protein of 116 kDa consistimng of three domains: the N- terminal DNA. binding domain containing two zinc fingers, the automodification domain and the C-terminal catalytic domain. It is preseent in almost all eukaryotes. "The enzyme synthesizes poly(ADP-ribose), a branched pol=ymer that can consist of over 200
ADP-ribose units. The protein acceptors of poly(ADP—ribose) are directly or indirectly involved in m_aintaining DNA integrity. They include histones, topoisomerases, DNA and RNA pols/merases, DNA ligases, and Ca®- and M g**-dependent endonucleasess.
PARP protein. is expressed at a high level in many tisstaes, most notably in the immmme system, heart, brain and germ-line cells. Under normal physiological conditions, there is minimal PARP activity. However, DNA damage catases an immediate activation of
PARP by up to 500-fold.
Among the m any functions attributed to PARP, and es—pecially PARP-1, is its major— role in facilitating DNA repair by ADP-ribosylation armd therefore co-ordinating a number of DNA repair proteins. As a result of PARP =activation, NAD" levels significantly decline. Extensive PARP activation leads to severe depletion of NAD ~in cells suffering from massive DNA damage. The short half-life of poly(ADP-ribose-) results in a ragpid turnover rate. Once poly(ADP-ribose ) is formed, it is quickly degraded by the constitutively active poly(ADP-ribose=) glycohydrolase (PARG), together with phosphodiesterase and (ADP-ribose) promtein lyase. PARP and PARGG form a cycle that converts a large amount of NAD* to ADP-ribose. In less than an hour, over-sti mulation of PARP can cause a drop of N_AD" and ATP to less than 208% of the normal level. Such a scenario is especially detrimental during ischaemia when deprivation of oxygen has alr-eady drastically compromised cellular energy output.
Subsequent free radical prodiaction during reperfusion is asswumed to be a major cause of tissue damage. Part of the _ATP drop, which is typical in many organs during ischaemia and reperfusion, could be linked to NAD" depletion due to poly(ADP-ribose) turnover. Thus, PARP or PAIRG inhibition is expected to pre=serve the cellular energy level thereby potentiating the= survival of ischaemic tissues after insult.
Poly(ADP-ribose) synthesis #s also involved in the induced expression of a number of genes essential for inflammatory response. PARP inhibitors suppress production of 100 inducible nitric oxide synthasse (iNOS) in macrophages, P-ty—pe selectin and intercellular adhesion molecule-1 ICAM— 1) in endothelial cells. Such activity underlies the strong anti-inflammation effects exhibited by PARP inhibitors. PARP inhibition is able to a reduce necrosis by preventin g translocation and infiltration of neutrophils to the injured tissues. 1s ©. PARP is activated by damag-ed DNA fragments and, once activated, catalyzes the ) attachment of up to 100 ADP-ribose units to a variety of nuclear proteins, including ’ : histones and PARP itself. D uring major cellular stresses the= extensive activation of . - PARP can rapidly lead to cell damage or death through depE etion of energy stores. As four molecules of ATP are consumed for every molecule of NAD regenerated, NAD* is-depleted by massive PARP activation, in the efforts to re—synthesize NAD", ATP may also become depleted. }
It has been reported that PARP activation plays a key role ir both NMDA- and NO- 2-5 induced neurotoxicity. This “has been demonstrated in corticzal cultures and in hippocampal slices wherein prevention of toxicity is directly correlated to PARP inhibition potency. The pote=ntial role of PARP inhibitors ix treating neurodegenerativee diseases and head trauma hams thus been recognized even if the exact mechanism of action has not yet been elucmdated.
Similarly, it has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caussed by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these s-tudies, a single injection of 3-armino-benzamide (10 mg/kg, either one minute before oceclusion or one minute before repoerfusion, caused similar 255 reductions in infarct size in the heart (32-42%) while 1,5- dEihydroxyisoquinoline (1 mg/kg), another PARP irshibitor, reduced infarct size by acomparable degree (38- 48%) These results make it= reasonable to assume that PARSP inhibitors could salvage previously ischaemic heart «or reperfusion injury of skeletal muscle tissue.
PARP activation can also be used as a measure of damage following neurotoxic insults resulting from exposure to any of the following inducers like glutamate (via NMDA receptor stimulation), re active oxygen intermediates, amyloicl B-protein, N-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP) or its active metalbolite N-methyl-4 phenylpyridine (MPP"), which participate in pathological comditions such as stroke,
Alzheimer's disease and Parkinson's disease. Other studies Fave continued to explore the role of PARP activation in cerebellar granule cells in vit—o and in MPTP neurotoxicity. Excessive neural exposure to glutamate, whic h serves as the predominate central nervous system neurotransmitter and acts upon the NW-methyl D-aspartate (NMDA) receptors and. other subtype receptors, most often eoccurs as a result of stroke or other neurodegenerative processes. Oxygen deprived neurons release glutamate in great quantities during ischaemic brain insult such as during= a stroke or heart attack.
This excess release of glutamate in turn causes over-stimulaation (excitotoxicity) of N- methyl-D-aspartate (NMDA), AMPA, Kainate and MGR re=ceptors, which open ion : channels and permit uncontrolled ion flow (e.g, Ca?* and NJa" into the cells and K* out of the cells) leading to overstimulation of the neurons. The -over-stimulated neurons secrete more glutamate, creating a feedback loop or dominO effect which ultimately . results in cell damage or death via the production of proteases, lipases and free radicals.
Excessive activation of glutamate receptors has been implicated in various neurological diseases and conditions including epilepsy, stroke, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington™s disease, schizophrenia, chronic pain, ischemia and neuronal loss following hypoxia, hypoglycemia, ischemia, trauma, and nervous insult. Glutamate exposure and stimulation has also been implicated as a basis for compulsive disorders, particularly drug dependence. Evidence includes findings in many animal species, as well as in cerebral cortical cultures treated with glutamate or NMIDA,, that glutamate receptor antagonists (i.e., compounds which block glutamate from binding to or activating its receptor) block neural damage following vascular stroke. Attempts to prevent excitotoxicity by blocking NMDA,
AMPA, Kainate and MGR receptors have proven difficult because each receptor has multiple sites to which glutamate may bind and hence findlling an effective mix of antagonists or universal antagonist to prevent binding of glutamate to all of the receptor and allow testing of this theory, has been difficult. Moreower, many of the compositions that are effective in blocking the receptors are also toxic tO animals. As such, there is presently no known effective treatment for glutamate abnormalities.
