Title of Invention

"2-HYDROXYALKYL-CARBOXYAMIDE AND - METHYLENAMINE DERIVATIVES OF GENERAL FORMULA I"

Abstract This invention describes the new, nonsteroiclal gestagens of general in which A, B, Ar, R1 P,2 and R3 have the meanings that are indicated in more detail in the description. The new compounds show a very great affinity the gestagen receptor, They can be used alone or in combination with the estrogens in contraceptive preparations. In additioy they can be used for treating endcmstriosis. Together with estrogens, they can also be used in preparationa for treating gynecological disorders, for treating pren 1 symptoms and for substitution therapy. Based on the androgenic action, they can also wed be used for male birth control, male HRT and hormone therapy and for treating andrological disease agents.
Full Text This invention reler-es to ncnirercids.! compounds, which have a high gestaganic activity.
In addition to a lares number of steroid co':vDour.d~ with •gestagenic action, gestagens that are not steroids are also known (for example from SP 0 253 £00 Bl and WO £4/Gl~i2; cf, J. Med. Chetn. 38 (1995) 4S7S) .
This invention describes the eortitsounds f>f sfis.-ri.sraj. fen-Mul
(Figure Remove)
in which
R1 and H2 ara the sarns or clif fsresnt and starid for a
hydrogen atom,, a C.-C5 &Ikyl group or a halogen atom, and also together with, the ^--atom of the chain stand, for a ring with a total of 3-7 links,
R3 stands for a Gj-C; alky! group or a partially or completely frlucrin&tsd C,-C3 alkyl gx-oup, stands for = monocyclie or hicyclic aromatic ring that is cptic-nally substituted by one or more radicals, selected from halogen atoms, Cx~ C5 alkyl groups, C2-C5 alkenyl groupe -CRS=CR'R7/ whereby R5*, R° and R7 are the same or different and, independently e>£ orie another., m^an hydrogen stores or C,-CS alkyl grouips; hydroxy groups, hydroxy groups that carry a C.,-C10 acyl group, a C5-CU, carbalkoxyalki-1 group, a C5-C5 cyanalkyl group, &. C,-Cli;- nnsubstifated or substi'tutsd allyl croup, a. Cj-C,s v.nsufasnituted or substituted propargyl group, a CL-CS
Ar
partially or oorupl-tfely substituted by fluoric atoms, the cyans or -nitre? group, C:-C3 alkoiy QircuTD", C, -C« alkylthio crrcu^S. Tnorio- osr d,i substituted Ci-C,,, amino groups or partially or completely fluoridated C..-CE alky?, groups, for an ester group -COOx*. whereby RJ means; a.
/"• /~» •—., "V 1 r-i- — ") i—o- -v- -~. -. -^ -r-H
v_- -^ — *>-* ft d -L Jv V ~L wj x i. J Li y f
£cr a C2-C5 alkenyl group -CR5=CE^'; ^hexeby &,
Re and E7 are the same or different, and,
independently of one another, rnea.:^ hydrogen
atoms, halogeii atoms, aryl radicals or CV-Cr.
alkyl groups,
for an alkinyl group -C^CR:', whereby Fi;' means a
hydrogen, atom or a C:i--Cs alkyl groiip,
fcr a partially or completely fluorinated ^-€'5
a1ky1 group/
stands fv'jr a carbonyl ^roup or a CHS groiip, arid
st«nds for a rin^ system, selected from the
group; o± geiierai partial formulas 2-li,
.


(Figure Remove)* rt
s v/
(Figure Remove)
11
radicals X26, X4, X% X7 (in partial formula 2}, X\ S6, X7 (in partial formulas 2 ana 4), X3a, X~b, X*, Xs, X7 (in partial formulas 5, 6 arid 7) or Y4, Ys, Y7, y£ (in partial fornix.ilas S, 9, id and 11) are the same or different and $r£ selected from hydrogefi atoms, C^Cj alkyl -groups, v?hich in addition ce^ contain a hydroxy group that is cptiorially etherlfied with a G,-C5 alkyl grcup or ester if led vit,h a C^C*, allcanoyl group, partially or completely fluorinated Ci-Cs alkyl groups,- C2-CS alkenyl groups
-CR5=CS6R7, whereby R5, Rsf and R7 havs "lie above -nisntioned meaning, alkinyl groups -C=CR5, wnersby R5 has th= above -mentioned meaning,
radicals X3S and Xs" &lso together with the. C- 5 torn cf
ring system 5, S or 7 can form a :ring wi"h a
total of 3-7 links,
and moreover, radical® X*, X6, ^ V-T. partial formulas 2, 3, 4, 5, 6 and 7) or Y4, Y5, r, -YE (in partial formulas 8, 9, 10'and 11} are selected'from halogen acorns, hydroxy groups, C,-C= slkoxy groups or C^-Cg alkanoylcxy groups,
also if B 'in general formula I Suends for a CHi: group, Ar in
addition "stands for a phenyl radical of general partial
formula 12, s

