CA2149147C - Pharmacologically active pyrimidineamine derivatives and processes for the preparation thereof - Google Patents

Abstract

Described are N-phenyl-2-pyrimidineamine derivatives of formula (I) wherein R1 is a substituted cyclic radical, the cyclic radical being bonded to a ring carbon atom in each case and being selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, -C(=O)-OR3, -C(=O)-R4, -SO2-N(R5)-R6, -N(R7)-R8, -OR9 and fluorine-substituted lower alkyl, wherein R3, R4, R5, R6, R7, R8 and R9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and R2 is selected from halogen, cyano, carbamoyl, -C(=O)-OR10, -C(=O)-R11, -SO2-N(R12)-R13, -N(R14)-R15, -OR16 and fluorine-substituted lower alkyl, wherein R10, R11, R12, R13, R14, R15 and R16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino. Those compounds can be used, for example, in the treatment of tumour diseases.

Description

WO 95/09851 ' ' ~ ~ PCT/EP94/03148 Pharanacolo 'call active idineanline derivatives and rocesses for the re aration thereof The invention relates to 1~1-phenyl-2-pyrilnidineamine 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 ~eatanent of warn~-blooded animals.
The invention relates to N-phenyl-2-pyriznidineamine derivatives of formula I

(~
~~
wherein Rl is a substituted cyclic radical, the cyclic radical being honded to a ring carbon atom in each case and being selected from phenyl, pyridyl, PYraainyl, thiazolyl, pyrimidinyl, pYriYl and imida~l~l; and the substituents of the above-mentioned cyclic radical being selected frown one or snore of the groups halogen, cyano, carbarnoyl, -C(=t~)-C)R3, ..~(_p)-~. _sp2°N(~s)..~9 -N(R7)-R~, -C~~ and fluorine-substituted lower alkyl, wherein R3, R4; Rs, Rb, R.t, R8 and R9 azu each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by anono~ or di-lower alkylamino; and R~ is selected ~o~n halogen; cyano, carbaznoyl, -C(=~~~Rlo, -~(=-4)-Rll, ''~~2°~~12~"R13~'N~14)-X15~'~~16 ~d f~td~rAne-subst8tuted lower alkyl, wherein ' Rlo, Rllp Rla' 8139 R14~ Rls and Rl~ are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- yr di-lower alkylalnino, and to salts of such compounds having at least one salt-forming group.
A substituted cyclic radical Rl, such as, for example, a substituted phenyl radical Rl, can have several substituents, but especiaLty not more than 3 and, especially in the case of relatively large substituents, preferably only one substituent, which substituents are principally in the pcara- (or 4-position) and/or preferably a~aeta-position {or 3-position) with .. . .. . : . .., .. __... ;_ .,;.,.. .,.,;; ,:..,.. .,.; ,.:. -.: y. , -:. .>
~- ;..,, . .
., .., ;., . .. , .: : .. : : . :.:, ., . . . ~ .. .. .., , ., ; ,. .,: ,. .
.. ;; .. , ,. .
... ; . . .. ,:. , . , . .. . .~ .. .,...: . ~. : : ;;. : ~ ,..... ..;,_.,;
.." . : . . ; ,... ;, S .om,?.,~ ., ,. "~. :..'. ....,.:. .. :.'.' :.. " ... .. ., , . ....::, .,.,.::'. ...o.:.............;, ~. ~: :. ,.~. ~ ,.. ... ~,.;, . ; .,.,..:: ..
.
1~~.,~,..~~... ...: .. . .. ......:._ .....;. ,. .. ~; . . ..,. ., .. ,..: .
.,.~:, .. ., . ......,.. ...,~ .. u.: ~..... ........ .... . ..., ._:

wp 9519851 , PCT/EP94/03148 _2_ respect to the bonding site of the cyclic radical R1. The above-mentioned substituted cyclic radicals Rt other than phenyl generally have up to two and preferably only one substituent, which issare especially in the pare-position and/or preferably rneta-position with respect to the bonding site of the cyclic radical Rl.
Pyridyl bonded to a ring carbon tam is 2- ar preferably 4- or 3-pyridyl, especially 4-pyridyl. In a mono-substituted pyridyl radical Rl, the substituent is preferably in the ortho-position with respect to the pyridine ziitrogen.
Halogen in a radical Rl is preferably chlorine or fluorine.
Halogen-substituted phenyl Rl is preferably 2-, 3- or 4-chloro-phenyl; 2,4-, 3,4~- or 2;5-dichloro-phenyl or 2;3,4-trichlorc-phenyl:
Fluorine-substituted lower alkyl R$ is lower alkyl that carries at least one, but preferably several, fluorine substituents, especially 1,1,2,2-tetrafluoro-ethyl or mare especially tri-fluaromethyl.
lVlono- ar di-lower alkylamino is, for ea~aa~ple, methylaanino or di~ethylamino.
within the scope of this text, the term "Ia~uver" denotes radicals having up to and including 7preferably up to and including 4; carbon atoms.
Unless otherwise indicated in the cante~t concerned, loever alkyl is preferably gnethyl or ethyl.
R~ ,and R~ are preferably hydrogen. R8 is preferably dower aryl; such as especially n-propyl, Rg is preferably hydrogen or methyl.
Salt-fornurtg gr~ups in a ca~paund of fa~ryula I are groups or radicals having basic or acidic prapc~tiesCa;ngaunds having at least one basic group or at least one basic radical, for example a mono-lower alkylatnino group, a pyraainyl radical or a pyridyl radical, can farz~ 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- ar di-carboxylic acids, such as trifltaoroacetic acid, acetic acid, propionic acid; glycolic acid, succinic acid, maieic acid, fumaz-ic acid, hydroxymaleic r.....~...: ;~.,... , ,...".,.,. ,", ,,.. ~ .-.;:~;, , ~.,~.. ', r:~: . .~' ."~ . . ::'.~ ~ ..,...~'. ~,.'.-, ~.-:-.' , ~.':~ , .;:.. ..: '":,. ~ ..;~ , .., ,:.~ . ' ;. ~...
~'f v f :; ~ ';,..., .,.,,..., ;;,'' ...i,.. . ~;:,. ;, :;..'~. ";.,:: ,.,_ .,.,.,.
:.,.:,~.: ,.;,..,... .,. ;..::'~. ~.. :.'~ ;.:,.'. ~.':~ ,..'.:;::.. ...:.~...
, , ..: , .. .;. .:. _ .
n.....,., . . .. .... .. .. .. : . . . . _ .. .. .. , ~ ". ~..... .. . , ....
., ... . , W O 9SI098S 1 ~~ PC~'/EP94/03148 acid, malic acid, tartaric acid, citric acid, oxalic acid or amino acids, such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-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- ar 2-hydroxy-ethane-sulfanic acid, or aromatic sulfonic acids, for example benzene-, p-taluene- or naphthalene-2-sulfonic acid. If several basic groups are present, mono- or poly-acid addition salts can be fornned.
Compounds of formula I having acidic groups, for example a free carboxy group in the radical Rl, can form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or anlmoniurn salts with ammonia or suitable organic amines, such as tertiary monoamines, for example tri-ethylamine or tri(2-hydroxyethyl)amine, or heterocyclic bases, for example N-ethyl-piper-idine or N,N'-dimethyl-pigerazine.
Compounds of formula I that possess both acidic and basic groups can form internal salts.
For the purpose of isolation or purification and also in the case of the compounds used further as intermediates, it is also possible to use pharmaceutically unacceptable salts.
C?nly the pharmaceutically acceptable non-toxic saps are used therapeutically, however, and those are therefore preferred.
In view of the close relationship between the novel compounds in free form and in the form of their salts, including also salts that can be used as intermediates, for euample in the purification of the novel compounds or in order to identify those compounds, herein-before and hereinafter any refemnce to the free compounds is to be understood;as ~cluding also the corresponding salts, where appropriate and expedient.
The compounds of formula I exhibit valuable pharmacQ.'.agical properties: for example, they inhibit the enzyme protein kinase C with a high decree of selectivity.
Phospholipid-and calcium-dependent protein kinase C occurs in cells in a number of forms and parti-cipates in various fundamental processes, such as signal transmission, proliferation and differentiation, and also the release of hormones and neurotransmitters. The activation of that enzyme is effected either by receptor-mediated hydrolysis of phospholipids of the cell membrane or by direct interaction wvith certain tumour-promoting active substances. The CVO 9SI098S1 PCTfEP94/03148 _4_ sensitivity of the cell to receptor-mediated signal transmission can he substantially influenced by modifying the activity of protein kinase C (as a signal transmitter).
Caanpounds that are capable of influencing the activity of protein kinase C
can be used as tumour-inhibiting, antiinflammatary, ~munomodulating and antibacterial active ingredients and may even be of value as agents against atherosclerosis and disorders of the cardiovascular system and central nervous system.
Formerly, porcine brain pratein kinase C purified in accordance with the procedure described by T. lJchida and C.R. Filburn ih J: Biol: Chew. 259. 12311-4 (1984) was used to determine the inhibitory action on protein Icinase C, and the inhibitory action on protein kinase C was determined in accordance with the pracedua~e of D. F~bbro st ~., Arch.
Biochem. Biophys. 239:102-11I (1985).
Ths parcine brain protein kmase C formerly used is a mixture of various sub-types (isotypes) of protein kinase C. If pure recombinant isotypes are used instead of parcine brain protein kinase C in the above test it is found that the compounds of formula T inhibit the "convenrional" isotype oc greferentially whereas the other "conventional"
isotypes ~-1, ~-2 and ~ and especially the "non-conventional" asotypes s, E and n and the "atypical"
isaforrn ~ are generally inhibited to a distinctly lesser extent and in some cases hardly at all.
Recombinant PKC isotypes are cloned; expressed and purified in the followazag manner.
The production of various proteins with the aid of baculaviruses, and their cloning and isolation from Sf9 insect cells are carried out as described by M.D. Summers and t~.F.
Smith, "A manual nethod for baculovirus vectors and insect cell culture procedure", Ted Agricul. F,~ptl: Station Bull. (1987),1555. The construction,and isolation of , recaanbinant viruses for the expression of PKC-~c (bovine), PKC-~1 (human), PKC-~2 (human) and PKC-y (humanlbovvae hybrid) in Sf9 cells ire effected in the manner described by Stabei et al. [S. Stabel, M. Liyan~~ge and D. Frith, "Expression of protein kiiaase C is~zymes in insect cells and isolation of recombinant groteins", lVieth. Neurosc.
( 1993)]. 'The production c~f the PKC isotyges in Sf9 cells is carried out in the manner ~dicated by Stabel et r~X. (see above), and the purification of the enzymes is effected in . accordance vrith the method described in the publication by McGiynn et al.
[E. McGlynn, 1. Liebetanz, S. lZeutener, J: 'load; N.B: Lydon, H. Hofstetter, M. Vanek, T.
Meyer and T.3: Fabbro, "Expression and partial characte~izadon. of rat protein kinase C-s and protein kinase C-~ in insect cells using recombinant baculovirus", J. Cell. Biochem.