The stimulation of NIMDA receptors by glutamate, for example, activates the enzyme neuronal nitric oxide synthase (nNOS), leading to the forrmation of nitric oxide (NO), which also mediates neurotoxicity. NMDA neurotoxicity _may be prevented by treatment with nitric oxide synthase (NOS) inhibitors or through targeted genetic disruption of nNOS in vitro.
Another use for PARP inhibitors is the treatment of peripheral nerve injuries, and the resultant pathological pain syndrome known as neuropathic pain., such as that induced "by chronic constriction injury” (CCI) of the common sciatic nerve= and in which transsynaptic alteration of spinal cord dorsal horn characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called "dark" neurons) occurs.
Evidence also exists that PAIRP inhibitors are useful for treating inflammatory bowel disorders, such as colitis. Sp ecifically, colitis was induced in rats by intraluminal administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Treated rats received 3- aminobenzamide- , a specific inhibitor of PARP activity. Inhibition of PARP - activity reduced the inflammatory response and restored the mor—phology and the enesgetic status of the distal «<olon.
Further evidence suggests th at PARP inhibitors are useful for tre=ating arthritis. Further,
PARP inhibitors appear to be useful for treating:diabetes. PARE inhibitors have been . shown to be useful for treatitag endotoxic shock or septic shock. 20.
PARP inhibitors have also been used to extend the lifespan and gproliferative capacity of cells including treatment of cliseases such as skin aging, Alzheimer's disease, atherosclerosis, osteoarthritis, osteoporosis, muscular dystrophy ., degenerative diseases of skeletal muscle involving replicative senescence, age-related muscular degeneration, immune senescence, AIDS, sand other immune senescence disease; and to alter gene expression of senescent cellss.
It is also known that PARP i nhibitors, such as 3-amino benzami de, affect overall DNA repair in response, for exampple, to hydrogen peroxide or ionjzin g radiation. 30 .
The pivotal role of PARP in the repair of DNA strand breaks is ~well established, especially when caused directly by ionizing radiation or, indirec=tly after enzymatic repair of DNA lesions induc ed by methylating agents, topoisom erases I inhibitors and other chemotherapeutic agerts as cisplatin and bleomycin. A variety of studies using “knockout” mice, trans-domminant inhibition models (over-expre-ssion of the DNA- binding domain), antisense and small molecular weight inhibitors have demonstrated the role of PARP in repair amd cell survival after induction of DNA damage. The inhibition off PARP enzymatic activity should leacl to an enhanced sensitivity ofthe tumor cells towards DNA damaging treatments.
PARP inhibitors have been reported to be effective in radiosensitizing (hypoxic) tumor cells and effective in preventing tumor cells from recovering from potentially lethal and sublethal damage of DNA after radiation therapy... presumably by their ability “to prevent
DNA strand break rejoining and by affecting seve=ral DNA damage signaling Pathways.
PARP inhibitors have been used to treat cancer. Mn addition, U.S. Patent No.5 ,177,075 discusses several isoquinolines used for enhancin gthe lethal effects of ionizing radiation or chemotherapeutic agents on tumor ce=lls. Weltin et al., "Effect of &( - ~ Phenanthridlinone, an Inhibitor of Poly(ADP-ribozse) Polymerase, on Cultured Tumor
Cells", Oncol. Res., 6:9, 399-403 (1994), discusse=s the inhibition of PARP ac®ivity, reduced prosliferation of tumor cells, and a marked synergistic effect when tuncor cells are co- treated with an alkylating drug. oo A recent coanprehensive review of the state of the art has been published by Ii and
Zhang in Drugs 2001, 4(7): 804-812. cn .
There continues to be a need for effective and postent PARP inhibitors, and moore particularly PARP-1 inhibitors which produce mi_nimal side effects. The prese=nt invention provides compounds, compositions for_, and methods of, inhibiting PARP activity for treating cancer and/or preventing cellular, tissue and/or organ darmmage resulting from cell damage or death due to, for ex=ample, necrosis or apoptosiss. The compounds and compositions of the present invemntion are especially useful in enhancing the effectiveness of chemotherapy andi radiotherapy where a primamry effect of the treatrment is that of causing DNA damage i nthe targeted cells.
Background prior art
EP 371564, published on June 6, 1990, discloses (1H-azol-1-ylmethyl) substituted quinoline, qquinazoline or quinoxaline derivatives . The described compounds suppress the plasma elimination of retinoic acids. More in particular the comp=ounds 6-[(1 H-imicdazol-1-yl)(4-methoxyphenyl)methyl] -3-methyl-2(1 H)-quinoxalincone (compound. No. 128 of the present application) , S-ethyl-6-(1H-imidazol-1- ylphenylmesthyl)-2(1 H)-quinoxalinone (compound No. 127 of the present application) and 6-[(4-chlorophenyl)-1H-imidaz.eol-1-yimethyl}-3-methyl-2(1.41)- quinoxalinone (compound No. 146 of the present application) are disclosed.
A ~ ~ Sp cS Vr :
H compound 128 compound 1227 1
N nn
Ca NT
Pig 3 compound 146
Descriyption of the invention
This invention concerns compounds of formmula (I) . R4 R? (CH) Xx R! 2.
