AU739382B2 - Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase - Google Patents

Description

Regulation 3.2(2)

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT C C

C

Application Number: Lodged: Invention Title: ARYL AND HETEROARYL QUINAZOLINE COMPOUNDS WHICH INHIBIT CSF-1 R RECEPTOR TYROSINE KINASE

CC".

CC..

C. *C C C The following statement is a full description of this invention, including the best method of performing it known to US ARYL AND HETEROARYL

QUINAZOLINE

COMPOUNDS WH-fICH INHIBIT CSF 1 R RECEPTOR TYROSINE

KINASE

BacgrundoftheIneim This aPPlication is a continuation-inpar application of United States Serial No. 08/299,886, filed April 19, 1994, Which is a con tnuation.in..par of Serial No. 08/16,199, filed December 10, 1993, which is a continuation-in.part of Serial No. 07/988,515, filed December 10, 1992, which Is a cofltifluatofl..il.

part application of United States Serial No. 07/898,420O, tiled May 10, 1991 and a continuatlon-ln..part application of PCT International Applli*cation Serial No.

PCT/US92/03736, filed May 6, 1992, which has entered the U.S. National Stage as Serial No. 08/146,072, filed November 8, 1993.

Fil.f.h aafo T h i in e t o r e a e o t e m d l to*n r n i i i n o a l s g a i g c ell p r lf r t o ,t e c n r lo.b o m a a l g o t n a lI f a m t r Nor al el grwt isbeieved to e tie re y h xp sr o h Thluarsinetireate s to onheo mo dulwt actons eand/rpnhbii of hcae Isunlin, Selldermlferatonth coro f anormlalellerv growth andctl Inlamory ecptr f. or sch growth fato b rei mobede tinered byete tougho the cellular membrane. The initiation of cellular reproduction is believed to occur when a growth factor binds to the corresponding receptor on the external surface of the cellular membrane. This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor which exists within the cell and which functions a3 an enzyme to catalyze Phosphorylation of either an intracellular substrate or the receptor itself, the latter being referred to as autophosphorylation. Exam~ples of such Phosphorylating enzymes include tyrosine kinases, which catalyze phosphorytlion of tyrosine amino acid residues of substrate proteins.

Many d~sease states are characterized by the unlcontrolled growth of calls. These disease states Involve a variety of cell types and include disorders such as cancer, leukemia, psoriasis, inflammatory diseases, bone diseases, atherosclerosis and restenosls occuring subsequent to angioplastic procedures.

The Inhibition of tyrosine kinases is believed to have utility in the control of deregulated cellular proliferation, cellular proliferative disorders.

Initiation of autophosphorylatio, phosphorylation at the growth factor receptor Itself. and of the phosphoryiatlori of a host of intracellular substrates are .20 some of the biochemical events which are involved in mediator release and cell proliferation.

*.dZJWmet Sanlsn L Celep9o,87.Thed Incluode mondthtsr otn u Anseritos of p56 1 1 ro-sin kirlasehave b been reported n thBieaure by A.a aol.n t e. CASem.et. 1992 43, 1771;lJ. MeT. Ce. 7 1993 215.

J. Med iChnK ne.Can d n. 1993, 304.) ahthv oet 5kihbtnd auiysPntial.

30 ntheeutcv i~afrsetv nhibitorsssc as stuoprnehc iscmeitie wi eth f o au selectie shas teuc favooi qretoij rhitsonraslnrjcin p56hkr, which is a non-receptor tyroalne kinase, has been shown to be Important in intracellular signaling in T-cells. It IS assumed that inhibitors of p56ICk kinase activity perturb the activation of T-cells and therefore a selective Inhibitor could prove useful in the treatment of T-ceI mediated conditions Such as organ rejection, rheumatoid arthritis or other auto-immune diseases.

SUMM21y Of the Invention The present invention describes compounds which are inhibitors of thle colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activty and have activity in a pS6ICk cell-free assay. These compounds do not appear to have any significant serine/threonine kinase inhibitory activity and in addition, compounds within the scope of this invention do not demonstrate significant PDGF-R activity in a cell-free assay. Compounds of this invention are also weak inhibitors of PDGF-lnduced mitogenesle which may suggest that these compounds inhibit other sic-like tyrosine kiflases Involved in the signal transduction pathway.

Compounds within the scope of this Invention are InhIbItors of the colony stimulating factor- 1 receptor tyrosine kinase, CSF- 1R, activity. A selective inhibitor of the tyrosIne kinase activity of this receptor, which Is closely related to the platelet-derived growth factor receptor (PDGF-R), has never been reported.

25 Compounds of this invention are selective inhibitors of CSF-IR tyrosine kinage activity and are useful for elucidating the ilioranoe of CSFi1 anid CSF-i P.receptor signaling in bone remodeling and hemnatopoeirsis. In addition compounds inhibiting growth factor-induced CSF anid/or Ick signalling are described herein.

In accordance with the present Invention, there is provided pharmaceutical compositions for Inhibfting ab owmaJ cell proliferation and/or differentiation or mediator release in a patient suffering from a disorder *.characterized by such prolifferation activity, comprising the administration to a patient a tyroSIne kinase composition which effectively inhibits CSF-1 R tyrosine klnase activity In a CSF-1 R inhibiting effective amount of a mono- aryl or heteroaryl quinazoline compound exhibiting inhibition of differentlation, proliferation or a

S..

*5

S

S S 7.

/1.

mediator release activity wherein each aryl group is a ring system containing 0-4 hetero atoms, said compound being optionally substituted or polysubstituted.

According to another aspect of this invention, there is provided a method for inhibiting Colony Stimulating Factor-1 receptor tyrosine kinase modulated cell proliferation, differentiation or mediator release in a patient suffering from a condition characterized by such proliferation, differentiation or mediator release comprising administering to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a pharmaceutical composition comprising a pharmaceutically effective carrier in admixture with a compound of the formula: Rs X( A r

R

6

N

N

wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero 15 atoms selected from N, 0 and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, 0, S, SO, SO 2

OCH

2 C=C, C C,C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R together may also form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof; with the exception of compounds in which: Ar is a phenyl ring; X is NH; and the phenyl ring represented by Ar carries one or two R groups that independently include hydrogen, hydroxy, halogen, CF 3 amino, nitro, cyano and alkyl; and R5, R6 and R7 are independently alkyl, hydroxy, alkoxy, carboxy or carbalkoxy; or (ii) the phenyl ring represented by Ar carries one halogen, CF 3 nitro, cyano, alkyl, alkoxy, mono- or di-alkylamino or alkylsulfonyl group represented by R; and one of R5, R6 or R 7 represents hydrogen or CF 3 and the other two represent hydrogen.

