Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

• This invention relates to pyrido[2.3-d]pyrimidine-2.7-diamines that inhibit cyclin-dependent serine/threonine kinases and growth factor-mediated tyrosine kinase enzymes, and as such are useful to treat cell proliferation diseases and disorders.
• Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L.. "'Chemical Inhibitors of Cyclin-Dependent Kinases,"
• Typical enzymes include serine/threonine kinases such as the cyclin-dependent kinases (cdks) cdkl, cdk2, cdk4. cdk5. cdk ⁇ . as well as tyrosine kinases involved in cell cycle regulation. Increased activity or temporally abnormal activation or regulation of these kinases has been shown to result in development of human tumors and other proliferative disorders. Compounds that inhibit cdks.
• cdks cyclin-dependent kinases
• flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur et al., J. Natl. Cancer Inst.. 1992:84: 1736-1740; Int. J. Oncol. 1996;9: 1143-1168). The compound has been shown to inhibit cdk2 and cdk4.
• Olomoucine [2-(hydroxyethylamino)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely et al.. Eur. J. Biochem.. 1994:224:771 -786). and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham et al.. Biology of the Cell 1995:83: 105-120). More recently, the purvalanol class of cdk inhibitors has emerged as more potent derivatives of olomoucine (Gray N.S. et al.. Science. 1998:281 :533-538).
• Tyrosine kinases are essential for the propagation of growth factor signal transduction leading to cell cycle progression, cellular proliferation. differentiation, and migration.
• Tyrosine kinases include cell surface growth factor receptor tyrosine kinases such as FGFr and PDGFr. as well as nonreceptor tyrosine kinases. including c-Src and lck. Inhibition of these enzymes has been demonstrated to cause antitumor and antiangiogenesis activity (Hamby et al., Pharmacol Then. 1999:82(2-3): 169-193).
• the present invention provides such compounds, their pharmaceutical formulations, and their use in treating proliferative disorders.
• This invention provides novel pyrido[2.3-d]pyrimidine-2.7-diamine compounds which function as inhibitors of cell cycle regulatory' kinases such as the cyclin dependent kinases as well as the growth factor-mediated tyrosine kinases.
• these compounds are useful to treat cell proliferative disorders such as atherosclerosis and restenosis; cancer: angiogenesis: viral infections including DNA viruses such as herpes and RNA viruses such as HIV; fungal infections; type 1 diabetes, diabetic neuropathy and retinopathy: multiple sclerosis; glomerulonephritis: neurodegenerative diseases including Alzheimer ' s disease; autoimmune diseases such as psoriasis, rheumatoid arthritis, and lupus; organ transplant rejection and host versus graft disease; gout; polycystic kidney disease; and inflammation including inflammatory bowel disease.
• cancer angiogenesis: viral infections including DNA viruses such as herpes and RNA viruses such as HIV
• fungal infections type 1 diabetes, diabetic neuropathy and retinopathy: multiple sclerosis
• glomerulonephritis neurodegenerative diseases including Alzheimer ' s disease
• autoimmune diseases such as psoriasis, rheumatoid arthritis, and lupus
• R14 and R15 are independently hydrogen, or lower alkyl, lower alkenyl, or lower alkynyl. each of which is optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro, -R 9 , -NR 9 R! °. -OR 9 . -(CH2) n CO 2 R 9 ,
• -NR 9 SO 2 R 10 or a heterocycle optionally substituted with up to 3 groups independently selected from -R 9 . -NR 9 R 1 0 , -OR 9 . -NR 9 COR 1 0 . -COR 10 . -(CH2) n SO 2 R ⁇ . -(CH ⁇ R 1 1 , or -(CH 2 ) n R l - optionally substituted with up to 5 groups independently selected from halogen, cyano, nitro. -R 9 , -NR R 1 0 . -OR 9 , -(CH 2 ) n CO 2 R 9 . -(CH 2 ) n S0 2 R 1 1. -(CH ⁇ R 1 1. -COR 9 .
• R 9 and R 10 are independently hydrogen, or lower alkyl. optionally substituted with up to 3 groups selected from the group consisting of halogen, amino. mono- or dialkylamino, hydroxy. lower alkoxy. phenyl or substituted phenyl, or when taken together with the nitrogen to which they are attached, R 9 and R 1 ° form a ring having from 3-7 members, up to four of which
• 0 may be selected from p . O. S. and NR-0. where R ⁇ O is
• R 1 ! is a heteroaryl or a heterocyclic group:
• R 1 - is a cycloalkyl. a heterocyclic. an aryl, or a heteroaryl group; n is 0. 1. 2, or 3: and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
• the present invention also provides a composition that comprises a compound of Formula 1 together with a pharmaceutically acceptable carrier, diluent, or excipient.
• the present invention also provides methods for inhibiting cyclin- dependent kinase and growth factor-mediated kinase enzymes.
• the present invention also provides a method of treating subjects suffering from diseases caused by cellular proliferation. The method comprises inhibiting proliferation of tumorigenic cells of epithelial origin and vascular smooth muscle proliferation, and/or cellular migration by administering a therapeutically effective amount of a compound of Formula I to a subject in need of treatment.
• the present invention also provides a method of treating subjects suffering from diseases caused by DNA tumor viruses, such as herpes viruses comprising administering a compound of Formula I.