(1992)]. For the generation of recombinant PKC-s (rat), PKC-~ (rat), PKC-~
(rat) and PKC-n (mouse), and their expression and purification, the procedure described by Liyanage et al. ["Protein kinase C group B members PKC-a, -~, -~ and PKC-~:
Comparison of properties of recombinant proteins in vitro and in viva", Biochem. J. 283.
781-78?
(1992)] and McGlynn at al., respectively, (see above) is followed, with the add~tionat feature that the transfer vector pAc360 is used for the expression of PKC-n [V. Luckow and M.D. Summers, "Trends in the development of baculovirus expression", Biotechnology 6 47-55 (1988)].
The measurement of the activity of the recombinant PKC isotypes obtained by the above method is carried out in the absence of lipid and calcium (co-factors).
Prota~nine sulfate phosphoryhued in the absence of co-factors is used as the substrate. l7ie activity of the enzymes reflects the transfer of 32P from ~-[32P]-ATP to pmtamine sulfate.
Protamine sulfate is a mixture of polypeptides each comprising four C-terminal arginine residues.
Phosphate incorporation is measured under the following conditions: 100 ~1 of the reaction mixture comprise in final concentrations 20 mM TRIS-HCl pH 7.4, 10 mM
Mg[N03]2~
0.5 mg/ml of protamine sulfate,10 ~M ATP (0.1 ~Ci ~-[32P]-ATP; 10 Ci/mol;
Amersham, Little Chalfont, United Kingdom), various concentrations of the inhibitory compounds and 0.5-2.5 U (units: a unit is the amount of enzyme that, in one minute and per milligram of protein, transfers one nanomole of 3zP from the above-mentioned r-[32p]-ATP to histone Hl [Sigma, type V-S]) of the enzymes. The reaction is started by the addition of the enzymes and transfer at 32°C. The reaction time is 20 minutes. The reaction is then stopped by dripping aliquots of 50 ,~l onto P81 chromatography paper (VVhatman,~"
Maidstone, United Kingdom). After removing unbound ~-[32P]-ATP and nucleotide fragments by washing operations as described by J.J. Witt and R. Roskoski, "Rapid protein kinase assay using phospho-cellulose-Paper absorption", Anal. Biochem.
66, 253-258 (1975), the substrate phosphorylation is determined by scintillation measurement.
In that test, the compounds of formula I inhibit the a isotype of protein kinase C (PKC) at an ICS of as low as approximately from 1 to 75 ~rnoUlitre, generally approximately from 1 to 10 wnolllitre. In contrast, the other isotypes of PKC are generally inhibited only at distinctly higher concentrations (i.e. at concentrations up to more than 300 times higher).
As may be expected purely on the basis of the above-described inhibitory action on protein kinase C, the compounds of formula I exhibit antiproliferative properties which can be demonstrated directly in another test described in the following in which the inhibitory action of the 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 596 (v/v) foetal calf serum has been added, in a humidified incubator at 37°C and with 5~o by volume of C02 in the air. The carcinoma cells (1000-1500) am sown in 96-well micxotitre plates and incubated oven~ight 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 four cell divisions. After incubation, the cells are fixed with 3.396 (w/v) aqueous glutaraldehyde solution, washed with water and stained with 0.0596 (weightwolume) aqueous methylene blue solution. After washing, the dye is eluted with 396 (w/v) aqueous hydrochloric acid. The optical density (OD) per well, which is directly proportional to the number of cells, is then measured at 665 nm using a photometer ('I~tertek multiskan). The ICS values are calculated with a computer system using the formula ODD (test) minus ODDS (start) x 100 ODs (control) minus ODD (start) The ICS values are defined as being the concentration of active ingredient at which the number of cells per well at the end of the incubation period is only 5096 of the number of cells in the control cultures.1n the case of the compounds of formula I, the ICS values so ascertained are generally approximately from 1 to 20 lrmoUlitre.
The anti-tumour activity of the compounds of formula I can also be demonstrated in viva:
Female Balb/c hairless mice with s.c. transplanted human bladder tumours T24 are used to determine the anti-tumour activity. On day 0, with the animals under peroral forene narcosis, approximately 25 mg of a solid tumour are placed under the skin on the animals' left flank and the small incised wound is closed by means of suture clips. On day 6 after the transplantation, the mice are divided at random into groups of 6 animals and treatment commences. The treatment is carried out for 15 days with peroral or intraperitoneal_ administration once daily of a compound of formula I in dimethyl sulfoxideJTweenTM 8Q/
sodium chloride solution in the various doses. The tumours are measured twice a week with a slide gauge and the volume of the tumours is calculated. In that test, the peroral or intraperitoneal administration of a compound of formula I brings about a marked reduction VVm 9510981 ~ ~ ~ PCT/EP94l03148 in the average tumour volume in comparison with the untreated control animals.
(fin the basis of the properties described, the compounds of fornnula I can be used especially as tumour-inhibiting active ingredients, for example in the treatment of tumours of the bladder and the skin. V~Then the compounds of formula I are used in the treatment of cancer in combination with other chemotherapeutic drugs, they prevent the development of resistance (multidrug resistance) or eliminate an already existing resistance to the other chemotherapeutic drugs. 'Irhey are also suitable for the other uses mentioned above for' protein kinase C modulators and can be used especially in the treatment of disorders responsive to inhibition of prbtein kinase C.
Some of the compounds of formula I also inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGG. What receptor-speciEc enzyme activity plays a key role in signal transmission in a large number of mammalian cells, including human cells, especially epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. In the case of various types of cell; the EGF-induced activation of the receptor-associated tyrosine protein kinase (EGF-R-~'PI~) is a pre-requisite for cell division and accordingly for the proliferation of a cell population. the addition of EGF-receptor-sgscaf"ic tyrosine kinase inhibitors thus inhibits the replication of those cells.
Inhibition of EGF-receptor-specific tyrosine protein kinase (EGF-R-'I~I~) can be demon-strated, for example, using the method of E. lvlcGlynn et ail., Euxop. J.
Biochem. 207, 265-275 (1992). The compounds according tb the invention inhibit the ehzyme activity by SU~'o {IC50) for example at a concentrateon of from 0.1 to 10 Sri.
'tee compounds, of formula I that inhibit the tyrosine kinase activity of he receptor for the epidermal growth factor (EGF) can accordingly be used, for example, in the treatment of benign or malignant tumours. Z°hey are able to bring about tumour regression and tea prevent metastatic spread and the growth of rnicrometastases. They can be used especiall a in the case of epidermal hyperproliferation (psoriasis), in the treatment of neoplasia of epithelial character, for example mastocarcanoma, and in the case of leukaemia. 'I°he compounds can also be used in the treatment of disorders of the immune system and inflammation if pr~tein kinases are involved. Furthermore, those compounds of formula I
can be used in the treatment of disorders of the central or peripheral nervous system if signal transmission by protein kinases is involved.