According to a further aspect of this invention, there is provided a method for the treatment of bone disease characterized by Colony Stimulating Factor-1 receptor tyrosine kinase activity in a patient suffering therefrom, comprising administering to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a composition comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula: wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, S, SO,, OCH 2 C=C, C C,C=S, SCH 2 I OF NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R5, R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof.

*i According to another aspect of this invention, there is provided a method for the treatment of a T-cell mediated condition characterized by p 5 6 Ick kinase 15 activity in a patient suffering therefrom, comprising administering to said patient a p 5 6 1 ck kinase inhibiting amount of a composition comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula: wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO2, OCH 2 C=C, C= C, C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2;

AT

0) R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention there is provided a method for the treatment of inflammation characterized by Colony Stimulating Factor-1 receptor tyrosine kinase activity in a patient suffering therefrom, comprising administering 15 to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a composition comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula: R7 Ro

N

R6-j r -N wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO 2

OCH

2 C=C, C C,C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2; 4d R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof; with the exception of compounds in which: ;Ar is a phenyl ring; X is NH or NR4, wherein R 4 is alkyl; the phenyl ring represented by Ar is unsubstituted or carries one halogen, alkyl or alkoxy group represented by R; and one of R5, R6 or R 7 represents hydrogen, halo or CF 3 and the other two represent hydrogen.

Preferred Ar monocyciic aryl or neteroatyl rings incILudeLsttedo un~usttut~benzene, pyrrole, thiophaig, fUra. thiazale, Iindazcla, pyrazole, 1.2 4 -triazole, Pyridin, 2( 1H)-oyrfdone, 4 IH)-pyridone, pyrazine. Pyrimicline, pyridazing, isothiazole, isoxazole, oxazole and tetrazole.

Preferred Ar bicyclic aryl or heteroaryl rings include substted and unsubstituted naphthalene, tetralin, naphthyridine, benzfran benzothiophene, indole, 2 3 -d~hyciroindole 1 H-indazcle, indolIne. benZoPyrzole, 1,:3. benzodioxwe, benzox-=le, purine, coumnarin, chrornone, qUinoline, tetrarlydroq u incoline, isoquinaline, benzimidazole, quinazo line, pyrido(2.3- bipyrazine. py!d(,4bJpyrzjne, pyrido 3 .2-Clpyridazine, pyrido(34b~pyridine, I1H- PYrazleP 3 -py~1.midne, pteridine, 2(1 H)qufioone l( 2 H)-isoquinolone, l, 4 -benzsoa~zne, benzothiazole quinoxa'rne, qIuinoline-N-oxide isoquinahine-. N-oxide. qunoaleNOde quinazoline-N-o 0 xje, berizoxaine, phthalazijne, or c inno line.

More Preferred Ar rings include substituted and unsubstitued benzene. pyridine, thioph~ee naphflhaiene, quinolina, indole, 1 H. pyrazolef,4-d.

SPyrimidine and PrefeirW R substtuents incaide hyrogen. alkyl, alkenyi, hydroxy, alkoxy, halo, halcalkyl, arnino. mono-and dl-alkylamrrinc, acylamnino, crboxy, carba&knY, amid, Mcno and di-aikyfamido, N,N4-cycleaJkyamido, alkytthio, 35 akylsutyl. alkylsulfoiyl or suffamoyf, alkyl. alkery, phenyl, aralkyl, araikenyf, and R may also form a keto group.

As employed above and throughout this disclosure (including the claims), the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Co.mprises/comprising"i when used in this specification is taken to specify the presence of stated features, integers, steps or components. but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

.4 4* *4 *4 4. 4* 4 "Monocjyclic aryl or haterToatyr moans ~~ICci cr helerocyci aromatic ring. Preferred rings include phenyf, Ihienyl. pyridyt, 2(1 H)-pyridnyi, 4 (li-1)-pyridonyi, furyt, pyrimidinyl. imidazoy 1 thiazoiyt, oxazolyl and tetrazolyi.

TM

SicYclic aryf or hetercaryfo Means a bicyclic ring system Composed of two fused carbocyclic and/or heterocycliic aromatic rings. Preferred rings include naphthyl, indolyl, benzothieiyl, benzofurany quinolinyl, chromonyl, l( 2 H)-isoquinolono, isoqu inolinyl. benzim idazoyi, bqnzo iazoiyi *qu InoxaffnyI, naphthyridirl, Cinnolinyl, pht~alazinyl. pyrido(23-bjprazny, pynido(3,4bjpyraziny, pyrido(3,2.clpyidazjnyl, pyrndo(3. 4bJ-pyrfdiflyl, pteridinyl, and quinazoinyL.

*Aikyr means a saturated aliphatic hydrocarbon, eihr brnhd or straight-chained. Preferred alkyl is tm oweraikyg having about 1 to about 6 carbon atoms. Examples orf alkyl include methyl, ethyt, n-propyl, isopropyl, butyl, sec-butyl, t-butyl, amyl and hexyl.

9 Cycloalkyr means a cyclic aliphatic group comprising from about three to about seven cerbon atoms. Preferred cCclOakyl groupas include cyclopropyl, Cyclobutyl, cyclohexyl and cyclofteptyl.

"~Alkoxy refers toalkyi-O-group. Preferred alkoxy groups include methoxy, ethoxy, propoxy and butoxy.

-Ary*oxy refers to an ariOgru. The Preferred aryioxy group is *9 phenaxy.

9. Araikyr* means an afikyl group SUbstitued by an aryl radical The preferred aralkyf groups are benzyl or phenethyl.

The preferred aradkoxy groups are benzyloxy and phenethaxy.

9. 9.35 99 The preferred acyloxy groups are acetOXY and benzyloxy "Halo" means halogen. Preferred halogens include chloride, bromide and fluoride.

The preferred haloalkyl groups are mono., di. and trifluoromethyl.

The more preferred compounds of this invention include those compounds of Formula I whore Ar is phenyl or naphthyl; 8 Is hydrog .en, alkyl, alkoxy, hydroxy, halo or trifluorom ethiyl.