• the compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
• R ⁇ . R6. R7_ anc j R8 are as defined above for Formula I;
• R 6 R! 7_ and R 1 8 are as defined above for the (CH 2 ) n R 1 - substituents. and preferably are independently hydrogen, halogen, amino. mono- or dialkylamino. hydroxy. lower alkyl. lower alkoxy. cyano. nitro, carboxy, carboxyalkyl. aminocarbonyl. mono- or dialkylaminocarbonyl, alkylcarbonyl. -S0 3 R 9 . -SO NR 9 R 10 , -SO 2 R 9 , -SR 9 . -PO 3 R 9 R 1 0, -POR 9 R 10 . -PO( R 9 R 10 ) 2 . -NR 9 COR 10 , -NR 9 CO 2 R 10 . -NR 9 CONR 9 R 1 0 . -NR 9 SO 2 R 1 0 ; or
• R ⁇ is a carbocyclic group containing from 3-7 members, up to 2 of which members are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with 1 , 2. or 3 groups as defined above, but preferably are independently selected from the group consisting of halogen, hydroxy. lower alkyl, trifluoromethyl. lower alkoxy. amino. mono- or dialkylamino. aryl. heteroaryl. arylalkyl. heteroarylalkyl. heteroarylsulfonyl. heteroarylsulfonylalkyl, heterocyclylalkyl. heterocyclylsulfonyl. or heterocyclylsulfonylalkyl.
• R 3 is hydrogen or lower alkyl
• R ⁇ is hydrogen, lower alkyl, cyano or halogen
• R 1 ⁇ and R 18 are independently hydrogen, halogen, amino. mono- or dialkylamino. hydroxy, lower alkyl. lower alkoxy, aminocarbonyl. mono- or dialkylaminocarbonyl,
• R 16 is optionally substituted N-piperidine.
• N-piperazine. or N-pyrrolidine for instance where the ring substituents are selected from -R 9 . -NR 9 R 10 , -OR 9 . NR 9 COR 10 . and COR 10 .
• R ⁇ -. R 5 , and R" are as defined above for Formula I:
• R 19 is hydrogen, or lower alkyl. lower alkenyl. or lower alkynyl, each of which is optionally substituted with up to 5 groups independently selected from halogen. amino. mono- or dialkylamino. hydroxy. lower cyano, nitro. carboxy. carboxyalkyl. aminocarbonyl. mono- or dialkylaminocarbonyl, lower alkylcarbonyl. -SO3R 9 , -SO 2 NR 9 R 1 0 , -SO 2 R 9 . -SR 9 . -PO 3 R 9 R 1 0 , -POR 9 R 1 0 . -PO(NR 9 R 10 ) 2 . -NR 9 COR 10 . -NR 9 CO 2 R 10 . -NR 9 CONR 9 R 10 .
• R 9 and R 10 are as defined above, or aryl. heteroaryl, arylalkyl. heteroarvlalkyl. cycloalkyl or cycloalkyl-alkyl. where each aryl, heteroaryl or cycloalkyl group is optionally substituted with up to 5 groups independently selected from halogen, amino. mono- or dialkylamino, hydroxy, lower alkoxy. cyano. nitro. carboxy, carboxyalkyl. aminocarbonyl. mono- or dialkylaminocarbonyl. alkylcarbonyl. -SO 3 R 9 , -SO2NR 9 R 10 ,
• -NR 9 COR 10 , -NR 9 CO 2 R 10 , -NR 9 CONR 9 R 10 , -NR 9 SO 2 R 10 . or a (CH2)n-carbocyclic group containing from 3-7 members, up to 2 of which members are heteroatoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with 1. 2. or 3 groups independently selected from the group consisting of halogen, hydroxy, lower alkyl. trifluoromethyl. lower alkoxy. amino. mono- or dialkylamino. aryl. heteroaryl, arylalkyl. heteroarvlalkyl. heteroarylsulfonyl. heteroarylsulfonylalkyl. heterocyclylalkyl, heterocyclylsulfonyl, or heterocyclylsulfonylalkyl; and
• R ⁇ 1 is hydrogen, lower alkyl. or lower alkyl substituted with phenyl or substituted phenyl.
• R ⁇ is hydrogen or lower alkyl.
• R ⁇ is hydrogen or halogen.
• R ⁇ - is optionally substituted phenyl;
• R ⁇ 1 is hydrogen or methyl:
• R 19 is optionally substituted lower alkyl, cycloalkyl, or (CH2) n -carbocyclic.
• An especially preferred group of pyrido[2.3-d]pyrimidines have Formula IV:
• R 5 . R 6 . R 1 6 . R 1 7 . R 1 8 , R 1 9 . and R 21 are as defined above.
• Preferred compounds of Formula IV are those wherein R 21 is hydrogen or methyl.
• Another especially preferred group of invention compounds have Formula V:
• R 5 . R 6 . R 1 6 . R 1 7 . R 1 8 . R 19 . and R 21 are as defined above.
• Preferred compounds of Formula V are those wherein R- 1 is hydrogen or methyl.
• the most preferred invention compounds have Formula VI wherein R 5 . R 6 . R 1 7 . and R 1 8 are as defined above, and R-- and R ⁇ 3 independently are hydrogen or alkyl.
• alkyl straight or branched chain alkyl groups having 1 to 10 carbon atoms, preferably Cj-Cg alkyl.