12
in which R9 arid Rlf> are the same or different and mean a eyano
group, a nitro group, a halogen atom, .=;. C%-C£ "alky! group, a C,-C5 alkoxy group, a partially or completely fluDrinated C,-CS alkyl group, a CS-CS alkylthio group, a C,-C5 alkylsulfinyl group or a C,.-CS alkylsulfonyl group,
and it E stands for a CHa group, the physic'logicsilly compatible salts of the compounds of'general fonrrala I with acids,
The compounds according to the invention ars distinguished from the known nonsteroida.1 corapouinds v/ith qastagenic action by the substitution pattern on the aryl radical that, is on the right in general formula I. In the compounds that, are present here, Ar is a benEocondensed, bicycl'ic ring system, while in the structures thst are known from £P Q 253 500 31 and that can be considered as the closest compounds, a phenyl radical that is substituted in one, two or three places is at this point.
The compounds of general formula I according to the invention can b« present ss different stereoise-msrs because of the presence of asymmetry centers. Both, the racernates and the stereoisomers that are detached ars part of the subject cf this invention.
The substituents that are defined as groups in rh& compounds o£ genaral formula I can h&ve th» followina meaning* in each case .
Ci-C. Alkyl groups can readily be a. methyl/, ethyl, n-prcpyl, isopropyl, zi- .- isc-, ts'rt- butyl group or an r.-pentyl, 2,2-dimethylpropyl or 3 -iristhylbutyl group, -A methyl cr ethyl group is preferred,
A fluorine, chlorine; brorrdne or iodide atom can stand for a halogen atom. Here, fluorine, chicrin- or bromine is
If R1 and Rs together with th* C-atom of the cha-?i form a 3-7-membered ring, this is, for example, a cyalo]propyl, cycle-butyl, cyclopentyl or -cyclohexyl ring-, The eyclopropyl ring is preferred.
For a partially or completely fluoridated C;.-CS alkyl group, the perf luorinated alkyl groups that appear above and of the latter mainly the trif luorotnethyl group or p&ntaf luoroethyl group as wall as partially fluorinated alkyl groups, for example, the 5, 5, 5,4, 4-pentaf luoropentyl group or 5r 5 . 5 .4 , 4 , 3 , 3-heptafluoropeintyl group are consi dared.
As a Cj-Cj alkenyl group, fox- example , a vinyl-, allyl- or 2, 3 -dimethyl -2 -propenyl group can &ppes.r; if aromatic compound A is substituted with an alker.yl group, preferably it is a vinyl group .
'-.•-.- Representatives of a Cj.-Cs alkotry group are selected from rnethoxy, stiiojcy, n-prcpoxy, iso-propoxy, n-, isc-, tert-butoxy —oups or n-per.toxy, 2 , 2-dimethylpropoxy or 3-methylbutoxy oups, A methoxy or ethoxy group is preferred.
C^-Cj Perf luoroalkoxy groups are the corresponding rfluorinatad radicals of the C,-C5 alkoxy group. s above.
Monocyclic or bicyclic arorratic ring ft,, which can be bstitured, is a carbocydic or hsterocyclic arvl radical.
In rhe first ease, this is, for example, a phenyl' or naphthyl radical,, preferably a phenyl radical.
As s heterocyclic radical/ for example, a monocyclic seterocyclic radical can bs.. for example, the thienyl, furyl. pyrariyl, pyrrolyl, imidaEolyl, pyrasoiyi, pyridyl, pyrssiir/I, syrimidinyl, pyridasinyl, thissolyl,- oxazolyi, furasanyl, pyrrol inyl, - ami da sol ir.yl, pyra sol ir.yl, thiazol inyl, tri azolyl. retrasolyl radical,, specifically all possible isomfers relative :.o the -positions of the heteroatortis. The thisnyl radical is sreferred as he.teroa.ryl radical A.
For R", 8, methyl, ethyl/ n- or iso-prcpyl g::oup is preferred as a C^C5 alkyl group in es.ter group -COORAs a Cj-C, alky! group for ether i float ion of hyclroxy jroups, the above-mentioned. _alky 1 groups are suitable, primarily a methyl or ethyl group,.
.As a •Ci-C5 alltanoyl group for e~terif i cat ion of hydrcxy groups, a fornyl, ecetyl, propionyl, butyryl, isobutyl/ valeryl or isovaleryl group is suitable, preferably an acetyl group.
If XSa and X3t togsthsr with the G-atom of the benzocondensed ring system forni a 3-?-msmbered ring, this is, for example, a cyclopropyl, cyclobutyl,. cycloper*tyl or cyclohexyl ring. The cyclopropyl ring is preferred.
&s 3. c^Cs alkanoyloxy group for X\ Xs, X7, Y", Ys, Y7 or Yfi,. a foinmyloxy, acetoxy., prGpinoyloKy., butyryloxy,. iso-butyryloxy, valeryloxy or isovaleryloxy group is suitable, preferably an acetoxy group.
The above? ,-jnent icned C^-CS alx:yl groups can sit and for C.±-C-alkyl within the C,_-CS alkylthio, C.^Q5 alkylsulfi.nyl or C,.-C5 alkylsulfonyi group.
if the compounds of general formula I (3 = -CK,) are present as salts, this car; be -in the forffi of, fct' example,. hyar-ockloride, sul£&te, titrate;, ' ta.rfcrat6 SSf b
If the compounds according to the invention are present as racemic mixtures, they c&n be separated into pure, optically active forms according to the methods oc racemate separation that are familiar to one skilled in the art. For example,, the rsLcemic mixtures can be separated by chromatography into purs isomers on an even optically active carrier msteriatl (CHJR&LPAK ADl'R;") . It is also possible to esterify the free hydrcxy group in 3 racemic compound of general formula 1 with an optically active acid and to separate the diastereoiscrneric esters that are obtained by fractionated crystallisation or- by ehrcraatography, and to saponify t-ne separate esters in each case into the optically pure isotners. For example, mandelic acid, csmphorsulfonic acid or tartarie acid can be used as optically active acid.
Preferred according to this invention are thcs* compounds of general formula I, in which:
R1 and R2 are the same or different and stand for a
hydrogen atom, a methyl or ethyl group, and also together with the c-atorft of "he. chain stand for a cyclopropyl ring, and/or
R5 stands for a C-^C, perfluoroalkyl group, and/or A stands for a benzene, naphthalene or thiophene ring that is optionally substituted fay one or •more radicals, selected from flucrine atoms, chlorine atoms, bromine atoms, methyl croups, ethyl groups, (CHs)fl group (11=3,4,5), -which with 2 adjacent C atoms of aromatic compound & forms .a ring with n+2 links and can contain unsaturations,- vinyl groups, hydroxy groups, methoxy groups, ethoxy groups, and/or either stands for & hydrogen atom or a C±-C5 alkyl group, or
K3a and X3£ are the sam-i or different arid star.a tor a
hydrogen anorn or s. CL-CB alkyl grcup and/or X1. x- ar.ri X7 are the same or different, and stand for, independently of one another, a hydrogen acoiti or a halogen atom, sold/or Y"* stands for a C,-C= alky! group or a Ci-C5
perfiuoroalkyl group, arid/or
Y5,. Y7 and -Y* are the same or different and, independently of one another,, stand for a hydrcoen atcrt: or a halogen atom,
arid the other su.bstitusn.ts all have the meanings that are indicated, in Formula 1.
In addition, those compounds of general formula I in which Ar stands for a ring system1 of partial foriTaila 5, 7, 1C or 11 are preferred.
The compounds that, are mentioned, below ar& -sspecially preferred according to the invention.:
4 -Bromo-5-(2 -hydroxy-4 -methyl-4 -phenyl-2 -1r i fluoromethyl-
valeroylamirio} -phthalide.
6 -bromc- 5 - (2 - hydroxy » 4 - methyl - 4 -phsnyl - 2 • ;:i i f luoromst hyl -valeroylamirio} -phthali.de,
5 -(2-hydroxy-4-methyl-2-pent afluoroethyl-4-phenyl-
valeroylamino}-phthalide,
5-[2-hydroxy-4-(3-msthcxyphsnyl)-4-methyl-2-tri-f luoromethyl -valeroylarriino] -phchs.1 ide,
5- [2- (hydroxy»4- (4-rnetho^yphenyl} -4-methyl-2-trifluoromathyl-valeroylarrdno] -phthalide,
5-[2-hydroxy-4-(2-hydroxyphenyl)-4-methyl-2-tri£luor-omESthyl-valeroylamino] -phthalide,
5- [4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trif luoromsthyl-valeroylarrdno] -phthalide,
5-[4-(4-fluorcphenyl)-2-hydrcxy-4-methyl-2-trif luoromethyl - v&l'Srcylsjnirio] -phtnal ids t
5- [4- (4-chlorcphsnyI) -2-hydroKy-4-rriSthyl-S-trif luoronisthyl-valsroylaminol -phLhalide,
S-[4,.(4-hromophenyl)-2-hydroxy-4-m6thyl-2-tri-f luoromethyl-valfercylamino] -phthalids,
5- [2-hydroxy-4-Tnethyl-4- (4-tolyl) -S-trifluorometbyl-valeroylatnino] -pht.hal ide,-
5- [2-hydrcxy-4-methyl-4- (3-tolyl) -2-trifl-acrorr.e:thyI-vaieroylamino] -phthalicie,
5_ [4_ (4-cyanophenyl) -2-hydroxy-4-Trlethyl-2-trif luoromsthyl-valeroylaminoj - phthalicie.,
5-[4-(3,4-dimethylpbenyl)-2-hydrcxy-4-m£thyl-2-crifluoromethyl-valsroylamino]-phthalide,
5-[4- (3,S-dimsthylphenyl)-2-hydroxy-4-raethyl-5~ t r if luoromethyl -valeroylsmino] -phthalide,.
5- (2- hydr oxy - 4 - (2 •• methory»3 -me t hylph.en.yl) - 4 ~ trie thy I - 2 -fcrif luoromethyl-vale-roylamino] -phthalide,
5- [4- {5-chloro-2-hydroxyphsrryl) -2-hydroxy-4 -methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5 - [.4 - (5 - £ 1 uoro- 2 -hydrosyph-sny 1} - 2 - hydroxy- 4 -rne thyl - 2 -trif luorornsthyl-valeroylaminol -phthalids,
5- f2-hydroxy~4- (2-hydrcxy-5-me-thylphen.yl} -4-methyl-2-trif luororaethyl-valeroylamino] -phthalids,
5- [4- (5»flucro-2-inethoxyphenyl} -2-hydroxy-4~methyl-2-trif luororaet,hyl -val eroy 1 araino] -phthalide „
V,- 5-[4-(2~fluoro-4-msthoKyphenyl)-2-hydroxy-4-methyl-2-trif luoromethyl -val eroylatninol -phthalide,
5- [4- i3-fluoro-4-methcxyphenyl) -2-hydx-oxy-4-rnathyl-2-trif luororaethyL-valeroylamiuo] - phthal ide,
5- (2-hydroxy-4-phenyl-2-trif luoromethyl-va.l£rcyiamino) -phthalide,
5- [2-hyd±'cxy-4- (2-msthoxyphsnyl) -4-methyl-2-
-phthalids,
trif luorotnethyl-valsrcylatdno] -phth^Iide,
phthalide,
5- (2- hydrcoiy - 4-r!flstnv.i-"-4-pusnyj.-2- tri£iU.oi.C5"':£•;Lny~ -pentylamino)-phtnalide,
5_ [4- (4-fluorophenyl}--2-hydroxy-4-'~etbyl-2-trifluoromethyl-pentylamino]-phthalide;
5- [4- (5~J:li:Gro-2-hydro?cyp>h.anyl • -2-hydrcxy- 4-methyl-2-trif luoromethyl. -pentviand no] -phthelide.
6~acetyl --5- (2 -hydrcsry-4-methyl-4-pbenyl-2-
5- [4- (3-fluoro-4-hydrcxyphenyl) -2-hydroxy~4"-rasthyl--2-trif luorotriethyi -yaleroylarru.no] -phthalids,
5- [4- (3-fiuorophenyl} -2-hydxiC!xy-4-msthyl-2-
t r i f luorome t hyl - va 1 e r oy 1 arrd.no ] - ph t ha i i d.e,
S~ (3-hydrcxy-3-msthyl-l-butinyl) »3~ (2-hydrcxy-4-iTiethyl-'{ phenyl-2-trifluorom.'Sthyl-valeroylandiio} -phthalide,
e - [2 -hydroty- 4 -methyl - 4 -pheriyl - 2 - trif luoron.ethyl •-valeroylarnino) -4-methyl-2,3-benso>;,&2ir;-l-one..
6- (2 -hydroxy- 4 -methyl -4 -pher^yl - 2 - trif I uoroniethyl-
valsroylamino j -4 -1 rif luoro'itietbyl -2 .. 3 - b&nsoxazin-1 -or*s,
4-ethyl-6- •'2-hydro5cy-4-pher.yl-2-triflucromethy.i-pentylamino)-2,S-bensoxasia-l-one,
>,. 4 - e t hyl - £ ~ [ 2 - hydroxy- 4 - (2 - me t hoxypheny 1} - 4 - me t hyl - 2 -trif lucromethyl -valeroyl ami no] -2 , 3 -bensoxasrin-1 - one,
6-[2-hydrcxy-4-(2-mfethoxyphenyl)-4-methyl-2-trifluoromethyl.-valeroyl amino 3 -4 -tnsthyl -2,3- b$.r_? oxasin-1 -one,
4-ethyl-b- [2-hydroxy-4-Tnethyl-^- {4-methylpt.enyl) -2-trif luoromethyl-valsroylaTT-inoj -2,. 3-ber.zoxazin-l-one,
g-r 4-(4 -bromcpheny1)-2-hydroxy-4 -methy1-2 -trif luoromethyl-valercylafnino] -4-ethyl-2 , S-benscxaain-l-one,
4-ethyl-£- [4- ;5-fluorc-2-n'iethox'yp-r--"iy-) -2-h/drc.:xy-4-rnethyl-2-tri£luorC'Tiiethyl-V£.---roylaniinoJ -2, S-b-n^-xasin-l-o
g_ [4_ (5-£luoirci.-2-tr,ethc.xyphsnyI} -2-hydrcxy-4-iT;ethyl-2-trifluoromethyl-yalsroylamincj-4-methyl-2,3-ben2DX£2in-I-o
on
t r i f 1 uoromet hy 1 - 2 -- pent, e.nol /
1- (4-nitro-3"tri£luorom~thyl aniline) -4-ph.enyI -2-tri fluorotnethyl - 2 - pent anoi ,
5- (2-hydrcxy-4 ,. 4 -dimethyl ™ 2-- trif 1 -;oromethyl -R-hexenoylamino) -phthalide ,
5- [2-hydroxy-3- (l-phenyl-oyclopropyl} -2-trifluoromethyl propionyiamino] -phthai idle ,
5- [2-hydroxy-3- (l -phenyl-cy^Iobury1!) ~2-triflu.oromsth.yl-propionyl.amino] -phthalide,
5- [2-hydroxy»2> (1-phenyl-cyclob.exyi) -2-trif luoromethyl-propionylamino] -phthal ide ,
2-hyciroxy-4-»sthyl-2-trif luoroTiiethyl -4- (4-virjylphenyl) -
yai'Snc 'acid,
4 - ( 4 - acetylphenyl } -2 -hyclroxy- -i - methyl - 2 - 1 rif luoromethyl • valeric acid,
4 - { 4 - acetyl - S -m£t hoxypheny 1 ) - 2 -hydr oxy- 4 - me thyl - 2 -crif luo.r ome thy 1- valeric acid,
4 - (4 - cyanophenyl } - 2 -hycircxy-4 -niethyl -2 - trif luororn^thyl -valeric acid,
"•':..•-.' 4- (4-carbarnoylphenyl) -2-hydricxy-4~msthyl-2-trifluoromethyl -valeric acid,
4 - ( 4 - cyano -• 2 - tnet hoxypheny 1 } - 2 - hydroxy - 4 -me t hy 1 - 2 -trif luoromethyL- valeric acid,
4 - ( 3 -bromo- 4 -methoxyphenyl ) -2 -hyc.ro>:y- 4 -niet hyl -2 -trif luoromechyl -valeric acid,
2-Hydroxy-4-imet:hyl-4- (3-nitrO-4-tTi€iC-hOK;yph.en^l] -2-trif luoromethyl -valeric acid.,-
4_ (4-iodo-2-m6thoxyphenyl } ^4-Tnethyl-2-oxo-v5,leric acid,
4- (3-chlorophenyl} -4-uvethyl-2-o3io-vsls;ric ac*.cif
4-(S-brcrnophsnyl)-4-rfiethyl-2~oxo~- 4- (2-icdcphenyl) -4-m~£hyl-2--cxo-V3.1eric acid,
4- (3-iodophenyl) - 4-methy1-2-oxo-valeric aci6,
4-(4-iodophenyl)-4-tns;thyl~2-oxo-v£l1aric acid,
4- (5-fluoro~2-TTiethoxvphsnyi) -4-methyl -2-oic-valeric acid,
4- (4-bromo-2-Tr.eth.oxy-ph.enyl) -2-or-LO-vsleric acid,
3-(l-phenylcyclopentyl)-pyruvic acid,
S-[3-{l-ph^nyl-eyclopropyl)-2-cxo-propionylamincj-4-methyl-2,3-bensoxasin-1-one,
[3- (1-phenyl-cyclobiityl) -2-cxo-propicnr/l«mino3 -4-
metb.yl-2, 3 -benzoxazin-1-one,
[3- {l-phenyl-cyclohtaxyl} -2-o:x.o-prc>pionylamino"j -4-
msthy1-2,3-benzoxazin-1-one,
5- [4- (4-iod.o-2-methoxyhaiiyl) -4-methyl-2.-ttxc-' valeroylaminoj-phthaliae,
5-[4-(4-iodophenyl)-4-methyl-2-cxo-valeroylamino)-phthalide,
5- [4- (3-iodophenyI) -4-nisthyl-2-oji:o-valerGylaTnino) --phthalide,
5- [4- (4-brcTT!0-2-msthcxyhsnyl} -2-oxo-valeroylswinc) -phthalide,
5- [3- (1-phenyl-cyclcpan.fcyl) -• 2-cxo-propioiiylaTni.no] -phthalide, X....... 6- [4- (5-fluoro-2-methoxyhenyl) -^-raethyl-2-cxo-
vale±-aylatnino) -4-methyl-2, S-benaoxazin-l-orie,
[4- (5-f lucro-2-n\eth&xyphsnyl) -4-msthyl-2~oxo-
valeroylarnino) -.4-ethyl-2.. J-benzoxasin-Z-one,
(2-hydroxy-2,4-dimethyl-4-phsnyl -valercylarnino) -4-
methyl-2,3-banzoxa2in-l-one,
5- [4- {3-chloro~4-methcxyphenyl} -2-hydro>:y-4"rr.ethyl-'-trifluoromethyl-valeroyl£.mino) -phthalids.
5- [4- {3-chloro-4-hydroxyphenyl) -2-hydro5:y--0-!r.sthyl-2-trifluororasthyl-valercylamino]-phthalide.
All above-mentioned compounds are especially preferred in the forra of the optical antipodes or the separate cliastiereomers„
in the gestagsn rsosptor bonding rss" ou, ^xi-E w^jB-w^^enic action using cytcsol frora rabbit Taterus hotnogen.a':e and fro^n JH-progsaT;eron.e as a reference substance; the new c<: shew a strong to very affinity the gsstagen receptor remove> In addition to their gestagenic action, which is pro­nounced to different degrees dsper-ding on the coripound of-general formula -I that is considered, the new coripcuncls also are distinguished by a mere or less strongly pronounced affir ity to the androgen receptor. The ancro'gen receptor bonding test, on androgenio action v;as carried cut using oytcsol that consists of rat prostate horiogenats anci ^-irtethy? trienolone a a reference substance.
The nsv? compounds are thus represented relsi;ivc tc the gesfcagenie compounds from B;P 0 253 500 31 as compounds with c quits novel mix profile, which consists of gestagenic arid, androgenic action.
For the compounds of general formula I according to the invention, in this case all three of the esses.- that are pos­sible below are found, which, based, on the conrpet Ltion factors on progesterone receptor (XF^J and anirogen. rfetftptoi" (KP^^j are classified within the scope of this inventica as follows:
Compounds with stronger geste.genic .action, and less
pronounced androg&nic action (KFProg
5);
Compounds with stronger androgenic .action and less •
pronounced geet;£s.eriic action (KPv^^,,
1);
3) Compounds with pronounced, gsstagenic snd pronounced
androgenic action (KFj,,.^ Depending on thsir classification according to 1), 2} or •3). the new compounds according to the invention can be used for different rrradical or pharmaceutical purposes.
In the case of the compounds that are classified under 1} with stronger cfestagenic sdticn and less prcnounced androgenic action, these are very effective gestagens, which, like the already numerous known ges'c.agenic corripounds, are suitable for
iirStrs.'!" "i cr and in i.hs c&s~. J. orsl avpinstrs-tiot..
In combination with an estrogen, combination preparations
are obtained that ca:i be ixsed for contraception and, for the.
treatment of 'inencjpausai ^yrnptGms. • - -
£w!picj,ci^ C'~^"i t^T'S"1' "t' ^"1"' '"'^ G'SS^" ^^"-^-t r' '~iO'~ "' ••*'"^t . n-^S ""^^U' r'O^Tl^OD**iQ- of gsnerail formula I that are rls.?^:if led -,jn.der :i} c.-r; be used, for example, slone or in combination with estrocens i~, contracepti've prep a rat-ions.., However, all ether applications that are knc'tfii foi" otstsian s.re now cpfe; to the-.se new compounds (seer e^g., "Kon.trasept.ion mil:. Hormoner; [Contraception with Hormonss]," Hans-Dieter Taubart and Herbet Kiihl, Georg Thieme Verlag Stuttgart - New York, 1SSS) , Suitable dossgss can be determined as a matter of routine: e,g'.,- by deterraining the bioequivalency, for es-zample in the [email protected] test, ralati-- to a kno^^ qestagan. fcr a specific use, for example .; amount tnat is bioeqiiivalent to 30 to 150 teg of levonorcjestrsl for contraception.
The dosage of the compounds according to the invention under 1) in contraceptive preparations is preferably ™c- be 0.01 to 2 mg per day.
The gestiga-nie and astrogenic active ingredient components ars preferably administered orally together in contraceptive preparations. The daily dose is? preferably administered once.
As estrogens, all natural and synthetic compounds that are known as es-trogsnically active are suitable.
As natural estrogens, these are especially es~radial and' also ins longer-act ing ester's, such as valerate, stc. or estriol.
Preferably,- howsver. synthetic estrogens such 5.3 ethinvl-festr&diol, l^o . 2Vct'-st-hano-3,,. 3 . 5 CIO) -33tr5.tri3ns-3~17'3-dicl (WO
38/01275) , 14«,17a-ethar!.Q-.I,3,5 (10} - estratriff=r.ft-3 , l£c?f 1"S-triol (WO 91/03219} or the 15,15-diallyl derivatives of the estradiol, -and of these especially 15 . l6-dirn~r,hvlestradicl (WO 95/04070} can be mentioned. As a synthetic estrogen., ethinylestracLC'l- is preferred.
Also, th,6- astratrieij-2 -siminosul f c-r.Liitss that have become known recently (v?0 S6/0521S and WO 95/05217} , derived from sstrsoliol or si. th; tT"rl The estrogen is administered in an Emount th:st corresponds to that of 0.01 to 0.05 rn« of etbinylestradic-1.
The new compounds of general formula I that are classi­fied under 1} can also be used'in pr©psrations for treatment of gynecological disorder* and for substitution therapy. Because of their advantageous profile of action, these compounds .accordingr to ths- invention ire sspscip.iiy well suited for treat merit, of premenstrual symptoms, s-ich as headaches/ depres-sior., water retention and mast.^dvnia. Th-a daily dose in the treatment of premenstrual symptoms is approximately i to 20 tP.g.
Analogously to what is already • known for ot.ner gestagens, the new compounds can also be used for- treating sntiamstricses.
Finally, these new compounds can also be us50. as gestagsnic components in the con-positions for female birth control that hav& r~eefifcly b&come kncv.'n and that are distinguished by the additional use of a competi'iive progesterone antagonist (H. B, Croxattc a.nd A. M, Salvati^rra in Female Contraception and Mais Fertility Regulation, sd. by
Runrjebaum, ?;&b£ & Kiessl - Voi , 2, Advances in- Gynecological and Obstetric Research Series ,. Parthenon Publish.:. n-g Group -IS91, page 245; WO 93/17685, WO 93/21527, US-Pat . =,=21,156).
The dosage lies in the range that is already .indicated, and the fornvulation can be carried cut as in coir.re£~icnal OC-pr^parations . The administration of the addi'lonel, competitive progesterone, antagonist car. in this case also ba performed. sequentially,
Those corripounds or the general ' formal a , v^hi^h. sirs, to be categorised as above under 2} and 3), i.e.,- compounds that have a strong androgenia action (sndrogeiii- gest^cens) , can be used for ths production, of pharmaceutical preparations- for male .birth control .
Currently, in several WHO' studies, the contraceptive action of a combination that consists of an -orally administered, geetagen (D-spc?t-ir.edrcvy progfestercr^ acetate, levonorgestrel ester, cyproterou$ acetate) is tested on men with a parent er ally administered, androgen (testosterone
Sy contrast, birth control in men is possible with these compounds in one de-sage form,- specifically an oral dosage form or a dosage form that is to be administered trar^sderrnally., In addition, the compounds according to the invention with androgenic action can be used with older males for male HRT (Hormone Replacement: Therapy) »
Those compounds of : general formula I, which can more likely be classified, under 2), i.e,, compounds • v.lth mainly androgenic act ion and. ws&ker gestc.g'snic action, can be used for male hcrmori* therapy. Preparations for tree ting a hyper -gonadiam ar.d for treating male infertility and disturbances of potency can be produced with them.
For trials birth control and fax- treating the- above -mentioned, androgenic disease agents, the ccirrponrids according
to the invention are uesi in the dosages that are equivalent' in action to the testosterone oe:ianth.at: .Amounts that ars equivalent in action are those amounts that,- in the t-5St on andrcgenic action on the seminal vesicles and/or prostate cf the rat (Hershberger Test) , a.chievs comparable action.
For HRT in. man, to date a substitution close cf a'DDroxi-nately 10 mg/day of testosterone oensnthate is uwsd.
For male birth control studies that are performed by the 7HO, different testosterone esters (oenanthate, bucyclate, indecanoate) are used in the range of approximately 10-30 g/day.
At this point it- should be pointed out that tha transi-lions between 1) , 2) and 3J , as regards the corrslatiorj iccording to the invention of variou£3 indications with these •arying mix profiles I}/ 2) and 3), etre smooth. The compounds ^hat. • more likely lie on the edge of the indicated KP areas based-on their KP^eg and/or KF^,^, can easily be used also for the indications that ar* assigned to the adjacent tr.ix profile.
The compounds of general formula 1 also partially snow actions on th«s glucocorticoid and/or mineral corticoid receptor.
: -.- The frtrmulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient, optionally in combination with an estrogen, being processed with the vehicles that are ,o—l* used in galenical., diluents, optional* taste
^ =nd conveyed in the desired 3:orm of correctives, e^-/ —
administration.
Per the preferred oral adr~i:ii£trstior;f •ssptclsA ly tablets, coated tablets, pills, suspension or solutions are • suitable.
For psrenteral administ-rstion. especially c-ily solutions, such as, for example', solutions ir. sesame oil, castor oil and cottonseed oil, are suitable. To increase scli±ility, solubilizers, such as, for ex.5-rr.pl e, b-snryi benscsts or benzyl alcohol., can be added.
The compounds of general formula T cs-n a.lse be administered continuo-usly by an intrautsrine re!'.:?;..s-e system (intrsuterine system = TITS; e.g., MIRE>iACR)) ; the release rate of the active compound (s) , is selected in this c-s.ye in such a way that the dose that is released daily !JU;s wlth;.n the already indicated dosage ranges. It is also possible to incorporate the substances according to the invention in a transdermal system and thus to' administer them trarisdermally.
The' compounds of general formula I according to the invention can be produced as described below.
Production Process A'carbcnyl compound of general formula II

