CA2093203C - Pyrimidine derivatives and processes for the preparation thereof - Google Patents

Pyrimidine derivatives and processes for the preparation thereof Download PDF

Info

Publication number
CA2093203C
CA2093203C CA002093203A CA2093203A CA2093203C CA 2093203 C CA2093203 C CA 2093203C CA 002093203 A CA002093203 A CA 002093203A CA 2093203 A CA2093203 A CA 2093203A CA 2093203 C CA2093203 C CA 2093203C
Authority
CA
Canada
Prior art keywords
pyridyl
lower alkyl
compound
phenyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002093203A
Other languages
French (fr)
Other versions
CA2093203A1 (en
Inventor
Jurg Zimmermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=4202064&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2093203(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Publication of CA2093203A1 publication Critical patent/CA2093203A1/en
Application granted granted Critical
Publication of CA2093203C publication Critical patent/CA2093203C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/42One nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Macromonomer-Based Addition Polymer (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Paints Or Removers (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

There are described N-phenyl-2-pyrimidine-amine derivatives of formula I
wherein R1 is pyrazinyl, 1-methyl-1H pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each cast is free, alkylated or acylated, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstitut ed or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 are each nitro, fluoro-substituted lower alkoxy or a radical of formula II
-N(R9)-C(=X)-(Y)n-R10 (II), wherein R9 is hydrogen or lower alkyl, -X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydrox-imino, Y is oxygen or the group NH, n is a or 1 and R10 is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoro-methyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy.
These compounds can be used, for example, in the therapy of tumoral diseases.

Description

21489-8646 (S) Pyrimidine derivatives and processes for the preparation thereof The invention relates to N-phenyl-2-pyrimidine-amine derivatives, to processes for the preparation thereof, to medicaments comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals.
The invention relates to N-phenyl-2-pyrimidine-amine derivatives of formulal R R ~ ~ Rs N CI).
R / ~~N R4 ~H
'N

wherein R, is pyrazinyl, 1-methyl-1 H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, 1 H-indolyl or 1 H-imidaiolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, Rs, R, and R8 are each vitro, fluoro-substituted lower alkoxy or a radical of formulall -N~Rs)'C~=X)-(Y)n-R~o wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, 21489-8646 (S) Y is oxygen or the group NH, n is 0 or 1 and Rlo is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, and the remaining radicals R4, R5, Rs, R~ and Rg are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoro-methyl, free, etherified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, and to salts of such compounds having at least one salt-forming group.
1-Methyl-1H-pyrrolyl is preferably 1-methyl-1H-pyrrol-2-yl or 1-methyl-1H-pyrnol-3-yl.
Amino- or amino-lower alkyl-substituted phenyl Rl wherein the amino group in each case is free, alkylated or acylated is phenyl substituted in any desired position (ortho, meta or para) wherein an alkylated amino group is preferably mono- or di-lower alkylamino, for example dimethylamino, and the lower alkyl moiety of amino-lower alkyl is preferably linear Ct-C3alkyl, such as especially methyl or ethyl.
1H-Indolyl bonded at a carbon atom of the five-membered ring is 1H-indol-2-yl or 1H-indol-3-yl.
Unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom is lower alkyl-substituted or preferably unsubstituted 2-, 4- or preferably 3-pyridyl, for example 3-pyridyl, 2-methyl-3-pyridyl or 4-methyl-3-pyridyl. Pyridyl substituted at the nitrogen atom by oxygen is a radical derived from pyridine N-oxide, i.e. N-oxido-pyridyl.
Fluoro-substituted lower alkoxy is lower alkoxy carrying at least one, but preferably several, fluoro substituents, especially trifluoromethoxy or 1,1,2,2-tetrafluoro-ethoxy.
When X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydrox-imino, the group C=X is, in the above order, a radical Cue, Cue, C=N-H, C=N-lower alkyl, C=N-0H or C=N-O-lower alkyl, respectively. X is preferably oxo.

~~1fi~1 /~ 5,~
f.J a ~ V r~1 n is preferably 0, i.e. the group Y is not present.
Y, if present, is preferably the group 1V13.
The term "lower" within the scope of this text denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms.
bower alkyl Rl, Rz, R3 and R9 is preferably methyl or ethyl.
An aliphatic radical Rto having at least 5 carbon atoms preferably has not more than 22 carbon atoms, generally not more than 10 carbon atoms, and is such a substituted or preferably unsubstituted aliphatic hydrocarbon radical, that is to say such a substituted or preferably unsubstituteri alkynyl, alkenyl or preferably alkyl radical, such as CS-C~alkyl, for example n-pentyi. An aromatic radical Rlo has up to 20 carbon atoms and is unsubstituted or substituted, for example in each case unsubstituted or substituted naphthyl, such as especially 2-naphthyl, or preferably phenyl, the substituents preferably being selected from cyano, unsubstituted or hydroxy-, amino- or 4-methyl-piperazinyl-substituted lower alkyl, such as especially methyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino and free or esterified carboxy. In an aromatic-aliphatic radical Rto the aromatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Ct-C2alkyl, which is substituted or preferably unsubstituted, for example benzyl. A cycloaliphatic radical Rto has especially up to 30, more especially up to 20, and most especially up to 10 carbon atoms, is mono- or poly-cyclic and is substituted or preferably unsubstituted, for example such a cycloalkyl radical, especially such a S- or 6-membered cycloalkyl radical, such as preferably cyclo-hexyl. In a cycloaliphatic-aliphatic radical Rto the cycloaliphatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Ct-C.zalkyl, which is substituted or preferably unsubstituted. A heterocyclic radical Rtp contains especially up to 20 carbon atoms and is preferably a saturated or unsaturated monocyclic radical having 5 or 6 ring members and 1-~ hetero atoms which are preferably selected from nitrogen, oxygen and sulfur, especially, for example, thienyl or 2-, 3-or 4-pyridyl, or a bi- or tri-cyclic radical wherein, for example, one or two benzene radicals are annellated (fused) to the mentioned monocyclic radical. In a heterocyclic-aliphatic radical Rtp the heterocyclic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Ct-Czalkyl, which is substituted or preferably unsubstituted.

fix, i1. ~ j ~a . e.9 r'~-t !,~ =~
<;
Etherified hydroxy is preferably lower alkoxy. Esterified hydroxy is preferably hydroxy esterified by an organic carboxylic acid, such as a lower alkanoic acid, or a mineral acid, such as a hydrohalic acid, for example lower alkanoyloxy or especially halogen, such as iodine, bromine or especially fluorine or chlorine.
Alkylated amino is, for example, lower alkylamino, such as methylamino, or di-lower alkylamino, such as dimethylamino. Acylated amino is, for example, lower alkanoyl-amino or benzaylamino.
Esterified carboxy is, for example, lower alkoxycarhonyl, such as methoxycarbonyl.
A substituted phenyl radical may carry up to 5 substituents, such as fluorine, but especially in the case of relatively large substituents is generally substituted by only from 1 to 3 substituents. Examples of substituted phenyl that may be given special mention are 4-chloro-phenyl, pentafluora-phenyl, 2-carboxy-phenyl, 2-methoxy-phenyl, 4-fluoro-phenyl, 4-cyano-phenyl and 4-methyl-phenyl.
Salt-forming groups in a compound of formula I are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example a free amino group, a pyrazinyl radical or a pyridyl radical, may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, malefic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenaxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane-or 2-hydroxy-ethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed.
Compounds of formula I having acidic groups, for example a free carboxy group in the radical Rto, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, poeassium, magnesium or calcium salts, or ammonium 2 ~~ a ~~L~W~~3 salts with ammonia or suitable organic amines, such as tertiary monoamines, far example triethylamine or tri-(2-hydroxyethyl)-amine, or heterocyclic bases, for example N-ethyl-piperidine or N,N'-dimethyl-piperazine.
Compounds of formula I having both acidic and basic groups can form internal salts.
For the purposes of isolation or purification, as well as in the case of compounds that are used further as intermediates, it is also possible to use pharmaceutically unacceptable salts. Only pharmaceutically acceptable, non-toxic salts are used for therapeutic purposes, however, and those salts are therefore preferred.
Owing to the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, fox example in the purification of the novel compounds or for the identification thereof, hereinbefore and hereinafter any reference to the free compounds should be understood as including the corresponding salts, where appropriate and expedient.
The compounds of formula I have valuable pharrmacological properties and can be used, for example, as anti-tumoral drugs and as drugs against atherosclerosis.
The phosphorylation of proteins has long been known as an important step in the differ-entiatian and proliferation of cells. The phosphorylation is catalysed by protein kinases which are divided into serine/threonine kinases and tyrosine kinases. The serine/threonine kinases include protein kinase C and the tyrosine kinases the PDGF (platelet-derived growth factor)-receptor tyrosine kinase.
The compounds of formula I wherein R4 and Rg are hydrogen selectively inhibit the enzyme protein kinase C.
Several species of protein kinase C, which is dependent on phospholipids and calcium, occur within cells (distribution of the species is tissue-specific); protein kinase C partici-pates in various fundamental processes, such as signal transmission, proliferation and differentiation, as well as the release of hormones and neurotransmitters. The enzyme is activated either by means of receptor-mediated hydrolysis of phospholipids of the cell membrane or by direct interaction with certain tumour-promoting agents.
Cellular functions that are controlled with the aid of protein kinase C can be influenced by ct f. ~1 ~~. s~ ~~F v"r E,, ~, ~ ~ a i7 modulation of the enzyme activity of protein kinase C.
To determine protein kinase C-inhibiting activity, protein kinase C from pig brain purified in accordance with the procedure described by T. Uchida and C.R. Filbrwrr in J. Biol.
Chem. 259, 12311-4 (I984) is used. The protein- kinase C-inhibiting activity of the compounds of formula I is determined by the method of D. Fabro et al., Arch.
Biochem.
Biophys. 239, 1U2-111 (1985). In that test the compounds of formula I inhibit protein kinase C at a concentration ICSO of as low as approximately from U.1 to 10 ~,mol/litre, especially approximately from 0.05 to 5 ~,mol/litre. On the other hand, the compounds of formula I inhibit other enzymes, for example protein kinase A, phosphorylase protein kinase and certain types of tyrasine protein kinase, for example the tyrosine protein kinase of EGF (epidermal growth factor) receptors, only at a far higher concentration, for example 100 times higher. That is an indication of the selectivity of the compounds of formula I. With a view to reducing undesired side effects, it is important for the protein kinase C-inhibitors to be as selective as possible, i.e. inter _alia to have as little effect as possible on other enzymes, especially when the effect of the activity of those other enzymes has no equivalent or synergistic effect on the disease to be treated.
Owing to their inhibiting activity towards protein kinase C, the compounds of formula I
wherein R4 and Rx are hydrogen, and their pharmaceutically acceptable salts, can be used as tumour-inhibiting, immunornodulating and anti-bacterial active ingredients and, further, as drugs against atherosclerosis, the immunode~ciency disorder AIDS, and diseases of the cardiovascular system and the central nervous system.
As might already be expected on the basis of the inhibiting action on protein kinase C
described above, the compounds of formula I wherein R~ and Rs are hydrogen, and their pharmaceutically acceptable salts, have anti-proliferative properties which can be demonstrated directly in the following, different test. In that test the inhibiting action of compounds of formula I on the growth of human T24 bladder carcinoma cells is determined. Those cells are incubated in "Eagle's minimal essential medium", to which % (v/v) foetal calf serum has been added, in a humidified incubator at 37°C and with 5 percent by volume C02 in the air. The carcinoma cells (1000-1500) are transferred to 96-well rnicrotitre plates and incubated overnight under the above-mentioned conditions.
The test compound is added in serial dilutions on day 1. The plates are incubated for 5 days under the above-mentioned conditions. During that period the control cultures undergo at least 4 cell divisions. After the incubation, the cells am fixed with 3.3 0l0 (g/v) ~~ t ~ e3 ~e'~ ~.~
_7_ aqueous glutaraldehyde solution, washed with water and stained with 0.05 %
(weight/-volume) aqueous methylene blue solution. After washing, the stain is eluted with 3 %
(g/v) aqueous hydrochloric acid. Then the optical density (OD) per well, which is directly proportional to the number of cells, is measured using a photometer (Titertek multiskan) at 665 nm. The ICSp values are calculated by means of a computer system, using the formula OD665 (test) minus OD665 (sty) x 100 ~D665 (~Oritr01) mlnuS OD665 (Start) The ICSo values are defined as that concentration of active ingredient at which the number of cells per well at the end of the incubation period is only 50 % of the number of cells in the control cultures. The ICSO values thus determined are, for the compounds of formula I, approximately from 0.1 to 10 pmol/litre.
Owing to the properties described, the compounds of formula I wherein R4 and R8 are hydrogen can be used especially as tumour-inhibiting active ingredients, for example for the treatment of tumours of the bladder. In addition, they are suitable fnr the further applications mentioned above for protein kinase C-modulators and can be used especially in the treatment of diseases that respond to inhibition of protein kitiase C.
Some of the compounds of formula I wherein R4 and Rg are hydrogen inhibit not only protein kinase C but, at a concentration ICSp as low as approximately from 0.01 to ~.mol/litre, especially approximately from 0.05 to 1 umol/litre, also certain tyrosine kinases, such as especially PDGF-receptor kinase or abl-kinase, for example v-abl-kinase.
Compounds of formula I wherein at least one of the radicals R4 and R8 is other than hydrogen and is, for example, lower alkyl, such as methyl, are especially selective for the above-mentioned PDGF-receptor and abl-tyrosine kinases and inhibit protein kinase C
virtually not at all.
PDGF (platelet-derived growth factor) is a very frequently occurring growth factor which plays an important role both in normal growth and in pathological cell proliferation, such as in carcinogenesis and disorders of the smooth muscle cells of blood vessels, for example in atherosclerosis and thrombosis.
The inhibition of protein kinase C and of PDGF-receptor kinase has in this sense a ~; a'~ ~°s '..> '~' ~v ~t; ~s ~3 ws ~~ e~
_g_ virtually synergistic effect in the same direction vrith regard to the regulation of cell growth.
The inhibition of PDGF-stimulated receptor tyrosine kinase activity in vitro is measured in PDGF receptor immunocomplexes of BALB/c 3T3 cells, analogously to the method described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992). The compounds of formula I described in detail above inhibit PDGF-dependent cell-free receptor phosphorylation at concentrations of frnm 0.005 to 5 ltmol/-litre, especially from 0.01 to 1.0, more especially from 0.01 to 0.1 pmol/litre. The inhibition of PDGF-receptor tyrosine kinase in the intact cell is detected by means of Western Blot Analysis, likewise analogously to the method described by E. Andrejauskas-Buchdunger and U. Regenass in Cancer Research 52, 5353-5358 (1992).
In that test the inhibition of ligand-stimulated PDGF-receptor autophosphorylation in BALB/c mouse cells is measured with the aid of anti-phosphotyrosine antibodies. The compounds of formula I described in detail above inhibit the tyrosine kinase activity of the PDGF receptor at concentrations of from 0.005 to 5 ~.mol/litre, especially from 0.01 to 1.0 and more especially from 0.01 to 0.1 p.mol/litre. At concentrations below 1.0 p,mo1/litre, those compounds also inhibit the cell growth of a PDGF-dependent cell Line, namely BALB/c 3T3 mouse fibroblasts.
The above-mentioned inhibition of v-abl-tyrosine kinase is determined in accordance with the methods of I~1. Lydon et al., Oncogene Research 5, 161-173 (1990) and J.
F. Geissler et al., Cancer Research 52, 4492-4498 (1992). In those methods [Vats]-angiotensin_ II and [T s2P]-ATP are used as substrates.
Owing to the properties described, compounds of formula I can be used not only as tumour-inhibiting active ingredients but also as drugs against non-malignant proliferative diseases, e.g. atherosclerosis, thrombosis, psoriasis, sclerodemtitis and fibrosis. They are also suitable for the further applications mentioned above for protein kinase C-modulators and can be used especially in the treatment of diseases that respond to the inhibition of PDGF-receptor kinase.
In addition, the compounds of formula I prevent the development of resistance (multi-drug resistance) in cancer treatment with other chemotherapeutic drugs or remove existing resistance to other chemotherapeutic drugs.