X Is a bond, NH- or NP 4 and Rs. Rr, and R 7 are independently hydrogen or alkoxy.

The most preferred compounds are those described where Ar is phenyl; X is NH or NMe; and Rs. R 6 anid R 7 are independently hydrogen or methoxy.

It is Intended that 'N-oxides of the above described aminoquinazoljnes are encompassed within the scope of this invention, 4* Special embodiments of this invention inhibiting the growth factor or tyroslne kinase include the following: C Sf A. Compounds of Formula I where: X is a bond,

NR

4 S or 0, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by CSF-1 activity.

B. Compounds of Formula I where, X Is a bond, NH, S or 0, the inhibiting Cell Proliferation and/or cftfferentiation or mediator release Is especially characterized by IckIEGF activity.

C. Compounds of Formula I where: X Is a bond and Ar is phenyl, indolyl, pyrrolyl, thlenyl, Pyridyl, naphthyi, a bicyclic aryl, a bicyclic heteroaryl or substituted phenyl, indolyl, pyrrolyl, thienyl, pyridyl, naphthyl, bicyclic aryl, bicyclic heteroaryl, the inhibiting cell proliferation and/or differentiation or mediator release is especially characterized by Ick activty.

D. Compounds of Formula I where: X IsNH, Re and R 7 are alkoxy and Ar Is phenyl having at least one substijuent in the 3, 4 and or 5 positions of hydroxy or aikoxy, the inhibiting cell proliferation and/or differentiation or -mediator release is especially characterized by Ick activity.

The compounds of this invention may be useful in the form of the free base, In the form of salts and as a hydrate. All forms are within the scope of the invention. Acid addition salts may be formed and are simply a mare convenient form for use; and in practice, use of the saft form inherently amounts to use of the asa orm.The acids which can be used to prepare the acid addition salts Include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the animal organism in phraetcldoses of the sas, so that the beneficial properties inherent in the free base are ndt vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if teparticular salt per is desired only as anintermediate product as, for example, when the salt is formed only for purposes of purification and identification, or when it is used as an intermediate In preparing a pharaceticllyacceptable salt by ion exchange. procedures.

Pharmaceutically acceptable salts within the scope of the invention include those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamnic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid. malonic acid.

9 methanesuffonlc acid, erthanesutfonic acid, benzenesUifonic acid, p-tolueflesulfonjc acid, cyclohexyisuffamic acid, quinic acid, and the like.

The corresponding acid addition salts Comprise the following.

hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrte, m ethanesulfonate, ethanesuffonate, benzenesuffonate, p-toluenesuffon ate, cyctohexytsuflamate and quinate, respectively.

The acid addition salts of the compounds of this Invention are prepared either by dissolving the free base In aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and Isolating the sail by Qvaporating the solution, or by reacting the free base and acid in an organic solvent, In which case the salt separates directly or can be obtained by concentration of the solution.

The compounds of this invention may be prepared by employing procedures known in the literature starting from known compounds or readily prepared intermediates. Exemplary general procedures follow.

PO 2 In general the compounds usefl for the method of Inhibiling cell prlie.*lo and/or differentiation or mediator release may be prepared by the :coupling reaction of a palladium catalyzed aryl or heteroaryistannane with an aryl or heteroajyihalide or triflate.

RS A

R

7 "JN~ Pd(O)) RrX

A

IG

N

A

5 ~Pd(OjV

R

7 O cX

N

where A Is halogen or trifate and B is trialkylstannane and R Is as previously described.

The 4 -haloquinazolinG starting materials are Prepared in the classical way using anthranilic acid derivatives and formamide at reflux to provide the intermediate quinazolinones. Subsequent treatment with 130% 3 at about 110 TC for about two hours provides the chloroquinazolines The final products are prepared via a condensation with the appropriate aniline deivative in a polar solvent such as ethanol, In the case of the phenoxy or thlopherioxy derivatives, the metal salt (preferably Na) is prepared and refluxed for several hours with the appropriate haloquinazolin.e In a -Solvent such as THFM.

RGO RS 0 0 F or a mic e R 6N

H

NH

2 5 A POA3 A The ary! and heteroarylstannanes mybe prprdfrom the c: :orresponding halide (preferably brmd riodide) byconversion to the aryilithrum by reaction wth t-butyllithium at decreas ed temperatures, Preferably about -78' C followed by reaction with a halotrialkylstannane.

a ~SnM., R N Of course ths rdcsmyalso be prepared In the reverse mne using the aryl or hete roaryih al ides with the the corresponding stannane, Fts SnMe 3 OrT R r, R7 R7 The quinazoline stannanes intermediates may be prepared by the action of trimethyltin sodum on aryl halides as described in ChM hr-Bl. 1982, ~,1731-1737., The preparation of the compounds useful In this invention are described in Applicants' copanding applications U. S. Serial No. 08/166, 199, filed December 10, 1993 and U.S. Serial No. 08/229,886, filed April 19, 1994 of which this application claim priority. U.S. Serial No. 08/16,199 anid U. S. Serial No. 08/229,886 are hereby incorporated herein by reference, Further, the following examples are representative of the processes used lo synthesis the compounds of this invention.

The below examples and fthse described in U.S. Serial No. 08/166,199 may be followed to prepare any of the desired compounds of this Invention. A representative list of compounds which may be prepared is shown below.

-EXAMPLE 1 4-(3-chlo roohenoxv)-68.7-dimethoxyuinazoline 25THF (5 ml) and NaH (60% dlisp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. 3-Chlorophenol (0.09 g) is added as a soln. In THF (1 mL) and stirring is continued until the solution became clear. 4-Chloro-6,7-dirnethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution Is partitioned between 0H 2 C1 2 and 5% NaOH. The organic layer is washed wfth brine, dried (Na 2

SO,

4 and concentrated. Flash column chromatography EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-(3-chlorophenoxy)-6,7.

dim ethoxyqulInazo line (0.05 white needles, m.p. 152-1530C.

EXAMPI

E

4-(1-Methv ufohonldol.3.yfl..5 7 dimthoxrauo liune StgN-rnethylU-tfonl.3-trMethvlspnl~indole A solution of 5 g (15.57 mmol) of N-methyfauffonyl3-iodoinle (5.1 g; 15.57 mmol) of hexarnethyditin and 0.89 g (0.78 mmol) of Pd (PPh 3 4 in 75 mL of dry toluene is flushed thoroughly with nitrogen and heated to 90CC for A hours. The mixture, is the evaporated and chromatographed on silica gel (eluting with hexane and then with 10% ethyl acetate/hexane to give N- methylsulfonyl-3-trimethylstannyjlndol which is used directly in the next step.