AX 0
R3 RS H the N-Oxide forms, the addition salts and tae stereo-chemically isomeric forms thereof, wherein nis 0, lor2;
XisN or CR’, wherein R’ is hydrogen or t-aken together with R! may fomrm a bivalent radical of formula -CH=CH-CH=CH-;
R!is C,4alkyl or thiophenyl;
R? is hydrogen, hydroxy, C1.calkyl, Ca.salicynyl or taken together with R= may form =0;
Ris a radical selected from -(CHy)s- NR'R’ (a-1), -0-H (a-2), -O-R'® (2-3), -s-R" (a-4), or
- —C=N (a5), wherein sis 0,1,20r3;
R®, R' and R"" are each indegpendently selected from -CHO, Ci-alkyl, hydroxyCi alkyl, C1.¢alkylcaarbonyl, amino, Ci.¢alkylamino, di(C,-salkyl)aminoC;.¢alkyl, «Cy ¢alkyloxycarbonyl, C,salkylcarbeonylaminoC, ¢alkyl, piperidinylC, salkylaminocar-bonyl, piperidinyl, piperidinylCi.sak kyl, piperidinylC,_salkylaminocar-bonyl, C..¢alkyloxy, thiophenylC,.¢zalkyl, pyrrolylC; salkyl, arylCi.salk ylpiperidinyl, arylcarbonylC, salkyl , arylcarbonylpiperidinylC;.saltkyl, haloindozolylpiperidinylC;_¢alkxyl, or ary 1C 1.¢alkyl(C 1-salkyl)aminoC, alkyl; and
R’ is hydrogen or Cy.ealkyl; or R® is a group of formula -(CH2)-2 Cb-1), wherein tis0,1,20r3; -Z is a heterocyclic ring systesm selected from - 12 3 aS Oy INOS on INS Cn
Spin \Segn2 \—/ — [Y] (c-2) (c-3) (c-4) . RY R N {ae NE £3 (+ ©) ©6) © 0 8 rR o 74 NN 12 Ps 12 -
J £37 we
H
(9) (c-10D (c-11)
=. wh-erein R'? is hydrogen, halo, Cy6alkyl, aaminocarbonyl, amino, hydroxy, aryl, — ng) Op , —C, alkane” o ,
C1—¢alkylaminoCj.salkyloxy, C)¢alkyloxyC; 6alkyl, C,.salkyloxyCy alk -ylamino, ary1Cy alkyl, di(phenylCz salkenyl), pipe-ridinyl, piperidinylC; alkyl,
Cs cycloalkyl, Cs.10cycloalkylC alkyl, aryloxy(hydroxy)Ci.ealkyl, haaloindazolyl, arsylC, galkyl, arylCz.salkenyl, arylC,.¢alk—ylamino, morpholino, C-¢alkylimidazolyl, or pyridinylC;salkylamino;
RY 3 is hydrogen, piperidinyl or aryl;
R® R’andR® are each independently selected from hydrogen, halo, trihadomethyl, tarihalomethoxy, Cisalkyl, Ci.calkyloxy 5 amino, aminoC.¢alkyl, di(C1 —salkyl)amino, 3i(Cy.salkyDaminoC; ealkyloxy or C.¢amlkyloxycarbonyl, or Ci.galkyl ssubstituted vith 1, 2 or 3 substituents independent] y selected from hydroxy, C;.¢aalkyloxy, or zAaminoCj.galkyloxy; or } whenR® and R® are on adjacent positions ®they may taken together form aa bivalent radical of formula -0-CH-O (d-12, E -0-(CHz).-O- (d-2D, -CH=CH-CH=CH- d-3D,o0r -NH-C(O)-NR'*=CH- (d4D, wherein R' is Cy.galkyl; ary-1is phenyl, phenyl substituted with hal_o, Cisalkyl or Ci.salkyloxy; witch the proviso that when m is 0, X is N, R'is Cr.¢alkyl, R? is hydrogen, R® is a group of formula (b-1),tis 0, Z j= the heterocyclic ring system (c-2) wh -erein said heterocyclic ring system Z is attached to the rest of the molecule witl a nitrogen atom, and R'? is hsydrogen or
Cisalkyl; then at least one of the substituents R%, R® or R¢ is other than hydrogen, hal o, C.¢alkyloxy and trihalomethyl.
Whenever the heterocyclic ring system Z= contains a —CH,-, -CH=, or -INH- moiety the substituents R'? and R™ or the rest of the molecule can be attached to tine carbon or nistrogen atom in which case one or both Thydrogen atoms are replaced.
Oo
The compounds of formula (I) may also exisstin their tautomeric forms. Such forms alttmough not explicitly indicated in the above formula are intended to be include=d within the scope of the present invention.
A maumber of terms used in the foregoing definitions and hereinafter are explaine=d her<under. These terms are sometimes usedl as such or in composite terms.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, brosmo and iodo; C, alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 2-methylprop yl, 2-mnethyl-butyl, 2-methylpentyl aand the like; C, salkanediyl defines bivalent straight and branched chained saturated -hyedrocarbon radicals having from 1 to 6 caxbon atoms such as, for example, methylene, ". 15. 1;2-cthanediyl, 1,3-propanediyl 1,4-butanedliyl, 1,5-pentanediyl, 1,6-hexanediy and the - branched isomers thereof such as, 2-methyl pentanediyl, 3-methylpentanediyl, 2,2- dixpethylbutanediyl, 2,3-dimethylbutanediy’1 and the like; trihalomethyl defines methyl containing three identical or differemt halo substituents for example trifluoromethyl; C, (alkenyl defines straight and branched chain hydrocarbon r=adicals co-ntaining one double bond and having from 2 to 6 carbon atoms such as, for e=xample, ethneny), 2-propenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, aned the likze; C, calkynyl defines straight and branch chained hydrocarbon radicals con®&aining ore triple bond and having from 3 to 6 carbon ators, such as, for example, 2-peropynyl, 3—butynyl, 2-butynyl, 2-pentynyl, 3-pentyn.yl, 3-hexynyl, and the like; Cs.10cyc loalkyl in cludes cyclic hydrocarbon groups having from 3 to 10 carbons, such as cyclopropyl, cy~clobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl , cy-clooctyl and the like.
The term “addition salt“ comprises the salts which the compounds of formula «() are able to form with organic or inorganic bases such as amines, alkali metal bases and earth alkaline metal bases, or quaternary axnmonium bases, or with organic or irorganic acids, such as mineral acids, sulfonic acids, carboxylic acids or phossphorus containing acids.
The term “addition salt“ further comprises pharmaceutically acceptable salts, wmmetal complexes and solvates and the salts thereof, that the compounds of formula (TT) are able to form.
The term “pharmaceutically acceptable salts” means pharmaceutically accegptable acid or base addition salts. The pharmaceutically aczceptable acid or base addition salts as mentioned haereinabove are meant to comprise athe therapeutically active nom-toxic acid and non-toxic base addition salt forms which tiie compounds of formula (I) are able to form. The ccompounds of formula (T) which hae basic properties can be comverted in their pharmzaceutically acceptable acid additiorm salts by treating said base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic 2xcids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; pheosphoric and the like acidlls; or organic acids such as, for example, acetic, propanoic, hydmroxyacetic, lactic, pyruwic, oxalic, malonic, succinic (i.e. beutanedioic acid), maleic, fumaric, malic, tartaric, citr-ic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluene=sulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic zand the like acids.
The compowunds of formula (I) which have aciclic properties may be converted in their pharmaceutically acceptable base addition salt s by treating said acid form with a 15 . suitable orgzanic or inorganic base. Appropriate base salt forms comprise, feor example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithiu-m, sodium, : potassium, -Tnagnesium, calcium salts and the Li ike, salts with organic bases,. e.g. the : benzathine, N-methyl-D-glucamine, hydrabanine salts, and salts with amiro acids such : as, for example, arginine, lysine and the like.