U
in which £, S, .kr, R* and Rz have the meaning that; is irj.diC5.ted in formula I, is react&d with a compound of general formula C^F-.^-SiR3, in which R: has the'meaning that is indicated in general formula 1, in the presence of a catalyst or with an alkyl metal compound, for example a Qrignard reagent or e lithium alkyl, to a compound of formula I, 'As catalysts, fluoride salts or basic cortipounds such as alkali, carbonates ars suitable (J. Amer. Chew, Soc. Ill, 393 (1989)). 2, A compound of general formula III

HI
in -vhieh' A, 3, RS R2 and R2 have the yearling that, is indicated in formula 1 and FG means a leaving group, is reacted with a compound Ar-NK-R11, whereby Rn uie&r.s a hydrogen atom or a. C;,-C? acyl group, and Ar has the meaning that is indicated in general formula. I, whereby optionally then radical R11 is cleaved off to obtain a compound of formula I. :.n this case, the compound of general formula III optionally can be formed only as an intermediate product, e.g., this can be an acid chloride that is ferried as an intermediate product from a corresponding carboxylic acid. As leaving groups

IV
formula I, is reciCted, with a compound of £o.rrriul£ Ar-NH-R4'", v/hereby Fc.- and Ar have T:he aloe-ve-i^^.ics^ed ra,ear^ncrr, whereby opcionally then radic&l R~" is cleaved off, tc olitcin a compound of formula I with B in the r;eaning of 2 CH2 groi:p, 4. A compound cf formula 1, which In radical A or in radicsl. Ar contains the grouping aryl-X, whereby- "SLryl" means an isocyclic or h^terocyclic sromatic cowpoxmci the." corresponds to the definitions that arc* giv^n fc-r forrrrula I and X means a bromine or iodine atom or the grotp -O~S02H17f in which R1" means a C^-Cs perf liioroalkyl group, is ::e&cted under rnstal catalysis to compound' aryl-R1J according to processes that are knqvjn in the art with a cornpoancl of fci-Tnula R1J-Y, whereby J?13 represents an optionally su.bi?tit.ut-3d aryl , ethenyl or ethinyl radical and Y represents . a. hydrogen 5, to™ (J. Org. Chera. 43, 2947 (1^73)5, group B (0-ku), (J. Org, Chem. 5S; 2201 (ieS3}} or Sn(R15)j £j. Org. Chem, 52, 422 (19S75) with R" and R*5 meaning a phsnyl radical or CX-C3 alkyl a:id R14 also ffep resents hydrogen, Mg-halccen or an alkali metal atom,
5. In a compound of formula I, which conte.ins an &lkcxy 01- acyloscy substituent in A or Ar, ths CH group is released/ and o'Dticnally -etherif isd or est>srif led in another reaction or, after conversion into a I-phenyl-S-tetrasolylsth^r, is completely el i-n.in.ated by hydrogenaticn (J, Amer. Chsrn. Soo. 88, 4271 (196S) ) .
Or all the foregoing process variants,, l, and 2, are suitable for the production.of all compounds that fall under: general formula I.
Compounds of general formula I can be .produced with th* third variant, in which 3 stands for a -CH2 group..
Using the fourth and fifth process variants, functionaJ izations of already existing compounds of general formula I can be undertaken.
Compounds chat were produced according to one of the processes shove and in which A is an optionally substituted aromatic: ring, optionally can be selectively substituted at this aromatic radical according to jcriot^n processes. Example of this process are the catalytic hydrogenation cf multiple bonds, nitration and halogenation.
The starting -materials that are used in the examples az-s produced as follows;
Production of Starting Materials 4-Methyl-4-phe-tiyl- 2 ~oxcvalerit acid
A Grignard solution that is produced from 2f?,4 g .or magnesium and 162 ml of 2-niethyl-2-phenyI-l-chICv:oprcpane in 150 ;nl of diethyl ether vas acdefi in drops to £0;) ml of oxalic acid di&thyl ester at -3Q°C. After 2 hours at rcorn temperature, it was added to ammonium chloride solution., extracted with die-clay 1 ether, dried (Ka^SO,} and. .Sistilled ir_ fracticnatsd form; 84 g of ethyl ester (boiling point 115-12C°C/0.03 h?a) , which is dissolved in 1 1 .of math-anal, is obtained, mixed wirh 500 ml of 1m sodium hydroxide and stirr&d. for 1.5 hours at room temperature. After the rriethanol is evaporated in a vacuum, the residue is dispersed between water-arid diethyl ether, the aqueo'as phase is acidified with hydrochloric acid and extracted with diethyl ether. After concentration'by evaporation, 57 g of 4~rnethyl-.4-ph.e3T/l~2-. oxovaleric acid is obtained as a thick oil,
4,4-Dimethyl-2-oxo-5-hexenoid acid
36 g of 3,3-dimethyl-4-penterjoic acid is obtained as an oil from 50 g of 3,3-dimethyl-4-pentencic acid methyl ester by saponification with 10% potassium hydroxide. By stirring with thionyl chloride (20 hours, room temperature), the acid chloride is obtained,, boiling point 59°C/30 hPa. 16 g of it is stirred with 15 g of trimefchylsiiylcyanide and 0.16 g of zinc iodide for 4 days. After distillation, 13 g of 4,4-dimethyl-2-oxo-5-hexerio;ic acid nitrile, boiling point 75-£.5°C/30 hPa, is obtained. 2 g jof it is saturated with G_S ml of methanol in 13 ml of hexane v;hile being cooled with ice with hydrochloric-acid gas, and it is mixed for 2 hours with water. From the hexane phase, after drying {NasSO4) and concent ratios, by evaporation, 0.55S g of 4, 4-dimethyl-2--oxo-5-hexcrioic acid methyl ester, boiling point 4B°C/0.003 h?a, is obtained. 0.535
-g of it is So/son if i&ci with I > 3 *nl cf 3'C sodium hvdroxjds solution, -thereby 0.32 3 of « , 4-dimethyl- 2 -oxo-Ei-h/sxenoic acid is obtained as a yellowish liquid.
3- (1-Phenyl-cyclofautyl) -2~w&c?-p2X 10 g of 1-phenyl-cyclobutanecsrhoitdtril sf dissolvea u; /u ml of toluene., is mixed, with 5£ ml of diisctoutylalurainuin hydride in toluene (1.2 molar} at -72 to ~e$*C. After 4 hours at -75°Cf 30 ml or &thyl acetate i« added, in drops. After heating to room temperature; 'additional ethyl acetate: and. water are added. It is filtered, on di.atouia.caou;-; earth, the organic pha.se is separated, drivel (Ns3S04; strict concentrated by evar>oration. After chromatography on silica gel. (hexane with 0-10% ethyl acetate), 1..B g of l-phenyl-cyclofoutanecarbalde-hyde is obtained, 3 g of it is dissolved in 10 ml of tetrahydrofuran and. added in drops at 0°C to a solution, in which previously 5 g of trie-thyl-2-ethox^hosphono&eetate in
70 ml of tetrahydrofuran was mixed- at 0°cl with 10.3 ml or a molar solution of lithium, diisopropylandde in t€:tr«hyciro.-f ursn/hfipta.!!© -^'SthvlbSirissrus . Aft€;r 20 h,*yuirs st i'"ocrri tstripsra-turer water is added; it is extracted, with ethyl acetate, dried (Na^SO^} and concentrated by e vapor at. ion, 2 g of this crude product is saponified with 23 nu of IN soc.iuTr. hydroxide solution. 1.32 g of the acid, which is heated for 20 hours to $o°c with 25 ml cf I molar sulfuric acid while being stirred vigorously,- is obtained. After extraction with ether, drying (NasSO.) and concentration by evaporation, O.S9 cr of 3- (1-phenyl-cyclobutyl) -2-oxo-propionic acid is obtained, as a yellowish 3- [1- (2-Hstho:cyphenyl) -cyclopropylj -2-o:-:,o~propicnic acid
Corresponding to 3. Crg . Cheiru 40 (1975) 3-597, 16^7 g of 2-rnethoxyphenylacetonitrile/ 15S nil cf lithium criiscpro'Dyl-
amide (2 rr.cl solution) and 45.7 ml of I ^-dichlorosthsne in 95 ml of tscrahydrofuran and 53.6 ml of hexan-thylphosphcric acid triatnide are reacted with &ns another. 5.S g of 1- (2-metho^y-phenyl)-eyclopropyl-carboriitrile, boiling point 104-115°C/Q.1 rnbar, which v;;;i.£ also reacted as described- for 2-• (l-phsr;yl-cyclobutyl•-2-oxo-propionic acid, is obtained. 3-[1-(2-Methoxyphanyl;-cyclopropylj-2-ox:c-propionic aclc!- is thus obtained as an oil.
Analogously to the process thot is described for 2- (I-phenyl-cyclob'jtyl)-2-oKo-prcpj.oiii"-1 acid and for 3-[l-f2-methoi:yphenyl)-cyclopropyl]-2-oxo-propionic acid, the scids thar. are described, in Table 2 were obtained..
Table 2
2?


