PH26232A - Condensed pyrazole 3-oxo-propanenitrile derivatives - Google Patents

Description

Pee Co | G32 ’ ] “ . . . . . - . n : : v 26232 0 ’ Co CONDENSED PYRAZOLE 3-OXO-PROPAMENITRILE DERIVATIVES AND’

PROCESS FOR THEIR PREPARATION :

Co The present invention relates to condensed pyrazole to

Co : 3-oxo-propanenitrile derivatives, to a process .for their , 5 preparation and to pharmaceutical compositions containing .

EE. them. .

The compounds of the invention have the general }

Ee formula (I)

Pe 2 1 . - . Lo 7

Co Pe . ~ 7 oo _ cocH” : REE 3 ; 7 ~~ No

Dob 6 X : : {ol R 5 : Co . | 3 oo : . * “ - . - : 10 wherein ’ Co ) i . X represents: : CT oo

Po a) a ~CH- group wherein R, is hydrogen, C,-Cy4 alkyl or a do ; R, : Co :

Po R » % ; : -N group wherein each of R’ and R" independently ‘is { . Ngo } To . . : ; 1 . = . . . . ; BE : C,-C, alkyl or R’ and R", taken together with the nitrogen - atom to which they are linked, form a heterocyclic ring - .

J © which is selected from N-pyrrolidinyl, N-piperazinyl, - Co hexahydroazepin-1-yl, thiomorpholino, morpholino and : piperidino and which is unsubstituted or substituted by } Cc,-C, alkyl; or : - 20 b) an oxygen atom or a -S(O) - group, wherein n is zero, 1 : i : or 2; . .

Ry represents C, -C, alkyl, pyridyl or phenyl, the phenyl : being unsubstituted or substituted by one or two substituents chosen independently from halogen,

. y \ hE 0

C250 - oo 26232 + 0 ! _ 2 a _- . trifluoromethyl, c, -C alkyl, C, -C, alkoxy, nitro, amino, formylamino and C,-C, alkanoylamino; each of R, and R, is independently: Co : a’) hydrogen, halogen , C,-C alkyl or trifluoromethyl; b’) hydroxy, C,-C; alkoxy or C, or C, alkenyloxy; : ¢') nitro, amino, formylamino ot C,-C, alkanoylamino; oo . R'. | . } . . / : : " dr) di(c, -C alkyl)amino or a -CH,N wherein rR’ and R"

Ngo are as defined above; . e’) CH,OH, CHO, COOH or C,-C, alkoxycarbonyl; £') a ~CONRCH-COCR, group wherein R, is hydrogen or C, -Cq - R,_ ’ \ alkyl and R_ is hydrogen, phenyl or the side-chain of an.. . a—aminoacid; ! g') a -NHCOCH-NH, group, wherein R_ is as defined above;

R_ 0 OR 0 _~ . : h', a -CH,P’ , ‘a -CH,OCO(CH,) COOR or a -NHCO(CH, ), A COOR — ) . oR : group, wherein n is as define? above and R is hydrogen or : c,-C, alkyl; : . : : k') a -CH=N-OR' group wherein R’, is hydrogen or a -CH, COOH

Co © group; i’) a —-CH=N-NH-R', group wherein R’, is hydrogen, -CH, CH, OH,

Cy ~~ 20 c, or Cy alkoxycarbonyl or a -(CH,) -R', group wherein p is ( . 1 or 2 and R’, is COOH or C,-C, alkoxycarbonyl; wt : LE : : : J 1’) a —CH=N-N=CH-N group wherein R’ and R" are as =

Cf © Dee

Cd i : defined above; of } 1 vo : ‘R! !

B ; m') a cin” group wherein R’ and R" are ‘as defined above; or in Ng oR g 25 n') a C,-C5 alkoxycarbonyl group substituted by a Na group,

Co wherein R' and R'" are as defined above; and i . ) } . oor oe a R | AER

Te oo hogy . C3 4g) p

Q represents hydrogen, carboxy, c,-¢, alkoxycarbonyl or a -CON group wherein R, represents hydrogen or €¢, -C,, h ;

Ry } ~ ' . alkyl and Rj represents C, -C,, alkyl, a -CH-COOR group .

R, wherein R and R_ are as defined above or a -(A), -R, group wherein m is zero or 1, A is a C -C, alkylene chain and R, ’ . 18 . a") c,-C, cycloalkyl; b") pyridyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, Cc, -C, alkyl and C, -C, alkoxy; : c") phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, CF,, C -C; oo alkyl, C,-Cs alkoxy, amino, nitro, formylamino, C,-C,

I alkanoylamino, di(C, -C, alkyl)amino, hydroxy, CH,OH, COOH, = : c,-¢, alkoxycarbonyl, formyloxy, c,-C, alkanoyloxy and a i R' : : _cu, vn" group wherein R' ,and R" are as defined above;

Ngo . a") 2-thienyl, 2-furyl or 1-(C, -C, alkyl)-pyrrol-2-yl; or e") a heterocyclic ring which is selected from 2-pyrimidyl,

Lo 2-thiazolyl and 3-isoxazolyl and which is unsubstituted or - substituted by C,-C alkyl; } : ’ and the pharmaceutically acceptable salts thereof. : oo © ihe present invention includes within ths scope all !

Co possible isomers, stereoisomers and optical ‘isomers and ’

FL their mixtures, and the metabolites and the mdtabolic i 25 precursors of bioprecursors of the ‘compounds (ff formula (1). 1 It has be to be noticed that the compounds off} formula (1) : may be represented also by a tautomeric struqture, namely the enol structure of formula (Ia) ) ; , ho ! lero ORIGIN. A ro ND

E Ce oo RE ) Ooze . 20 de pe . . wherein ‘ Co

Xx, Ry» R,» Ry and Q are as defined above.

However, the compounds of formula (la), which fall within the scope of the present invention tco, are described in the present specification as compounds of formula (1).

A halogen atom is preferably chlorine or fluorine.

The alkyl, alkylene, alkanoyloxy, alkoxy and alkanoylamino groups may be branched or straight chain groups.

A €, C50 alkyl group is preferably a €,Cq alkyl group. 1% A C, Ce alkyl group 1S, €.8., methyl, ethyl, propyl, iso- propyl, butyl or tert.butyl, more preferably methyl, ethyl , or tert.butyl. : oo

A C, or Cs alkenyloxy group is preferably allyloxy.

A C, Ce alkoxy group is, e.g., methoxy, ethoxy, propoxy, i 15 isopropoxy, butoxy or tert.butoxy, preferably it is meth- , ory, ethoxy or propoxy .

A C.—Cqg cycloalkyl group is preferably cyclopentyl or . cyclohexyl. } :

A C,Cq alkanoylamino group is preferably acetylamino or

To 20 propionylamino. ; . A C,=Csq alkanoyloxy group is preferably acetoxy or propionyoxy. - ! oo

A ¢5C, alkoxycarbonyl group 1s preferably a C,~Cq alkoxy- carbonyl, group, in particular a C, or Cy alkoxycarbonyl one. . ! Hh }

A C)-Celptylene chain is preferably a C,7 Cs alkylene chain, such as a ~CH_-, -(CH.) 5= -(CH,) =» -CH-or .-CH- chain. . : ni

CH 4 Cas . : i i « oo \ GAD ORIGINAY J a | Ooms oo oo CL 26 239 aw : R— N—N | :

CX c=—C¢ | oo ~~ L No (1a - R, .

R. . 3 - oo

* oo Deegy 269232 - 5 ~

A di(cC, -C, alkyl)amino is preferably a di(c, -C, alkyl)amino group, in particular a di(C, or C, alkyl)amino one. In a -CH-COOR group, wherein R is as defined above and

R, . , . R_, is as defined above except hydrogen, the asymmetric - - oo carbon atom to which -R_ and -COOR are linked may have either the R or S configuration. The side-chain of an i a—aminoacid is specifically the residue obtained from an «—aminoacid by removing the amino and the carboxy groups . together with the a-carbon atom to which they are linked.

The side-chain of an e-aminoacid as defined above is preferably the side-chain deriving from a naturally occurring aminoacid.

Examples of such aminoacids are alanine, valine, : leucine, iscleucine, phenylalanine, proline, hydroxyproline, serine, threonine, cysteine, cystine, methionine, tryptophan, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginins, histidine and phenylserine.

LL Preferred examples of said chains of the above mentioned aminoacids are ~CH, (deriving from alanine), : 20 -CH,=CH(CH, ), (deriving from leucine) and -CH,-C.H, (deriving from phenylalanine).

Cs oy Examples of pharmaceutically acceptable salts are

A either those with inorganic bases such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases such as lysine, arginine, N-methyl-glutamine, triethylamine, ; triethanolamine, dibenzylamine, methylbenzylamine, oo i di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine,

a A)

Co | Leese

SE | | 26232 : ] _ 6 - “ .

N,N-diethylaminoethylamine, N-ethylmorpholine, g-phenethylanine, N-benzyl-g-phenethylamine, N-benzyl-N,N- dimethylamine and the other acceptable organic amines, as : well as the salts with inorganic acids, e.g. hydrochloric,

S “nitric, hydrobromic and sulphuric acids and with organic } acids, e.g. citric, tartaric, maleic, malic, fumaric, ; methanesulphonic and ethanesulphonic acids. Preferred salts of the compounds of formula (I) are the sodium and the : potassium salts thereof.

As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors {otherwise known as pro-drugs) of the compounds of formula (1), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon : 15 administration to 2 human being are converted directly or indirectly in vivo into a compound of formula (I). : preferred compounds of the invention are the compounds of formula (I), wherein X is: a"') a -CH-group wherein R', is hydrogen, C,-C, alkyl or a . Ry

R'’’ : 7 group wherein each of gr’ and R'' independently

NREY : | : is .C, or c, alkyl or R''' and r'7, taken together with the nitrogen atom to which they are linked, form a heterocyclic oo, ring which is selected from N-pyrrolidinyl, N-piperazinyl, ! i morpholino and piperidino and which is unsubstituted or og | substituted by methyl; or b'’') oxygen or a -s(0)_- group, l wherein n is as defined above; : i R, represents unsubstituted pyridyl; or phenyl unsubstituted i" or substituted by one or two substituents chosen independently from halogen, trifluoromethyl, C,-Cq alkyl, ‘30 ~ C,-Cq alkoxy, nitro, amino and C,-C, alkanoylamino; vo R, and R, each independently is y a®) hydrogen, halogen, hydroxy, COOH, CHO, CH,OH, CFy Cy=Cy i . alkoxycarbonyl, nitro, amino, C.-C, alkyl, C.-C, alkoxy Or ! \

7 YD)

SE oo | C922 . : 3 7 a oC . | } ~ i €) 2, Do ’ ~ RY! ’ 2623 ) oo : a cin group wherein R''' and RR" are as defined -above; oo be) a ~CONHGH-COOR 4 group wherein Ry is hydrogen or C,-Cq alkyl 6 . c and R, is hydrogen, phenyl or the side-chain of an™ -zmino- acid as defined above; c®) a ~HCOgH-H, group, wherein R, is as defined above; c de®) a - C H_. R - wha re i ) CH,0 o(c POR q ore NHCO(CH,,), COOR group, wherein n and Ry are as defined above; e®) a -CH=N-OR, group, wherein RJ is hydrogen or a -CH COOH group;

R''! ’ f°) a ~=ch-n_ Lv group wherein R''' and RY are as defined

R . above;

AR g°) a C,-C, alkoxycarbonyl group substituted by a Nv : group, wherein R''' and rt are as defined above; “15 Q represents hydrogen, C,-Cg alkoxycarbonyl or a -CONR' R’, group wherein R’, is hydrogen or c,-¢C, alkyl and R’, is

Cc, -C, alkyl, a CH-COOR, group wherein R_ is hydrogen - . R_ " : . . or C,-C, alkyl and R_ is as defined above, or a-(A’')_-R’, group wherein m is zero or 1, A’ isi a c, -C, 50 alkylene chain and R', is: ~ : : f a’; unsubstitutsd pyridyl; cr phenyl unsubstituted. or substituted by one or two substituents chosen independently . : 5 . from halogen, CF,, C ,-C, alkyl, C -C, alkoxy, nityl, CH, OH,

COOH, di-(C,-C, alkyl)amino, hydroxy, formylo:ty, a} -c, alkanoyloxy and a f )- Y ; vd . J -CH,N group wherein R’’'’ and R'' are as defined above:

Ngtv Ll

R ! . | \ i ee Ce —" . - i ‘ . = . A, , an . .

Bl 0 VD 0 : . eo : : =" Croge

Co | | 26 . - 8 - Bh 2392 be p'?) 2-thienyl or 2-furyl; or ’ c¢') a heterocyclic ring which is selected from 2-thiazolyl or 3-isoxazolyl and which is unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the : . compounds of formula (I) wherein X is oxygen, sulphur or a -CH- group . R", ’ Pa . ’ wherein R'" is hydrogen, methyl or a -N group a SNR wherein R''' and RY are as defined above; ], represents phenyl unsubstituted or substituted by 2 substi- tuent selected from nitro, halogen, CF 4» C, Ca alkyl and C, C4 alkoxy; each of R, and R independently is

Cod - . 20°) hydrogen, talcgen, COOH, CHO, CH, OH, C,-Cq alkoxycarbonyl, CF, nitro, amino, hydroxy, C.1-C4 alkyl, C Cy alkoxy, or a

Qt . : . pd : iv . . cH -N o. e i 1 . fine

CH, Srv group wherein R and R are as -defined above; : : b°°) a ~CONHEH-COOR 4 grote: wherein R'y 1s hydrogen or C,=C4 c } . ’ alkyl and R is as defined above; ‘ : c®°) a TNHCOTH-H, group wherein BR, is as defined above! oo c Co dee - CH COOR' - H ) ; ei .