The terms acid or base addition salt also compmrise the hydrates and the solwent addition forms whic h the compounds of formula (I) are= able to form. Examples of ssuch forms are e.g. hycGrates, alcoholates and the like.
The term ‘““mmetal complexes” means a complex formed between a compourd of formula (I) and one or more organic or inorganic meta salt or salts. Examples of samid organic or inorganic s alts comprise the halogenides, nitreates, sulfates, phosphates, acetates, trifluoroace=tates, trichloroacetates, propionate-s, tartrates, sulfonates, e.g. methylsulfeonates, 4-methylphenylsulfonates, salicylates, benzoates and the like of the metals of thhe second main group of the periodical system, e.g. the magnesium or calcium salts, of the third or fourth main group, e.g. aluminium, tin, lead ass well as the first to the eighth transition groups of the perisodical system such as, for ex ample, chromium, manganese, iron, cobalt, nickel, copper, zinc and the like.
The term s-tereochemically isomeric forms of compounds of formula (I), ass used hereinbefo=re, defines all possible compounds made up of the same atoms bonded by the same seque=nce of bonds but having different sthree-dimensional structures which are not interchang=eable, which the compounds of formnula (I) may possess. Unles s otherwise mentioned _ or indicated, the chemical designation of a compound encompamsses the mixteare of all possible stereochemically isomeric forms which said compound may posse ss. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereOchemically isomeric forms of the comp ounds of formula (D) both in pure form or in admixture with each other are intencled to be embraced within the scope of the present invention.
The N-oxide forms of the compounds of formula (I) are meant to comprise those comprounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein one or more of the piperidine-, piperazine or pyridazinyl-nitrogens are N-oxidized.
Whenever used hereinafter, the term "compounds of formula (1)" is meant to include also the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and all stesreoisomeric forms. :
The compounds described in EP 371564 suppres s the plasma elimination of retinoic acids . 6-[( 1 H-imidazol-1-y1)(4-methoxyphenyl)rmethyl]-3-methyl-2(1H)-quinoxalinone . : (compound No. 128 of the present application) , 3-ethyl-6-(1 H-imidazol-1- ylphesnylmethyl)-2(1H)-quinoxalinone (compound No. 127 of the present application) and 6-[(4-chlorophenyl)-1H-imidazol-1-ylmethy 1}-3-methyl-2(1H)-quinoxalinone (compound No. 146 of the present application) Ihave been disclosed in EP 371564.
Unexpectedly, it has been found that the compounds of the present invention show
PARP inhibitory activity.
A first group of interesting compounds consists ©f those compounds of formula (I) wherein one or more of the following restrictions apply: a) R! is Cealkyl; b) R™ is a radical selected from (a-1), (a-2), (a-3) or (a-5) or is a group of formula (b-1); c)sis0,1lor2; d)R™ and R" are each independently selected from —CHO, Cy.¢alkyl, hycdroxyC 1 salkyl, di(C 1 salkyl)aminoC -galkyl >
C,- alkylcarbonylaminoCi.¢alkyl, piperidinylC ; alkyl, pip eridinylC; salkylaminocarbonyl, C,¢alkyloxy, thiophenylCjsalkyl, pyrrolylCy.ealkyl, arylC.salkylpiperidinyl, ary JcarbonylCysalkyl, ary-lcarbonylpiperidinylCi.ealkyl, haloindozoly1piperidinylC,.¢alkyl, or ary-1C;.galky}(C1.salkyl)aminoCy.calkyl; e)tis0or2;
f) Z is a heterocyclic ring syste=m selected from (c-1), (c-2), (c4). (c-6), (c-8), (c-9), or (c-11);
Cammln( g) R" is hydrogen, Ci.¢alkyl, aaminocarbonyl, ,
C,.salkyloxyCy.alkylamino, di(phenylCz alkenyl), piperidinyl~C;.galkyl,
Cs.ycycloalkyl, Cs.10cycloal kylCealkyl, haloindazolyl, or aryRC;.salkenyl; h) RY, RS and R® are each indegpendently selected from hydrogen, halo, trihalomethyl, trihalomethoxy, Cr.ealkyl, C 1salkyloxy, di(C, salkylaimino, di(C1salkyl)aminoCi.salkyloOxy or C,.¢alkyloxycarbonyl; and i) when R® and RS are on adjacent positions they may taken together form a bivalent radical of formula (d-1) or («d-2). :
A second group of interestingz compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply: aynis 0; b)Xis CR’, wherein R’ is hy-drogen or taken together with R! mnay form a bivalent radical of formula -CH=CIX-CH=CH-; c) R'is Cyealkyl; d) R? is hydrogen; So e) R3is a radical selected fromm (2-1), (a-2) or (a-3) or is a group~ of formula (b-1); fsisOor2; g)R® and R" are each independently selected from —CHO, Ci .salkyl, di(Cisalkyl)aminoCy.ealky], piperidinylC,.¢alkyl, arylcarbonylpiperidinylC- ealkyl, haloindozolylpiperidinylC; alkyl, or arylCy.¢alkyl(C).salkyl)aminoC,.calkyl; h)tisOor2; i) Z is a heterocyclic ring sysstem selected from (c-1), (c-2) or («c-6); aa j) R" is hydrogen, , C1.¢alkyloxyC; _salkylamino, or piperidinylCi.calkyl; k) R!3 is hydrogen or aryl; 0D R* R® and R® are each inc3ependently selected from hydrogen or trihalomethyl; and m) when RS and RS are on adjacent positions they may taken teogether form a bivalent radical of formula (d-1) ox (d-2).
A third group of interestingz compounds consists of those compounds of formula (I), the first group of interesting compounds or the second group of interesting compounds wherein Z is a heterocyclic ring system other than the heterocyclic ring system of formula (c-2) or (c-4).
