Process for producing quinazoline derivatives and pharmaceutical compositions comprising same

* The subject of the present invention is a process for the administration of quinoline sols and ruminescenceUsg alcapaceous eons »valsaint · * acting as a sludge-containing antispasmodic agent for the production of antiseptic delays.

One of the opioid inhibitors of tea inhibitors is as antiatobo · Hereac, including as minopterin and ® netrexate, which inhibit the onset of anti-hassles that inhibit the folic acid derivatives. and ontimetabolites «« newer chemical for sport · 2,065 ej} ss · great-britaniian asabadslal description tenor · made in CBJ717 code material * amly very promising in clinical trials · never and this compound has a promising effect » * crabs and bites of liver cancer have the disadvantage of causing "toxic" symptoms on the bones of ostealars, "and especially of the bones of the beast cause £ T. Clin · Omol & amp; & gt; 1245 (1986); Cenoer Sreotnent Reporta 1555 (1986) | J. Replace # & 59 (19S7) | lur. J · Canoer Clin · Onool. 201 (1983), gj, 735 (1988) «g $, 769 (193817).

Current lemmeths have been shown to inhibit the action of CB5717-type compounds by inhibiting this tBBidylate synthase by catalysing the metabolism of deoxyuridine aonophosphate by DWS-binding. In vitro inhibitory effect of CBJ717 on thaidylate synthesis on ais * cell lines in cancerous cell lines »and L1210 agar in the lymphatic cell line» myanel cancer myeloma cheese strains solved inhibitory effect by riasg

Other CB5717-like compounds • 5 · Tn-inhibitory effect and onlite ιηιίκ · »and cancer cell line can be compared with the activity of C35717 in the tympanic inhibition of the affected cuckoo.

Antine pumping inhibitors of the enainsk function of the foliage-ex eczema »such as aninopterln and s notothrexate» various allergic diseases »eg allergic mucous membrane ^ ulcerative * etopic skin inflammation and psoriasis» so allergic conditions can be expected in the healers »for example for the treatment of pooriesis ·

European 316,657 ss. Discloses quinazoline prices which lack the amino acid residues on the CB> 717 type compound. and the inventors therein known the inventors of thymidylate asynthetic inhibitory effect on soil * and some of the compounds described therein are quinazoline-xxes, in which ® CB> 717 * contains 5 amino acids from soils. your substitute ye ·

The 365,763 SS · European Gateway Document also indicates that the CB3717 etiquéu quinazoline moieties having, for example, a halogen moiety at the amino acid site retain their thi ·

I was astonished »that I would find oserin-producing milk compounds with activity CB57X7« tüpueu as normal ·

FIELD OF THE INVENTION The present invention relates to a process for the preparation of general stoneware platinum, quinazoline salts, and therapeutic salts thereof, in the following formula: · · • · · · ······························································································································································•

R¹ Meaning: hydrogen atom, annoeol, 1-4 C 1-4 alkyl, 1-4 alkenoxyalkyl, 1-4 C 1-6 fluoro-ternaryloxy, substituted with 1-5 fluoro-torso substituents, 1-3 C-alkenyl group, up to 3-alkenoxy-hydroxy radicals. an alkoxy group, and the clolsolin ring moiety may be optionally bonded to an additional balogen *, 1-3 •• enutonate or 1 * 3 olefinic substituent,

R² hydrogen · tonct buy up to 4 carbon atoms alkyl, alkene, elkinyl, hydroxyalkyl, hslogin-elkyl, cyano-alkyl oeoport

R ^ is hydrogen or 1-3 carbon atoms removed

Arophenene or heterocyclylceoport means that one or two halogen, hydroxy, anino, nitro, 1-3 alkyl esters, 1-3 alkoxylated and / or halogenated 1-3 substituents. 3 shingles elkil-ezubestltuene can be connected,

L -Co-KB ·, - «Η-CO», -UWIR **, -SR * -CO-, -CH · Cf - or

-C? -0- and in the formulas R * 1-4 are salts having alkyl groups which represent a hydrogen atom or a 1-3-membered ring substituent, a bond or 1-4 carbon atoms. means an alkylene group

THE² a valence bond, or a 1-4 carbonyl group, an alkylene group, an A * bond, or a 1-4 acetic acid residue, which has a methylene linkage optionally substituted with an hydroxyethylene of the parent, thio, sulfinyl, eaulfonyl, group consists of ϊ² halogen ton, hldroxyl, βαίηο, ele-vsgy trtluoro-eoethyl-ceoport, up to 4 Se-atoms eloxoxy, al · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ···· ···· ··· ····

- 5 · ν

ϋΐ-βηίηο, dialkylanino, haloalkyl, alkyltlo, slkylsulphinyl, alkyleeulphonyl, alkanoyloxy, 1hanyl · or hydroxyelkenol groups, up to 10 carbon atoms aryl , srl-thio, arylsulfinyl or aryl-sulfonyl, or heteroaryl, heteroaryl-thio, heteroaryl-sulfinyl or heteroaryl-8Sulfonyl-denotes 4 "x * as' £ % meaning Meaning, ssulfo, S-hydroxy t-carbazoyl, JUc leuoxrba »oll-_tkerbasoll or sulfonoyl, up to 4 ezenatonoe N »81kil-ssulf« HiQll- | M_tMÍelkll-esttlfanoÍl- | N-Acyl-eaulfsulfioyl-1 H-alkylcarbamoyl, K »- - Dialkyl Carbsaol ~₉ N-Elkylxrbanoyloxy, H_tE-dialkyl * carbaoyl-allyl or S-alkylsulfonylcarbaoyl group · N-phenyl-1-sulfonylcarbazoyl group or 5-5-trimethylsilyl group Represents the aryl *, erlyl * listed above , srl-sulfonyl, ar11-sulfonyl, heteroaryl-heteroaryl-thio, heteroarylsulfonyl-heteroaryl-sulfonyl optionally having two identical or different sub-substituents, namely, haloethane »hydroxy oxo thioxo-anino, nitro, cyano or carbaoyl sweepers | up to 4 easterlyl-alkyl-ΐ-alkylcarbeaoyl, h ′, N-dielkyl-κ-bromooyl, elkyl-tlolo, alkylsulphinyl, alkylsulphonyl, alkoxy, or haloalkyl; A 10-membered phenyl alkyl esopter or phenyl group may be attached₉

The 4a s phenyl and phenyl elkyl substituent or s H -phenylsulfonylcarboxymethylphenoporthos may optionally be attached to a nitro, cyano, halo, 1-3 azoalkyl or 1 * 3 sulfur substituent, etc. provided that in the--I * X group an «ethylene or ·-6 m mines is attached to more than one heteroaryl that is not a heteroaryl ring *

In the description and claim s, I denote the general ** subgroup * as the alkyl groups of both the straight and branched chain · In the case of sagging of individual alkyl groups, it is specifically mentioned in the rain_t thus, for example, this propyl group * denotes straight-chain radicals * As well as other generic terms, their cloneezolln derivatives of formula (I) consider one or more tri-cosubstituted derivatives to be imibe, and their racemates and optins © may exist. Our claim for protection is this formula (I)! Clnezolln listings are rheo-labeled and all such optically ectl modifiers also produce extensive and desirable antitumor effect ©! have · m-idze veins from your coagulum to separate the individual optically © ktiv isomers.

wherein L is -0Η to 0Η-, is a compound of formula (I); We can form two geo-ether isomers for several weeks. The need for this geo-ether isomer of compounds of formula (I) thus extends to · which β have the desired antitumor activity · the individual geometric isomers can be isolated by known techniques ·

The compounds of formula (I) may optionally be in the form of thiomorphic modifications. Although the formulas suggest one of the possible teutomoric forms, these formulas represent 6 other possible teutomoric forms. This claim relates to the production of all the tumorigenic effects of the compounds of formula (I) in the production of folk power of a representative of the Chinese formula (I) in the occasionally solved torso. There is a need for extinguishing *% 1 of oessoa of the compounds of formula (I) in the form of an oleaginous form which has an anti-emetic effect.

Aa b \ It² or R * or an aryl-aryl-thio * t er-sulfonyl-aryl-aryl-sulfonyl, be-terryl, hatiosryl-thioph, heteroaryl-sulfonyl or heteroaryl-sulfonyl optionally substituted with 1 Examples of * 4 alkylation of alkyl * groups include ethyl *, ethyl * »propyl» isopropyl, butyl *, isobutyl »they-butyl * or tert-butyl * c.

; .z or standing in the ring of embarrassment_t1-5 of this natosoa-sityl group is optionally substituted with Ar or either a fed * or lentidylkll * substituent * hsa or an ash-phenylsulfonyl-kerbanoyl group, e.g._t can be ethyl, propyl or isopropyl ·

Examples of 2-alkenyl groups include prop-2-enyl-but-2 * -enyl * »but-5-one or 2-methyl * prop-2-ynyl-cysteine. and an alkynyl group can be, for example, iop-2 * nnyl or but-5Anyl *.

As R. \ I² either stationary or © rll-_t aryl-tla- »aryl * ezsulfinyl * t -Silylsulfonyl-» hetercaryl *, heterosrylthio *, heteroeryl-esulfinyl * -hetereroaryl-sulfonyl-ceopithos optionally substituted as a substituent on a 1 * 4 aznatoe alkoxy group such as,_# Can be «taxi» propori, isopropaxi »but * oxy *» isobutoxy * or tert-butoxy

For example, the 1 * 5 carbonyl moiety of the quinazoline ring moiety, the above * or phenylalkyl substituent or the n-phenylsulfonylcarboxyl group optionally referred to as the silver substituent, is, for example, netoxy, ethoxy »propoxy. · ♦ · · · · · · · · · · · ············································································sed srl, aryltlo, aryllethylphenyl, aryl azulfonyl, heteroeryl, heteroarylthio, 1-4 azenstonone alkylthio groups which may be attached to seven arylsulfinyl or heteroerylsulfonyl groups optionally substituted as esubstitens, for example, nethyltlo, ethylthlo, propylthio, isopropylthio, butylthio- or an isobutylthio group? or $ stationary, buy quinazoline ring price, for price group, it is er-, aryl-tlo-, er-esalfinyl-, aryl * -zulfulfonyl, seven-roaryl, httrooryl-thio, hetero-caryl-azulfonyl-chemical, hctorosryl-physulfonyl- tube_t The halogen optionally attached to the ortho, phenyl or phenyl-alkyl-alkyl substituent optionally attached to the H-phenyl-sulfonyl-carba-bioyl substituent may be, for example, fluorine, boron or trushtho.

Examples of 2-substituted substituted alkyl groups include fluoro-natyl, difluoroacetyl, trifluoro-cetyl, 2-fluoro-ethyl, p-fluoro-propyl, hydroxy-Getyl, 2-hydroxy-ethyl or 3-hydroxyethyl. -hydroxy-propyl-propyl.

..ζ the substituent substituent at the * position is, for example, 2-hydroxy-atoal, 2-C3-oxy * ethoxy, J-ethoxypropoxy or

It may be 2-atoxy-ethoxy-1.

for example, 2-hydroxyethyl, 3-hydroxy-propyl, 2-fluoro-ethyl, 2-chloro-ethyl, 2-bromo, e.g. -ethyl, & gt; -fluoropropyl, J-chloro-_rro_zII *> cyanoacetyl *, 2-cyanoethyl may mean 3-clanopropyl.

price-priced phenylcarboxylate, for example, 1,3 or

1,4-phenylene-dripped bacrocylcleo group can be, for example, five-membered or six-membered arosus (i.e., tecsec unsaturated), at most bar alt * ························································································· · ♦ · · ······················································································································································································································································································· For example, as an alkyl sub-bisubbene, a fluoro-aebll-difluoro-ethyl or a trifluoro-ethyl-group ² and '<? an aryl group at the 3-position of the arylthio-erlyl-ylnyl or arylsulfonyl group, for example, may be a font or a n-methyl group.² and in place allé heteroerll-knocked »valsnint as i² a heteroaryl group capable of being part of a heteroaryltlo, butteroyl azulfinyl or heteroaryl sulfonyl group, for example, containing 1-3 oxygen, nitrogen and / or sulfur beteroatons, having five or six membered internal fused heterocyclyl moieties. group »such as furyl» thienyl, pyridyl, quinolyl »isoclonol *» pyrazinyl, pyrimidinyl, pyridazinyl, cloxyoxylinyl, kinesel nyl, cinnolinyl, indolyl, iadesdesolyl, benzothiazolyl, pyrezolyl » -, lsoxeaolll-, half- »

It may be 1,2,3-triazolyl or 1,2,4-triisolyl. The heterocyclic groups listed above may be attached to any other substituent on the ring (including this azubstitutable nitro gene) by any of their substitutable ebons, and may have one or two substituents attached to the ring - optionally ® tailed to the nitro nitrone ·

M

The seven roartl groups at - and y are »valeainb» zi² and a heteroaryl forming a gaping heteroarylbio, heteroarylsulfinyl or heterosrylsulfouti group, in particular furyl, thienyl, pyridyl, imidazo111, oxazolyl, isoxezolyl, halogen, 1,2,3-triazolyl • · ♦ or 1,2,4-triazolyl-ceoport; »sons may have a barely-substitutable stop on the other part of the aolskule · ϊ y & gy í? for example, a & quot; & quot; and & quot; streaming & quot; groups bearing the brain or two oxo or t-xxo-azo substituents (the same groups may form totoroarylthio substituted with oao or blozoic moiety, a heteroaryl moiety of a heteroaryl-sulfinyl-III or a neteroaryl-sulfonyl) ι 1,2-dihydro-2-oxo-quinolinyl-GaQpQrt (primarily 1,2-dululdro-2-oxo-quinol-5-yl or 1,2-Dinxuro-2-oxo-quinolyl-6-yl (carbonyl), 1,4-dibidro-4-oxo-chloro-2-yl-carbonyl (reduced by 3,4-dihydro-4-oxo-k.utaolin-5) yl, 3,4-dihydro-4 * oxo ** -quiazaolix> -6-yl, 5,4-dihydro-4-oxo-clinosozolin-7-yl-Vugy 5,4-dihydro-4-oxo -kiufiιοί in-3-yl-group,> -axo-l_t2_t4-trityl-3-yl-azopyrr (preferably 5-oxa-1,2,4-triaol-5-yl); 1,2-dibromo-a-2-cxopyridyl (precursor 1);_t2-didxido [2-oxo-pyrid-3-yl] -opooro, 1,2-di-dihydro-2-oxo-pyrrol-4-yl-piper or_e2-diyldro-2-oxo-pyrid-G-yl-tert-1,4-dihydro-4-oxo-pyridyl-G8opyrr (preferably

1,4-dlb.hydro-4-oxo-pyrid-2-yl or 1,4-dihydro-4-oxo-pyrid-5-yl), 3,4-dihydro-4-oxo-pyrididinyl ( preferably

3,4-Dihydro-4-oxo-pyrrolidin-2-yl-chemical (pt-dihydro-α-oxo-pyrrolidin-5-yl-6O-part), 1,2,4,4-tetra-dihydro-2,4-dioxo-_ipyridyl group (preferably l_t2 ', 4'-6-terttriaro * - ^, G' dioxopyrrolidin-4 * yl or '1,1,3,4-Utrohydro-2,4-dioxopyrrolidin-1-yl), and no ^ Xelelo Thioxo-az8 Tyls ·

A ·, Λ² and, e.g., sulfenylsulfuric acid may be selected from the group consisting of, for example, netylene, ethylene, ethylidene, triaotyl, propyldidone, isopropylidene, propylene, 1-ethyl-1-bbilin, tetra biline or isobutylidene. instead of a netylene group, it contains oxl, thio, eaulXinyl, S3ull onyl, isino or hydroxyethylene.