Co 20 } a CH ,0CO( 2h 00 4 °F a NHCO(C 5) ,COOR d group, wherein n and R' 6 are as defined above; . : ) d R'"! . . . ~~ iv - : e®9) a -N=CH-N Lv group, wherein R'"' and R are as defined 1

NR above; tr! : feo) a C,=Cy alkoxyearoonyi group substituted by a + group, wherein R''' and R are as defined above; ei em es aan ORIGu.

N a0 30 cr ° . : A 7 © - - . —_

C7 20%,

CL 26232 = Cg. J -

Q represents hydrogen, c, or c, alkoxycarbonyl or a - : : ~CONR" R", group wherein R" is hydrogen or C -C, alkyl and 3 R", is C,-C, alkyl, a -CH-COOR, group wherein R, . ! R_ \ and R_ are as defined above or a -(CH,) -R", group in which p is zero, 1 or 2 and R", ‘is: . - co a’) unsubstituted pyridyl; or phenyl unsubstituted or : oo substituted by one or two substituents chosen independently from nitro, halogen, CF,, c, -C, alkyl, c, -C, alkoxy, CH,OH, cooH, di(cC, or C, alkyl) amino, hydroxy, formyloxy, C,-C,

R’’* | . - alkanoyloxy and a can” group wherein R’'’' and R'Y are

N gLv : as defined above; b¥) 2-thienyl or 2-furyl; or

Co c') a heterocyclic ring which is selected from 2-thiazolyl or 3-isoxazolyl and which is unsubstituted or substituted by methyl; and the pharmaceutically acceptable salts thereof.

Examples of particularly preferred compounds of the "invention are: : . 2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-clpyrazol-3-yl)- oC 3-oxo-N-pheayl-propanamide; : 20 .5-¢yano-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno(l,2-cIpyrazol- 3-yl)-3-oxo-N-phenyl-propanamide; - : . 2—cyano-N-(4-fluoro-phenyl)-3—[L— ( 4-fluoro-phenyl)-1,4-dihydro-

Co ’ indeno (1, 2-clpyrazol-3-yl]-3-oxo-propanamide; Co : 2-cyano-N-(4-fludro-phenyl)-3-(1,4-dinydro-7-methyl-1-phenyl- : indenol1,2-clpyrgzol-3-yl)-3-oxo-propanamide; CL . ) 4, . : : . N-(3-chloro-pherjfl)-2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydra= indeno[1,2-dlpytdazol=3-yl)-3-oxo-propanamide; : : 2 cyano-N-(4-fljoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno ,2-c-Jpyrazol-3-yl)-3-oxo-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno i [1,2-cIpyrazol-3-yl)-3-oxo-propanamide; : . ) \

BAD ORIGINAL J

’ ” Co. .- f——- - . - - . fn co Lo oo)

Cos . Co Dos 26232 - = 10 - JF CL »—cyano-3-(1,4-dinydro-4-methyl-l-phenyl-indenoll,2-clpyrazol- : 3-yl)-3-oxo-N-phenyl-propanamide; : > —cyano-3-(1,4-dinydro-7-methyl-1-phenyl-indeno(l, 2-c]oyrazol- 3-y1)-3-oxo-N-phenyl-propanamide; ] BN 5 © [—cyano-3-(1,4-dinydro-L-phenyl-indenoll,2-cTpyrazol-3-y1)- ) 3-oxo-propanoyl]-glycine methyl ester; | : - N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno fl, 2-clpyrazol-3-y1)- '3_oxo-propanoyll-glycine; a 7 yano-3-oxo-3-(1-phenyl-1H-benzothieno [3,2] pyrazol-3-y1)-

N-phenyl-propanamide; i »—cyano-N-(4-Fluoro-phenyl)-3-0x0-3-(1-phenyl-1H-benzothisnc 3,2-clpyrazol-3-yl -propanamide; > cyano N-(4-fLuoro-phenyl)-3-[1-(4-fluoro-phenyl}-1Hi-benzothieno [3,2-clpyrazol-3-yl}-3-oxo-propanamide; : > cyano_ti-(4-fluoro-phenyl)-3-(7-fluoro-1, 4-dihydro-i-phenyt- . indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; : 3 (7-amino_1,4-dinydro-1-phenyl-indeno[l,2-clpyrazol-3-yl)-2- ) cyano-3-oxo-N-phenyl-propanamide; - re gano-3-(5-e thoxycarbony 1, d-dihydro-1-phenyl-indeno[1, 2-] . 20 byrazol-3-yl)-3-oxo-i-phenyl-propanamide; . : - .

M_[L, 4-dinydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacezyl)-indenc ‘ (1,2-c]pyrazol-7-yl}carbonyl-glycine methyl ester; > eyano3-(7-sthoxalylanino-1,4-dihydro-1-phenyl-indenoll,2=c] . oyrazol-3-yl)-3-oxo-N-phenyl-propanamide; . 2% eyanooa-(1, 4-dinydro- 7-1, N-dine thyLaminos thoxyearoony L-L-pnenyL- : indenofl,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; i 3 (7-tert. butyl-1,4-dihydro-1-phenyl-indero (1,2) pyrazol-3-yl)-2-cyano= _N-(4-fluoro-phenyl ) ~3-oxo-propanamice; »—cyanoN-(4-fluoro-phenyl) -3-(1,4-dihydro-1-phenyl-7-trifluorame thyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; . - —

~ So So). Po

EE a 232 ! - . ] E LL. 269232 1 ’ ~- : and the pharmaceutically acceptable salts thereof, in

Co } particular the sodium and the potassium salts. hn The compounds of formula (I) and the salts thereof can be prepared by a process comprising: . 5 a) reacting a compound of formula (II) [ ! : : R——MN—N : 2 Y (II) . 2 ’ . X

N " : | 3

Co wherein :

Co Xx, R, R, and Ry are as defined above and Y is carboxy . i. or a reactive derivative of a carboxy group, with a com-~ pound of formula (III) Toa i ! ’ . : } : CH (11m) ; 2 : : TT Lo i wherein : oo

Q' is as Q defined above, except carboxy; so aebtaining a - 4 . . . i compound of formula (1), wherein Q is as defined above except carboxy; or oo oo) . yo)

Co oo Clos . » ra 26 De . RE

I. oo “3d b) reacting a compound of formula (IV) - : —N ——————N

RJ

(Iv)

COCH, CN

ANN 2

Ry \ \

X

_R 3 wherein ’ | oo { : Xx, R,» R, and Ry are as defined above, with a compound formula (V)

R,-N=C=0 (V) - wherein :

Ry is as defined above, SO obtaining a compound of , formula : (I) wherein Q is a -CONHR, group, wherein Ry is as defined oo { : : : above; or ; 2 : : ! . c) reacting a compound of formula (VI) “ . ' i . . i : R —— N ————1 : i 1 i bi : : ' AN . . = COCH

IANS iE ~~, . (VI) 2 Eo

X i \

R : 3

CL omar gAD OR!

. ; Ry Rh Ct ’ } G23? . } ; - : LL. i ’ - . — 13 - 2 6 23 9 Ch wherein . - } x, R R, and R, are .as defined above and Z is a react- : ive derivative of a carboxy group, with a compound of for- mula (VII) ) - - | LF ’ oo E - See : . . a .

HN :

TT | (VII) : b : wherein : } : o . ! R, and R are as defined above, so obtaining 2 compound of

T formula (I) wherein j Ra = i Q is a —-CON". group, wherein R_ and Ry are as defined : fo NR a f . b . above; or

Co d) hydrolysing a compound of formula (1), wherein Q is a a €,-C, alkoxycarbonyl or “oN group in which R, . i [H-coon :

Lo : R } c and R, are as defined above and R is C,-Cq alkyl, so’ as to : ~ obtain the corresponding compound of formula (I), wherein l | A,

Q is a free carboxy group or a -CON group; in \ CH-COOH . : R c . . - ’ . : : 'BAD ORIGINAL Pp) . . ’ } - TTT

So - . . : oo ] oo :

‘ oo! be (oo ©5,001 3anoQe pue D,0 3INOAE usar °Q st © BUulAdeA salnajeJadwsy eB 1® ‘sprwewJoJyTAy3I WIP ‘ouEX0IP . oo suey; 2AXOU3BWIP-2 ‘1 se yons JUBATOS 1d8UT ue uf ‘opTx04Id E ‘snoTTeUy ‘epixoinqri wntssejod ‘apTIPAY wNIpos se fons; aseq Buouais ®B JO souasaad ayy ut ‘grduexs a0} ano POTLIEE aq Kew (III) EinwIoj JO punoduwod © pue dnoa8 AxoqJed oz ® JO SAJ3IBATISP 3ATIOESM e sT A utsJaum (II) BINWIOJ punodwcd © Usemisq UOT3IOEaI SUL “D005 3INOCAQE pu®B 5,0 Co 3noqay usamyaq RiTAaea sanyesadwsly e 21® op wewI0 I TAU SWTP - se yons 3USATOS 3J3Ul UE ut ‘uTWETAY23 TI se yons a5%Q

Be JO souassad sya ut « a3euoydsoydoueAd TAuyzarp s2 Ydns 1 ~qusBe Buisuspuod ® jo souassaad aul Ul ts17dwexe J03F ‘ano psi1aJded 2Q Aew (III) ernuaoj jo punoduod’ ® pue Axogied ST

A utagaum (II) ernwJoj Jo punodwod ® ussmi aq uotaoead aul . .dnodB TAUOQJIEBDAXOMTE €,-%, ® A1qeas sad ‘dnoa8 1Auo0QuEBIAXOATE Ln Cy ge Jo ‘dnca3 ot.

TAUOQIEBOOJIOTYD a AiqeJsjsid ‘1 dnoad 1Aucqled0TEU © tg1dwexa J0OJF ‘st 31 ‘dnoaB AxoQJed ® IO SATIBATISP anl3oEB8d B ST A uaum “SJ3WOST 218uts 8uj oaut ‘(1) elnWIOF JO punodwod © B JO SJ3WOST 0 sanaxtw B Butjegedss ‘psaissp JT ‘10/ PU® | : ‘punodwod $313 E oj3uTl 37ES ® BUT3JI2AUOD ‘psaisap JT ‘10/pue g © ates s1qe3dsooE A{Teor3nsoswreud ® o3ut (I) e(nwioy Jo ’ punodwoo B BUT3JI8AUCD ‘paatsep JT ‘JO/PUE (1) elnwiIojy jo punodwod Jsyjoue o3ul (1) Binwaojy 3o punodwod ® BUTIISAUCD . ‘psiisep JT 'pue !@n0Qe PSUIISP se sJe “uy pue Fu yorum : ot : — pT - oo gAD ORIGINAL 0 tbe 2% 270C Co I to “Ce CL i oo IRA Copan, 26232 . © —- 15 -¢ ‘ -

The reaction between a compound of formula (IV) and a compound of formula (v) may be carried out, for example, : in the presence of a base such as sodium hydride or triethylamine, in an inert solvent such as toluene,

S "dioxane, tetrahydrofuran, dimethylformamide, at a tempera- ture varying between about 0°C and about 100°C. "In the compounds of formula (Vi), Zz is, for example, a halocarbonyl group, preferably a chlorocarbonyl group, or ’ a €,-C, alkoxycarbonyl group, preferably a C,-Cy alkoxycar- bonyl group. oo The reaction between a cempound of formula (VI), wherein i Zz is a halocarbonyl group, and a compound of formula (VII) ’ “may be carried out, for example, in an inert solvent such ; as dichloroethane ,dioxane, dimethylformamide, in the pre- } 15 sence of pyridine or triethylamine as acid acceptor, at a : temperature varying be twesn about 0°C and about 100°C. oo

The reaction between ~ompound of formula (VI), wherein 2 . ” (is C,-Cg alkyl ester, and a compound of formula (VII) nay be carried out, for example, by heating at the reflux oo © 20 temperature in an aromatic hydrocarbon such as toluene or ; xylene, preferably distilling off slowly together with the |! Ji diluent the free CC alkyl alcohol generated during the . reaction. ‘ . , hh

Hydrolysis of a compound of formula (1), wherein Q is 5 : : I

Ra ; a C,-C, alkoxycarbonyl group or a ~CON in which i ;

CH-COOR - k a . c | \ t : ; ee . aap ORIGINAL J i oo - | ’ :

CL ) 202 => - | | 26232 - : 16 - | ST .

R, and R_ are as defined above and R is C,-C_ alkyl, according to process - variant d) above, may be performed by selective basic hydrolysis, using e.g. aqueous sodium or potassium hydroxide in a solvent such as dioxane,ethancl or dimethylformamide at a temperature varying be tween about } 0°C and about 80°C. : :

A compound of formula (I) may be converted, as stated : above, into another compound of formula (I) by known me thods; for example, in a compound of formula (I) a nitro group may be converted into an amino group by treat- ment, for example, with stannous chloride in concentrated = hydrochloric acid, using, if necessary, an organic cosolvent such as i acetic acid, dioxane, tetrahydrofuran at a temperature varying between room temperature and about 100°C. Furthermore, for example, an amino 1S group may be converted into a formylamino or a C,=Cq alkanoylamino group, } for exarple by reacting with formic acid or with the suitable C,Cq alkarovyl . E anhydride without ary solvent ‘or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine, at a temperature varying between 0°C ard about 100°C. Furthermore, for example, a -tH, or a -CH=N-TH,, group may be ’ converted into a Nec, or into a -CH=C-N=CH-N Zn group, wherein R' and R" are as defined above, rescectively, by reaction with a guatemary nitrogen compound of formula (Vila) o : R!