A group of preferred compounds consists of those compounds of for-mula (I) wherein
R'is C).galkyl; R3is a radical selected from (a-1), (a-2), (a-3) or (a—>5) or is a group of formula (b-1); sis 0, 1 or 2; R® and R' are each independently sele=cted from —CHO, C;.¢alkyl, hydroxyCy.salkyl, di(Ci.salkyl)aminoC alkyl,
C1.salkylcarbonylaminoC 1 —¢alkyl, piperidinyliC;.¢alkyl, piperidinylC,_salkylaminocarbonyl, C.salkyloxy, thiophenylC; sallkyl, pyrrolylCy.alkyl, arylC, salkylpiperidinyl, arylcarbonylCi salkyl, arylcarbonylpiperidinylC1 _¢alkyl, haloindozolylpiperidinylC; ¢alky~], or arylCy.salkyl(C1.salkyl)aminoCi.ealkyl; t is 0 or 2; Z is a heterocyc lic ring system selected from (c-1), (c-2), (c-4), (c-6), (c-8), (c-9), or (c-1 1); Ris hydrogen,
Baa
C.¢alkyl, aminocarbonyl, N C.¢alkylox yC1salkylamino, di(phenylC,.alkenyl), piperidinylC; ¢alkyl, Cs 1ocycloalkyl, Ca joc=ycloalkylCy salkyl, haloindazolyl, or arylC, alkenyl; R*, R® and R® are each independ ently selected from hydrogen, halo, trihalomesthyl, trihalomethoxy, Ci.¢alkyl, Ci-salkyJoxy, di(C,.¢alkyl)amino, di{C;—galkyl)aminoC; salkyloxy or C..salkylox_ycarbonyl; and when R® and R® are on adljacent positions they may taken together— form a bivalent radical of formula (d-1) or (d-2).
A further group of preferred compounds consists of those compourads of formula @ wherein n is 0; X is CR’, wherein R is hydrogen or taken togethe=r with R' may form a bivalent radical of formula -CH=CH-CH=CH-; R'is Cy.¢alkyl; BR is hydrogen; R’is a radical selected from (a-1), (a-2) or (a-3) or is a group of formula (b-1);sis 0 or 2;
R® and R'? are each independently selected from ~-CHO, Cy ¢alkyl , di(C;salkyl)aminoC;.¢alkkyl, piperidinylC;.alkyl, arylcarbonylpiperidinylC alkyl, haloindozolylpiperidinylC,.salk=yl, or arylCi.salkyl(Cy.salkyl)axminoC, alkyl; tis O or 2; Z is a heterocyclic ring system —c en selected from (c-1), (c-2) or (c-6); R'? is hydrogen, ,
C,.alkyloxyCy.salkylamino, or piperidinyiCy.calkyl; R' is hydro gen or aryl; RY RS and R® are each independently selected from hydrogen or trihalor methyl; and when R® and R® are on adjacent positions they may taken together form a Yoivalent radical of formula (d-1) or (d-2).
An even further group of preferred compounds consists of those compo unds of formula (@), the group of preferred compounds or the further group of preferr=ed compounds wherein Z is a heterocyclic ring system other than the heterocyclic rinmg system of formula (c-2) or (c-4).
A group of more preferred compounds consists of those compounds of formula (I) wherein n is 0; X is CH; R is Cy.¢alkyl; R? is hydrogen; Ris a group of formula (b-1); tis 2; Z is a heterocyclic ring system selected from (c-1); R!?is- hydrogen; R"? is hydrogen; and R® and R® are on adjacent positions and taken togeth_er form a bivalent radical of formula (d-2).
The most preferred compounds are compounds No 16, compound No R44, and compound No. 145. ® ¢ ® compound 16 Compound 144 Compound 145
The compounds of formula (ID can be prepared according to the general methods described in EP 371564. ]
A number of such preparation methods will be described hereinafter in more detail.
Other methods for obtaining final compounds of formula (I) are describwed in the examples.
Compounds of formula (I) wherein RZ? is hydrogen and R? is -NR*-CHO wherein and
R’ is hydrogen or methyl, herein referred to as compounds of formula (I-b), can be prepared starting from compounds of formula (I), wherein R? taken togeether with R> forms =0, herein referred to as compounds of formula (I-a), in the prese=nce of formamide or methylformami de, here indicated as intermediates of forrmula (ID), and formic acid.
Ho 0
R
Rr ] XR Rr? N” xR
NE (CH, XI T NHR-CHO —> yo ng TL
Ze N70 Ne 0 {-a) { Cb)
Commpounds of formula (I), wherein R> is hydroxy, herein referred to ass compounds of formmula (Ic), can be prepared by converting the keton moiety of compeounds of formula (I-a) into an hydroxy group, with an appropriate reductant, e.g —, sodium borohydride in a suitable solvent, e.g. amethanol and tetrahydrofuran.
Q H : . 4 Xx _R* 4 XR (CH, a CHp), =x
Ty TU DNAS
Pp. = N O 5 \g N [6] oe ) SC } (I-a) I-<)
Compounds of formula (I-a) can be prepared by converting compound. s of formula ’ ~ (I--c), wherein R? is hydrogen, herein referred to as compounds of formula (I-c-1), in the pressence of a suitable oxidant such as chromium trioxide and an acid such as sulfuric : ac—id, in a suitable solvent such as 2-pr-opanone. - rR ? (CH) Xs’ ¢ (CH). Xs
Ry Oy CX
Ne NTO ¢ N” So es i es H (I<-1) (I-am)
Ceompounds of formula (I) wherein R= is hydrogen and R3 is aradical of formula (c-1), herein referred to as a compound of formula (I-f), can be prepared by xeacting compounds of formula (I) wherein RZ is hydrogen and R3 is a radical ef formula (c-8), herein referred to as compounds of formula (I-d), with an amine of formula (III), wherein R? is an appropriate radical, iin the presence of a suitable solvent such as methanol and a suitable reagent such as sodium cyanoborohydride.
Claims (16)