V · ι ················· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Λ

- 11 * balose 1-4 eseno-bonoe alkyleneo group example Your followers oa groups Mean! 2-o »-trimethylene-, 2» exaM »tranethylene ~_t> oxetetretrene lene, 2-thi * trinethylene, 2-thetetranethyl-, 2, 2-thiotrinethylene_t 2> 2-41οι14ο • 2-Bi- brinethylene * · 2-esa-trinebile, hldrexebeebene-

2-hydroxyethyl & lt; / RTI & gt; & lt; 2 & gt;

As ϊ² living in my place or er. er-, er- thio-, er- allylsulfonyl, aryl-eeulfonyl-, heteroaryl-, heteroaryl-tto-, heteroaryl-aleall-yl- or beteroaryl-eeulfonyl-ceoportokbos given as an alkylene-eno-alkylene-dinyl- Examples of baloge-alkyl, elkylsulfonyl, elkyl *, alkanoyl-oxy, olkenol, and hydroxy-elen-xenoyl ceoports can be examples of ethyl-aslno-, ethyl-aelno-, proll-ael -, lsepro pyl-e-nitro, butyl-eaino, dinethyl-aslno, M-ethyl-M-ethyl-sslno-, dle til-emiao-, ^ * ®etll N nropil ~ «elno-_t N.aatll-N-iso ·. propyl-ialno ·, fluoro-methyl, dirluoroethyl ·, trifluoro-© ethyl-,

2-fluoroethyl, 5-fluoro-propyl, pentafluoro-ebyl, hexafluoropropyl, chloromethyl, dichloromethyl, net »esulfinyl-₉ otll «eululphinyl, propylsulphonyl», ieoprol-esulphinyl, butyl-esulphinyl, netll-osulphonyl, ethyl-eaulphonyl, propylene-sulphonyl, isoropyl-eululphonyl, butyl-sulphonyl, aethoxy, pro; lonyloxy, butyryl-oxy, acetyl, propionyl, butyryl, 2-hydroxyacetyl, and 3-hydroxypropylone ·

N, N-methylcarbenoyl, N, Nd-methyl-1-sulfenoyl, N-ethylcarbamoyl, K-alkylcorbenzol, N, N-alkylcarbenoyl, N As N'-elkll-aealphonyl-kerbanoyl * e, the például-dielkyl-kerbenolyl moieties include, for example, ϋ-Methyl-axalfenyl, ε-ebil-esalfanoyl, K, δ-dinyl-oxalimoyl <, N-oeothyl * asalfe no no11-. , N-ethylcarbanoyl, N-ethylcarbanoyl, N-ethylcarbanoyl, α, α-di-ethylcarboxyl-α, a-ethylcarbonyloxy, h-ethylcarbanoyl-t , l <, b -dia »ethylcarbanoyloxy, H-Ethyl-esalfunyl-carenoyl, h -phenylethylsulfonylcarbanoyl, N -propyl-sulfonyl-ceranoyl, or N-iBO-propylsulfonyl-carbonyl-anoylcarbonyl may be substituted -610-, arylsulphonyl, srilsulphonyl, butyl & lt; + & gt; aryl, & lt; 6 & gt; ethyl carbamoyl, b-otylcarbonyl or w-propylcarbamoyl, for example, 1 *, 4'-dialkylcarboxylic acid is substituted by, for example, 1-carboxylic acid is substituted for methyl, while phenyl is selected from benzyl, phenyl-ethyl, phenyl-propyl or Xenyl-. can be butyl group *

4th Suitably basifcus (1) quinoline-SBuraLBökoK, a ionic formula of the ionic formula, salts of alkaloids with ser vet leu or sservic acids such as hydrochloric acid, niorogeuroberoid, cinic acid, phosphoric acid, trichlorofluoroacetic acid, citric acid pharmaceutically acceptable salts of the compounds of the formula (I) with an acid which are suitably acidic, such as salts having a hashish, such as acidic salts (e.g. tetrs- (2-hydroxyethyl) -unsun salts and therapeutics can be many with 6 hash organic organic hashs such as netanyl aniline, srinethyl-eBinnsl or trlBz (l-hydroxyethyl) - «aine *« ζ (1) Kinesazoline salts of the formula altalunoe and their compounds are the colo groups of their lse slower salts and

R^x a hydrogen atom or an amino, a 1-4 heteroatom alkyl or a 1-4 carbon atom »alkoxy, or R^3, a hydroxyl group or a 1-5 alkene-substituted alkyl group substituted with 1-5 fluoroethers * represents a hydroxyalkyl group of 1-4 carbon atoms or an alkoxyalkoxy group of up to 4 carbon atoms, optionally selected as such. iMlogeneton or 1-5 aenatoaoa boys11- or alkoxy groups attached * a² denotes hydrobeaetonate or up to 4 scenes at alkyl-alkenyl- • quinyl · -hydroxyalkyl · halcgin-elkyl or Gisno-olkll-cw port · Irish Hydrogen Acid or 1-5 Sethenone Aixyl Sweep * * r Phenyl or natero-cyclenic swabs means a snifter optionally a cut. two identical or different substituents * namely balogen atom * hydroxylGuine * aineo group * nitro group or up to 5 alkylene-alkenyl * alkoxy or httlegeu-alkyl groups KSpGsoledbst *

-w —w-wrii— * —im-HIU— * —CU— * - nR ^ Qú— * —or -U'J — U— 980 * represents port * in chance H⁴ Represents a 1-4 alkylene group * and represents a group of formula (a) * wherein tT appears to be hydrogen or a 1-5 alkylene group *

THE¹ ** & stands for coil rope or 1-4 scenes elphcylene group *

The valence codet or 1-4 ssonakane alkyl lattice represents the * valence bond or the 1-4 sexton carbon lattice group * p

halogeno * hydroxy * enino * cyano or trifluoro * -acatyl * up to 4 carbon atoms alkoxy * alkyl- »ina * alkalixyl-alaino * helogon-elkyl * -kylthia-*» · ♦

-14alkylsulfanyl, alkylsulfonyl, alkanoyloxy, altanoyl or hydroxyalkanoyl ceoporto, log to the right of the aryl, erthio, arylsulfinyl or erne-asphenyl group or hateroaryl -carbonyl, carboxylic acid, carboxylic acid, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, carbonyl, , dialkyl-8selfaoyl, N-aoyl-asulfealyl, R-alkyl-kerbanoyl, en, N-dialkylcarbaoyl · N-alkylcarbaoyloxy, ϋ, Α-dielidyl-11-carboxyoyl or X 4 -alkylsulfonylcarbooyl, Wenylsulfonylcarbamoyl or 5- denotes a tetrazolyl group, and the aryl, <RTIgt; aryl, </RTI> thio, erllsalfinyl, art1-sulphoxyl and hwGerool. & lt; RTI ID = 0.0 & gt; aryl & lt; / RTI & gt; αχό-, thioxo, ealuo, uitro, cyano-carbanoyl groups, alkyl up to 4 salts, α-olkyl-xbarboyl, ϋ, ϋ-dialkyl-xrb & allyl, alkyl-tlo-, alkyl-azolfinyl, alkylsulphoalkyl-alkoxy or telogen-alkylceoport, phenyl or up to 10 carbon atoms may be attached and & lt; RTI ID = 0.0 & gt; phenyl & lt; / RTI & gt; -alkyl substituent or s-k-phenylsulfonyl-kerbanoyl-caoparthoa optionally substituted with ss-bastitaenakeneb halo-alkoxy or u-nitro, cyano, 1-5-as-natonua alkyl or 1-5-carbono-alkoxy; that in group b-χ, the brain is attached to more than one hoteroaboahos, which is known as neteroaryl ring salt in the ethyl ether> n- or se-trin ·

Α »is another separate class of compounds of formula (1) and their pharmaceutically acceptable salts, and in the case of ss & raxexes, X represents the esopgr · • · • 15 and ·

e) R¹ or a fluoro, chloro, br 6, R & lt; 6 & gt; -ethyl, or setoxl-ee substituent, while R², R ^, Ar, L, a¹, the², i² ee has the meaning given above obsession

b) R² hydrogen, or Betti, ethyl · propyl, prop-2-enyl, prop-2-ynyl, 2-hydroxyethyl, 5-hydroxypropyl,

A 2-fluoroethyl, i-bromoethyl or oleo-methyl group and a quinoline ring-linked substituent and also a, Ar_t L, a¹· the², A ', R ^, x² eee means above! obsession

c) denotes hydrogen, hetero-moieties or ethyl and s quinoline ring optionally linked ssnbsatituons; and κ², αγ, L, a², Ρ, í? - \ í * and has the meaning of | above obsession

(d) Unsubstituted or one or two of the fluorine, chlorine, bromine, nlaroxyl, anino-nitro, methyl, non-taxi and / or trifluoromethyl SBUbsatubates on 1,4-phenylene ceoport or tlenylene -, pyridylene, pyridinidinylene or thiolinene, ee e quinoline ring optionally linked to additional ssabestitueBS, and R²· R '', L, a ^, a², a · ^, x² ee has the meaning given above obsession

o) X »-CO-atyl-, -gcm®⁴- or -Gu-ü-, where R is⁴ © represents an ethyl or staple group · and the ringworm may optionally contain additional ssubeatituents, wlasint ti², i ^ »price, á \ a², a ', x² and x ^ is as defined above! obsession

£) a¹ solid blue stone or cetylene, ethylene · ethylidene.

• · • · · · · · ·

- 16 cascades of triaethylone, propylidene, propylene, oephersmafeilu n or laobutylidene,² valence bond or methylone, • halide *, ethylidene *, feriaethylone, propylidene *, 'propylene, brush * resmphelene * or isobut means 11 groups, and the chemical substance is sytylene, ethylene *, ethylidene, trinefeline. , propyl * diene *, propylene », tetraethylidene, iaobylideneidene, 2-oxo-triethylethane», 2-tris-trimethylone, x * oxo-2-thia * triae phenane, 2,2 -dioxy * do-2-Fe-ferisethyl.m *, 2-ester-trinetileu, hdrexylethyl ^ xin ·,

2-hydroxyethyl or 2-yloxy ferrate denotes a group, and & quot; & quot;_£<caclódó further ssub «aöituens, es. * 3, oh², Ar, ü, x² and j? report · above! obsession

g) thi is independently selected from the group consisting of chloro boa or hydroxy, amino, eleene, trifluoroacephel, methoxy, -ropoxy, butoxy, tert-butoxy, methylamino, ethylxino, dimethyl-enino, diefeU-agino, trifluoro-setyl, matyl-thio *, ethyl-610-, necylsulfinyl, phenyl-aza-phenylnyl, nephel-salphonyl, acyl-sulfonyl, acetoxy, propionyl oxyl, scetyl, 2-hydroxyacatyl, phenyl *, phenylthio *, phenyl-sulfinyl, phenyl-eaulfonyl, thienyl, pyridyl, quinolyl,, lrinidinyl, quinazolyl, inidaxolyl-benzalidaxolyl *, isoxozolyl-, thiazolyl-, 1,2,5-triazolyl-, 1,2,4-triazolyl-, 1,2,4 * triazolyl-tl-, 1,2,4-triazole * lylsulfinyl or 1,2,4-triesoylsulfonyl, wherein the sogedofet is optionally substituted with one or two hydroxy *, oxo *, tloxo, amino, nitro, cyano groups for aryl * or netroaryl groups -, carbamoyl, fluoro *, chloro, bromo, aefcyl, ethyl, methylmethyl-kerbamoyl, X <, -diethyl-xarene-11-, not thi-Ια-, oefeyl- Ezulfin *, Aotylsulfonyl, methoxy or trifluoromethylsububic acid may be attached and may be further bonded to the Clolenoling ring; ₉ Ar, b, a, a,

<img file="HUT57739A_D0001.tif" />

···· ·· • · · ··· · ·· « · • · · · · · • · • · · · · · ·

-17*

<img file="HUT57739A_D0002.tif" />

and R * is β above * or

h) 1 hydroxyl, aino, cyano, cetoxyl, ecoxy, propoxy, tert-butoxy, cetylseino, βyl-βαίηο, disethyl-esino, diethyl-snino, © ethyl-tlo -, ethylthio, acetylsulfinyl, ethylsulfinyl, cetylsulfonyl, ethylsulfan, ethoxy, proplonyloxy, LC / R, or proylun sweepers, and phenyl, phenylthio. , phenylsulfinyl, phenylsulfonyl, thienyl, thiosulyl, pyridyl, 1,2,4-trisalyl, 1,2,4-triazolylthio, l_t2_tDenotes a 4-trissolyl-axulfinyl or 1,2,4-triesolylsulfoulyl group, the latter 11 being optionally substituted with one or more hydroxy, aalnu, altro, cyano, fluoro, alpha, from bromo, notyl, ethyl, methoxy V £ g2 trifluor-ca # * til-substituentGuens bond * ve la aint as i^4- to any of the last five groups listed in the report, optionally oxo7.

v &amp; fcj ticxo-saabfcZtifcaens kapouol ^ dóot, etc. S fanyl, theayl, pyridyl, inidosal 1-, uxazolyl, isoxazolyl, tUzolyl or 2, 2_tMeans a 4-trioxysilyl bump which may be optionally substituted by one or two hydroxyX, anlao *, ultro, cyano, fluoro, chloro, bromo, phthyl, cetylthio, methyl in the case of a sulfinyl, acetyl azulfonyl, aethoxy, or trifluuromethylsububstitute, and in the case of a pyridyl or 1,2,4-triazolyl group, the oxo or thioxo-azo substituent may also be optionally cooled and the clozolyl ring optionally with additional substitution, velanin C?% * * »r * a, i ?, and has the meaning given above * or

1) x optionally represents one or more of the phenyl groups of hydroxy, εκina, εtre, cyano, fluoro, χ1 ~ · γ, bromo, acetyl, setoxy or trifluoroethyl ester substituent, and x⁵ denotes sulpho, N -hydroxy-carboxyl * A-cyano-carix aoyl, carbazolyl-sulphanoyl, h-astyl-sulphanoyl *, l -styl-carboxyl • · · · · · ··· · · · · · · · ··· ··· ···

- Shoot .

N, N-methylcarbamoyl, N-ethylsulfonylcarbamoyl, N-phenylsulfonylcarbamoyl, or N-totrazolylcarboxylic acid the group may optionally be linked to an aethoxyl-β-azabutylated nitro-cyano, fluoro-chloro-methyl compound, and further sub-substituents optionally attached to the quinazoline ring, and¹»Η²»Π ^» Do »ο» a¹" the²» $_e Meaning # 5 * above #

MM1 with the proviso »that in the -0-1 group there is more than one heteroat which is not part of the heteroaryl ring attached to a methylane or methineaeport · Bim ·

The present invention is a further class of thousands of compounds of formula (I). quinazoline derivatives and their pharmaceutically acceptable salts »in which the hydrogen atom or the amino, ethyl» ethyl, oethoxy or x'luoromethyl group is selected »• the quinazoline ring salt optionally has an additional fluorine» chlorine »methyl or ethoxy group; -asubaetituens are connected,

Vagy hydrogen or emyl »ethyl» propyl, prop-2-enyl, prop-3-ynyl, 2-aidhoxyethyl »-1-hydroxyprop, xyl-_t 2-Xluoroethyl, 2-bromoethyl or cyanomethyl; &amp; quot; P &amp; quot; hydrogen atom; or an ethyl group; Ar is optionally one compound of two fluoro »chloro» bromo »hydroxyl groups; , 1-α-phenylene, thienylene, pyridylene, pyrimidylene, substituted with amino, ultraviolet, methyl, ethoxy and / or trifluoromethyl substituents.

L-C-yl- »-Cu-ο» or -Cu-KK * - means "in which R * represents a methyl or ethyl group" and a group of the formula (a) in which

Π * 'hydroextractor »methyl group07. or ethyl group »• ·

- 19 * «Λ chemoprotein bond« ethylene, ethylene »ethylene, trimethylene» propylidene n, propylene, tetraethylene rag; means isobutllidon-ceoport »a² denotes or denotes a group of ethylene, ethylene, ethylidene, trastylene, n-propylidene, propylene, tetrsaethylene or iaobutylid.n, a valence fifth of which is ethylene, ethylene, ethylidene, triacyl. , propylidene, propylene, tetraethylene means isobucylenyl, chloroethane, hydroxy, eaina, cieno, trifluoroacetyl, xCl, otoxy, □ ·. ethylamoyl, ethylamino, ethylsulfinyl, ethylsulphuoyl, ethylsulpholoyl, ethylsulfonyl, acetyl, propyloxy, ecstyl, 2-hydroxyacetyl -, phenyl, phenyl, thiophenyl, phenylalulfinyl, phenyl-exulfonyl, thienyl, pyridyl, quinolyl, pyrialdinix, xinazolinyl, ialideeolyl, boazidazole, thiol, 1,2,5 -triazolyl or 1,2,4-triscis-1-cacyl and denotes the groups listed in the &amp; quot; group &amp; quot ;, or &amp; quot; ealyloo, &amp; lt; 1 &amp; gt; -hyloxy-carbaoyl, &amp; lt; / RTI &amp; gt; -, xr-free, sulfinoyl, u-eoethylsulfeanyl »h -ethylsulfonylBuoyl, t-tolylsulfenoyl, x-« ethylxarbaoxyl, A-ethyl-urboyloyl, --ostylsulfosoyl-uxi-, &amp; Quot; -Qtylethylsulonyl &amp; lt; / RTI &amp; gt; carbonyl, &amp; lt; 8 &amp; gt; -thio, fanyl-esulfin-1-yl, phenylsulfonyl-oaryl groups, optionally one or two halo'oxyl, οχο-, eioxo, saioo, nitro, cieno, ksrbaaoil-, fluoro, bromo, ol, ethyl, nitro, cyano, l-xctil-kciX'boa-M.il, yl, butyl ether, b-ethyl thio-, aatll20

-Sulfinyl, Cetyl-sulfonyl, Sethoxyl, Trifluoro-notyl, Phenyl / or beryl substituent may be attached and phenyl or benall-sulfubeseaseashea or N-phenylsulfonylcarbaoyl-osoporthos may optionally be a nitro, cyano, fluoro, chloro *, cetyl or netoxy-eaubeat substituents may be attached, provided that in the -Lx group the brain is attached to a cetyl or nickel group at more than one border, a further group of compounds that can be obtained from sselyin are the quinazoline salts of the formula (1) and the pharmaceutically acceptable salts thereof, wherein a is a group selected from the group consisting of cetyl, ethyl *, prop-2-ynyl and S. is fluoroethyl, in the case of kinsolol and the other is attached to the fluorine or Boti 1 -ununatoluene in position 7,