A solution of 1.33 g (4.01 rnmol) of N-ehl foyl3 rmehl stannytlndole, 750 mg (3.34 mmol) of 4 -chloro-6,7-dirnethoxyquinazojje and 0.19 g (5 mol 0.16 mmol) of Pd (PPh-3) 4 in 10 ml of dry dlmnethylformamide Is flushed thoroughly with nitrogen and heated to 900C for 12 hours. The reaction mixture is diluted with methylene chloride washed with 10% ammonium hydroxide and stirred vigorously and then washed.with water and the combined organics are washed with brine (75 mL). dried (MgSO 4 and evaporated to dryness. Recrystallizatlon from ethyl acetate yields 4 -(1-methyisulphonyllndol-3 ~.20

Y-

6 7 -dmehoxyquinazoline >220*C).

The above examples may be followed to prepare any of the desired compounds of this invention. A representative list of compounds wilch may be prepared are shown bWow.

6,7dmehx--ahhln2yehnfunz ie m. p. 158-161 0

C

*3 aaM.P. >270 0 C (dec) 4-(naphthalen-1 7 -dmethoyquinazoline, m.P. 144-1 470C 4 -(naphthalen-2-yi)6s7dimethoxyquinaoline M.P. 11 S-118 0

C

13 4 -phenylacetyleriyl-6,7.dim ethoxyquinazoulne, m.p. 146-1 48 0 0 4-3fur--ehxpoy)-,.lehxqiaois m~p. 207-21 0 0

C

4 3 -phen ypheny)6,7dimethoxyquinazoline, m.p. 160-1 63-C 4-(2-phenyiethylenyl)-6, 7-dimethoxyqulnazolime, m.p, 168-1 69 0

C

4-2mtoyydn6y)e7dmtoyuiaois m.p. 175-1 76 0

C

4-(1-benzyllndo l- 3 -yt)- 6 a 7 -dimethoxyquunazoline, rn.p. 148-1 4 -(ifldoI-3.yl).6,7dImethoxyquinazoline m.p. >2400C (dec) 1-methyindol3yi)-67dmethoyuinzline hydrochloride, imp. >230'C (dec) 4-(i-methlsulphony indo 3y)- 6 7 -dimethoxyquinazoline, .22 0 C (dev) 4 -(4-phenylpperldin-1 -yl) e,7-dimetho quinaoline, m.p. 150-151*C 4 -[4-(3-chlorophentyi)piperazln-1 yI- 6 ,7-dimethoxyquinazoline, m.p. 155-1 5600 m.p. 149-151 0C -)-4-(2-methyl- 1234ttayrqlol-1y)87dmehxqiaoln hydrochlorie, m.p. 198-201*C (dec) 4-1234ttayrqioi-1y)67dmtoyunzln hydrochloride, m.p.

195-1 97 0 C (dec) 4 -(N-methy- methoxyaniino)-.6,7-dimethoxyquinazolile hdohoie m.p. 202-2050C 4-Nmty--hoonlno-.-ietyunzln hydrochloride, m.p. 220-2220C 14 4-(2,3-dihydroindol. l-Y)-6.7-dimethoxyquinazoi me hydrochloride, m.p. 226-229 0 C (dec) N-67dmtoy iaoi--f--ehk-3tilooehlhnla n hydrochloride, mn.p. 240-2430C N- 3 -chlorophenyl)-N-(6 7-dimethoxyqu inazolin-4yi)-N-mthyai me hydrochloride, m.p. 235-237 0

C

101 N-3clrpeAN(unzln4y)Nm~mn hydrochloride, m.p. 233- 235*C 6,-iehx--ahhlr)ly-tyyqiaoie m.p. 1 75-1 77 0

C

4 -(thien-3-yl)6,7-djmmthoxyqulnazoli, mn.p. 148.5-151 .5 0

C

4 -benzy.6,7-dimethoxquinazoljne, m.p. 122.5-1 25 0

C

(6,7-dim elhoxyquinazoin4yi)5-indazolylamine hydrochlobride, 261-263*C (deo) 7-dim ethoxyquinazolin4y)Npheny..N-ethyla me hydrochloride, m.p. 227-230 0 C (dece) N -b e z y i N .7 i m e h o x q ui n z ol n -4 A -p h n y l m e h y d ro c h lo r id e m.p. 269-2710C 'N'--(6horqiIzoi--y4I'I -Nimetry-N-pnyamine, m.p. 1061080C N (-hfr- oy)N(,-imt oyuiaoi--l-Nehyamn hydrochloride, mn.p. 261-263C N-(67-dmetoxyuinzoln-4yi)N-mthy-N--toyleinehydrochloride.

m.p. 230-234*C (dec) N-benzy.N-(6,7-cirnethoxyquinazoimn-4..yl)amine. m. p. 220-225"C N-(4-methoxybenzy}.N-(6 7-dim ethoxyquin azolin-4-yl)amine, m.p. 194-1 98C N-35dmtoyezl--67diehxqiaoi--lann hydrochloride, m.p. 2W52690C 4 3 ,4,5-trimethoxyphenoxy)-6,7.dimethoxyquin~ 0 Jjne m.p. 228-232 0

C

N-qiaoi--l--pey--ohlmn hydrochlorm. 242-2460C (dec)I N-67dmtoyunzln4y)--4mrhln4ypey~mn hydrochlIoride, m.p. 231-235 0 0 (de) 4 -($-methoxthophenoxy)67dimeoyuinazoins, m.p. 139.5-141 4-N(-nay~mnF.7dmtoyunzln hydrochloride, m.p. 24.4-246'00 (dec) 4-3clrtlpeoy-,-iehxqiaoie m.p. 152-1 53.59C 4 3 -aminopyrazoy),7imethoyuinzoine hydrochloride, 262-264"C (dec) 25 l.