.21489-8645(S) _g_ Preference is given to compounds of formula I wherein one or two of the radicals R4, R5, Rs, R, and R8 are each nitro or a radical of formula II
wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and R,o is an aliphatic radical having at least 5 carbon atoms or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical, and the remaining radicals R4, R5, RB, R~ and Re are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, atkylated or acylated amino or free or esterified carboxy, and the remaining substituents are as defined above, and to salts of such compounds having at least one salt-forming group.
Preference is given especially to compounds of formula I wherein R, is pyrazinyl, 1-methyl-1 H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is tree, alkylated by one or two lower alkyl radicals or acylated by lower alkanoyl or by benzoyl, 1 H-indolyl or 1 H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, .
R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, RB, R~ and Rg are each nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen pr the group NH, n is 0 or 1 and Rio is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl or naphthyt radical each of which is unsubstituted or substituted by cyano, lower alkyl, -10- ~i)~W ~~
hydroxy-lower alkyl, amino-lower alkyl, (4-methyl-piperazinyl)-lower alkyl, tri-fluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or by lower aikoxycarbonyl, or phenyl-lower alkyl wherein the phenyl radical is unsub-stituted or substituted as indicated above, a cycloalkyl or cycloalkenyl radica:
having up to 30 carbon atoms, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl each having up to 30 carbon atoms in the cycloalkyl or cycloalkenyl moiety, a monocyclic radical having 5 or 6 ring members and 1-3 ring hetero atoms selected from nitrogen, oxygen and sulfur, to which radical one or two benzene radicals may be fused, or lower alkyl substituted by such a monocyclic radical, and the remaining radicals R4, R5, R6, R~ and Rg are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by amino, lower alkyl-amino, di-lower alkylamino, piperazinyl, piperidinyl, pyrrolidinyl or by morpho-linyl, or lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or lower allcoxycarbonyl, and to salts of such compounds having at least one salt-forming group.
Special preference is given to compounds of formula I wherein Rt is pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, RZ and R3 are each hydrogen, R4 is hydrogen or lower alkyl, RS is hydrogen, lower alkyl or fluoro-substituted lower alkoxy, R6 is hydrogen, R~ is vitro, fluoro-substituted lower alkoxy or a radical of formula II
wherein R9 is hydrogen, X is oxo, n is 0 and Rto is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl radical that is unsubstituted or substituted by cyano, lower alkyl, (4-methyl-piperazinyl)-lower alkyl, lower alkoxy, halogen or by carboxy; a cycloalkyl radical having up to carbon atoms or a monocyclic radical having 5 or 6 ring members and 1-3 sulfur ring atoms, and Rg is hydrogen, and to pharmaceutically acceptable salts of such compounds having at least one salt-b c fiz ~ '~ ~~ ~v fd Y.~s,~ x~ ø,e ~.~ r~

forming group.
Special preference is given especially to compounds of formula I wherein RI is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom, R2 and R3 are each hydrogen, R4 is hydrogen or lower alkyl, RS is hydrogen, lower alkyl or trifluoromethyl, R6 is hydrogen, R~ is nitro, fluoro-substituted lower alkoxy or a radical of formula II
wherein R9 is hydrogen, X is oxo, n is the number 0 and Rlp is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4.-methyl-piperazinyl-methyl, or CS-C~alkyl, thienyl, 2-naphthyl or cyclohexyl, and Rg is hydrogen, and to pharmaceutically acceptable salts of such compounds having at least one salt-forming graup.
Preference is given above all to compounds of formula I wherein R4 and R8 are each hydrogen or wherein at least one of the radicals R4 and Rs is lower alkyl, and the other of the radicals R4 and Rx and the remaining radicals are as defined above, and to pharmaceut-ically acceptable salts of such compounds having at least one salt-forming group.
Preference is given above all especially to compounds of formula I wherein Rl is pyridyl bonded at a carbon atom, R2, R3, Rn, R5, R6 and Rg are each hydrogen and R~ is nitro or a radical of formula II wherein R9 is hydrogen, X is oxo, n is the number 0 and Rtp is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by fluorine, chlorine, cyano, lower al.koxy, carboxy, lower alkyl or by 4-methyl-piper-azinyl-methyl, or CS-C~alkyl, thienyl or cyclohexyl, and to pharmaceutically acceptable salts thereof.

~~t.~~~~;3 _ 1~ _ Most especially preferred are the compounds of formula I described in the Examples and pharmaceutically acceptable salts of such compounds having at least one salt-forming group.
In view of their inhibition of protein kinase C, greatest preference is given to those above-mentioned compounds of formula I wherein R4 and R8 are each hydrogen and the remaining substituents are as defined above, and to pharmaceutically acceptable salts of such compounds having at least one salt-forming group.
The compounds of fornmla I and salts of such compounds having at least one salt-forming group are prepared in accordance with processes known per se. The process according to the invention is as follows:
a) a compound of formula III
Rt O

NrRtt R3 Rtz wherein Rlt and R12 are each independently of the other lower alkyl and Rt, R~
and R3 are as defined above, functional groups present in a compound of formula III, with the exception of the groups participating in the reaction, being if necessary in protected form, or a salt of such a compound, is reacted with a compound of formula IV

NH (IV), NHz H
wherein the substituents are as defined above, functional groups present in a compound of >'t . ~i r3 s"' ''~ " ~
~r ''~' 3 e3 !~ ~~ '~' formula IV, with ih; exception of the guanidine group participating in the reaction, being if necessary in protected form, or with a salt of such a compound, and any protecting groups present are removed, or b) for the preparation of a compound of formula I wherein the radicals Rh, R5, R6, R7 and Rg are as defined above with the exception of nitre and fluc~ro-substituted lower alkoxy, a compound of formula V
Rts Rts R' Rt ~ ~ Rt4 N (V)~
R2 ~ ~ Ns Rya N
- N

wherein one or two of the radicals Rlg, Rt4, R15, R16 ~d Rc7 ~'e each amino and the remaining radicals Rt3, Rt4, R15, Rts and Rt7 are each independently of the others hydrogen, lower alkyl that is unsubstituted ar substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morphalinyl, or lower alkanoyl, trifluaro-methyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino or free or esterifted carboxy, and the remaining substituents are as defined above, functional groups present in a compound of formula V, with the exception of the amino groups) participating in the reaction, being if necessary in protected foam, is reacted with a compound of formula VI
I-IO-~:(=X)-('Y)n Rto (VI), wherein the substituents and symbols are as defined above, functional groups present in a compound of formula VI, with the exception of the I-IO-C(=X) group participating in the reaction, being if necessary in protected form, or with a reactive derivative of a compound of formula VI, and any protecting groups present are removed, or c) for the preparation of a compound of formula I wherein Rt is pyridyl substituted at the nitrogen atom by oxygen, and wherein the other substituents and symbols are as defined above, a compound of formula I wherein l~l is pyridyl is converted into the N-oxido compound with a suitable oxidising agent, and, if desired, a compound of formula I obtainable by any one of processes a to c is converted into its salt, or an obtainable salt of a compound of formula I is converted into the free compound.
The procedure for the above-mentioned process variants is explained in detail below:
General notes:
The end products of formula I may contain substituents that can also be used as protecting groups in starting materials for the preparation of other end products of formula I. Thus, within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of formula I is designated a "protecting group", unless the context indicates otherwise.
Protecting groups, and the manner in which they are introduced and removed are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "lVlethoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. ill, Georg-Thieme-Verlag, Stuttgart 1974 and in Theodore W.
Greene, "Protective Groups in Organic Synthesis", John Whey & Sons, New York 191. E1 characteristic of protecting groups is that they can be removed readily, i.e.
without the occurrence of undesired secondary reactions, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.
Hydroxy-protecting groups are, for example, acyl radicals, such as unsubstituted or substituted, for example halo-substituted, lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carbonic acid semiesters, especially tert-butoxycarbonyl, unsubstituted or substituted benzylaxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or diphenyl-rnethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or formyl, or organic silyl or stannyl radicals, and also readily removable etheri-fying groups, such as tent-lower alkyl, for example tent-butyl, 2-oxa- or 2-thia-aliphatic or 2-oxa- or 2-thia-cycloaliphatic hydrocarbon radicals, especially 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, for example methoxymethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thiacycloalkyl having ~ or 6 ring atoms, for example tetrahydrofuryl or 2-tetrahydro-pyranyl or corresponding this analogues, and unsubstituted or substituted 1-phenyl-lower ., p' ~ S 3 ' 3 e9Fa~

alkyl, such as unsubstituted or substituted benzyi or diphenylmethyl, suitable substituents of the phenyl radicals being, for example, halogen, such as chlorine, lower alkoxy, such as methoxy, and/or vitro.
A protected amino group may be, for example, in the form of a readily cleavable acyl-amino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-en-yl-amino, silyl-amino or stannylamino group or in the form of an azido group.
In a corresponding acylamino group, aryl is, for example, the aryl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an alkanecarb-oxylic acid that is unsubstituted or substituted, for example, by halogen or by aryl, or of a benzoic acid that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by vitro, or of a carbonic acid semiester. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-brorno-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, benzoyl that is unsubstituted or substituted, for example, by halogen, lower alkoxy or by vitro, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower allcoxy-carbonyl that is branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, especially tart-lower alkoxycarbonyl, for example tent-butoxy-carbonyl, arylmethoxycarbonyl having one or two aryl radicals which are preferably phenyl that is unsubstituted or mono- or poly-substituted, for example, by lower alkyl, especially tart-lower alkyl, such as tart-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/or by vitro, such as unsubstituted or substituted benzyl-oxycarbonyl, for example 4-vitro-benzyloxycarbonyl, or substituted diphenylmethoxy-carbonyl, for example benzhydryloxycarbonyl or di(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein the amyl group is preferably benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phenacyloxy-carbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2-(trisubstituted silyl)-ethoxy-carbonyl wherein each of the substituents, independently of the others, is an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 15 carbon atoms that is unsubstituted ar substituted, for example, by lower alkyl, lower alkoxy, aryl, halogen or by vitro, such as corresponding unsubstituted or substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxy-carbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxy-carbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

G xa~
2~ »je Other acyl radicals that are suitable as amino-protecting groups are corresponding radicals of organic phosphoric, phosphoric or phosphinic acids, such as di-lower alkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diiso-propylphosphoryl, dicycloalkylphosphoryl, for example dicyclohexylphosphoryl, unsubstituted or substituted diphenylphosphoryl, for example diphenylphosphoryl, unsubstituted or substituted, for example vitro-substituted, di(phenyl-lower alkyl)-phosphoryl, for example dibenzylphosphoryl or di(4-nitrobenzyl)phosphoryl, unsubstituted or substituted phenoxy-phenyl-phosphonyl, for example phenoxyphenyl-phosphonyl, di-lower alkylphosphinyl, for example diethylphosphinyl, or unsubstituted or substituted diphenylphosphinyl, for example diphenylphosphinyl.
In an arylmethylamino group that is a mono-, di- or, especially, tri-arylmethylamino group, the aryl radicals are especially unsubstituted or substituted phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- and especially trityl-amino.
An etherified mercapto group in an amino group protected by such a radical is especially arylthio or aryl-lower alkylthio, wherein aryl is especially phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tent-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by vitro. A corresponding amino-protecting group is, for example, 4-nitrophenylthio.
In a 2-acyl-lower alk-1-en-1-yl radical that can be used as amino-protecting group, aryl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by vitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester.
Corresponding protecting groups are especially 1-lower alkanoyl-prop-1-en-2-yl, for example 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarbonyl-prop-1-en-2-yl, for example 1-edioxycarbonyl-prop-1-en-2-yl.
JPreferred amino-protecting groups are acyl radicals of carbonic acid semiesters, especially tert-butoxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted, for example, as indicated, for example 4-vitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroetlioxycarbonyl, also trityl or formyl.
The removal of the protecting groups that are not constituents of the desired end product c ~; "~ ~~ ~~ ~ '~~
I~ 'tJ ~ r.~ ra "vi :3 of formula I is effected in a manner known per se, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or chemical reduction, as desired stepwise or simultaneously.
A protected amino group is freed in a manner known her se and, according to the nature of the protecting groups, in various ways, preferably by means of solvolysis or reduction..
2-Halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroyl-rnethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid.
Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and ~1-vitro-benzyloxycarbonylamino can be cleaved also by treatment with an alkali metal dithionite, for example sodium dithionite.
~Tnsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino ar 2-tri-substituted silylethoxycarbonylamino can be cleaved by treatment with a suitable acid, for example formic or trifluoroacetic acid; unsubstituted or substituted benzyloxycarbonyl-amino can be cleaved, for example, by means of hydrogenolysis, that is to say by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst; unsubstituted or substituted triarylmethylamino or formylamino can be cleaved, for example, by ~eatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected by an organic silyl group can be freed, for example, by means of hydrolysis or alcoholysis. An amino group protected by ~,-haloacetyl, for example 2-chloroacetyl, can be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl can also be converted into the free amino group by treatment with a salt of hydrofluoric acid yielding fluoride anions.
A hydroxy group protected by a suitable acyl group, an organic silyl group ar by unsubstituted or substituted 1-phenyl-lower alkyl is freed analogously to a corresponding-ly protected amino group. Hydroxy protected by unsubstituted or substituted 1-phenyl-lower alkyl, for example benzyl, is preferably freed by catalytic hydrogenation, for example in the presence of a palladium-on-carbon catalyst. A hydroxy group protected by ~~i~~i~~v~i 2,2-dichloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy group etherified by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or 2-oxa- or 2-this-cyclo-aliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid.
Hydroxy etherified by an organic silyl radical, for example trimethylsilyl, can also be freed by a salt of hydrofluoric acid yielding fluoride anions, for example tetrabutylammonium fluoride.
Process a:
Preferably Rtt and R~2 are each methyl.
Free functional groups in a compound of formula III that are advantageously protected by readily removable protecting groups are especially amino groups in the radical Rt and the imino group of 1H-indolyl. The latter can be protected, for example, by benzyl.
Free functional groups in a compound of formula IV that are advantageously protected by readily removable protecting groups are especially amino groups, but also hydroxy and carboxy groups.
A salt of a compound of formula IV is preferably an acid addition halt, for example a nitrate or one of the acid. addition salts mentioned for the end products of formula I.
The reaction is carried out in a suitable solvent or dispersing agent, for example a suitable alcohol, such as 2-methoxy-ethanol, or a suitable lower alkanol, for example isopropanol, at a temperature of from room temperature (approx. 20°C) to 150°C, for example under reflux. Especially when the compound of formula IV is used in the form of a salt, that salt is converted into the free compound, preferably in situ, by the addition of a suitable base, such as an alkali metal hydroxide, for example sodium hydroxide.
It is preferable to use as starting materials compounds of formula IV wherein one or two of the radicals R4, Rs, R6, R~ and Rs are each nitre and the remaining radicals Rn, R5, R6, R~ and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino or free or esterified carboxy.
The starting material of formula III is obtained by reacting a compound of formula VII