w0 95/09851 PCTIEP94I03148 The compounds of formula I and salts of such compounds having at least one salt-forming group also inhibit the enzyme p34'~'~Icycline B'~13 kinase. That kinase controls, in addition to other cdc:2-related kinases, specific phases of cell division, especially the trhnnsition from the G1-phase to the S-phase and more especially the transition from the Gz-phase to the NI-phase.
In chronological order, the cycle of a eukaryotic cell consists of the intnrphase and the lit-phase. The interphase is accompanied by an increase in the size of the cell. In chreno-logical order, the interphase consists for its part of the G1-phase, the S-phase and the GZ-phase. In the ~., -phase ((i = gag) biosynthetic processes take place in the cell. In the S-phase (synthesis phase) the I~1~1E1 doubles. The cell then enters the: GZ-phase which ends with the commencement of mitosis.
In chronological order, the M-phase for its part consists of the division of the cell nucleus (mitosis) and the division of the cytoplasm (cytokinesis).
The above-mentioned inhibition of the enzyme p34~2/~ycline 8~1~ kinase can be demonstrated by the followingtest:
~A~I 1-methyl-adenine nre used to anduce starfish oocytes to enter the PdI-ghase. The oocytes are then frozen in liquid nitrogen and stored at -g0°C. If necessary; the oocytes are homogenised and centrifuged, as described in D. Anon et at., Cell 55, 371-37~
(19g8) and 'V. l2ialet and L. I~feijer, ,A.nticancer ltes.11,1581~1590 (1991). In order to purify the F34~~/cYe~e ~~Cq3 ~~e~ ~~ upernataatt of the oocytes is added to p9C~~_ Sepharose gains prepared from recombinant hurl~an protein pgc~~, as described ira L. Azzi et al., Eur. J. Biochem. 203, 353-360 (1992). ,after 30: minutes; at 4°C, while being turned constantly, the grains are washed thoroughly and the active p34~C2/cyeline ~~13 .
k.inase is eluted with free, pretein p9~~~ (3 m~/~1). The eluted l~inase as tested using histone H1 as substrate, as described in I:; ll~eijer et al., O ~. ~; 2275-222 (1989) and F..lI~IBO ~. 10,1545-1554(1991). In that test; the compounds of formula i and salts of such compounds having at least one salt~farr~ing gr~up exhibit an inhibiting concentration lC~o [~o~tre~ of apgroxiunately frown 0.01 to 2.
That finning weuld also lead to the expectation that the compounds of foranula I and salts of such compounds haring at least one salt-folTning group can be used in the treatment of wCi 95/09851 r.~ PCT/EP94/0314~
llyperproliferative disorders, such as tumours and psoriasis.
The compounds of formula I also inhibit the production of HIV viruses, as shown by the test below, and can accordingly be used as agents against the immune deficiency disease AIRS. The initial syrraptoms observed after HIV infection in humans is followed by a clinical latency period which can last several years. After that period, the ,stage known as ATDS occurs and usually progresses w death. The latency peziod is attributed to several factors: immune response, occlusion of the viruses in lymph nodes or other tissue and entry into a stage of molecular and viral latency in which the infected cells do not complete the viral cell c°.~~Ie, which is why infectious viruses cannot be produced and the infection cannot spread. 'inat stage of molecular latency has been investigated using cell models, such as the ACH-2 cell line [K. Clouse et al:, J. Immunol. 142. 431 (1989)] and the U1 cell line (T. folks et ul., 3. Immunoi. 140. 11? (1988)x. Those cells are infected with HIV-1 viruses, but have only a low content of infectious viruses. If, however, those cells are stimulated with hysiologically relevant factors that are known to be increased in AIRS patients, such as ~ . .aour necrosis facwr; inter~~ulcin-6 etce, or with chemical induc-tors, such as phorbol diesters, for example 13-O-acetyl-12-O-n-tetradecanoyl-phorbol, a massive production of virus follows. The ACIrI-2 a~~d UI cells are representatives of two different cell families that are targets for HI'tT infection, namely lymphocytes and macro-phages.
Hitherto, effective prevention of the progression of HIV infection to the outbreak of AIDS
has not been possible. Ivlany attempts have been made to prevent virus replication after the outbreal~ of AIDS, that is to say, in a stage in vvh~ch viruses are produced on a massive scale. In contrast, the compounds of formula I interfere with cell processes that lead to tile activation of l~tentiy infected HIV cells without impairing normal cell processes, such as cell division.
If the above-mentioned IJ 1 or ACH-2 cells are used as a model for viral latency, it can be demonstrated that HIV varus production induced by 13-C)-acetyl-12-Q-n-tetradecanoyl-phorbol or tumour necrosis factor alpha are effectively inhibited by the compounds of formula I at a concentration of approximately ~rom 0.001 to 1 ~.unolllitre, for example at 0.03 ~,unoulitre.
preferred are compounds of formula. I wherein \ R1 is substituted pyridyl bonded to a ring carbon atom, the substituents of the above-:r ,::... . .:. . . : ,,. : -; _ " ..; : : , _: :..;:. . :: , . ",: , . , ., .
_ ... .. : ;
. a. . ~.. . .:. . :: ., . ~ " < : . . . ,. . ..:: . ..: . - .. , w0 95/0981 PCT/EP94/03148 to -mentioned pyridyl radical being selected from halogen, cyano, carbamoyl, -C(=fl)-~R3, -N(Ry)-R8 and -Qit~, wherein R~, R~, R$ and R~ are each independently of the others hydrogen or lower alkyl; and . -Ra is selected from halogen -C(~)-OR~~, wherein .
Ry is hydrogen or lower alkyl, and from fluorine-substituted lower alkyl;
and salts of such compounds having at least oaae satt-forming group.
l~efenred are especially compounds of formula I wherein .
Ri is a pyridyl radical substituted by halogen, eyano; carboxy, carbam4yl, hydroxy or by N-lower alkyl-aanino, and R~ is halogen or fluorine-substi~sted Iower alkyl, ' and the :. is thereof.
~P~~y ~'~~erred are compounds of formula I wherein R1 is a 4-pyridyl radical substituted in the 2-position by chlorine, cyano, carboy, carbanaoyl; hydroxy or by I~-propyl-a~.ino and ' Rx is chlarine c~<~ xifluoromethyl, and the salts thereof.
Very preferred are also compounds ~f formula I wherein Rl ~ a ~,.pyridyl radical substituted in the 2-position with respect to the pyridine nitrogen by chlorane; cyano, carboy, carbaln~yl; hydroxy; amino, N-propyl-strain~, N,I~T~diruethyl-umi~no or by N-butyl-amino, and Rz is chlorine, trifluorortnethyl; carboxy or lower al~oxycarbonyl9 .
and the salts thereoF
.~
More especially Preferred are the ct~mpounds of formula I described in the Ex~mmples.
The compounds of formula I end the salts of such compounds haring at least one salt-forming gr~up ate prepared in accordance with processes known per se: 'The proccess according to the inventibn is effected as:fallows.
a) a compound of formula II
Rl~~(=~)_CH =CH-N(R~~)-Ris (B)~
!
J . -.
t .4 _':
.no,~!.7..
e~? , 1 .

.,.,.3.. ~, ~' t ....1~
. ~::.- r a C.
7 . . ~~ . ~; ø ; ( ~ t .
V p, .7 .., , ,. -pn.
uRr ~ n....~ 9. .; F
i ..
t .. ;s .
l Y .w'... , ! ::. i ..Y, rC.ln 4 , ~:f f " , n ' Se - . Y. .. . . . $ , . . .,. . . . . S ~.. , . ~ , ~3~....,..... ,.., r.. . . .;::~,,n", ".,.. ." t..~i....~ t..ri"~:.,_.. . .r ,'.af~~,x a..,._.. ... , ,., . ,.. . ) ...... ., . .. ,t.', , . . , . , .. . .
... .. . . . . ,.

w~ 95/09851 ~ "~, ~ ~ PCT/EP94/03148 wherein Rl' and Rlg are each independently of the other lower alkyl and Rl is as defined above, functional groups present in a compound of fordnula II, with the exception of the groups participating m the reaction, being, if necessary, in protected form, or a salt of such a compound is reacted with a compound of foranula ITI
NH

wherein Ra is as defined above, functional groups present in a compound of formula 1~, with the exception of the gunnidino 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 comppund of formula I wherein Rl is pyridyl, Pyra~inyl, thiazolyl, PY~Y~~ pY~YI ar imidazolyh each of which is substituted by a radical ci~ the formula -bt(R')-R,s; and RZ hay any one of the above-nnentioned meanings, a compound of formula I wherein Rl is pyridyl, Py~axinyl, thiazolyl, pyrimidinyl, PY~-dazinyl or imidazolyl, each of which is substituted by a leaving group, is reacted with an amine of formula (~), HIV(R..~)Rs whoreiui the substituents are as defined above, functional groups present in a compouaid of formula IV, with the exception ~f the amino group participating in the reaction, being, if necessary, in protected form, and any protecting groups present are removed, or c) for the preparation of a compound of formula I wherein Rl is any one of the above-mentioned cyclic radicals substituted by carbamoyl or by a radical of the formula -C(= O)-OR3, wherein R~ is hydrogen, and RZ has any one of the above-mentioned meanings, a compound of formula I wherein Rl is any one of the above-mentioned cyclic radicals substituted by c~rano is h_ ~drolysed, or . . . . .,... ._.... , ..:.. .. . .. ,.,. .,, . .. ;: : ;.: :-: . . . ;:::. ':
r-, , . ; .
y . ..,... ,:....:.~., ,.~.., ., ?...,.~. .,..,..,... - : ~ - r ~ ,.~.-:..'...'.'.,, . ,.' ., . ..,..... ....,.r ..: ~'.,~'....r..:.... . .r!..,,;
,.,. . .,._ St :....' ~..; .. ,. : .. ., r? ~~ ... .:. ..~.:._ ~:;". . , . , ~..:.....,..
, :' .. . ',. ;,~;~.... :..:. ~. .... .. .,,.:., .~,.,..~. . . . .r:.' .. , , ..
.1... '...'.~.. ..; .:....:.. .._..,. .'.. . .,.'.. .n. .,... ,.;.
;....,.:..,. .-....'..., . . . .. ...-.. .::~ . :.,..,. . ,r. .. : ~. :.n:..~
. ..:. .. :.~.'..'. : ~.