R 4 is hydrogen. it means₍, r a-k-ι group s 2 hslyastbee carrier 1,4-phenyl η-, thien-2,5-dyl-, pyrld-2,5-di-v-thi &amp; 2ol-2,3-dill- or &lt;RTI ID = 0.0&gt; 3-ol &lt;/RTI&gt; 2-fluoro-1,1'-phenyl-n-position substituted at position 1,

Denotes 1 -Gb-idi, i denotes a group of the formula (a), denotes a hydrogunaton or a letter group in your songs, denotes an ethylene or atylone group, a bond or an ethylene or ethylene group, x

&lt;»Represents a bond, a ethyl group or an ethylene group, ··· 21 chlorine or hydroxy, amino, cyano, oethoxy, methylamino, ethylamino, dissfU-emino, diethyl-amino, ethyl-tl. , -, ethylthio, acotoxyl, phenyl, phenyl-2-thienyl, 1-, β-pyridyl, 3-pyridyl, 4-pyridyl, o-_tlriolyl, &amp; gt; quinolyl, 4-quinolyl,? -pyridyl &amp; lt; / RTI &amp; gt ;, 4-pyrixidinyl, 6-amazolyl, 2-cellulose, 2-t ₄ozo111-, 5-thiazylyl, 1, c, 4-tri 'ώθΙ-1-ix- or 1,2,4-trisvl-&gt; - yl-C8.^c The groups enumerated at the meaning of this report are represented by, or not, tix-k? Röamo 11-,;.-Acetylsulyl-unil-kerbemuiil, λ-1'snylsulxouix-L.örbtmwil- or '&gt; -tetr «zoli 1 -cssport., and added to the listed χ'οοιι, feml-tlu or neo-roaryl groups, &lt;&amp; gt; or kot, as well as to the hydroxy-, uxc-, amino-, nitro-, cyano-, carbonyl-, fluorine, chlorine, ethyl, aethoxy, trifluoro-a, ethyl, or e. and for the benzyl substituent or the N-phenylphenylsulfonylcarboxylate, as expected, nitro, fluoro, chloro, methyl, or methoxy substituent, Ezol c. provided that no more than one week &lt;4 fibers, which is part of the heteroaryl ring, is cleaved to any of the ethylene compounds in the -w- ~ group, «.-Pezlk are those pharmaceutically acceptable salts of the quinazoline of formula (u) al-vl ^ nose • azoreazósvk tin, in which the terminal port represents a methyl, ethyl or pro-2-xni 1 moiety and added to the quinol xylene product at position 7 in a fluorine &amp; g; zietil-oaootltuena is linked, hydrogen atom, yew, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · what as - 22 - * 1,4-Phenyl-6-yl or 2-diyl-purpur, or the tleao-1-2,5-diyl group formed in the? for the -la group, this refers to the 2-fluoro-1,4-phenylene moiety attached at the L-position, x1-1-v ^. denotes a cs port and denotes a group of the formula x (b? oIc &amp; IaHos, likely a vegj or ^ or neo-porto, a valence or non-valent,

P represents a bond or an ethylene group,

P ishloroxyl, cyano, acetoxy or 1,2-dihydro-2-oxopyridophenyl or optionally nitro, chloro, ethyl, siloxide or tritluoromethyl; ethyl-cxopvrttol ssnbsstltuo.lt denotes phenyl or Xtail-tloceopcrtr, and denotes the groups listed in the y &amp; z P report, or l-cetylsulfonyl-iterobenzoylcarbonate, 5-tetr®&gt; 8-ol 1-group * or, in the other case, nitro-, chloro-, atyl- or a-oxy-ssuUstltuenü-1 steam salt L-phenylsulfonyl-corbcnoyl-Cfc'Oρor Lake J, Ut, dig. ua aa - caoy ^ rtbsa is a setil.-c- and aatinceoporthos teo kopc is derived from several of its tarostoa, feaely ues Letéroari.-ring, 1.x.1αxny sserin, are a preferred group of compounds which are (li china cozoliu-mud ooo coals »and their beds are salted with,;¹ as a matter of fact, do not mean down to the lake of dust,

Á s &lt;. a methyl, ethyl, prop-2-yl-1 or 2-fluoroethyl group, and in the case of kinesolino ring position 7, in the case of an additional fluorine,_t throne-vsgy-nebil-sub-lltaeus is connected,

<img file="HUT57739A_D0003.tif" />

- 25 hiarotene * coma Report for z &lt;r ss-u-x group 1,4 ~ ί &lt;η11ύη-, tieu-2,&gt; - 4111-, plrld-2 | p-diyl-vsgy tUzo1 -2.5-4111-csc. · Car for Jelet or as -i- .. in position 1 with 2-fluGr-l_f4-phenyl, n-oso; - i &lt;4 means ex parte and ϊ (ej represents a pseudorandom suppository group in which hydrogen is hydrogen or methyl group, v is a vapor or mecilonecopurt, if it is a blood vessel, it is not Ivocaopcrt or ethylene group,&gt; 3). or a mixture of ethylene, ethylene, triacetylone, 2-thia triacetyl-n or lixuroxyl-n-xyl-n-cx._veI &lt;-nt,. 'IXUX'öX ϊ **', íi liv -, CXvtlv—, ií2 £? · \ J »&gt; ί -, etúXX—, t're — out ^. ·» -, aeöli- * stno-_t uia ··· tll-alaiiK · -, α ·: tylthio, methyl 11-sulfinyl, methylsulXuail, ethoxy-butyl, or a particular group of n-hydroxyl, nitric, fluorine, chlorine -, caetil, a®toxi- vo_i:The carrier for the substitution of trimethylmethyl substituent is phenyl, phenyl 1-thiol, tiesolxl, 1,2,2-trixisolyl, 1,2,4-trie301x1-tiv, 1,2,4-trisolyl. -flux- or 1,2,4-triesolyl azulfonyl-ionsport, etc.

THE

Said eeotbeu is a terminal well containing a chloro, nitro, fluoro, chloro, ethyl, ufecoxy and / or triylouryl ethyl substituent on a folyl, tanyl, yyridyl, isoxesolyl end, thiazolyl group, julent, © wherever oxo-substitution may be attached to this pinyl ester oxide, they are a further preferred class of compounds of the present invention. «8 (ij. Disulfanic clnazoliu-s-raozek-j *; vs. medicinal-esotylg i-salzbot salts, in &lt;places ·« ····························································································· · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 24 γΛ Meaning,

K² represents an ethyl, ethyl, yrop-2-iminyl or 2-fluoroethyl group, the β-quinol solBB1'bubble optionally contains another iluor, chloro, bromo - or a methyl substituent is attached,

3. ^ ChlorogaDt means toaot, price for this group is 2-ea UoljZetbeu so * p tube based 1,4-Xenyl..a-, thien-2,5-di-yl, _t irld-2,5-diyl-like-tie - &lt;, 5-diyl-sports or 2-fluoro-1,4-enenyl-ceoporto attached to position 1 of the - "- X group,

-ύι-μϋ- denotes a group x (c) _weleut, antly cut íP hiurogonnet- denotes *&gt; tilecroup Represents, i&gt; denotes a bond or notil-ncooporty, x² optionally bearing an excess of nitro, chloro, ethyl, ethoxy, or trixluoromethylsuccinate, meaning &lt;RTI ID = 0.0&gt; L-Nethyl-chlorobenzoyl, &lt;/RTI&gt; -? - ebylsulXonyl - / erbeiauil- you are

5-UtriSolyl or unsubstituted, unsubstituted, unsubstituted, substituted, unsubstituted, n-dioxo-xenix-sulfonyl-kerbunoyl-co-xyl.

Further, the compounds of the present invention form a further preferred ceoproctate of quinzoline-suraezckox oo of the formula ss (1) -Islonve.¹ ί-qualitatively or five-ethyl thiurturt

is a bunch of methyl, ethyl, or Γoρ-2-yn 1, and looks like an in-y item optionally in position 7a with an additional 11a, chloro, bron or ® ethyl substituent®, S? hiirogér ^ tosaot well ·, nt, ·· ·· ··. · ·· ·· ······ ::,, ... ··· · · · · · · · · ·············································································· ed The thiazole-2,5-diyl group attached to this 2-hydroxy group, or the 2-fluoro-1,4 -1eniluo -group means 40leat, - - '·' - .. xi-, and. (d... sign a generic group ©, where &lt;ta chemistry.st, a Million group, or etllZn group,

Z 've &amp; lt; / &amp; gt; -. &amp; Gt; stands for methylone group,

Zluuroxyl, clonu, aetoM, osoxyl, tert-butoxy, methyl-α-α, phenyl, 1,2,4-triazol-p-ylthio or 1,2,4-triazyl * 5 ~ II-saulfiuli osoportct _ual-ut, and sZ-phenyl-5-altrophenyl-cc · ..port * xi tsluLiuhj according to el-ali linotc add 0 feminine group «Ikotjua &amp; &amp; cisululin xation salts thereof, wherein &amp; lt; 1 &amp; gt;^x aetyl means yelvnt, .'Λ hurry !,, mii or prop-2-inii, this chinaaollngy store edo^r.the case in the z-position of their additional fluorine, methyl, bromine, methyl substituent, Morogó means nMus, «• rl, α-feuyl · .r.- so thea-2,5-methyl- group, or this for the -χ.-ϊ group s 2-holotocene ^^ fused thiazole-l-2,5-di-iso_rvrt or this is a 2-fluoro-1,4-phenylene-c-port attached to the 1-position, a * »-Cu-yl group, and a zeo of formula (e)_vstands for ortho in which ./phenyl cut. ntro- £ cnll «* c-xo ^ ortot, and

1'-Ethylsulfonylcarbamoyl-g-5-tert-triazolyl-c-oxo-chemical substituted with a nitro, chloro, wtyl or raethoxy substituent -h-phenyl-aza-sulfonylcarbacoyl- eeoportot Significantly, λ is a particularly preferred group of compounds that can be produced by essrin and other kinezolone derivatives of formula (i) alpha-lene and their salts.

R¹ means aetiloeoport,

R is cetyl or prop-2-ynyl and optionally attached at position 7 with an additional fluorine, bromine or nethyl-ebsorbate,

R · ** H represents a 1,4-phenylene-C6-pojyt or a 2-fluoro-1,4-endo-* n-terminal 2-fluoro-1,4-phenol moiety , ó -Gú - * »n represents a group of the formula '* s' (£) altel / ιηοβ, in actalia&gt; *« represents an ethylene or ethylene group, ^c hiaroxilc. She_; ortot Mean and ϊ? Compounds which can be prepared from 3-nitrophenyl group are further preferred groups which are pharmaceutically acceptable salts of the compounds of formula (1), acyls and xji. Denotes a 2-inyl group, in the case of the quinoline green, in the above case, a further fluorine or netyl substituent is added at position 7, R '' is hydrogen,

-r 1,4-phenyloyleopath or aa -L-; and in position 1, Moce-olad means 2-fluoro, 4-phenylene-oeoaort, · ♦ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· ** x&gt; -Cu-toü- denotes * ée i (e) Álwölaüüö. dude vvtctct. excl ^ boa stops nitro-allylcarbonate yslant * and h a-eaecylsulXonyl * carbaeoyl-_t b * £ eaXl means »ulXonyl-borboroyl-χά (4-ΰα &amp; οχχ-χ« ηίΐ) -ozuixoaix-Xsrbeno.il or 5-tetrezolX-group · «according to telalauxny - outstanding advantages the following compounds of formula (x) xltaIonic * zolyls and their physiologically acceptable salts: ii «* ^?« 4xidruxx * l- (5-altro-Xeuil) -e 6ΐΧΓ * ρ- £ ύ- (2-ηα t il-4 * oxo -&gt; * 4-dichloro-k 1 u i, 11 η-6-yl-s t 1) -x- (pro-2-i-1) -a® xu £ - azesil * P “Z? * (2 t 7 ~ he. in® til-4 * oxo-5 * 4 * dihydro-uro-quinol (6-yl) -h · (prop-2-yl) -az. ·, υ ^ 7 -ο- ^ Σ-ίχ1αχΰχ x-1- (5 * ul tro-Xeni 1) -et ij / -zxsid * p * £ jU (2 * 7-oh x «11 Χ-4-οζο · 3» 4- diaiúro * kina zol i u-6-ll- &amp; e 111) &lt;·; »- (prop-2-iaiXí -feaxE. ^ to-xluur-ft-x ^ -hiax'axi-l-Cd-aicro-xeaii). ti j7-bs nzx xxu * p - ^&gt; - (2 * 7 — cxi-üé t il — 4— oxo — 5 * 4 * daiara-tortoz olin * 6 * il — a »· til j - x— -ne 611-e &lt;- £ &lt;c -xxar c.xi-1- - (5-ux trc-lei 1) s ^ Z-bsuze a id * jS

7-bromo © -2-netyl-4 * δxo-5t4-uiuxdro-kiacclia-6 * yl-i.ethyl} -ft- (prop-2 -xxi 1) -e slngZ - "- Z ^ shi uxx-xi -i- (5-nitro-fe all) -ethyl / benzene ·

4th sc. In further embodiments, the compounds of formula lulaony are preferred and the following are represented by the following general formula (1) needle quinzulin-aza-azz-z and its pharmaceutically acceptable salts o-fluoro-β-4- (2-acyl-4-oxa-5 → 4). -oiuiuro-kineszol-6-yl- «e til) -&gt; - (pro-2-i i) -®a lu ^ / - h- ^ J-ni sro-o-i 5-tc trez oil 1). -όθηζίχΓ-bőnzoaid * p - ^ - ík »'7-niifti. til - ^ - oxu-pf ^ -úihAuro-teas-G-yl-uethyl) -ú44 ··· «··

- 2Ö ·

- (prop * 2 «inll) -®ain ^ -yl- / J-ni tro-α- (γ-threzolyl) -benzyl-7-benzamide ^ • ^ • ('/ • Fluor-g-natyl) -α-oxo-N, 4-dihydro-quinazolin-6-ylmethyl) -4 - [(prop-2-ynyl) -phenyl] -7H-N, N-nitro-c- (5-thiazolyl) ) Benzyl-7-benzoate, 1'-Zp- (Wi-methyl-4-oxo-1,4-dibromo-quinogol-6-yl) -ethyl-h- (prop-2-yn) -amino. ) -Internal il- (&gt; -ni tr o -phenyl) -glycine-d -VH-ethyl »uxi-phenylZ-sulfenyl · - &amp; mid_t ás ί &lt;«τ £ ρ» (&amp; - / 2, 7-d lse til-4-αχ - »J_t4-Dihydro-quinolin-2-yl-O-yl-ethyl. - (prop-2-yl-4-Elixiw) -benzoyl - (&gt; - nxtru-feuyl) -glieln-xx- (®Btil-ssuifüt.i1) - &amp; mid · ils (1) ulta Ionic quizoline starch derivatives and words in the pharmaceutical formula xg Salts * of any related structure may be prepared by any known method. For example, the compounds of formula -4 (X) are treated with the following uasol.

e) (a) Copy of aIícIauoo tu. Preferably, the compounds of formula (II) from formula (III) are compounds of formula (III) wherein the compound of formula (III)¹ rigidly-containing mint, hioru-1-4 alkyl, or u * droxy-elkoxy-cuyortb&gt; .uu ts.nu-vt,_JV hi'AroxiiCöOporthoa Known Protective KspcsGlobal »hydroge &amp; tuaot or protective group j · down oa leaky group jeleut - liúú ^ - price · - · * general picture · let-χ compound · beckel re agai tt- - -» ίί% -r_t and i jelmuee above; with the proviso that in the group «S« r or i, one-group smialoxy, alkylamido groups indicate a normal protecting group, and this group is present in the same groups as hydroxy-thioportes, or in free state, then c \ fa * -.x 'and * ceopurtou in the cdott case l «cf.

<img file="HUT57739A_D0004.tif" />

<img file="HUT57739A_D0005.tif" />

<img file="HUT57739A_D0006.tif" />

<img file="HUT57739A_D0007.tif" />

<img file="HUT57739A_D0008.tif" />

protecting group (k®).