• alkyl groups include methyl, ethyl, n-propyl, isopropyl. n-butyl. sec-butyl, tert-butyl. pentyl. 2-pentyl. isopentyl. neopentyl, hexyl. 2-hexyl. 3-hexyl. decyl. octyl. and 3-methylpentyl.
• These groups may be substituted, for instance with halo.
• alkenyl straight or branched chain alkyl groups having 1 to 10 carbon atoms and having 1 or 2 nonadjacent double bonds.
• alkenyls include, but are not limited to, 3-butenyl and l -methyl-3-pentenyl.
• alkynyl. " '"lower alkynyl. " and (C2-C] o)-alkynyl is meant straight or branched chain alkyl groups having 1 to 10 carbon atoms and having a triple bond.
• Typical alkynyl groups include 2-propynyl and l .l -dimethyl-3-butynyl.
• Substituted alkenyl and alkynyl groups include 4.4-dibromo-2-pentenyl and 3-amino-5-hexynyl.
• alkox ⁇ . " "lower alkoxy. " or “(Ci-Cjo alkoxy " in the present invention is meant straight or branched chain alkoxy groups having 1 to 10 carbon atoms, such as. for example, methoxy. ethoxy. propoxy. isopropoxv n-butoxy, sec-butoxy. tert-butoxy, pentoxy. 2-pentyl. isopentoxy. neopentoxy. hexoxy. 2-hexoxy, 3-hexoxy. and 3-methylpentoxy.
• alkanoyl means an alkyl group bonded through a carbonyl moiety. Examples include acetyl and pentanoyl. "Aminoalkanoyl” means the alkyl group is substituted with an amino group. Examples include aminoacetyl and
• '"Alkylaminoalkanoyl means an aminoalkanoyl group wherein the amine is substituted with a C] -C ⁇ Q alkyl group, and includes methylaminoacetyl and 4-(isobutylamino)-octanoyl.
• "'Dialkylaminoalkanoyl' means an N.N-di-substituted aminoalkanoyl group such as diisopropylaminoacetyl.
• halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
• 'aryl' * means an unsubstituted aromatic carbocyclic group having a single ring (e.g., phenyl). multiple rings (e.g.. biphenyl). or multiple condensed rings in which at least one is aromatic (e.g.. 1.2.3.4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
• ' substituted aryl means an aryl substituted by 1 to 4 substituents selected from alkyl. O-alkyl and S-alkyl. -OH, -SH, -CN, halo, 1.3-dioxolanyl, -CF 3 . -NO 2 .
• heteroaryl is meant one or more aromatic ring systems of 5-. 6-, or 7-members containing at least 1 and up to 4 heteroatoms selected from nitrogen, oxygen, or sulfur.
• heteroaryl groups include, for example, thienyl, furanyl, thiazolyl. imidazolyl. (is)oxazolyl. tetrazolyl, pyridyl. pyrazinyl. pyrimidinyl, pyrazolyl, (iso)quinolinyl, napthyridinyl, phthalimidyl. benzimidazolyl, benzoxazolvl.
• a “"substituted heteroaryl “ group can be substituted with 1, 2, 3, or 4 of the groups mentioned above for “substituted aryl. " such as 2.3.4.6- tetrachloropyridyl and 2-methoxy-3-trifluoromethylthien-4-yl.
• heterocyclic group means a non-aromatic ring having 5-. 6-. or 7-ring atoms, from 1 to 4 of which are selected from nitrogen, oxygen, or sulfur.
• heterocyclic groups include morpholino. piperidino. piperazino. pyrrolidinyl. and tetrahydrothienyl. Such groups can be substituted with the same groups described above for substituted heteroaryl.
• a “carbocyclic group " or "'cycloalkyr * is a nonaromatic cyclic ring or fused rings having from 3- to 7-ring carbon members. Examples include cyclopropyl, cvclobutyl. and cycloheptyl. These rings may be substituted with one or more of the substituent groups mentioned above for aryl, for example alkyl, halo, amino. hydroxy. and alkoxy. Typical substituted carbocyclic groups include 2-chlorocyclopropyl, 2.3-diethoxycyclopentyl, and 2.2.4,4-tetrafluorocyclohexyl. The carbocyclic group may contain 1 or 2 heteroatoms selected from oxygen, sulfur, and nitrogen, and such ring systems are referred to as "heterocyclyl " or
• heterocyclic examples include piperidyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, and dioxanyl. These heterocyclyl groups may be substituted with up to 4 of the substituent groups mentioned for aryl to give groups such as 3.5-dimethylpiperazin-l-yl. 3.3-diethylpiperazin-l-yl. 3,3,4.4-tetramethylpyrrol- idinvl. 3-chloro-2-dioxanyl, and 3.5-dihydroxymorpholino. These can also bear a keto group, for instance, 3-ketopiperidyl.
• cancer includes, but is not limited to. the following tumor types: breast, ovary, cervix, prostate, testis. esophagus, glioblastoma. neuroblastoma. stomach, skin, keratoacanthoma, lung, epidermoid carcinoma. large cell carcinoma, adenocarcinoma, bone, colon, adenoma, pancreas, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin ' s. hairy cell carcinoma, cancer of the buccal cavity and pharynx (oral), lip. tongue, mouth, pharynx, small intestine, colon, rectum, large intestine, brain and central nervous system; and leukemia.
• the compounds of Formulas I to VI can exist as pharmaceuticalK acceptable salts, esters, amides, and prodrugs.