Ni =e at) (Vila) , RY wherein R' and R" are as defined above, in an organic inert solvent, such as dioxane, tetrahydrofuran, chloroform, dichloromethane, 1,2-dichlcrecethane, \

BAD ORIGINAL d

- : ‘ Coz a 26232 benzene or toluene, in the presence of a tertiary amine, such as triechyl- amine, at a temperature varying between about -20°C and the room terperature, . : according to the experimental procedure described in British patent specifi- cation 1293590 and in U.S. patent a, 047,432. Furthermore, for example, an amino group may be converted irito a HOCH, group, wherein R. is as oe defined above, by reaction with a suitably protected aminoacid of forrula

HOOC-GH-1TAY, wherein R, is as defined above and W is a protective group, such as a benzyloxycarbonyl or a tert-butoxycarboryl group, in the presence of : dicyclohexylcarbodiimide, as condensing agent, in inert organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a temperature varying between about 0°C and the room temperature, so as to obtain the protected ~NHCOCHNH group, wherein R, and VW are as defined above, which in tum is deprotes Sa : using well known methods in organic chemistry. Furthermore, for exarple, a : carboxy group may be converted into a ~CONHGHOOCH group, wherein R_ is as defined above; by reaction with an esterified od -aminoacid of formula oo H-gH-coom, wherein R is CC, alkyl and R_ is as defined above, in the -. presence of dicyclohexylcarbodiinide as condensing agent, in an inert : ) organic solvent such as dioxane, tetrahydrofuran or acetonitrile, at a : temperature varying between about 0°C and the roam temperature, so as to . 290 obtain the esterified ~CCEH-COR group, wherein R, and R are as defined

So - above, which in turn is, hydrolized to yield the -CONHCH-COCH group, wherein

R, is 25 defined awove, following methods well known fe the art, for example, those described for the processquar ant d) above. Furthermore, for exarple, an alkoxycarbonyl aro, a ~cH,P on group, a ~CH ,0C0(CH,,) COOR group or a in . 25 ~NHCO(CH,),_COOR group! 'wherein n is as defined above and R is C,C, alkyl, may be converted inte the corresponding -CCCH, HB ~CH,0CO(CH,) Cock : i

Co | (24D ORIGiNAL 9

. . - CN 3 - ’ ‘ . : | 202g : - 18 - | 269283 9 i and ~NHCO(CH,) COOH group, respectively, wherein n is as : defined above, by treatment with aqueous sodium or potas- sium hydroxide in a solvent such as dioxane, methanol, ’ ethanol or dimethylformamide, at a temperature varying between about o°C and about 80°C.

The optional esterification of a free carboxy group as well as the optional conversion of a carboxylic ester into the free carboxy derivative may be carried out according to known methods in organic chemistry.

Process-variants b) and c¢) described above may be considered as examples of conversion of a compound of formula (I) into another compound of formula (I) too. Also the opticnal salification of a compound of fortula (1) as well as the conversion of a salt into the free coamound and the separation of'a p mixture of isomers into the single isomers may te carried out by conventicnzal 1s methods. For exarple, the separation of optical isomers may be carried out ’ by salification with an optically active vase or acid and by subsequent

Co fractional crystallization of the diasterecisameric salts, followed by : reccvering of the optically active isomeric acids or, respectively, bases.

The compounds of formula (11), in which Y is a ¢,-C, alkoxy- carbonyl group and X, being as defined above, is

JE 80 ORIGINAL 9 . | :

oo CD . - <Q UI22 ‘ : : oT 19 - | } . - . oo oo - 26232 - ~ 7s . : other than a __CH-N group, wherein R' and R" are as : Re defined above, may be prepared, for example, by reacting a compound of formula (VIII) BN } : 0 3 COCOOR 6

R. ~ 2 } (VIII)

R i 3 i : : 5 wherein | . ” ] . : ) R, and Rg are as defined above, E is as X defined above

Po . ~R! : except a _=cnn group, wherein R' and R" are as ° rR" . . defined above,and R, is C -C. alkyl, preferably c -C, alkyl, :

L with a compound of formula (IX) : oo

Ch Co i 10 : ~NHNH IX : i ) R, INH, (IX) . wherein

Ry is as defined above. ! ! ’ ’

Po coo. BAD ORIGINAL o))

CL : Co Ch Clvge . | Co

I wo 26232 . The reaction between a compound of . formula (VIII) and a compound of formula (IX) may be carried out, for example, in a solvent such as c,-Cq alkyl alcohol, dioxane, tetra- hydrofuran, dimethylformamide, acetic acid, at a tempera

S ture varying between about 0°C and about 150°C. )

The compounds of formula (11), in which Y is a €,-C, . a alkoxycarbonyl group and X is a ~ cin” groun, wherein

NR"

R' and R" are as defined above, may pe prepared, for example, DY reacting a compound of formula (II), wherein X : is CH, with an N-halosuccinimide, preferably

N-bromosuccinimide, in an inert solvent such as carbon : tetrachloride or chloroform, at a temperature varying from about 20°C to the reflux temperature, SO obtaining the respective intermediate haloderivative of formula (11) in which X is } 15 a — CH-Halo group, in particular a — CHBr group, which i R' in turn is reacted with a compound of formula hn , . co . NR" wherein R' ‘and R' are as defined above, in a solvent such . as dimethyl formamide, acetone, 2-putanone, in the presence of sodium carbonate or potassium carbonare, at a tempera-’ : ture varying between about 0°C and spout! 100°C. }

The compounds of formula (11), wherein ¥ is carboxy may be prepared, for example, DY nydrolysis of {the corresponding compounds of formula (11) wherein Y is c,-¢, alkoxycarbonyl, according to standard methods well known in the art, for ~~ : . : leno ORIGINAL J

. : :

SE So | Loz example, by basic hydrolysis, carried out e.g. by treatment with sodium or potassium hydroxide in a solvent such as water, €."% alkyl alcohol, dioxane, dime thylformamide and their mixtures, at a temperature varying between about 0°C and about 80°C.

The compounds of formula (II), wherein Y is halocarbonyl, pre- ferably chlorocarbonyl, may be prepared, for example, by reac- tion of the corresponding compound of formula (II), wherein

Y is carboxy, with the suitable acid halide, for example oxalyl 1c chlcride, thionyl chlcride, PCL, PBr,, in an inert solvent ’ such as ether, benzene, dichloroethane, dioxane or without any solvent, at a temperature varying between about 0°C and about 100°C. : The compounds of formula (III) are, in some cases, commer- cially available products, or may be prepared by methods well . known in the art. For example a compound of formula . ’ N : SR : . , . } (Z1II1), Wherein Q is a TNR group, wherein R, and R_ . : b : are as defined above, may be prepared by reacting cyano- } acetic acid with a compound of formula (VII) in the presence . - 20 of a condensing agent such as dicyclohexylcarbodiimide, 1,1- -carbanyldiimidazole and the like, in an inert organic solvent : . such as benzene, dioxane, acetonitrile, at a temperature vary- ing between about 0°C and about 50°C. oo 0 The compounds of formula (IV) are compounds. of general formula } 25 (1), wherein Q is hydrogen and may be obtained by process a) above, for example, by reacting a compound of formula (11),

So soonan §)

Cy = . - ’ 20237 } - 22 a? ’ ‘ : wherein ¥Y is c,-C, alkoxycarbonyl, with acetonitrile, in the presence of a strong base €.§8. sodium hydride, potassium tert.butoxide, in an inert organic solvent such as benzene, dioxane, tetrahydrofuran, at a temperature varying between about 0°C and about 100°C.

The compounds of formula (VI),wherein Z is €,-C, alkoxy- carbonyl, are compounds of general formula (I) wherein Q is

C,-C, alkoxycarbonyl and may be obtained by process a) above, for example, by reacting a compound of formula (II) with a compound cf formula (X) co i

HC (X) ~~ COOR., wherein . ) R, is C.-C alkyl, using the same experimental conditions . as described above for the reaction between a compound of formula (II) and a compound of formula (III). oo ] The compounds of formula (VI), wherein Z is halocarbonyl, may be prepared, for erample,.by basic hydrolysis of a . compound of formula (VI), wherein Z is C,-Cy alkoxycarbonyl, bsina for example, the same experimental conditions describ- ed above for the hydrolysis of the compounds of formula (11), ‘whefein Y is C,-C, alkoxycarbonyl, in order to obtain the corliesponding carboxy derivative, which in turn may be transform- . ! ea!lnto a compound of formula (VI), wherein Z is halocarbonyl, preferably chlorocarbonyl, using, for example, the same exper- imental conditions described above for the preparation of the compounds of formula (II), wherein Y is halocarbonyl.

Co ! ap ORIGINAL bp] . | —

E CZ 23 - 6 23 2 1 . o . , . Tt

The compounds of formula (VIII) may be prepared, for ex- ample, by reacting a compound of formula (XI) : 0 + | oo (XT)

Rs £

R

: | wherein :

Co 5 E, R. and Ry are as defined above, with a compound of : < . formula (XII) ~. COOR . : : (XII) ; , . - COOR 8 wherein oo C. oT : . . each of Rg and Rg. being the same or different, is C,-Cq alkyl, preferably methyl or ethyl. Co } yi :

The reaction between a compound of formula (XI) and a’ IE . compound of formula (XII) may be carried out, for example, J . . . Sy according to the methods described in J:.C.S., 101, 1731 I == k . (1912) and Ann., 405, 391 (1914). Co ! ft

The compounds of formula (XI) may be prepared by synthetic ; methods well known in the art, for example, according to ! the methods described in J.A.C.S., 75, 1891 (1953) and Cod i i

Advances in Heterocyclic Chemistry, 11, 225 (1970); ibidem 7 18, 432 (197s).

BAD ORIGINAL 9 . - Cem oe a oe Co. ——en 1 ce Lo 0) 20232

Coa - Coad I B

The compounds of formula (Vv), (VII), (IX), (X), and (XII) Co are known products and may be prepared by conventional methods: in some cases they are commercially available products. oo ) ’ 5 when in the compounds of the present invention and in the intermediate products thereof, groups are present, such as CHO,

COOH, NH, and/or OH, which need to be protected before submitting them to the hereabove illustrated reactions, they may be protected pefore the reactions take place and then deprotected, according to well known methods in organic chemistry.

The compounds of formula (I) possess immunomodulating activity and can be used for example as immunostimulant agents e.g. in the treatment of acute and chronic infections of both bacterial and viral origin, alone or in ’ associatiecn with antibiotic agents, and in the treatment } of neoplastic diseases, alone or in association with " antitumoral agents, in mammals. :

The immunomodulating activity of the compounds of the inven-. : 20 tion is proved, for example, by the fact that they are effective in potentiating the cytotoxic activity of the ‘ ’ . macrophages towards tumor cells in vitro. }

The experimental procedure to evaluate this activity is as 5 follows: groups of 4 mice are treated 1i.p. with the tested compounds and then, seven days later, peritoneal cells are collected and plated for 2 hours at 37°C. After this period the walls are washed to eliminate the non adherent cells, tumor target cells are then added and the incubation } \

So BAD ORIGINAL I)

So } I

. t Y

DE | 2ue32

EE oT ARN : _ sq _ Fs Cat) ’ prolonged for 48 hours. At the end of this period the ) target cells viability is sviluated by the MTT colori- metric method (Abstracts of VIII European Immunology

Meeting, Zagreb, 1987, pag 94 n° 2105) based on the optical density (0D) evaluation at 570 nm. | - To

Percent specific cytotoxicity (%C) is calculated as % inhibition of TU-5 tumor cells (Immunology, 1984, 166, 251) growth using the following formula: %e = (1 - (effector + target ) OD - effector OD ) . 100 . target OD ‘

The following Table I summarizes the immunostimulating activity data of some representative compounds of the inven- tion, obtained according to hereabove experimental procedure, i: towards TU-5 tumor cells. } . TABLE 1 : 15 EFFECT OF FCE 25276, FCE 25648, fCE 25651 and FCE 25047 ON THE

CYTOTOXIC ACTIVITY OF PERITONEAL MACROPHAGES TOWARDS TU-5 TUMOR ol .. CELLS. : . . Macro cyt i tivit,

BE Compound i ; Effector:Target CC ( Ts eon eo 10mg/kgfio.

FCE 25276 p Lo 5:1 93 : 20 FCE 25648 h 5:1 77 i

FCE 25651 | i 5: 1 79

FCE 26047 ! 5:1 82

Vehicle ’ 5:1 : 24 : — 4 animals were used for each dose. ’ t } ono ORIGINAL 9

: To ™ oo ~ ) 2 : . | Goze - c oo . a. 26232 lat UN Et

FCE 25276 means 2-cyano-3-(1,4-dihydro-l-phenyl-indeno [1,2-cJpyrazol-3-yl)-3-oxo-N-phenyl-propanamide;

FCE 25648 means 2_cyano-3-(1,4-dihydro-1-phenyl-indeno. : [1,2-clpyrazol-3-yl)-N-(4-fluoro-phenyl)-3-oxo- . propanamide; . : -

FCE 25651 means N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1- : phenyl-indeno[1,2-clpyrazol-3-yl)-3-oxo-propanamide;

FCE 26047 means 5 _cyano-3-oxo-3-(1-phenyl-1H-benzothieno (3,2-¢lpyrazol-3-yl)-N-phenyl- propanamide.

By virtue of their immunomodulatory activity the compounds of : the invention proved to be active also in models of infection in mice. For example, the compounds FCE 25276, FCE 25648,

FCE 25651 and FCE 26047 are strongly effective against : Pseudomonas aeruginosa infection, performed in Cyclophospha~ mide immunosuppressed mice according to Cryz S.J. et al,.,

Infect. Imm., 1983, 39, 1067.

The experimental procedure to evaluate this activity is as . follows: mice are immunosuppressed 4 days before the bacterial challenge by a single dose of 200 mg/kg of Cyclophosphamide

Co 20 given intraperitoneally. . Tested compounds are administsred i.p. on days + 1 and + 3 relative to Cyclophosphamide administra- tion. Clinically isolated Pseudomonas aeruginosa is administered } intravenously in amount of 8 LDgqy- Host resistance to infection is estimated by the number of mice surviving 10 days arter the " 55 bacterial challenge. ‘BAD ORIGINAL dD - Y ‘

SN

- A nl * * . ° Cogo oe 26232 : ld OO) Fa a oe

The following Table 2 summarizes the obtained results.