. reaction is preferably carried out with a base such as an alkali metal such as εΐ-

<td>kalii * oldf -2&gt;:. srt</td><td>or you are</td><td>-You can (like k'iliuta kerbonate,</td>

<td>riüQ-^;_{; t} rboL Λ- ,;</td><td>·.; · LCiUn -: ': ·'</td><td>rbon-it, soda * us-hydroxide vtgy potassium-</td>

<td>-hisroxis; v</td><td></td><td>torture base (ie; iridine, 2,6-lutidine,</td>

<td>&lt;t 311 iáin, 4 ~ Aili</td><td>.Mié v LX ** v * · Ul i · Π</td><td>pyrroline, triethylamine, aurfoline</td>

vftgy ói »·· za — v * cx - · Ι ^ Ά * .4 ·» ^ y ^ un..oc * · / ** “-... j ·· .xfi .aí .- 'jt bsn νό , 'ΈΚΖ ifc. · Recycle solvent in diluent, Lg,. i-G i. XX ** X vi ''? Ul a, U i3 ·: 'Ii 9 ►' g. \ - 0i'3-; t il-oceteai ·. ocn, c * l-_t-.rr / 11 * ''. -L-anbsn vy áag ^ 11_THE-4ZUll'0AÍ2 ^ n

<td>FINALLY &lt; '. ·. meadows</td><td>AA 'w · *</td><td>· .sórsé.uot .; Fri '</td><td>id.s. 25-1&gt; ··· ° ν, preferably Ju ° 'd</td>

<td>or zuse to that</td><td> *1</td><td>ortóii ie:; * t ·</td><td></td>

<td>'Α · Λ · ν V »'</td><td> -I -W »% M</td><td>1C; OpúriIX VCU</td><td>c ..&gt;.&gt; · xxxx ripening ·</td>

<td>Cu c.oyertot, i.</td><td></td><td>ccctll- or m ·</td><td>ru »ik.salt cartoon can be taken Z-^: r.</td>

<td>... uti x. W *, d L · ~ Λ. u '.</td><td></td><td>UX * Í * .U ± V Á ·. · Ϊ td · '</td><td>..1, lyy n itrluo-nenrox iü</td>

<td>iGnl.tóc ^ nv é</td><td> w ü</td><td>hydrolysis 1</td><td>fíxVuxl r &lt;tlt jjUtí. 61 ».14? , U í? *</td>

<td>Η * νΜ £ »X 4? .J? ', /' £ · .. '· ti</td><td>J</td><td>^z -. Q «y ΐ» X ·· V v / x. '</td><td>who owns Lcooport, the conduit..s guard-</td>

... for example -Aj.-rij-oil ·, ii-ceop ^ rúuix · t, so benzyl opera is also * tuu .., the food of tii us hiév / .Dozéxel tóvo · it hsa

<img file="HUT57739A_D0009.tif" />

<img file="HUT57739A_D0010.tif" />

<img file="HUT57739A_D0011.tif" />

z., duo- 1 / dL-lialüb-Ci ^ portr ·. as a protecting group, for example, d v, i ~_sxrbönil ~ beaker, tcrc-butodi-orberyl-bioreactor-Tt, which is organized; acid, such as trifluoroacetyl ··. you:. zv.1 - esel hasithetae, 7eJ · οοο, sulfur benzyl-O2I-i • - • i'bonyl-potopurl may be referred to as u.i.8 ssvvol, for example boron triL ~ 2 (trifluoroacetate) was treated with CsvoXe.

oiiüsc juporúrs vé&gt; c ·. as an opunt f tHoiicsupur ······························································································• · ·· ··

<img file="HUT57739A_D0012.tif" />

tlix · ilixu strain »eait slkyl-ethin (thus dit» tll-8ffinopropyl-eainn) or bldraz inhal end can be removed by cellulose · protective tube dust outside eg pivtloyloxymethyl-CBopertot ^ U'htü.at ·. The group é may be eliminated by treatment with a base (such as sodium; idx * oxyl) in a solvent such as phenol or ethanol, in the presence of a base (such as carbon, gas). »(11) i.ltLlú.nos kl.lf; vo ears A for example helogel * Ceaut L «; ulfonii-ωι i-ct ·. ^ crtot, i », y kl vrfctüffik't» bromine, • .tán-sul'onyl-OÁí * vr_t'y y-tuluoi-aouLConi 1-ox —c νú ρ'. r to a - x · j al * - L ·

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V * - V- * '·' ALD -v J. · · - ·. '' ·, J Á '| ', j V l

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formula i. Ά k η)? k .. 'let. v ··. £ · -letokKel. ro ^ gl v&gt;? t jur: -

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/ • ili-l .n-js' ·. vftu cL-rbonsa'r- x re ekeié— &lt;Qí!

e

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• caution: - · Price í - t '-Á Λ /. J. ' â &amp; # x20AC; &amp; # x201C; Insufficient sevechloride (e.g. thionylchloro · α) sisclMg ...; '. L -&gt; id: -H. · Cake ου blood yc, mixed? Nh idril s, so word carboxylic acid in the brain to clear acid ester (^ for example

Anhydrides, reactive esters such as eaebed carboxylic acid with a phenol (e.g. pentafluorophenol) or an alcohol (e.g. 1-hydroxybenzotriazole), an acid anhydride, e.g. derivatives of the carboxylic acid and derivatives of an acid, such as diphenylphosphoryl azide; or derivatives formed by the reaction of free carboxylic acid with brain carbodylmide, such as dicyclohexylcarbodynide.

HSR used as starting material in the process described above²Compounds of the formula -Ar-LY * wherein L is -NH-C. - or -KR⁴&amp; Quot; CO- and H * are as defined above, which can be prepared by reacting compounds of formula HNR 1 -Ar-Mig or HSR 1 -N Ar-NHR * with carboxylic acids of formula HOX-Y or a dry reactant thereof R⁴, price and Y have the meanings given above, provided that this is the price and the amino, alkyl-aa, and hydroxy groups in the ΐ group have the usual protecting group or the hydroxyl groups may be present in the free state ·

Those are the House²The starting materials of the formula -Ar-L-'i in which L represents a -CH®CH- group may be prepared by reacting the aldehydes of the formula: reaction with phosphonium salts - in the formulas G¹ an amino protecting group such as an elaxycarbonyl group and a Z-anion such as broaldlon; the conventional protecting group is attached or the hldr&gt; 2 oxy groups are present in the free state.

. ··. The reaction may be carried out in a solution of disethylsulfoxide in the presence of di- methylsilylsodium sodium. The G * conduit port is then cooled in leached salt, and the resulting assay HgU-Ar-CHCH-x is obtained.²Is reacted with a compound of formula Z wherein R is² and Z is as defined above. BRANCH¹ is preferably chosen so that when cleaved, the protecting groups applied to the esino, alkyl osino, or amino groups in the Ar and ϊ groups via the brain pathway remain in the subunit.

In the above reaction, the triphenylphosphonium salts of the starting compounds (Ph 2 - 3 -? Hg · Z **) can be prepared by reacting the compounds of the formula 1-CH 2 -Z in which ϊ and Z are as defined above with triphenylphosphine.

spades e I »HR²The starting materials of the formula Ar-LX, where applicable L * Gfi »CH-, may also be prepared by reacting the aldehydes (Ph)₅x '* - CH₂- triphenylphenyl salts of the formula Z *! reacting * in these formulas, Ζ *, X and Ar are as defined above, provided that the amino, alkyl-esino and hydroxy groups of the as Ar and I groups are attached or that the hydroxyl groups are free.

The reaction is carried out in a solution of diacetylsulfoxide in the presence of disethylsilyl sodium, and then the nitro group of the resulting compound is reduced to isocerated aminoceoporte and the resulting amino compound is charged with R²* Is reacted with a token of a compound of formula Z wherein R² and Z is as defined above.

The salts of the parent compound of the formula W ^ -Ar-Δ-Y, or, in the odds, L-Cv-O-, can be set as follows. ·· •, ··. · · «· · ..

• · · ·..

ι «· * ···· ··· ··« · ·

that a carboxylic acid of formula OglWr-COOH or the reaction of the rain may be reacted with the alcohols of the general formula H * I - in which the formula Ar and a is the same as above with the proviso that α, el * kilo-emino and hydroxy groups are bonded with an asocratic protecting group · The nitro group of the resulting compound is reduced in a known manner, and the worn amino compound is then R²- they reacted with the genes of the general formula ve * - in which R² and 2 have the meanings above ·

b) Salts of compounds of formula I wherein L-CG-ΐΐΗ or -CCWLR⁴a further preferred method may also be prepared by reacting the general formula (HI) carboxylic acids (H1) or the reactive esters of ethers with HgH-ϊ or R⁴Chemical formula HH-Y! - in the formulas R^X, R², R⁵, R⁴, Ar and í and R⁶ has the meaning given above, with the proviso that the arine, alkylamino and hydroxy groups in the group Ar and the group ϊ are attached or the hydroxyl moieties are present in your case.

For example, the reaction mixture of the cerbons resin of formula XII with o-acids such as acid chlorides, mixed onhydrides such as chlorobenzoate and chlorobenzoate ), with the reaction of snhydrides, rectal treatment and sterols, thus, salts formed by the reaction of carboxylic acid with a phenol (e.g., pentafluorophenol) or an alcohol (e.g., 1-hydroxy-1-benzotriazole), acid acids, such as the free carboxylic acid and an azide, such as diphenylphosphoryl azide, sovn. trills, for example

<img file="HUT57739A_D0019.tif" />

derivatives of nitriles formed by the reaction of sebacic kerbonic acid with a cyanide, such as diothylphosphoryl, or the free carboxylic acid, may be derivatives formed by reaction of a kerbodiidic acid, such as a dicyclic hexyl fatty acid; thus net lene chloridebsu, H, ad iae ti 1-f oraem time, ü₉in dimethyl acetic acid, H-acetylpyrrolidin-2-one or diethyl-3-sulfoxide · The reaction temperature is, for example, 10-1 '.₉ usually at or near room temperature, the starting material (1X1) may be used. Carboxylic acids can be prepared by reacting compounds of formula II with HI²can be reacted with compounds of the formula -AR-G-UR 1 - wherein 2,4 &amp; amp; Ar is as defined above and 9? does it mean a protecting group is it 9? We will release the protection group ·

3? for example, it may be methyl or * otyl, which may be cleaved by alkaline hydrolysis in the presence of sodium hydrosol, or t-butyl, which may be cleaved with an organic acid such as trifluoroacetic acid; for example, a protecting group may be an ester group which is removed during removal², price, and min protecting moieties on the Smino alkyl anino and bidroxyl groups on the molecule ©

c) Compounds of Formula I wherein L is a L-co-ο group in vultures may be prepared according to another preferred batch process by reacting the carboxylic acids of Formula III with reactive derivatives thereof in the presence of a base with compounds of Formula Hu-I react

in the formulas,¹, H², r \ R ^, price and 1 have the meaning above,

- 55 ι?

ζ «1 ® provided that R, i?^e_f To the anino ·, elkylamino · · · · hydroxy groups in the Ar and 5 groups, the usual protective tube · powder is attached nejd the protective tube ports are cooled in a known manner *

the reaction is preferably carried out in the presence of a suitable solvent diluent such as N, N -dimethylformamide, N, N-dimethyl-scetalide, N-acetylpyrrolidin-2-one or ditrethylsulfoxide. for example, the reaction temperature is 1% 100⁰G, preferably room · may or may not be ·

d) wherein the compounds of formula (I) in which the alkoxy, hydroxy-oxo-alkoxy, or alkoxy-alkoxy-ceoportate is in place can be prepared so that the compounds of formula (e) above and 3 * "Meaning &amp; quot; &amp; d) provided that the hydroxy lepepert has the usual protective Leo purity - reacted with compounds of formula SSR ^ -Ar-L-ϊ · in the formula

R, Ar, and i are as defined above, with the proviso that as

The amino, alkyl-a-α-ye groups in the ar and x groups are attached to a standard protecting group, or the hydroxy groups ® are taken in the nasal state &lt;present - and then the known protecting group s ports are removed and 4 of this kinase ring is the site group is removed by hydrolysis in the presence of a base such as sodium hydride ·

e) In aase I, the compounds of formula (I) which are tertiary alkylsilylsulphinyl, srilsulphinyl, heterocrylsulphonyl, alkylsulphenyl, srilulphonyl, may also be prepared by reacting ϊ to oxidize compounds of formula (la) with an alkylthio, srlthio or heteroarylthio moiety

As oxidation traps, the thiol group is sulfinyl or sulfo · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· «·· ·· ··

Oxidation of the J 6 · nyl group can be achieved by the sale of a known reagent, such as hydrogen n-peroxide, persuate (such as 3-chloroperbenzoic acid, X 1 / hydroxyacetic acid) or chromium trioxide. It is desired to prepare H.sub.2-sulfinyl compounds by using an oxidizing agent on a fissionchioskylic acid in order to obtain the sulfonyl moieties; · Mild oxidizing agents such as n.xtriunv or killun acetic anodioiodate lg can be used to produce Ez-Ifin11 or fragrances. · The sulfinyl containing compounds of formula (I) contain thio groups, or ) can be prepared by oxidation of compounds of formula

f) a compound of formula (I) containing ananyl-oxy-co-oxo in one to five groups; Compounds can be prepared from the corresponding compounds of formula I which are spaced by the hydroxyl group in the Y group.

In the case of the soil, these hydroxyl or salts are reacted with the corresponding reactants of the corresponding compounds of formula (I) and the corresponding alkylating salts of the compounds of formula (I) can be prepared, for example, by Compounds of formula (II) are reacted with the appropriate acids or bases in conventional manner. The optically active compounds of formula (I) may be prepared using optically inactive starting materials or by resolution in known manner.

As stated above, compounds of general formula (I) have a tuning inhibitory action. For example, the pharmacological activity of the compounds of formula I is the following: methods!

····· · ·· • · «·· ··· · · « · · · · · ·

..········· ·· · ·

- 37 s) In vitro hydrolysis of compounds inhibiting histidylate synthase enzyme inhibition. «·. thymidylate synthesis can be isolated from partially purifyingδ formabsn bl216 mouse leukatie cells · Whole sprout Jackckn et al. (Ceucer He®. &amp; amp; 231v. 1966 /) and liqueur et al. (biochem. herm. col. 3Z, 4C47 / 1983). method.

b) Investigate how the drug inhibits the growth of s * 1210 oocyte lineage (leukemic s-cell line) in cell cultures. Examine L by the method of Jom @ et al., J. ded. Chem.

065 653 se * to the lozenges described in British Patent Specification.

c) Investigate how active ingredient s inhibits the growth of? -Ch-7 human breast cancer cell line in cell cultures. . · VizrgalBt. ippmen et al. (Cancer &amp; quot; 16, 4594 (1976)).

d) In vitro, cytotoxicity of L51731 TE lymphcms to cell line by cloning assay. The L51731 TE - / · cell line lacks the thymidine kinase &lt;· enzyme, which phosphorylates at midin and thus thymidylate nose¹1 is formed by inhibiting the fresh synthesis of t · thymidyl see with an effective amount of a thymidylate synthase inhibitor. Please comply with L5173&gt; lí. - / · cell line cloning! is very sensitive to these thyridylate synthesis inhibitors in water.

kz L51731 was constructed with a mutation of 111 - / - cellular cells at s *&gt; 5178; alep cell line (this basic cell line is described by Eiacber et al. | - 'etheds tend', et al., 10, 247 (1964)). similar to the method of Lourten &amp; y et al. (British J. Csncer 39/1976 /), double layer soft

<img file="HUT57739A_D0020.tif" />

<img file="HUT57739A_D0021.tif" />

«· · · · Using the mouse clonosis technique. the test compounds were pre-incubated at pre-concentric concentration at 6 µl / lll for this exponential growth phase, L5173: TK - / - cells were transfected into cell culture, the cells were incubated for 13 hours, harvested, washed with fresh medium and soft egers are transplanted for evaluation · After about 12 peoples, these cell colonies are stained and counted.

Noho this is a unique process for the synthesis of kimsdln derivatives of the general formula (I) and the structure of these compounds. Depending on the batch, the kessolin derivatives of formula (I) in these above assay cases have generally been shown to be effective in the following dose range:

(s) Assay for test 0.005-V ^ mole of test (b): 0.1-13 ^ mole of test (c)! IC ^ q! 0.1-10:&gt; yumol (d) exams! A dose of 1-100 µmol is required to reduce the surviving cell fraction to 10 0.

knsns.olir-lenses with extremely beneficial effects of formula (I) have generally been shown to be refractory in the following dose range!

(e) test IC;_Gi 0, XJ-2 yumol (b) exams! Assay of 0.1 to 10 µmol (c): Assay of IC ^ ji οοχΐΐ ^ ^mol (d): The dose required to reduce this survivor to 11 is 1-50 µmol.