,1,,'ta~e~~'"~~

R~
R (v~>

wherein the substituents are as defined above, with a compound of formula VIII
OR~9 ~ it RtBO ~ \ (VIII), wherein RtR and Rt9 are each lower alkyl and the remaining substituents are as defined above, in a manner analogous to that described in the European Patent Application having the Publication No. 233461. Typical representatives of a compound of formula VIII are N,N-dimethylformamide-dimethylacetal and N,N-dimethylacetamide-dimethylacetal.
The reaction is carried out with heating of the reactants of formulae VII and VIII
for several hours, for example for from 4 to 24 hours, at a temperature of approximately from 50°C to 15a°C, in the absence or, if necessary, in the presence of a solvent.
The starting material of formula III is alternatively obtained by reacting a compound of formula VII with an ester of the formula R3-C(=O)-O-CH2-CH3 wherein R3 is as def°med above, and reacting the resulting product with an amine of the formula H-N(Rtt)-Rt2 wherein the substituents are as def'med above.
The starting material of formula IV is obtained in the fozm of an acid addition salt by reacting a compound of formula IX
R7 Rs R5 (1X)>
N .Rd i HI
wherein the substituents are as defined above, with cyanamide (NC-NI-I2). The reaction is ~~~~'~e~.3w3~~
r~ ~t carried out in a suitable solvent or dispersing agent, for example a suitable alcahol, for example a suitable lower alkanol, such as ethanol, in the presence of equimolar amounts of the salt-forming acid at a temperature of from room temperature to 150°C, for example under reflux.
Process b:
Free functional groups in a compound of formula V or VI that are advantageously protected by readily removable protecting groups are especially amino groups, but also hydroxy and carboxy groups, that are not intended to participate in the desired reaction, for example amino in the radical Rt.
A reactive derivative of a compound of formula VI wherein X is oxo is especially a reactive (activated) ester, a reactive anhydride or a reactive cyclic amide.
The same is true for the derivatives wherein X has one of the other definitions given above.
Reactive (activated) esters of an acid of formula VI are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as actual vinyl esters (obtainable, for example, by transesterification of a corres-ponding ester with vinyl acetate; activated vinyl ester method), carbamoylvinyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or l-lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxy-acetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide;
carbodi-imide method), or N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide method), suitable aryl esters, especially phenyl esters suitably substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonyl-phenol, 2,4,5-tri-chlorophenol, 2,3,4,5,6-pentachloro-phenol or 4-phenyldiazophenol, in the presence of a condensation agent, such as N,N'-dicyclohexylcarbodiimide; activated aryl esters method), cyanomethyl esters (obtainable, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl esters method), thio esters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treatment of the corresponding acid with unsubsdtuted i~e ~.' ; ~ ei '~ t>

or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method; activated thiol esters method), amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxy-amino or N-hydroxy-amido compound, for example N-hydroxy-succinirraide, N-hydroxy-piperidine, N-hydroxy-phthalimide or 1-hydroxy-benzotriazole, for example by the anhydride or carbodiimide method; activated N-hydroxy esters method), or silyl esters (which are obtainable, for example, by treatment of the corresponding acid with a silylating agent, for example hexamethyl disilazane, and react readily ~.vith hydroxy groups but not with amino groups).
Anhydrides of an acid of formula VI may be symmetric or preferably mixed anhydrides of that acid, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiderivatives, such as corresponding esters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with haloformic, such as chloroformic, acid lower alkyl esters or with a 1-lower alkoxy-carbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; mixed O-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus oxychloride;
phosphorus oxychloride method), or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or substituted lower alkane- or phenylalkane-carboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corres-ponding acid, with a suitable organic sulfonic acid halide, such as lower alkane- or aryl-, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method), and symmetric anhydrides (obtainable, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1-diethylaminopropyne;
symmetric anhydrides method).
Suitable cyclic amides are especially amides with five-membered diazacycles of aromatic ~"v8 character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole;
imidazolide method), or pyra.zoles, for example 3,5-dimethyl-pyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone;
pyrazalide method).
Derivatives of acids of formula VI that can be used as acylating agents can also be formed in situ. For example, N,N'-disubstituted amidina esters can be formed in situ by reacting a mixture of the starting material of formula V and the acid used as acylating agent in the presence of a suitable N,N-disubstituted carbodiimide, for example N,N'-dicyclohexyl-carbodiimide. In addition, amino or amido esters of the acids used as acylating agents can be formed in the presence of the starting material of formula V to be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexyl-carbodiimide, and an N-hydroxy-amine or N-hydroxy-amide, for example N-hydroxysuccinimide, where appropriate in the presence of a suitable base, for example 4-dimethylamino-pyridine.
The reaction is preferably carried out by reacting a xeactive carboxylic acid derivative of a compound of formula VI with a compound of formula V wherein ltte amino group or hydroxy group participating in the reaction is in free form.
The reaction can be carried out in a manner known her se, the reaction conditions being dependent especially on whether, and if so how, the carboxy group of the acylating agent has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and, if necessary, in the presence of a condensation agent, which, for example when the carboxy group participating in the reaction is in the form of an anhydride, may also be an acid-binding agent, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, especially approximately from 0°C
to +100°C, preferably from room temperature (approx. +20°C) to +70°C, in an open or closed reaction vessel and/or in the atmosphere of an inert gas, for example nitrogen.
Customary condensation agents are, for example, carbodiimides, for example N,N'-diethyl-, N,N'-dipropyl-, N;N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide, suitable carbonyl compounds, for example carbonyidiimidazole, or 1,2-oxazoliurn compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroduinoline. Customary acid-binding a ; r1 ':7 '~ ';'~ ~3 ~a'~ ~ tJ'i'~e'' condensation agents are, far example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (customarily together with a sulfate), or organic bases, such as, customarily, pyridine or sterically hindered tri-lower alkylamines, for example N,N-diisopropyl-N-ethyl-amine.
The starting material of formula V is obtained by reduction of the nitro groups) in a compound of formula I wherein one or two of the radicals R4, R5, R6, R~ and Rg are each nitro. That reduction can be carried out, for example, by catalytic hydrogenation in a suitable solvent, such as a suitable acyclic or cyclic ether, such as in tetrahydrofuran.
There is preferably used as hydrogenation catalyst palladium on active carbon (S °/a) and in that case the hydrogenation is preferably carried out under normal pressure.
Process c:
A suitable oxidising agent for converting a compound of formula I wherein Rt is pyridyl into the N-oxido compound is preferably a suitable peracid, for example a suitable perbenzoic acid, such as especially m-chloro-perbenzoic acid. The reaction is carried out in an inert solvent, for example a halogenated hydrocarbon, such as preferably methylene chloride, at temperatures of approximately from -20°C to +1S0°C, especially approx-imately from 0°C to the boiling point of the solvent in question, in.general below +100°C, and preferably at room temperature or at slightly elevated temperature (20°C-70°C).
Acid addition salts of compounds of formula I are obtained in customary manner, for example by treatment with an acid or a suitable anion exchange reagent.
Acid addition salts can be converted into the free compounds in customary manner, for example by treatment with a suitable basic agent.
Mixtures of isomers can be separated into the individual isomers in a manner known her se, for example by fractional crystallisation, chromatography, etc..
The processes described above, including the processes for removing protecting groups and the additional process steps, are, unless otherwise indicated, carried out in a manner known per se, for example in the presence or absence of preferably inert solvents and diluents, if necessary in the presence of condensation agents or catalysts, at reduced or elevated temperature, for example in a temperature range of from approximately -20°C to approximately 1S0°C, especially from approximately 0°C to approximately +70°C, tf~~~~fr~~5;~'i Ca ~.: :.s ~ ~a "tD z~