4 -benzodloxan-6.y amlno)-6,7-dlmethoxyquinazoline hydrochloride, m.p. 267-269 0 C (deo) 6, .m t o y4 tya n~ un z lIah d ohoie 5 6 7 -dimethoxy4-(anaphthylam ino)quinazoline hydrochloride, m.p. >250*C 4-ccoeyaiio-,-iehxqiaoie m.p. 239-244'C 4 3 4 ,S-trimethoxyaniino)-6,7-dimethoxyquinazoline hydrochloride, m.p. 260-26510C 6 7 -dimesthoxy-4-(N-methyfanuliho)quinazoljne hydrochloride, m.p. >230 0

C

4 3 -chlorophenoxy)-6,7rdimethoxYqUjnazoline, m.p. 1 52-1 S3aC 6, 7 -dimethoxy-4-(1.-naphthytth io)-quinazoline, m. p. 1714.5-1 76.5 0

C

6 7 -dimethoxy4(2naphthjho)qunazolne. m. p. 178-1 79 0

C

6,7-dimethoxy-4-(1 -naphthyloxy)-quinazolzns, M. P. 21 4-2 15.5 0

C

6,-iehx--2nptyoyqiaoi6 m. p. 1 69 1 70 0

C

N- (6,7-dimetoyqinlzln4-l -nahh2yh.-tyaine hydrochloride, m. p. 236-239-C (dec) 6 7 -dmhoxy4(napatene-2sufy)qunazoline m. p. 182.5-1850C 6,-iehx--nptane2sloy~unzln 4 -(3-chioroaniino)..6,7-dimethylquinazoine hydrochloride, m.p. 271 -274C0 4- uuietyaniino)6,1-lmehyquinzolne hydrochloride, >2756C 4 -(N-methyl4methylaniino)6,7-dimethyuina:oline hydrochloride, 25 235-2380C 6,7-dimethyl-4-(1 -naphthylam ino)quinazoline hydrochloride, m.p. 244-247 0

C

8,-iehl4(-rfurmthl34dhdo2-unln -yl)quinazotine hydrochloride, m.p. 240 0

C

eU -etyaiin)S -dmtyqunzln hydrochloride, m.p. 205-207 0

C

4-3clrpeyti)6.-iehlunzln hydrochloride, m.p. 197-202"C 17 4-(1 -naPhthYJ lO)-67.dfrnethyquinjne hydrochloride, M.P. 204-2096C 4-34dmt~yhnthoqiacie M.P. 115-1 17-C reLoaration of Pharmauca Co on

MW~~

Ts Scio Compounds within the scope of this invention exhibit Significant ac-tivty as protein tyrosine kInase inhibitors and Possess therapeutic value as cellular antiproliferatlve agents for the treatment of certain conditions including psoriasis, atherosclerosis and restenosis injuries. Further, specfic inhibitors of CSF-1 R tyrosine kiase activty are useful for elucidating the imponc of CSF-1 and CSF-i receptor signaling in bon6 remodeling and hematopoesiss Compounds within the scope of the present invention exhibit the modulation and/or inhibition of cell signaling, cell proliferation, cail inflammatory response, the control of abnormal cell growth and can be used In preventing or delayfig 20 the occurrence or reoccurrence of such-conditions or otherwise treating the condition.

To determine tMe effectiveness of compounds of this invention, the .ph arm acoilogical tests described below, which are accepted in the art and recgnirzd to correlate with pharmacological activity in mammals, are utlized.

Compounds within the scope of this invention have been subjected to thee v~riots tests, and the results obtained ar believed to correlate to useful cellular differentiation mediator activity. The below described testis are useful in determining the inhibition of the colony stimulating factor-i receptor tyrosine 30~ kinase (CSF-1 R) activity. The ability to inhibit the p56k'ktyrosine kinase activity of compounds disclosed herein is described. The resutts of these teats are believed to provide sufficient information to persons skilled in the pharmacological and medicinal chemistry arts to determine the paramneters for using the studied compounds in one or more of the therapies described herein.

EGF-Recptor. Purification 18 EGF-receptor purification Is based on the procedure of Yarden and Schlessinger. A431 cells are grown i 50 cm 2 bottles to Conhluency (2 x 107 cells per battle). The cells are washed twice with PBS and harvested with PBS containing 11.0 mmol EDTA (1 hour at 370" C, and centrifuged at 600g for minutes. The cells are solubiliz ed in 1 ml per 2 x 10~7 cells of cold solubilization buffer (50 mmol Hepes buffer, PH 7.8, 1% Tifton X-1 00, 150 mmol NaCi, mmol EGTA, 1 mrnol PMSF, 50 ggfrnl aprotlnIn, 25 mmol benzarnidine' 5 grnl leupprtic, and 10 I.9ml soybean trypsfri inhibitor) for 20 minutes at 40 C. After centrifugation, at 1 00,000g for 30 minutes, the supernatant is loaded onto a WGA-agarose column (100 1 .d of packed resin per 2 k 107 cells) and shaken for 2 hours at 4"C. The unabsorbed material Is removed and the resin washed twice with HTN buffer (50 rmci Hepes, pH 7.6, 0.1% Triton X-100, 150 mmol NaCi), twice with HTN buffer containing 1 M Nedl, and twice with HTNG buffer mmol Hepes, p1-17.6. 0.1 Triton X-1 00, 150 mmol NaGi, and glycerol). The EGE receptor Is elUted batchwise with H-TNG buffer containing M N-acetyl.D-glucosamne~ (200 141 per2 x 107 cells.). The eluted material is stored in aliquots at -70 0 C and diluted before use with TMTNG buffer (50 rmcl Tris-Mes buffer, pH 7.6, 0.1 Triton X-1l00, 150 mmol NaCI. 10% glycerol).

WGA-purffied EGF receptor from A431 cells (0.5 J.Lg/assay is activated with EGF (0.85 jIM) for 20 minutes at 4*C. The assay is performed at 15 0 C and ::*initiated by addition of Mg(Ac) 2 (60 mmol), Tris-Mes buffer, pH 7.6 (50 mmol), [32P]AW (carrier free. 5 p.CL'assay), and Increasing concentrations of noraiatieTP The asa Is terminated after 10-sec by addition of SOS sample buffer. The samples are run on a SDS polyacryiemide gel. The gel Is dried and auto radiographed as described above. The relevant radioactive bands are cut and counted in the Oerenkov mode. The Km for ATP determined .in this fashion is found to be 7.2 gM. With use of the 1 0-sec assay protocol, the 30 EGF concentration dependence of EGF-RK autophosphorylation~ is determined.