S TABLE 2 oo } EFFECT OF FCE 25276, FCE 255648, FCE 25651 AND FCE 26047 ON

PSEUDOMONAS AERUGINOSA INFECTION IN CYCLOPHOSPHAMIDE IMMUMO- . 5 DEPRESSED MICE

Compound treatment % survival

Pso

FCE 25276 © 10 mg/kg/i.p. 30

FCE 25648 10 mg/kg/i.p. so co FCE 25651 10 mg/kg/i.p. 20 f

FCE 26047 10 mg/kg/i.p. 70 . Vehicle © mmmmm—— 0 : : 10 animals were used for each dose. . “The compounds of the invention can be safely used in . medicine by virtue of their negligible toxicity.

Co 15 °, The therapeutic regimen for the different clinical : syndromes must be adapted to the type of pathology taking : into account, as usual, also the route of administration, the form in which the compound 'is administered and the age, weight and conditions of the subject involved. © The oral route is employed, in general, for all conditions requiring such compounds. Preference is given to intravencus : injection or infusion for the treatment of acute infections. :

For maintenance regimens the oral or parenteral, e.g. intra- muscular or subcutaneous, route is preferred. laa ORIGINAL 9 . a

\ Cn coo : | 2Gogz O

BN . Re232 } For these purposes the compounds of the invention e.g. 2-cyano-3-(1,4 -dihydro-1-phenyl-indeno [1,2] pyrazol-3-yl) - 3-oxo-N-phenyl-propanamide, can be administered orally at doses ranging e.g. from about 0.5 to about 10 mg/kg of pody weight per day in adult humans.

Doses of active compounds ranging e.g. from about 0.2 to about S-mg/kg of body weight can be used for the parenteral administration in adult humans. Of course, these dosage : regimens may be adjusted to provide the aptimal therapeutic response.

The nature of the pharmaceutical compositions containing the compounds of this invention in association with pharmaceutically acceptable carriers or diluents will, of course, depend upon the desired route of administration.

The compositiors may be formulated in the conventional

Lo manner with the usual ingredients. For example, the i compounds of the invention may be administered in the form . of aqueous or oily colutions or suspension, tablets, pills,

Ts gelatine capsules, Syrups; drops or suppositories. . . 20 Thus, for oral administration, the pharmaceutical compositions containing the (compounds of this invention; are preferably tablets, piTls of gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, [fnannitol, sorbitol, cellulose; lubricants, for! insiance silica, talc, stearic acid, magnesium Or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as

A i oo BAD ORIGINAL i w i oo oo oo 0) Zag zo

Co 26232 ~ 29 - . Co . ~ starches, gelatine, methylcellulose, carboxymethylcellulose, EB gum-arabic, tragacanth, polyvinylpyrrolidone; disaggregating . agents, such as starches, alginic acid, alginates, sodium ‘starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pnarmacologically inactive substances used in pharmaceutical formulations.

Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions. _ The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or . sorbitol. The suspensions and the emulsions may contain oo “as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carbexymethylcellulose, or polyvinyl alcohol. oo

The suspensions or solutions for intramuscular injections oC may contain together with the active compound a . pharmaceutically acceptable carrier, e.g. sterile water, ‘ olive oil, ethyl oleate, glycols, e.g. propylene glycol, oo and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions. :

aR a. ) 26 © a . . J Ce oo we 26232 - The suppositories may contain together with the active com- pound a pharmaceutically acceptable carrier, e.g. cocoa- . butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the in- vention: i : ¥o Co : ul

Co I . : ' 1 . i , .

} Le ¢ : ‘ 2 } £6235 : . ae - 262392 . Example 1 2-Ethoxalyl-indan-1-one(6 g) is reacted with phenylhydrazine (3.1 g) in acetic acid (45 ml) at 50°C for 3 hours. After - ~ cooling the reaction mixture is diluted with ice water and then neutralized with 35% NaOH. Extraction with ethyl acetate and evaporation of the solvent in vacuo to dryness gives a residue, which is purified over a sio, column °° using hexane/chloroform 6 :4 as eluent. Main fractions are crystallized from isopropyl ether to yleld 1,4-dihydro-1- nv phenyl-indenoli,2-¢) pyrazole-3-carboxylic acid, ethyl ester, m.p. 110-112°C (5.7 g), which is reacted with : acetonitrile (14 ml) in dioxane (14 ml) in the presence of 50% sodium hydride (0.9 g) under stirring at 60°C for 15 . | minutes. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The

Lo precipitate is filtered and purified over a S10, column using ethyl acetate as eluent. Crystallization from : "+. dichlo romethane/isopropyl alcohol gives 3-(1,4-dihydro- -phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanenitrile, m.p. 189-160°C (2.8.g), which is reacted with phenyl oo isocyanate (1.17 g) in dimethylformamide (22 ml) in the presence of triethylamine: (1.06 g) at 25-30°C for 25

Co minutes. The reaction mixture is diluted with ick water i oo and acidified with 2N HCl to.pH 3. The precipitgte is riltered and washed with water. Crystallizationiffrom : dichiorrmethane/methanol gives 3.5.g of 2leyard-3-(1, 4c dihydrc | phenyl-indenof1, 2-c] pyrazol-3-yl)-3-oxo-N- phenyl-propanamide,m.n. 273-277°C, NMR (coc1,) 8 ppm:3.91s) , } i : el BAD ORIGINAL 2

Ce - . ) ces -32 - : oo oo oo 26232 (2H, C4 srotons), 7.1-8.0(m) (15H, phenyl protons and - _CONH-),16.2 (bs) (1H, -OH).

By proceeding analogously the following compounds can be prepared: . 2-cyano-3-[1-(4 —fluoro-phenyl)-1,4-dinydro-indeno(1,2-c] pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; 3-[1-(4-chloro-phenyl)-1,4-dihydro-indeno(1,2-cJpyrazol- : 3-yl])-2-cyano-3-oxo-N-phenyl-propanamide; 3-[1-( 3—chloro-phenyl )-1, 4-dinydro-indeno(1,2-c]pyrazol-3-y1]- 2_cyano-3-oxo-N-ghenyi-propanamide; 3-[i-(2-chloro-phenyl)-1,4-dihydro-indeno(l,2-clpyrazol- i 3-y1}-2 —cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-[1-(3-fluoro-phenyl)-1,4-dihydro-indeno[1,2-c] oyrazol — 3-y1l-3-oxo-N-phenyl-propanamide; : 2_cyano-3-(1,4-dihydro-1-(4-methyl-phenyl)-indeno(l,2-c] pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; - »-cyano-3-[1, 4-dihydro-1-(3-methyl-phenyl)-indeno (1, 2-c] oo : pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; . : >-cyano-3-[1,4-dihydro-1-(2-methyl-phenyl)-indéno(1,2-c] oo 20 pyrazol-3-yl] -3-oxo-N-phenyl-propanamide; - : >_cyano-3-[1,4-dihydro-1-(4-metnoxy-phenyl)-indeno(l,2-c] : pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; »—cyano-3-[i, 4-dihydro-1-(3-me thoxy-phenyd-indeno(1,2-c] oyrazol-3-y11-3-oxo-N-phenyl-propanamide; : 25 2-cyano-3-[1,4-dihydro-1-(4-nitro-phenyl)-indeno(1,2-cl : pyrazol-3-yl]-3-oxo-N-phenyl-propanamide;

A o- So BAD ORIGINAL &y i . “ :

CN

! ) . # . Gozo

Cas -. ru oo 26232 . A O fo Ce : 2-cyano-3-[1,4-dihydro-1-(3-nitro-phenyl)~-indeno[1,2-c] - pyrazol-3-yl]-3-oxo-N-phenyl-propanamide; and 2-cyano-3-(1,4-dihydro-1-methyl-indeno[1,2-c] : pyrazol-3-yl)~3-oxo-N-phenyl-propanamide. " : Example 2

By proceeding according to Example 1, using the suitable isocyanates, tne fellowing compounds can be prepared: i N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1l-phenyl- . indeno (1, 2-c]pyrazol- 3 -yl)-3-oxo-propanamide, m.p.269-271°C;

N-(4-chloro-phenyl)=2-cyano-3-(1,4-dihydro-1-phenyl-

Cod . indeno[1l,2-c]pyrazol-3-yl)-3-oxo-propanamide;

M-(2-chloro-phenyl)-2-cyano-3-(1,4-dihydro-l-phenyl- , indeno(1,2-c]pyrazol-3-yl)-3-oxo-propanamide; } oo 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl- indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide, m.p.295-297°C; pi 15 2-cyano-N-(3-fluoro-phenyl)-3-(1,4-dihydro-l-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; ; } . 2-cyano-3-(1,4-dthydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)- ’ ] ; ’ 3-oxo-fl-(3-trifluoromethyl-phenyl)-propanamide, m.p.278-284°C; 2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-yl)- } 1

N-(4-nethyl-phenyl)-3-oxo-propanamide; : : in oo : 2-cyal}o-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-y1)- ! [i . .

N-(3-methyl-phenyl)-3-oxo-propanamide; : ; i 4 . ] - 0 . \ (NAL d

3 B \ | oS N

Co | oo Cloz2 oo Co. 269232 1 > cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c)pyrazol- - 3-y1)-N-(2-methyl-phenyl)-3-oxo-propanamide; ’ »—cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2~c]pyrazol- 3-y1)-N-(4-methoxy-phenyl)-3-oxo-propanamide; } , : 5 2-cyano-3-(1,4-dihydro-l-pnenyl-indenoll,2-c]pyrazol- : 3-y1)-N-(3-methoxy-phenyl)-3-oxo-propanamide; ] : »-cyano-3-(1,4-dihydro-1-phenyl-indeno (1,2-c]pyrazol- 3-y1)-N-(3-nitro-phenyl)-3-oxo-propanamide, m.p.280-284°C; 2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol- 3-y1)-N-(4-nitro-phenyl)3-oxo-propanamide;

N-(3-bromo-phenyl)-2-cyano-3-(1,4-dinydro-1-phenyl-indeno : : [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; eo, N-benzyl-2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c] pyrazol-3-yl)-3-oxo-propanamide, m.p. 289-2290°C;

N-benzyl-2-cyano-3-[1-(4-fluoro-phenyl)-1,4-dihydro- indeno[1,2-c]pyrazol-3-yl]-3-oxo-propanamide; : 2_cyano-N-(4-fluoro-phenyl)-3-[H{4-fluoro-phenyl)-1,4- : ] dinydro-indeno[l,2-c]pyrazol-3-yl]-3-oxo-propanamide,m.p.281-286°C «

N-(3-chloro-phenyl)-2-cyano-3-[1-(4-fluoro-phenyl)-1,4- - . 20 ‘dihydro-indeno[1,2-clpyrazol-3-yll-3-oxo-propanamide, m.p .288-291°C

N_butyl-2-cyano-3-(1,4-difiydro-1-phenyl-indenol1,2~c] i - pyrazol-3-yl)-2-oxo-propanamide; and © tert. butyl-2-cyano-3-(1,4-dihydro-1-phenyl-indeno i i [1,2-c]pyrazol-3-yl)-3-oxo-propanamide. . | Cl - . ‘ h \

I~ eo BAD ORIGINAL 2d } ST,

")

SI : - Ze ogo oo ' | E C as 26239 7

Example 3 | : ’ By proceeding according to Examples 1 and 2, starting from } suitable indan-1-ones, the following compounds can be : prepared: . 2-cyano-3-(1,4-dihydro-4-methyl-1-pheryl-indeno (1, 2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-S-methyl-1-phenyl-indeno(1,2-c] ‘ pyrazol-3-yl)}-3-oxo-N-phenyl-propanamide; : 2-cyano-3-(1,4-dihydro-6-methyl-1-phenyl-indeno[1,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; ’ 2-cyano-3-(1,4-dihydro-7-methyl-1-phenyl-indeno[1,2-c]. pyrazol-3-yl)-3-oxo-N-phenyl-propanamide ,m.p. 249-251°C; : 3-(5-chloro-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamjde; 3-(6-chloro-1,4-dihydro-1-phenyl-indeno[1,2-c]lpyrazol-3-y1)- . 2-cyano-3-oxo-N-phenyl-propanamide; ) 3 (7-chloro-1,4-dihydro-1-phenyl-indeno[1,2-c]lpyrazol-3-yl)- 2-cyano-3-oxo-N-phenyl-propanamide; : 2 cyano-3-(7-fluoro-1,4-dihydro-1-phenyl-indeno[1,2-c] . pyrazol-3-y1)-3-oxo-N-phenyl-propanamidé, m.p.259-263°C; : . 2-cyano-3-(1,4-dihydro-5-methoxy-1l-phenyl-indeno{l,2-c] pyrazol-3-y1)-3-oxo-N-phenyl-propanamide oo ) : Lo 2-cyano-3-(1,4-dihydro-7-dimethylamino-1-phenyl-indeno [1,2-c]pyrazol-3-yl)3-oxo-N-phenyl-propanamide; - »_cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-7-trifiuoro= methyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide;

N-(3-chloro-phenyl)-2-cyano-3-(1, 4-dihydro-1-phenyl-7-trifluoro- me thyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide;