preferably from approximately +10°C to approximately +50°C, and more especially at room temperature, in a suitable vessel and if necessary in an inert gas atmosphere, for example a nitrogen atmosphere.
In those process steps, taking account of all the substituents in the molecule, if necessary, for example when readily hydrolysable radicals are present, especially mild reaction conditions should be used, such as short reaction times, the use of mild acidic or basic agents at low concentrations, stoichiometric quantity ratios, and the selection of suitable catalysts, solvents, temperature and/or pressure conditions.
Z'he invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or the process is interrupted at any stage or a starting material is formed under the reaction conditions or is used in the form of a reactive derivative or salt.
It is preferable to begin with those starting materials which in accordance with the process result in the compounds described above as being especially valuable.
The present invention relates also to novel starting materials and/or intermediates and to processes for the preparation thereof. The starting materials used and the reaction conditions chosen are preferably those which result in the compounds described in this Application as being especially preferred.
The invention relates also to a method of treating warm-blooded animals suffering from a tumoral disease, which comprises administering to warm-blooded animals requiring such treatment an effective, tumotar-inhibiting amount of a compound of formula I
or of a pharmaceutically acceptable salt thereof. The invention relates further to the use of a compound of formula I or of a pharmaceutically acceptable salt thereof for inhibiting PDGF-receptor kinase or to the use of a compound of formula I wherein R4 and R8 are each hydrogen, or of a pharmaceutically acceptable salt thereof, for inhibiting protein kinase C in warm-blooded animals or for preparing pharmaceutical compositions for use in the therapeutic treatment of the human or animal body. Effective doses, for example daily doses of approximately from t to 1000 mg, especially from 50 to 500 mg, are administered to a warm-blooded animal of approximately 70 kg body weight according to species, age, individual condition, mode of administration and the individual syndrome.
The invention relates also to pharmaceutical compositions comprising an effective _~5_ ~'e~~~~~
amount, especially an amount effective in the prevention or therapy of one of the above-mentioned diseases, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration, and may be inorganic or organic, solid or liquid. For oral administration there are used especially tablets or gelatin capsules comprising the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
Tablets may also comprise binders, for example magnesium aluminium silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavourings and sweeteners. The pharmacologically active compounds of the present invention can also be used in the form of parenterally administrable compositions or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which, for example in the case of lyophilised compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, can be prepared before use. The pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions which, if desired, may comprise further pharmaco-logically active substances, such as antibiotics, are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1 % to 100 %, especially from approximately 1 % to approximately 20 %, active ingredient(s).
The following Examples illustrate the invention but do not limit the invention in any way.
The Ftt values are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany).
The ratio to one another of the eluants in the eluant mixtures used is given in proportions by volume (v/v), and temperatures are given in degrees Celsius.
Abbreviations:
HV: high vacuum n: normal (straight-chain) Example 1: 41.3 g (0.17 mol) of 3-nitrophenyl-guanidine nitrate, made into a slurry in 50 ml of isopropanol, are added to a solution of 30 g (0.17 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one described in EP-A-0 233 461] in 250 ml of isopropanol.
After the addition of 7.49 g (0.19 mol) of sodium hydroxide, the yellow suspension is boiled at reflex for 8 hours. After cooling to 0°, the mixture is filtered and washed with 200 ml of isopropanol. The filtration residue is made into a slurry in 300 ml of water and stirred for 30 minutes, filtered and washed with 200 m1 of water. After again making into a slurry in 200 ml of ethanol and washing with 200 ml of ethanol/diethyl ether (1:l) there is obtained N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 212-213°, Rf =
0.75 (chloro-form:methanol = 9:1).
The starting material is obtained as follows:
Step 1.1: 42 ml (0.6 mol) of nitric acid (65 %) are added dropwise to a yellow suspension of 82.88 g (0.6 mol) of 3-nitroaniline in 200 ml of ethanol. After the exothermic reaction has subsided, 75.7 g (0.9 mol) of cyanamide (50 % in water) are added and the reaction mixture is boiled at reflex for 21 hours. After cooling to 0°, the mixture is filtered and washed six times with ethanol/diethyl ether (1:1). Drying under HV at 40° yields 3-nitro-phenyl-guanidine nitrate; m.p. 205-207°.
Step 1-2: 8 g (0.35 mol) of sodium are placed in 260 ml of toluene and at 100° made into a suspension using a vibromixer. After cooling to 0°, 17 ml (0.42 mol) of methanol are added dropwise, with cooling, and the mixture is then stirred for 45 minutes at 75°. At 25°
and with ice-cooling, a solurion of 38.5 ml (0.35 mol) of 3-acetylpyridine and 28 ml (0.35 mol) of ethyl formate in 300 ml oftoluene are added dropwise in the course of 45 minutes.
The yellow suspension is stirred for 16 hours at 25° and then 23.7 g (0.52 mol) of dimethylamine are added. After the addition of 100 rnl of toluene, the mixture is stirred for 45 minutes at 25°, and then at 0° a solution of 20 rnl of acetic acid in 150 ml of toluene is added dropwise in the course of 30 minutes and the mixture is then boiled at reflex for 1 hour. After cooling to 25°, the mixture is filtered and washed with 500 ml of toluene/-hexane (1:1) and the filtrate is concentrated until crystallisation begins.
Cooling to 0°, filtration and drying at 80° under HV yield 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one; m.p. 81-82°.
Example 2: 100 mg (0.38 mmol) of N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine are dissolved in 5 xnl of pyridine; 58.5 p.1 (0.46 mmol) of 4-chlorobenzoyl chloride are added and the mixture is stirred at room temperature for 24 hours. 10 ml of water are added to the reaction mixture which is then cooled to 0° and filtered.
Washing with water and drying yield N-[3-(4-chlorobenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
m.p. 238-240°, Rf = 0.66 (chloroform:methanol = 9:1).
The starting material is obtained as follows:
Step 2.1: A suspension of 17.0 g (0.058 mol) of N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 1700 ml of tetrahydrofuran is stirred with 1.7 g of palladium tin active carbon (5 %) under a hydrogen atmosphere at normal pressure fox 21 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The yellow solid product that remains behind is stirred overnight in 200 ml of methylene chloride.
Filtration and drying yield N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
m.p. 89-90°, Rp = 0.38 (chloroform:methanol = 9:1 ).
Example 3: 53 p,1 (0.46 mmol) of benzoyl chloride are added to a solution of 100 mg (0.38 mmol) of N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 5 ml of pyridine and the mixture is stirred under a nitrogen atmosphere for 24 hours at room temperattue.
ml of water are added to the reaction mixture which is then cooled to 0°, filtered and washed with water. Drying under HV yields N-(3-benzoylamidophenyl)-4-(3-pyridyl)-2-pyritnidine-amine; m.p. 207-209°, Rf = 0.53 (chloroform:methanol =
9:1).
Example 4: A solution of 100 mg (0.38 mmol) of N-(3-aminophenyl)-4-(3-pyridyl)-pyrimidine-amine and 59 mg (0.46 mmol) of 2-pyridinecarboxylic acid chloride in 5 ml of pyridine is stirred under nitrogen for 24 hours at room temperature. After the addition of 30 mg (0.23 mmol) of 2-pyridine-carboxylic acid chloride, the mixture is stirred for 18 hours and then a further 25 rng (0.19 mmol) of 2-pyridinecarboxylic acid chloride are added and the mixture is stirred for 72 hours at 25°. After the addition of 10 ml of water and cooling to 0°, the mixture is filtered and washed with water.
Separation by chromato-graphy (silica gel, CH(Cl~/MeOf-I = 9:1) yields N-[3-(2-pyridyl)-carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 18 7-190°, Rf = 0.58 (chloroform:methanol = 9:1).
Example 5: Analogously to Example 4, N-[3-(3-pyridyl)-carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 3-pyridinecarboxylic acid chloride;
m.p. 217-220°, Rf = U.29 (chloroform:methanol = 9:1).
Example 6: Analogously to Example 4, N-[3-(4-pyridyl)-carboxamido-phenyl]-4-(3-~i~~~J~~e~3 pyridyl)-2-pyrimidine-amine is synthesised from 4-pyridinecarboxylic acid chloride;
m.p. 224-226°, Rf = 0.29 (chloroform:methanol = 9:1).
Example 7: 63 w1 (0.46 mmol) of pentafluorobenzoyl chloride are added to a solution of 100 mg (0.38 mmol) of N-(3-aminophenyl)-4-(3-pyridyl~2-pyrimidine-amine in 5 rnl of pyridine and the mixture is stirred under nitrogen at room temperature for 17 hours. 10 ml of water are added to the brown reaction solution which is then cooled to 0° and filtered.
The residue is recrystallised from ethanol/acetone and yields the crystalline product N-(3-pentafluorobenzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 234-244°, Rp =
0.41 (chloroform:metha~no19:1).
Example 8: 28 mg (0.19 nunol) of phthalic acid anhydride are added to a solution of 50 mg (0.19 mmol) of N-(3-aminophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 1 ml of pyridine. After 2.5 hours, a further 14 rng (0.095 mmol) of phthalic acid anhydride are added to the yellow reaction solution and the mixture is stirred for 20 hours at 25°. The suspension is f°lltered and washed with a small amount of cold pyridine. The residue is digested with 2 x 2.5 ml of absolute ethanol and yields N-[3-(2-carboxybenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 206-209°, Rp = 0.07 (chloroform:-methanol = 9:1).
Example 9: A solution of 100 mg (0.38 rnmol) of N-(3-aminophenyl)-4-(3-pyridinyl)-2-pyrimidine-amine and 105 p.1 (0.46 mmol) of caproic acid anhydride in 5 ml of pyridine is stirred under a nitrogen atmosphere for 24 hours at 25° and then concentrated in a rotary evaporator. The residue is purified by flash chromatography (silica gel, chloroform:-methanol 95:5), yielding N-(3-n-hexanoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 180-184°, Rf = 0.78 (chloroform:methanol = 9:1).
Example 10: 1 g (5.68 rnmol) of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one [EP-A-233 461] is dissolved in 8 ml of isopropanol, and 1.38 g (5.68 mmol) of 3-nianphenyl-guanidine nitrate are added. After the addition of 0.25 g (6.24 mmol) of sodium hydroxide, the yellow suspension is heated at reflux for 20 hours, then cooled to 0°, filtered and washed with 30 rnl of isopropanol. The filtration residue is stirred in 15 ml of ethanol for 20 minutes, filtered and washed with a small amount of cold ethanol, yielding N-(3-nitrophenyl)-4-(2-pyridyl)-2-pyrimidine-amine; m.p. 213-219°.
Example 11: 1.38 g (5.68 mmol) of 3-nitrophenyl-guanidine nitrate and 0.25 g (6.24 mmol) of sodium hydroxide are added to a solution of 1 g (5.68 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [LJS Patent 4 281 000] in 8 ml of iso-propanol. The yellow suspensian is heated at reflux for 20 hours and then cooled to 0°.
After w4shing with 30 ml of isopropanol the filtration residue is made into a slurry in successian in 15 ml of ethanol and then in I5 ml of water and filtered each time. Drying under HV yields N-(3-nitrophenyl)-4-(4-pyridyl)-2-pyrimidine-amine; rn.p. 282-284°.
Example 12: Analogously to Example 2, N-[3-(2--methoxybenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 2-methoxybenwyl chloride; m.p.
115-117°, Rf = 0.76 (chloroforrn:methanol = 9:1).
Example I3: Analogously to Example 2, N-[3-(4-fluorobenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 4-fluorobenzoyl chloride; m.p.
215-216°, Rr = 0.34 (chloroform:methanol = 9:1 ).
Example 14: Analogously to Example 2, N-[3-(4-cyanobenzaylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 4-cyanobenwyl chloride; m.p. 220-222°, Rf = 0.31 (chloroform:methanol = 9:1).
Example 15: Analogously to Example 2, N-[3-(2-thienylcarboxamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 2-thiophenecarboxylic acid chloride;
m.p. 139-141°, Rf = 0.35 (chloroform:methanol = 9:1).
Example 16: Analogously to Example 2, N-(3-cyclohexyl-carboxamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine is prepared from cyclohexanecarboxylic acid chloride;
m.p. 205-206°, R f = 0.36 (chloroform:methanol = 9:1 ).
Example 17: Analogously to Example 2, N-[3-(4-methylbenwylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 4-methylbenwyl chloride; m.p. 214-216°, R f = 0.64 (chloroform:rnethanol = 9:1).
Example 18: Analogously to Example 2, N-[3-(4-chloro-benzoylamido)-phenyl]-4-(4-pyridyl)-2-pyrimidine-amine is prepared by treatment of 100 mg (0.38 rnmol) of N-(3-aminophenyl)-4-(4-pyridyl)-2-pyrirnidine-amine with 58 ltl (0.46 mmol) of 4-chloro-benzoyl chloride; m.p. 258-261 °; R f = 0.37 (CHCl3:methanol = 9:1 ).

I' e~, -30- ~~,}~~~~~4:3 The starting material is obtained as follows:
Step 18.1: Analogously to Step 2.1, N-(3-aminophenyl)-4-(4-pyridyl)-2-pyrimidine-amine is obtained by treatment of 3~ mg (1.0 mmol) of N-(3-nitrophenyl)-4-(4-pyridyl)-2-pyrimidine-amine (see Example 11) under a hydrogen atmosphere; m.p. 200-202°, Rf = 0.27 (CHCl3:methanol = 95:5).
Example 19: Analogously to Example 2, N-{3-{4-(4-methylpiperazinomethyl)-benzoyl-amido]-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 98 mg (0.3 mmol) of 4-(4-methyl-piperazinomethyl)-benzoyl chloride; m.p. 198-201°.
Example 20: A solution of 8.0 g (28.85 mrnol) of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine and 4.0 rnl (34.6 mmol) of benzoyl chloride in 320 ml of pyridine are stirred under nitrogen at room temperature for 23 hours. The reaction mixture is concentrated under HV; 200 ml of water are added and, after cooling to 0°, the mixture is filtered. After drying at 80° under HV, the crude product is made into a slurry with CH2Ch/methanol (95:5) and filtered, yielding N-(5-benzoylamido-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine. After separation by chromatography there are obtained further amounts of that product; m.p. 173-176°, Rf = 0.65 (CHCl3:methanol = 9:1).
The starting material is obtained as follows:
Step 20.1: 9.1 ml (0.13 mol) of 65 % nitric acid are added dropwise in the course of 5 minutes to a yellow suspension of 20.0 g (0.13 mol) of 2-amino-4-nitrotoluene in 50 ml of absolute ethanol. When the exothermic reaction has subsided, 8.32 g (0.198 mol) of cyanamide dissolved in 8.3 ml of water are added. The brown reaction mixture is boiled at reflex for 25 hours, cooled to 0° and filtered. Washing with 4 x 100 ml of ethanol/-diethyl ether (1:1) and drying yield 2-methyl-5-nitrophenyl-guanidine nitrate;
m.p. 219-226°.
Step 20.2: 24$.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate ~~re added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 litres of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflex for 12 horars. After cooling to 0°, filtration, washing with 2.0 litres of isopropanol and 3 x 400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitro-phenyl)-4-(3-pyridyl)-2-pyrirnidine-amine, m.p. 195-198°, Rf = 0.68 (methylene chloride:-methanol = 9.1).
Step 20.3: A suspension of 143.0 g (0.46 mol) of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 7.15 litres of ethyl acetate is stirred with 14.3 g of palladium on active carbon (10 % Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator.
The crude product is recrystallised from methylene chloride, yielding N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. I38-140°, Rf =
0.36 (methylene chloride:methanol = 9:1).
Example 21: Analogously to Example 20, N-{ 5-[4-(4-methyl-piperazino-methyl)-benzoyl-amido]-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 10.68 g (32.8 mmol) of 4-(4-methyl-piperazinomethyl)-benzoyl chloride; m.p. 211-213°, Rf= 0.33 (methylene chloride:methanol:25 % aqueous ammonia solution = 95:5:1).
Example 22: Analogously to Example 20, N-[5-(4-methyl-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 0.23 ml ( 1.7 mrnol) of p-toluoyl chloride (p-toluyl chloride); m.p. 102-106°, Rf = 0.4 (methylene chloride:-methanol = 9:1 ).
Example 23: Analogously to Example 20, N-[5-(2-naphthoylamido)-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 330 mg (1.73 mmol) of 2-naphthoyl chloride; m.p. 97-101°, Rf = 0.45 (methylene chloride:methanol = 9:1).
Example 24: Analogously to Example 20, N-[5-(4-chloro-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is synthesised from 0.22 ml (1.73 mmol) of 4-chlorobenzoyl chloride; m.p. 216-219°, R f = 0.39 (methylene chloride:methanol = 9:1).
Example 25: Analogously to Example 20, N-[5-(2-methoxy-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine is prepared from 0.28 ml (1.87 mmol) of 2-methoxybenzoyl chloride; m.p. 88-92°, R f = 0.45 (methylene chloride:methanol = 9:1 ).
Example 26: Analogously to Example 1, N-(3-trifluoromethoxy-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine is obtained from 1.0 g (5.68 mmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 1.53 g (5.68 mmol) of 3-trifluoromethoxyphenyl-guanidine nitrate;
Rf = 0.7 (chloroform:methanol = 9:1).

x~ r.) #et ~ c~

The starting material is obtained as follows:
Step 26.1: Analogously to Step 1.1, 3-trifluoromethoxy-phenyl-guanidine nitrate is prepared from 2.0 g (11.3 mmol) of 3-trifluoromethoxy-aniline and 1.4 g (16.6 mol) of cyanamide (50 % in water); Rf = 0.1 (methylene chloride:methano1:25 % aqueous ammonia solution = 150:10:1 ).
Example 27: Analogously to Example 1, N-(3-[1,1,2,2-tetrafluoroethoxy]-phenyl)-4-(3-pyridyl)-2-pyrirnidine-amine is obtained from 1.0 g (5.68 mmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 1.78 g (5.68 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)-phenyl-guanidine nitrate; Rf= 0.75 (chloroform:methanol = 9:1).
The starting material is obtained as follows:
Step 27.1: Analogously to Step 1.1, 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate is prepared from 2.09 g (10 mmol) ef 3-(1,1,2,2-tetrafluoroethoxy)-aniline and 1.26 g (15 mol) of cyanaznide (50 % in water); Rf = 0.15 (methylene chloride:methanol:-25 % aqueous ammonia solution = 150:10:1).
Example 28: Analogously to Example 1, N-(3-nitro-5-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine is obtained from 1.0 g (5.68 mmol) of 3-dimethylamino-l-(3-pyridyl)-2-propen-1-one and 1.46 g (5.68 mmol) of 3-nitro-5-methylphenyl-guanidine nitrate;
Rf = 0.72 (chloroform:methanol = 9:1).
The starting material is obtained as follows:
Step 28.1: Analogously to Step, 1.1, 3-nitro-5-methyl-phenyl-guanidine nitrate is prepared from 1.52 g (10 mrnol) of 3-nitro-5-methylaniline and 1.26 g (15 mot) of cyanamide (50 in water); Rp = 0.1 (methylene chloride:methano1:25 % aqueous ammonia solution =
150:10:1).
Example 29: Analogously to Example 1, N-(3-nitro-S-trifluoromethylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine is obtained from 1.0 g (5.68 rnmol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 1.76 g (5.68 mmol) of 3-nitro-5-trifluoromethylphenyl-guanidine nitrate; R f = 0.8 (chloroform:methanol = 9:1).

The starting material is obtained as follows:
Step 29.1: Analogously to Step 1.1, 3-vitro-5-trifluoromethylphenyl-guanidine nitrate is prepared from 2.06 g (10 mmol) of 3-vitro-5-trifluoromethylaniline and 1.26 g (15 rnol) of cyanamide (50 % in water); Rp = 0.2 (methylene chloride:methano1:25 % aqueous ammonia solution = 150:10:1).
Example 30: 200 mg (0.6$ mmol) of N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine are suspended in 5 ml of methylene chloride, and 225 mg (0.71 mmol) of 3-chloroper-benzoic acid are added. After 2 hours a further 10 ml of methylene chloride are added.
The suspension is stirred for a further 20 hours at room temperature.
Filtration and flash chromatography of the residue (methylene chloride:methanol:25 % aqueous ammonia solution = 90:10:1) yield N-(3-vitro-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine;
Rf = 0.4 (methylene chloride:methanol:25 % aqueous ammonia solution = 90:10:1 ), m.p. 252-25$°.
Example 31: 150 mg (0.39 mmol) of N-(3-benzoylamido-5-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine are suspended in 6 ml of methylene chloride, and 129 mg (0.41 mmol) of 3-chloroperbenzoic acid are added. After 22 hours, the mixture is filtered and the residue is purified by flash chromatography (methylene chloride:methano1:25 %
aqueous ammonia solution = 90:10:1), yielding N-(3-benzoylamido-5-methylphenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine; Rf = 0.3 (methylene chloride:methano1:25 %
aqueous ammonia solution = 90:10:1), m.p. 295-300°.
Example 32: Tablets comprising 20 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 31, and having the following composition are prepared in customary manner:

Composition:
active ingredient 20 mg wheat starch 60 mg lactose 50 mg colloidal silicic acid 5 mg talc 9 mg magnesium stearate 1 mg 145 mg Preparation: The active ingredient is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste, on a water bath, with five times the amount of water and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.
The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are again forced through a sieve. Then the remainder of the wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed to form tablets weighing 145 mg and having a breaking notch.
Example 33: Tablets comprising 1 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 31, and having the following composition are prepared in customary manner:
Composition:
active ingredient 1 mg wheat starch 60 mg lactose 50 mg colloidal silicic acid 5 mg talc 9 mg magnesium stearate 1 mg 126 mg Preparation: The active ingredient is mixed with a portion of the wheat starch, with the ~~9~~~J

lactose and the colloidal silicic acid and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste, on a water bath, with five times the amount of water and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.
The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are again forced through a sieve. Then the remainder of the wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed to form tablets weighing 126 rng and having a breaking notch.
Example 34: Capsules comprising 10 mg of active ingredient, for example one of the compounds of formula I described in Examples 1 to 31, are prepared in customary manner as follows:
Composition:
active ingredient 2500 mg talc 200 mg colloidal silicic acid 50 mg Preparation: The active ingredient is intimately mixed with the talc and the colloidal silicic acid and the mixture is forced through a sieve of 0.5 mm mesh size and then introduced in 11 mg portions into hard gelatin capsules of a suitable size.