By way of example, this is K- (dlphen11-met11) -p-E1- (2-acetyl-4-oxo-J, # -di hld ro-carbones-c11n-6-yl-ethyl) -K- (prop- 2-ini1) -emlnsT'-benzsBld 1C ^_SHE the value of this (e) water is 2 µmol in this, 7 µmol in this (b) water and e (c) water, 1.5 µmol / l of H- / 2-S®tll-4-oxo-3,4 -dihldro-clnszolln-G-yl-methyl 1 / - ···· ······· * 39 »2-i- / prop-2-ynl-amino) -beazo -á7- (3- ni-cro-pheyl) -gl 1c-α- (4-methoxyphenyl-salonyl) amide_SHE value of öz (e) in viagra is oh_tΜl / µmol, u (b) more than 25 µl / well, and µl / µmol / µl | p- [4- (2,7-Dimethyl-4-oxo-3,4-dihydro-chlozolin-1-yl] -ethyl) -N- (prop-2-yl) -amino] -7- »- N, N -hydroxy-1- (3-nitx-O-phenyl) ethyl7-beazaBid 1G_SHE and es in test (a) v, J2 / µmol, in test (b), 3.4 yum, and in test &amp; (o), u, l / yol (values ​​quoted are approximate).

if the parent compounds of formula (1) may be active in their onsagnes, or they may be converted into in vivo bundles / rock salts of the urine, they may become a compound * &lt;.z (1) alLulu.E.us its therapeutic salts are to be used in the form of pharmaceutical preparations for the treatment of blood, including humans. In addition, the pharmaceutical agent contains pharmaceutical diluents, carriers and / or other excipients.

orally administered medicinal salts (such as tablets or capsules), injectable repellents for preoperative administration (such as latravenous, subcutaneous, intramuscular, and creams) and rectal dosage forms (such as suppositories) may be * ά pharmaceutical preparations. the clnazalln petals produced according to the present invention may optionally contain one or more other anti-tuning agents, such as &amp; lt; RTI ID = 0.0 &amp; gt; leotactic &amp; lt; / RTI &amp; gt; alkylated saline vessels such as ciazplatin, carboplatin and clofoazolides such as γ-fluor ursoll, cytosine arabinoids ························································································································ · · • t · · · · ········································································································································································································eded. bed .a old antibiotics, Thus, bleuolinin enzymes live on the adrle, thus ospraginating topoisomerase inhibitors such as etoposfd and agents modifying this biological regimen, such as interferons, can be prepared by known medical technology using conventional pharmaceutical additives and excipients.

The quinazoline-l'-rtaez-kota is usually administered in 50-5030 mg / s body surface area, eagle about 1-100 members / kw in the form of dosage units for the &lt;RTI ID = 0.0&gt; 3 &lt;/RTI&gt; airlifters * Dosage units such as tablets are usually 1-25. '' contains ag active substance · Hf pellets do not. Preferably, for example, a dose of 1 to 50 µg / kg may be used. · It will be appreciated that the daily dose will vary according to the particular condition of the subject, the dosage and the severity of the disease being treated, so that the optimum dosage should be unambiguously determined.

THE;; (I) generic k'platform compounds are expected to exert anti-tumor activity in the acorn · '&gt; 033717 Promising anti-tunic Serbs have been shown to treat human breast, ovarian, and zebra | Thus, these compounds of Formula I are expected to be active on carbon with these types of cancer. · It is expected that the compounds of Formula I will exhibit different types of leukeaal®, malignancy with lymphatic genes and "solid tumors (such as gonorrhea and esophagus) will also be effective in the day · These types of tuffs will require thiadidine anophessphate as an essential nucleotide for your cell? ) in the presence of the clnazoline-v * g compound of the formula:

<img file="HUT57739A_D0022.tif" />

As the lord said, and the healing of kineao · lio-sarcasas of the formula (I) Heg ylolssshatc salts &amp; allergic sticks and conditions, pyodol pseriesis k »r. two roudsaerins he '^J· ** ^ 3 o / X / V ag / is used in the body surface dali for the treatment of allergic disorders, such as peoriesie, rendsaerin locally fdhasin overdose retardants are prepared by: the neck is usually snow-fed at a daily dose of 1-5 sg / kg.update, this procedure is described in detail in the following examples, without limiting the scope of the invention. (*) o evaporated in rotary evaporator collectors under reduced pressure, and solid products were filtered off prior to grounding. (II) o leaves at room temperature, »s» 13-20 °, in a gas gas (polo-argon) staircase sphere (ill) tz column crown milk Price (high-speed chromium-j-f-»-ho») y e. medium pressure flushes -artogr? trees whcs Round kieseIgei Art ·&gt; 335 type native gel or waist üchroprep ÖVV13 reverse phase, .'rt · 9&gt; &lt;J type silica gel (pyártj 'as ·. · waist firm, Mbrao'tedt, á.'aether) ) | (Arch) ® reported data is for reference only, and nex is necessarily a taste α-understand anxiety-v (v) -ase (1) of the general formula Compounds for rectification Fdotel and spectuE-r-drtcl slüte.aExposed to the expected ss « -rkeseteket | it &amp; 2 &amp; H spectra Jeol i ·. · 90 .. or burter in sector AK2C0, recorded at 2GC MHz, and ® delayed shift values ​​are in tetraethylsane internal standard »delte akalai, m long time needles aeg | ε Stuffing Trunks • · · · ···· · · ·

- 42 on a VG i «nalytical / u / J type spectrometer, fast atoa-boybasic bases» i (i.n.n), xenon gas whey was taken in half (vi) the tea products were drunk in the net, and their purity was thin-layer, infra red spectrum or - »price spectrum!

(vii) Uncorrected values ​​determined on the melting pan on the Ü262 Automatic Melting Point, Koffler or Oil Bath.

First uéfcfo,

0.504 g of p - [N - (2-methyl-4-oxo-2-piveloyl-&gt; 3xi-ethyl] -5,5-dichloro-cinac-lic-6-yl-xe tyl). -A * (pro-p-2-yn-1) -ea iodobenzoic acid in a solution of 13 drops of ethylene chloride in 4 drops of DMSO at u-5 ° C with stirring for 2 minutes 0.214 g of oxellyl chloride are added dropwise. «- light yellow« for 2 hours u-5^SheAfter stirring at u, the solvent was evaporated under reduced pressure. the residue is suspended in 15 l of anhydrous ethylene chloride and a mixture of (154 g) of (-) - (2 '') - 2-amino-2-phenylethanol and t&gt; 4 g of triethylphenin is added to the suspension. The solution was stirred at 20 ° C for 16 h, diluted with methylene chloride (4 mL), washed with water (20 mL), dried over anhydrous sulfate and sued. The residue was chromatographed on silica gel using ethyl acetate / hexane with increasing polarity as eluent.

A mixture of 0.46 g of the product thus obtained, 4 liters of ethanol and 2 ml of 2 ml of aqueous sodium hydroxide solution was stirred at room temperature under argon for 2 hours, and the resulting aqueous solution was diluted with 15 ml of water. éa 1 K In a solution of hydrochloric acid in water, the mineral is pii 3. the liquid is filtered. m is washed three times with 1 ml of water three times and then closed. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

.... ···· ··· ·· * · pitches are dried at 60 ° C under pressure. Ű_t5 &amp; ​​g p- £ 1 -42-ae-thi-4-oxo-5,4-di-bi-quina aolin-6-y-1-ae 611) -M (pr-2-yn 1) azine / -4 m.p. 2) -hydroxy-1-JC-cylcyl-benzamide (1 equivalent of water-containing material) * m.p. 159-157%.

MR spectral data (i.hc-d ^) t 2.56 (a, 5u, GHj), 5.16 (t, in, GSUO, 5.59-5.75 (η, 5H, GH ^ OH), 4.52 (bs, cfg / g), G, O4 (d, 2H, 4.77 (a, 2H, C 1 H 2 R), 4.95-5, Cd (η, 1H, Gum). arona), 7.15-7, 4u (s, 5H, arosa), 7.55 (d, 1Η, arona), 7.65-7.61 (a, ph, arona), 7.97 (d, Ili, dow), o, 27 (d, lh, ΔH), 12.2 (broad a, lü, Rh) «data spectrum (+« Αϋ) ιη / ο (141) 467 back to formula page »asanitotti Cl 69.4%, Hl 5.3 iC, Hl 11.6; * found&gt; Cl 69.6 Hl 5.7%, p l 11.9% ·

The starting material was labeled with p - [4- (2-n-6-yl-4-oxo-5-pi-valoyloxy-yl) -5,4-dibromo-quinazolin-6-yl]. -ae 111) - ** - (prop-2-ynyl) -azole-7-6enzoefl8VB is prepared as follows from p-tprop-δ-enin-D-eninobansoseave tert-butyl ester (described in 259 of European Publication 11). 6- (bromo-6-yl) -2-gecyl-4-oxo-5- (pivsololl-oxy-6-yl) -5,4-dibydro-quinazoline (the compound disclosed in European Patent Application 259 &amp; amp; , lú sl 2,6-lutidine and 4&gt; u ni á₉The mixture of α-dinethyl acatenide was kept overnight in an argon atmosphere at 55 ° C, poured into 40 µl of water, two thousand µl of ethylene chloride were extracted, the organic extracts were combined, dried and dried over magnesium asalXate. Meridians are purified by silica gel column chronatogra &amp; lt; RTI ID = 0.0 &amp; gt; eluting &amp; lt; / RTI &amp; gt; eluting agent. ····························································································································· · ·· 70 volumes of caraway, followed by 111 volumes of hexane - ethyl

-acetat bisacetate · blend the "sprouted areas" 4, "al trifluoroacetic acid aav" for 4 'minutes "" oboe thermometer Weekly · &lt;"dust the o'idóascre, and start the BBrats in a silicone ossolterograph · »1 torah taranyu, then 4» 1 vol. Gstaranyu hexane-vinegar mixture, finally elute the eluent with netilone chloride · 26.3 g of p-£ * ((2-a-ethyl-4-χχο -&gt; - / pivsloyl-vxi * a4) ti l / * 3,4-dihydroquinazole ln -6-yl-ae til) - (pro-2-yn 1) -aln-benzoate.

In Example 2, Example 1, we use l-radicals, using azo instead of (-) - (2i) * 2-enino-2- (10-yl) -ethanol in the ozone. Mixtures ·. -They are very low, the aain-rggents are made available with the available or mountainous salt salts. · The compounds listed in Table I are obtained, which have been analyzed and analyzed. vart sserkez &lt;Uket ·

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leVsor-R² R x Op. ° G ^ to ^ ''

SZ.xOB '

<td> 1.</td><td>prop-2-ynyl;</td><td>phenyl.</td><td> 2,5</td><td colspan="2"> 153-161</td>

<td> 2·</td><td>prop-2-ynyl;</td><td>4-chlorophenyl</td><td> 2,75</td><td>Λ 2? ​​-2 ·.&gt; 6</td><td></td>

<td> 3·</td><td>prop-2-ynyl;</td><td>&gt; - (trixluoro-thiophenyl) -phenyl-</td><td>o, 5</td><td>1C3-1ŰÖ</td><td>(Phenyl}</td>

<td> 4.</td><td>prop-2-ynyl;</td><td>4-tolyl</td><td colspan="2"> &lt; ,75 230-255</td><td>(B)</td>

• «• ··· * ·· · · · · · · · · · · · - · 45 * (s) μ as reagent up to · 2. xi-2- (5-trifluoromethyl-benzyl) -6'-yl-5- (trifluoroacetyl) -benzeldebid is slurried in vacuo. 266 (1965) kosleaéay was prepared from 2-hydroxy-2- (4-yl) -styl-amethyl 4-ethyl ethyl-beacaldole by cxbssl · (ο) * enskoot. -ae ^ · 266 (1965) nesonió «1 jar, - £ s» l · * s 1. Example 5 is followed by the use of anxiety, instead of azuuben (-) - (2n) -2-allyl-2-ylail-esanol. recón eh ^ H. We have u-ast in our infants, and eaiu-reegen! «·% * &lt;Chemicals available in the e-bar with a number of soda replacements. In Table 11, we make upturned compounds with &amp; lt; tb &amp; gt; t &amp; lt; t &amp; gt; &amp; gt; spectra &amp; lt; &amp; gt;

<td>-' the- let's go ^r* SZ-lffiS</td><td></td><td>., 2 THE</td><td></td><td>M.p.</td><td>Comment</td>

<td>1. prvp-2-inyl-</td><td> -</td><td>cyano</td><td>phenylc, 5</td><td> 145-146-</td><td>(S)</td>

<td>2. Prop-2-inyl-</td><td>^WTI2</td><td>phenyl-ti.</td><td>&gt; - phenyl-G, 5</td><td> 137-139</td><td>(B)</td>

(a) The group plvellell oxyacetyl-val · * · is as follows lived by tivoliths

G, 4J g X- (a-cisno) -^veDzll-p- ^ F- (2-ylatyl-3- / piveloyl-osyl-4-OKO * 3,4-dlhldro * klna Zoll-C-yl-yl) -H * (prop-2-lnyl) -sm! n ^ 7-bznzr; aid 10 ml of a solution of set-nolle '»» · · · β · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···························································································································································································································································• 5 ml) of tetrachloride.'uranium to form an adulterated, bulging-homogeneous solution. from the meridians ^:remainder of the starting residue by means of ethyl acetate-aldorose lye · The resulting sulfate was purified by column chromatography on silica gel using an increasing volume of ethyl acetate-methanol as eluent · G, u63 g of a white solid, m.p. -bEAZyl) -p-4 - [(2-Bis-ethyl-4-oxo-5,4-dihydro-quinolin-6-yl] -yl] -1- (prop-2-ynyl) -phenyl] -7 we get a gasoline o ^ ·: 14&gt; -146⁰t · (b) the (O-1-phenyl-2 - (phenylthioethyl) amine used as amine resin is prepared as follows:

To a solution of 5.0 g of (-) - (2d) -2-feaino-2-phenylethanol in 1 ml of dimethylformamide was added 36.4 ml of 1h aqueous solution of citric acid and then 75 g of di-tert-butyl -ditorbonut is added, and the mixture is vigorously stirred at azo temperature for 72 hours · the mixture is sued, and the arid is negatively shaken between 2ι · 0 bowls of ethyl acetate and 2νλ αΐ water. the aqueous phase is extracted twice with&gt; 0 l ethyl acetate · the organic phases are combined, washed twice with 2 ml each of 10% w / w aqueous aqueous citric acid solution, 200 ml water, 200 ml aqueous sodium chloride solution, dried over magnesium sulphate and evaporated · 2.76 g of white solid 2- (tert-butoxybenzylamino) -2-phenylethanol are obtained. ο, ·: 137 ° 0 · l, v 6 ifcü obtained compound, u, 6&gt; ml triethylamine and

2 ml of methylhydrochloride was added dropwise at 5 ° C, 3 ml of aethanesulfonyl chloride was added dropwise · The mixture was heated to 0-5 ° C for 1 minute, ···························································································· ·· «·· · * * 47 then beat, and the bite 5 &lt;^; between the organic ethyl acetate and 50 aliquots of water, the organic fusion is separated, washed twice with 5 µl of a saturated aqueous solution of nutrient-hi.rogon-kerbonat and washed with yu al, dried over anhydrous sulfate and powdered. Dissolve in a large volume and add a solution of u, 5&gt; U g of nutriuaquiophenolut in 10 volumes of diurethane-1-urea solution · and stir for 2 hours. and the vegetable mixture is partitioned between ethyl acetate and water. The organic phase is washed with aqueous sodium chloride solution and then dried over magnesium sulfate. After evaporation, 5 g of cinnabar ore is dissolved in 5 ml of trifluoroacetic acid. Stir for 2 minutes at 2 ° C-vn and then evaporate · 0.52 g of (1α) -1-fsull-2- (phenyltiv) ethyl smiari-triX'luoroacetic acid is worn ·

4 · Example

0.15 g of p-4o- (2-methyl-4-oxo-1,4-dihydro-cisoleol-6-11-methyl) -h- (prop-2-10-yl) -eiuT-h- (2) -hydrocl-2-phenyl-ethyl) benzemide was dissolved in 5 µl of ethyl acetate, and to the solution was added 54 µg of acetic anhydride, 27 µg of pyridine · The mixture was stirred for 24 hours at 2 ° C. .8 triturate the ® fragment with 5 ® 1 water · &amp; filter solid, wash with water, 5 g of h- (2-ethoxy-2-ynylethyl) -p-XT- (2-methyl-4-oxo-5,4-dihydro-quiaza-ol-6) are dried in the air. il-ethyl) * h- (pro&gt; -2 * lnyl) * eain ^ -beasemidepunkf ορ · ι 205 · -2% by weight · tetrachloride spectral data 2.04 (a, 5H, ta.x) .

2.55 («, 5H» CU3), 5.1d (t, 1H, (taxi), 5.4 * 5.65 &lt;»2d, MX ^ g),

4.5 δ (broad ε, 2xi, GMgsv), 4.75 (λ2, 5.02-5.55 (a, 111, Chx.j), 6.8 (d, 2h, aromatic), 7, 2d-7.4O (κ, 5M, oroaeal),

7.55 (d, bridge, power plant), 7.65 * 7.75 (a, M, eroaas), 7.56 (d, lu, * 9

- 4sroads), 3.3- (fibrous t, lü, ϋ ·· .. · ΜΙ), 12.1 (windy s, 14, 44) · loaeg spectroscopy (fl '.- 4) ia / β G&gt; 1 )&gt; G9. ..leusus ot sweep száaitotci road 68.4,._t H, $ 5.7, B: 13.6 ,;

t®Iáitι vi 63.5 &lt;*, ** ip, 4. , γ »· lv,&gt; z₉

5&gt; oil stroke_r .- as in Example 4, but p- ^ J # - (no 2 1-4-oxo-5,4-di hl dz * o-who does not?&gt; Η-ύ-yl -se til) -H- (pro-2-yn-1) -οκίη 4 -ΐ- (2-bldroxy-2-xenyl-ethyl) -bututalde

1.7 We call alcohols · 7. III. We set up the 81 p. listed in the tublroHt., Analyzes of the condition and the wavelength spectra of the wavelengths corresponded to these light gray needles.