A431 cells are grown to confluonce on human fibronectin coated* tissue culture dishes. After washing 2 times with ice-cold PBS, cells are lysed by the addition of 500 VV dish of lysis buffer (50 mmol H-epes, pH 7.5, 150 mmcl NaCI, mmol MgCI 2 1 mmcl EGTA, 10% glycerol, 1% triton X-100, 1 mmcl PMSF, 1 mg/ml aprotinln, 1 mg/mI leupeptin) and incuba(ing 5 minutes at 4 0 C. After EGF stimulation (50 pgml 10 minutes at 37*C) Immnunoprecipftatlon is performed with anti EGP-RI (Ab 108) arnd the autophosphorylation reaction (5o gd aliquots, 3 fLCl 32 PJATP) sample is carried out in the presence 01 2 or 10 g~M of compound of the present invention, for 2 minutes at 4 0 C. The reaction is stopped by adding hot electrophoresis sample buffer. SDA-PAGE analysis els) is followed by autoracliography and the reaction is quantitated by densitornetry scanning of the x-ray films.

Cel1 Cutture Cells termed HER 14 and K721 A are prepared by iransfecting NIH3T3 calls (clone 2.2) (From C. Fryling, NCI, NIH), which lack enldogenous EGE-receptors, with cDNA constructs of wild-type EGF-receptor or mutant

EGF-

receptor lacking tyrosine kinase activity (in which Lys 721 at the ATP-binding site is replace by an Ala residue, respectively). All cells are grown in DMEM with 10% calf serum (Hyclone, Logan, Utah)._ Further tests which show the effectiveness and selectivity of compoundjs of this invention to inhibit cell proliferation and/or differentiation or mediator so. release are as follows.

CQSFRR Celr AuDhholylation Assay For a regular 28 tube assay (14 samples per 15 well gel): In Z2ml eppondorf tube: 140 mg protein A sopharose (5 mg/sample) Swell in 20 mM Hepes pH 7.5 and wash 2.x in Hopes Add 280 X cx-CSF- 1 A 20min RT shaking Wash 3x In HNTG pH 7.5: 20 mM Hepes 150 mM NaCI 0. 1 tritan glycerol In 15 mil tube: 2.8 ml lysate tysis buffer: 20 mM Hepes mM M9CI2 150 mM NaCI 1 mM EGTA glycerol 1 triton X. 100o Protease inhibitors added fresh: PMSF: 8 mg/ml-2500x In 100% EtOHI store frozen, add 100)V10 ml lysis buffer Aprotinin: 10 mglml=2S0x in H20, store frozen, add 40X/10 ml lysis buffer Leupeptin: 1 mg/ml=250x in H20, store frozen, add 40WJO mi lysis biuffer Add washed beads to stimulated lysate and incubate 90 min 4 0 C on rotator or shaking prepare 28 compound tubes: make 40 mnM solutions of compounds in 100% DMSO make serial dilutions in 50 mM Tris pH T.5 10 mM MnCI 2 aliquot 101 compound solution into each 1 ml eppendodf reaction tube waiting on ice, control blanks get 10). burffer Wash beads ix HNTG, 2x 10mM Tris pH Add 1lOX ATP solution: 312-X 50 mnM Tris pH- 7.5 10 mM MnC12 2.7; cold ATP (stock of 10 mM in 50 mnM jiM final) 351 32 P-ATP (l0gC~sample) Vortex, incubate 10 min on ice.- :Add 45% 2x SIDS-sample buffer, heat 95 0 C 6 mln 7.5% SDS-PAGE, fix, dry, expose (usually 4 hes) Ick Kinase: Immunoorecipi tated from Jurkat lysate.

4444 A. Jurk~t cells (human T-cell leukemia, AICC clone #E6-1) are grown in suspension in RPM[ 1640 medium with 10% fetal calf serum, 100 U/mi 4* 4 pen Icillin/streptomycin, and 2 mM L-glutamine in a 37*C incubator at 5% C02.

B. Cells are grown to 1-1.5 x 106 cells/mIl media, pelleted by centrifugauion, and lysed in lysis buffer at 108 cells/mI buffer (50 mM tris (pH 8), 150 mM NaCl, 5 mM EOTA, 10% glycerol, and NP-40, to which fresh protease and phosphatase inhibitors are added as described above for A431 lysate). Lysates stored at -700C.

C. lmmunoprecipitatlon: 3-4 mg Protein-A sepharose/sample washed 2x 20 mnM Hepes (pH 1 ul a-Ick antibody (prepared as polyclonals in rabbits using a Peptide antigen corresponding to the N-terminal region of human c) per sample added to the Protein-A and shaken 20 min at room temperature. After washing 3X HNTG, lysate from 2 x 106 cells Is added to each sample, rotated 2 hr at 4T0, then washed 3x HNTG (2nd wash containing 0.5 N NaCi). If all samples contain identical concentrations of the enzyme, then the lmmuno-precipitanlon can be done In bulk and ailoquoted to appropriate numbers of tubes prior to assay set- up.

D. Compound screening in te cell-free Ickkinase assay: Compounds (40 mM stocks in DMSO) are initially screened at concentrations of 100 uM In samples containing Ick immuno-precipitated from 2 x 106 cells, 6 uM cdo2 (a p34cdC 2 -derived synthetic peptide (NG.20) prepared by R. Howk, RpR) 7 5 mM MnC12, 5 uM ATP and 30 uCI g 32 P-ATP (GOOOCi/mmoi, NEN) in mM hopes (pH 7-5) for 5 min at 30"C. Samples are analyzed by 5-15% SDS-PAGE and autoradiography as described for EGFR kinase assays.

E. Intact call activationfinhibltion studles:-S x 10o 7 cells per sample in 1 ml media are activated with either 10 ug a-CD3 (clone Cris 7, Blodesign) for '1 0 20 and absence of compound (added earlier so that the total time of compound incubation is 30 min). Incubations are terminated by centrifugation and tysis (as described). Samples are analyzed by immunoprecipitation (aPY (100 uVl 08 cells), a-PLC (100 uVlO0 8 cells), or a-zeta (20 ut/l08 calls)), followed by SDS- PAGE and western blotting onto nitrocellulose and immunoblotting using recombinant aPY-HAP Transduction Labs) and ECL (Amersham).

cAMP-deoendent Poten Kinase (PA Assay 30 Selecdvity assay for compounds is performed as follows. Each sample contains 0.4 pmolar units PKA (from rabbit muscle, Sigma), 1lUM CAMP, 50 uM see* Tris-HCL (pH7), 10 mM MgAe, 50 ug B3SA. 16 uM Kemptide substrate (specific S cAMP kinase phosphate acceptor whose sequence corresponds to the pig liver pyruvale kinase phosphorlyation efte), 16 UM ATP, 16 uCI 32

P-ATP

(GOOOCVrnmol, NEN), compound and dH 2 Q to a final volume of 200 ul.