1. A compound of formula (I), 4 2 Rr!
RN . (CH, XS i ® RR H the N-oxide forms, the addition salts and the stereo-chemically isomeri c forms thereof, wherein } nis0,1 or2; X is N or CR’, wherein R is hydrogen or taken together with R! may form a bivalent radical of formula -CH=CH-CH=CH-,; R'is Cyalkyl or thiophenyl; R? is hydrogen, hydroxy, C;.salkyl, Cs.salkynyl or taken together witha R® may form =O; R%is a radical selected from (CHy)s- NR®R® (a-1), -0-H (a-2), OR" (a-3), -8-R! (a4), or —C=N (a-5), wherein sis 0,1,20r 3; R®, RY and R* are each independently selected from CHO, C, saRkyl, hydroxyC,.¢alkyl, C;.salkylcarbonyl, amino, C;-salkylamino, di(Cy.¢alkyl)aminoC;.¢alkyl, «C, salkyloxycarbonyl, C1.¢alkylcarbomylaminoC, alkyl, 3«0 piperidinylCi.ealkylaminocarbonyl, piperidinyl, piperidinylCysalk yl, piperidinylC;.¢alkylaminocarbonyl, C,.salkyloxy, thiophenylC;.¢ak kyl, pyrrolylC, .galkyl, arylC,.qalkcylpiperidinyl, arylcarbonylCi.salkyl, arylcarbonylpiperidinylCi.a kyl, haloindozolylpiperidinylC,.salk =i, arylC.¢alkyl(Cy.salkyl)aminoC, alkyl, and =5 R’ishydrogen or Ciealkyl; or R? is a group of formula
WO 2005/054201 PCT/EZP2004/013163 -(CHa)Z (b-1), =wherein ®is0,1,20r3; —~7 is a heterocyclic ring system selected from 12 SexeR NA XN mJ ay N HSS R12 LN R12 R12 \—~ R12 \—/ \d cD (c-2) (c-3) (c4) AN — R? x A / N\ 12 XX x _ > 12 N 12 —R HN NH R R & J L’ ©) 6) ©D 0 8 Rr! 0) 4 Nn 12 vl —R —— —R J CF Oa [ H “10 Se 9) (c-10) 11) } - wherein R'? is hydrogen, halo, Ci.salkyl, a minocarbonyl, amino, hydroxy, aryl, —C, em) ) NH NL —Cyqalicanedi yt 0
Ci.salkylaminoC;.¢alkyloxy, Ci-salkyloxyCi.salkyl, C;-galkyloxyCi.salky-lamino, arylC alkyl, di(phenylC;.¢alkenyl), piperddinyl, piperidinylC, alkyl,
Ca.iecycloalkyl, Can ocycloalkylC, ealkyl, aryloxy(hydroxy)Ci.ealkyl, hall oindazolyl, arylCy.¢alkyl, arylC» galkenyl, arylC;.alky/lamino, morpholino, CisalkyRimidazolyl, pyridinylCi.salkylamino; and R'? is hydrogen, piperidinyl or aryl; R= R® and R® are each independently selected from hydrogen, halo, trihalomethyl, trihalomethoxy, Ci.salkyl, Ci.salkyloxy, amino, aminoCy.salkyl, di(C,-s:alkyl)amino, di(C.¢alkyl)aminoC;.ealkyloxy or C:.salkyloxycarbonyl, or Ci.¢alkyl substituted with 1, 2 or 3 substituents independently selected from hydroxy, Ci.¢allkyloxy, or aminoC) salkyloxy; or when R® and R® are on adjacent positions they may taken together fosrm a bivalent radical of formula : -0-CH,-O (d-1), -0-(CHz),-O- (d-2), -CH=CH-CH=CH- (d-3), or -NH-C(0)-NR'*=CH- (d-4), wherein R!* is Cygalkyl; aryl is phenyl, phenyl substituted with halo, C).salkyl or Cy.salkylox sy; with the proviso that when nis 0, X is N, Rlis Cy¢alkyl, R?is hydrogen, R? is a group of formula (b-1), tis 0, -Z is the heterocyclic ring system (c-2) wherein said heterocyclic rings system -Z is attached to the rest of the molecule with a nitrogen atom, and Ri s hydrogen or Cisalkyl; then at least one of the substituents TR, R® or R® is other than hydrogen, halo, Ci.¢alkyloxy and trihalomethyl. Co
2. A compound as claimed in cXaim 1 wherein . R'is Crealkyl; R3is a radical selected from (a-1), (2-2), (a-3) or «(a-5) or is a group of formula (b-1); § is 0, 1 or 22; R® and R'° are each independently selected from —CHO, C.¢alkyl, hydroxyCi _ealkyl, di(C;.salkyl)aminoC, alkyl. C, ¢alkylcarbonylaminoC, alkyl, piperidinylC,.salkyl, piperidinylC; alkylaminocaxbonyl, C;ealkyloxy, thiophenylC;.s alkyl, pyrrolylCi_salkyl, arylC, galicylpiperidinyl, arylcarbonylCi galkyl , arylcarbonylpiperidinylCi.salkyl, haloindozolylpiperidinylCi.sallkyl, or arylC;.salkyl(Ci-salkyl)amin©Cygalkyl; tis 0 or 2; -Z is a heterocyclic ring system selected from (c-1), (c-2), (c—4), (c-6), (c-8), 9), or (c-11); R'? is hydrogen, can
Ci.salkyl, aminocarbonyl, , C1.salkyloxyCh.galkylamino, di(phenylC; alkenyl), piperi dinylC 16alkyl, Cs.1cycloalkyl, Cs 1ocycloalkylCh.ealky}, halwindazolyl, or arylCs alkenyl; R*, R_% andR® are each independently selected from hydrogen, halo, trihalomethyl, triha_lomethoxy, C1salkyl, Ci.alkyloxy, di(C 1alkyl)amino, di(Ci.¢alkyl)aminoC 1¢alkyloxy or
C.¢alkyloxycarbonyl; and when RS and R® are on adjacent positiions they may taken together form a bivalent radi cal of formula (d-1) or (d-2). :
3. A compound according to claim 1 amnd 2 wherein n is 0; X is CH; R'is Ciealkyl; R*is hydrogen; R%is a group of fomula (Bb-1); tis 2; -Z is a heterocyclic ring system selected from (c-1); IR" is hydrogen; R=” is hydrogen; and R® and R® are oan adjacent positions and take n together form a beivalent radical of formula (d-2).
4. = compound according to claim 1, 2 and 3 wherein the compouncl is c¢ ompounds No 16, compound No 14-4, and compound No. 145. oo SOMesS - SN N (¢] compound 16 C ompound 144 Conapound 145
5. Ms compound of formula (VII-a), RS RS 7 4 | SN R! x 0 rR’ 6 R H the NJ-oxide forms, the addition salts and. the stereo-chemically isome-xic forms thereof, wherein R! RR’ RR and aryl are as defined in claim 1; R°is hydrogen or taken together with R? may form a bivalent radical of formula ~(CH;)-NRP-(CHp)- (e-1), or -CH,-NR'-(CHy)5- (€-2), wherein RY and R'6 are each independently selected from hydrogen_, Crsalkyl, — my) y L —Cpglkamediyl Oc, alkyloxyCalkyl,
: piperidinylC; gal kyl, Cs.iocycloalkylCyealkyl, arylo-xy(hydroxy)Cy ealkyl, arylCr.ealkyl, or arylCs.ealkenyl; or R%is di(C;.ealkyl)a minoCi.salkyl or piperidinylC.gall=yl.
5 .
6. A compound as claimed in any of claims 1 to 5 foor use as a medicine.
7. A pharmaceutic al composition comprising pharmas ceutically acceptable carriers and as an active ingwedient a therapeutically effective ammount of a compound as claimed inclaim 1 to 5. .