IAS-J

<td>: Chem</td><td>ile 2</td><td></td><td>··.. She_P</td>

<td>their name to Sors</td><td></td><td></td><td>Λ 4 .- '· ^w</td>

<td> 1*</td><td>nrop-2-ynyl;</td><td>5- (trifluoromethyl »8 tII) - -feiiil-</td><td> 0,5 185-188</td>

<td> 2·</td><td>prop-2-ynyl;</td><td>4 tőül-</td><td>'3.5 13'4-2 Cj</td>

L, 3u 6 p- £ ~ - {2-a »tile-4-ÜAv-p_t4-Fluoro-Glycan, 6-yl-1- (4-fluorophenyl) -4- (yrop-2-ynyl) -4- (tert-butyl) -2- (tert-butoxybenzo) rb &lt;»nyl-eaLuc) -2-phenylethyl-4-benzoic acid 1 l trifluoroacetic acid solution dissolved per minute, &lt;sswbsb. . The precipitated white solid was filtered off, soaked in bioisolated 5 liters of diatyl ether and dried.^:-2-β «ηού -.- 1 · ^ nyl-ethyl /^r^ -p-_&gt;~ - (2-Oeyl-4-oxo-5,4-dihydro-kiosk oil n-6-yl-1-yl) -4- (pro-2-yn-1) -eamino-7- beef (1.5 equivalents of viaeb .4 2.5 equivalents of trifluoro * * • 49 —- tean beans) bakonx! up.s 12.j-1&gt; vó_v&gt; «Ό» spectrum ad &amp; cal (^ ó »jd ^) 3 2.57 (a, G'hj),

5, -6 (pronunciation s, lu, C 1-6), 3.50-3.50 (e, 3H, * »52 (

Xea 2ϊί, fig³- ^), 4.40-4.55 (broad a, lh, G3), $ 4.7 (s, 25, GHg0, 6, $ 2 (4, 2H, eroaay, 7.36 * 7.50) (a, Si, aroaae),

7.56 (d, Li, difference), 7.66 (d, 25, aromatic), 7.72 (da, la, aro), 7.96 (4, la, arosa), 6.31 (t, g, Gglg), 6.4 (wide s,&gt; 1, HP), 12.2 (fiber · S, Cli),

Peak Spectrum Spectrum (+ yw) i (* 41) 466 «Analysis a ^ 2 ^ 27 ^ 5 ^ ¾ ·²»&gt; Cx ^ ossXM · 1.5 MgU Formulated 1 V 51» ^ '*&gt; beat 4.2 y, 5.4 5.4 * | tal-alpha ui&gt; 1, υ,., s 4, u /, i&gt;, I »t 5.4&gt; v« Xeliw rails of the particular substance p - ^ - (2-ethyl-4-oxo) p, 4-i h i d r o -k i n o 1-u-6-i 1 -ethyl) - &lt;* - (pro-2-yn-1) -aa ic ^ / - U-4J21.i; -2- (t-tert-butoxyl-k.carbuoyl- © a ino) -2- (e) tijpT-inclusion is prepared as described in the 1 psloab, except that (*) * (2 ^) Instead of -2-methyl-2-Xanyl-ethenol, (2R) · -2 * (tert-butosyl-xbronone-1-amino) -2-phenylethyl-1-caine is used. we get tertclaezo urns! op »i 222-224 ° G ·

i. (2a; -2- (tert -butoxycarbonyl-allyl) -2-phen 11-ethylosine is prepared as follows: g (210-2- (tert -butyloxycarbonyl-acyl) -2-xenyl-ethenol ( From a solution of (- / - / 2R / -2-yno-2-ylamino) (a compound prepared as described in Table 1 (b) (a) &amp; lt; tb &amp; gt;) in 25 µl of methyl chloride at M-5 ° C, 32 µl. triethyl ether, ® - jd -&gt;, 16 al asyl chloride · The mixture is stirred at u-5 ° for 30 minutes · the mixture is evaporated, and • * &amp; # x; &amp; m &amp; rr dákot al-ali- acetate and -1 water are seeded · the organ phase is twice. The reaction mixture is washed with 5 ml of aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. Dissolve the residue in V ml of dimethyl boron, i.e., 21g n * eria time. we give you salt. the solution is kept under argon at 5Λ for 16 hours, then cooled and the solvent is evaporated off · - the residue is taken up in 5 ml of ethyl aoethane and 5 * 1 liter of aqueous solution of 25 ml of aqueous nutrious chloride solution. Wash the residue with magnesium sulfate and evaporate · - · The residue x, 55 &amp; lt; / RTI &amp; gt; is dissolved in 1 mL of otyl acetate and 6 g of 10% palladium / osontuzene totolizer is added. · λ catalyst is dried out, and brew the filtrate · 5 g of the desired compound ·

5 g of p - [4- (2-methyl-4-GXyl-3,4-dihydro-quinol-6-yl) -methyl] -prop (2'-ynyl) - [mu] m. To a solution of O-oso'v (a compound disclosed in European Patent Publication No. 259,562) in 2 ml of diethyl 11-sulfoside was added 55 ml of triethylamine followed by 55 ml of diphenylphosphoryl azide. The mixture is stirred at 1.5 ° C for 1.5 hours. To the mixture is added 0.5 g of diphenylacetyl aulene, and the mixture is stirred at 4 ° άτ ^ η at 2 A. Pour the matter into water, cool into z'X'-xti, and do not crush for 15 minutes. The precipitated solid is suctioned off, washed three times with aloe vera, and pressed tightly with u. m.p. 1) -p- (4-oxo-5,4-dihydro-4-oxo-5,4-dihydro-kinase oil α-6 · ϋ- (β 1) - .. (prop-2- inil = -aaxu ^ -btDZSide (oh, containing 'Z equivcleno water) * op ·: 22? -251 ° G · spectral data 2.55 (s, 5-u, Cd-),

- 5Χ *

3.19 (ss'iiefl s, 1x1, U-ui), 4, pk (stioea a, 2 * 1, wxsgv-vj, 4.77 (s, 2ii, GÜgh) · C ', 37 (d, lu , Guuáóóf 6,84 (d, 21i, aroSU &amp; amp; S ;, 7, lp.-7.45 (· xyl, erosafi), 7.53 Cd »ui, aromatic), 7.68 (lil, dd, aroa) (s), 7.80 (d, 2H, aromatic)_t 7.96 (d, la, aromatic), 8.33 (d, X-, v Ji «^ x # 4I),

Tomato spectral data m / a (-1) 511 · mlernaviS a ^c 53 ^ 28 ^ 4 ^ 2 * '^ · ^ branch according to the formula tvi Gi / 3.6 H, Hl; 5.6 L_t * &lt;: lu, cn bowl tltl. í 7p&gt; P -&gt; pseud 5f6 r-, El Horse, 4, ·· »· áa-x-Üaa

1· _tProceed as described above to replace (-) - (2RU-2-thio-2-yl-allyl-ethanol) with (h -) -? - alBlno-4-yl-4-phenyl-propyl. lonitrile (Compound 4) (J. J. + Beta.Hem * ^ lla · Tber · j. 117, 1975) was treated with * &lt;(2- &lt;lsnu-l-phenyl). -prop-2-yl) -? -? - (2-α-methyl-4-oxo-5- / pyrrolo-1-oxyl-1,1? -3,4-dlyl-dicyclo) 6-LI &amp; alpha) -. - (prvi -2-iso; 11) - Einaldehyde / -bxxiZ 'imidate is dissolved in Ugara saturated methenol and the mixture is stirred for 24 hours at room temperature. ? - (2-Visno-1-phenyl-pro-y-2-yl; -₄ -? 7- (2-qtyl-4-oxo-5,4-hydroxyquinozolin-6-ylmethyl) -f-propprop-s-inl-D-eeingT'-benzeneBidot_rOnk | op. 12-28-29 ° C, 3ol g of sj - (2-ethyl-4-oxy-3- / pivaloyl) oxy * methyl] -3,4-dihydro-cu coli η-6-yl. ethyl) -1'- (pryp-2-xenyl) -all7-beuzoic acid, phenylsulfonylphenyl ester, 13β- (1,2-dihydro-2-oxopyrid-6-yl) -benzaldehyde A mixture of 0.51 ml of triethylemine, &lt;g g of α-hydroxybenzotriol and 2 ml of dimethylformamide was stirred for 16 hours at room temperature. The mixture was evaporated and the marshmallow cinnamon was triturated with diethyl ether (0.22 g) of p-N- (2-ethyl-4-oxo-3- / pentyloxy) α 1 (-5,4-O-Hydro-quinazol-6-yl-acetyl) -N- (prop-2-yn-1) -eamino-1,2-dihydro-2-oxopyride -6-yl) -basic iZ-benzemido c keotmk · / s The product thus obtained was mixed with horse-saturated aqueous effi-nium hydroxide solution and 2 µl of ethyl acetate for 16 hours at room temperature with stirring · The methanol was distilled off · λ k filtering out precipitation&gt; these filters, &lt;, 11 g (61%) of p- [1 T- (2-astll-4-oxo-3,4-dihydro-cln-8 -olin-6-yl] -e 111) -α- (prop-2-yl) ) -amingZ-H- [E - (1,2-dihydro-2-oxo-pyrid-6-yl) -benzene] -brazane, m.p.

The starting material was p-L-penyl- (2 »-ethyl-4-oxo-3 * / pivaloyloxy-ethyl / -5,4-dihydroquinoline» ol-6-11-astyl) -h- (Prop-2-inyl) -eaino-7-benzoesBv- (pentafluorophenyl) ester is prepared as follows:

13.03 g of p- (β- (2-ethyl-4-oxo-5-pivaloyl-oxyl-ethyl) -3,4-dihydro-clenezolln-6-yl) -11) -) - ( To 450 mg of ethyl pentafluorophenol in propyl 2-yn-1-yl] -7,7-benzoic acid and 5.52 g of ethyl pentafluorophenol was added 6.0 g of dichloromethane and the mixture was stirred for 1 hour at room temperature. The mixture is azurized and the filtrate is stripped · The fragments are purified by silica gel column chromatography, eluting with 1: 1 hexane / ethyl acetate, 15.9 g of the desired starting material are obtained, m.p. 143-144 ° C.

The salt of o- (1,2-dihydro-2-oxo-pyrid-6-yl) -benail-aine is prepared as follows: o, 96 g of bromo-mole, o, 146 g of aegene, 1 g of diethyl ether and &gt; al toluene blenders render Grigzard reagent sufficient »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 5ρ * is prepared in a solution of r, 22 g of 6-cuuo-e-met &amp; x ..-yiridiu lu al ltl teriquefluent tuxuol - diethyl ether e ^ K-gtetyÜ, ancient e oputt «uagyst 2 arun at vls ^ ZA-stream public space X'arx'el. The mixture was then dropped into a solution of ethyl acetate in saturated aqueous solution, and the reaction mixture was triturated with ethyl ether, dried over anhydrous EtOAc and evaporated. the polyvalent toluene-styloacetate flies growing as a leader with columnar ethers were found. 71 g (55,7 2-oetox. &lt;-plrid-6-yl-phenyl-ketone). bile e ^ eatru® β de tel (dia ^ -d ^ i 5 »35 (»&gt;, 7) , 1 (d,

Iii), 7, ö (m, Te, 7, V? (T, 1 * 3, d, * .. / (d, 1.,.)) ·

6.25 µl of aqueous eGaoniua-bidroid solution (aura, 91 g / l) and y, l&gt; Bl usngyaeav ylv-ifc lCu^Sheor heating is carried out, this mixture is distilled from a mixture of alu-alpha-α, 71 g of d-Betoxyl; 4rid-6-yl-4&gt; nyl-acetone, This mixture is stirred for 22 hours. y% - © c They are. Irish «be let to your room ... temper, 25 * 1 visee saline * solver in oduuk bus, and o drown« flame S guard ^ u - ^ boil »-f clystae. · · the -? fly in the air. ·. lock 1 ml of vlzbua, ·. © this solution for 1 h of water? sodium hydroxide sitting &amp; # x201; &amp; # x201C; &amp; # x20AC; &amp; # x201D; first, the filtrate is exonated with Mew 2u ethyl acetate. The extracts were combined, dried over MgSO4, and the cells were extracted as guslezer, bob spoxtrus a total of 4.91 (s, l.-&gt;), 6.2 (a). , 2h), 7&gt; 4 (®, 6-Ό · • ·· V

- ρ4 ·

..... xatiM g l-4-UX0 -&gt; - /_v15V-10-QX-Cötl / -5, 4 «di-hydro-growing au 11 u -6-l-ac-λ) -A- (pro, - 2-10 ll) -ea fagjbaazoeeav 15 in a solution of ethyl acetate, which is doped with »2 oaepp of a solution of dimethylformamide · υ-5 ° · οα, stirring is added dropwise over a period of 2 minutes, u» 12&gt; g of oxyryl-chloroquine 2. hour ug u-5 ° &lt;^ oa t-av-rúny, soojd for scissors diminished ib nyoiaaáou dust *. &lt;* sara dó kot o-5^Sheo »15 ml of ae t Hone Chloride Sulfur Oil * and wood phase g (? - (-? - nitrophenyl))? glycyl» xi ~ (? 4 -? - moxylenyl) -azulA'onyl; a solution of triethyl · amine (2C6 g) was added · the solution was stirred at 20 ° C for 16 h · the solution was diluted with 4 ml of ethyl acetate, twice with 2V aliquots of MoE and SA. ulütt osurit juk, ^ jd bapároljuá ·. »brewers oilixególea Done krj-aotugrokdlusecl tiebitjut, as eluant, a mixture of ethyl acetate and hexane was used as the eluant, 5 ^ 2 g of 1 * · ^ · (ά »/ 1 * · -οtyl-4-οχύ) • 5- (pivsluil« oxyl-ethyl). -5,4-Dihydro-quinazoline-benzyl-acetyl-propyl-2-ynyl-4-alkyl (5-alpha-phenyl) -glycine-1 H -ethoxy- feuyl / azalfunilylcid 0 t OUR * The above theft was filled with aogieau, and then a mixture of 4 g of boiled pellets, 5 ethanol and 1 tb l of potassium methoxyl hydroxide was stirred in argon and tmoBZidboa for 2 hours. ·

<td>.-s iicsault</td><td>dust ®, the ski ^ tc water is cooled with 15 »l of water</td>

<td>gituk, and</td><td>Acidified with 1 x aqueous hydrochloric acid to pu 5 · V '</td>

<td>ΑΆ oh no</td><td>filtered, the solid aays. uroasor 1 ·. ·· with water</td>

<td>wash and</td><td>at reduced bite ύν% · οη serite yak · -., 1/5 g</td>

<td>x.- £ j * - (l '- / 2-</td><td>111-4-0x0-5,4-Dihydro-kinase-6-yl -.</td>

- / pr u ρ-2-iax 1 -as ino) -bz o (5-u tio-phenyl) - (glycyl) - ((4-ootoxyphenyl / sulfonyl) amide. (the product contains 2.5 equivalents of water® z | op ·:

<img file="HUT57739A_D0024.tif" />

<img file="HUT57739A_D0025.tif" />

<img file="HUT57739A_D0026.tif" />

epecru * a de tel (Vkjx-KL ·) t 2.55 (?, 5H, CH?), 5.14 (?,?, s, la, C = Cs),?, Cl4 (?, 5H,? CH2), 4.52 (1H &amp; lt; 2 &amp; gt;, 2H, UI)₂), 4,? 6 (axeUs e, 26, υΗ ^), 5.21 (d, lti, CHc.), 6.62 (d, Xa, &amp; rosds ;, 7, m5 (d, 2n, erotaaai, 7 , 5-7.64 (a, 9H, sroa), 7.96 (broad s, 16, sroa), 6.12-6.20 (a, 2H, araoa), 6.70 (d, In, aro) ), lj, 2 (color, 16, pond) · coefficient (+ rOi a / e (r * l) 695).

Italian a 655 ^ 50 ^ 6 ^ 3 ^ · * · - * d ^ o formula e lopjam tfZdnitottl 61 56, d 4, Hi 4.7. *&gt;, Ml 11.4% | m / z 56.5 v, v 4.2 4.2, M 14.9%.

n Kiiouul &amp; ali suyagktnt lleal (p) - (5-nitrophenyl) * glyclb-iw »(/ 4HMto * l-£ oniV-ssullioni D-emiaot on the top of the allitjuz front

5 µg of (-uC ^-nitrophenyl) glycine (as described in the formula 2591/1965) 50 µl of a solution of 25 µl of 1 N aqueous solution of diaethyl 4 or ab sodium hydroxide solution, 6.4 g of allyl tert-butyl dicarbonate. 8 mixture is stirred at 2U for 6 hours · The mixture is sued and the residue 0 is dissolved in 156 ml of water · the solution is acidified to pH 5 with 20% aqueous citric acid solution and extracted with 2 ml of ethyl acetate each time. . «Organic phase in 100% aqueous solution, hydroazorized with 10 uL of citric acid solution, cellular volume Several times per ml with water, dried over anhydrous, solubilized solution and 5 x 57 g of siliceous matter.