Co oY

So oo SE 2¢232 oo | 26232 1 . Cy

N-(3-chloro-phenyl)-2-cyano-3-(7-fluoro-1,4-dinydro-1i-

NB Shenyl-indeno(1,2-c] pyrazol-3-yl)-3-oxo-propanamide; 3-(7-tert.butyl-1,4-dihydro-l-phenyl-indeno[1,2-c|pyrazol- 3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; . 3-(7-tert.butyl-1,4-dihydro-1-phenyl-indeno[1,2-c}pyrazol- 3-41) -2-cyato-N-(4-fluoro-phenyl)-3-oxo-propanamide »-cyano-3-(1,4-dihydro-7-morpholinomethyl-1-phenyl-indeno [1,2-c]oyrazol-3-yl)-3-oxo-N-phenyl-propanamide; ’ >-cyano-3-(1,4-dinydro-6-morphol {nome thyl-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-5-morpholinomethyl-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; cee 4-(3_chloro-phenyl)~2-cyano-3-(1, 4-dihydro-7-methyl-1- : : ph=nyi-indeno(1,2-clpyrazol-3-yl)-3-oxo-propanamide; : - 15 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-methyl-1- henyl-indenoll, 2-c]pyrazol-3-y1)-3-oxo-propananide ’ 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1, 4-dinydro-1i-phe- nyl-indeno[l,2-c] pyrazol-3-yl-3-oxo-propananide; and a 2-cyano-3-(1, 4-dihydro-1-phenyl-7-trifluoromethyl-indeno i - 20 (1,2-c]pyrazol-3-y1)-3-oxo-N-phenyl-propanamide. : . Example 4 | i | ; - ii : 1, 4-Dinydrd-1-ghenyl-indeno[1, 2-c]pyrazole-3-carboxylic acid, ethyl ester (7.35 g), prepared according to

Example 1, 1s dissolved in carbon tetrachloride (100 ml) and reacted with N-bromo-succinimide (4.75 g) under stirring at the reflux temperature for 2 hours, in the - presence of benzoyl peroxide (150 mg). After cooling the } - SU Lo "GAD Oras gl o oD oo ; . i . . Seon ; : Caro | . } ol | 26232 - | » : reaction mixture is filtered and the solution is evaporated in vacuo to a small volume. The precipitated product is - : : purified with hot isopropyl ether to give 4-bromo-1, 4- oo dihydro-1l-phenyl-indeno (1,2-c]pyrazole-3-carboxylic acid,etnyl

S | ester, m.p. 181 - 182°C (9.28) which is reacted with . morpholine (2.5 g) in dimethylformamide (175 ml), in the . presence of anhydrous potassium carbonate, under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water until neutral. Crystallization from dichloromethane / isopropyl ether gives 1,4-dihydro-4- morpholino-1-phenyl-indeno[1,2-c]pyrazole-3-carboxylic acid, ethyl ester, m.p. 150-151°C (5.4 g), which is = . hydrolized by treatment with 1% KOH in 95% ethanol solution } 19 (93 ml) at the reflux temperature for 20 minutes. After cooling the reaction mixture is diluted in ice water and . acidified with citric acid to pH 4. The precipitate is . filtered, washed with water until neutral and crystallized 7 from dichloromethane/ethanol to yield l,4-dihydro-4- morpholino-l-phenyl-indeno(1,2-c]pyrazole-3-carboxylic ' acid, m.p. 244-245°C (4.15 g), which is reacted with thionyl . chloride (1.65 ml) in dioxane (200 ml) at the reflux temperature for 1 hours. After cooling tne reaction mixture is evaporated to dryness in vacuo to give 1,4-dihydro-4- morpholino-1-phenyl-indeno[1,2-c]pyrazole-3- carbonyl chloride as crystalline residue. The crude product is dissolved in anhydrous dioxane (300 ml) and reacted for 2 hours under stirring at room temperature with the carbanion co | | ; 2eoz2 oo CE Lg 20232

SL obtained by treatment of 2-cyano-acetanilide (1.87 g) with oo 50% sodium hydride (1.2 g) in anhydrous dioxane (100 ml) at oo 25 room temperature. The reaction mixture is neutralized by - treatment with N HCl (7 ml) and then concentrated in vacuo : 5 . toa small volume.

The residue is diluted with ice water and acidified with " N HCl to pH 4. The precipitate is filtered, washed with : water and then crystallized from dimethylformamide to give | 2.2 g of 2-cyano-3-(1,4-dihydro-4-morpholino-1-phenyl- indeno[l,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide,

Co m.p. 272-277°C dec. oo :

Ll By proceeding analo gously the following compounds can be oo prepared: : 2-cyano-3-(1,4-dihydro-1-phenyl-4-piperidino-indeno(1,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-[1, 4-dihydro-1-phenyl-4-(pyrrolidin-1-yl)-indeno (1,2-c]pyrazol-3-yll-3-oxo-N-phenyl-propanamide; 2—cyano-3-[1,4-dihydro-4-(4-methyl-piperazin-1-yl)-l-phenyl- indeno1,2-c]pyrazol-3-yl]-3-oxo-N-phenyl-propanamide;

SN

. . | . | oo ~ 39 -— . | , . oo 0 26232 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-4-morpholino-

I-phenyl-indeno[l,2-c]pyrazol-3-y1)-3-oxo-propanamide ;and

N-(3_chloro-phenyl)-2-cyano-3-(1,4-dihydro-4-morphol ino- —phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide.

Example 5 : . 4-Dinydro-1-phenyl-indeno[1,2-c)pyrazole-3-carboxylic acid, ethyl ester (3 g), prepared according to Example 1,

Lo is heated with 1% KOH solution in ethanol (100 ml) at reflux temperature for 20 minutes. The reaction mixture is oo 10 diluted with ice water and acidified to pH 3 with 37% HCl.

The precipitate is filtered, washed with water until neutral and dried in vacuo to give 1, 4-dihydro-1-phenyl- , : indenof{1,2-dpyrazole-3-carboxylic acid (2.5 g) which is reacted with thionyl. chloride (1.2 ml) in ‘dioxane (60 ml) at the reflux temperature for 2 Pours. After cooling the reaction mixture is evaporated to dryness in vacuo to give : } 1,4-dihydro-1l-phenyl-indeno(l,2-c]lpyrazole-3-carbonyl : i chloride as crystalline residue. The crude product is : dissolved in anhydrous dioxane (30 ml) and reacted for

Z hours under stirring at room temperafure with the : .carbanion obtained by treatment of 2-chano-acetanilide (1.6 g) with 50% sodium hydride (0.5 &) in anhydrous dimethylformamide/dioxane 1:1 (10 m1) fx room temperature. The reaction mixture is then diluted with; ice water and acidified to pH 2 with HCl. The precipitate is filtered ! i : } prem aac i i BAD Uriteuiink 5

- ~ 3 ’ lege oo Ce. 2692392 a and washed with water until neutral. Crystallization from . dichloromethane/methanol gives 1.6. g of 2-cyano-3-(1,4- dihydro-1l-phenyl-indeno(1,2-c]pyrazol-3-yl)-3~oxo-N-phenyl- propanamide, m.p. 273-277°C."* i Co. oo

By proceeding analogously the following compounds can be prepared: 2-cyano-N-(4-fluoro-benzyl)-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)3-oxo-propanamide; 3-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c}pyrazol-3-y1)- 3-o0xo-N-(2-pyridyl)methyl-propanamide; »—cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-y1)- 3-0x0-N-(3-pyridyl)-propanamidey 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-y1)- 3-oxo-N-phenethyl-propanamide; : 15 o-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-clpyrazol-3-y1)-

N-(4—-dimethylamino-phenyl)-3-oxo-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-2-y1)-

N-(2-morpholinomethyl-benzyl)-3-oxo-propanamide; - 5-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-y1)- be 20 N-{3-morphiolinomethyl-benzyl)-3-oxo-propanamide; : 2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-¢]pyrazol-3-y1)-

N-( 2-morpholinomethyl-phenyl)-3-oxo-propanamide; 2-cyano-3-(1, 4-dinydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)- : . N-( 3-morpholinomethy 1-phenyl)-3-oxo-propanamide; > oyano-3-(1, 4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-y1)-- (3-dimethylaminomethyl-phenyl)-3-oxo-propanamide; 2_cyano-3-(1, 4-dihydro-1-pheryl-indeno/1, 2-¢/pyrazol-3-y1)-N-(3-hydroxy- -4-hydroxyme thy 1 -phenyl) -3-oxo-propanamide; i : : -

Lo C0 C0) £6237 26232 ‘ ‘ : \ o/ 5-cyano-3-(1,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3-y1)-

N-(2-dimethylaminomethyl-phenyl)-3-oxo-propanamide; . : 2_cyano-3- (1, 4-dihydro-1-phenyl-indeno[1,3-c]pyrazol-3-yl- 3-0x0-N-[2-(pyrrolidin-1-yl)methyl-phenyl]-propanamide; 2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)=-

Co N-[24-methyl-piperazin-1-yl)methyl-pheny] -3-oxo-propanamide; 2-cyano-3-(1,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3-yl)-

N-( 2-me thoxy-3-morpholinome thyl-phenyl)-3-oxo-propanamide ; 2_cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-y1)- 1Z N.{2_methoxy-S-morpholinomethyl-phenyl)-3-oxo-propanamide; 2_cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-yl)- : N-methyl-3-oxo-N-phenyl-propanamide; oo oo 2-cyané-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-yl)- 3-oxo0-N-(2~thenyl )-propanamide; - ; | 15 2-cyano-3-(1,4-dihydro-1i-phenyl-indeno[1l,2-c]pyrazol-3-yl)- . N- { 4-me thoxy-3-morpholinome thyl-phenyl)-3-oxo-propanamide :

Co 2-cyano-N-(2-furfuryl)-3-(1,4-dihydro-1i-phenyl-indeno } ’ (1,2-c]pyrazol-3-yl)-3-oxo-propanamide; . 2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-yl)- ; 20 N-(1-me thyl-pyrrol-2-yl)ethyl-3-oxo-propanamide; 2-cyano-3-oxo-3-(1-phenyl-1H-benzothieno[3,2~c]pyrazol-3- / y})-N-phenyl-propardanide, m.p. 288-291°C;" : 2 cyano-N-(4-fluoro-pnenyl)-3-0x0-3-(1-phenyl-1H-benzothieno ‘ [3,2-clpyrazol-3-y1)-propanamide; and ) | 1f-(3-chloro-phenyl)-2-cyano-3-oxo-3-(1-phenyl-1H-benzochieno i [5,2-c]pyrazol-3-y1)-propanamide; 2-cyano-N-( 4-fluoro-phenyl)-3- [1-(4-fluoro-phenyl)-1H-benzo- thieno[3,2-c]pyrazol-3-yl]-3-oxo-propanamide. 3 1 'aAD ORIGINAL Yl

Lo

Co : : _ ap — co ; }

AEE 26232

Example 6

Ethyl cyanoacetate(l.4 g) is treated with 50% sodium hydride (0.58 g) in anhydrous dioxane (20 ml) under stirring at room temperature until the effervescence subsides. To this solution 1,4-dihydro-1-phenyl-indenoc [1,2-c]pyrazole-3-carbonyl chloride (3 g), prepared according to Example 5,dissolved in anhydrous dioxane (50 ml) is added under stirring at room temperature. The reaction mixture is allowed to react for 20 hours, then it

Co 10 is diluted with ice water and acidified to pH 3 with 37% HCl.

The precipitate is extracted with ethyl acetate and the ; organic solution washed with water and then evaporated to dryness in vacuo. The residue is purified over a 510, ’ g C column, using hexane-ethyl acetate 80:20 as eluent, to give a. 1s 2—cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-y1)- 3-oxo~propanoic acid, ethyl ester (2.2 g), which is reacted

Hr - with aniline (3.4 g) in xylene (100 ml) at the reflux temperature ; | for 48 hours. After cooling the precipitate is filtered ’ and washed with xylene, then crystallized from dichloro- i “20 me thane/methanol to give 1.2 g of 2-cyano-3-(1,4-dihydré- : 1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl- rn propanamide, m.p. 273-277°C. oo : fe : j ii

A : : | i

\ TTS

Co | Co Se, oo : Se

Ce | Caz. EE - 26232 1 ] Example 7 } Co - : \. 4-Dihydro-1-phenyl-indeno(1,2-c}pyrazole-3-carbonyl : chloride (2.3 g), prepared according to Example 5, is

Po dissolved in anhydrous dioxane (35 ml) and reacted for 2 hours under stirring at room temperature with the carbanion . obtained by treatment of N-cyanoacetyl-glycine; methyl ester (1.45 g) with 50% sodium hydride (0.54 g) in ; anhydrous dimethyl formamide/dioxane 1:1 (30 ml) at room . temperature. The reaction mixture is ther a:l.t2d with ic ice water and acidified tc gl. 3 rill ce. nicl.

Co The precipitate is filtered and dissolved in ethyl acetate, then the organic solution is washed with N HCl and then

Co with water until neutral. Evaporation to dryness yields a residue which is purified over a Flash column using } ’ 1s chloroform/methanol/30% NH OH 85:15:0.5 as eluent. Final } - treatment with acetone of the purified fractions gives 1.5 g oo of N [2-cyano-3-(1, a-dihydro-1-phenyl-indeno[1,2-c]pyrazol- oo : 3-y1)-3-oko-propanoyl]-glycine, methyl ester, m.p.253-255°C. ’ By proceeding analogously the following compounds can be . 20 prepared: | - : No [2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2~c]pyrazol- a 3-yl)-3-oxo-propanoyl]-DL-leucine, methyl ester; i N-[2-cyano-3-(1,4-dihydro-1-phenyl-indenoll,2<Jpyrazol- 3-y1)-3-oxo-propanoyl]-DL-phenylalanine, methyl ester; ’ 25 N- [2-cyano-3-(1, 4-dihydro-1-phenyl-indeno(1,2-c]pyrazol- 3-y1)-3-oxo-propanoyl]-DL-phenylglycine, methyl ester; and

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol- 3-yl)-3-oxo-propanoyl]-DL-isoleucine, methyl ester. — 8

BAD ORIGINAL I oo - Sy 3 : , - ~ - 44 - : , oo 26232 : Similarly the pure D and L enantiomers of the above-listed compounds can be prepared.

Example 8

N- [2-Cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol- : 3-y1)-3-oxo-propanoyl]-glycine, methyl ester (1.7 g), is suspended in 1% KOH solution in 95% ethanol (60 ml) and : heated under stirring at the reflux temperature for 30 : mimates. After cocling the precipitate is filtered and washed with ethanol, then dissolved in water. The . , aqueous basic solution is extracted with ethyl acetate and ! ©. then acidified to pH 3 with 2N HCl. The precipitate is : . extracted with ethyl acetate and the organic solution : , washed with N HCl and then with water. until neutral.