(Table Remove)
3- (1-Fhenyl-eyclopropyI) -2-sK&-prc?pior.ie acid
is obtained analogously to the process that is described for
3~(l-phenyi-cyclobutyi)~2-oxo-propianic acid,
i
3- (l-Pheayl-cyolohearyl) -2-O3£S-p*r0pionid acid
is obtained analogously to the process -chat is described for 3-(1-phenyl-cyclobutyi)-2-oxo-propionic pcid.
4- (3-KethQ3cyph>&2iyl} -4-srteth.yl-2--C!3:a-valeria acrid
4.2 ml o£ a O.e rr> solution of 3-iiiethoxYphsnyImagnssiurf, bromide in tetrahydrof-aran is mixed at -?0°C with 257 mg of copper broraide-dimathylsulfide complex and then stirred at -40°C for 20 minutes. It is cooled again tc -70*0, and 0.33 ml of 1,3-dimethyl-tetrahydro~2-lH-pyriiTiidi?i.orje and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Idebigs Annalsn [Liebigs Annals] 1974,. 477} and 0.71 ml of trimethylchlorosilans in 3.5 ml cf tscrahydrofuran are slowly added. It is stirred for one hour at "70CC and then heated to room temperature. Then, 2N hydrochloric1 acid and ethyl acetate are addsd, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethaae. After 200 mg cf tetrabutylarmtionium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethans phase is d-rfed (lsTa,S04) and concentrated by evaporation. After chroma-togrephy on silica gel with hexane/ethyl acetate {97:3}, 63 mg of 4- (3-methoxyphenyl) -4-methyl-2-oxo-valeric ac:Ld-taechyl ester, which is-mixed with 1 ml of potassium hydiroxide in tnethanol (10%), is obtained. After 45 minutes, :Lt 'is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is "hen acidified with 5N hydrochloric ecid and. extracted with diethyl ether. The diethyl ether phase is dried (Na3S6j and ccncen-
trated by evaporation. SO mg of 4-{3-methoxyphenyI}-4-methy2 2-oxo-valeric acid is obtained.
2-Hydroxy-4-methyl-4-piienyl-2-tri£luoroir.ethyl-va:Leric acid
The Grignard reagent is produced from 1.5 g of magnesium and 10 g of 2-methyl-2-phenylpropyl chloride in :LOO ml of iiethyl ether, which yields 9.5 g of 2-hydroxy-4--methyl-4-phenyl-2-trifluoromethyl-valeric acid ethyl ester, boiling point 90°C/0.045 hPa, after reaction with 10 g of trifluoro-pyruvic acid ethyl ester.
7.5 g of the ethyl ester is refluxad with 100 tr.l of potassium hydroxide in methanoi (10%) for 18 hours. After concentration by evaporation in a vacuum, the residue is iissolved in water and extracted with ciiethyl ether. The aqueous phasfi is acidified with 2N hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation. 3.2 g of 2-hydroxy->:—methyl-4-phenyl-2-trifluoromethyl-valeric acid is obtained as colories* crystals, boiling point 124-126°C.
4- (5-Fluoro-2-methoxyphenyl) -2-hydroxy-4-iaethyl-J:-trifluoromethyl-valeric acid
1.3 g of anhydrous zinc chloride and 13.2 g of granular manganese are heated to boiling in 100 ml of tetrahydrofuran and boiled with 0.2 ml of methallyl bromide for 20 minutes. Then, the solution of 25 g of methallyl bromide s.r.d 17 g of trifluoropyruvic acid ethyl ester in SO ml of tetrahydrofuran is added in drops at boiling heat over 2 hours, e.nd boiled for another hour. Then, while being cooled with ice, saturated ammonium chloride solution and 300 ml of ethyl acetate are added, stirred for 30 minutes at 0°C, and the separated ethyl acetate phase is washed with saturated ammonium chloride solution and three times ;with water. The solvent is dried
(Na-SOj and. cancan-rated by evaporation; -and the residue 'is distilled in a vacuum.- 17.5 g of 2-hydroxy-4-in5~nylene~2-tr if luorome-hyl -valeric acid ethyl est=r, boiling point 4£cC/i hPa, is obtained.
0,8 g of anhydrous aluminum chloride is added to 5 ml of 4'-fluora.nisole and. 0.2 g of 2-hydroxy-4-~ieth.yle,Ks-2-trif luoromethyl -valeric acid ethyl ester. After 40 hours of stirring &t room tempera ttire, it is added to ice -cooled 2K hydrochloric acid and extracted with *thyl acetate. The ethyl acetate phase is washed with IN hydrochloric acid and water, dried (Ha;s04) and concentrated by evaporation. After chroma tography cn silica gel with hexane, /ethyl a-:>sr.ate (1:1), 1 g of 4- (5-fluorcj-2-nistth"o.xyphenyl) -2-hydroxy"4-Tr1ethyl-2-trif luoromethyl -valeric acid ethyl ester, melting point 33-39°C, is obtained..
1..9 g of 4- (5-fluoro-2-;r;ethc:':yphe-nyl) -2-hydro>r.y-4-raethyl-2-tr.i.fluoromethyl-valeric acid ethyl ester is re fluxed with 40 til of potassium hydroxide in methanol (10%) for 2 hours. \fter the solvem; is concentrated by evaporation in a vacuum, tfater is added, it: is extracted with hexane, and the separated iv'ater phase is; acidified with 6'S hydrochloric acid. After extraction with erhyl acetate,, the ethyl acetate phase is vashed with water, dried (Ne^SO..) and concentrateid by evaporation, Th* residue is crystallised frorti hexane. 1,55 g ?f 4- (5-f luoro-2-rnethoxyphenyl) -2-hydroxv--4-rnethvl-2-:rifluoromethyl-valsric acid, melting point 102-104CC, is >btairied,
-4- C2- thienyl) -2-tr££ luorcsaetiyl- val eric .cid and 2~Hydroxy-4-methyl-4- {3-thiesiy!} -2-tri.2.!luc-rosa.ethyl-aleric acid
The mixture of 2.-hydroxy-4~Tnethvl-4- (S-thisjnvl) -2-
trif luoromethyi -valeric 'aoiil and 2-lrydrcxy-T-met:hyl-4- (3-
thienvl) -2-trifluorouiethyl-valeric acid (5:1), melting pom: ISO-IBI'C, was produced analogously.
The acids of Tabls 3 were prefaced anal


s-
T~
(Table Remove)
3y conversion according to th -.Hy"iRylphenyl) -valeric aid
By heat ir.,,., :i--b±omophenyl) -2-hydroxy-4-tn*thyl-'2-rifluoromethyl -valeric. acid ethyl sst;er, tributylvihyluin, ri-o-tolylphosphine s.nd bis-tri-o-tolylphosphine-alladium(ll) chloride in di methyl forraemide to 120*0, 2-ydroxy-4 -me thy I - 2 - 1 ri f luoromfet hyl - 4. - (4 -vinylpher.yl } -valeric cid ethyl ester, which provides th* title compourid., melting oint 73-74°c, by alkaline saponif icaticn, is obtained.
. - (4-Acetylpb.en.yl) -2-valeric acid
Analogously to the compound above of 4 - ( 4 - broraophenyl ) - 2 hydro3cy-4-taethyl-2.-trifluororaethyl -valeric acid ethyl sster, tributyl-l-ethoxyvinyltin, tri-o-tolylphosphine cind bis-tri-o tolylphosphine -palladium (II) chloride in dimethyl form.5irdde to .120°C and subsssquent acidic hydx^olysis of the enoi sther and alkaline saponif Icata-on, trie It ing point 158~iS2°C,
trifluoromethyl- valeric acid
Analogously to the compound above of 4- (4~brcTr.c-3~ methoxyphenyl } - 2 -hydroscy- 4 -methyl - 2 - 1 r i f luorometliyl -valeric acid ethyl ester, tributyl-1-fethoxyvinyitin, tri-o-tolylphosphine ana bis-tri-o-tolylphosphine-palladium(ll) chloride in dimethyl formamids to 120°Cf oil.
4-(4-C
acid
From 4 - (4 -broraophenyl} -2 -hydroxy-4 -methyl - 2 -trifluorame-thyl-valeric acid ethyl sster, sine cvani.de and t &t raki a -1 r iphenylphosphine --pal 1 adi urr, in dims thy.L f. orm-a^i de s t 140*C, After saponificaticn, the title acid is obtained as a foam.
4- f 4 - CarbeaoylpkeriyI} - 2 -hydrssry-4-esstiiyl- 2 -trif 1 •j.erossethyl-valeric acid
. 'is obtained by treating the ethyl ester of the acid abov 4 ~ ( 4 .. cy ana - 2 -me tiiOKypheny 1 } - 2 - hydrosy - 4; -351$. thy 1 - 2 - • trif luorojnetlzyl-valaric acid
From 4 - (4 -bromo-2 -methcxypheriyl } - 2 -'hydroxy-4 -methyl - 2 -t-tif I uorcmethyl- valeric acid ethyl ester, zinc cyanide arid tietrak.ig-triphenylphosphine-palladiviiTi in dim&thvlform&TOide at i4Q°C, After saponif ication, the title acid is obtained =>*, an amorphous powder .
4 - ( 3 - B rojrio - 4 -3ns th,o.*frfpheny 1 } - 2 - hydr oxy - 4 -ata t by 1 - i -
trifltioromethyl- valeric acid
: • Prom 2 -hydroxy-4- (4-raethoxypiisnyl) -4 -me thy.] -2-
trifluoromethyl -valeric acid ethyl ss^er by brotiistion with N-bronosuccinimide in dimethylformarai-de at 0CC and subsequent saponif icatiori; Melting point 94-96c'C.
2 -Hydroxx-- 4 -las thy 1 -4 - '(3 - ni t sro - 4 -aae thoxyfisheaiyl ) - i! -trifluoromethyl- valeric acid
This compO'jrid is obtained by reaction of 2,5 g of 2-hydroxy-4- (4-rrt*thoxypheny! ) -4 -methyl -2 ~ trif 1-ucron-etiivl -valeric
acid ethyl ester with 4- ml of 100% nitric acid in 12 ml of trifluoroa.cetio acid for one hour at 0°C, meltinc} point 79-20°C.
4- (4-I&do-2-ffietho;^^h&aya} ^4-s;et.hyl-2 -fcxc-vals^ic acid
3,2 g of 4-iodo~2- rnethoxybsrisoic acid -methyl ester in 1C ml of di&tlryl ether is addsd to 24-2- mm;?! of methyj-rDagnesiu" bromide in 23 ml of di&thyl ether. After 20 hours, ammoiiixim chloride solution is added, the ether phass is separated, dried and concentrated by evaporation, 2.4 g of the residue is dissolved in 10 nl of dichloromstharie, mixed with 714 mg of 2 -trim3thvlsilylc>ry --acrylic acid-ethyl ester, ccolecl to -70C'C and mixed with '0.27 ml of tin (IV) chloride, After 15 minutes, the solution is added no potassium carbonate solution. After extraction v;ith disthyl ethsr, the organic phase is washed with water, 'dried and concentrated by evaporation. 500 mg of the 4- (4-iodO"2-methoicyphe,r//13 -4 -methyl -2 -cxo- valeric acid =thyl ester that is thus obtained is stirred with S . 5 ral of 1 vi sodium hydroxide in ethanol/ water (2:1, v/v) tor 3 hours at room temperature. After water is added, it is extracted with iiethyi ether., the aqueous phase is acidified with 1 in wdrochloric' acid and extracted with diethyl ethsr. After Irving and concentration by evaporation, 410 rag of 4-(4-iodc-J-methoxyphenyl) -4 -Tnethyl-2-oxc- valeric acid is obtained as a rel-lowish oil ,
) -4-aiethyl-2-03£0-valeric acid is obtained analogously to the embodiment s.bove of an amorphous powder.
4 - ( 3 - Broniopheny 1 ) .- 4 -as t Jiy 1 - 2 - O3to - val esri c acid
is obtained snalcgously to the sishodiment E.bcve o£ an amorphous p
is obtained analogously to trie tmboiiraent: above as an norphous powder .
- ( 3 - Jodoph&zvyl ) -4 -methyl - 2 -oxo- valeric acid
is obtained analogously to the embodiment sibe-ve of an powder.
- (4-loa.ophenyl) -4-Hi&tiiyI-2 -ostc-v&lsric acid
is obtained, analogously to the embodiment sibove as? an 11.
- ( 5 - F Itio s?o - 2 --ae thcssyphsny 1 } - 4 - m-a thy 1 - 2 - coco - valssr i c ao id
is obtained analogously to the en'i>odiment ^bove, rrielting Dine 53-60eC.
4- (4-BroEio-2-iaet.h»3typ*ieriyl} « 2 -oxo- valeric scid
is obtained, analogously to- the e;r.:bcdime:r.it cibcve as an oil .
3 - { 1 - Plienylcyolespenfcyl } -pyruvic acid
is obtained analogously to the ernbodiment £.bove from i-phenyl cyclope:^ tanol with 2 -trimethylsilyloxyGcrylic acid-ethyl ester and tin (IV). chloride as an oil,
4-ToIuenesul£onic acid- (2 -feydroxy -4 -ph.sn.yl - 2 - trif lx\orc?methyl -pentyl) ester
A Grignard solution, to v;hich 15 ml of oxalic acid diethyl estsr is -added s.t, -30°C within 30 minutes, is prepared from 2.5 g of magnesium chips and 15 ml of 2 -phenyl -1-chloropropans in diethyl ether. It is stirred for one hour at -20°C and for 2 hours at O'C, and then mixed with "saturated ammonium chloride solution. The diethyl ether r>hase is
separated, dried (Ka...s04) and concentrated - by «"c.pors.ticn and distilled in a vacaun. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 9£-100*C/0.02 h?a. is obtained.
4,4 g of 2-oK£>~4-phe-nyl valeric acid ethyl ester is
dissolved in 40 ml of. ^enrabydrofursn .and mixed at -78°C v;ith
3*5 ml of trifluorotne'thyl-trirnethylsilane and 2 mi of I'M-
tetrsbutylammoriium fluoride in tstrahydrofiirEri, After 24
hours at -7S°C, another 20 ml of I M tetrabutylaiiTnainuttt
fluoride in tetrahydrofuran is added. It is stirred for 1,5
hours at 0*0, ethyl acetate and saturated common salt solution
are added., the organic phase is separated, and it is washed
with saturated common salt solution and water., Then,, it is
dried .(Na'2SOi) and concentrated by evaporation arid' distilled on
a bulb tube. 4.4 g of 2-hydroxy-4-phenyl-2-trifiuoromeTihyi-
- valeric acid sthyl ester, ^boiling point 95-100QC/0. 04 hPa, is
obtained, • • -
4.35 g of 2-hydroxy-4-phanyl-2-trifluoromethyl-valeric acid ethyl ester is dissolved in 100 iril of diethyl ether and stirred at 0"'C with 1.3 g of lithium aluminum hydride for -one hour at O^C and for IS hours at room'temperature. A little water is added while being cooled, and it is stirred." for one, hour. The diethyl ether phase is separated, dried (Na2SQ4) and concentrated by evaporation and distilled on a bulb tube. 4.1 g of 4-phenyl-2-trifluoroniethyl-l,2-pejitanediol. boiling point 12D°C/0,04 hPa, is obtained.
4.25 g of 4-phenyl-2-1rifluoromethyl-1,2-pentsnediol in 30 ml of pyridins is mixed at 0°C with 3.8 g of 4^ tolussnesulfonic acid chloride. After 16 hours ;at 0°Cr it is concentrated by evaporation in a vacuum, mixed with ethyl scetate, washed with water, dried {Na2S04} and concentrated by evaporation. 3y crystallisation from ethyl acetate/hexane, 4/9 g of 4-roluenesulfonic acid-{2-hydroxy-4-pr,enyl-2-
:r ifluorcme thy" -pentyl) ester, melting pel n't 55-36°C, is >bt.ained,
Analogously, 4-toluenesuIfonic scid- (2-hydroxy-4-in*t;hyl--phsnyI-2-tr:Lf luororriethyl-psntyl; estsr, melting point 7S°C, is obtained.
Analogously, 4-toiuenssu.lfonic acid- [4- (4-f luerophenyi) --hydrcxy-4 -methyl -2 -trif I'liorozrietbyL-pentyi j esvsr,- melting oint 80-Sl°C, *nd 4-tcluen*sulfordc acid- [2-hydroxy-4- (2-ethory-B-f luorophsnyl ~i ~ 4 -methyl - 2-trif iucrcraethyl -entyl] ester, melting point S3~S*5C'C.. vj«re prodMC'&d.
400 ffig of 4-tcluen-ssulfor,ic acid- (2-hycircKy-4-phe;nyl-2-L-ifluoromethyi-pentyl) ester ir^ 5 rr,l of dime thy 2 formamide is ixed at 0°c' with 35 mg of sodiura hydride (S0% in mineral oil) -.fter one hour at C'C, it is diluted with water and extracted tfith dichloromethane. The dichlcrorrte thane phase; is washed trith 'water, dried (Na2S'0.) and concentrated by evaporation. The residue is distilled, 200 mg of 2- (2-phenylpropyl) -2-:rifluorpmethyl-oxiran, boiling point 110CC/1 hPa, is obtainad.
: -Bromo- 5 - amirnophfchalide
23 g of .3-bronto-4-nitro-l,2-xylene is susp«jnded in 200 ml if pyridine and SCO ml of water and mixed at 60°C in portions •ith 260 g of potassium permanganate., whereby the temperature ises to SOSC. It is hsated for 2 more hours to 95°C.. filtered, the filtrate is acidified with hydrochloric acid and extracted with diethyl ether. After the solvent is concentrated by evaporation, 27 g of 3-bromo-4-nitrophthalic acid is obtained.
12 g'of acid is heated for 15 minutes to 2:;00C and then distilled on a bulb tube. . At 0.03 h&a, 10 g of 3-bromo-4-nitrophthalic acid anhydride is distilled.
The anhydride is dissolved, in 120 ml of directhylfcrrnsrrdde
and is slowly mixed at: 0CC wich 7S,£ ml - Of s 0.5 M solution of -
sodium borchyiride in. din^sthylfonnamid*, After 3 hours at 0C'C,
2i\r hydrochloric acid is earsfully added, £,nd it is extracted
with ethyl acetate. After washing with potassivira bicarbonate
solution, drying' (Na-.SO.,) and,concentration by evaporation of
the athyl aostate phase,. &. £ a of 4~brorio-5-;aitrophthalide is
obtained. . •
6.6 3 of 4-broTr>o~5~nitropbthalide i,« dissolved, in 45 nil of ethanol and added in drops to a triixture of 5^ g of iron (II) sulfate, 2SO :til of water and 65 ml cf anwonia (";?%) that is heated to 60QC and. stirred well. After 2 hours at 50CC, the mixture is absorptively precipitated five -times with 200 ml of diethyl erher. The diethyl athsr phases are cor;centrated by evaporation. As a residue, 4.1 g of 4-~brorriO-5-atnirjOphthalide is obtained, melting point. 17o-lSC°C.
6 - Bromo - 5 - aminoph thalide
4-Brorno-S-nitrophthaIic acid, anhydride is producsd analogously to the'process cf 4~broTr.o-S-riit.ro-l, 2-xylene that is described above.
By boiling with ethanol, s mixt/ars of 2-brc!mo-6-ethoxycarbcnyl-S-nitrobenzoic acid arid 3-bromo-:*.-ethoxy-carbonyl-4-nitrobensoic acid i-s obtained from the above. : , 1.2 ml of oxalyl chloride is carsfully added in drops to 7.2 ml of Si 0.36 rr. solution, of dirnethylfcrmamide in iiichloro" methane a.t 0°C'. The solution is stirred for 1 hour at 0°C and for 5 minutes at room temperature. After ccncer-.tration by evaporation in a vacuum, the residue is suspended, in 7 tnl of acetonitrile, cooled to -35°C and mixed drop by irop with 1.5 g of the estsr mixture. After one hour at the same temperstur^s, it is cooled ~o -70°C, £nd 2.4 ml of a 2 rn solution of. sodium borohydride in dimethylforrnamide is added in drc.ps. It is
stirred for 20 hours st room cevnperature, water is added, alkalized with potassium carbonate ana extracted, with diethy] ether. Tha diethyl ether phase is dried (Na.2SOJ and concen-
trated by evaporation. A mixture of S-brc-mo-S-r-Itrcphthalide and S-brotnc-S-nitrophthalide, which Is separatee, on silica ge with hexane/ethyl acetate (95:5), is obtained,
Ths reduction to aminophthalide is carried out as described above. S-Bromc-S-arninophthalide, melting point 235 241°C, is obtained.
5-Amiao-3-(1-propenyl)-phthalide
5 g of 2-brom.o-4-nitroban2pic acid, is converted into aci - This material is dissolved in 35 ml of eths.nol and added in drops tc a mixture of 50 g of iron(II) sulfate, 170 ml of wat-er and 50 ir.l'of ammonia (33%) that is heated to 60°C and stirred well. After 2 hours at SQ^C, the mixture is absorp--tively precipitated 5 times with 200 ml of dietJr.yl ether/ the diethyl ether phases are concentrated by•evaporation/ and the residue, is crystallised with hexane. 3.1 g of 4-amino-2'-bromo-benzoic acid-allylamide, melting point .115-1I7°C, is obtained. .
11 g of 4-arr.ino-2-broTnober.2Oic acid-ally! air ids, 5,2 ml of
acetonylacstone and 200 tng- of 4-toluenssulfonic acid are
lnxed for 1.5 hours- with e water separator. Then, the solution is diluted with ethyl acetate, washed v.'ith IN hydrochloric acid and theii. with potassium carbonate -solution,, dried (i\suS04) and concentrated by evaporation. The residue is crystallised with hsxians, 13.4 g of K'-s.llyl-2-35rGTno-4- (2, 5-ditnethylpyrror.-1-yl) -bensarrida, melting point.136-13S^C, is obtained.
2 g of N-allyl-2-broTuo-4- i.l g of 5 - (2,. 5 - dime thylpyrrol -1 -y 1) - 3 - {l - r. ropenyl) -phthalide, 8.56 g of hydrcxylamine-hydrochlcrids and 4.5S g of potassium hydroxide in 73 ml of ethane I/ water {15:5,3, w) are heated for 24 hours at 120°C. The solvent is distilled off, the residue is mixed -with water and extracted with ethyl acetste. The ethyl acetate phase is dried. (Na2S3j ar\d concentrated by evaporation, and chrorrs&tographed on silica g«l. S40 mg of 5-s.ffi3.no-3- (1-propenyl) -phthalide, melting point 125-130°C, is obtained with dichloroiriethar.e/methanol (99:1). The phthalides of Table 4 are obtained analogously.