8. A process of preparing a pharmaceutical composit=ion as claimed in claim 7 w herein the pharmaceutically acceptable carriers and a coranpound as claimed in claim 1to5 are intimately mixed.
9. Use of a compound for the manufacture of a mediecament for the treatment of -a E PARP mediatec disorder, wherein said compound is a compound of formula (_I) 4 2 XR R AX N~ To . 5 6 RR H the N-oxide forms, the pharmaceutically acceptable adlldition salts and the stereo- chemically isomeri« forms thereof, wherein nis0,lor2; X is N or CR”, whe rein R’ is hydrogen or taken together with R! may form a bivallent radical of formula -CH=CH-CH=CH-; R'is C.ealkyl or thiophenyl; R? is hydrogen, hydroxy, Cy.alkyl, Cs.alkynyl or take=n together with R® may forran =O; R?is a radical selected from (CH,)s- NRR? (e-1), -O-H (a-2),
OR" (a-3), -S-R" (a-4), or — CN (a-5), whereira sis0,1 ,20r3; R®, R'® and R" are each independently selectec® from -CHO, Ci.¢alkyl, hydrox s/Cy.galkyl, Cy.galkylcarbonyl, amino, Cy alkylamino, di(C;_¢alkyl)aminoC, galkyl, Ci-salkyloxycarbomyl, Ci.galkylcarbonylaminoC)saalkyl, piperidi nylC;.salkylaminocarbonyl, piperidinyl_ piperidinylC;.salkyl,
piperidi nylC;.¢alkylaminocarbonyl, C.salkylox_y, thiophenylC,.salkyl, pyrrolyRCy_galkyl, arylC,.salkylpiperidinyl, arylecarbonylCh salkyl, arylcarbonylpiperidinylCi.ealkyl, haloindozolyl piperidinylC;.salkyl, arylCy.¢ alkyl(C.salkyl)aminoC; alkyl, and
R’ is hy-drogen or Cy.salkyl; orR*isa group of formula : (CHo)Z (b-1), . wherein . tis0, 1, 20r3; -Z is a hneterocyclic ring system selected from
~Se>RT SA \N NN m0) HN N HN D gn HEN D p12 REI Wi SN \—/ ey (cD) (c2) (c-3) (c-4) 12 H O {c-5) (c-6) © O (8 13 0 4 NL 12 XX 12 - } Je £30 a H (c-) (c-10) (c-11)
wherein R'? is hmydrogen, halo, C;.¢alkyl, aminocarE>onyl, amino, hydroxy, arsyl, Tome) Cp N , —C, galkanediyt” oO ,
C.salkylaminoC, salkyloxy, Cy salkyloxyCi.¢alkyl, Ci.salkyloxyC;.salkylamimno, arylCy.galkyl, di«(phenylC;.¢alkenyl), piperidinyl, pigperidinylC,_galkyl,
Cs.jocycloalkyl, Cj jecycloalkylCalkyl, aryloxy(h ydroxy)Ci.salkyl, haloindazolyl, arylC; salkyl, ar—yICy alkenyl, arylC, salkylamino, rmorpholino, Ci¢alkylimidaazolyl, pyridinylC; salk_ylamino; and R" is hydrogen, piperidinyl or aryl; R* R®andR® are each independently selected from hydrogen, halo, trihalomethmyl, trihalomethoxy—, C;-salkyl, Ci.salkyloxy, amino, amminoC) salkyl, di(Ci.¢alkyl Damino, di(C, ealkyl)anminoC;.¢alkyloxy or Ci¢alkyloxycar-bonyl, or Cy.salkyl substitmited with 1, 2 or 3 substituents independently selected £rom hydroxy, Cy¢alkylox~y, or aminoC,.¢alkyl-oxy; or when R® and R® ar—e on adjacent positions they may ta=ken together form a bivaleent radical of formula -0-CH;-O (4-1), -0O-(CHz),—0- (d-2), -CH=CH-CH=CH- (d-3), or -NH-C(O)—NR!=CH- (d-4), "wherein R'is C21 6alkyl; aryl is phenyl, phe=nyl substituted with halo, Cr.salkyl or Cygalkyloxy.
10. Use of a comp=ound according to claim 5 for the manufacture of a medicame=nt for the treatment cof a PARP mediated disorder.
11. Use according to claim 9 and 10 wherein the treatment involves chemosensitizaation.
12. Use according to claims 9 and 10 wherein the treatment involves radiosensit=ization.
13. A combination_ of a compound with a chemotherapeutic agent wherein said compound is a compound of formula (I) )
4 S XR PERC CS the N-oxide forms, the pharmaceutically acceptable addition saalts and the stereo- chemically isomeric forms thereof, wherein nis 0, 1 or2; X is N or CR”, wherein R” is hydrogen or taken together with IR may form a bivalent radical of formula -CH= CH-CH=CH-;
R'is Cy.salkyl or thiophen. yi; R? is hydrogen, hydroxy, €.alkyl, Cs.alkynyl or taken togetkner with R? may form =O; _15 Ris aradical selected from -(CHp)s- NR°R’ (a-1), -0-H (a-2), -O-R' (a-3), -S-RM (a4), or
—C=N (a-5), wherein sis0,1,20r3;
R®, R'® and R"! are each independently selected from ~CHO, Cy.¢alkyl, hydroxyC;.salkyl, Ci.¢alkylcarbonyl, amino, C).salkylamino,
di(Cy.¢alkyl)aminoC;saalkyl, C-salkyloxycarbonyl, Ci.¢alky=lcarbonylaminoC alkyl, piperidinylC;.salkylami nocarbonyl, piperidinyl, piperidinyl<C,.¢alkyl, piperidinylC;.¢alkylami nocarbonyl, C1.salkyloxy, thiophensyIC) alkyl, pyrrolylCi.salkyl, arylC, salkylpiperidinyl, arylcarbonylCiesalkyl, arylcarbonylpiperidinyMC,.salkyl, haloindozolylpiperidinyl Ci galkyl,
arylC,.salkyl(Csalkyl aminoCigalkyl, and R’ is hydrogen or Ci.calkyl;
or R? is a group of formula -(CHx)-Z (b-1), wherein tis0,1,20r3; .