'WO 9S/09851 PCTIEP94l03148 . ' d) for the preparation of a compound of formula I wherein Rl is a pyridyl radical substit-uted by cyano or by -ORg, wherein R~ is hydrogen or lower alkyl; and R2 has any one of the abo~re-mentioned meanings, in an N-oxido-pyridyl compound of foranula 'VIa ('vllI)~
- t~ H
whereita R21 is N-oxido-pyridyl bonded to a sing carbon atom and R2 has any one of the above-mentioned meanings, the rT-oxido group is converted inter a leaving group and the resulting leaving group is removed from the molecule by nucleophllic substitution in the ortho-position with respect to the pyridyl nitrogen using a nueleophile that introduces hydroxy, cyano or unsubstituted or halogen-substituted lowea~ alkoxy, ar ~) for the preparation of a compound of formula I wherein Rl is a gyridyl radical substit-uted by chlorine and RZ has any one of the above-mentioned meanings, are l~-o~ido~
pYridYl compound of fomaula YRI
~~
~ (~), ~N
wherein ~2~ is N-oacido-pyridyl bonded to a ring carbon at~rn and ~t2 has any one of the above-mentioned meanings, is reacted with a reagent that introduces chlorine in the ortho-pasition with respect to the N-o~ido group, and, if desired, a compound of formula I obtainable in accordance with any one of processes a-a is converted into its alt, or an obtainable salt of h a~znpound of formula I is concerted into the flee compound:
°The pnaniler in which the above-mentioned process variants are carried out is explained in PCTlEP94/~3148 6~t? 951U98~1 detaal hereinafter.
General:
The end products of formula I may comprise substituents that can also be used as protecting groups in starting materials for the preparation of other end products of foranula. I. Within the scope of this text, therefore, unless the context indicates othene~rise, only a readily reanovable group that is not a constituent of the particular end product of formula I desired is referred to as a "protecting group".
Protecting groups and the manner in which they are introduced and removed are described, for example, in "Pirotective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in "Methoden der organischen Chemie", I-Iouben-Weyl, 4th edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974 and in Theodore W.
Greene, "Protective Groups in Organic Synthesis", John Wiley ~z Sons, New York 1981. A
charac-teristic of protecting groups is that they can be readily'removed, that is to say, without undesired secondary reactions taking place, for example by solvolysis, reduction, photol-ysis or also under physiological conditions.
I3ydroxy-protecting grougs are, for example; ~cyl radicals, such as unsubstituted or substituted, for example halogen-substituted, lower alkanoyl, such as 2,2-dichloroacetyl, or acyl radicals of carb~nac acid semiesters, especially tart-butoxycarbonyl, ansohstitufed or substituted benzyloxycarb~onyl, for example 4-nitrobenxyloxycarbonyl, or Biphenyl-metho~ycarbonyl, ~x 2-halo-lower alkoxyc~bonyl, such a<s 2,2,2-txiuhloroethoxycarbonyl, and also trityl or formyl, er organic silyl or stannyl radicals, and also readily removable etherifying g.-.;. :ps, such as tart-lower alkyl, for example tart-butyl, 2-oxa- or 2-thia-aliphatic or -cycloaliphatic h~drocarbpn radicals, especially 1-lower alkoxy-Lower alkyl or l-lower alkylthio-lower ~1ky19 for example znethoxymethyl, lrrnheth~xy~~ethyl, ~1-etho~y-ethyl, methylthiomethyl, 1-m~thylthioethyl or 1-ethylthio~thyl, or 2-oxa- or 2-this-cyclo-alkyl having S or 6 ring atorus, for example tetrahydrofuryl or 2-tetrairydropyranyl or corresponding this anal~gues, and also unsubstituted or substituted 1-phenyl-Lower alkyl, such as unsubstituted or substituted ben~yl dr diphenylmethyl, suitable substituents of the phenyl radicals being, for exempla; halogen, such as chlorine, lower alkoxy, such as methoxy, and/or iaitro.
A protected amino group may, for example, be in the form of a readily cleavable acyl-amino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower elk-1-en-yl-aynino, silyl-a,..~:.., .: . . . . : .. . ; .: : . . ~ : - : . , ,. ,... , . ...,, :".: , .:., .: .:~ ;; . . .. ; ; . .
., . ; ... .. . .,:. .. ,. . ...:; , : :.,,.. : . ,. . .. ,;. . . . . . ... ..
. ;
. . .,. . . ; .. , ..... < .:. .,, : . . . .. . . . , ,.. . . . , . , ::. .., .. ., -. ,. ..
., ;.; ...., .., .. . . . . :. ;: ., .. . . . ... . , , ,, ,. ,., .. . . , ....... _ .r .. : ... . . . ,.: . ,. . ,. ,. . . . .. ... .. .
. . , . .
.. . .. , . . . . . ..

'UVO 951fl9851 PCT/EP94/fl3148 f ~~~3ETC -amino or stannylamino group ar in the farm of an azido group.
In a corresponding acylaynina group, aryl is, f~r example, the acyl radical of an organic carboxylic acid having; for example, up to 18 carbon atoms, especially of an alkane-carboxylic acid that is unsubstituted or substitute, for example, by halogen or by ~rryl, or of a benzoic acid that is unsubstituted or substituted, far example; by halogen, lower alkoxy or by vitro; or of a carbonic acid semiester. Such acyl groups are, far example, lower alkanoyl; such as farmyl; acetyl or propionyl, halo-lower alkanoyl, such as 2-halo-acetyl; especially 2-chloro-, 2-bromo-, 2-iodo-, 2;2,2-trifluoro- or 2;2;2-trichloro-acetyl, benzayl that is unsubstituted or substituted; for example, by halogen; lower alkoxy or by ~tro; for example benzoyl, 4-chlorobenzayl, 4-anethoxybenzoyl or 4-nitrobenzoyl, or .
lower alkoxycarbonyl that is branched in the 1-position of the lower alkyl radial or suitably substituted in the I- or 2-gosition; especially tent lower alkoxycarbonyl, for example tent-butoxycarbonyl; arylmethaxycarbonyl having cane or two aryl radicals that ~e preferably phenyl that is unsubstituted or mono- ar poly-substituted, for example; by lower alkyl: especially tert-lower alkyl, such as tert-butyl, lower alkoxy, uch as methaxy, hydroxy; halogen, for examgle chlorine, and/or by vitro, such as unsubstituted or subs-titut~d benzyloxycarbonyl, for example 4-nitxabenzyloxycarbonyl; or substituted diphenyl-znethoxycarbonyl, for example benzhydryloxycarbonyl or rli(4-methoxyphenyl)methoxy-carbonyl, aroylmethoxycarbonyl wherein the aroyl groug is preferably benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for example phen-acyloxycarbonyl, 2-halo-lower alkoxycarbonyl; for example 2,2,2-trichloroeth~acy-carbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbanyl; or 2-(trisubstituted' silyl)-ethoxycarbonyl wherein the substituents are each independently of the others an aliphatic, aralighatic, cycloaliphatic or aromatic hydrocarbon radical that is unsubstituted or substit->uted; for exaanple; by lower alkyl, lower alkoxy, aryl; halogen or by vitro, and contains up ' ~ to l5,carbon atoms, such! as corre$ponding unsubstituted or substituted lower Alkyl; , , , phenyl-lower alkyl, cycloalkyl or phenyl; for example 2-tri-lower alkylsilylethoxy-carbonyl, such as 2-trianethylsiiylethoxycarbon~l or 2-(di-n-butyl-methyl-silyl)-ethmxy-carbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbenyla Othei acyl radicals suitable as amino-protecting groups are a~sa corresponding radicals of ~rgc phosphoric, phosphoric or phosphinic acids, such as di-lower alkylphosphoryl, far example dimethylphosphoryl; diethylphosphoryl, di-n-progylghosphoryl or diisopropyl-phospharyl; dicycloa.lkylphosphoryl, far example dicyclohexylphosphoryl, unsubstituted or substituted diphenylphosphorylfor example dighenylphospholyl; unsubstituted or r.
r e, .
a a .. . . ... . .. . ,. .. . -f . ,... ,. ~ , . ., < ~ . . . . . , .,. . , , v~b , n . .. , .. , . . . .. ,. ,. ... .. . .. .. , . c . . . ...,... . , . .
. . . .. ... . .... . .., , a .. ..

W~ 95109851 PCTlEP94/03148 substituted, for example vitro-substituted, di(phenyl-lower alkyl)phosphoryl, far example dibenzylphaspharyl ar di(4-nitrobenzyl)phospharyl, unsubstituted ar substituted phenyl-oxyphenylphosphonyl, for example phenyloxyphenylphosphanyl, di-Iawer alkylphos-phinyl, for example diethylphosphinyl, or unsubstituted ar substituted diphenylphosphinyl, for example dighenylphasphinyl.
In an arylanethylamino group that is a mono-, di- or, especially, tri-arylmethylamina group, the aryl radicals are especially unsubstituted or substituted phenyl radicals. Such groups are, far example, benzyl-, diphenylmethyl- and, especially, trityl-amino.
An etherif"~ed 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 tart-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by vitro. r~ corresponding ar~aino-protecting group ic, for example, 4-nitrophenylthio.
In a 2-acyl-lower alk-1-en-1-yl radical that can be used as an amino-protesting group, acyl is, for example, the correspondihg radical of a lower aIkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, far example, by lower alltyl, such as anethyl or tart-butyl, lower alkoay, such as methoxy; halbgen, such as chlorine, andtor 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-yI, for example 1-ethoxycarbonyhprop-1-en-2-yI.
Preferred amino-protecting groups are aryl radicals of carbonic acid semiesters, especially tart-butoxycarbonyl, benzyloxycarbonyl that is unsubstituted or substituted, for;example, . ~ ~ ~dicated, far example 4-vitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-lower afkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonylR and also trityl or foranyl. The removal of the protecting groups that are not eonstituenLs of the desired end product of formula I is effected xn a manner known per se, for example by solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogsnolysis or chemical reduction, as appropriate stepwise or simultaneously.
A protected amino group is freed in a manner known per se and, depending on the nature of the protecting groups, in various manners; preferably by solvolysis ar reduction.
.., . , . ~:. :. -~ -: : ~'.. ...
: .;.. . _: ," .: ; . . . v ::. . . : :': ~ . . . . , : .. .~ . . . . . - .., .
.,. > .~.
Al ~ '~5.~.. .,~ . . .: ..... .. _,,'... ....: . ',.... , ' ~ . .~..~. ~: ~.-.,.;:;..,; . ...... ., .. :J ~ ..:, , ".... . . ,: .:, ,.:' . . . , ~. ::.'.:, ,.a.~;:~.......w ,;..:.w.-: ...,. _...~.'~. ~ .: ~, , _ -.::. . ,;
..,~.~. . :...,"'. :.., . ~ . .. ~.~.~. : :.:..,... . ,,,:., . . ~. ,..:' ~ ' . ..~..'.... - ... ".;, ..
.4.n..., ~.~~ . ~ ;:.; .',;:' . ',..,..;.,; ...,.,~,:. , ,'.~.::_,.. ' ;., ."....,. , ;.;.. ,:., :..::. " ,.~ ..'~.:. ~. .,. ~w , , ..,; ~... ~.,~. ~ ..
..' ..,. :' ..~:r... ..