L
Analogously to the production of 4-bron'io-5- (4-methyl-2-oxo-4-phenyl-vaieroylamino)-phthalide, the compounds of Tables 5 and 6 are obtained.
(Table Remove)

4 -Brcjfio-- 5 - {4 -methyl - ii -oxa -* -prtesyi- v=.i«_ ^ *«*~.i2is' ~ph.tha.Xids
412 -rag or 4-rriethyI-4-phenyl-2-oxc"=ieric ac:.-d is dissolved in 10 ml of dimethyl acet amide and mixed under argor at -8°C with 261 rng of thionyl chloride. After 20 'minutes of stirring at -3 to -i-3°C, 22 B rng of 4 -bro-Tso-B-airiincphthalide is added. It is stirred for 1 . 5 hours at room temperature, trier mixed with water, extracted with ethyl acetate r -hs organic phase is washed with water., dried (Ks.^SOj and afuer the solvent is concentrated by evaporation and after treatment with diethyl ether, 360 rng of 4-broTTio-S- (4-m©thyl-2-oxo-4-phenyl-valferoylamino) -phth&Iide, malt.in.g point .I.5Q-152°C, is obtained.
5- [3- ( 1 - Pheny 1- eye lop ropy 1} -S-aso-propioriylaaiisicJ -pfethalide.
was obtained analogously to the process that is describe^ for 4-bromo-S- (4~msthyl-2~o>:.o-4-pli'£nyI-valeroyl5mino) -phthalide from 5-aminophthalids and 3- (i -pherryl- eye lopropyl) -2-oxo-propicriic acid,, meltir.g point 132-13S°C.
5- [3- (I-Pheiiyl-ayclobiityl) -2-03:6-propicriy2,siaino! -phtheli'ds
was obtained analogously to the process th?;t is described for 4-bromo-5- (4-msthyI-'2-oxo-4'ph6riyl-valsroyi^mir].o) -phthalide from 5-eiminophthe.liae and ?- ( i-phenyl-cyclobut-yl} -2-. oxo -prop ionic acidf melting point 142"I4S°C.
5- IS- (l-?iis«yl-cycloJifexyi) -2«oxo-prop£onyia3iiriO:;; -phthalids
was obtained analogously to the process that is described for 4-bramo-5 - (4 -methyl- 2 -&: The compounds of Table 6 were also produce ir