Claims (48)

1. An N-phenyl-2-pyrimidine-amine derivative of formula I
wherein R1 is pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated by one or two lower alkyl radicals or acylated by lower alkanoyl or by benzoyl, 1H-indolyl or 1H-imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 are each nitro, fluoro-substituted lower alkoxy or a radical of formula II
-N(R9)-C(=X)-(Y)n-R10(II), wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-Imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and R10 is an aliphatic hydrocarbon radical having 5 to 22 carbon atoms or an aromatic radical having up to 20 carbon atoms, an aromatic-aliphatic radical wherein the aromatic radical has up to 20 carbon atoms and the aliphatic moiety is lower alkyl, a cycloaliphatic radical having up to 30 carbon atoms, a cycloaliphatic-aliphatic radical wherein the cycloaliphatic radical has up to 30 carbon atoms and the aliphatic moiety is lower alkyl, a heterocyclic radical containing up to 20 carbon atoms or a heterocyclic-aliphatic radical wherein the heterocyclic radical contains up to 20 carbon atoms and the aliphatic moiety is lower alkyl, and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by amino, lower alkylamino, di-lower alkylamino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or lower alkoxycarbonyl, or a salt of such a compound having at least one salt-forming group.
2. A compound of formula I according to claim 1, wherein one or two of the radicals R4, R5, R6, R7 and R8 are each nitro or a radical of formula II wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and R10 is an aliphatic hydrocarbon radical having 5 to 22 carbon atoms or an aromatic radical having up to 20 carbon atoms, an aromatic-aliphatic radical wherein the aromatic radical has up to 20 carbon atoms and the aliphatic moiety is lower alkyl, a cycloaliphatic radical having up to 30 carbon atoms, a cycloaliphatic-aliphatic radical wherein the cycloaliphatic radical has up to 30 carbon atoms and the -37a-aliphatic moiety is lower alkyl, a heterocyclic radical containing up to 20 carbon atoms or a heterocyclic-aliphatic radical wherein the heterocyclic radical contains up to 20 carbon atoms and the aliphatic moiety is lower alkyl, and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by amino, lower alkylamino, di-lower alkylamino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or lower alkoxycarbonyl, and the remaining substituents are as defined in claim 1, or a salt of such a compound having at least one salt-forming group.
3. A compound of formula I according to claim 1, wherein R1 is pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated by one or two lower alkyl radicals or acylated by lower alkanoyl or by benzoyl, 1H-indolyl or 1H-imidazolyl bonded at a five--membered ring carbon atom, or unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each independently of the other hydrogen or lower alkyl, one or two of the radicals R4, R5, R6, R7 and R8 are each nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein R9 is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl-hydroximino, Y is oxygen or the group NH, n is 0 or 1 and R10 is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl or naphthyl radical each of which is unsubstituted or substituted by cyano, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, (4-methyl-piperazinyl)-lower alkyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or by lower alkoxycarbonyl, or phenyl-lower alkyl wherein the phenyl radical is unsubstituted or substituted as indicated above, a cycloalkyl or cycloalkenyl radical having up to 30 carbon atoms, cycloalkyl-lower alkyl or cycloalkenyl-lower alkyl each having up to 30 carbon atoms in the cycloalkyl or cycloalkenyl moiety, a monocyclic radical having 5 or 6 ring members and 1-3 ring hetero atoms selected from nitrogen, oxygen and sulfur, to which radical one or two benzene radicals may be fused, or lower alkyl substituted by such a monocyclic radical, and the remaining radicals R4, R5, R6, R7 and R8 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by amino, lower alkylamino, di-lower alkylamino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, benzoylamino, carboxy or lower alkoxycarbonyl, or a salt of such a compound having at least one salt-forming group.
4. A compound of formula I according to claim 1, wherein R1 is pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R2 and R3 are each hydrogen, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl or fluoro-substituted lower alkoxy, R6 is hydrogen, R7 is nitro, fluoro-substituted lower alkoxy or a radical of formula II
wherein R9 is hydrogen, X is oxo, n is 0 and R1o is an aliphatic hydrocarbon radical having 5-22 carbon atoms, a phenyl radical that is unsubstituted or substituted by cyano, lower alkyl, (4-methyl-piperazinyl)-lower alkyl, lower alkoxy, halogen or by carboxy; a cycloalkyl radical having up to 30 carbon atoms or a monocyclic radical having 5 or 6 ring members and 1-3 sulfur ring atoms, and R8 is hydrogen, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.
5. A compound of formula I according to claim 1, wherein R1 is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom, R2 and R3 are each hydrogen, R4 is hydrogen or lower alkyl, R5 is hydrogen, lower alkyl or trifluoromethyl, R6 is hydrogen, R7 is nitro, fluoro-substituted lower alkoxy or a radical of formula II
wherein R9 is hydrogen, X is oxo, n is the number 0 and R10 is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C5-C7alkyl, thienyl, 2-naphthyl or cyclohexyl, and R8 is hydrogen, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.
6. A compound according to any one of claims 1 to 5 of formula I, wherein R4 and R8 are each hydrogen or a pharmaceutically acceptable salt of such a compound having at least one salt--forming group.
7. A compound according to any one of claims 1 to 5 of formula I, wherein at least one of the radicals R4 and R8 is lower alkyl, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group.
8. A compound according to claim 1 of formula I, wherein R1 is pyridyl bonded at a carbon atom, R2, R3, R4, R5, R6 and R8 are each hydrogen and R7 is nitro or a radical of formula II wherein R9 is hydrogen, X is oxo, n is the number 0 and R10 is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by fluorine, chlorine, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C5-C7alkyl, thienyl or cyclohexyl, or a pharmaceutically acceptable salt thereof.
9. N-(3-Nitro-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
10. N-[3-(4-Chlorobenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
11. N-(3-Benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
12. N-[3-(2-Pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
13. N-[3-(3-Pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
14. N-[3-(4-Pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
15. N-(3-Pentafluoro-benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
16. N-[3-(2-Carboxy-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
17. N-(3-n-Hexanoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
18. N-(3-Nitro-phenyl)-4-(2-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim1.
19. N-(3-Nitro-phenyl)-4-(4-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
20. N-[3-(2-Methoxy-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
21. N-[3-(4-Fluoro-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
22. N-[3-(4-Cyano-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
23. N-[3-(2-Thienylcarboxamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
24. N-(3-Cyclohexylcarboxamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
25. N-[3-(4-Methyl-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
26. N-[3-(4-Chloro-benzoylamido)-phenyl]-4-(4-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
27. N-{3-[4-(4-Methyl-piperazinomethyl)-benzoylamido]-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
28. N-(5-Benzoylamido-2-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
29. N-{5-[4-(4-Methyl-piperazino-methyl)-benzoylamido]-2-methyl-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
30. N-[5-(4-Methyl-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
31. N-[5-(2-Naphthoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
32. N-[5-(4-Chloro-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
33. N-[5-(2-Methoxy-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
34. N-(3-Trifluoromethoxy-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
35. N-(3-[1,1,2,2-Tetrafluoro-ethoxy]-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
36. N-(3-Nitro-5-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
37. N-(3-Nitro-5-trifluoromethyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine or a pharmaceutically acceptable salt thereof according to claim 1.
38. N-(3-Nitro-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine according to claim 1.
39. N-(3-Benzoylamido-5-methyl-phenyl)-4-(N-oxido-3-pyridyl)-2-pyrimidine-amine according to claim 1.
40. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group together with a pharmaceutical carrier.
41. A pharmaceutical composition for the treatment of tumours in warm-blooded animals, comprising, in a dose effective against tumours, a compound of formula I according to any one of claims 1 to 39, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutical carrier.
42. A pharmaceutical composition according to claim 41 for the treatment of tumours in humans.
43. A pharmaceutical composition according to claim 40 for the treatment of atherosclerosis.
44. A process for the preparation of a compound of formula I according to claim 1 or of a salt of such a compound having at least one salt-forming group, which comprises a) reacting a compound of formula III

wherein R11 and R12 are each independently of the other lower alkyl and R1, R2 and R3 are as defined in claim 1, functional groups present in a compound of formula III, with the exception of the groups participating in the reaction, being if necessary in protected from, or a salt of such a compound, with a compound of formula IV

wherein R4 to R8 are as defined in claim 1, functional groups present in a compound of formula IV, with the exception of the guanidine group participating in the reaction, being if necessary in protected from, or with a salt of such a compound, and removing any protecting groups present, or b) for the preparation of a compound of formula I
wherein the radicals R4, R5, R6, R7 and R8 are as defined in claim 1 with the exception of nitro and fluoro-substituted lower alkoxy, reacting a compound of formula V

wherein one or two of the radicals R13, R14, R15, R16 and R17 are each amino and the remaining radicals R13, R14, R15, R16 and R17 are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino or free or esterified carboxy, and R1 to R3 are as defined in claim 1, functional groups present in a compound of formula V, with the exception of the amino group(s) participating in the reaction, being if necessary in protected form, with a compound of formula VI

HO ~ C (~ X) ~ (Y)n ~ R10 (VI), wherein X, Y, n and R10 are as defined in claim 1, functional groups present in a compound of formula VI, with the exception of the HO-C(=X) group participating in the reaction, being if necessary in protected from, or with a reactive derivative of a compound of formula VI, and removing any protecting groups present, or c) for the preparation of a compound of formula I
wherein R1 is pyridyl substituted at the nitrogen atom by oxygen, and wherein the other substituents and symbols are as defined in claim 1, converting a compound of formula I
wherein R1 is pyridyl into the N-oxido compound with a suitable oxidising agent, and, if desired, converting a compound of formula I obtainable by any one of processes a to c into its salt, or converting an obtainable salt of a compound of formula I into the free compound.
45. A use of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group for the preparation of a pharmaceutical composition for use in the treatment of atherosclerosis.
46. A use of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group for the preparation of a pharmaceutical composition for use in the chemotherapy of tumours.
47. A use of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group for chemotherapy treatment of tumours.
48. A use of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group for treatment of atherosclerosis.
CA002093203A 1992-04-03 1993-04-01 Pyrimidine derivatives and processes for the preparation thereof Expired - Lifetime CA2093203C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH108392 1992-04-03
CH1083/92-1 1992-04-03

Publications (2)

Publication Number Publication Date
CA2093203A1 CA2093203A1 (en) 1993-10-04
CA2093203C true CA2093203C (en) 2002-11-26

Family

ID=4202064

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002093203A Expired - Lifetime CA2093203C (en) 1992-04-03 1993-04-01 Pyrimidine derivatives and processes for the preparation thereof

Country Status (29)

Country Link
EP (1) EP0564409B1 (en)
JP (1) JP2706682B2 (en)
KR (1) KR100261366B1 (en)
CN (1) CN1043531C (en)
AT (1) ATE188964T1 (en)
AU (1) AU666709B2 (en)
BR (1) BR1100739A (en)
CA (1) CA2093203C (en)
CY (2) CY2229B1 (en)
CZ (1) CZ283944B6 (en)
DE (2) DE59309931D1 (en)
DK (1) DK0564409T3 (en)
ES (1) ES2142857T3 (en)
FI (1) FI109534B (en)
GR (1) GR3032927T3 (en)
HU (2) HU227080B1 (en)
IL (1) IL105264A (en)
LU (1) LU90908I2 (en)
MX (1) MX9301929A (en)
NL (1) NL300086I2 (en)
NO (2) NO302473B1 (en)
NZ (1) NZ247299A (en)
PT (1) PT564409E (en)
RU (1) RU2125992C1 (en)
SA (1) SA93140441B1 (en)
SG (1) SG43859A1 (en)
SK (1) SK280620B6 (en)
TW (1) TW225528B (en)
ZA (1) ZA932397B (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697348B2 (en) 2001-06-14 2014-04-15 The Regent Of The University Of California Mutations in the Bcr-Abl tyrosine kinase associated with resistance to STI-571
US9567304B2 (en) 2012-04-24 2017-02-14 Chugai Seiyaku Kabushiki Kaisha Quinazolinedione derivative
US9695118B2 (en) 2012-04-24 2017-07-04 Chugai Seiyaku Kabushiki Kaisha Benzamide derivative
US10005739B2 (en) 2013-10-23 2018-06-26 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
US10092564B2 (en) 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation
US10112947B2 (en) 2012-08-06 2018-10-30 Duke University Substituted 6-aminopurines for targeting HSP90