01- -Z is a heterocyclic ring system selecte-d from 12 SR XN ‘ m9 HN OSS IS i RY \org® \—./ \7/ (c—1) (c-2) (c-3-) c-® \ R12 3H L J No XTX J al I oe : —R HN NH R R — TNS — (5D (c-6) Ce) 0 (c9 rR? 0) 4 Ni 12 A ISERIES TE OW NN NI R! ! H ©9) (c-10) (c-11) whemrein R'? is hydrogen, halo, Cy gall=yl, aminocarbonyl, amino, hydroxy, aryl, ase Cp N , —C, gallanediyl” 0 ,
C1.¢=alkylaminoC,.salkyloxy, C 1-¢alkyloxyC;.galkyl, Cy.salkyloxyCi_ealkylamino, aryleC, galkyl, di(phenylCa.salkenyl), wpiperidinyl, piperidinylC;salk yl,
Cs.1mocycloalkyl, Cs jocycloalkylCi gal kyl, aryloxy(hydroxy)C,.ealky~1, haloindazolyl, aryleCy_galkyl, arylC; salkenyl, arylC;_ealkylamino, morpholino, C,.ssalkylimidazolyl, pyri_dinylC.¢alkylamino; and R'? ishydrogen, piperidinyl or aryl; R*, R-3 and RE are each independently selected from hydrogen, halo, tzrihalomethyl, trilhalomethoxy, Cy.salkyl, Ci.¢alkyl oxy, amino, aminoC;.salkyl, d_i(C,.salkyl)amino, dicCC,.salkyl)aminoC,.salkyloxy or C,galkyloxycarbonyl, or C.saE kyl substituted wi_th 1, 2 or 3 substituents independently selected from hydroxy, CC). salkyloxy, or anminoC;.galkyloxy; or wherm R® and R® are on adjacent positions they may taken together fom a bivalent radic al of formula
-O-CH,-O (d-1), -0-(CH,)-O- (d-2), -CH=CH-CH=CH- (d-3), or -NH-C(O)-NR"=CH- (0-4), wherein R' is C; ¢alkyl; aryl is: phenyl, phenyl substituted with halo, Cy.alkyl or Cisalkyloxy. :
14. A combination of a compound accordimg to claim 5 with a chemoth=erapeutic agent.
15. A process for preparing a compound ass claimed in claim 1 orclaim $5, characterized by a) the hydrolysis of intermediates of formula (VIII), according to art-knmown methods, by= submitting the intermediates of forrmula (VIII) to appropriate reagents, such as, tirachloride, acetic acid and hydrochloric acid, in the presence of a re=action inert so lvent, e.g. tetrahydrofuran, Coe XR —_ XR" gh R (CH), Xs} OC yO Fe ° a" H (VI ® b) the cyclization of intermediates of formmula (X), according to art-kno=wn cyclizing preccedures into compounds of formula (I) wherein X is CH herein referred to as co-mpounds of formula (I-j), preferably in the presence of a suitable= Lewis Acid,
e.=2 aluminum chloride either neat or ira suitable solvent such as, f=or example, an areomatic hydrocarbon, e.g. benzene, chalorobenzene, methylbenzene= and the like; ha_logenated hydrocarbons, e.g. trichlor-omethane, tetrachloromethare and the like; an_ ether, e.g. tetrahydrofuran, 1,4-diox zane and the like or mixtures of such solvents, ‘ Rr? « R CH, ~~} R (CHa) n aaa CUE I NO G6 = NH—C—CR'=C— X FO Hs RES )
(0.9) ap c) the comdensation of an appropriate ortho -benzenediamine of formula (XI) with an ester of formula (XII) into compounds eof formula (I), wherein X is N and R? taken together with R? forms =O, herein refer—red to as compounds of formula (I-a- 1), in the p-xesence of a carboxylic acid, e.g. amcetic acid and the like, a mineral acid such as, for example hydrochloric acid, sulfuric acid, or a sulfonic acid such as, for example, methanesulfonic acid, benzemesulfonic acid, 4-methylbenzenesulfornic acid =and the Like, Re (CH, wy J : CH, NR ye — iy TOE o Xe NH, 0 h LX, ) 2) xD Xm (-a-1) d) hydroslysing intermediates of formula (\/1), wherein R3 is a group of formula «b-1) or a racdical of formula (a-1) wherein s is other than 0, herein referred to as RE, according to art-known methods, such as stirring the intermediate (VI) in an aque=ous acid solution in the presence Of a reaction inert solvent with the formmation of irmtermediates and compounds of formula (VII), wherein R% and R°® are appropriate radicals or taken together with the carbon to which they are attached, oo fornm an appropriate heterocyclic ring ssystem as defined in -Z, rR rR = CH,), Xs ® ROS (CH, XR INCI G GUE lp § AX NO LX p yoo R =e - R R H VI) VI e) converting intermediates of formula (VII), by a selective hydrogenation of said inte<rmediate with an appropriate reduecing agent and an appropriate reductamtina suit able solvent with the formation of compounds of formula (T) wherein R= is hyd_rogen and RE is as defined above, herein referred to as compounds of fo mula aid.
RAL pi R 4 1 Rr! 4 rR! Cy — yO A NC [6] C4 ¢ [0] FX H FX H (Vip Ii)
16. A processs for preparing a compound as claimmed in claim 5, characterized bey a) reacting sa compound of formula (VII-a), wher—ein R® taken together with R™ forms a bivalent radical of formula (e-1) or (e-2) (e.g- a bivalent radical of formula (e-1)) and RS «or R* (e.g. R') are hydrogen, herein referred to as compounds of formula : (VI-a-2 ), with an intermediate of formula (X_IX) wherein W is an appropra ate - leaving gzroup such as, for example, chloro, baromo, methanesulfonyloxy or benzenessulfonyloxy and R* or R! (e.g. R'®) are other than hydrogen, witha the formaticen of compounds of formula (VII-a-1>), defined as compounds of fo xmula (VI-a), wherein R® taken together with R¢ forms a bivalent radical of forrmula (e-1) or (e-2) «(e.g. a bivalent radical of formula (e- 1)) and R¥orR!® (e.g. R") amre other than hydrogen, in a reaction-inert solvent; or . } ES 15 H %
N. - ? 7 4 x R! 4 rR! © + WRYS —» IN ES AX Yoo 9 Z Ne N Oo RRS i RS Xo A (VII-zaa-2) XIX) (VI-a-1) b) reacting ae compound of formula (VII-a-2) witha an intermediate of formula (=XX) wherein R iss an appropriate substituent whit the formation of compounds of fo-xmula (VII-a) wherein RP orR! (e.g. RY) are aryloxy(Ehydroxy)C,salkyl, herein refe=tred to as compounds of formula (VII-a-3), in the presence of 2-propanol.
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