(Table Remove)
5- l%~ (l-^henyl-cyclopropyl) -2-o%o-propiciri\"lsard».c«3 -4-methyl-
2,- 3 -benzoacaziii- 1-one
v,?as obtained analogously to the process ths.t is described
"or 4-brbmo-£- (4-raethyl-2-o3to-4-phenyl-vs.lisrcylc.!r1ino} -Dhthalide from S-amino-4-msth*/I-2, B-bsnzo&asin-l -one and 3-(l-phenyl-cyclopropyl)-2-oxo-propicnic acid, meltir,.g point 197-
S- [3- (I 'benzoxazin-1-one-
was obtained analogously ' to S- [3- (1-phenyl-cycloprdpyl)-2~cxo-prcpionylarrdrio] -4 -methyl -2, 3-ber~oxasin-.l-cne using 3-(i-phenyl-cyclobutyl) -- 2 -cko-- prop ionic acid, melting point, 155-156°C.
S- [S- (l^Fheayl-c^clohexyl; -2-ojtc?-prc'piortyIa.T.iao] -4-s$^thyl-2.. 3-benzoxaz in- 1 -one
was obtained analogously to £- [3- (1-phenyl-cyclopropyl) -2 -0X0 -propionylamino] -4 -methyl -2,3 -bensoxasir, - 1 - one using 3 -(i-phenyl-cyclohexyl) -2-oxo-propionic acidf Tn^lting poir^t 132-134°C , ' .
5 - ( 4 , 4 -Dimethyl - 2 - oko » 5 -hfeicstEt
was obtained analogously to the process that is described for 4 -bromo- 5- (4-methyl-2-oxc---4-pheriyl-valeroyla.mir,o) -phthalide from 5-aminophthalids and 4. , 4-diritethy:.-2-oxo-5" hsxenoic acid, melting point 103-104°C.
S -Brorao- 5 - (4 ~:&athyl - 2 ~o?:o -4 -phesyl - valer
Analogously to the example abovs, 1.7 g of 6 -bromo- 5- (4-TAsthyl-2»oxo-4-phenyl-valeroylamino} -phthalide :.s obtained from 2.0 g of 4-tnfethyl-4-phenyI-2-oxovaleric ac:.d and 1.11 g q£ ,e -bromo -5- asinoph thai ids with 1,57 g of thionyl chloride in SO ml of dime thy lacet amide, melting point 148-l,!jODC.
5. [4_ (4.-phthalide
vjss obtained analogously to the process that is describ-for 4-bromo-5- (4-Trtethyl-2-cxc-4-pher-yl-valercylanLino} -phthalids frotr. 5-aminophthalide. and 4- (4-iodo-2-msthoxvohftnyl)-4-metliyl-2-oxo-vai6ric acifi a§ s foam.
5- [4- (4-Iodophenyl) -i-ffistliyl-S-'SKc-va.leroyasss.iKCi; -pbthalide
was obtained analogously to the process that is described
for 4-bromo-S- {'4-methyl-2-oxo-4-phenyl-valercyl3ittiinc-) -
phthalide frora B-aminGphthalide sr;d 4- H-iodophenyi) -4-trtethyl-
2 -oxa- valeric acid 'as an oil. •
S_ [4- {S-Todaphenyl} -4"iss.tliyI-2»oxD"\ifaI&'rcyi®saino} -plfethalid.®
was obtained analogously to" che process that is described for 4-brGt»c-5» (4-m&thyl-2-cxc--4-rh-"yl-vaieroyl®ird^o} -phthalide from S- am nophthali.de and 4- (3-iodopneinyl) -4 -methyl -2-oxo-vale.ric acid, melting point 1$Q-1616C.
) -2"»cKC"Valer&ylasfarj.&} -phthalide was obtained analogously 1.0 the process that is described for 4 -brorao - 5 •- (4 -me t hy 1 ••• 2 - oxo - 4 - pheriyl -vs. 1 ercyl amino ) -pht ha -lide from 5-aminophthalide and 4- (4-bromc-2-iTiethoxyrjheriyl) -2-oxo-valeric acid, melting point 136-14Q°C.
5- [3- (l-Phen.yl~cy.clopen.tyl) -2-o5£O-propioK.ylsjBirtc.3 -phthalide
was obtained analogously to the process the.t is described. for 4-brome>-5- (4-methyl-2-oxo-4-pheny3 -valercyls.mino) -phthalids from 5-feffdrjophthalide and 3- U-phenyl-cyclopentyl) -2-oxo-propionic acid, melting point 140-144°C,
4 -methyl -2,3 -benaaxaain- 1 -one
was obtained analogously to the process ths.t is described. for 4-b£-ono-5-.54-methyl-2-oxo-4-phenyl-\T-aleroyl£.tnino) -phthalids from 4-methyI-2,3-bensoxazin-:i-ane anc! 4- (5-fluorc-2-methoxyphenyl) -4-methyl-2-oxo-v£lsric acid,- malting point 171 _
$. [4- (S-Fluaro-2-3ttisthoxyhftayl) -4-a3asthyl-2-oxo-valsroylaaii»o -
4-ethyl-2f 3 -beiriZcxszia-l-sis.® :
was obtained analogously to ths process that is described for 4 -bromo-5 - (4 -methyl -2 -oxc-4 --phenyl - valerc-y lan-ino) -phthslide fron 4-ethyl-2, S-fasnscxarin-l-one and 4- (5-fIxicro»2-methoxyphenyl) -4~m&thyi-2-oxo-valeric acid, melting point 157-
158°C,
60 g of 2 -methyl -S-nitroacetcplienor.e, 38.5 g of 2,2-dimethyl-l/3-propanediol and 6 g of p-'toluenesulforiia acid are boiled in 1 1 of toluene with a water separator until water is no longer produced. The solution is washed with potassium bicarbonate, dried (KTsuSGJ end concentrated by evaporation. 71.7 g of the crystalline ketai is obtained front psntane.
The latter is oxidised, in 1,5 1 of pyridir;* and 4,5 1 of water with 350 g of potassium perir.anga.nate, as described above in the production of 4. -brorno-5-aminophCbali.de>., 56.4 g of .4-' . nitro-2- {2,S,5-trimet,hyl-l,3-dio>:an-3-yl) -bensoic acid is obtained.
S2 g of the acid is hydrogenat&d in 500 ml of methanol and 500 t?il of- ethyl acetate with 10 g of palladium/carbon (10%) „ 4S-5 g of the crystalline ami no compound is obtained from pentane.
':-"-* 10 ^ cf the amine is rfefluxed with 100 ml of concentrated hydrochloric acid for 2 hours. The solvent is concentrated by evaporation in a vacuum, and the residue is refl.uxed with 15.7 g of hydroxyiamine hydro chic ride, 8.4 g of pota«sium hydroxide, 120 ml of ethe.no! and 50 ml of water for 12 hours. It is diluted with water, and the crystals are auctioned off. After drying, 3.5 g of S-atrdno-4 -methyl -2, 3-ben:*c-xazine-l-one, melting point. 291-29S°C, is obtained.
6 - Amino - 4 - & tliy 1 « 2 , 3 - fosn 2 cstes ir. - 1 - oae
is obtained analogously from 2-rriethyl-5-nit:ropropiophenonef
melting point B9-93°C.
S-Amino-1'iaethyi-lH-beE.sotriazole
is described in Heterocyclss 36, 259 (1993) .
5-£aii:n.c~bens [I.- 2 , 5] oxadiaeole
is described in Boll.' Sci. F s.c . Chim. Jnd, Bologna ^ 22, 33r 36, 37 (1954) .
S-Aminc-beae [1,2, 5] -thiasole
is described in J. Keterooycl. Chem. 11, 777 (1574).
5 - Amino- 1 - indanorxe
is 'described in J. Org. Chsm. 27. 70 (1362),
l,. 2, 3 ,4-tetrahydrc»-l-iias>hthalin.c5^e is described, in j. Org.. Chew.,. 27, 70 (1962) .
& -tasd.no -3^4- dihydro - IH- 2 -benacpy r an - 1 - gsjs
is produced by catalytic hydroger;,&tion (pal ladiuiu/ carbon) in ethanol from the corresponding nitro compound (Can&d. J. Chem. 61, 2643 (1983) .
The examples balow are used for a more detailed explanation 'of the invention. Other compounds can be produced by using homologous /analogous reagents. The required starting compounds are -described above under "Starring Compounds."
Example 1 (Process 1)
4 -Bream - 5 - ( 2 -hydroxy - 4 -methyl ~ 4 -pb.er.yl - 2 - tr i f 1 uo: rose thy 1 -•valeroylsmino} -phthalide
250 mg of 4-bromo-5- (4-msthyl-2-o>:O"4-phenyL-valeroyl-amino} -phthalide is '-dissolved under 'argon ir, 15 ;nl of dims thy Iformami die and mixed with 0,77 "mi of trif LucroTP.ethy! trimethylsilane and 350 rng of cesium carbonate w.iile being cooled with ice. After 2- hours of stirring at rsotn tstnseri ture, 5 ml of a I M solution of tetr&butylamrnoniurn fluorids tetra.hydrafij.ran and some drops of water are added and ssira for one hour at room temperature. After 100 ml of watsr is added, it is ex~ractsd wir.h ethyl acetate,, the organic phas is dried {Na,S04) and concentrated by evaporatior.. 250 mg ( 4 -broma- 5 - (2 -hydroxy - 4 -methyl -4 -ph-nyl - 2 - 1 rif lucrometnyl -valeroylamino] -phthalide, melting point IST-lS-I^C, is ob.tsi
Example 2
6 -Bronte) - S - ( 2 - hydr oxy ~ 4 -methyl - 4 - pheny 3, - 2 - 1 r i f liic/rose thyl -valeroylamino) -phthalide
is obtained analogously to Example 1 from 1.6 g cf 6-brorac-5-(4-raethyl-2-oxo-4-phenyl-v£leroylaridno} -phthalide, 3.5 ml of trif luoromethyltrirnethylsiiane and- 1.6 g of cesium carbonate, melting point 205-210°C.
':- • ' Example 2
5 - ( 2 -Hydroxy--* -saeth.yi - 2 -pentaf ItiGroethyl - 4 -p&eriyl -valeroylamino) -phtlialide
is obtained analogously ts Example 1 from 20 tng of 5- (4-methyl-2-oxo-4-phenyl-valeroylatrJL.no) -phthai ide , 0,1 rr.l of trim^thyl-penrafluorcethylsilane and 20 mg of cesium carbonate,, melting point 187-189filC.
5 - £2 -Eydroxy-4 - ( 3 -zRsthc-arjrahssiyT} - 4 -methyl - 2 - tr i J'luttreaiMsthyl-
is obtained analogously to Example 1 .from 30 mg of 5- [4- (3-methoxyphenylj -4-methyl-2-o?:o-yaleroy: smino] -phthali-ds,. 0.13 ml of triflucroTnethyltrir!i€thylsi.4,an= and 30 mg of cesium carbonate, melting point 173-178°C.
Example 5
5 - 02 - Hvdroxy - 4 / 4 - diift® t hy 1 - 3 - 1 r i f 1 uo rcias tby 1 - £ - bt-xeuoy l aanino } phthalide
is obtained analogously to Ssatnpie I from 200 mc-f of 5-(4,4-dimethyl-2-oxo~5-hexenoylarTiinQ5 -phthalid-, 0.22 ml of trifluorcmeth.yl-trimethylsi.lane and 2E3 rng of -ceisium carbonate, melting point 153-157°C.
Analogously to Example I; the corcpounds of Table 7
(Table Remove)
If, instead cf the aminophth*lids, S-affiinc-4-methylbsiiz-i-ric-rje is u&sd. in .Example 1, the compounds that are listed in Table S ax-«s obtained.
(Table Remove)
Ex-ample 40
fi- (2-Kydroxy-2,4-di3ietHyl4-pheis.yl-valeroyl32RiriCj) - 4 -methyl-2 ', 3 -beszoxazin-1-one
72 tng of 5- (4 -tnethyl4-phenyl-2-oxo-vaIeroyletrp.ino} -4-methyl-2,3-benzoxazin-1-one in 4 ml of tetrahydrofuran is mixed with 3 ml or methylmagnesium brorrude (3 mb.'L) at 0°C; After 30 minutes, airxncniura chloride solution is added, the organic phase is separated, dried and concentrated by evaporation. After chrcrnatograpby en silica gel (hexane/ethyl acetate 1:1), 39 mg of 6- (2-hydroxy-2.4~diTnethyli-pher.yl--valeroylamino) -4-methyl-2,3-bsrisoxasin-l-one., melting point l73-175eC, is obtained.
Example 41 (Process 2)
5 - (2 -Hydroxy-4 -phetftyl-2 - trif lucfromethyl-valeroy 1 EEiin'o} -phthalide
500 rug of 2-h.ydroxy-4-phenyl-2-trifluoroTnet.hyl-valeric acid (Eur. Appl. 0 253 500 {Imperial chemical Indus-cries}) in 10 ml of- dimethylacetamide is mixed a't ~150C with 0.14 ml of thionyl -chloride. After 3 hours of stirring at -15°C, 600 mg of 5-sminophthalide (test) is added. .The solution is "stirred for 2 hours at -15°C and then left for IS hours at room temperature, then mixed with water, and extracted with ethyl acetate. The ethyl .acetate phase is dried (Ns^SC.) and concentrated by evaporation. The residue is stirred with diethyl ether and suet.ioned off. 290 mg of 5- (2-hydroxy-4-phenyl-2-triflubrornethyl-vsleroylainino) -phthaliis, roelting point 1SG-168°C', is obtained.
Sbcaasple 42
3- {2-Kydroxy-4-sifit;hyl-4-piiaKyl-2-tr'ifl'ac>roa5ethyl -velsroy mino) «4-aiethyl-2/ 3-beziBCotazin-l-c-iie
Ls obtained analogously to Example 41 frcn 734 rr-g of 2- . iydroxy-4-pber5yl-2-trifluorcttethyl-valeric- acid :Ln 1.7 nil iimethylacetatride and 500 n\g of a-arrd",o-4-Tf,e1c.hyl-'2,3-sensoxazin-l-one, mslting point 172-173°C.
Th* ccmpounds that are presented in Table 10 ars produced inalogously to Example 41:


(Table Remove)
v( / -.0__ "*1^—
CH~CH=CE-

(1) The optically active compounds that are presented in Table
10 were separated analogously to Example St.
In methanol.
Formation'of a 1-isochromanc-ne.
• - Example 102
(+} and {-) 5 - [2 -Hydr&sey-4 -methyl - 4 - {2 --methcxypJienyl) - 2 -
fcrifluoroBiethyi-valersylafllino] -phtbalicse
The esian'iiotner mixture of Sxample 73 is separated by chromatography on 'chiral carrier material (CHIRziPAK ADCS), DAICEL Company) with hex&ne/2-prop2LnoI/ethanol ! 900:25:25, vw) . Thus, fror, .200 mg of racemate, there ara obtained
A 33
73 mo of (-J-form, melting point r3€-i37°CV [alc = -1*, fo = 0.5 in chloroform )
59 mg of (+}-fcrtri, melting point 135-13€°C, i (c » 0.5 in chloroform) , .
Exssipla 103
- '
ssiirio] -phthalide and'
5- F2~Eydroxv*-4~znetIiv'l-4- {3-thie*iyl} -2-cri£I valeroylsajiirtc] -phthalide
The mixture of 3-hydroxy-4 ( + ) -5- [2-hydroxy-4-methyl-4- (2 -thi enyl) -2-trifluorornethy] valeroyl amino] -phthalide, rrselting point 1S60C, [jf]p = -f 163. 6s ( = -0.5 in chloroform), (-} -5- [2-hydroxy-4~metbyl-4- f 2 -thi enyl } -2- crif luoromethyl - valeroyl ami 710] - phthalide y rtislt.ing point, •166*0, [ot]E, = -16 0.3° (c * 0.5 in chloroform},. (•* > -S- [2-hydroxy 4 -methyl- 4- (3,-thi.enyl) -S-trifluoromethyl-valeroylamino] -phthalide, melting point" I35°C and (-) -S- [2-hydioxy.-4-!T.ethyl-4-(3-thienyl) -2-trifluororriethyl-valercylamino] -phthalide, -melt in point 135°C.
104 (Process 3) 5 - (2 -Sydroscy- 4-pheayl -2 - trif luorometiiyl -psstyl.asiao}' -phthalide
76 D mg of 5-acet£Kiido-phthalide in 20 ml of
dimethyl formami-de is mixed at 0PC with 144 mg c:: sodium hydride (60% in mineral oil) , and/ after 20 minutes/ with SOO tng of 4-tolusnesul f onic acid- (2 -hydroxy-4 -phsrsyl - 2 - trif luoronie thyl -^jgrttyl) -estsr. After 15 hours at 60°C, the solvent is C p^cent ratad by "evaporation in a vacuum, the residue is'
in ethyl acetate, washed with water, dried (Na2S04)
and concentrated by evaporation. After chrcvnac-oaraphy en silica "gel. with eyclohexaiie/ethyl -acetate (2;l), 266 mg of 5--'-2 - •h.vdLjrcxv - 4 -^h-envl - 2 ^ tri f llior'-ouistiiyl -D©nt yl s~in.o) --phth.sl ics, melting point 110°C, is obtained.
The compounds cf Tabla 11 are-obtained =na-logously to Example 104.


(Table Remove)
The optically active compounds that are presented in Table
11 were ssparated analogously to example 102.
In tnethano'l
Formation of a 1-isochromanone.
In chloroform.
Example 117
4 -Ethyl - S - (2 - hyc£r03-r/-4 -ph«ayl-2 - trif lu 2 , 3 -bansoxas in- 1 - one
The compound is obtained analogously to Example 104 from 151 rag of 6-acetairddG--4~ethyl-2, 3-bensoxazir:-2-one, 208 rag of-4 - 1 oluenesul f oni'c ac id- ( 2 -hydroxy- 4 - phenyl - 2 ~ t r:. f luoromethyl -pentyl/ ester and 35 mg of sodium hydride, melting point 161-163°C-
Example 118
trifluoroaisthyl -2 *--pentanol
100 mg of 4-nitro-3-trif Iuoromethyls.cet6.n.ilide in 2 nil cf iimethylformarcida is 'mixed at 0°C with 12 mg of sodium hydride (80% in mineral oxl) and, aftsr 20 minutes, 'with 150 mg of 2.-(2-phenylpropyl) -2-trifluoromethyl-oxiran. It is stirred for 16 hours at 60°C, diluted .with water ar;d extracted with ethyl acetate. After washing with water, the ethyl acetate phase is dried (Kia2SOJ and concentrated by evaporation. SO mg of N- (2-hydroxy- 4 -methyl - 4. -phenyl - 2 - trif luoroarte thy 1-valfcroyl ) - 4 - ni tro-3-trif luoromethyl aniline, melting point' 119-12Q°C/ is obtained.
After racemate separation analogously to E?:atnple 102, there are. obtained
the {-}-£or'm, [o]a = -49.££' (c = 0.5 in chloroform), the O) -form, [alg = +43.3° (c = O.B in chloroform).
Sxsoaple 113 (Process .4}
6- (3~HVcLroxy~3-methyI-l-butinyl} -S- (S-hydroK-y-^ phenyl-2 - trif 1'uoromethyl-valfercylaiiiino} -phtbalicle
150 mg of the bromine compound cf Example 2 is dissolved together with 30 mg of 2-methyl-3-butin-2-ol, 0.24 tng of copper- (I) iodide and 0.9 trig of tripbenylphosphir,* in 1.5 ml of pyridine. and inixsd under argon with 0,25 mg of bis-