Families Citing this family (345)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
GB9212673D0 (en) * 1992-06-15 1992-07-29 Celltech Ltd Chemical compounds
US6171786B1 (en) 1992-09-17 2001-01-09 Board Of Trustees Of University Of Illinois Methods for preventing multidrug resistance in cancer cells
US5972598A (en) * 1992-09-17 1999-10-26 Board Of Trustess Of The University Of Illinois Methods for preventing multidrug resistance in cancer cells
GB9222253D0 (en) * 1992-10-23 1992-12-09 Celltech Ltd Chemical compounds
GB9304920D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
GB9304919D0 (en) * 1993-03-10 1993-04-28 Celltech Ltd Chemical compounds
JPH08503971A (en) * 1993-10-01 1996-04-30 チバ−ガイギー アクチェンゲゼルシャフト Pyrimidineamine derivatives and methods for their preparation
US5543520A (en) * 1993-10-01 1996-08-06 Ciba-Geigy Corporation Pyrimidine derivatives
WO1995009851A1 (en) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof
ATE208772T1 (en) * 1993-10-01 2001-11-15 Novartis Erfind Verwalt Gmbh PHARMACOLOGICALLY ACTIVE PYRIDINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
GB9325217D0 (en) * 1993-12-09 1994-02-09 Zeneca Ltd Pyrimidine derivatives
GB9326600D0 (en) * 1993-12-22 1994-03-02 Celltech Ltd Chemical compounds
ATE260911T1 (en) * 1993-12-22 2004-03-15 Celltech R&D Ltd TRISUBSUTITUTED PHENYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS PHOSPHODIESTERASE (TYPE IV) INHIBITORS
US6245774B1 (en) 1994-06-21 2001-06-12 Celltech Therapeutics Limited Tri-substituted phenyl or pyridine derivatives
US5786354A (en) * 1994-06-21 1998-07-28 Celltech Therapeutics, Limited Tri-substituted phenyl derivatives and processes for their preparation
GB9412573D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412571D0 (en) * 1994-06-22 1994-08-10 Celltech Ltd Chemical compounds
GB9412672D0 (en) * 1994-06-23 1994-08-10 Celltech Ltd Chemical compounds
US5756527A (en) * 1995-06-07 1998-05-26 Ontogen Corporation Imidazole derivatives useful as modulators of multi drug resistances
GB9523675D0 (en) 1995-11-20 1996-01-24 Celltech Therapeutics Ltd Chemical compounds
GB9526245D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9526246D0 (en) * 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Chemical compounds
GB9608435D0 (en) * 1996-04-24 1996-06-26 Celltech Therapeutics Ltd Chemical compounds
EP0812829A1 (en) * 1996-06-14 1997-12-17 Ontogen Corporation Substituted imidazoles as modulators of multi-drug resistance
EP0812830A1 (en) * 1996-06-14 1997-12-17 Ontogen Corporation Modulators of multi-drug resistances
GB9619284D0 (en) * 1996-09-16 1996-10-30 Celltech Therapeutics Ltd Chemical compounds
GB9622363D0 (en) * 1996-10-28 1997-01-08 Celltech Therapeutics Ltd Chemical compounds
GB9625184D0 (en) * 1996-12-04 1997-01-22 Celltech Therapeutics Ltd Chemical compounds
AU5330698A (en) * 1996-12-23 1998-07-17 Celltech Therapeutics Limited Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors
GB9705361D0 (en) * 1997-03-14 1997-04-30 Celltech Therapeutics Ltd Chemical compounds
GB9713087D0 (en) * 1997-06-20 1997-08-27 Celltech Therapeutics Ltd Chemical compounds
CO4940418A1 (en) * 1997-07-18 2000-07-24 Novartis Ag MODIFICATION OF A CRYSTAL OF A DERIVATIVE OF N-PHENYL-2-PIRIMIDINAMINE, PROCESSES FOR ITS MANUFACTURE AND USE
GB9914258D0 (en) 1999-06-18 1999-08-18 Celltech Therapeutics Ltd Chemical compounds
US6316444B1 (en) 1999-06-30 2001-11-13 Merck & Co., Inc. SRC kinase inhibitor compounds
EP1206260A4 (en) 1999-06-30 2002-10-30 Merck & Co Inc Src kinase inhibitor compounds
JP2003523942A (en) 1999-06-30 2003-08-12 メルク エンド カムパニー インコーポレーテッド SRC kinase inhibitor compounds
GB9919778D0 (en) 1999-08-21 1999-10-27 Zeneca Ltd Chemical compounds
JP3892296B2 (en) 1999-09-10 2007-03-14 メルク エンド カムパニー インコーポレーテッド Tyrosine kinase inhibitor
GB9924862D0 (en) 1999-10-20 1999-12-22 Celltech Therapeutics Ltd Chemical compounds
HUP0301117A3 (en) * 2000-02-17 2004-01-28 Amgen Inc Thousand Oaks Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them
GB0004886D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004888D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004887D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
US7087608B2 (en) 2000-03-03 2006-08-08 Robert Charles Atkins Use of PDGF receptor tyrosine kinase inhibitors for the treatment of diabetic nephropathy
GB0007371D0 (en) 2000-03-28 2000-05-17 Astrazeneca Uk Ltd Chemical compounds
US7030219B2 (en) 2000-04-28 2006-04-18 Johns Hopkins University B7-DC, Dendritic cell co-stimulatory molecules
PT1315715E (en) 2000-08-18 2008-10-30 Millennium Pharm Inc Quinazoline derivatives as kinase inhibitors
GB0022438D0 (en) * 2000-09-13 2000-11-01 Novartis Ag Organic Compounds
WO2002034727A2 (en) * 2000-10-27 2002-05-02 Novartis Ag Treatment of gastrointestinal stromal tumors
AU2002217999A1 (en) 2000-11-01 2002-05-15 Cor Therapeutics, Inc. Process for the production of 4-quinazolinylpiperazin-1-carboxylic acid phenylamides
GB0103926D0 (en) * 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
EP2269603B1 (en) 2001-02-19 2015-05-20 Novartis AG Treatment of breast tumors with a rapamycin derivative in combination with exemestane
SE0100569D0 (en) * 2001-02-20 2001-02-20 Astrazeneca Ab New compounds
RU2313345C2 (en) * 2001-02-27 2007-12-27 Новартис Аг Combinations containing transduction signal inhibitor and epotilone derivative
DK1392313T3 (en) 2001-05-16 2007-06-25 Novartis Ag Combination comprising N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine and a biphosphonate
EP1721609A3 (en) * 2001-05-16 2007-01-31 GPC Biotech AG Pyridylpyrimidine derivatives as effective compounds against prion diseases
WO2003000186A2 (en) 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Novel phenylamino-pyrimidines and uses thereof
AU2002346053B2 (en) 2001-06-22 2008-03-13 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2003003006A2 (en) * 2001-06-29 2003-01-09 Ab Science New potent, selective and non toxic c-kit inhibitors
US20040266797A1 (en) * 2001-06-29 2004-12-30 Alain Moussy Use of potent,selective and non toxic c-kit inhibitors for treating tumor angiogensis
DE60216281T2 (en) 2001-06-29 2007-07-05 Ab Science THE USE OF TYROSINE KINASE INHIBITOR FOR THE TREATMENT OF ALLERGIC DISEASES
DK1401416T5 (en) 2001-06-29 2007-03-19 Ab Science Use of C-kit inhibitors for the treatment of inflammatory bowel disease
DK1401415T3 (en) 2001-06-29 2006-10-16 Ab Science Use of N-phenyl-2-pyrimidinamine derivatives for the treatment of inflammatory diseases
CA2461183A1 (en) * 2001-09-20 2003-05-15 Ab Science Use of tyrosine kinase inhibitors for whitening human skin and treating melanocyte dysfunction associated diseases
WO2003040141A1 (en) * 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Oxazolyl-phenyl-2,4-diamino-pyrimidine compounds and methods for treating hyperproliferative disorders
ATE490308T1 (en) 2001-10-05 2010-12-15 Novartis Ag MUTANT OF THE KINASE DOMAIN OF THE OBL
GB0201508D0 (en) 2002-01-23 2002-03-13 Novartis Ag Organic compounds
GB0202874D0 (en) * 2002-02-07 2002-03-27 Novartis Ag Organic compounds
AU2007203463B2 (en) * 2002-02-07 2010-12-23 Novartis Pharma Ag N-phenyl-2-pyrimidine-amine derivatives
GB0202873D0 (en) * 2002-02-07 2002-03-27 Novartis Ag Organic compounds
ATE326970T1 (en) * 2002-02-22 2006-06-15 Us Gov Veterans Affairs USE OF 4-(4-METHYLPIPERAZINE-1-YLMETHYL)-N 4-METHYL-3-(4-PYRIDINE-3-YL) PYRIMIDINE-2-YLAMINO) PHENYL BENZAMIDE FOR THE TREATMENT OF SEMINOMAS
WO2003072106A2 (en) * 2002-02-27 2003-09-04 Ab Science Use of tyrosine kinase inhibitors for treating substance use disorders
WO2003072090A2 (en) * 2002-02-27 2003-09-04 Ab Science Use of tyrosine kinase inhibitors for treating cns disorders
JP2005519080A (en) * 2002-02-28 2005-06-30 ノバルティス アクチエンゲゼルシャフト N- {5- [4- (4-Methyl-piperazino-methyl) -benzoylamide] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine coated stent
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
GB0209265D0 (en) * 2002-04-23 2002-06-05 Novartis Ag Organic compounds
AU2003231231A1 (en) * 2002-05-06 2003-11-11 Bayer Pharmaceuticals Corporation Pyridinyl amino pyrimidine derivatives useful for treating hyper-proliferative disorders
MXPA04011384A (en) 2002-05-16 2005-02-14 Novartis Ag Use of edg receptor binding agents in cancer.
WO2004000318A2 (en) 2002-06-21 2003-12-31 Cellular Genomics, Inc. Certain amino-substituted monocycles as kinase modulators
WO2004026930A2 (en) * 2002-06-26 2004-04-01 The Ohio State University Research Foundation The method for reducing inflammation using sti-571 or its salt
PT1533304E (en) * 2002-06-28 2010-02-08 Nippon Shinyaku Co Ltd Amide derivative
GB0215676D0 (en) * 2002-07-05 2002-08-14 Novartis Ag Organic compounds
US6872724B2 (en) 2002-07-24 2005-03-29 Merck & Co., Inc. Polymorphs with tyrosine kinase activity
CN100491374C (en) * 2002-08-02 2009-05-27 Ab科学公司 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as C-KIT inhibitors
GB0222514D0 (en) * 2002-09-27 2002-11-06 Novartis Ag Organic compounds
WO2004032925A1 (en) * 2002-10-11 2004-04-22 Novartis Ag Use of imatinib (glivec, sti-571) to inhibit breast cancer resistance protein (bcrp)-mediated resistance to therapeutic agents
GB0224455D0 (en) * 2002-10-21 2002-11-27 Novartis Ag Organic compounds
US7094785B1 (en) 2002-12-18 2006-08-22 Cornell Research Foundation, Inc. Method of treating polycythemia vera
US7144911B2 (en) * 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
GB2398565A (en) * 2003-02-18 2004-08-25 Cipla Ltd Imatinib preparation and salts
KR20060002933A (en) * 2003-04-04 2006-01-09 베이코 테크 리미티드 Blood vessel stent
WO2004099186A1 (en) * 2003-05-06 2004-11-18 Il Yang Pharm Co., Ltd. N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
AU2004251146A1 (en) 2003-05-19 2005-01-06 Irm, Llc Immunosuppressant compounds and compositions
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
EP1631291B1 (en) * 2003-05-27 2009-08-12 Robert P. Hägerkvist Use of tyrosine kinase inhibitors to treat diabetes
PL1635835T3 (en) * 2003-06-13 2010-06-30 Novartis Ag 2-aminopyrimidine derivatives as raf kinase inhibitors
NZ601544A (en) 2003-08-27 2013-11-29 Ophthotech Corp Combination therapy for the treatment of ocular neovascular disorders
DK1686997T3 (en) 2003-11-18 2009-07-27 Novartis Ag Inhibitors of the mutant form of KIT
RU2410375C9 (en) * 2003-12-25 2017-08-02 Ниппон Синяку Ко., Лтд. Amide derivative and medication
DE602005023587D1 (en) 2004-01-21 2010-10-28 Univ Emory COMPOSITIONS AND USE OF TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF PATHOGENIC INFECTIONS
AR047530A1 (en) 2004-02-04 2006-01-25 Novartis Ag FORMS OF SALT OF 4- (4-METHYLIPIPERAZIN-1-ILMETIL) -N- (4-METHYL-3- (4-PIRIDIN-3-IL) PIRIMIDIN-2-ILAMINO) PHENYL) -BENZAMIDA
CA2555804C (en) * 2004-02-11 2012-06-26 Natco Pharma Limited Polymorphic form of imatinib mesylate and a process for its preparation
CN1309719C (en) * 2004-02-18 2007-04-11 陈国庆 Derivative of phenylamide pyrimidine and application thereof
KR20080083220A (en) 2004-04-07 2008-09-16 노파르티스 아게 IAP inhibitor
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
CA2578122A1 (en) * 2004-08-27 2006-03-02 Gpc Biotech Ag Pyrimidine derivatives
KR101348625B1 (en) 2004-09-02 2014-01-07 씨아이피엘에이 엘티디. Stable crystal form of imatinib mesylate and process for the preparation thereof
HRP20070146B1 (en) 2004-09-09 2015-12-04 Natco Pharma Limited Novel phenylaminopyrimidine derivatives as inhibitors of bcr-abl kinase
US8735415B2 (en) 2004-09-09 2014-05-27 Natco Pharma Limited Acid addition salts of (3,5-Bis trifluoromethyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2ylamino)-phenyl]-benzamide
US7939541B2 (en) * 2004-09-09 2011-05-10 Natco Pharma Limited Intermediates and a process employing the intermediates for the preparation of (3-trifluoromethylsulfonyl)-N-[4-methyl-3-(4-pyridin-3yl-pyrimidin-2ylamino)-phenyl]-benzamide
WO2006054314A1 (en) * 2004-11-17 2006-05-26 Natco Pharma Limited Polymorphic forms of imatinib mesylate
SI1833815T1 (en) * 2004-12-30 2011-01-31 Inst Farmaceutyczny A process for preparation of imatinib base
CN1939910A (en) * 2004-12-31 2007-04-04 孙飘扬 Amino-metadiazine compound and its salt, its preparation and pharmaceutical use
CN1972917B (en) * 2004-12-31 2010-08-25 孙飘扬 Aminopyrimidine compounds and their salts, process for preparation and pharmaceutical use thereof
AU2006207321B2 (en) 2005-01-21 2012-09-06 Astex Therapeutics Limited Pharmaceutical compounds
BRPI0609296A2 (en) 2005-05-02 2010-03-23 Novartis Ag use of pyrimidylaminobenzamide derivatives for the treatment of systemic mastocytosis
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
UA96139C2 (en) 2005-11-08 2011-10-10 Дженентек, Інк. Anti-neuropilin-1 (nrp1) antibody
PT2275103E (en) 2005-11-21 2014-07-24 Novartis Ag Mtor inhibitors in the treatment of endocrine tumors
CN102351842B (en) 2005-11-25 2014-07-23 诺华股份有限公司 F,G,H,I and K crystal forms of imatinib mesylate
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
EP2314297A1 (en) 2006-04-05 2011-04-27 Novartis AG Combinations comprising bcr-abl/c-kit/pdgf-r tk inhibitors for treating cancer
EP2591775A1 (en) 2006-04-05 2013-05-15 Novartis AG Combinations comprising mtor inhibitors for treating cancer
PE20110235A1 (en) 2006-05-04 2011-04-14 Boehringer Ingelheim Int PHARMACEUTICAL COMBINATIONS INCLUDING LINAGLIPTIN AND METMORPHINE
AU2007247112B2 (en) 2006-05-09 2010-08-26 Novartis Ag Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
US20060223817A1 (en) * 2006-05-15 2006-10-05 Chemagis Ltd. Crystalline imatinib base and production process therefor
CA2651368A1 (en) 2006-06-01 2007-12-06 Japan As Represented By Director General Of Agency Of National Cancer Center Tumor suppressor
CN101516885A (en) 2006-09-29 2009-08-26 诺瓦提斯公司 Pyrazolopyrimidines as PI3K lipid kinase inhibitors
EP2073803B1 (en) 2006-10-12 2018-09-19 Astex Therapeutics Limited Pharmaceutical combinations
EP2073807A1 (en) 2006-10-12 2009-07-01 Astex Therapeutics Limited Pharmaceutical combinations
EP2076507A2 (en) * 2006-10-26 2009-07-08 Sicor, Inc. Imatinib base, and imatinib mesylate and processes for preparation thereof
US8168787B2 (en) 2006-11-16 2012-05-01 F.I.S. Fabbrica Italiana Sintetici S.P.A. Process for the preparation of imatinib and intermediates thereof
CN101245061B (en) * 2007-02-13 2012-09-19 天津天士力集团有限公司 N-(5-amido-2-methyl phenyl)-4-(3-pyridinyl)-2-aminopyrimidine nitric oxide donating derivant, production method and uses thereof
WO2008100985A2 (en) 2007-02-15 2008-08-21 Novartis Ag Combination of lbh589 with other therapeutic agents for treating cancer
RU2329260C1 (en) * 2007-02-20 2008-07-20 Юрий Иосифович Копырин Method of obtaining 2-anilinopyrimidines or their salts (options)
CA2680249A1 (en) * 2007-03-12 2008-09-18 Dr. Reddy's Laboratories, Inc. Imatinib mesylate
WO2008117298A1 (en) * 2007-03-26 2008-10-02 Natco Pharma Limited A novel method of preparation of imatinib
US7550591B2 (en) 2007-05-02 2009-06-23 Chemagis Ltd. Imatinib production process
WO2008136010A1 (en) * 2007-05-07 2008-11-13 Natco Pharma Limited A process for the preparation of highly pure imatinib base
US8367686B2 (en) 2007-06-07 2013-02-05 Intra-Cellular Therapies, Inc. Heterocycle compounds and uses thereof
EP2166860B1 (en) 2007-06-07 2016-09-21 Intra-Cellular Therapies, Inc. Novel heterocycle compounds and uses thereof
PT2200436E (en) * 2007-09-04 2015-04-29 Scripps Research Inst Substituted pyrimidinyl-amines as protein kinase inhibitors
WO2009060463A1 (en) * 2007-11-05 2009-05-14 Natco Pharma Limited An environmentally friendly process for the preparation of imatinib base
EP2062885A1 (en) * 2007-11-21 2009-05-27 Eczacibasi-Zentiva Kimyasal Ürünler Sanayi ve Ticaret A.S. Acid addition salts of imatinib and formulations comprising the same
RU2493152C2 (en) * 2008-02-01 2013-09-20 Акинион Фармасьютикалз Аб Novel compounds, use and production thereof
KR101673621B1 (en) 2008-03-24 2016-11-07 노파르티스 아게 Arylsulfonamide-based matrix metalloprotease inhibitors
MY150437A (en) 2008-03-26 2014-01-30 Novartis Ag Hydroxamate-based inhibitors of deacetylases b
CN101584696A (en) 2008-05-21 2009-11-25 上海艾力斯医药科技有限公司 Composition containing quinazoline derivatives, preparation method and use
NO2300013T3 (en) 2008-05-21 2018-02-03
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
PL215042B1 (en) * 2008-08-01 2013-10-31 Temapharm Spolka Z Ograniczona Odpowiedzialnoscia Method of imatinib manufacturing
UY32030A (en) 2008-08-06 2010-03-26 Boehringer Ingelheim Int "TREATMENT FOR DIABETES IN INAPPROPRIATE PATIENTS FOR THERAPY WITH METFORMIN"
WO2010018217A2 (en) 2008-08-15 2010-02-18 Boehringer Ingelheim International Gmbh Organic compounds for wound healing
WO2010027423A2 (en) 2008-08-25 2010-03-11 Amplimmune, Inc. Compositions of pd-1 antagonists and methods of use
US20110223241A1 (en) 2008-10-16 2011-09-15 Celator Pharmaceuticals, Inc. Combination methods and compositions
EP2186514B1 (en) 2008-11-14 2016-06-29 Kinki University Treatment of Malignant Peripheral Nerve Sheath Tumors
EP2379499B1 (en) 2008-12-18 2014-04-09 Novartis AG Hydrochloride salt of 1-(4-(1-((E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl)-2-ethyl-benzyl)-azetidine-3-carboxylic acid
PL2676953T3 (en) 2008-12-18 2017-09-29 Novartis Ag Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3 -trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid for use in the treatment of lymphocyte mediated diseases
RU2011129230A (en) 2008-12-18 2013-01-27 Новартис Аг NEW POLYMORPHIC FORM 1- [4- [1- (4-Cyclohexyl-3-trifluoromethylbenzyloxylimino) Ethyl] -2-Ethylbenzyl] Azetidine-3-Carboxylic Acid
KR20110103968A (en) 2008-12-23 2011-09-21 베링거 인겔하임 인터내셔날 게엠베하 Salt Forms of Organic Compounds
TW201036975A (en) 2009-01-07 2010-10-16 Boehringer Ingelheim Int Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
JP2012516345A (en) 2009-01-29 2012-07-19 ノバルティス アーゲー Substituted benzimidazoles for astrocytoma treatment
TWI466672B (en) 2009-01-29 2015-01-01 Boehringer Ingelheim Int Treatment for diabetes in paediatric patients
BRPI1013639A2 (en) 2009-02-13 2016-04-19 Boehringer Ingelheim Int antidiabetic medicines
EP2400985A2 (en) 2009-02-25 2012-01-04 OSI Pharmaceuticals, LLC Combination of an either an anti-igf-1r antibody or an igf binding protein and a small molecule igf-1r kinase inhibitor
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
JP2012519282A (en) 2009-02-27 2012-08-23 オーエスアイ・ファーマシューティカルズ,エルエルシー Methods for identifying mesenchymal tumor cells or agents that inhibit their production
US8642834B2 (en) 2009-02-27 2014-02-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
UA103918C2 (en) 2009-03-02 2013-12-10 Айерем Элелси N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators
TW201102068A (en) 2009-06-02 2011-01-16 Novartis Ag Treatment of ophthalmologic disorders mediated by alpha-carbonic anhydrase isoforms
KR101360725B1 (en) 2009-06-26 2014-02-07 노파르티스 아게 1,3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp17
WO2011014520A2 (en) 2009-07-29 2011-02-03 Irm Llc Compounds and compositions as modulators of gpr119 activity
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
US8497368B2 (en) 2009-08-12 2013-07-30 Novartis Ag Heterocyclic hydrazone compounds
PE20170003A1 (en) 2009-08-17 2017-03-15 Intellikine Llc HETEROCYCLIC COMPOUNDS AND USES OF THEM
KR20120089463A (en) 2009-08-20 2012-08-10 노파르티스 아게 Heterocyclic oxime compounds
CN102574785A (en) 2009-08-26 2012-07-11 诺瓦提斯公司 Tetra-substituted heteroaryl compounds and their use as MDM2 and/or MDM4 modulators
WO2011029915A1 (en) 2009-09-10 2011-03-17 Novartis Ag Ether derivatives of bicyclic heteroaryls
CA2776296C (en) 2009-10-02 2017-11-07 Boehringer Ingelheim International Gmbh Therapeutic uses of pharmaceutical compositions
CN102686579A (en) 2009-10-09 2012-09-19 Irm责任有限公司 Compounds and compositions as modulators of GPR119 activity
PL389357A1 (en) 2009-10-22 2011-04-26 Tomasz Koźluk Tartaric acids derivatives imatinib salts and process for the preparation thereof
EP2496575B1 (en) 2009-11-04 2014-04-30 Novartis AG Heterocyclic sulfonamide derivatives useful as mek inhibitors
US20110237540A1 (en) 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
US20120289501A1 (en) 2009-11-25 2012-11-15 Novartis Ag Benzene-fused 6-membered oxygen-containing heterocyclic derivatives of bicyclic heteroaryls
KR20190071840A (en) 2009-11-27 2019-06-24 베링거 인겔하임 인터내셔날 게엠베하 Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
US8394858B2 (en) 2009-12-03 2013-03-12 Novartis Ag Cyclohexane derivatives and uses thereof
BR112012013735A2 (en) 2009-12-08 2019-09-24 Novartis Ag heterocyclic sulfonamide derivatives
AU2012265844A1 (en) 2009-12-08 2013-05-02 Novartis Ag Heterocyclic sulfonamide derivatives
US20110306763A1 (en) 2009-12-10 2011-12-15 Shanghai Parling Pharmatech Co., Ltd. Process for the preparation of imatinib and salts thereof
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (en) 2009-12-22 2015-09-29 Novartis Ag ISOQUINOLINONES AND REPLACED QUINAZOLINONES
US20110178287A1 (en) 2010-01-19 2011-07-21 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
WO2011099039A1 (en) 2010-02-15 2011-08-18 Reliance Life Sciences Pvt. Ltd. Process for the preparation of alpha form of imatinib mesylate
PL390611A1 (en) 2010-03-04 2011-09-12 Tomasz Koźluk Process for the preparation of polymorphic alpha form and new polymorphic form of imatinib mesylate
WO2011114337A1 (en) 2010-03-15 2011-09-22 Natco Pharma Limited Process for the preparation of highly pure crystalline imatinib base
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2011119995A2 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations and methods of use
US8609842B2 (en) * 2010-04-23 2013-12-17 Fujian South Pharmaceutical Co., Ltd. Method for synthesizing Imatinib
EP2382976A1 (en) 2010-04-30 2011-11-02 Hiroshima University Use of pdgf-r inhibitors for the treatment of lymph node metastasis of gastric cancer
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
CN102947274A (en) 2010-06-17 2013-02-27 诺瓦提斯公司 Biphenyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
JP2013532149A (en) 2010-06-17 2013-08-15 ノバルティス アーゲー Piperidinyl-substituted 1,3-dihydro-benzimidazol-2-ylideneamine derivatives
WO2011157450A1 (en) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto New polymorphic form of imatinib base and preparation of salts thereof
WO2011160798A1 (en) 2010-06-21 2011-12-29 Zaklady Farmaceutyczne Polpharma Sa Pharmaceutical compositions comprising imatinib or pharmaceutically acceptable salt thereof and processes for the manufacture thereof
AU2011268940B2 (en) 2010-06-24 2015-05-21 Boehringer Ingelheim International Gmbh Diabetes therapy
UA112517C2 (en) 2010-07-06 2016-09-26 Новартіс Аг TETRAHYDROPYRIDOPYRIMIDINE DERIVATIVES
AU2011274528B2 (en) 2010-07-09 2015-04-23 Genentech, Inc. Anti-neuropilin antibodies and methods of use
US8697739B2 (en) 2010-07-29 2014-04-15 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
EP2603288A1 (en) 2010-08-11 2013-06-19 Synthon BV Pharmaceutical granulate comprising imatinib mesylate
TR201007005A2 (en) 2010-08-23 2011-09-21 Mustafa Nevzat İlaç Sanayi̇i̇ A.Ş. Imatinib base production method
US8946260B2 (en) 2010-09-16 2015-02-03 Novartis Ag 17α-hydroxylase/C17,20-lyase inhibitors
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
TR201010618A2 (en) 2010-12-20 2012-07-23 Bi̇lgi̇ç Mahmut An oral dosage form comprising imatinib and the manufacture of an oral dosage form
JP2014500308A (en) 2010-12-21 2014-01-09 ノバルティス アーゲー Biheteroaryl compounds as VPS34 inhibitors
WO2012090221A1 (en) 2010-12-29 2012-07-05 Cadila Healthcare Limited Novel salts of imatinib
WO2012107500A1 (en) 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
WO2012116237A2 (en) 2011-02-23 2012-08-30 Intellikine, Llc Heterocyclic compounds and uses thereof
CZ305457B6 (en) 2011-02-28 2015-09-30 Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. Pyrimidine compounds inhibiting formation of nitrogen monoxide and prostaglandin E2, process for their preparation and use
JP2014507465A (en) 2011-03-08 2014-03-27 ノバルティス アーゲー Fluorophenyl bicyclic heteroaryl compounds
PL394169A1 (en) 2011-03-09 2012-09-10 Adamed Spółka Z Ograniczoną Odpowiedzialnością The pharmaceutical composition of imatinib mesylate for filling unit dosage forms and the method for its preparation
EP2508525A1 (en) 2011-04-05 2012-10-10 Bayer Pharma Aktiengesellschaft Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts
EP2702173A1 (en) 2011-04-25 2014-03-05 OSI Pharmaceuticals, LLC Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment
MX359399B (en) 2011-04-28 2018-09-27 Novartis Ag 17a-HYDROXYLASE/C17,20-LYASE INHIBITORS.
EP2704572B1 (en) 2011-05-04 2015-12-30 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in egfr-driven cancers
CN102796110B (en) * 2011-05-23 2016-03-30 复旦大学 Aniline pyrimidine compound and its production and use
US8859535B2 (en) 2011-06-20 2014-10-14 Novartis Ag Hydroxy substituted isoquinolinone derivatives
US8859586B2 (en) 2011-06-20 2014-10-14 Novartis Ag Cyclohexyl isoquinolinone compounds
US9750700B2 (en) 2011-06-22 2017-09-05 Natco Pharma Limited Imatinib mesylate oral pharmaceutical composition and process for preparation thereof
MX2013015001A (en) 2011-06-27 2014-03-31 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives.
ITMI20111309A1 (en) 2011-07-14 2013-01-15 Italiana Sint Spa PREPARATION PROCEDURE OF IMATINIB MESILATO
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
WO2013035102A1 (en) 2011-09-05 2013-03-14 Natco Pharma Limited Processes for the preparation of imatinib base and intermediates thereof
JP5957526B2 (en) 2011-09-15 2016-07-27 ノバルティス アーゲー 6-Substituted 3- (quinolin-6-ylthio)-[1,2,4] triazolo [4,3-A] pyrazine as tyrosine kinase
CA2853961C (en) 2011-11-01 2016-09-20 Modgene, Llc Compositions and methods for reduction of amyloid-beta load
RU2486180C1 (en) * 2011-11-02 2013-06-27 Общество с ограниченной ответственностью "ТехноХим" (ООО "ТехноХим") Method for preparing 2-arylamino-4-hetarylpyrimidines
EP2785717B1 (en) 2011-11-29 2016-01-13 Novartis AG Pyrazolopyrrolidine compounds
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
CN103159739A (en) * 2011-12-09 2013-06-19 天津市国际生物医药联合研究院有限公司 1, 4-disubstituted-1, 2, 3-triazole compounds and preparation method thereof
MA37142B1 (en) 2011-12-22 2019-07-31 Novartis Ag Derivatives of dihydro-benzo-oxazine and dihydro-pyrido-oxazine
EP2794594A1 (en) 2011-12-22 2014-10-29 Novartis AG Quinoline derivatives
EP2794592A1 (en) 2011-12-23 2014-10-29 Novartis AG Compounds for inhibiting the interaction of bcl2 with binding partners
JP2015503516A (en) 2011-12-23 2015-02-02 ノバルティス アーゲー Compound for inhibiting interaction between BCL2 and binding partner
US9126980B2 (en) 2011-12-23 2015-09-08 Novartis Ag Compounds for inhibiting the interaction of BCL2 with binding partners
US20140357666A1 (en) 2011-12-23 2014-12-04 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
JP2015503518A (en) 2011-12-23 2015-02-02 ノバルティス アーゲー Compound for inhibiting interaction between BCL2 and binding partner
US20130178520A1 (en) 2011-12-23 2013-07-11 Duke University Methods of treatment using arylcyclopropylamine compounds
US20130172244A1 (en) 2011-12-29 2013-07-04 Thomas Klein Subcutaneous therapeutic use of dpp-4 inhibitor
PL226174B1 (en) 2011-12-30 2017-06-30 Inst Farm Combination therapy of non-small-cell lung carcinoma
UY34591A (en) 2012-01-26 2013-09-02 Novartis Ag IMIDAZOPIRROLIDINONA COMPOUNDS
GB2514285B (en) 2012-02-13 2018-07-18 Grindeks Jsc Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors
IN2012DE00728A (en) 2012-03-13 2015-08-21 Fresenius Kabi Oncology Ltd
EP2834246B1 (en) 2012-04-03 2021-07-28 Novartis AG Combination products with tyrosine kinase inhibitors and their use
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
WO2013169401A1 (en) 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in egfr-driven cancers
WO2013171167A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome
WO2013171166A1 (en) 2012-05-14 2013-11-21 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis
CN104321325B (en) 2012-05-24 2016-11-16 诺华股份有限公司 Pyrrolopyrrole alkanone compound
EP2854812A1 (en) 2012-05-24 2015-04-08 Boehringer Ingelheim International GmbH A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
JP6427097B2 (en) 2012-06-15 2018-11-21 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドThe Brigham and Women’s Hospital, Inc. Compositions for treating cancer and methods for producing said compositions
WO2014016848A2 (en) 2012-07-24 2014-01-30 Laurus Labs Private Limited Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof
WO2014041551A1 (en) 2012-09-14 2014-03-20 Natco Pharma Limited Formulation comprising imatinib as oral solution
CN103664787B (en) 2012-09-17 2015-09-09 南京圣和药业股份有限公司 Alkynes heteroaromatic ring compounds and application thereof
WO2014052619A1 (en) 2012-09-27 2014-04-03 Irm Llc Piperidine derivatives and compositions as modulators of gpr119 activity
JP2015531355A (en) 2012-09-28 2015-11-02 ハンジョウ ベンシェン ファーマシューティカル シーオー., エルティーディー.Hangzhou Bensheng Pharmaceutical Co., Ltd. Pharmaceutical composition for tumor treatment and application thereof
WO2014055938A1 (en) * 2012-10-04 2014-04-10 Inhibikase Therapeutics, Inc. Novel compounds, their preparation and their uses
CN110787285B (en) 2012-11-05 2025-06-13 达纳-法伯癌症研究所股份有限公司 XBP1, CD138 and CS1 peptides, pharmaceutical compositions comprising the peptides, and methods of using the peptides and compositions
TW201422625A (en) 2012-11-26 2014-06-16 Novartis Ag Solid form of dihydro-pyrido-oxazine derivative
CN103848812B (en) * 2012-12-04 2016-08-03 北大方正集团有限公司 The method of refined imatinib
CN103044394A (en) * 2012-12-20 2013-04-17 北京理工大学 Phenyl aminopyrimidine derivant and preparation method and application thereof
EP2749271A1 (en) 2012-12-31 2014-07-02 Deva Holding Anonim Sirketi Optimized manufacturing method and pharmaceutical formulation of imatinib
EP2948451B1 (en) 2013-01-22 2017-07-12 Novartis AG Substituted purinone compounds
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
WO2014124860A1 (en) 2013-02-14 2014-08-21 Boehringer Ingelheim International Gmbh Specific pde4b-inhibitors for the treatment of diabetes mellitus
EP3626741A1 (en) 2013-02-20 2020-03-25 The Trustees Of The University Of Pennsylvania Treatment of cancer using humanized anti-egfrviii chimeric antigen receptor
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
KR20150128726A (en) 2013-03-15 2015-11-18 베링거 인겔하임 인터내셔날 게엠베하 Use of linagliptin in cardio- and renoprotective antidiabetic therapy
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
WO2014155268A2 (en) 2013-03-25 2014-10-02 Novartis Ag Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
ES2683361T3 (en) 2013-05-14 2018-09-26 Hetero Research Foundation Imatinib compositions
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
UY35675A (en) 2013-07-24 2015-02-27 Novartis Ag SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA
WO2015022663A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
WO2015022664A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
AU2014321420B2 (en) 2013-09-22 2017-06-15 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use
CA2927708C (en) 2013-10-17 2021-05-25 Sartar Therapeutics Ltd Compositions comprising phosphodiesterase inhibitors for use in the treatment of a solid tumor in a human patient
TW201605450A (en) 2013-12-03 2016-02-16 諾華公司 Combination of Mdm2 inhibitor and BRAF inhibitor and their use
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
WO2015145388A2 (en) 2014-03-27 2015-10-01 Novartis Ag Methods of treating colorectal cancers harboring upstream wnt pathway mutations
US9394281B2 (en) 2014-03-28 2016-07-19 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
JP2017513931A (en) 2014-04-03 2017-06-01 インビクタス オンコロジー ピーヴィティー.リミテッド Supramolecular combinatorial treatment
US9630944B2 (en) 2014-04-04 2017-04-25 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for preparing Imatinib and salts thereof, free of genotoxic impurity F
US20170027940A1 (en) 2014-04-10 2017-02-02 Stichting Het Nederlands Kanker Instituut Method for treating cancer
WO2016011658A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
WO2016016822A1 (en) 2014-07-31 2016-02-04 Novartis Ag Combination therapy
WO2016059220A1 (en) 2014-10-16 2016-04-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Tcr-activating agents for use in the treatment of t-all
CN105585556A (en) * 2014-11-13 2016-05-18 连云港杰瑞药业有限公司 Synthetic method of imatinib
WO2017044434A1 (en) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
WO2017129624A1 (en) 2016-01-25 2017-08-03 Krka, D.D., Novo Mesto Fast dispersible pharmaceutical composition comprising tyrosine-kinase inhibitor
WO2017184956A1 (en) 2016-04-22 2017-10-26 Duke University Compounds and methods for targeting hsp90
JP2019517542A (en) 2016-06-10 2019-06-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Combination of linagliptin and metformin
EP3257499A1 (en) 2016-06-17 2017-12-20 Vipharm S.A. Process for preparation of imatinib methanesulfonate capsules
CN107652269A (en) * 2016-07-26 2018-02-02 江苏豪森药业集团有限公司 Methanesulfonic acid fluorine imatinib purification of intermediate method
US20190209669A1 (en) 2016-08-23 2019-07-11 Oncopep, Inc. Peptide vaccines and durvalumab for treating breast cancer
WO2018039203A1 (en) 2016-08-23 2018-03-01 Oncopep, Inc. Peptide vaccines and durvalumab for treating multiple myeloma
CN107805240A (en) * 2016-09-08 2018-03-16 中国科学院合肥物质科学研究院 A kind of new PDGFR kinase inhibitors and application thereof
US20200055917A1 (en) 2016-09-27 2020-02-20 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules
US10207998B2 (en) 2016-09-29 2019-02-19 Duke University Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
EP3333162A1 (en) 2016-12-12 2018-06-13 Silesian Catalysts sp. z o.o. Metod for preparing n-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine
CN107089969B (en) * 2017-04-26 2020-04-24 黑龙江鑫创生物科技开发有限公司 Method for synthesizing imatinib intermediate
WO2019067328A1 (en) 2017-09-26 2019-04-04 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules and methods of use
WO2019083960A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. Peptide vaccines and hdac inhibitors for treating multiple myeloma
JP2021500409A (en) 2017-10-24 2021-01-07 オンコペップ, インコーポレイテッド Peptide vaccines and pembrolizumab for treating breast cancer
WO2019099311A1 (en) 2017-11-19 2019-05-23 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
US11602534B2 (en) 2017-12-21 2023-03-14 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Pyrimidine derivative kinase inhibitors
KR102737185B1 (en) 2018-01-20 2024-12-05 선샤인 레이크 파르마 컴퍼니 리미티드 Substituted aminopyrimidine compounds and methods of use thereof
US12291557B2 (en) 2018-03-28 2025-05-06 Cero Therapeutics Holdings, Inc. Chimeric TIM4 receptors and uses thereof
WO2019191339A1 (en) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Expression vectors for chimeric engulfment receptors, genetically modified host cells, and uses thereof
EP3774865A1 (en) 2018-03-28 2021-02-17 Cero Therapeutics, Inc. Cellular immunotherapy compositions and uses thereof
BR112020024793A2 (en) 2018-07-17 2021-03-02 Boehringer Ingelheim International Gmbh cardiosafety antidiabetic therapy
AU2019306036B2 (en) 2018-07-17 2025-05-15 Boehringer Ingelheim International Gmbh Cardio- and renosafe antidiabetic therapy
EP3826988A4 (en) 2018-07-24 2023-03-22 Hygia Pharmaceuticals, LLC COMPOUNDS, DERIVATIVES AND ANALOGS AGAINST CANCER
AU2020312840A1 (en) 2019-07-15 2022-01-20 Intas Pharmaceuticals Ltd. Pharmaceutical composition of imatinib
EP4038097A1 (en) 2019-10-03 2022-08-10 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
EP4058465A1 (en) 2019-11-14 2022-09-21 Cohbar Inc. Cxcr4 antagonist peptides
WO2021233534A1 (en) 2020-05-20 2021-11-25 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
WO2021185844A1 (en) 2020-03-16 2021-09-23 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
EP4136228A4 (en) 2020-04-15 2024-09-11 California Institute of Technology THERMAL CONTROL OF T-CELL IMMUNOTHERAPY BY MOLECULAR AND PHYSICAL ACTIVATION
WO2021228983A1 (en) 2020-05-13 2021-11-18 INSERM (Institut National de la Santé et de la Recherche Médicale) A pharmaceutical composition comprising an arsenic compound, an inductor of type-1 ifn and a protein kinase inhibitor for treating cancer
WO2022029220A1 (en) 2020-08-05 2022-02-10 Ellipses Pharma Ltd Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor
WO2022036265A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Chimeric tim receptors and uses thereof
WO2022036287A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Anti-cd72 chimeric receptors and uses thereof
WO2022036285A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Compositions and methods for treating cancer with chimeric tim receptors in combination with inhibitors of poly (adp-ribose) polymerase
WO2022047259A1 (en) 2020-08-28 2022-03-03 California Institute Of Technology Synthetic mammalian signaling circuits for robust cell population control
TW202237638A (en) 2020-12-09 2022-10-01 日商武田藥品工業股份有限公司 Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
US20240218390A1 (en) 2021-02-26 2024-07-04 Kelonia Therapeutics, Inc. Lymphocyte targeted lentiviral vectors
EP4376874A1 (en) 2021-07-28 2024-06-05 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
KR20250065819A (en) 2022-08-02 2025-05-13 국립대학법인 홋가이도 다이가쿠 Methods for improving cell therapy using organelle complexes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1570555A (en) * 1977-04-05 1980-07-02 Taiho Pharmaceutical Co Ltd Anti-cancer composition
DE3751742T3 (en) * 1986-01-13 2002-11-21 American Cyanamid Co., Wayne 4,5,6-substituted 2-pyrimidinamines