• pharmaceuticalK acceptable salts, esters, amides, and prodrugs refers to those carboxy late salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are. within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity. irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. as well as the zwitterionic forms, where possible, of the compounds of the invention.
• salts refers to the relatively nontoxic.
• salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free base form, for example, with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate. stearate. laurate, borate. benzoate. lactate, phosphate, tosylate, citrate, maleate, fumarate. succinate. tartrate.
• salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium. and the like, as well as inorganic bases such as ammonium, quaternary ammonium, and other amine cations including, tetramethylammonium. tetraethylammonium. methylamine. dimethylamine. trimethylamine. triethylamine. ethylamine. and the like.
• esters of the compounds of this invention examples include Cj -C ⁇ alkyl esters, wherein the alkyl group is a straight or branched hydrocarbon, substituted or unsubstituted. Esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl and triphenylmethyl. C 1 -C4 Alkyl esters are preferred, such as methyl, ethyl.
• esters of the compounds of the present invention may be prepared according to conventional methods, for example by reaction of an acid with an alcohol.
• Examples of pharmaceutically acceptable amides of the compounds of this invention include amides derived from ammonia, primary Cj -Cg alkyl amines and secondary Cj -Cg dialkyl amines, wherein the alkyl groups are straight or branched. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing 1 nitrogen atom. Amides derived from ammonia. C 1 -C3 alkyl primary amines, and C 1 -C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods well-known to the medicinal chemists.
• prodrug refers to compounds that are rapid transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood or stomach fluids.
• prodrugs refers to compounds that are rapid transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood or stomach fluids.
• Representative compounds of the present invention which are encompassed by Formula I. include, but are not limited to. the compounds in Table 1 and their pharmaceutically acceptable acid or base addition salts, ester or amide analogs, and prodrugs thereof.
• the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
• Some of the compounds of Formula I have one or more chiral centers, and can thus exist as individual stereoisomers and mixtures thereof. Other compounds can exist in more than one geometric form.
• This invention includes all optical and geometric isomers and forms, and mixtures thereof. Racemic mixtures of invention compounds are readily resolved into individual isomers by routine methods such as chromatography. fractional crystallization, and classical resolution using optically active acids and salts.
• the individual isomers can also be prepared by chiral synthesis, including chiral hydrogenations and the like using commercially available chiral catalysts.
• the compounds of the present invention are useful for treating cancer (for example, leukemia, and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases, including, but not limited to, psoriasis. HSV. HIV. restenosis. and atherosclerosis.
• cancer for example, leukemia, and cancer of the lung, breast, prostate, and skin such as melanoma
• other proliferative diseases including, but not limited to, psoriasis. HSV. HIV. restenosis. and atherosclerosis.
• a patient having cancer is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising an invention compound.
• a further embodiment of this invention is a method of treating patients suffering from diseases caused by vascular smooth muscle cell proliferation.
• Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration.
• the method entails inhibiting vascular smooth muscle proliferation, and/or migration by administering an effective amount of a compound of Formulas I to VI to a subject in need of treatment.
• ""Subject " and “patient” as used herein, is a mammal such as a human. but also includes horses, cattle, sheep, and companion animals such as dogs and cats.
• the compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formula I.
• a further embodiment of this invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formulas I to VI together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
• pharmaceutically acceptable carriers can be either a solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules.
• a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
• the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component.
• the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
• the formulations of this invention preferably contain from about 5% to about 70% or more of the active compound.
• Suitable carriers include magnesium carbonate, magnesium stearate. talc, sugar, lactose, pectin, dextrin, starch, gelatin. tragacanth. methylcellulose. sodium carboxymethylcellulose. a low melting wax, cocoa butter, and the like.
• a preferred form for oral use are capsules, which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
• cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
• a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
• the active component is dispersed homogeneously therein, as by stirring.
• the molten homogenous mixture is then poured into convenient size molds, allowed to cool, and thereby to solidify.
• Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions.
• liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline. 5% aqueous glucose, and the like.
• Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
• Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose. sodium carboxymethylcellulose. or other well-know ⁇ suspending agents.
• liquid form preparations that are intended to be converted, shortly before use. to liquid form preparations for oral administration.
• liquid forms include solutions, suspensions, and emulsions.
• These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants. thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles, and the like can be utilized to prepare sustained-release dosage forms.
• osmotic pumps can be employed to deliver the active compound uniformly over a prolonged period.
• the pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
• the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation. such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
• the therapeutically effective dose of a compound of Formula I will generally be from about 1 to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 to about 800 mg per day.
• the quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 to about 500 mg, preferably about 0.5 to 100 mg according to the particular application and the potency of the active component.
• the composition can. if desired, also contain other compatible therapeutic agents.
• a subject in need of treatment with a compound of Formula I is administered a dosage of about 1 to about 500 mg per day. either singly or in multiple doses over a 24-hour period.
• the compounds of the present invention are capable of binding to and inhibiting the activity of proteins having the ability to phosphorylate other proteins, such as cdks, PDGFr. FGFr, c-Src. and EGFr. Cdks form complexes with cyclins. and these complexes phosphorylate key proteins allowing cells to proceed through the cell cycle (Meijer L., Progress in Cell Cycle Research. 1995:1 :351-363).
• the compounds of this invention inhibit this phosphorylation and therefore can be used as anti-proliferative agents for the treatment of cancer and/or restenosis and other proliferative diseases.