(Table Remove)
(*} Obtained from the vinyl corrrpound by catalytic hvdroaenation.
{**) Obtained from the enol ether by- mild acidic hydrolysis
triphenylphosphine-palladiumdl) chloride. Aft^r 5 hours of reflux bailing, another 30 nig of 2-mBthyl-3-but:.-n-2-cl is added, and it is refluxed for 20 hours. It is diluted with water and extracted, with ethyl acetate. The ethyl acetate phass is dried (Na2SOJ and concentrated by evaporation. The crude product is chromatogrsphed on silica gel. With cyclohexane/ethyl acetate (l:l)f SO inq of crystalline S-(3-hydroxy-3 -methyl - 1-but inyl} -5 - (2-hydroxy-^-methyl -4 -phenyl -2 -trifluorornethyl-valercylavrdno) -ph.ths.lide, melting point 162-168°C, is obtained.
Example 120
S-iLcetyl-5- (2-hyd.rcrX.y-4-SKethyl-4~pheiiyl~2-txif Itiosoisiethyl-valeroylaiftitio) -phthalide
100 mg of the bromine compound of Example 2 is dissolved together with 95 nig of tributyi- (l-etnoxyvinyl) -tin and B mg of Ms-triphenylphosphine-palladium(II) chloride in 4 ml- of toluene under argon. After 5 hours of reflux boiling, another .451 mg of bis-triphenylphosphine-paliadium(II} chloride is addisd, and it is refluxed for 20 hours. IN hydrochloric acid is added and extracted with ethyl acetate. Th* ethyl acetate phase is dried (Na,SGJ and concentrated by evaporation. The crude product is stirred in 3 ml of tetrahydrofuren and 3 ml cf 2N hydrochloric acid for 2 days at room temperature. It is mixsd with water and extracted with ethyl acetate, After washing with water, it is dried (Na3SO The compounds of Table 12 are obtained analogously to Examples 119 and 120.
Example 134 {Process 5} 5 - [4 - (3 -Fluoro«• 4 - hydraxyphessyl} - 2 -hydrosry-4, -metry 1 - 4 - 2 -
fcrif ltiorcmethyl-valeroyl$3£iriol -phthalide
.132 rag of 5- [4- (3-fluoro-4-inathoryphenyl) -2-hydrcxy-4-Tnethyi-4-2 -trifiuoromsthyl-valeroyiarriino] -phthal ide (Example 50} is dissolved in 15 ml of dichloromethan? sric. rrd^ced at 0°C with 1.2 ml of a 1 M solution of boron tribromice in diohlorornethane. 'After 15 hours at C^C, ice/ ottiyl acetate ar potassium bicarbonate are added to the mixture, and the ethyl acetate phase is separated, dried {Na2SQj and. concentrated by evaporation. 120- rng of 5- [4- (3~fluoro-4-hydroxyphenyl) -2-hydroxy-4-ffieti:ryl-4"2-triflucrcmethyl-va.ieroyIamino] -phthalide melting point 13S-140°C, is obtained from ethyl acetaee/diisopropvl ether/hexane.
The compounds that are presented in Tabla 13 are obtained analogously to Example 134.
(Table Remove)


The optically active compounds that are presented in Table
13 were separated s-nslogously td. ^-vBtrinle IC2.
In, mefchanol.
152
S - T4 - i 3 -PluoropHenyl } - 2 -hydroxv- 4. -me thyl - -S"- 2 - trtf luc rasas thy 1 -valeroylamiiio] -pfethalida
£6 rag of (3-fluoro-4-hydrcx;>7pner.yl) -2-ky.drc:xy~4-rr,et£iyl-4-2-trirluoromethyi -valeroylarrd.no] -ph thai ids is stirred with 126 mg of potassium carbonate and 108 mg cf •5-chlore-~l~phenyl~lK-tetrazols in 3 ml of ditr,ethyl£ortnamid-= for 16 hours. Tiien, the dimethyl formsmide is distilled off in a vacuum, and the residue is dispersed between IN hydrochloric acid -5.nd ethyl acetate. After washing with water, the ethyl acetate" phafie is dried (Ma^SOj and concentrated by svsporation, and th;? residue is chj"omstographed on silica gel with hexane /ethyl acetate (1:1). The product .is hydrogenated. in 10 nil of tnethancX with 30 mg of palladium/carbon (10%) , After the catalyst is removed and' the solvent is "concentrated by evaporation, the product is chroma tographsd on silica gel with bexane/ethyl acetate (1:1), 4S mg of 5- [4- (3-fl-uorophenyl) -2-hyo.roxy--4-tnsth.yl-4-2-trifluoromethyl-valeroylsminoj Lphthalids; melting point 157°C, is obtained.
By racemate cleavage analogously to Example 102, the {'-s-)--forir. is .obtained with melting point "l^S-141ftC, arid the (-)-form is obtained with melting point 141°C.
\5-. [2-Sfydroxy-4-.ttiethy3.-4- (3-tolyl) -2-tri£lw»r«ae-;:.hyl-•'•aleroylaoninoj -phthalide
The compound, is produced analogously to thie , melting -. 152-153°C.
'•?y racatr^te cleavage analogously to Example 102, the (*)-\ obtained 'with-' melting- point 14S-14.SC'C, ajid th* (-)-foz -firiQ ooint 145-14£°C.
Example 154
5- [4- (S-Flucrc'-2~ethoxyprienyl) -2 trifluarometh.yl-yaleroyl8aB.ino] -phtlxalide
44 mg of 5- [4- (5-fluoro-2-hydrczyphsr.yl} ^-hydr rri3thyl-4-2-trifIuoramethyl-valeroyIaT?.irjoj -phthalide is stirred in 1 tTil of diiriethylftrrnarriide with 28 mg of potassium carbonate and 50 mg of ethyl iodi.de for 24 hours at rsotn tsmpsrsture. It is then mixed with water, extracted with ethyl acetate, the organic phase is washed with wetter, dried (Na^SGJ' and after the solvent is concentrated by evaporation, 35 m= of S-[4-(5-fluoro-2-ethos:yphenyI) -2-hydroxy-4-methyl-4-2-trif lucrornethyl -valeroylsmino]-phthalide, melting point 10S"C. ir= obtained.
Analogously to Example 154, .the compounds of Table 14 were produced:
Table 14
o
QHCF,

(Table Remove)
Example 162
5- [4- (3-ChlerQ-4-3&fefchc3cyphsayl/ «2-hy-d ' "tr rfTub'rcme tHy I -vsife-rcyx-BEiiii'o'}- -p-hths'll w -
22 mg of 5- [2r-hydroxy-4- (4-ruethoxyphenyl) - 4 -methyl -2-trifluoromethyl-valeroyiarnino] -phthsuide 'is stirred in 1.5 nil of metha.Aol with 20 mg of N-chlorosuc-cinimids for 5 hours. The mixture is then dispersed in ice water,, sodium bicarbonate solution and ethyl acetate, the ethyl acetate phase is dried, and it is concentrated by evaporation. 20 rag of 5- [4- (3-bromo-4 -methoxyphenyl ) -2 -hydroxy- 4 -methyl - 2 - trif luororr^ethyl -valeroyla.min.Qj -phthalide, which rrtelus after recrystallisation from isopropyl ether at 139-191°C, is thus obtained.
S- [4- {3
trifluoromethyl-valeroylaaaino] -phthalide
is obtained from 5- [4- (3 -chl 02:0-4 -methoxyphenyl) -2-hydroxy-4 -methyl -2 -trif luoromsthyl -valeroylaminc:] -phthalide by ether cleavage analogously to. Example 134, melting point 105°C.
The 2, 3-bensoxazincne and phthals-zincne derivatives of Table 15 were produced according to ths above -mentioned. processes.
(Table Remove)
(1) The optically active compounds that are presented in-Table
IS were separated analogously to Example 102.
(2) In methanol.
M) In chloroform.
207
5 - ( 2 -Hydroxy- 4- phenyl - 2 - tr i flue rose thy I - vs.1 erc-y 1 anisic 5 -benz [1,2, 5] oxadlazole
The compound was obtained from 2-hydro?;y-4-ph©nyi-2-trifluoromethyl- valeric acid and. 5 -ami no -bens [1 .. 2 , 5] oxs analogously to Example 41. Melting point 192°C,
Example 203
S- (2»Hydro2r.y-4-phsu.yl-2-t:rif Itsoro2a-sthyi-";-alsrcyls be&EO [1, 2 , 5] thia.d.iaaole
The compound was obtained from 2-hydroxy-4-phenyl-2-triflucrotnethyl-vaiferic acid and 5-amino-
benzo [1,2,5] thiatiiazole analogously to Example 41. Melting point 166-167"C.
209
o- (2-Hydrox5r-4-phenyl-2-trif luorosftethyi-vslercsylaiaino} - 1-mst±Lyl-ben.zotriazole
The compound, was obtained from 2-hydroxy-4-phenyl-2-t t if luorcjitsethyl - valeric acid, and S-amino'-l-methyl-bensotriazol^ analogously to Example 41. Melting point 1S4-1='S°C.

Claims
1. ' Compounds of general formula I
in which
R1 and R2 are the same or different and stand for a
hydrogen atom, a C-C5 or a halogen atom, and also together with the C-atom of the chain stand for a. ring with a total of 3-7 I'.nks,
R3 stands for a C^C, alkyi group or a partially or completely fluorinated C^-Cg alkyi group,
A stands for a monoeyclie or bicyc'.ic aromatic ring that is optionally substituted by one or more radicals,, selected from halogen atoms, Ct-C5 alkyi groups, C,-C5 alkenyl groups -CR5=CR£R7.. whereby R5/ Rs and R7 are the same: or different and, independently of one another, mean hydrogen atoms or CL-C5 alkyi groups; hydroxy groups, hydroxy groups that carry a C^C^ acyl group, a C3-C10 carbalkoxyalkyl croup, a C2-CS cyanalkyl group, a C3-C10 unsubstituted or substituted allyl group, a C3-C10 unsubstituted or substituted propargyl group, a CS-C5 alkoxyalkyl grcupy a C^~CS alkyi group that is partially or completely substituted by fluorine atoms, the .nyano or nitrp group, Ca-C3 alkoxy groups, Ci-Cs alkylthio groups, mono- or disub«tituted C-^-C^ amino groups or partially or completely fluorinated C^C, alkyi groups,
for an aster group -COOR*, whereby R* means a C^-C5 alkyi group,
for- a C2-C5 alker.yi group ~CR5=CR6E7, whereby R.5,
•^•arrd-R7 ar-e t-he same or -different, and,
independently of one another, mean hydrogen
atoms, halogen atoms, aryl radicals or Ct-Cs
alkyl groups,
for an alkinyl group -C=CR5, whereby R5 means a
hydrogen atom cr a C^-CS alkyl grcup,
for a partially or completely fluorinated C,-CS
alkyl group,
stands for a .carbonyl group or a CK2 group, and
stands for a ring system, selected from the
group of general partial formulas 2-11,










in which
radicals X3a, X4, X*, X7 (in partial formula 2), X4, X6, X7 {in partial formulas 3 and 4), X3a, Xib, X*, X6, £7 (in partial formulas 5, 6 and 7} or Y4, Ys, Y7, Y8 (in partial formulas S, 9, 10 and 11) are the same or different and are selected from hydrogen Atoms/ C^-C5 alkyl .groups, which in addition can contain a hydroxy group that is optionally etherifiad with a Cj-Cg alkyl group or esterified with a Ci-C3 alkanoyl group, partially or completely fluorinated C-CS alkyl groups, C2-CS alkenyl groups
-CRS=CR6RV, whereby R5, R6, and R7 have the above-mentioned meaning, alkinyl groups -C=CR5, v;hereby R5 has the above-mentioned meaning,
radicals X3a and X5b also together with the C-ato'n of benzocondensed ring system 5, 6 or 7 can. form a rin and moreover/ radicals X4, X6, X7 (in partial formulas 2, 3, 4, 5, 6 and 7) or Y*, Y5, Y7, Y8 (in partial formulas 8, 9, 10 and 11) are selected from halogen atoms/ hydroxy groups, C:-CS alkevxy groups or Gj-Cg alkanoyloxy groups.
also .if B in general formula I stands for a CK2 -group, Ar in addition stands for a phenyi radical of general partial formula
in which R9 and Ri0 -are the same or different and mean a cyano group, a nitro group, a halogen atom, a Ci-Cg alkyl group, a d-Cs alkoxy group, a partially or completely fluorinated C^-Q^ alkyl group, a Cj.-Cs alkylthio group, s. C,.-C5 alkylsulfinyl group or a C^-CS alkylsulfonyl group,
and if B.stands for a CH2 group, the physiologically compatible salts of the compounds of general formula I with acids.
Compounds of general formula I according to claim l in
the form of the racemate or diastereomer mixture.
Compounds of general formula I according to claim 1 in
the form of separate optical iseiners.
Compounds of general formula I according to claim 1,
characterized in that R1 and R2 are the same or different and
stand for a hydrogen atom, a methyl or ethyl group, and also
together with the C-atom of the chain stand for a cyclopropyl
ring.
Compounds of general formula I according to claim l,
wherein R3 stands for a Ci-Cg perfluorcalkyl group.
Compounds of general formula I according to claim l,
wherein A stands for a benzene, naphthalene or ':hiophene ring
that is optionally substituted by one or more radicals,
selected from fluorine atoms, chlorine atoms, bromine atoms,
methyl groups, ethyl groups, (CH2/n group (n=3,4,5), which with
2 'adjacent C atoms of aromatic compound A forms a ring with n+2
links and can contain unsaturations; vinyl groups, hydroxy
groups, methcxy groups, and ethoxy groups.Compounds of general formula I according to claim 1,
wherein X3a stands for a hydrogen atom or a Cj.-C5 alkyl group.
Compounds of general formula I according to claim I,
wherein X5a and X5b are the same or different and.stand, for a
hydrogen atom or a C^-C5 alkyl group.
Compounds of general formula I according-to 'claim 1,
wherein X*. X5 and X^ are the same or different a:ad stand for,
independently of one another, a hydrogen atom or a halogen
atom.