Evaporation to dryness in vacuo gives a residue which is . 15 crumbled with ethanol to yield 1.2 g of N-[2-cyano-3- : : . { ; . RE oF , . . (1,4-dinydro-1-phinyl-indenofl,2-cpyrazol-3-y1)-3-oxo- propanoyl]-glycine, m.p. 247-249°C dec. ) : yo : } By proceeding anglogously the following compounds can be oo prepared: i 3 . . : i ! '

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno[(1,2-c]pyrazol- 3-yl)-3-oxo-propanoyl]-DL-leucine;

N-[2-cyano-3-(1,4-dihydro-1-phenyl-indeno(l,2-c]pyrazol-

Fo 3-yl)-3-oxo-propanoyl]-DlL-phenylalanine; \ ano oncra J)

0-45 - Lh

Co 969232

Sd ~ Cy : : LT

N-[2-cyano-3-(1,4-dinydro-1-phenyl-indeno(1,2-c]pyrazol- co 3-y1)-3-oxo-propanoyl]-DL-phenylglycine; and

No [2-cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol- 3-yl)-3-oxo-propanoyl]-DL-isoleucine. : 5 Similarly the pure D and L enantiomers of the above-listed compounds can be prepared. ~ Example 9 2-Cyano-3-(1,4-dihydro-1-phenyl-indenofl,2-dpyrazol-3-y1)-.

N-(3-nitro-phenyl)-3-oxo-propanamide (4.5 g) is treated with SnCl,.2H,0 {22.5 g) in 37% HCl (16 ml) and: acetic ) acid (144 ml) under stirring at 50°C for S hours. After : Co cooling the precipitate is filtered and washed with acetic : ) Bh | acid, then dissolved in dimethylformamide/2N NaOH 1:1. oo / ; Dilution with excess aquecus NaH, PO , gives a precipitate 1s [ which ‘is filtered, washed with water and crystallized .

CL | from dimethylformamide to yield 2.3 g of N-(3-amino-phenyl)- ol h 2-cyano-3-(1, 4-dihydro-1-phenyl-indeno(1,2-c]lpyrazol-3-y1)- “3 . 1 nn 3-oxo-propanamide. . : By proceeding analogously the following compounds can be ‘orepared:

J i i

Co

Co Co) Co. - AR - oo 3032 : 20 fed a

N-(4-amino-phenyl)-2-cyano-3-(1,4-dihydro-1-phenyl-indeno CL : [1,2-c]lpyrazol-3-yl)-3-oxo-propanamide; and 3-[1-(4-amino-phenyl)=1,4~-dihydro-indeno[1,2-c]pyrazol- BN } 3-y1] -2-cyano-3-oxo-N-phenyl-propanamide. - "5 Example 10 -

N-(3-Amino-phenyl)-2-cyano-3-(1,4-dihydro-1l-phenyl-indeno : i . [1,2-clpyrazol-3-¥y1l)-3-oxo-propanamide (1.8 g) dissolved in cimethyl formamide (30 ml) is reacted with acetic anhydride (5 ml) in the presence of pyridine (5S ml) at 40°C for 8 : 10 hours. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water crystallization from dimethylformamide gives 1.2 g of N-(3-acetylamino- : ’ : phenyl) _2-cyano-3-(1, 4-dihydro-1-phenyl-indeno[1,2-c] pyrazol-3-yl)-3-oxo-propanamide. ’ 15 By proceeding analogously the following compounds’ can be : i f, "prepared: oo [ -. : I, oo N-(4-acetylamino-phenyl)-2-cyano-3-(1,4-dihydro<1-phényl- : : : 4 : indeno[1, 2-¢]}pyrazol-3-yl)-3-oxo-propanamide; and i : 3. [1-(4-acetylamino-phenyl)-l,4-dihydro-indend [1,8-c] I"

I pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide. . ot i }

Lo ! C p . : BAD ORIGINAL J oo } J - = LL oo | : ese

TT Co -a7 - 5 - SE Ek a at . 26232 4 ~ Example 11° : oo To '2-Cyano-3-(1,4-dihydro-1-phenyl-indeno(1,2-c]pyrazol-3-yl)- : 3-oxo-N-phenyl-propanamide is dissolved by treatment with = - : : : ; the stoichiometric amount of sodium ethoxide in ethanol. ’ : 5 The solution is evaporated to dryness in vacuo and the } : " product is crumbled with acetone. Filtration and washing with acetone gives the pure sodium salt of 2-cyano-3- : (1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N- phenyl-propanamide, m.p. > 300°C. ' . ; 10 By proceeding analogously the sodium salts of the follow- 1} ing compounds can be prepared: " 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanamide; . - 2-cyano-N-{ 4-fluoro-phenyl)-3-]1-(4-fluoro-phenyl)-1,4- dihydro-indeno(1,2-c] pyrazol-3-yl) -3-oxo-propanamide; , 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1- " phenyl-indéno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; . : } 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-methyl-1- _phenyl-indeno[I,2-c]pyrazol-3-yl)-3-oxo-propanamide.

Example 12 :

By proceeding according to Example S, starting from suitable oo ~,72tert-butoxycarbonyl-1,4-dihydro-1-phenyl-indeno[1,2-c]

: ; Ce ~ - . . So - - nT 20, . ! ~ “32 ~ 48 - : so co EH) 3 at 26232 0 . pyrazole-3-carboxylic acid ethyl esters, the following com- pound can be prepared: oo - 3_(5-tert-butoxycarbonyl-1,4-dihydro-i-phenyl-indeno1l,2-c] pyrazol-3-y1)-2-cyano-3-oxo-N-phenyl-propanamide, m.p. 253- 255 °C; } 3-(5-carboxy-1,4-dihydro-l-phenyl-indeno[1,2-c]pyrazol-3- y1)-2-cyano-3-oxo-N-phenyl-propanamide, m.p. 265-268°C dec; ’ 3_(7-carboxy-1,4-dinydro-1-phenyl-indeno[t,2-c]pyrazol-3- y1)-2-cyano-N-(4-fluoro-phenyl)-3-oxo-propanamide; ae 3_(7-carboxy-1,4-dihydro-l-phenyl-indeno[l,2-c}pyrazol-3- i y1)-2-cyano-N-(3-chloro-phenyl)-3-oxo-propanamide; ¢ 4 (7-tert-tutoxycarbonyl-1,4-dinydro-1-phenyl-indenol1,2-c] oo oyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; and ' . 3_(7-carboxy-1,d-dihydro-1l-phenyl-indenoll,2-c]pyrazol=3- : 15 y1)-2-cyano-3-oxo-N-phenyl-propanamide. i . CL) . . \ i . : Example 13 | : :

A

. t ~ - ; 3_(5-Carboxi-1,4-dinydro-l-phenyl-indenoll,2-c|pyrazol-3- ! y1)-2-cyand-3-oxo-N-phenyl-propanamide (2.3 g) dissolved in dimethylformamide (25 ml) is reacted with ethyl iodide (1.55 g) ini the presence of anhydrous potassium carbonate ? \ aS

N

BAD O°"

3 I | YY) eo i . . Cog : So - : m2

Ce oo . ie | : co ; “Nh I” 26232 i ~ (1.4 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipi- ; } tate is filtered, dissolved in chloroform and washed with 1N HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH,C1,/ : methanol to yield 1.9 g of 2-cyano-3-(5-ethoxycarbonyl- : 1, 4-dihydro-1l-phenyl-indeno{1,2-c)pyrazol-3-y1)-3-oxo-N- phenyl-propanamide, m.p. 233-236°C dec. ‘ By proceeding analogously the following compounds can be prepared: .

Cy 2-cyano-3-(7-ethoxycarbonyl-1,4-dihydro-1-phenyl-indeno - (1,2-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide; 2-cyano-3-(7-hexyloxycarbonyl-i,4-dihydro-1-phenyl-indeno } [1,2-c]pyrazol-3-yl)-3-0xo-N-phenyl-propanamide; . ' 2-cyano-3-(7-ethoxycarbonyl-1,4-dihydro-1-phenyl-indeno _ : [1,2-c]pyrazol-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide; oo and } . . oo N-(3-chlors-phenyl)-2-cyano-3-(7-ethoxycarbonyl-1,4-dihydro- i 1-pnenyl-indeno[1,2-¢]pyrazol-3-yl)-3-oxo-propanamide. / : pe . .

oD COD Ze,

CV | | 32 : 26232

Ch : Example 14 | | i

Glycine methyl ester hydrochloride (0.7 2) suspended in an- hydrous acetonitrile (250 ml) is treated with triethylamine ) (0.56 g) under stirring at room temperature. To .the susoen- sion first 3-(7-carboxy-1,4-dihydro-kphenyl-indeno|1,2-c] oyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propananide (2.3 g) and then dicyclohexylcarbodiimide (1.25 g) are added. The reaction mixture is kept under stirring at room temperature for 4 hours and then is basified to pH 8 by adding dimethyl- : 10 aminoethanol. The precipitate is filtered, washed with ace- tonitrile and then eliminated. The organic solution is con- centrated in vacuo to a small velume, diluted with water, . acidified to pH 2 with 1N HCl and then basified to pH 8 with ’ 1N NaOH. The obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with 1N HCl and : then with water until neutral. The organic solution is . CL evaporated in vacuo to dryness and the residue is purified ) over a S10, column using CHC1,/me thanol 90/10 as eluent. ! Final crystallization from CH,Cl,/ethyl acetates yields 1.2 g oC © of pure N-[1,4-dinyaro-1-phenyl-3-(2-phenyloarbanoyl-cyano- - : acetyl )-indenc[1,2-c] pyrazol-7-yl]carbonyl-glycine methyl ) ; : ester.

By proceeding analogously the following compounds can be pre- pared: . n-[1,a-dinydro-1-phenyl-3-(2-pnenylearbamoyl-cyanoacs yl)

I OD

) | oo oo oo Clos,

BN - - Cos oo . ’ So oo 26232 . indenof1,2-c]pyrazol-7-y1]carbonyl-L-alanine methyl ester; v-{1,4-dinydro-1-pnenyl-3-(2-phenylcarbanoyl-eyanoacetyl)- indeno(1,2-c]pyrazol-7-yl]carbonyl-L-leucine methyl ester; : v-[1,4-dinydro-1-phenyl-3-(2-phenylearbamoyl-cyanoace yl) indeno[1,2-c]pyrazol-7-yl|carbonyl-L-phenylalanine methyl : ester; . N- | 3-[2-(a-f1voropnenylearbanoyl)eyanoace yl) -1, a-dinyero-

L-phenyL-tneno [1 2-c] pyrazol-7-v1 | carbonyl-glycine methyl ester; and } oe }

N-{1,4-dinydro-1-phenyl-3-(2-phenjlearbamoyl-cyanoacetyl)- ‘ ! indeno[1,2-c] pyrazol-5-y1]carbonyl-glycine methyl ester.

BE ©. Example 15 } ; : N-[1,4-Dinydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- : : : ~T- Ova , : . . ; tndeno[1, 2c] pyrazol 5-4] cdrbonyl-glycine methyl ester (0.84 g) is suspended in 1 % KOH solution in 95 % ethanol - (22.3 ml) and heated under stirring at the reflux tempera- ) ture for 30 minutes. ater fooling the reaction mixture is acidified to pH 2 with 23 # HCl and then diluted with ice water. The precipitate is filtered, washed with water and then crystallized from CH,C1,/ ethanol to yield 0.65 g of }

Daa ~

BAD ORIGINAL 9) . } . IR . :

: CY) FY 0) oe

Ces | } . ~ 1 ) H A 26232 1 pure N-| 1, 4-dihydro-1l-phenyl-3-(2-phenylcarbamoyl-cyano- acetyl)-indeno(1,2-c)pyrazol-7-y1]carbonyl glycine.

By proceeding analogously the following compounds can be prepared:

N-[1,4-dinydro-1-phenyl-3-(2-phenylecarbamoyl-cyanoacetyl)- indeno[l,2-c]pyrazol-7-yl|carbonyl-L-alanine;

N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbanoyl-cyanoacetyl)= indeno[1,2-c]pyrazol-7-y1|carbonyl-L-leucine; : r

N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl)- indeno(1,2-c]pyrazol-7-yl]s2rbonyl-L-phenylalanine;

N- { 3-[2-(4-f1uoropnenyloarbanoyl)-cyanoacetyl] 1, ¢-dinyiro- i .

L-phenyl-indeno[1,2-c]pyrazol-7-yL | carbonyl-glycine; and n-{1,4-dinydro-1-phenyl-3-(2-phenylcarbamoyl-cyanoacetyl) = . - indeno(1,2-c]pyrazol-5-y1]earbonyl- glycine. } .