• the compounds of the present invention are also useful research tools for studying the mechanism of action of those kinases. both in vitro and in vivo.
• Typical hydroxy protecting groups include ether forming groups such as benzyl, and aryl groups such as tert-butoxycarbonyl (Boc). formyl. and acetyl.
• Amino protecting groups include benzyl, aryl such as acetyl. and trialkylsilyl groups.
• Carboxylic acid groups typically are protected by conversion to an ester that can be easily hydrolyzed. for example, trichloroethyl. tert-butyl. benzyl, and the like.
• some of the invention compounds have one or more chiral centers, and thus can exist as individual optical isomers and geometric isomers. and mixtures thereof.
• Compound 106 Some of the invention compounds have one or more chiral centers, and thus can exist as individual optical isomers and geometric isomers. and mixtures thereof.
• the 5-hydroxymethyl analog which in turn is oxidized to a 5-formyl derivative.
• the 5-formyl group is converted to an unsaturated (acrylate) group, which is cyclized to form a pyrido[2.3-d]pyrimidine.
• the pyridopyrimidine is converted to a key intermediate, nameh 2-methylsulfanyl-pyrido[2.3-d]pyrimidine-7-ylamine. which is readily oxidized to give a 2-methylsulfinyl analog.
• the 2-methylsulfinyl group is easily displaced by reaction with an amine R 2 NH2 to provide the invention compounds of Formula I.
• N ⁇ -Phenyl-pyrido[2,3-d]pyrimidine-2, 7-diamine A suspension of 0.44 g (2.1 mmol) of 2-methanesulfinyl-pyrido[2.3- d]pyrimidin-7-ylamine (Example 8) and 0.39 mL (4.2 mmol) of aniline in 2 mL of dimethylsulfoxide is heated at 100°C overnight. The resulting solution is cooled and poured into water. Ethyl acetate is added to the suspension, and the solid is collected by filtration. The solid is purified by flash chromatography. eluting with gradient of 0% to 20% methanol/dichloromethane during 30 minutes to give
• EXAMPLE 14 4- ⁇ 4-[7-(3-tert-Butyl-ureido)-pyrido[2,3-d]pyrimidin-2- ⁇ amino]-phenyl ⁇ - piperazine-1-carboxylic acid tert-butyl ester
• 4-[4-(7-amino-pyrido[2.3-d]pyrimidin-2-ylamino)- phenyl]-piperazine-l -carboxylic acid tert-butyl ester (Example 13 ) for N ⁇ -phenyl- pyrido[2.3-d]pyrimidine-2.7-diamine in Example 10.
• Example 14 By substituting isopropyl isocvanate for tert-butyl isocvanate in Example 14. 0.909 g (69.9%) of the product is obtained as a solid.
• Example 24 By substituting cis-3.5-dimethyl-l -(4-nitro-phenyl)-piperazine (Example 24) for l-(4-nitrophenyl)-piperazine in Example 11. 14.87 g (92.8%) of the product as a solid is obtained.
• Example 25 By substituting cis-2.6-dimethyl-4-(4-nitro-phenyl )-piperazine- 1 -carboxylic acid tert-butyl ester (Example 25) for 4-(4-nitro-phenyl)-piperazine- 1 -carboxylic acid tert-butyl ester in Example 12. 5.03 g (64.7%) of the product as a solid is obtained.
• Example 26 By substituting 4-(4-amino-phenyl)-cis-2.6-dimethyl-piperazine- 1-carboxylic acid tert-butyl ester (Example 26) for aniline in Example 9. 0.6463 g (59.8%) of the product is obtained, mp 245°C (dec). MS (APCI) M ⁇ l : Calcd 450.3: Found 450.3.
• Example 28 By substituting 4- ⁇ 4-[7-(3-tert-butyl-ureido)-pyrido[2.3-d]pyrimidin- 2-ylamino]-phenyl ⁇ -cis-2.6-dimethyl-piperazine-l-carboxylic acid tert-butyl ester (Example 28) for 4- ⁇ 4-[7-(3-tert-butyl-ureido)-pyrido[2,3-d]pyrimidin- 2-ylamino]-phenyl ⁇ -piperazine- 1 -carboxylic acid tert-butyl ester in Example 15 is obtained 0.0910 g (92.9%) of the product (compound 49). mp 245°C (dec).
• Example 28 By substituting cyclohexyl isocvanate for tert-butyl isocvanate in Example 28. 0.1156 g (60.8%) of the product is obtained as a solid.
• Example 13 in 2 mL of dimethylformamide. cooled in an ice bath, is added 0.022 g (0.54 mmol) of 60% sodium hydride. The cooled solution is stirred for 15 minutes, then treated with 0.088 g (0.54 mmol) of carbonyldiimidazole. The cooled solution is stirred for another 30 minutes, then treated with 0.071 mL (0.72 mmol) of cyclopentylamine. The resulting solution is stirred at room temperature for 1 hour, then added to cold water. The solid is collected by filtration to give a first crop of material. The aqueous filtrate is then extracted with dichloromethane.
• Example 34 By substituting 1 -(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanol ( Example 34) for (4-amino-2-methylsulfanyl-pyrimidin-5-yl )-methanol in Example 3 and conducting the reaction at 80°C in toluene. 3.74 g (72%) of the product as a solid is obtained. MS (APCI) M+l : Calcd 184.0; Found 183.9.