Reactions proceed for 5 min, at 30 0 C, and are terminated by the addition of 100 ul 375 mM H 3 P0 4 50 ul each sample spotted onto Whatman P81 22 phosphocellulose filters, which are washed 3X (15 min.) in 75 mM H 3 followed by an acetone rinse and dry (Cerenkov) counting.

In view of the results of the above test compounds of the present inventlon can be shown to be selective.

The following tables show examples of representatjve compounds of this Invention and their test results as determined by the above inhibition of CSR- 1 R arnd Ick procedures.

Structure Ickactiy

IC

50 (pM) CSF-R activity 1CSO (a"M *Q MoN MeN1

HNOM

HNI~h~M 50 50 50 7 0.18 100 >100

IO

Ma H"C 10 1 3

S"'OM

0Me &0M 2.9 The results obtained by the above experimental methods evidence the useful CSF-1R receptor protein tyrosine kinase inhibition properties of compounds within the scope of the present Invention and possess therapeutic value as cellular aritiproliferative agents. The above pharmacological test results may be used to determine the dosage and mode of administration for the particular therapy sought.

The compounds of the present invention can be administered to a mammalian host in a variety of forms adapted to the chosen route of administration, orally, or parenteraly. Parenteral administration In this respect includes administration by the followving routes: intravenous, intramuscular, subcutaneous, intraocular 1 intraeynovial, transepithelial including transderrnal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermnal, ocular, rectal and nasal inhalation via insuflation and aerosol and rectal systemic.

24 The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or It may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensionls, syrups, wafers, and the like. Such compositions and preparations should contain at least 0. 1% of active compound. The percentage of the compositions and preparations may, of course, be varied and mray goflveniently be between about 2 to about 6% of the weight of the unit. The amount of active compound in such therapeutically usefu compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains 15 between about 1 and 1000 mg of active compound.

.The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacaith, acacia, corn starch or gelatin; xcipients such as dicaiclum phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, It may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatlpgs or to otherwise modify the physical form of the dosage unit.

For Instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor, Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sutie-ees preparations and formulations.

The active compound may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmnacobogilly~ acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the for must be sterile and must be fluid to the extent that easy syringability exists. It may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

15 The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.

25 Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various S sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.

The therapeutic compounds of this invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as 26 noted above, the proportion of which is determined by the solubiit and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.

The dosage of the present therapeutic agents which will be most suitable for prophylaxis or treatment will vary wit the form of administration, the.

particular compound chosen and the physiological characteristics of the particular patient under treatment. Generally, small dosages will be used initially arnd If necessary, will be increased by small increments until the optimum effect under the circumstances is reached. The therapeutic human dosage, based on physiological studies using rats, will generally be from about 0.01 mg to about 100 mg/kg of body weight per day or from about 0.4 mg to about 10 g or higher although it may be administered in several dIfferent dosage units from once to several times a day. Oral administration requires higher dosages.

Claims (16)

1. A method for inhibiting Colony Stimulating Factor-1 receptor tyrosine kinase modulated cell proliferation, differentiation or mediator release in a patient suffering from a condition characterized by such proliferation, differentiation or mediator release comprising administering to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a pharmaceutical composition comprising a pharmaceutically effective carrier in admixture with a compound of the formula: (R)o-3 Ar R* N wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero o atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO 2 OCH 2 C=C, C=C,C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R together may also form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof; with the exception of compounds in which: Ar is a phenyl ring; X is NH; and the phenyl ring represented by Ar carries one or two R groups that independently include hydrogen, hydroxy, halogen, CF 3 amino, nitro, cyano and alkyl; and R5, R6 and R7 are independently alkyl, hydroxy, alkoxy, carboxy or carbalkoxy; or (ii) the phenyl ring represented by Ar carries one halogen, CF 3 nitro, cyano, alkyl, alkoxy, mono- or di-alkylamino or alkylsulfonyl group represented by R; and one of R5, R6 or R 7 represents hydrogen or CF 3 and the other two represent hydrogen.

2. A method for the treatment of bone disease characterized by Colony Stimulating Factor-1 receptor tyrosine kinase activity in a patient suffering therefrom, comprising administering to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a composition comprising a **pharmaceutically acceptable carrier in admixture with a compound of the formula: S*7 about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO 2 OCH 2 C=C, C2C, C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof.

3. A method for the treatment of inflammation characterized by Colony Stimulating Factor-1 receptor tyrosine kinase activity in a patient suffering therefrom, comprising administering to said patient a Colony Stimulating Factor-1 receptor tyrosine kinase inhibiting amount of a composition comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula: /F (R)o-3 Ar R- N 7 JR7 N wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, 0 and S provided said hetero atoms are not vicinal oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, O, S, SO, SO 2 OCH 2 C=C, C C, C=S, SCH 2 s NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof; with the exception of compounds in which: Ar is a phenyl ring; X is NH or NR 4 wherein R 4 is alkyl; the phenyl ring represented by Ar is unsubstituted or carries one halogen, alkyl or alkoxy group represented by R; and one of R5, R6 or R 7 represents hydrogen, halo or CF 3 and the other two represent hydrogen.