VVCD 95/09851 PCT/EP941(i3148 2-halo-lower alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lawer alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroyhnethoxycarbonylamino 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.
Aroylmethoxy-carbonylamino can also be cleaved by treatment with a nucleophilic, preferably salt-foraning reagent, such as sodium thiophenolate, and 4-vitro-benzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite.
ZTnsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-~i-substituted silylethoxycarbonylamino can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, unsubstituted or substituted benzyloxy-carbonylamino, for example, by hydragenolysis, that is to say by treatment v~ith hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, unsub-stituted or substituted triarylmethylaW ino or fornaylamino, for example, by treatment with an acid, such as a mineral acid, for example hydrochlbrie acid, or an organic acid, for example foranic, acetic or trifluoroacetic acid, where appropriate in the presence of water, and an amino group protected by an organic silyl grpup can be furred, for example, by hydrolysis or alcohoiysis. An amino group protected by 2-haloacetyl, for exaanple 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 the 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 hydrofluoric acid salt yielding fluoride anions.
A hydroxy group protected by a suitable ~cyl group, an organic silyl group or by unsubstit-uted or substituted I-phenyl-Lower alkyl is freed analogously to a correspondingly P~otect~d amino group. ~iydroxy protected by unsubstituted or substituted I-phenyl-dower alkyl, for example benzyl; is freed preferably by catalytic hydrogenation, for example in the presence of a palladium-on-carbon catal~rst. A hydro~cy group protected by 2,~-dichloroacetyl is freed, for example; by basic hydrolysis, and a hy~roxy group etherif'~ed by pert-lower alkyl or by a ~-axa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by acidolysis; for example by Treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetac aeid. ~lydraxy etherif'ied by an organic silyl radical, for example trimethylsilyl, can also be freed by a hydrofluoric acid salt yielding fluoride anions, for example tetrabutylamm~nium fluoride.

~O 95/09851 ~ P~T/EP94103148 Process a:
Preferably, Rm and Rlg are each methyl.
Free functional groups in a compaund of formula II, which are advantageously protected by readily removable protecting groups, are especially amino groups in the radical Rl.
Free functional groups in a compound of formula IIF, which 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 II or III is preferably an acid addition salt, for exaanple a nitrate or one of the acid addition salts mentioned for the end products of formula I.
The reaction is cazried out in a suitable solvent or dispersing agent, for example a suitable alcohol, such as 2-methoxy-ethanol or a suitable l~wer all~anol, for example isopropanol or isobutanol, at a temperature of from room temperature. (approximately 20°C} to 150°C, for example under reflex. Especially when the compound of formula II 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.
The starting material of formula II is obtained by reacting a compound of formula Y

~ (Y)~
CHI
r wherein Rl is as defined aboue, with a compound of formula ~lI
H N (VI) (?R2o R1a wherein R19 and R2a are each lower alkyl and the other substituents are as defined above, analogously to the procedure described in the European Patent Application having the WO 95I098S1 . PCT/EP94/03148 publication number 233 461. Typical representatives of a compound of formula VI are N,N-dimethylformamide dimethylacetat and N,N-dimethylformamide diethylacetal.
The reaction is effected while heating the reactants of formulae V and VI, for example for 1-24 hours, in the absence or, if necessary, in the presence of a solvent, at a temperature of approximately from 50°C to 1S0°C.
~A.lternatively, the starting material of formula II can also be obtained by reacting a connpound of formula V with formic acid ethyl ester of the formula H-C(=~)-O-and reacting the resulting product with an amine of the formula H-N(R~~)-Rig wherein the substituents are as defined above.
The starting material of formula III is obtained in the form of an acid addition salt by reacting an aniline derivative of formula VII
Rz wherein Rz is as defined above, ewith cyananiide (NC-NHS. The reaction is effected in a suitable solvent or dispersing agent, for example a suitable alcohol, for example a suitable lower alkan:ol, such as ethanol; for example ~c) in the presence of equimolar amounts of the salt-forming acid, for example nitric acid, or (3) in the presence ~f a clear, for example 60%, excess of a mineral acid, such as hydro-chloric acid, an ammoniyn salt of the desired salt-forming acid, for exaanple ammonium nitrate, being added when the reaction is complete, at a ter~aperature of from room temperature to 150°C, for example under reflex.
lProcess b:
t~ leaving group is reactive esterif'ied hydroxy, for example hydroxy esterified by a strong inorganic or organic acid, such as by a mineral acid, for example a hydrohalic acid, such as hydrochloric, hydrobroanic or hydriodic acid, also sulfuric acid or a sulfuryl halide, for example sulfuryl fluoride, or by a strong organic sulfonic acid, such as a lower atkane-sulfonic acid that is unsubstituted ~r substituted, for example, by halogen, such as fluorine, .,.: . .... :::- -: ., .. ;,.,. ... ; ,., :;.. _ . :;: ::~ :.. .. .:. , ,,. :
::,- . .. : >.:. -:~ :::.: ., ,: .:
.. .. , . . , . : : : .;., . ... , , . .. . . . . . :. . . . :... . ., . " , ._ ,.,. : _ :: . . , . ,. ..
.. . . . :. . . . . :.. . . ~ .. . . ..:. . , ... .

WtD 95I09~51 PCT/EP94l03148 or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, halogen. such as bromine, andlor by vitro, for example a methanesulfonic, triftuoromethanesulfonic or p-toluenesulfonic acid.
A
preferred leaving group is halogen, such as, especially, chloaine.
°The reaction is preferably carried out in the presence of an excess of the amine of formula IV, which can, where appropriate, also be used as solvent, and, if necessary, in the presence of as ixrert solvent; such as dinnethyl sulfoxide, at a temperature of from room temperature to +150°C, for example at 100°C.
Process c:
'The hydrolysis of cyano to carbamoyl can be carried out in the presence of a'suitable weak base, such as an allrali metal carbonate; for example sodium carbonate. In order to prevent the hydrolysis from continuing partially to c~rboxy; it is recomzalendable to carry out the hydrolysis with hydxogen peroxide in the presence of a suitable olefin, such as preferably a lower alkene, for example 1-hexerae, in the presence of an alkali metal carbonate, for example sodium carbonate, izi a suitable solvent, such as an alcohol, such as preferably ethanol, at room temperature.
1'he hydrolysis of cyano to carboxy is carried out in a suitable solvent, such as an alcohol, such as ethanol, for example in the presence of a. suitable base, such as aqueous sodium hydroxide solution, at teaxxperatures of frorra moan temperature to +150°C, for example at 60°C.
Process d:
The conversion of the h3-oxido group into a leaving group is effected, fpr example, by roaction with a suitable reactive carboxylic or sulfonic acid. derivative; for example with a suitable lower alkanoic acid chloride, lower allcanoic acid anhydride, such as acetic y~de, ~T,N-dimethyl-carbanioyl chloride; toluenesulfonyl chloride, methanesulfonyl chloride or trifluor~metharresulfnnyl chloride: A nucleophile that introduces cyano is, for example, a suitable silyl cyanide, such a.s tri-lower altcyr-silyl cyanide, for example tri-methylsilyl cyanide. A nucleophile that introduces lower alkoxy or halogen-substituted lover alkoxy is, for example, a corresponding lower alkanol, or a suitable metal salt, such as, far example, an alkali metal salt; thereof, that is to say, a corresponding lower all~canolate. ~iydroxy can be introduced, for example, by reacting a compound of fornnula V~ with a suitable acid anhydride and hydrolysing the resulting intermediate.

'9VO 95/0951 ' PCT/EP94I03148 -ao-Process d is carried out in a suitable solvent, such as acetonitrile, at temperatures of approximately from 0°C to 150°C, preferably approximately from room temperature to Io0°C.
'.l~he starting material of formula Y~I is obtained, far example, by oxidising a coraes-ponding pyridyl compound analogous to formula VIII, wherein RZl is pyridyl bonded to a ring carbon atom, with a suitable oxidising agent, such as hydrogen peroxide or a suitable peracid, for example a suitable perbenzoic acid, such as especially m-chloro-perbenzoic acid, in an inert solvenfi; such as methylens chloride, at room temperature.
.alternatively, the starting material of formula VIII can be obtained, for example, by first oxidising acetyl-Pyridine, such as 4-acetyl-Pyridine; with m-chloro-perbenzoi~
acid in a suitable solvent, such as methylene chlorade, for example under reflux, to acetyl-pyridine N-oxide, such as 4-acetyl-pyridine hI-oxide, then converting the resulting acetyl-pyridine hd-oxide, such as 4-acetyl-Pyridine 1~-oxide, with dirnethylformamide diethylacetal, which, for example, simultaneously serves as solvent, for example at approximately 110°C, into 3-dimethylamino-1-(i~T-bxido-pyridyl)-2-propen-1-one, such as ~-dimethyl-amina-1-(ht-oxido-4-pyridyl)-2-propen-1-one, and then reacting the latter with an R~-phenyl-guanidine wherein RZ is as defined above, or preferably with a suitable salt, for example a nitrate, thereof in a suitable solvent, such as isopropanol, and in the presence of a suitable base, such as soditaan hydroxide, for example under reflux, to fornn a compound of formula VIII.
In anbther method of preparing the staz~ting material of formula YIR, the above-mentioned ~etYl-PYndane N-oxide, such as 4-acetyl-Pyridine N-oxide, is converted with phosphorus oxychloride it1 a suitable inert solvent, such as toluene, for example at approximately 100°C, first into acetyl-2-chloro-pyridine, fir example 4-acetyl-~-chl~ro-pyridine. a resulting acetyl-~-chioro-pyridine, far examgle 4-acetyl-2-chloro-Pyridine, is then converted with dimethylformamide diethylacetal, which for example;
simultaneously serves as solvent, for example at approximately 110°C, into 3-dimethylamino-1-(2-chloro-pyridyl)-2-propen-lone; such as 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one, which is then reacted with a suitable salt, for example a nitrate, of an R2-phenyl-guanidine, wherein R2 is as defnned above, in a suitable solvent, such as isopropanol, and in the pretence of a suitable base, such as sodium hydroxide, for example under reflux, to form a compound of formula VIIT.
... .......... ..,. . . ....,"".... . ....f"." ., ,. ....,:".. ...!,' r ..'!' ,.. .....5 . ~ ;':; .,. , ._,., r[ ..
.<..., : ~.. .'. -,...y . .''......,.,., . ,........ ... . .,...:: ...'~"..
:.' . , .',..'..:".: ',. ~~.... .....,.:.: ....y .~~ .-;:~', . .. ~~' ;,'.,.~
'.'.'. ~: ;. . .~ , :' , 7 .
1 , v :.. .. .,.' n ' . :.:.:. ,...;;~ .. W ,- ~ '~;'~. .. .', '~ . ;:. .t .. '~ , ..v .' /. ''... .:. , . ..; ,! .. '.:.' . . ~. - ,: .
1... ,:''~. . , .: . ..:, , ...:, . , _ ,~ .:...... ., .... _ ... ..: .,..
.......: e. '.". ~ : .,:.;.. ...._ . ~ . .: ~.~'~ ,:.. .. . .. , f ~..,.. ._ .. . S. ~:.~ ' . . ,..'~.. p.. :.:. .. :'..:.. ...
...'.' ' ' ,.. ,,' .~...:;:~:, ~...;. ~ ~ . . ~.. ...,..........:.. n.~. -,.~...~. . ....e...., .....'.. ... "... /....,...:. , a ..m : . .. .. r,. , .
. ., ~ ' 5.v. :~..:'. ,. ..". . :. .....' :~. . . ~. ...:. ... ~,...,... .,.'...,. ....
...::~....:.... , ... ....... .w. .....:. ~.~.:.'... .. '.. '.. .... -. -~,.
.. .. , .. ":. . . .v~