• Example 36 By substituting 1 -(4-amino-2-methanesulf ⁇ nyl-pyrimidin-5-yl)-ethanone (Example 36) for 2-methanesulf ⁇ nyl-pyrido[2.3-d]pyrimidin-7-ylamine in Example 13, 4.04 g (65%) of the product as a solid is obtained.
• EXAMPLE 38 4-[4-(7-Amino-5-methyl-pyrido[2,3-d]pyrimidin-2- ⁇ amino)-phenyl]-piperazine- 1-carboxylic acid tert-butyl ester
• To a suspension of 0.58 g (14.6 mmol) of 60% sodium hydride in 10 mL of tetrahydrofuran. at 0°C. is added dropwise 2.58 g ( 14.56 mmol) of diethyl (cyanomethyl) phosphonate. The reaction mixture is stirred at 0°C for 5 minutes, then at room temperature for 20 minutes.
• Example 35 By substituting 1 -(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone (Example 35) for 4-[4-(5-acetyl-4-amino-pyrimidin-2-ylamino)-phenyl]- piperazine- 1-carboxylic acid tert-butyl ester in Example 38. 0.97 g (85%) of the product as a solid is obtained. MS (APCI) M+ 1 : Calcd 207: Found 207.
• Example 47 By substituting 7-chloro-6-fluoro-2-methylsulfanyl-pyrido[2.3- djpyrimidine (Example 47) for 7-chloro-2-methylsulfanyl-pyrido[2.3- djpyrimidine in Example 7 is obtained 0.29 g (90%) of the product as a solid. MS (APCI) M+l : Calcd 211 : Found 21 1.
• Example 74 By substituting the product of Example 74 in Example 7. 2.09 g (82.9%) of the product is obtained as a solid.
• Example 75 By substituting the product of Example 75 in Example 8. 1.81 g (81.9%) of the product is obtained as a solid, mp 245°C (dec).
• EXAMPLE 84 4-[4-(7-Amino-6-bromo-pyrido[2,3-d]pyrimidin-2-ylamino)-phenyl]-cis-2,6- dimethyl-piperazine-1-carboxylic acid tert-butyl ester substituting the product of Example 76 in Example 27. 2.10 g (63.1%) of the product is obtained as a solid. MS (APCI) M-l : Calcd 528.2; Found 528.2.
• Example 84 By substituting the product of Example 84 in Example 16. 0.1750 g (70.7%) of the product is obtained as a solid.
• Example 97 By substituting the product of Example 97 in Example 16. 0.170 g (31.2%) of the product is obtained as a solid.
• Example 9 By substituting the product of Example 106 in Example 9. 0.1829 g (50.1%) of the product is obtained as a solid.
• Example 27 By substituting the product of Example 1 12 in Example 27. 0.22 g (49%) of the product is obtained as a solid.
• Example 116 By substituting the product of Example 116 in Example 8. 1.31 g (83.4%) of the product is obtained as a solid, mp 185°C.
• Example 120 Using the general procedure by which Example 120 is synthesized. 0.1366 g (95.6%) of the product (compound 106) is obtained as a solid, mp 170°C (dec).
• Example 15 Using the general procedure by which Example 15 is synthesized. 0.022 g (56%) of the product (compound 108) is obtained as a solid.
• Example 40 Using the general procedure by which Example 40 is synthesized, but using dimethyl sulfamyl chloride rather than cyclohexylisocyanate. the product
• Example 3 in 10 mL of tetrahydrofuran is added 0.126 mL (1.18 mmol) of ethyl cyanoacetate. The solution is cooled to -10°C, and treated with 2.36 mL (2.36 mmol) of titanium tetrachloride. To the solution is slowly added 0.52 mL (4.72 mmol) of N-methyl morpholine. The reaction is warmed to room temperature over 2 hours, and partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer is concentrated to give a solid. which is triturated with ether to give 0.30 g (96%) of the product as a solid. MS (APCI) M+l : Calcd 265.1 ; Found 264.9.
• EXAMPLE 13 1 2-[4-(4-tert-Butoxycarbonyl-piperazin-l-yl)-phenylatnino]-7-(3-tert-butyl- ureido)-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester
• Example 130 By substituting the product of Example 130 in Example 10. 0.05 g (48%) of the product as a solid is obtained.
• Example 52 Using the general procedure by which Example 52 is synthesized, but using l -(4-amino-2-methylsulfanyl-pyrimidin-5-yl)-ethanone (Example 35), 4-(4- amino-phenyl)-piperazine- 1 -carboxylic acid tert-butyl ester (Example 12). and isopropyl isocvanate as reagents, the product (compound 114) is obtained as a solid, mp 208°C (dec). MS (APCI) M+l : Calcd 439.2: Found 439.3.