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697348B2 (en) 2001-06-14 2014-04-15 The Regent Of The University Of California Mutations in the Bcr-Abl tyrosine kinase associated with resistance to STI-571
US9056924B2 (en) 2001-06-14 2015-06-16 The Regents Of The University Of California Mutations in the BCR-ABL tyrosine kinase associated with resistance to STI-571
US9085644B2 (en) 2001-06-14 2015-07-21 The Regents Of The University Of California Mutations in the Bcr-Abl tyrosine kinase associated with resistance to STI-571
US9994910B2 (en) 2001-06-14 2018-06-12 The Regents Of The University Of California Mutations in the Bcr-Abl tyrosine kinase associated with resistance to STI-571
US9567304B2 (en) 2012-04-24 2017-02-14 Chugai Seiyaku Kabushiki Kaisha Quinazolinedione derivative
US9695118B2 (en) 2012-04-24 2017-07-04 Chugai Seiyaku Kabushiki Kaisha Benzamide derivative
US10112947B2 (en) 2012-08-06 2018-10-30 Duke University Substituted 6-aminopurines for targeting HSP90
US10927115B2 (en) 2012-08-06 2021-02-23 Duke University Substituted heterocycles for targeting Hsp90
US10005739B2 (en) 2013-10-23 2018-06-26 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
US10092564B2 (en) 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation

Also Published As

Publication number Publication date
KR930021624A (en) 1993-11-22
MX9301929A (en) 1994-07-29
ES2142857T3 (en) 2000-05-01
NO931283D0 (en) 1993-04-02
RU2125992C1 (en) 1999-02-10
NO931283L (en) 1993-10-04
EP0564409A1 (en) 1993-10-06
EP0564409B1 (en) 2000-01-19
DE59309931D1 (en) 2000-02-24
HU227080B1 (en) 2010-06-28
JPH0687834A (en) 1994-03-29
CA2093203A1 (en) 1993-10-04
NL300086I1 (en) 2002-05-01
IL105264A0 (en) 1993-08-18
BR1100739A (en) 2000-06-06
JP2706682B2 (en) 1998-01-28
NL300086I2 (en) 2002-06-03
SA93140441B1 (en) 2005-12-14
ZA932397B (en) 1993-10-04
ATE188964T1 (en) 2000-02-15
GR3032927T3 (en) 2000-07-31
IL105264A (en) 1999-04-11
HU9300982D0 (en) 1993-06-28
SK280620B6 (en) 2000-05-16
CN1077713A (en) 1993-10-27
TW225528B (en) 1994-06-21
FI931458A7 (en) 1993-10-04
NO2002001I2 (en) 2007-01-29
KR100261366B1 (en) 2002-07-18
HU226488B1 (en) 2009-03-02
CY2229B1 (en) 2003-04-18
SG43859A1 (en) 1997-11-14
LU90908I2 (en) 2003-04-30
HUT64050A (en) 1993-11-29
AU3569493A (en) 1993-10-07
DK0564409T3 (en) 2000-06-19
AU666709B2 (en) 1996-02-22
CZ56093A3 (en) 1994-02-16
PT564409E (en) 2000-06-30
CY2003003I1 (en) 2010-07-28
NZ247299A (en) 1995-07-26
DE10299016I1 (en) 2002-08-29
NO302473B1 (en) 1998-03-09
SK28093A3 (en) 1994-04-06
FI109534B (en) 2002-08-30
CN1043531C (en) 1999-06-02
CZ283944B6 (en) 1998-07-15
FI931458A0 (en) 1993-03-31
DE10299016I2 (en) 2006-08-24

Similar Documents

Publication Publication Date Title
CA2093203C (en) Pyrimidine derivatives and processes for the preparation thereof
US5521184A (en) Pyrimidine derivatives and processes for the preparation thereof
EP0672041B1 (en) Pharmacologically active pyridine derivatives and processes for the preparation thereof
EP0672042B1 (en) Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof
US5612340A (en) Pyrimidineamine derivatives and processes for the preparation thereof
CA2149147C (en) Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof

Legal Events

Date Code Title Description
EEER Examination request