WO 9519851 ~ PCT/EP94IU3148 _21_ ProGeSS e:
A reagent that introduces chlorine in the orthfl-position with respect to the N-oxido group is, for example, phosphorus pentachloride, trifluoromethylsulfonyl chloridelHCl gas or preferably phosphorus ozychloride. By reacting a compound of formulz 'VIII
(for preparation see above under Process d) with such a reagent, such as esp,..::ally phosphorus ozychloride, a compound of formula I is obtained wherein IZl is a chlorine-substituted Pyridyl radical that no longer contains an ZeT-ozido group. 'The reaction with phosphorus oxychloride can be cazried out, for example, in the absence of a solvent at approximately 100°C. Alternatively, it is possible to use phosphorus ozychloride together with a suitable amine, such as diisopropylamine, in a suitable solvent, for example a chlorinated hydro-carbon, such as chloroform, at approximately room temperature. Another possibility is to use phosphorus oxychloride in a suitable solvent, such as chloroform, taiuene ~or zylene, at elevated temperature, for example under refluz.
Acid addition salts of compounds of fordnula I are obtained in customary manner, for ozample by treatment with an acid or a suitable anion exchange reagentr Acid addition salts can be converted in custannary manner into the free compounds, for example by treatment with a suitable basic agent.
Mi~ctures of isomers can be separated into the individual isomers in a manner known per ~e, for example by fractional crystallisation, chromatography, etc..
'I"he processes described above, including the processes for removing protecting groups and the additional process measures are, unless otherwise indicated, carried out in a manner known per se, fir example in the presence or absence of preferably inert solvents ' or ,diluents, if taecessary in the presence of condensation agents or catalysts, at,reduced or elevated temperature, for ezarriple in a temperature range of from approximately -20°C to approxinnately 150°C, especially from approximately 0°C to approximately ~-?0°C, preferably from approxunately +.: y to agprox~aately +50°C, principally at room teyperature, in a suit~.ble ~russel and, if necessary, in an inert gas atmosphere, for example a nitrogen atmosphere.
Taping into account all the subsiituents in the molecule, if necessary, for ezarnple if readily hydrolysable radicals are present, especially mild reaction conditions are to be used, such as short reaction times, the use of mild acidic or basic agents in low concen-rah -22- ' tration, stoichiometric ratios, and the selection of suitable catalysts, solvents, temperature conditions and/or pressure conditions.
The 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 process steps are carried out or the process is discontinued at any stage or a starting material is formed under the reaction conditions or is used in the form of a reactive deriva-tive or salt. The starting materials used are preferably those which, according to the process, result in the compounds described above as being especially valuable.
The present invention relates also to novel starting materials andlor intermediates and to processes for the preparation thereof. The starting materials used and the reaction cbnditions chosen are preferably such that the compounds described in this Application as being especially preferred are obtained.
The invention relates also to a method of treating warm-blooded animals suffering from a tumour disease, which method comprises administering to warm-blooded animals requiring such treatment an amount that is effective in inhibiting tumours of a compound of formula I or of a pharmaceutically acceptable salt thereof. The invention relates also to the use of a compound of formula I or of a pharmaceutically acceptable salt thereof in the inhibition of protein kanase C in warm-blooded animals or in the preparation of pharma-ceutical compositions for use in the therapeutic treatment of the human or animal body.
Depending on the species; age, individual condition, mode of administration and the particular clinical picture, t;ffective doses, for example daily doses of approximately I-1000 mg, especially 50-500 mg, are administered to a warm-blooded animal of approx-innately 70 kg body weight.
The invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the prophylaxis or treatment of one of the above-mentioned disorders, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be iazorganic or organic, solid or liquid. There are used for oral administration especially tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose andlor glycerol, andJor lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, andlor polyethylene glycol.

w~ 95/09851 , ,. ' .~ PCT~EP9.~I03148 Tablets may also comprise binders, for example magnesium aluminium silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethyl-cellulose and/or polyvinylpyrrolidone, and, if desired, disintegratars, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavourings and sweeteners. It is also possible to use the pharma-cologically active compounds of the present invention in the form of parenterally adminis-trable compositions or in the f~rm of infusion solutions. Such solutions are preferably isotonic aqueous solutions ar suspensions which, for example in the case of lyophilised compositions that comprise the active ingredient alone or together with a carrier, far example mannitol, can :~e made up prior to use. The pharmaceutical compositions may be sterilised andlor may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic gressu~e and/or buffers. The present pharmaceutical compositions, which may, if desired, comprise other pharmacologically active substances, such as antibiotics, are prepared in a manner l~nawn per se, for example by means of conventional mixing, granulating, confectianing, dissolving or lxophilising processes; and comprise approximately from I~ to 100, especially from approximately I~ to approximately 20~p active ingradient(s).
The following Examples illustrate the invention ewithout limiting it in any way. The R~
values are determined on silica gel thin-Layer plates ~erclc, Darmstadt;
Germany). The ratio of the eluants in the eluant mixtures used is indicated in parts by volume (v!v) and temperatures are indicated in degrees Celsius.
Abbreviations:
~y: high vacuum RT: room temperature Examoie 1: 31 mg (0.78 moral) of sodium hydroxide are added to a suspension of 15~ mg (0.7 mmol) of 3~dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one and 165 mg (0.7I mrnol) of 3-ehloro-phenyl-guanidine nitrate in 1.5 ml of 2-propanol.
After stirring.
under reflex for l8 ho~.rs, the reaction mixtuxe is cooled and filtered and the n~ateriat retained on the filter is washed thoroughly with water. After drying (6~°, IiV), I~-(3-Ghlora-phenyl)-4-(2-chloro-4-pyridyl)°2-PYrimidineatnine is obtained;
m.p. 19~-19&°, R~= f?.67 4methylene chlorid~:methanol = 95:5), FAB-lailS: 317 (Mø-~1).
The starting material is obtained in the following manner:

w0 9109851 PCT/EP94/43148 -.