• Example 96 Using the general procedure by which Example 1 7 is synthesized, but using 4-(4-amino-phenyl)-2.2-dimethyl-piperazine- 1 -carboxylic acid tert-butyl ester (Example 96). 0.95 g ( 100%) of the product (compound 115) is obtained as a solid. MS (APCI) M+l : Calcd 475.6; Found 475.3. Anal. Calcd for C 2 6H3 NgO ] -3 HCl-1 H 2 O:
• Example 29 Using the general procedure by which Example 29 is synthesized, but using the product of Example 135 as the starting material. 0.26 g (89%) of the product (compound 117) is obtained as a solid. MS (APCI) M+l : Calcd 463.6: Found 463.3. Anal. Calcd for C 2 5H 36 Ng ⁇ ! -2.4 HCl-1.75 H 2 O:
• Example 15 Using the general procedure by which Example 15 is synthesized, but using the product of Example 135 as the starting material. 1.02 g (100%) of the product (compound 118) is obtained as a solid. MS (APCI) M+l : Calcd 435.3: Found 435.3. Anal. Calcd for C 23 H 30 NgO 1 -5 HCM .75 H 2 O:
• Example 33 Using the general procedure by which Example 33 is synthesized, but using the product of Example 135 as the starting material, along with 4-(4-amino- phenyl)-cis-2.6-dimethyl-piperazine- 1 -carboxylic acid tert-butyl ester and isopropylamine as reagents. 0.130 g (100%) of the product (compound 119) is obtained as a solid. MS (APCI) M+l : Calcd 449.3: Found 449.3. Anal. Calcd for C24H 32 NgO 1 -3 HCI- 1.75 H2O:
• Example 33 Using the general procedure by which Example 33 is synthesized, but using the product of Example 135 as the starting material, along with 4-(4-amino- phenyl)-cis-2.6-dimethyl-piperazine- 1-carboxylic acid tert-butyl ester and clopropylamine as reagents, 0.099 g (100%) of the product (compound 120) is obtained as a solid.
• Example 137 Using the general procedure by which Example 137 is synthesized, but using (l-cyano-propyl)-phosphonic acid diethyl ester as starting material. 0.34 g
• EXAMPLE 142 The following compounds are prepared essentially according to the procedures described in Examples 1 -141 and shown in Schemes 1-4: (a) l-tert-Butyl-3-[2-(3-chloro-4-piperazin-l -yl-phenylamino)- pyrido[2.3-d]pyrimidin-7-yl]-urea (compound 2);
• the compounds of this invention are potent inhibitors of cdks. and accordingly, are useful in treating and preventing atherosclerosis and other cell proliferative disorders like cancer that are mediated by such cdk enzymes.
• the compounds exhibit excellent inhibitory activity against a number of cdk enzymes, including cdkcdkl/cyclinB. cdk2/cyclinA. cdk2/cyclinE, and cdk4/cyclinD. when evaluated in standard assays routinely utilized by those skilled in the art to measure cdk inhibitory activities.
• Typical assays are carried out as follows.
• Enzyme assays for IC50 determinations and kinetic evaluation are performed in 96-well filter plates (Millipore MADVN6550). The total volume is
• [32p]ATP [32p]ATP. and the plate is incubated at 25°C for 15 minutes. The reaction is terminated by addition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate is kept at 4°C for at least 1 hour to allow the substrate to precipitate. The wells are then washed 5 times with 0.2 mL of 10% TCA and J -P incorporation is determined with a beta plate counter (Wallac Inc.. Gaithersburg. MD).
• TCA trichloroacetic acid
• Enzyme assays for IC50 determinations and kinetic evaluation are performed in a 96-well filter plate (Millipore MADVN6550) in a total volume of 0.1 mL of 20 mM TRIS (tris[hydroxymethyl]aminomethane), at pH 7.4, 50 mM
• TCA and J -P incorporation determined with a beta plate counter (Wallac Inc., Gaithersburg. MD).
• Source of enzvme recombinant baculovirus-infected insect cell sf9-expressed recombinant cdk5-p25 complex.
• Purpose To evaluate the ability of test agents to inhibit cdk5/p25 phosphorylation of Histone HI .
• Baculovirus-insect cell His-tagged cdk5/Glu-tagged p25 (or GST-p25) enzyme complex is diluted to a concentration of 50 ng/20 ⁇ L in Enzyme Dilution Buffer (EDB - 50 mM Tris-HCl [pH 8.0]. 10 mM NaCl. 10 mM
• a 20 ⁇ L sample of test agent (diluted in EDB) is then combined with 20 ⁇ L of the of the final cdk5/p25 enzyme preparation and allowed to stand for 5 minutes at room temperature. Twenty-five microliters of substrate solution containing 1 15 ⁇ L/mL Histone HI . 30 ⁇ M ATP (vanadate-free). and 30 ⁇ Ci/mL ⁇ -3->P ATP (Amersham) in EDB is then added to the test agent/enzyme preparation and shaken at 30°C for 45 minutes. A 50 ⁇ L sample of the final preparation is added to 100 mL of 150 mM phosphoric acid on ice for 30 minutes to facilitate precipitation.
• the precipitate is then filtered through a 96-well phosphocellulose filter plate and subsequently rinsed 3 times with 75 mM phosphoric acid. Each well then receives 20 ⁇ L of scintillation cocktail, and the plates are counted for beta emissions using a Trilux Counter (33p filter protocol). Test samples are compared to Control (no test agent present: as 0% inhibition) and Baseline level (no enzyme, no test agent: as 100% inhibition) beta emissions to determine the percent inhibition of Histone HI phosphorylation.
• Control no test agent present: as 0% inhibition
• Baseline level no enzyme, no test agent: as 100% inhibition
• the compounds of this invention also are inhibitors of the growth factor receptor tyrosine kinase enzymes. FGFr and PDGFr. and of the nonreceptor tyrosine kinase enzyme. c-Src.
• FGFr and PDGFr and of the nonreceptor tyrosine kinase enzyme.