4. A method for the treatment of a T-cell mediated condition characterized by p 5 6 'ck kinase activity in a patient suffering therefrom, comprising administering to I00c said patient a p 5 6 ck kinase inhibiting amount of a composition comprising a pharmaceutically acceptable carrier in admixture with a compound of the formula: 0 R 0-3 R X NAr R5 R 6 N N wherein Ar is a substituted or unsubstituted mono- or bi-cyclic aryl or heteroaryl ring system of 5 to 12 atoms and where each monocyclic ring may contain 0 to about 3 hetero atoms, and each bicyclic ring may contain 0 to about 4 hetero atoms selected from N, O and S provided said hetero atoms are not vicinal 31 oxygen and/or sulfur atoms and where the substituents may be located at any appropriate position of the ring system and are described by R; X is a bond, 0, S, S SO 2 OCH 2 C=C, C C, C=S, SCH 2 NH, NHCH2, NR4 or NR4CH2; R independently includes hydrogen, alkyl, alkenyl, phenyl, aralkyl, aralkenyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aralkoxy, aryloxy, acyloxy, halo, haloalkyl, nitro, cyano, amino, mono- and di-alkylamino, acylamino, carboxy, carboxyalkyl, carbalkoxy, carbaralkoxy, carbalkoxyalkyl, carbalkoxyalkenyl, aminoalkoxy, amido, mono- and di-alkylamido and N,N-cycloalkylamido, sulfonyl, mono- and di-alkylsulfonyl, sulfamoyl, mono- and di-alkylsulfamoyl, halophenyl or benzoyl; or two of R may together form a ketone group; R4 is alkyl, aryl or alkylaryl; and R5, R6 and R7 are independently hydrogen, alkyl, alkylthio, cycloalkyl, hydroxy, alkoxy, aralkoxy, aryl, halo, haloalkyl, carboxy or carbalkoxy; or a pharmaceutically acceptable salt thereof.

The method of claim 4, wherein the T-cell mediated condition is the Srejection of a transplanted organ.

6. The method of claim 4, wherein the T-cell mediated condition is an auto- immune disease.

7. The method of claim 6, wherein the auto-immune disease is rheumatoid arthritis.

8. The method of claim 6, wherein the auto-immune disease is psoriasis.

9. The method of claim 4, wherein the T-cell mediated condition is an inflammation.

The method of any one of claims 1, to 4, wherein Ar is naphthyl or indole; R is hydrogen, alkyl, aralkyl, alkoxy, hydroxy, halo or mono-, di- or tri- fluoromethyl; X is a bond, NH or NR 4 and R 6 and R 7 are independently hydrogen, alkoxy, halo or mono-, di- or tri- fluoromethyl.

11. The method of claim 10, wherein X is a bond or NH and R 5 R 6 and R 7 are independently hydrogen or methoxy.

12. The method of any one of claims i to 4, wherein X is a bond, NR,SorO0.

13. The method of any one of claims i to 4, wherein X is a bond and Ar is phenyl, indolyl, pyrrolyl, thienyl, pyridyl, bicyclic aryl or bicyclic heteroaryl, or substituted phenyl, indolyl, pyrrolyl, thienyl, pyridyl, bicyclic aryl or bicyclic heteroaryl.

14. The method of any one of claims 2 to 4, wherein X is NH, R 6 and R 7 are alkoxy, and Ar is phenyl having at least one hydroxy or alkoxy substituent in the 3, 4 or 5 position. The method of any one of claims i to 4, wherein the compound is selected :f from: 4-(3,4,5-trimethoxyphenylamino)-6,7-dimethoxyquinazoline,4-(naphthalen- 2-ylethynyl)-6,7-dimethoxyquinazoline, 4-(4-hydroxyphenyl)-6,7-dimethoxyquinazoline hydrochloride, 4-(naphthalen-1 -yi)-6,7-dimethoxyquinazoline, 4-(naphthalen-2-yl)-6,7-dimethoxyquinazoline, 4-phenylacetylenyl-6,7-dimethoxyquinazoline, 4-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-phenylphenyl)-6,7-dimethoxyquinazoline, 4-(2-phenylethylenyl)-6,7-dimethoxyquinazoline, 4-(2-methoxypyridin-5-yl)-6,7-dimethoxyquinazoline, iST~c~~4-(l -benzyl-indol-3-yl)-6,7-dimethoxyquinazoline, S 4-(indol-3-yI)-6,7-dimethoxyquinazoline, 4-(l1-methylindol-3-yI)-6,7-dimethoxyquinazoline hydrochloride, 4-(1 -methylsulphonylindol-3-yI)-6,7-dimethoxyquinazoline, 4-(4-phenylpiperidin-1 -yI)-6,7-dimethoxyquinazoline, 4-[4-(3-chlorophenyl)piperazin-1 -yI]-6,7-dimethoxyquinazoline, 4-(N-methyl-3,4,5-trimethoxyanilino)-6,7-dimethoxyquinazoline, (±)-4-(2-methyl-1 ,2,3,4-tetrahydroquinolin-1 -yI)-6,7-dimethoxyquinazoline hydrochloride, 4-(1 ,2,3,4-tetrahydroquinolin-1 -yI)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-methyl-4-methoxyanilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-methyl-4-chloro-anilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(2,3-dihydroindol-1 -yl)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-methyl-3-trifluoromethylanilino)-6 ,7-dimethoxyq uinazoline hydrochloride, 4-(N-methyl-3-chloroanilino)-6,7-dimethoxyquinazoline hydrochloride, and 4-(naphthalen-1 -ylethynyl)-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.

The method of any of claims 1 to 4, wherein the compound is selected 4-(indazol-5-ylamino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-methylanilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-benzylanilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-ethyl-3-ch lo roan ilino)-6,7-d imethoxyq uin azol ine hydrochloride, 4-(N-methyl-4-methylanilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N-benzylamino)-6,7-dimethoxyquinazoline, 4-(4-methoxybenzylamino)- 6,7-dimethoxy-quinazoline,4-(3,5-dimethoxy-benzyl-amino)-6,7-dimethoxy- quinazoline hydro-chloride,4-(3,4,5-trime-thoxy-phenoxy)-6,7-dimethoxy- quinazoline, 4-(4-morpholin-4-ylanilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(3-methoxythiophenoxy)-6,7-dimethoxyquinazoline, 4-[N-(5-indanyl)amino]-6,7-dimethoxyquinazoline hydrochloride,

16. f rom: 4-(3-chlorothiophenoxy)-6,7-dimethoxyquinazoline, 4-(3-aminopyrazolyl)-6,7-dimethoxyquinazoline hydrochloride, 4-(1 ,4-benzodioxan-6-ylamino)-6,7-dimethoxyquinazoline hydrochloride, 4-(a-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride, 4-(b-naphthylamino)-6,7-dimethoxyquinazoline hydrochloride, 4-(cyclohexylanilino)-6,7-dimethoxyquinazoline, 4 -(3,6-dioxananilino)-6,7-dimethoxyquinazoline hydrochloride, 4-(N..methylanilino)-6,7-dimethoxyquinazoline hydrochloride, and 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof. DATED this 18th day of July 2001 AVENTIS PHARMACEUTICALS PRODUCTS INC. WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 32 AUSTRALIA Case: P1631AU01 LCG/ALJ1/PXT