To a solution of 6,546 g of carbonyl-alioid * sol in 1'l of tetrahydrofolanar is added dropwise a solution of 1 g of the resulting compound in a solution of ical tetrahydrofaxase, at 5 uC for 5 minutes, and for a minute. · boil at room temperature, and v »631 g of 4-setoxybenzenesulphonide &amp; nid lo ni t &amp; rehydrol'urane« 1 quinticetw ½ of the volume added in minutes to «air» 13 &amp; l, c »« dia »» - bicyclo ^ A solution of 4, 4-undec-7 in loi tetra-hydrolurane is added · * deep red solution is stirred for 1 hour at 20 ° C · 20 ml of aq. Hydrochloric acid is added and 100 ml of ethyl acetate are added and IvU sl water is divided. ·. · &amp; * z &amp; rvas phase is separated, and the aqueous solution was combined twice with ethyl acetate twice if the organic layer was dried, dried over sodium sulfate and evaporated to give 0.96 g of a yellow solid. 2u al netil_vTo a solution of? -chloride is added 1 »l of trifluoroacetic acid and the mixture is refluxed for 5 hours. The solution is evaporated, ie, it is chromatographed on a column of silica gel on a Barkac silica column using ascending hexane-ethyl-scatat-noot flies, and the desired material is obtained at a temperature of 212-213 ° C.

Ux Hwal

We use the procedure described in i · - · piuab with the difference · uog.y nitro-xenix)&gt; glycine - ((4-aethoxyl-phenyl / -a) ulfonii) -aBid use these corresponding sali · λ kiluuuxaol materials unless otherwise specified are commercially available or exyled by any of the methods and compounds of the formula · The compounds listed in Table IV are obtained which have an elasticity, nhR and call spectra matched expected structures · ··· * ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· j7 -

<td>ve 41let SOIW.&gt; sled »</td><td>· *% x^c</td><td></td><td>n</td><td>0 Gp · 6</td><td>4egJagyzós</td>

<td> 1. 4.-,</td><td>4-nitro-X :. alkynyl</td><td>4 a «til -. &lt;Arbi:« · the ski-</td><td> 5</td><td> 261-262</td><td>U)</td>

<td> 2.</td><td>5-phenyl-eítro</td><td>M e η 1 l-sz u Kohl L-kcrbamoil-</td><td> 5</td><td> 205-206</td><td>(B)</td>

<td> 5·</td><td>9 r.itr · ..- phenyl</td><td>Á -.- aK til-u^!; íu .főni 1-ke rbs female 1-</td><td></td><td> 159-165</td><td>(C)</td>

£^eSá® 1L^S .JL 5. ^ 2^rX (a) The starting material used (a-nitrophenyl-ssnin-N -'-a-yl-anide) is prepared as follows for al retanol -5^ofDuring the meal, 5.75 g of TCL are added in a blow so that the temperature of the mixture does not exceed 5 ° C. - Let it run for 50 minutes &lt;-5^theAfter stirring for 18 hours, the mixture was stirred for 18 hours, and the mixture was evaporated. 5.22 g of a white solid carpet were added. To a solution of 91 g of the thus obtained solution in 8 liters of methanol was added 10 x 25% by weight of a 7% solution of 7% aqueous acetyl in ethanol at 20 ° C. The mixture was stirred for 4 hours at 20 ° C. 'nsjd evaporate. u, 89 g of the desired starting material are obtained as pale narene-like solid material ($ 33 ​​i.b.b.H. (b) / (-?) - (J-nitrophenyl) -gllctn-X- (phenylsulfonyl) used as a bulking agent.¹ time was prepared as described in Example 1 for the preparation of the starting carpet, except that benzoic acid sulfonamide was used in place of hocy 4-methoxybenzenesulfonamide.

. ··. . · *. ί ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- i ·· piVülOki-OXÍ-Ufitíl Protective CoOpurtüc kOV «t &amp; βΖOf so far away»

2v ml, &amp;&amp; with ammonia gas was added to methanol v, 163 g (. ·. «) · -'-xi-u - / 2-s 1 -4-0 xo * 3- / p-lo 11-oxy- me b 11β-3,4-dihydro-quinazolin-6-yl. ϋ11 / -ά -. / ρΓθρ-2-1η11 / -β®ίη ^) * 4) 0ηζοίχ7- (3-ηί6 · x'û-f eníD-glyciu-, .- (Xanii-EsulfoneD-aaid 1 al ae · 1 1 * 1 uv.substituted o * di&gt; tut. »z mixtures are mixed at 42-run ut swab heat, then filtered, and the hairs are evaporated.« rublets are triturated with 122 ml. we get two from the Vúnysargfe in the form of azilurd clay.

(c) ·&gt; (FU) - (3-methylthiophenyl) -κ11οίη -..- (α · .tylsulfone 1-amide &amp; lt; 1 &amp; gt; It is stated that you eat ® the difference that 4-aa is replaced by methanesulfonyl instead of 4-oxa-benzyl-xyl-oxy-xyl-xylethyl protoxide x in (b) s. described by usxrinb away.

12th example δ, 2 gp -1 ^ - (2-meth * 1-4-oxu-p- / pivaloyl-yl-adCII) -Pta-dihydro-Kinbouli. Small_£.'-2-lullyl-7-yl-benzoic acid (^ enucxluur-xeullj - ο «space, ν, 1 g (. In a mixture of 3-allyl-ethyl-far-allyl-tri-ethyl-triethylamine, 5 µl of 1-hydroxybenzotriol-toluene are added and the mixture is stirred for 1 hour at room temperature. the residue is partitioned between ethyl acetate and water, the organic phase is dried over water, dried over magnesium sulfate and evaporated. Triturate the residue with diethyl ether · In an oil-pellet, 166 g of p-£ a- (2-aethyl-4-oxo-3- / pivalol 1-oxyl-methyl) · * ········································································ • · · · · · · ···· ············································································································································· —2— mii, · - siai Y ·· - ^ - nitro-x- (p-á trsznlilj-benzi ^ -bvnzemidot 'xe.unk.

Jeti

..p'Sktrua fl Irish *

<td>L, A. * j, 2 {A, ..- · /,</td><td> 4,21</td><td>f Π · '' i \ -4 f 4. - f</td>

<td>- * night? {d, ug, /, * i {A |</td><td> 1.3,</td><td>79b-s, 1</td>

<td>(&lt;S, 2 ..), d {-S, x</td><td> ).</td><td></td>

<td>~ »· * -Α g ίς.Χ¹ A5 _s</td><td>•there</td><td>buy lU t</td>

t

4.73 (ε.

<td>· *. □ -ίΛ. : Ύ · α y * lu ·. «. . '«D ·:. five UT - · U t.</td><td>.-Üödhlraéra.</td>

<td>· Z elxf Les 3 al vu: jud dián. · :, -s</td><td>.ze Things</td>

<td>s &lt;. voldst cl._Ss, .... &lt;v: opens. . . sz'liu</td><td>., cysget over</td>

<td>zel and dLethyl Ring h-sui; and xt ri</td><td>tj'U · ', -34</td>

<td>1-yl-4-o-y ^ p, · «- • alxi'.orw-zia^! · .. &lt;lin - * ..- ia-</td><td>-dtil) -: .- (;:</td>

idec on; -: ever—

32 [mu] l, viz.

ii? lvu »y Ál 'g íSj.cdm edeUi (1:. · -d ^): 2,&gt; 3 (g, 3.3, 3.19

4, »'{d, í ·.

V. 1 j

-teti'í z j111) into Αζϋ- ^ Είη-ΙιίΟΓυΐτ -.- 'είάοΙ states as follows .. eLf rays-hydrogens xrononate with 14 ml of water knife

Idctahcz 3, -d - g {dj- (3-uitrv- £ eail} -glicint&gt; »dunk,: s '-'^: VW * S d '- taste! -. »/ * Ο MU líÍS t} .-; *. . . · '·. 'C ··' * '·' A · J »X * 3 Ö. ~ 1 * 4 aircraft.

lead, tre fry head, 6.2 g chlorine *. * V

- k ·.

U t &lt;?. o let lo hour for 4 hours Ύ ml

Wash with 1 to 6 dags - aqueous Xa-zUt with 2 l of water and wash with ethyl acetate. . ·. organic f.'i &lt;

u · · · ·, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ···· ··· ····· »L&gt;

bonilj-O-nitro-fsniD-glycine image. «Act on mgise» you Ijuk ·

Ij g ij- ke _v therein, 4.6 g of triecylceine and 1 µl of tetrachid rufuruE were placed at -15 ° C. ..2 mixture 6.2 g chlorine * lx. ugpfe..avi. '. MMUti i-ét-zter po &amp; 1 tt trshidrofurünusl kóeslcett cidetat cce_t.v ^ U t jilk and stir * flies for 2 minutes at -15 ° · - 00. z elixpbt 1 ύταη at ^ m ^ tin guide, ue this mixture

A-ri · influence. &lt;: z eOne 16 hours:,. tt: clfcby®-? r &amp; kleten h-'wjuk, asjd beiuraljuk, .. rt? waekot their wet ketone will have a pound of zebra, t-U, so this is about 11 on a silica gel column crí3§ ögx's half of it zzü tız · lunxx ··. The volume of nt 19 * 1 is chorduric. A mixture of - -Cuaol was applied and 3.12 g of solid (11-ol-Urbvull) - (3-nitrocryl) -glycine base was applied.

t * ··· *,. · o ti vv - &lt;x ** · χ. K- aa * 3 jí * - s * X í&gt; * 3Lx * ö

.. Sun camouflage I -raah

-% o .. stir, organic fuziquix water over dilute VX u ^ Criua sulxut t; £ á t JU «í f AoJ-wf b X ^ U &amp; ·&gt; 1 &amp; έ3Χ * vX ^ üí X0p4J? SJS $ t kJ ^ ITbXüX '·· ^ **

S'- X t A-kiíZÍfi Ly - * f ii ü U'X wir. ΛΛ W¹ XU jr- Lxw wirS ^ XX * - * X * ** JQv Ul ** öti »ü» X ** •• -CöwtKV ί »X ·. ^._ν'ζ. ti * 4—1.2 Χμ, -α Xwiüh * &lt;X φ jf £ ji&gt; *** {Ο ΐέ * i * ü 11-űxÍ ** í M? X kp S .. · nil ;-( 3-nitrc-fcail; “olicir-o-nitrile cp · *&gt; 6 -&gt; $ ° C.

1, yeah yeah yeah₄ there tour .., y4g xuitriua-ezlá,., ^ 2 g &lt;· □ rbniua-chloris _s Arc cl diss ti 1-f r u g u s t o t h e r o u n d t h e case 13 hours ^ r beat&gt; 5^να a · · 2 lbs xxWrite the old v.j? latvt trotterset nyüsoun bake, 1 clause in water £ atux_tead-; lju »., xx s □ zusx_idilute aqueous salt of eation voldettsl y. Seven-fold open · Taste mixture with ethyl acetate, wash the λ thousands of phase with water, dry over anhydrous sulfate, and store. 1.71 g b &amp; lvu &amp; yeárgs • * · · t · ·· · ····························•

- 61 solid materials we get ·

As thus obtained the product is 5 ni 5^eC-rs cooler * Add 43% v / v vinegar to acidic hydrogen chloride solution. Stir As soft for 1 hour at BKobah, add 50 mL of dlethyl ether and stirring * Pour off the gum from the precipitate and rubbing gum gum with dlethyl ether to give 1.09 g of (RS) -3-nitro-α- (5-tetrazolyl) -benzyl-euine hydrobroide as a solid material in Saranoaesil ·

NMR: 6.47 (β, 1H), 7.82 (t,

1 H), 8.0 (m, 1 H), 8.35 (1 H), 8.55 (1 H), 9.5 (acee a, J H) ·

13 · example

The compounds of formula (Ia) listed in Table V · are prepared from the corresponding pentafluorophenylbenzoates and emines according to the procedure described in Example 12 · Unless otherwise stated, these starting materials are racemic mixtures · Analytical data, NMR and mass spectra of the products obtained supported by these expected structures · (IS) sltlliMl tAal «tÍi WCTülaUfc

<td>Serial number of compound t</td><td>R®</td><td>R^b</td><td>γ2</td><td>X</td><td>M.p.</td><td>Comment</td>

<td> 1.</td><td>CH?</td><td>H</td><td>5-nitro-phenyl-</td><td> 0</td><td> 229*233</td><td>(the)</td>

<td> 2·</td><td>F</td><td>H</td><td>3-nl tr of enil-</td><td>p 3</td><td> -</td><td>(B)</td>

<td> 3·</td><td>H</td><td>F</td><td>J-nitrophenyl</td><td> 0</td><td> -</td><td> (0)</td>

<td> 4.</td><td>H</td><td>H</td><td>phenyl</td><td> 0</td><td> 210-212</td><td>(D)</td>

• 4 ♦ · · »» »· ♦ ♦ ♦« ««.... 62 (β) p- / X- (2) used in the production of pentafluorophenyl l-benzoate_t7 &lt;^ liiaetll-4-oxo-3- / piwloil-oxy-u «methyl / -3» &lt;- dihydro-ktnazolin-6-yl-N-ethyl) -2-ynyl -Mpr ^) e »^ ing7-Benxi osev ε is prepared as follows * 2,6,7-TrIl Betll-5_f4-Dihydro-quinazoliu-4-Qnt (compound described in European Patent Specification No. 284,338) 239,362 e._tThe salt described for the conversion of the e-diacetyl-3,4-dihydro-quinazolin-4-one analog with pivellic acid chromephelic ester is reacted with 3- (xxelovaloyl-azetyl) -2,6,7-trinethyl-3,4- Dibydroquinazolin-4-one · The resulting tour is treated with N-Bron · -Zeucinucinide in the presence of bosulfuric peroxide as described in European Patent Specification 284 338 · 6- (Eeroethyl) -2,7-dimethyl-3- (pivaloyl * oxl-acetyl) -3,4-dihydrotinazoline &amp; gt;^eC ·

The compound thus obtained in Example 1 is prepared from 1-oxo-1-methyl-1, 3, 4-dihydroquinazolin-n-6-yl. - (R) -ethyl) -N- (prop-2-inyl) -anihs 7 * »benzoeaov is converted into benzoic acid as an acne · Two 70% * heroes in the space are cooled to 1 ° C · 226 ° C ).

(b) 0.3 equivalents of dlethyl ether and 1.5 equivalents of sodium. NMR (DMSO-d6) δ 2.32 (a, JH), 3.16 (t, 1H), 4.32 (d, 2H), 4.78 (s, 2H), 6.54 (β, 1H), 6.87 (d, 1H), 7.37 (d, 1H), 7.58 (t, 1H), 7.77-7.96 (®. 3H), 8.7 (q. 1H) , 8.28 (e, 1H), 8.83 (d, 1H).

To prepare the pentefluorophenyl benzoate starting material, p-IU (7-fluoro-2-α-methyl-4-QXO-3-pivaloyloxymethyl) -3,4-dihydro kin® z olin-6-ll-me feli) - &amp; · (prop-2-yn 1) • t · 9 9 • 9 999 999 9 9 • · 9 9 9 9 9 • • ·· 9999 999 99 99

- Preparation of 65-aa-benzoic acid according to 373 891 ss. European cuisine document isaertebi.

(c) data for the high level eponuclear region (DMSCM ^) 2.55 (a, 5H)_f 5.25 (a, 1H), 4.59 (β, 2H), 4.84 (a, 2H), 6.58 (t, 2H), 6.75 Wi W 7.52-7.88 ( a, 4M), 7_f95 (d, 1H), 8.01 (a, 1H), 8.2 (d, 1H), 8.42 (a, 1H), 9.19 (d, 1H).

O-Fluoro-β- [1- (2-cetyl-4-oxo-5- / pivsollolloxy-oxy] ethyl] -3,4-dihydro-quinolin-6-yl used in the preparation of tapaftafluorophenylbenzate starting material. »(E til) -H- (prop-2-ynyl) -amine / T-benzoessvat 6- (br 6a-oethyl) -2-cetyl-5- (pivaloyloxyethyl) -3,4-diMdro-cinnamoline -4-one was prepared according to the procedure described for the preparation of the starting material, except that p-amino-o-fluorobenzoic acid was substituted for p-amino-o-fluorobenzoic acid instead of bert-butyl p- (prop-2-ynyl) -anino-beSO4 tert-butyl ether (as in 89312986.6). o-fluoro-p- (prop-2-ynyl) -ethinobenzoic acid, prepared by the reaction of propergylbromide with 56% hose, and tert-butyl.