• c-Src Several of the invention compounds have been evaluated via standard assays that measure their ability to inhibit tyrosine kinase enzymes. These assays are carried out as follows:
• cDNAs for the mouse PDGF- ⁇ and human FGF-1 (fig) receptor tyrosine kinases are obtained from J. Escobedo and prepared as described in J Biol Chem.. 1991 :262: 1482-1487.
• PCR primers are designed to amplify a fragment of DNA that codes for the intracellular tyrosine kinase domain. The fragment is inserted into a baculovirus vector, cotransfected with AcMNPV DNA. and the recombinant virus isolated. SF9 insect cells are infected with the virus to overexpress the protein, and the cell lysate is used for the assay. Assays are performed in 96-well plates (100 ⁇ L/incubation/well).
• Specific enzymatic activity (enzyme plus buffer) is defined as total activity minus nonspecific activity.
• the % inhibition at 50 ⁇ M is determined, and for the more potent compounds the concentration of the compound that inhibited specific activity by 50% (IC50) is determined based on the inhibition curve.
• C-Src kinase is purified from baculovirus infected insect cell lysates using an antipeptide monoclonal antibody directed against the N-terminal amino acids (amino acids 2-17) of c-Src.
• the antibody covalently linked to 0.65 ⁇ m latex beads, is added to a suspension of insect cell lysis buffer comprised of 150 mM
• reaction components 10 ⁇ L c-Src beads. 10 ⁇ L of 2.5 mg/mL poly GluTvr substrate, 5 ⁇ M ATP containing 0.2 ⁇ Ci labeled 2p_ATP. 5 ⁇ L DMSO containing inhibitors or as a solvent control, and buffer to make the final volume 125 ⁇ L.
• the reaction is started at room temperature by addition of the ATP and quenched 10 minutes later by the addition of 125 ⁇ L of 30% TCA. 0.1 M sodium pyrophosphate for 5 minutes on ice.
• the plate is then filtered and the wells washed with two 250-mL aliquots of 15% TCA. 0.1 M pyrophosphate.
• the filters are then punched, counted in a liquid scintillation counter, and the data examined for inhibitory activity in comparison to a known inhibitor such as erbstatin. The method is also described in J. Med. Chem., 1994:37:598-609.
• the invention also provides pharmaceutical compositions comprising an invention compound admixed with a carrier, diluent, or excipient.
• a carrier diluent, or excipient.
• EXAMPLE 144 A pharmaceutical compositions in the form of hard gelatin capsules for oral administration is prepared using the following ingredients:
• a typical active ingredient is l -isobutyl-3-[2- ⁇ (2-chloro-4- piperazin-l -yl)-phenylamino ⁇ -pyrido[2.3-d]pyrimidin-7-yl]-urea.
• the composition is administered from 2 to 4 times a day for treatment of postsurgical restenosis.
• compositions for Oral Suspension are Compositions for Oral Suspension
• the sorbitol solution is added to 40 mL of distilled water, and the pyridopyrimidine is suspended therein.
• the saccharin, sodium benzoate. and flavoring are added and dissolved.
• the volume is adjusted to 100 mL with distilled water.
• Each milliliter of syrup contains 5 mg of active ingredient.
• the active ingredient, starch, and cellulose are passed through a No. 45 mesh US sieve and mixed thoroughly.
• the solution of polyvinylpyrrolidone is mixed with the resultant powders and then passed through a No. 14 mesh US sieve.
• the granules are dried at 50°C to 60°C and passed through a No. 18 mesh US sieve.
• the sodium carboxymethyl starch, magnesium stearate. and talc. previously passed through a No. 60 mesh US sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
• a typical active ingredient utilized in the above preparation is the compound of Example 40 (Compound 12). This composition is well-suited to treatment of diabetic retinopathy.
• EXAMPLE 144c A parenteral composition suitable for administration by injection is prepared by dissolving 100 mg of compound 77 in 250 mL of 0.9% aqueous sodium chloride solution and adjusting the pH of the solution to about 7.0. This formulation is well-suited for the treatment of breast cancer.
• a mixture of 500 mg of l-n-butyl-3-[2-(4-piperazin-l-yl-phenylamino)- pyrido[2.3-d]pyrimidin-7-yl]-urea and 1500 mg of theobroma oil are blended to uniformity at 60°C.
• the mixture is cooled to 24°C in tapered molds.
• Each suppositon- will weigh about 2 g and can be administered from 1 to 2 times each day for treatment of viral infections such as herpes and Hl ⁇ 7 .
• the invention compound is blended to uniformity with the other ingredients to make a thick suspension.
• the suspension is applied evenly to an adhesive backed polymeric film and cut into a 2-inch square.
• the patch is applied to the skin of a patient suffering from psoriasis.
• R "7 , R . 13, R14_ anc j R1:> are independently hydrogen, or lower alkyl. lower alkenyl. or lower alkynyl. each of which is optionally substituted with up to 5 groups independently selected from halogen, cyano. nitro. -R 9 . -NR ⁇ R ⁇ O ⁇ -OR9 -(CH 2 ) n CO 2 R 9 . -(CH2) n SO2R n . -(CH 2 ) n R ⁇ - -COR 9 , -CONR 9 R 10 . -SO3R 9 . -SO 2 NR 9 R 10 . -SO R 9 . -SR 9 . -P0 R 9 R 10 . -POR 9 R 10 . -PO(NR 9 R 10 ) 2 . -NR 9 COR 10 ,

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