Stake 1.1: 4.12 ml (39.12 mmol) of 3-chl~ro°aniline are placed in 25 ml of ethanol, and 3.3 g (78.4 mmol) of cyanamide are added. 5.3 ml (62.7 moral) of concentrated hydro-chloric acid are added dropwise to the brown solution. The reaction solution is then stirred for 20 hours at 78°. After concentration under reduced pressure, the residue is dissolved in 25 ml of water, and 6.3 g (78.4 mmol) of ammonium nitrate are added. The precipitated substance is isolated by filtration, washed with water and dried at 60°
under HV.
3-chloro-phenyl-guanidine nitrate is obtained;1H-NMR (dimethyl sulfoxide}: 7.2-7.8 (7H,m), 9.9 ( 1 H,br,s).
Stage 1.2: 24.61 g ( 177.62 mmol) of 2-chloro-4-cyano-pyridine are placed in 1.25 litres of diethyl ether under nitrogen; and 120 ml (22°!o in tetrahydrofuran, 353 mmol) ~of methyl-magnesium chloride are added. The red suspension is stirred for 40 hours at RT, poured onto 1.25 litres of ic~/water and 250 ml of 6N hydrochloric acid and stirred for 14 hours at RT. Extraction with diethyl ether and methylene chloride, drying with IVIgSC'r4 and concentration give 4-acetyl-2-chloro-pyridine; R~=0.5 (methylene chloride:methanol 9:1).
Stake 1.3: 16.2 g (104.2 mmol) of 4-acetyl-2-chloro-pyridine are stirred for 1 hour at 110°
with 116 ml of dimethyiformalnide diethylacetal. After cooling to 0°, filtering and drying at 60° under H'~, 3-dimethylamino-1-(2-chloro-~4-pyradyl)-2-propen-1-one is obtained;
1H-NI~R (dimethyl sulfoxide): 2.98 (3H,s), 3.2 (3H,s), 5.9 (lH,d}, 7.8 (3H,m), 8.5 (lH,d).
Example 2: Analogously to Example 1 there is obtained from 150 mg (0.7 mmol) of 3-dimethylamialo-l-(3-dhloro~4-pyridyl)-2-propen°1-one and 190 nag (0.71 mmol) of 3-tri-fluoromethyl-phenyl-guanidine nitrate N-(3-trifluoromethyl-phenyl)-4-(2-chloro-~pyridyl)..2_p~eamine; m.p. 168-171°, Rr--(1.67 (methylene chloride:methanol =
95:5).
The starting material is obtained in the following manner:
Stage 2.I: Analogously to Stage 1.1 there is obtained from 16.1 g (0.1 moI) of 3-trifluoro-methyl-aniline and 6.3 g (0.15 mol) of dyanamide 3-trifluoromethyl-phenyl-guanidine ~~a~;1H-(L?MSO): 7.6 (7H,m), 9.9 (lH,br,s).
Example 3: 0.8 g (2.41 mmol} of N-(3-trifluoromethyl-phenyl)-4-(N-oxido-4-pyridyl}_ dJ0 95!09851 ~ . (~ ~ ~~ PCT/~P941O3148 2-pyri~nidineamine i,S suspended in 40 ml of acetonitrile. 0.834 ml (6.65 mmol) of tri-methylsityl cyanide and 0.61I ml (6.665 mniol) of dimethylcarbamoyl chloride are added and the reaction mixtuau is stirred for 12 hours at 60°. After concentration under reduced pressure, crysta'Oisation is effected from tetrahydrofuranldiethyl ether. N-(3-trifluoro-methyl-phenyl~4-(2-cyano-4-pyridyl)-2-pyrimidineamine is obtained; m.p. I64-166°, Rf=0.40 (n-hexane:ethyl acetate = 1:1).
The starting material is obtained in the following manner:
Stage 3.I: 15.1 g (0.0567 mmol) mf.3-trifluoromethyl-phenyl-guanidine nitrate and 2.84 g (70.9 mmol) ~f sodium hydroxide are added to a suspension of 10 g (56."7 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-I-one [described in EP-A-0 233 461] in 300 ml of isopropanol. The reaction mixture is boiled under reflux for 24 hours.
After cooling, the product is isolated by filtration, washed with water and dried at 60°
under .: ~tt. N-(3-trifluoromethyl-phenyl)-4-pyridyl-2-pyrimidineamine is obtained; m.p. I97-198°, Rf-0.58 (ethyl acetate).
Stage 3.2: 10.57 g (33.4 mmct) of N-(3-triouoromethyl-phenyl)-4-pyridyl-2-pyrimidine-amine are suspended in 200 ~1 of methylene chloride, and 10.49 g (33.42 mmol, 55°b strength) of m-chlaroperbenzaic acid are added: After 2 hours, 200 ml of water are added.
The reaction product is isolated by filtration, washed with sodiuyn carbonate solution and water and, after drying, N-(3-triouoromethyl-ghenyl)-4-(N-oxido-4-pyridyl)-2-Pyruniidine-amine is obtained. More product is obtained by chromatography (methylene chloride:-methanol = 9:1) of the concentrated mother liqubr; Rf.---0.16 (methylene chloride:-methanol = 9:1).
Exam le 4: 100 mg (0.2,93 mmol) of N-(~-triouoromethyl-phenyl)~4--(2~cyano-4-pyridyl)-2-pyrimidineamine are stilled irg 15 ml of ethanol and 15 ml of 2N sodium hydroxide solution fox 3 hours at 60°. After acidifyiiag with 4N hydrochloric acid, N-(3-tsifluoro-methyl-phenyl)-4-(2-carboxy-4-pYridYl)-2'P~rimidineamine is obrained; m.p. 241-245°, FAB-MS: 361 (M*+H).

Wo 95/09851 PCT/EP94/03148 is isolated by filtration and washed with diethyl ether. Recrystallisation from tetrahydro-furan gives IV-(3-chloro-phenyl)-4-(2-cyano-4-PYridYl)-2-PYrimidineamine in the form of yellow crystals; m.p. 221-222°, R~.6 (hexane:ethyl acetate = 1:1).
The starting material is obtained in the following manner:
Stage 5.1: 2.8 g (12 mmol) of 3-chloro-phenyl-guanidine nitrate and 0.5 g (12 mmol) of sodium hydroxide are added to a suspension of 2.0 g (11.7 mmol) of 3-dimethylaanino-I-(4-pyridyl}-2-propen-I-one [described in EP-A-0 233 461] in 100 ml of isobutanol and the reaction mixture is boiled under refhax. for 5 hours. After cooling, the reaction product is isolated by filtration, washed with water and chromatographed (tetrahydrofuran). Afrter crystallisation (tetrahydrofuran/diethyl ether),1V-(3-chloro-phenyl)-.~.-pyridyl-2-PY~-midineamine is obtained; m.p. I67-I68°; Rf.--0:38 (methylene chloride:methanol = 9:I).
Stage 5.2: 1.0 g (3.54 mmol) of I~-(3-chloro-phenyl)-4.-(Pyridyl)-2-PYrimidineaunine ire suspended in 50 ml of methylene chloride, and 1.1 g of m-chloroperbenzoic acid (SO~k strength) are added. After stinxing for 18 hours at RT, the reaction mixture is filtered, the residue is dissolved in ethyl acetate/tetrahydrofuran (1:I) and extracted with 1T3 sodium hydroxide solution and water. The dried organic phase is concentrated and the residue is crystallised from diethyl ether/tetrahydrofa aax to give 1V-(3-chloro-phenyl)-4-(N-oxido-4-pyridyl)-2-pyrimidineamine; m.p. 268-270°, R~--0.6 (methylene chloride:methanol =
9:1).
Example 6: 50 mg (0.I6 mmol) of I~-(3-chloro-phenyl)-~-(2-cyano-4-pyrldyl)-2-pyri-midineamirle are stirred in 5 m1 of ethanol and 5 ml of 21~T sodium hydroxide solution for 2 hours at 60°. After cooling to 1ZT; the product is isolated by filtration and washed with ethanol/water (9:1) and dried at 50° under HV. The,sodium ,salt of 1V-(3-chloro-phenyl)-4-(2-carboxy-4-Pyridyl)-2-pyritnidineamine is obtained; m.p.>250~, Rt=<0.1 (methylene chloride:mettlanol = 9: ~).
Example 7: 50 mg (0. i 6 mmol) of Ie1-(3-chloro-phenyl)-4-(2-cya.no-4-pyridyl)-2-PYramid-ineamine are suspended in 2 ~nl of naethariol. 0.58 ml of hydrogen peroxide (30~
strength), 0.16 nal of 1-hexend and l l mg of sodium carbonate are added and the reaction rni3cture is stirred for l~ hours ~t RT. The product is isolated by filtration, washed (methanol:water = 1:1) and dried at 50° under HV. N-(3-chloro-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine is obtained in the form of a yellow powder; m.p.
245-247°, WO 95/~U9851 YCTfEP94/(13148 _z7-R~.-.--0.23 (n-hexane:ethyl acetate = 1:1).
Example g: 100 mg (0.293 mmol) of N-(3-trifiuoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 4 ml of methanol. 1.1 ml of hydrogen peroxide (30%p), 0.32 mLof 1-hexene and 22 mg of sodium carbonate are added and the reaction mixture.is stirred far 16 hours at IRT. The product is isolated by filtration and washed (methanol/water) to give N-(3-triftuoromethyl-phenyl)-4-(2-carbamayl-4-pyridyl}-2-pyri-midineamine; m.p. 240242°, FAB-iViS: 360 (M++I~.
Exa~:nple 9: lCn a manner analtDgaus to that described above and by simple conversion reaction,.e, known per se, of the products, the following compounds are prepared:
a) N-(3-chloro-phenyl)-4-(2-n-propylamino-4-pyradyl)-2-PYrimidineamiaae, b) N-(3-chlora-phenyl)-4-{2-amino-4-pyridyl)-2-Pyrimidineamine, c) N-(3-chloro-phenyl)-4-(2-hydro~cy-4-pYridYl)-2-PYrimidineamine and d) N-(3-chloro-ghenyi)-4-(2-methoxy-4-gyridyl)-2-pyrimidineamine.
Example 10: 300 mg (0.95 mmol) of N-(3-chloro-ghenyl)-4-(2-chloro~4--pyridyl)-2-pyri-midineamine (see Example 1); 5.3 ml of i,3-propanediol and 3.0 ml of dianethyl-farmamide are stirred for 43 hears at 105°. After concentxataon and repeated chromato-graphy (methylene chloride:methanol = 9g:2) N-(3-chloro-phenyl}-4-(2-dimethylamino-4-PY~dYI)-2-PY~i~eamine is obtained; ~.p. 176-178°, F~,B-ivlS: 326 (iVVI++I~.
Example l l: 14.5 g (5~.7 mmol) of 3-etho~cycarbonyl-phenyl-guanidine nitrate, 11.3 ~g :
(53.7 namol) ~f 3-dim~thylamino-l-{2-chloro-4-pyridyl)-2-propen-1-one and 2.4 g (60 mm~I) of sodium hydroxide are stirred in 150 ml ~f isobutanol far 14 hears at 110°.
After cooling, washing twice kith 100 Hn1 of ethanol each tune and crystallising (tetra-hydrofuran/ethanol), N-[3-ethoxycarbca~yl-phenyl-4-(2-chloro-4-pyridyl)-2-pyramidine-amine is obtained; m.p. 149-150°, FAB-IviS: 355 (iVl++~i).
Example 12: N-(3-isopropoxy~arbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-Pyrimidineamine Violated as a secondary product of Example 11; m.p. 130-131°, F~-1~5:
383 (ie~i++~).
. , . ., ,:.. ;:: ,, ..: . :: ; , :: .:. -, . ,;..::. ;:, ,,; , ~ : ,; . . .;
:, - ::
...... ,.: . ...., .. . .. , ; ..... .... .. . ... ......,. .. , .... ,... . .
.: .
,. .. ,:, .,. . ~ : . ~.. . :. . . :... .. . .. .. . .:. : .: , : . . ..: , ..
.. .. ,. ,. . .: : . . . .:
,.
> , : , . . :. . : .:; "~ ~ . :, , . .,::. .... . . ~~ :.::~ ; .. . ~: .-. ,:
. ;~: . ;. ,; ,,..:
.. ,.:.,:. . . . .. . . . .,,.. , , .,;..~ . . ::
.. .. ,.; ":,, ,... . ,.: ,. .. ..,. .: .,, ,.. . : : ...
yyy "," . .::,.. . . .... : ~. ...:. . .,:, , ".,.. .. . . "..,......, ~.~, .:. ~ . . . ~,.. ,..".. ,... . ....., ~6'O 95/0951 PC~'/EP94103148 Example 13: 9.4 g (26.5 mmol) of N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (see Example 11) and 50 ml of 2N sodium hydroxide solution are boiled under reflux in 300 ml of ethanol for 1 hour. After cooling to RT, the reaction mixture is acidified (4N hydrochloric acid} and the reaction product is isolated by filtra-tion. After drying at 50° under H°'l, lemon-yellow crystals of N-[3-carboxy-phenyl]-4-(2-chloro-4-gyridyl)-2-pyrimidineamine are obtained; m.p. 267-268°, FAB-MS: 327 (M++H).
Example 14: Analogously to Example 1 there is obtained from 100 mg (0.32 mmol) of N-[3-chloro-phenyl]-4-(2-chloro-4.-pyridyl)-2-pyrimidineamine and 3 ml (29.9 mmol) of n-1-butylamine N-[3-chloro-phenyl]-4-[2-(n-1-butylamino)-4-pyridyl]-2-pyrimidine-amine; m.p. 151-158°, FAB-MS: 354 (M++H).
Example 15: Tablets each comprising 20 mg of active ingredient, for example one of the compounds of formula x described in Examples 1-14, are prepared with the following composition in customary manner:
Composition:
active ingredient 20 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg anagnesiurn steasate 1 mg 145 mg Preparation: The active ingredient is mixed with a portion of the wheat starch, with the lactose and with the colloidal silica, and the mixture is forced through a sieve. A fiu°ther portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath, and the powder mixture is kneaded with the paste until a slightly plastic mass has been formed.
The plastic mass is pressed through a sieve of alsproximately 3 mm mesh size and dried, and the resulting dry granules are forced through a sieve again. The remainder of the wheat starch, the talc and the magnesium stearate are admixed and the mixture is wo gsio~ss~ ~ ~ ~ ~ ~ ~ ~ rc~rE~9aio3ias _Z9-compressed to fozan tablets each weighing 145 mg and having a breaking notch.
Example I6: Capsules each comprising 10 mg of active ingredient, for example one of the ' compounds of formula I described in Examples I-14, are prepared in customary manner as follows:
Ca__mPosition:
active ingredient 2500 mg talc ' 200 ang colloidal silica SO mg Pre,~aration: The active ingredient is intimately mixed with the talc and the colloidal silica, amd the mixture is forced thraugh a sieve of O;S mm mesh size and introduced in I I-mg portions into hard gelatin capsules of suitable size:
' ''~