Example 16 oo | . 6-Tosylamino-indan-1-one, m.p. 202-204°C, (4.2 g) is react- ed with diethyl oxalate (20.5 g) in anhydrous ethanol (125 : ml) containing sodium ethoxide (3.75 g) under stirring in : inert atmosphere at room temperature for 2 hours. The reac- : 20 tion mixture is diluted with ice water and extracted with hexane. The aqueous phase is acidified to pH 3 with N HCl

: : : es» - oo = | Lo : Ces oo “oo oo

SE oo 262392 - “and extracted with ethyl acetate. The organic solution is washed with water until neutral and then is evaporated to oo ) dryness in vacuo to give crude 2-ethoxalyi-6-tosylamino- i indan-1-one, which is reacted with phenylhydrazine (1.65 2)

S in acetic acid (60 ml) at 60°C for 2 hours. The reaction mixture is diluted with ice water and the precipitate is . filtered, washed with water, dissolved in CHCl, and evapo- - rated to dryness in vacuo. Purification over a S10, column using hexane/ethyl acetate 7/3 as eluent yields pure 1,4- ; . 10 dihydro-l-phenyl-7- tosylamino-indeno(1,2-c]pyrazole-3-car- boxylic acid, ethyl ester (3.3 g), which is reacted with acetonitrile (12 ml) in anhydrous dioxane (50 ml) in the n presence of 50 % sodium hydride (1.1 g) under stirring at . 60°C for 4 hours. After cooling the reaction mixture is di- luted with ‘ice water and acidified to pH 4 with citric acid. : , The precipitate is extracted with ethyl acetate, washed with i - S % NaHCO, aqueous solution and ‘then with water. By concen- ‘ tration to a small volume in vacuo the product crystallizes. i ; : The precipitate is filtered and washed with ethyl .acetate , [ 20 to yield pure 3-(1,4-dihydro-l-phenyl-7-tosylamino-indeno i (1,2-¢]pyrazol-3-yl)-3-oxo-propanenitrile (2.1 g), which is 4 reacted with phenyl isocyanate (0.55 g) in dimethylforma-

NE mide (15 ml) in the presence of triethylamine (0.65 ml) at room temperature for 30 minutes. The reaction mixture is oo 55 diluted with ice water and acidified to pH 2 with 2N HCL. ! i

Ce Co yO) oo : Deeg, : 26 239 Hil

The precipitate is filtered and washed with water until } neutral. Crystallization from chloroform/ethanol yields: oo »-cyano-3-(1,4-dihydro-1-phenyl-7-tosylamino-indeno[1,2-c] pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (2.3 g), which is treated with methanesulphonic acid (11 ml) in the presence ; of anisole (1.3 ml) under stirring at 50°C for 20 hours. : After cooling the reaction mixture is diluted with ice water and the precipitate is filtered and washed with water until neutral. Crystallization from CH, C1, /methanol yields 1:2 g y 10 of 3-(7-amino-1,4-dinydro-1-phenyl-indeno(1,2-c)pyrazol-3- . v1)-2-cvano-3-oxo-N-phenyl-propanamide.

By proceeding analogously the following compounds can be oo prepared: ' Co 7s (5.amino-1. 4-dinydro-L-phenyl-indenol1,2-c] pyrazol-3-y1)- 5_cyano-ti-(4-f Luoro-pheny)-3-oxo-propananide . 3-(7-amino-1,4-dihydro-i-phenyl-indeno[1,2-cIpyrazol-3-y1)- ‘ 2-cyano_N-( 4-fluoro-phenyl)-3-oxo-propanamide: oo 3_(7-amino-1,4-dihydro-l-phenyl-indenqll,2-c]pyrazol-3-y1)- . : 4-(3-chloro-pheny1)-2-cyano-3-oxo-prapanalilde; and 3 (7-amino-1,4-dihydro-1-phenyl-indeno[1/2-c]pyrazol-3-y1)-

Co 2-cyano-N-(3-teifluorome thy -phenyl)-3-ofp-propananide.

Ya ; : : | rh

Ll bo \ \ oy MN

BAD 07"

SE Lo 0) 2 “Ces, } : ~ 55 - | . B 26232

Car? Fob

Example 17 N 3_(7-Amino-1,4-dinydro-1-phenyl-indeno(1,2-c]pyrazol-3-y1)- oo i 2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in an- hydrous dimethylformamide (70 ml) containing pyridine (1 ml) is reacted with ethyl.oxalyl chloride (0.7 g) under stirring at room temperature for 6 hours. The reaction mixture is di- : luted with ice water and acidified to pH 4 with citric acid. . | The precipitate is filtered and washed with water. Crystal- oo lization from CHCL j/ethanol yields 1.1 g of 2-cyano-3-(7- ethoxalylamino-1,4-dihydro-1-phenyl-indenol(1,2-c]pyrazol- : 3-yl)-3-oxo-N-phenyl-propanamide. i

By proceeding analogously the following compounds can be : prepared: . i >_cyano-3-(5-ethoxalylamino-1,4-dihydro-1-phenyl-indeno [1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; ; 2-cyano-3-(7-ethoxalylamino-1,4-dinydro-1-phenyl-indeno [1 2-clpyrazdl-3-yl)-N-(4-fluoro-phenyl)-3-oxo-propanamide; and : .

N-(3-chloro-phenyl)-2-cyano-3-( 7-ethoxalylamino-1,4-dinydro- | -phenyl-indenof1,2-c]pyrazol-3-yl)-3-oxo-propanamide. . .

BAD ORIGINAL 9

Co Co) SY) LD : , : , Co fo oo 2 ; - 56 - oC . \ Ia ‘ . . \ 96232 , 6 ivi : {

IE | 3039

Example 18 so 2_Cyano-3-(7-ethoxalylamino-1,4=dihydro-1-phenyl-indeno : (1,2-c]pyrazol-3- '1)-3-oxo-N-phenyl-propanamide (1.1 g) is . treated with 1 % KOH solution in 95 % ethanol ( 34 ml) di- luted with 95 % ethanol (SO ml) under stirring at room tem- perature for 3 hours. The reaction mixture 1is concentrated in vacuo to a small volume and then diluted with ice water . and acidified to pH 4 with citric acid. The predipitate is filtered and washed with water. Crystallization from CHC1,/ ) 10 ethanol yields 0.65 g of 2-cyano-3-(1,4-dihydro-7-oxalamino- 1 . -pheny1-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propan- amide. ' : By proceeding analogously the following compounds can be prepared: . 15 2_cyano-N-( 4-fluoro-phenyl)-3-(1,4-dinydro-7-oxalamino-1- : ohenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; . N-(3=chloro-phenyl)-2-cyano-3-(1,4-dihydro-7-oxalamino-1- : , ohenyl-indeno(1,2-c]pyrazol-3-yl)-3-oxo-propanamide; and : ; J - ¢ : vo : 2-fyano-3-(1,4-dthydro-s-oxalamino-i-phenyl-indenolt, 2c] oyrazol-3-yl)-3-oxo-N-phenyl-propanamide. . Fl ’ : i .

Ty i fio t . 1 { . : ’ ! } - . BAD ORIN A, A)

: i A 2) ™ ’ 23, - 57 - : . i ’ Pp ) : 26232

Example 19 = . 3-(7-Amino-1,4-dihydro-1-phenyl-indeno[l,2-c]pyrazol-3-yl)~ _ ! 2-cyano-3-oxo-N-phenyl-propanamide (1 g) dissolved in anhy- } i drous tetrahydrofuran (23 ml) is reacted with succinic an- 3 5 hydride (0.71 g) at the reflux temperature under stirring for 3 hours. After cooling the reaction mixture is diluted . with ice water. The precipitate is filtered and washed with water. Crystallization from CHCl ,/methanol yields 0.75 g of 3-|7-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-indeno (1,2-c]pyrazol-3-y1]-2-cyano-3-oxo-N-phenyl-propanamide.

By proceeding analogously the following compounds can be prépared: : 3-|5-(3-carboxy-propanoylamino)-1,4-dihydro-l-phenyl-indeno i [1,2-c) pyrazol-3-y1]-2 - cyano-3-oxo-N-phenyl-propanamide; . i - 15 and : . . : iE 3-|7-(2-carboxyacetylamino)-1,4-dihydro-1-phenyl-indeno ; : : (1,2-c]pyrazol-3-yl]-2-cyano=3-oxo-N-phenyl-propanamide. ’ : . . . i J:

Co ’ . ’ ! IH

Lo Co + ~ | | | EE A - . 13 i Co Poor b ! ) i

. 0 5) ° co 2s . co _ : J : : , 26232 1

Example 20 : : o 6 _Tert_butoxycarbonyl-1,4-dihydrod-phenyl-indenof1,2-c] oo pyrazole-3-carboxylic acid ethyl ester (11 g), prepared ac- cording to Example 16, is treated under stirring with trio : ‘5 fluoroacetic acid (130 ml) at room temperature for 3 hours.

The reaction mixture .is diluted with ice water and the pre- cipitate is filtered and washed with water until neutral.

Crystallization from isopropanol yields 3-ethoxycarbonyl- ] | 4-dinydro-l-pnenyl-indeno[l,2-clpyrazole S5.carboxylic acid (8.4 g), which is reacted with thionyl chloride (5.3 ml) - in znhydrcus dioxane (90 ml) at the reflux temperature for : 5 hours. After cooling the solution is evaporated to dry-

Co } ness in vacuo and the residue, 3-ethoxycarbonyl-l,4-dinydro- - i |-phenyl-indeno(l,2-c]pyrazole-5-carbonyl chloride, is dis- = solved in anhydrous diglyme (100 ml) and added dropwise, cL under inert atmosphere, to a stirred solution of lithium

E tri-tert-butoxyaluminum hydride (15.4 g) in anhydrous di- . ’ : glyme (90 ml) in such a way as to maintain the temperature : between 0°C and a°C. The reaction mixture is allowed to re- act at about 0°C under stirring for 1 hour and then is di- Co - luted with ice water, acidified to pH 1 with 23 % HCL and . . extracted with chloroform.The organic solution is washed with water and then evaporated to dryness in vacuo. The residue is purified over a $10, column using hexane /ethyl acetate 7/3 as eluent. Crystallization from CH,CL,/isopropyl : Lo - ] BAD ORIGINAL » . —

i} oo ose - a : . . 03999 4 oo 26932 ether yields pure |, 4-dihydro-5-hydroxymethyl-1-phenyl- indeno{1,2-c]pyrazole-3-carboxylic acid ethyl ester (3.8 g), } which is reacted with 2-methoxyethoxymethyl chloride (2.1 g) in methylene chloride (60 ml) in the presence of diisopro- pylethylamine (2.96 ml) at room temperature for 20 hours. ; The reaction mixture is washed in a separatory funnel first with 5 % Na, HPO, solution and then with water until neu- tral. The organic phase is evaporated to dryness in vacuo . and the residue is crystallized from isopropyl ether to yield 1,4-dihydro-5-(2-méthoxyethoxymethoxy)methyl-l-phenyl- indeno[1l,2-c]pyrazole-3-carboxylic acid ethyl ester (4.65 g), which is treated with KOH (0.4 g) in 95 % ethanol (52 ml) under stirring at 45°C for 40 minutes. The reaction mixture is then diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, washed with water until neutral and dried in vacuo at 80°C to yield 1,4- dihydro-5-(2-me thoxyethoxyme thoxy) me thyl-1-phenyl-indeno . [1,2-c]pyrazole-3-carboxylic acid (3.95 g), which is dissolv- ed in anhydrous’ dicicane (50 ml) and reacted with oxalyl chloride (1.9 ml) in the presence of dimethylformamide (11 mg) ; at room temperaturd for {i hour. The reaction mixture is ; evaporated £6 dryrilss in vacuo and the residue, crude 1,4-dihydro- 5_(2-me thoxye thoxyme thoxy) me thy L-1-phenyl-indeno{1,2-c|pyrazole- 3-carbonyl chloride, is dissolved in anhydrous dioxane (50 ml) and reacted for | hour under stirring at room temperature with the carbanion obtained by treatment of cyano-acetanilide (1.76 g) with 50% sodium hydride (0.6 g) in anhydrous dioxane (140 ml). :

EE sro ORIGINAL 9

Lo oe DO Pen, . 2 “ E 50. ~

Ch | 26232 Mm “a

The reaction mixture is then diluted with ice water and

Co acidified to pH 3 with 2N HCl.

Lo The precipitate is filtered, washed with water and crystal- ’ - lized from CH,CL,/isopropanol to yield 2-cyano-3-[1,4-dinydro- oo “5 & _(2-me thoxye thoxymé thoxy )me thyl-1-phenyl-indeno[l,2-c|pyrazol- } 3-yL] ~3-0xo-N-phenyl-propanamide (1.5 g), which is suspended under stirring in methanol (800 ml) containing 37% HCL (8 ml) and heated at 45°C for 20 hours. After cooling the reaction mixture is concentrated in vacuo to a small volume and diluted with ice water. The precipitate is filtered and washed with . water until neutral. Crystallization from CH,Cl,/methanol yields 1.05 g of 2-cyano-3-(1,4-dihydro-5-hydroxymethyl-1- . phenyl-indeno[1l,2-c]|pyrazol-3-yl)-3-oxo-N-phenyl-propanamide. : By proceeding analogously the following compounds can be pre- pared: hE > cyano-3-(1,4-dihydro-7-hydroxyme thyl-1-phenyl-indero[1,2-c]

Co pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; : oo

N 2_cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-5-hydroxymethyl-1- . } phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide; and © - ‘

N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-5-hydroxymethyl-1- phenyl-indeno[l,2-c]pyrazol-3-yl)-3-oxo-propanamide. . Co . :

IEEE a oo oo oo 3 . Pog } Co c 26299 uy .

CL Example 21 eo 3_(7-carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol- ’ 3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.8 g) dissolved in : anhydrous acetonitrile (110 ml) is reacted with N,N-dimethyl- i 5 aminoethanol (0.73 g), in the presence of dicyclohexylcarbo- diimide (1.12 g) and 4-dimethylaminopyridine (0.265 g), under stirring at room temperature for 24 hours.

The precipitate is filtered off and the organic solution is concentrated in vacuo to a small volume. The residue is diluted with water, acidifiéd to pH 2 with N HCI and then basi- : fied to pH 8 with N NaOH. The precipitate is filtered and purified over a Sio, column using chloroform (methanol) 30%

NH OH 80/20/0.3 as eluent. The recovered product is dissolved in dimethylformamide (20 ml), acidified to pH 2 with 2N HCL, diluted with water (50 ml) and then basified. to pH 8 with 2N } NaOH. The precipitate is filtered and washed with water to yield 0.4 g of 2-cyano-3-(1,4-dihydro-7-N,N-dime thylamino- - e thoxycarbonyl-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3- oxG-N-phenyl-propanamide. oo : ’ 20 By proceeding analogously the following compounds can be pre- oo ! pared: So :

I 2—cyano-3-(1,4-dihydra-5-N, i-dime thylaminoe thoxycarbonyl-1- - “phenyl -indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; 2-cyano-3-(1,4-dihydro-7-morpholinoe thoxycarbonyl-1-phenyl- _indenof1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide; and : 2-cyano-3-(7-N,N-dimethylaminopropoxycarbonyl-1,4-dihydro-1- _phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide.