Compounds of general formula I according to claim 1,
wherein Y* stands for a C,-CS alkyl group or a Cj,--Cg
perfluoroalkyl group.
Compounds of general formula I according to claim 1,
wherein Y5, Y' and Y6 are the same cr different and stand for,
independently of one another, a hydrogen atom or a halogen
atom.
Compounds of general formula I according to claim l,
wherein R1 and R2 are the same or different and atand for a
hydrogen atom, a methyl or ethyl group, and also together witt
the C-atom of the chain stand for a cyclopropyl ring, and R3
stands for a C^Cg perfluoroalkyl group, A stands for a
benzene, naphthalene or thiophene ring that is optionally
substituted by one or more radicals, selected from fluorine
atoms, chlorine atoms, bromine atoms, methyl groups, ethyl
groups, (CHa)fc group (n=3,4,5),' which with 2 adjacent C atoms
of aromatic compound A forms a ring with n+2 links and can
contain unsaturations; vinyl groups, hydroxy groups, methoxy
groups, and ethoxy groups, and either-
X3a stands for a hydrogen atom or a C^-Cg alkyl group, or X3a and X3to are the same or different and stand for a hydrogen atom or a C,.-C5 alkyl group and X\ X6 and X7 are the same or different, and stand for, independently of one .another, a hydrogen atom or a halogen atom, or Y4 stands for a C-^C5 alkyl
group or a Compounds of general formula I according to claim 1,
in which Ar stands for a ring system of partial formula 6.
Compounds of general formula I according to claim 1,
in which Ar stands for a ring system of partial formula 7„
Compounds cf general formula I according to claim 1,
in which Ar stands for a ring system of partial formula, 10.
IS. Compounds of general formula I according to claim 1, in which Ar stands for a ring system of partial formula 11.
17, Compounds of general formula I according to claim 1, namely
4-Brcmo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifiuoromethyl-valeroylamino)-phthalide,
6-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2 -tri rlucromethyl-valeroylamino)-phthalide,
5-(2-hydroxy-4-methyl-2-pentafluoroethyl-4-phenyl-valeroylamino)-phthalide,
5-[2-hydroxy-4-(3-methoxyphenyl)-4-methyl-2-trifluorotnethyl-valeroylamino] -phthalide,
5-[2-(hydroxy-4-(4-methcxyphenyl)-4-methyl-S-trifluoromethyl-valeroylamino]-phthalide, :. ••• 5- [2-hydroxy-4- (2-hydroxyphenyl) -4-methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino].-phthalide,
5- [4- (4-f luorophenyl) -5-hydroxy-4-methyl-2-t.rif luoromethyl valeroylamino]-phthalide,
5- [4- (4-c.hlorophenyl) -2-hydroxy-4-methyl-2-trifluoromethyl valeroylamino]-phthalide,
5- [4- (4-bromophenyl) -2-hydroxy-4-n>t«tlayl-2-tsiifIucjrotnat.hyl-
valeroylamino]-phthalide,
5_[2-hydroxy-4~methyl-4-(4-toIyl)-2-trifluoromethyl-valeroylamino]-phthalide,
5-l2-hydroxy-4-methyl-4-(3-toIyl)-2-trlfluoromethyl-valeroylamino] -phthalide,.
5.[4.(4-cyanophenyl)-2-hydroxy-4-nethyl-2-trifluororaethyl-
valeroylamino]-phthalide,
5.[4-(3,4-dimethylphenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-valeroylamino]-phthalide,
5-[4-(3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyi-valeroylamino]-phthalide,
5- [2-hydroxy-4- (2-methoxy-5-niethyiphenyl) -4-methyl-2-fcrifluorornethyl-valeroylatnino] -phthalide,
5- [4- (5-chloro-2-hydroxyplienyl) -2-hydro3cy-4-methyl-2» trifluoromethyl-valeroylamino]-phthalide,
5- [4- (S-fluoro-2-hydroxyphenyl) -2-hydroxy-4--methyl-2-trif liioromethyl-valeroyiamino] -phthalide,
5- [2-hydroxy-4- (2-hydroxy-5-rr,ethylphenyl) -4--methyl-2-trifluoromethyl-valeroylamino]-phthalide,
5- [4- (5-fluoro-2-methoxypher.yl) -2-hydroxy-4--methyl-2-trifluorotnethyl-valeroylamino] -phthalide,
5- [4- (2-fluoro-4-methoxyphenyl) -2-hydroxy-4-iuethyl-2-trifluoromethyl-valeroylamino]-phthalide,
' 5-[4-(3-fluoro-4-methoxyphenyI)-2-hydroxy-4-Tnethyl»2-trifluoromethyl-valeroylamino]-phthalide,
5- (2-hydroxy-4-phenyl-2-trif luorornethyl-valoroylamino) -phthalide,
5-[2-hydrcxy-4-(2-methoxyphenyI)-4-methyl-2-trifluoromethyl-valeroylamino3-phthalide,
5-[4- 5- (2-hydroxy-4-phenyI-2-trifluorornet:hyl-peiit,ylamino) -
phthalide,
5-(2-hydroxy-4-methyl-4-phenyl-2-trifluorowethyl-
pentylamino)-phthalide,
5_[4_(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluorpmethyl-
pentylamino]-phthalide,
5-[4-(5-fluaro-2-hydroxypheiiyI)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylaminol -phthalide,
6-acetyi-5- (2 -hydroxy-4-methyl-4-phenyl-2-trif luoromethyl -valeroylatnino) -phthalide,
5_[4-(3-fluoro-4»hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthaiide,
[4- (3-flluorophenyl> -2-hydroxy-4-toethyl-2-t:rifluoronttthyl-
valeroylamino]-phthalide,
(3-hydroxy-3-nwsthyl-l-butinyl) -5- (2-hydroxy-4-methyl-4-
phenyl-2-trifluoromethyl-valercylamino)-phthalide,
S-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino) -4-methyl-2,3-benzcxaair.- 1-or.e,
6- (2-hydroxy-4-rnethyl-4-phe.nyl-2-trif lyoromethyl-valeroylamino)-4-trifluoromethyl-2,3-benzoxazin-l-one,
4-ethyl-6-(2-hydroxy-4-phenyl-2 -trifluoromethyl-pentylamino) -2,3-bensoxasin-l-or.e,
4-ethyl-S- [2-hydroxy-4- (2-methoxyphenyl) -4-T;iethyl-2-trifluoromethyl-valeroylarr.ino] -2, s-benaoxazin-l-bne, ':: -.- 6- (2-hydroxy-4- (2-methox.yphenyl) -4-methyl-2-trif luoromethyl -valeroylamino] -4 -methyl -2,3 -ben:soxasin-l -one,
4-ethyl-6-[2-hydroxy-4-methyl-4-(4-methylphenyl)-2-trifluoromethyl-valeroylamina!-2,3-benaoxasin-i-one,
6- [4- (4-bromophenyl) -2-hydroxy-4-tnethyl-2-t;rif luoromethyl-valeroylamino]-4-ethyl-2,3-benzoxazin-l-one,
4-ethyl-6- [4- (S-£lxioro-2-methoxyphenyl) - 2-hydro:cy-4-methyl-2-trifluoromethyl-valeroylamino]-2,3-benzoxazin-l-one,
6- [4- (5-£luoro-2-methoxyphenyl) -2-hydroxy-4-tnftthyl-2-trifluoromethyl-valeroylaminol-4-msthyl-2/3-bensoxasin-l-one, l-(4-nitro-3-trifluororaethylanilino)-4-phanyl-2-
trifluoromethyl-2-pentanol,
1-(4-nitro-3-trifluoromethylanilino)-4-phenyl-2-
trifluoromethyl-2-pentanol,
5-(2-hydroxy-4,4-dimethyl-2 -1rifluoromathyl- 5-hexenoy1amino}-phthalids,
5- [2-hydroxy-3- (1-pherxyl-cyclopropyl) -2-trif:luorbmethyl-
propionylamino] -phthalide,
5-[2-hydroxy-3-(l-phenyl-cyclobutyl)-2-trifluoromethyl-
propionylamino]-phthalide,
5- [2-hydroxy-3- (1-phenyl-cyclohexyl) -2-trif'.uororaethyl-
propionylamino]-phthalide,
2^hydroxy-4-methyl-2-trif luoromathyl-4- (4-v:.nylphenyl) -
valeric acid,
4_ (4-acetylphenyl) -2-hycro3cy-4-methyl-2-tri:;luo2:omethyl-
valeric acid,
4. (4-acetyl-3-methoxyphenyl) -2-hydroxy-4-mei;hyl-2-
trifluoromethyl-valeric acid,
4 -(4 -cyanophenyl)-2 -hydroxy-4-methyl-2-trifluoromethyl-
valeric acid,
4- (4-carbarnoylphenyl) -2-hydroxy-4-methyl-2- :rifluoromethyl-
valeric acid, • . 4-(4-cyai-.o-2-methoxyphen,yl) "2-hydroxy-4-m$t:T/l-2-
trifluoromethyl-valeric acid,
4- (3-bromo-4-methoxyphenyl) -2-hydrox.y-4-meth.yl-2-
trifluoromethyl-valeric acid,
2-Kydroxy-4-methyl-4- (3-nitro-4-methoxyphen.yl) -2-
trifluoromethyl-valeric acid,
4-(4-ioda-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid, 4-(3-chlorophenyl)-4-methyi-2-oxo-valeric acid, 4- (3-bromophenyl) -4-rnethyl-2-oxo-valeric acid,
4- (2-iodophenyl) -4-methyl-2-oxc-vaIeric acid, 4- (3-icdophenyl) -4-metiiyl-2~cxo-valerie acid, 4-(4-iodophenyl)-4-methyl-2-oxo-valeric acid, 4- {5-fluoro-2-methoxyphenyi) -4-methyI-2-oxo--valeric acid,
4- (4-brorao-2-mathoxypherAyl) -2-oxo-valeric acid,
3-(l-phenylcyclopentyl)-pyruvic acid,
6- [3- (1-phenyl-cyclopropyl} ~2.-oxo-propionylarr.ino3 -4-methyl-2,3-benzoxazin-l-one,
6- [3- (i-phenyl-cyclobutyl) -2-oxo-propionylainino] -4-methyl-2,3-benzoxazin-1-one,
g_ [3_ (i-phenyl-cyclohexyl) -2-oxo-propionylaiair.ol -4-methyl-1,B-benzoxazin-l-one,
5-[4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeroylamino)-phthalide,
5_ [4- (4-iodophenyl) -4-methyI-2-oxo-valsroyla7aino} -phthalide,
5- [4- (3-iodophenyl) -4-methyl-2-oxo-valeroyliimino) -
phthalide,
5- [4- (4-brotno-2-methoxyphenyl) -2-oxo-valeroylarnino) -phthalide,
[3- (1-phenyl-cyclopentyl; -2-cxo-propionylaTP.ino] -
phthalide,
[4-(5-fluoro-2-raethoxyphenyl)-4-methyl-2-oxo-
valsroylamino) -4-methyl-2, S-bensoxazir.-l-crie,
= .-... 6- [4- (5-f luoro-2-methoxyphenyl) -4-methyl-2-oxo-valeroylaminc)-4-ethyl-2,3-bensoxasin-l-one,
6- (2 -hydroxy-2,4-dimethyl-4-phenyl -valeroyl.amino5 -4-methyl 2,3-benzoxazin-l-one,
5-[4-(3-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamina)-phthalide,
5- [4- (3-chloro-4-hydroxypheziyl) -2-hydrcxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide.
IS, Pharmaceutical preparations that conta:'.n at least one compound of general formula I according to claii.i 1 as well as a pharmaceutically compatible vehicle.
19. Use of the compounds of general formula I according to claim I for the production of pharmaceutical preparations.
20'. ' Process for the production of compounds of general formula I
I
in which A, B, Ar, R1, R2 and R3 have the meaning that is indicated in claim 1, wherein a carbonyi compound of general formula II
(Figure Remove)
I)
in which A, B, Ar, R1 and R* have the meaning th 21. Process according to claim 20, wherein the catalyst is a fluoride salt or an alkali carbonate.
22. Process for the production of compounds of general formula I
(Figure Remove)

in which
A, 3, Ar, R1, R2 and R3 have the meaning that is, indicated in claim 1, wherein a compound of general formula III

in which A, B, R1, R2 and R3 have the meaning that; is indicated in general formula 1 and FG means a leaving group, is reacted with a compound Ar-NH-R11, whereby R11 means a hydrcc w a Ci-Cg alkanoyl group, snd Ar has the meaning tha" indicated in general formula I, and optionally th is cleaved off.
23. Process according to claim 22, wherein _. jup FC3 in connection with general formula III is a cruarine, bromine or iodine atom, a tosylate or rnesylate radical or a Ct-C4 perfluoroalkylsulfonyloxy radical.
24- Process according to claim 23, wherein the compound of general formula III is an acid chloride that is formed as an intermediate product from the corresponding carboxylie acid.
25. Process for the production of compounds of general formula I
in which
A, Ar, R*, R2 and R3 have the meaning that is indicated in claim 1, and B means a -CK2 group, wherein a compound of general formula IV

in which A, R1, R2 and R3 have the meaning that iss indicated in formula I, is reacted with a compound of formula Ar-NK-R11, whereby R11 and Ar have the meanings that are indicated ir. claim 23, and optionally then radical Ru is cleaved "'
Compound of general formula I substantially as herein described with
reference to the foregoing examples.
Pharmaceutical preparations that contains at least one compound of
general formula I substantially as herein described with reference to the
foregoing examples.

Documents:

960-DEL-2002-Abstract-07-04-2008.pdf

960-del-2002-abstract.pdf

960-DEL-2002-Claims-07-04-2008.pdf

960-del-2002-claims.pdf

960-DEL-2002-Correspondence-Others-07-04-2008.pdf

960-del-2002-correspondence-others.pdf

960-DEL-2002-Description (Complete)-07-04-2008.pdf

960-del-2002-description (complete).pdf

960-DEL-2002-Form-1-07-04-2008.pdf

960-del-2002-form-1.pdf

960-del-2002-form-13.pdf

960-del-2002-form-18.pdf

960-DEL-2002-Form-2-07-04-2008.pdf

960-del-2002-form-2.pdf

960-DEL-2002-Form-3-07-04-2008.pdf

960-del-2002-form-3.pdf

960-del-2002-form-5.pdf

960-DEL-2002-GPA-07-04-2008.pdf

960-del-2002-gpa.pdf

960-DEL-2002-Other Document-07-04-2008.pdf

960-DEL-2002-Petition-137-07-04-2008.pdf

960-DEL-2002-Petition-138-07-04-2008.pdf


Patent Number 219404
Indian Patent Application Number 960/DEL/2002
PG Journal Number 25/2008
Publication Date 20-Jun-2008
Grant Date 05-May-2008
Date of Filing 23-Sep-2002
Name of Patentee SCHERING AKTIENGESELLSCHAFT
Applicant Address
Inventors:
# Inventor's Name Inventor's Address
1 KARL-HEINRICH FRITZEMEIER
2 NIKOLAUS HEINRICH
3 ROLF KRATTENMACHER
4 PETER STREHLKE
5 KLAUS SCHOLLKOPF
6 HANS-PETER MUHN
7 MANFRED LEHMANN
PCT International Classification Number A61K 31/277
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 197 23 722.3 1997-05-30 Germany