Claims (16)

CLAIMS:

1. An N-phenyl-2-pyrimidineamine derivative of formula I

wherein R1 is a substituted cyclic radical, the cyclic radical being bonded to a ring carbon atom in each case and being selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, -C(=O)-OR3, -C(=O)-R4, -SO2-N(R5)-R6, -N(R7)-R8, -OR9 and fluorine-substituted lower alkyl, wherein R3, R4, R5, R6, R7, R8 and R9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and R2 is selected from halogen, cyano, carbamoyl, -C(=O)-OR10, -C(=O)-R11, -SO2-N(R12)-R13, -N(R14)-R15, -OR16 and fluorine-substituted lower alkyl, wherein R10, R11, R12, R13, R14, R15 and R16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino, or a salt of such a compound having at least one salt-forming group.

2. A compound or salt according to claim 1, wherein R1 is substituted pyridyl bonded to a ring carbon atom, the substituents of the above-mentioned pyridyl radical being selected from halogen, cyano, carbamoyl, -C(=O)-OR3, -N (R7) -R8, and -OR9, wherein R3, R7, R8 and R9 are each independently of the others hydrogen or lower alkyl; and R2 is selected from halogen, -C (=O) -OR10, wherein R10 is hydrogen or lower alkyl, and from fluorine-substituted lower alkyl.

3. A compound or salt according to claim 1, wherein R1 is a pyridyl radical substituted by halogen, cyano, carboxy, carbamoyl, hydroxy or by N-lower alkyl-amino, and R2 is halogen or fluorine-substituted lower alkyl.

4. A compound or salt according to claim 1, wherein R1 is a 4-pyridyl radical substituted in the 2-position with respect to the pyridine nitrogen by chlorine, cyano, carboxy, carbamoyl, hydroxy or by N-propyl-amino and R2 is chlorine or trifluoromethyl.

5. A compound or salt according to claim 1, wherein R1 is a 4-pyridyl radical substituted in the 2-position with respect to the pyridine nitrogen by chlorine, cyano, carboxy, carbamoyl, hydroxy, amino, N-propyl-amino, N,N-dimethylamino or by N-butyl-amino, and R2 is chlorine, trifluoromethyl, carboxy or lower alkoxycarbonyl.

6. A compound or salt according to claim 1, selected from N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine, N-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine, N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine, N-(3-trifluoromethyl-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-carboxy-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine, N-(3-trifluoromethyl-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-n-propylamino-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-amino-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-hydroxy-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-methoxy-4-pyridyl)-2-pyrimidineamine, N-(3-chloro-phenyl)-4-(2-dimethylamino-4-pyridyl)-2-pyrimidineamine, N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine, N-[3-isopropoxycarbonyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine, N-[3-carboxy-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine, N-[3-chloro-phenyl]-4-[2-(n-1-butylamino)-4-pyridyl]-2-pyrimidineamine, and pharmaceutically acceptable salts of such compounds having at least one salt-forming group.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group for treatment of a tumor in a warm-blooded animal.

8. A compound or salt of claim 7, wherein the warm-blooded animal is a human.

9. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group together with a pharmaceutical carrier.

10. A pharmaceutical composition for treatment of a tumor in a warm-blooded animal comprising a dose effective against the tumor of a compound of formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group together with a pharmaceutical carrier.

11. A pharmaceutical composition according to claim 10, wherein the warm-blooded animal is a human.

12. A use of a compound of formula I according to any one of claims 1 to 6 or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group in the preparation of a pharmaceutical composition for chemotherapy of a tumor.

13. A use according to claim 12, wherein the tumor is in a human.

14. A use of a compound of formula I according to any one of claims 1 to 6 or of a pharmaceutically acceptable salt of such a compound having at least one salt-forming group for chemotherapy of a tumor.

15. A use according to claim 14, wherein the tumor is in a human.

16. A process for the preparation of an N-phenyl-2-pyrimidineamine derivative of formula I

wherein R1 is a substituted cyclic radical, the cyclic radical being bonded to a ring carbon atom in each case and being selected from phenyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl and imidazolyl, and the substituents of the above-mentioned cyclic radical being selected from one or more of the groups halogen, cyano, carbamoyl, -C(=O)-OR3, -C(=O)-R4, -SO2-N(R5-R6, -N(R7)-R8, -OR9 and fluorine-substituted lower alkyl, wherein R3, R4, R5, R6, R7, R8 and R9 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino; and R2 is selected from halogen, cyano, carbamoyl, -C(=O)OR10, -C(=O)-R11, -SO2-N(R12-R13, -N(R14)-R15, -OR16 and fluorine-substituted lower alkyl, wherein R10, R11, R12, R13, R14, R15 and R16 are each independently of the others hydrogen or lower alkyl that is unsubstituted or substituted by mono- or di-lower alkylamino, or of a salt of such a compound having at least one salt-forming group, wherein a) a compound of formula II
wherein R17 and R18 are each independently of the other lower alkyl and R1 is as defined above, functional groups present in a compound of formula II, 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 III
wherein R2 is as defined above, functional groups present in a compound of formula III, with the exception of the guanidino 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 R1 is pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyridazinyl or imidazolyl, each of which is substituted by a radical of the formula -N(R7)-R8, and R2 has any one of the above-mentioned meanings, a compound of formula I wherein R1 is pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, pyri-dazinyl or imidazolyl, each of which is substituted by a leaving group, is reacted with an amine of formula HN(R7)R8 (IV), wherein the substituents are as defined above, functional groups present in a compound of formula IV, with the exception of the amino group participating in the reaction, being, if necessary, in protected form, and any protecting groups present are removed, or c) for the preparation of a compound of formula I wherein R1 is any one of the above-mentioned cyclic radicals substituted by carbamoyl or by a radical of the formula -C(=O)-OR3, wherein R3 is hydrogen, and R2 has any one of the above-mentioned meanings, a compound of formula I wherein R1 is any one of the above-mentioned cyclic radicals substituted by cyano is hydrolysed, or d) for the preparation of a compound of formula I wherein R1 is a pyridyl radical substit-uted by cyano or by -OR9, wherein R9 is hydrogen or lower alkyl, and R2 has any one of the above-mentioned meanings, in an N-oxido-pyridyl compound of formula VIII
wherein R21 is N-oxido-pyridyl bonded to a ring carbon atom and R2 has any one of the above-mentioned meanings, the N-oxido group is converted into a leaving group and the resulting leaving group is removed from the molecule by nucleophilic substitution in the ortho-position with respect to the pyridyl nitrogen using a nucleophile that introduces hydroxy, cyano or unsubstituted or halogen-substituted lower alkoxy, or e) for the preparation of a compound of formula I wherein R1 is a pyridyl radical substituted by chlorine and R2 has any one of the above-mentioned meanings, an N-oxido-pyridyl compound of formula VIII
wherein R21 is N-oxido-pyridyl bonded to a ring carbon atom and R2 has any one of the above-mentioned meanings, is reacted with a reagent that introduces chlorine in the ortho-position with respect to the N-oxido group, and, if desired, a compound of formula I obtained in accordance with any one of Processes a-e is converted into its salt, or a salt of a compound of formula I that is obtained is converted into the free compound.