Co) CY

Coen | oo 26232

Example 22 Ir > cyano-3- (1, 4-dihydro-5-hydroxyme thyl-1-phenyl= indeno [1,2-c)pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1,1 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45°C for 20 hours. After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH,C1,/ isopropanol yields 0.85 g of 3-[5-(3-carboxy-propanoyloxymethyl) : 1, a-ainydro-1-paenyl-indeno(1,2-c]pyrazol-3-y1]-2-cyano- 3_oxo-N-phenyl-propanamide.

By proceeding analogously the following compound can be prepared: 3 (7-(3-carboxy-propanoyloxyme thyl)-1, -dihydro-1-phenyl- indeno[1,2-c] pyrazol-3-y1]-2-cyano-3-oxo-N-phenyl-propananide.

Tablets, each weighing 150 mg and containing 50 mg of active substanca2, can-be manufactured as follows: ’ Composition (for 10.000 tablets) | : / > . i >-cyano-3-(1,4-dikydro-L-ghenyl-indero(1,2-c]pyrazol-3-y1) _3-oxo-N-phenyl-propanamide lL 500 g

Lactose ; ; h 710 g : Corn starch ’ i fh 238 g : Co 3 :

Talc powder i! 36 ¢

Magnesium stearate Lo 16 g i . . i

BE Com gap oRGNE TE oe oo oo E ya) 2 Co oe | Gos,

ST 96232." - °. - —— - or -.63 - . »—cyano-3-(1,4-dihydro-1-phenyl-indenol1,2-c|pyrazol-3-y1) oo . _3_oxo-N-phenyl-propanamide, lactose and half of the corn : starch are mixed: the mixture is then forced through a - sieve of 0.5 mm openings. Corn starch (18 g) is suspended oo } "8 in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of. 8 mm dia- oo 10 meter.

By proceeding analogously, tablets can be prepared having . the same composition, but containing, for example, as active - substance one of the following compounds: 2-cyano-N-(4-fluoro-phenyl)-3-[1-(4-fluoro-phenyl)-1,4-dihydro- indenof[1,2-c]jpyrazol-3-yl]-3-oxo-propanamide; - ) 2-cyano-N-(4-fluoro-phenyl)-3-(7-fluoro-1,4-dihydro-1-phenyl- indeno(1,2-¢]pyrazol-3-yl) -3-oxo-propanamide; and } . 2_cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-7-methyl-1-phenyl- : oo indeno[1,2-c]pyrazol-3-yl)-3-oxo-propanamide. Te

Claims (1)

1. Lo | 2¢ LD : oo Se i ‘ - 64 - . . co - oo CLAIMS 069239

   1. A compound of formula (I) . So | (1) BN 1? : coc 3 : 7 IAN AN

   ’ . 0 Ry ’ x 6 Rj 5 wherein .. X represents: a) a -CH- group wherein Ry is hydrogen, Cy1-Cg alkyl or . Ry . : R? .

   / . a -N group wherein each of R’ and R" \

   i . rR" : independently is Cy-Cg alkyl or R' and R", taken . together with the nitrogen atom to which they are linked, form a heterocyclic ring which is selectdd from N-pyrrelidinyl, : N-piperazinyl, : hexahydroazepin-1-y1, thiomorpheolino, morpholino ’ and piperidino and whieh is unsuhstituted or substituted by C,-Cq alkyl; or hb) an oxygen atom or a -8(0),~ group, wherein n is zero, 1 or 2; . Ry represents Cy1-Cg alkyl, pyridyl or phenyl, the phenyl being unsubstituted or guhstituted by one or two BAD ORIGINAL I —

   6s 262392 i . substituents chosen independently from halogen, : trifluoromethyl, C,-Cq alkyl, C,-Cgq alkoxy, nitro, ~ amino, formylamino and Co-Cg alkenoylaming: . each of Ry and Ry is independently: — a’) hydrogen, halogen, Cy-Cg alkyl or IE trifluoromethyl; - bb’) hydroxy, C;-Cg alkoxy or C4 or Cy alkenyloxy; Co ec’) nitro, amino, formylamino or Cy-Cg . alkanoylamino; a’) di(Cy-Cg alkyl) amino or a -CHgN wherein R’ and R" are as defined above; - e') “CH, 0H, CHO, COOH or C,-Cy alkoxycarbonyl; f') =a “NHeacH-Ni; group, wherein R, is hydrogen R,, phenyl or the side chain of an a-amino acid; g’) a -CH=N-OR’; group wherein R’y is hydrogen or B h a -CH, COOH group; Bh } © h') a -CH=N-NH-R’ , group wherein R'y is hydrogen, i -CH,CH,0H, Cy or Ca alkoxycarbonyl or a : -(CHy),;-R’3 group wherein p is 1 or 2 and R’4 ‘ is COOH or Cy-Cy alkoxycarbonyl; : Co \ = Q represents hydrogen, carboxy, C,-Cq alkoxycarbonyl or . : SNe oo | } } a —-CON group wherein R, represents hydrogen or ’ Sa, . . C1-Cop alkyl and Ry represents C;-Cgp alkyl, a -CH-COOR group wherein R and R, are as defined ahove or a -(A), -Rg group wherein m is zero or 1, A is a Cy-Cpg alkylene chain and Rg is a") Cg-Cq cycloalkyl; h") pyridyl, unsubstituted or substituted hy one Co [BAD ORIGINAL I i

   KL © Co Hz, 6232 - 66 - 2 se) . oo * or two substituents chosen independently from : . halogen, ¢,-Cq alkyl and Ci-Cq alkoxy; ° } ce") phenyl, unsubstituted or substituted by on» ] or two substituents independently chosen fiom halogen, CFq, C-Cg alkyl, €C;-Cg alkoxy, . amino, nitre, formylamino, Cy-Cg alkanoylamino, di(Cy-Cg alkyl) amino, hydroxy, CH,0H, COOH, Co-Cq alkoxycarbonyl, . R? : : / formyloxy, Cy-Cg alkanoyloxy and a ~CHp-N . Non group wherein R’ and R" are as defined above; 4") 2-thienyl, 2-furyl or 1-(Cy-Cg alkyl)-pyrrol- 2-y1; and the pharmaceutically acceptable salts thereof.

   - 2. A compound of formula (I) according to claim 1, wherein X ist } a"’) a -CH-group wherein Ry is hydrogen, C{-C,4 alkyl or I So / ] - a -N group wherein each of R*! and rIV : Nov : Co oo - independently is Cj or Cj alkyl or R’'’ and RIV, taken together with the nitrogen atom to which Co they are linked, form a heterocyclic ring which is . selected from N-pyrrelidinyl, N-piperazinyl, morpholino and riperidino and which is unsubstituted or substituted by methyl; or hh’) } oxygen or a -S(0),- group, wherein n is as defined above; Ry represents unsubstituted pyridyl; or phenyl AD ORIGINAL I Lo

   : ® oo "2s ST 26232

   Ca. . Co oo od ~~ oo oo unsubstituted or substituted hy one or two oo v substituents chosen independently from halogen, trifluoromethyl, Cy1-Cqg alkyl, Ci1-Cg alkoxy, nitro, : amino and C,-Cg alkanoylamine; oo : R, and Rj each independently is oo a”) hydrogen, halogen, hydroxy, COOH, CHO, CH, OH, } CFj3, Co-Cq alkoxycarbonyl, nitro, amino; Ci- . ] . R'"' /

   : . Ca alkyl, C1-Cyq alkoxy or Aa oH group priv , vherein R’’’ and RIV are as defined ahove; hb?) =a -NHCOCH-NH, group, wherein R., is hydrogen, phenyl or the side chain of an: a-amino acid; ec?) a -CH=N-OR’; group, wherein R'; is hydrogen or a -CH4, COOH group; ~~ Q represents hydrogen, Co-Cpq. alkoxycarhonyl or a ~CONR’ (Ry, group wherein R', is hydrogen or Cy-Cg ’ : alkyl and R’y, is Cy-Cgq alkyl, =a CH-COORg group . wherein Rg is hydrogen or C1-Cy alkyl and R. is . hydrogen, phenyl or the side chain of an a-amino i acid, or a-(A') -R'g group wherein m is zero or 1, : 25 A’ is a Cq1-Cq alkylene .chain and R’g is: - Co : alV) unsubstituted pyridyl; _ or rhenyl } nnsubstituted or substituted by one or two } ‘ ‘substituents chosen independently from halogen, CFgq, C1-Cy4 alkyl, Cy-Cy alkoxy, nitro, CH,0H, COOH, di-(C,;-C, alkyl)amino, hydroxy, formyloxy, Cp-Cg alkanoyloxy and a R’'? : / ~CHgN group wherein R’’’ and Ry are as \ gIV oro ORIGINAL 9 }

   2c, © Es - 68 - 26232 0 Lo “defined ahove; . fet } ~ . RIV) 2-thienyl or 2-furyl; : and the pharmaceutically acceptable salts thereof. 3, A compound of formula (I), according to claim 5 1, wherein X is oxygen, sulphur or a -CH- group wherein . . } ! oo . . R"4 : R'"? / R", is hydrogen, methyl or a -N group wherein R’’’ and \ IV R rIV are ag defined above; } R4 represents phenyl unsubstituted or substituted by a substituent selected from nitro, halogen, CFq, Cq- Cy alkyl and Cy1-Cy4 alkoxy; each of Ry and Rg independently is a®%) hydrogen, halogen, COOH, CHO, CHy0H, Cy-Cg - ‘alkoxycarbonyl, CFgq, nitro, amino, hydroxy, : . } : . R''? : / Lo C1-Cy4 alkyl, Gy-Cy alkoxy, or a -CHg-N CT - : Tv ’ R group wherein R'’’ and RIV are as defined ’ ahove; : } . : hb?) a -NHCOCH-NH, group wherein R_. is hydrogen, : = i ] Re phenyl or the side chain of an a-amino acid; Q represents hydrogen, Co or Cg alkoxycarbonyl or a CONR" RR", group wherein R", is hydregen or C;-Cy4 ’ alkyl and R", is C;-Cy alkyl, a -CH-COORg group “wherein Ry and R, are as defined ahove or a -(CHy) ,-R"§g group in which p is zero, 1 or 2 and : | ~

   : R. —- j oo | 3) oo BAD ORIGINAL €

   2¢ 0 . 0 > . vo oo 26232 1 © - 69 - : foo OD oC : oo } R"g ig: 3 . | - E a¥) unsubstituted pyridyl; or phenyl unsubstituted or substituted by one or two substituents chosen independently from nitro, - _ & } halogen, CFg, C1-Cy4 alkyl, C1-C4 alkoxy, ~ CH,0H, COOH, di(C; or Cy alkyl) amino, ) hydroxy, formyloxy, Cy-Cg alkanoyloxy and a . rR?’ ’ : . ’ / Iv’ -CHyN group wherein R’’’ and R are as \ iv R defined ahove; 10 bY) 2-thienyl or 2-furyl; and the pharmaceutically acceptable salts thereof, 4, 2-cyann-3-(1,4-dihydro-1-phenyl-indeno(1,2- clpyrazol-3-yl)-3-oxo-N-phenyl-propanamide and the rharmacentically acceptable salts thereof.

   5, . A pharmaceutical composition used as ; immunostimulate agent said composition containing a rharmaceutically acceptable carrier and/or diluent and, : as an active ingredient, a compound of formula (1) ’ , according to claim 1 or a pharmaceutically acceptable } salt thereof, IR 2-cyano-3-(7-fluoro-1,4-dihydro-1-phenyl- indenn[1,2-c]lpyrazol-3-yl)3-oxo-N-phenyl-propanamide or ’ the pharmaceutically acceptable salts thereof,

   7. 2-cvano-N-(4-fluoro-phenyl}-3-[1-(4-fluoro- phenyl)-1,4-dihydro-indeno(1,2-clpyrazol-3-yl}-3-oxo- BAD ORIGINAL 9

   . A .® ?3. a 26293 > } - 70 - . : oo EE propanamide or the pharmaceutically acceptable -salts - ees : thereof. | a

   8. 2-cyano-N-(4-fluoro-phenyl)-3-(1,4-dihydro-1- phenyl-indeno[l,2-c~-]pyrazol-3-yl)-3-oxo-propanamide or - the pharmaceutically acceptable salts thereof. . 9, N-(3-chloro-phenyl)-2-cyano-3-(1,4-dihydro-1- BN phenyl-indeno[1,2-clpyrazel-3-yl)-3-oxo-propanamide or : the pharmaceutically acceptable salts thereof.

   10. 2-cyano-3-(1,4-dihydro-7-methyl-1-phenyl- indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide or the pharmaceutically acceptahle salts thereof. ‘ 11. 2-cyano-3-oxo-3-(1-phenyl-1H-henzothieno(3,2- w]pyrazol-3-yl)-N-phenyl-propanamide or the " pharmaceutically acceptable salts thereof. ‘

   12. 2-cyano-3-(1,4-dihydro-5-morphelino-methyl-1- : phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl- .propanamide or the pharmaceutically acceptable salts thereof. . 13, 3-(5-tert, hutoxycarbonyl-1,4-dihydro-1- phenyl-indeno[1,2-c]lpyrazol-3-yl)-2-cyano-3-oxo-N-phenyl propanamide or the rharmaceutically acceptable salts thereof. Inventors: GIANFEDERICO DORIA ANNA MARIA ISETTA MARIO FERRARI DOMENICO TRIZIO - ” hf —— - - FE Ce = B . . i —— i it q LILIAN i Ly — GRIGINAL Yi . -