(d) the subjects were treated with 0.25 equivalents of trifluoroacetic acid, 12 · 1 pole. , except that p - ^% (2-ethyl-4-oxo-5- / piveloyl-oxyethyl) -3,4-dihydro-quinazolin-6-yl-a. N- (propyl-2- (propyl-2-ynyl) -eamino-7-benzoea-N- (pen-fluorophenyl) -ester instead of p-? F- (2-methyl-4-oxc-5,4-dihydro-quinazoline). -6-yl-ethyl) -N- (prop-2-ynyl) -enia-4-benzoyl azide, and (M) -5-nitro - &amp; lt; - &amp; gt; (5-tertiary) benzyl-azide. (R) -A- (5-tetrisol-4-benzyl-alenyl) and reacted with s-dunk l-hydrosb-benzotriazole ·

The starting material used is p-E-K- (2-®styl-4-ΟΧΟ-5,4-dihydro-kechel-ol-6-yl-aeyl) - &amp; lt; - &amp; gt; · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

5.0 g of p- [4- (2-Acetyl-4-oxo-5,4-dihydro-quinazol-6-yl-ethyl) -h- (prop * 3 * inyl) -eamino-benzoate v-Trifluoroacetic tea wn ao (a compound described in European Patent Application 259,562) and 55 aldialethylformates mixed with ice-cooling, at about 5 ° C, 2.60 »1 dlphenylphosphoryl ssid, nejd 5 59 [mu] l of triethylamine are added and the mixture is stirred for 5 hours at 5 [deg.] C. and left to stand overnight. The precipitated solid aaysgot is filtered off with dialyl and diethyl ether. 2.10 g of the desired starting material are obtained. MS spectral data (D10 -d6a 2.55 (a, 5a, CIIy, 5.24 (t, 1H, CC), 4.40 (azal s, 2H, GH8) , 4, 6 5 (a, 2H, 0¾) 6.69 (d, 2H, ominously), 7, $ 4 (d, 1H, rone), 7.67 (dd, 111, aroao), 7.76 ( d, 2H, aromatic), 7.95 (d, 1H, aroa), 12.2 (m / a, 1U, kH) · • Mass spectrum is oan value a / e (?) 572 · reagent resolved (R6) - * - ( 5-Tetrenolyl) -beaylenin is synthesized as described in Example 12 for the preparation of this (no) -5 * nitro-a- (5-tetrazolyl) -benzyleaine. with the difference that instead of (3) - (5-nitrophenyl) glycine, (RO) -phenylglycine was synthesized as described in Example 1, with the difference that (-) - (2H&gt; - Instead of 2-eaino-2-phenylethanol, β ne gf is preceded by aniline and, optionally, p-T- (2-ethyl-4-yco-5- / pivaloyloxyethyl) -5,4-dihydro- instead of using the corresponding inorganic acid * compound, instead of kinetic olin-6-yl-1-acetyl) -4- (prup-2-ynl) -eamino benzoate · If the acid is added in the form of a salt such as trifluoroacetic acid available, to the reaction air is added an additional aolequivalone triethyl anin * if it is not salted · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «· ·· - 65 - are reported, β starting materials are rec - x mixtures · Compounds of the VI · Tables * · bban are prepared with compounds of the formula (Π), which have analytical data and W and more spectra. expected structures * ¥ 1. Table &lt;m ait »Una · teSolata ramfftUtolí

<td>The compound is a serial number</td><td>r ·</td><td>R^b</td><td>X</td><td>M.p.</td><td>Comment</td>

<td> 1*</td><td>H</td><td>H</td><td>3-nitrophenyl-2</td><td> 163-167</td><td> (·)</td>

<td> 2·</td><td>Me</td><td>H</td><td>J-ui tro-phenyl-3</td><td> 155-150</td><td> ?·</td>

<td> 5·</td><td>H</td><td>H</td><td>eHydroxy-4-nitrobenzyl-1 * 5</td><td> 185-133</td><td>(B)</td>

<td> 4·</td><td>H</td><td>β</td><td>2-thienyl-1</td><td> 122-124</td><td>(C&gt;</td>

<td> 5·</td><td>H</td><td> 1'</td><td>J-ni tro-f enil- C</td><td> 130-135</td><td>U)</td>

<td> 6·</td><td>Me</td><td>í</td><td>3-nitrophenyl-0</td><td> 124-127</td><td> («)</td>

(a) 2-Eino-2- (3-nitrophenyl) ethenol used as starting material is prepared (Hu) - (trophenyl) glycine a). Examples of the preparation of the starting material θ in Example 1 can be reacted with di-tert-butyl dicyconate. (R 3) -2- (tert-Butosylcuronyl) -O-ni trophenyl) glycine

To a solution of J (G7 g) of the compound thus obtained in 25 ml of diaethiophosphoric acid (25 ml) was added potassium carbonate (1.43 g) and methyl iodide (1.37 ml) *, the reaction mixture was stirred at room temperature for 72 hours. acetate is dissolved in water ©. The organic layer was washed with brine and brine, dried over segnose sulfate and evaporated to give 3.23 g of ('U) -N- (tert-butoxycarbonyl).

V 9 9 9 9 9 ··· »···· ··· 99 9₉

- (5-Nitrophenyl) -glycine ethyl ether (2 x 6) A solution of the compound thus obtained in 5 µl of tetrahydrofuran was treated with 0.89 g of anhydrous lithium chloride and 15 g of sodium borohydride for 15 minutes. of the mixture is added dropwise to a solution of ni in tetrahydrofuran · The mixture is stirred for 1 hour with azobahnone, then 60 ni of this mixture are added and the mixture is stirred overnight at room temperature, then the bulk of the solvent is evaporated, * 8 a aradic acid is acidified to pH 4 with 1 ml of aqueous hydrochloric acid · the sevea flour is extracted with ethyl acetate.

The slurry is washed with water, dried over n-genesilene-8-sulfate and evaporated to give 11 g of (Sb) -2- (tert-butoxycarbonylanino) -2- (5-nitrophenyl-ethanol), m.p. · -90 ° ύ

0.66 g of the compound thus obtained is added to a side drink of 5 ml of methylene chloride and the mixture is stirred for 1 hour at room temperature and the mixture is evaporated and the slurry is triturated with diethyl ether. the desired starting material is obtained in the form of trifluoro-ecoteaW · salt · (b) followed by (2Η) -2-β-ηηο-1- (4-ni trophenyl) -pro pa-1,3-diol used as starting material set late · 13ι

10.2 g of a mixture of r-threo-1 - (dichloro-ethyl) -1- (4-nitrophenyl) -2-amino-propane-1,3-diol (chlorophenicol) and 14 ml of aq. hold in a boiling water bath. The reaction mixture is concentrated to a final volume of about 1 µl and the pH of the supernatant β is reduced to pH 9 with 2H aqueous sodium hydroxide solution. the precipitate was collected, washed with cold water and dried. 2.29 g of the desired starting material are obtained; mp 156-159 ° C.

· · · · · · · ······························································································Ed ((67) (c) á as a starting amount. used (^) - 2-sminc-2- (2-tisnyl) -e tin and following are prepared live (as described in Note ej), except that ('v) - (&gt; - nitrophenyl) - (o) -α-tlenylglycine is used in place of glycine · The starting material is obtained in the form of its trifluoroacetic acid salt · IR spectral data (DMSO-dg) t 3.7 $ (m, 2H), 4.64 (m, 1H ), 5.69 (s broad, 5H), 7.07 (ad, 1H), 7.2b (dd, 1H), 7.5S (dd, III), (d) Chromatograph on silica gel on a refluxing phase silica gel eluting with 45t55iO, 2 vol / vol TFA / TFA. λ obtained temples 0.67 equivalents of trifluoroacetic acid scratches · (e) E pivE'oyloxyloxyethyl Cvcurate is removed by hand treatment with 1 L of aqueous sodium hydroxide solution and the corresponding intermediate is removed by saturated with methanol.

The product was purified by chromium tographal chromatography on silica gel using a methanol-water-trifluoroacetic acid-decreasing polarity eluent. á The product obtained contains 1.3 equivalents of triflate (: r- * cet »y.

The starting p-S- (2,7-di-ethyl-4-χχο-3 ρ / ive 1-ol-1-oxy-ethyl 1 / -3,4-dihydro) used as the enycg is u-6-i-methyl) -K- (pror-2-ynyl) -amln ^ -o-flucr-bcn8oe.söwt *

0.9 g of 6- (bromo-glycyl) -2,7-diacetyl-5- (pivaloyl-cu-f-ethyl)

-5_&gt;4-Dihydro-quinolin-4-one, C, 60 g of o-fluoro-p- (prop-2-ynyl) -aminobenzoic acid tert-butyl ether, 0.691 g of potassium carbonate,

A mixture of 13-corone-6e (0.005 g) in ethyl pyrrolidin-2-one (20 ml) was heated to 9C for 1 hour.⁰Stir the mixture and evaporate and mix with ma.

- Coagulate the merve wood with water and an aqueous solution of n-trianchloride, dry over magnesium sulfate and evaporate · Purify the crumb on a silica gel cronatogel with increasing polysilene as eluent. chloride-ethyl acetate flies were used.

0 µg of the resulting mixture and 20 µl of trifluoro-e ceteate are stirred for 1 hour at ambient temperature · The mixture is concentrated and triturated with diatyl ether ® to give 0.64 g of the desired starting material as a solid. azanitotti C: 64.7 λ, Η »5.6 7, found G: 64.7 λ, Ηχ 5 * 5» »oz 1 ·, the difference being that Instead of (-) - (2R) * 2-aino-2-phenylethanol, suitable anins are used. Unless otherwise stated, ε starting materials are racemic mixtures, and commercially available chemical compounds * yield the compounds listed in Table VII », with analytical data and NMR and mass spectral data supported by · expected structures *

The formula Gk ^ COOH is based on 3.5% |

KI 3.2 A ·· ftlaczós a ^C27^23

<td colspan="2">/ chemical— le t row - RT number</td><td>i?</td><td>X</td><td>M.p.</td><td>V.egjegyzés</td>

<td> 1.</td><td>4-nitrophenyl</td><td>OH</td><td> 4</td><td> 264-267</td><td>(the)</td>

<td> 2.</td><td>phenyl</td><td>me ti 1-szALf inyl-</td><td> 5</td><td> 123-155</td><td>(bj</td>

<td> 5.</td><td>feni.-</td><td>methyl-sulfone</td><td> 1,5</td><td> 151-15*</td><td>(C)</td>

- 69 («ι 2-Amino-1- (4-nitrophenyl) ethenol used as a precursor is prepared as follows)

A mixture of 24.4 g of 4 µl of 1 1 ι-bride, 16 g of hexamethylene terstraine and 50 µl of toluene is heated to boiling in a water bath for 1 hour, and then left for a period of 16 hours. the precipitate was collected and washed with ice-cold ethanol. A mixture of the solid thus obtained, 120 L of concentrated aqueous hydrochloric acid and 15 L of ethanol is stirred at room temperature until a clear solution is formed and then allowed to stand overnight · The resulting precipitate is collected · 3 g of a solid ·

A solution of the product thus obtained in 175 µl of dloxane at 10 ° C was added dropwise to 10 g of sodium borohydride in 75 ml of anhydrous sodium hydroxide solution, and the mixture was stirred at room temperature for 16 hours. To the mixture is added $ 0 ®1 water, also tvc ^ ri; Aqueous hydrochloric acid was added and the mixture was acidified with ethyl acetate and diluted with dilute aqueous Utronitrile. extraction with ethyl acetate. The organic slurry was coagulated with water, dried over anhydrous sulfate and evaporated to give 2.7 g of the desired starting material: 127-133 ° C. (Tn A) PinylGlyloxycetyl-cypyrrole was made with 1 N aqueous sodium hydroxide solution. Instead of treatment, the appropriate intermediate is treated with methanol saturated with ammonia gas and the 2- (methylsulfinyl) -2-phenyl-ethyl used as starting material is prepared as follows:

1.5 g of 2- (tert-butoxycarbonyl-seino) -1-phenyl-ethnol,

2.64 al tri? tilsai η and 45 ml of set iléchlorl in ice

<img file="HUT57739A_D0027.tif" />

while cooling, A-ο η, 54 g of MSil chloride are added dropwise over 1 hour at 0 ° C. The mixture is washed with cold saturated aqueous sodium bicarbonate solution and water, and the fatty mouth of the flask is washed. add the so-worn pseudosilute to a solution of 0.66 g of sodium cetane thiolate in 10 µl of methyl methoxide and stir for 1 h at room temperature. the residue was purified by chromatography on silica gel using increasing amounts of poly (hexane-ethyl acetate) as eluent. O-Y (3 g) of h- (tert-butoxycarbonyl) -2- (cetylthio) -2-fannylethylaniline was obtained in the form of an oil. Γ0.86 g of the compound thus obtained were prepared in 20 ml of methanol, 10 ° C. 65 g of sodium metapsodium

A solution of 2.5 »1 of warmed water is added dropwise · the mixture is stirred for 1 hour at room temperature · the precipitated white precipitate is filtered off and the solvent is evaporated from the filtrate. The reaction mixture was taken up in ethyl acetate (1 L), washed with water, slurried with magnesium sulfate and evaporated to give 0.84 g of h- (teFC-butGxi-Ksrbonyl) -2- (methylsulfinyl) -2-phenylethylamine. · Canoeing

A mixture of 0.1 g of the compound thus obtained, 2 ml of trifluoroacetic acid and 1 ml of ethyl acetate is stirred for 1.5 hours at room temperature, and the mixture is concentrated to give 0.27 g of the extracted starting squeegee. . &lt;A * .í apestrum data (ó · ..3-dg) ι c, 15 es 2.41 (2a, 5h), 5.0-5 »? (a, 20), 4.17 yd 4.22 (m, ll), 7.35-7.50 (m, pta, 8, l) (br s, 3 * 3).

(c) wall-like material, wall-like, 2- (ethylsulfonyl) -2-xenylethylamine, is prepared as follows, 62 g of h- (tert-butyl &amp; lt; 1 &amp; gt; • · · · · · · · · · · · · · · · · ·

- 71 -2-phenylethylene with stirring in a solution of 20 ml of ethylene chloride - 52 g of 5-chloroperbenzene^suzo &lt;seev (8 u, purity of 50 ml of nettex: 0 drops of 0 ml of the lloride) · stir the mixture at room temperature for 1 l · 1 volume of water with 5 ml of aqueous sodium triisulfite solution. with water »natriu®-hydrogeic-kerbonut solution, finally wash with water, dry over magnesium sulfate, aejd evaporate ·

0.6 g of the product thus obtained, 2 ml of trifluoroacetic acid in 20 ml of ethylene chloride are stirred for 2 hours at ambient temperature. The mixture is evaporated. 0.69 g of the desired starting material is obtained in the faraide salt of trifluoroacetic acid.

K - ^ - 81droxy-1- (&gt; ni trophail) -a tij7 * P * ZF-U-ne 611-4-oxo-3, e-dihydro-clnaz οΐίη-β-11-txl) -ü - (Prop-2-lnll) -α-η 7 -benzamide is reacted with the nitric acid anhydride described in Example 4. &amp; gt; -Z-, cetoxyl-3- (6-phenyl) -ethyl] -p- [T- (2-s] -111 -4-oxo-3,4-dl'ii dr ok 1 na z 011 u-6-i 1-a-111) -4- (pro-2-yl) 1 H -anizo-F-benzaldehyde (2 equivalents of visa · tar) is obtained 56 Ua3 ®aa®l&gt; op .: 155-155^SHESHE·

Beat.......

^^ - Hydro.xi-2- (4-nil tro -fan 11) -e thi ^ p - ^ - (2-ae t11-4-OXO-3,4-di bi dro-ki aa z oline -6-yl-ae-11) -d- (pro-p-2-yl) -eamino-benzo-dimethyl-4 *, as described in Example 4, was reacted with this ketone and its v-enedride. nltro-íeni l) -e tlj ^ -p- £ i £ ·

- (2-vw 111-4-0 '£ 0-5? 4-di-dr o-kiue z 01 in-6-yl-1-yl) -2i- (prop-2-yl) -O® in benzene (2.3 equivalents of water) was obtained (83-150 c.p. 190-205).

_t.4.Ua _t, - ^ - (2 ~ f * thi-4-oxo-5- [pi] ilcyl-oxy-α®-tyl -5,4-4.1-72 hydroquinoline-ol-6-yl-m · tll) -N- (prop-2-ynyl) -one-7-benzo [beta] -v- (pentafluorophenyl) and Btert e 12 ·. Example sserin (R) - (-) - 2-aaino-3β-tnll- N- (X-Cl-hydroxy-3-phenyl-1-prop-2-l-7-β-ethyl-4-oxo-3,4-dl-hldro-quinazolln-6-yl-ethyl) * H- ( prop-2-ynyl) -eBinp7-benzyl (42 equivalents) of hosonaol cp 165-167¾ (1 equivalent of sodium chloride tertalnes).

14 · nr Ida

0.49 δ - trans - (4-oxo-N-methyl-oxy-ethyl) -5,4-dihydro-quinol-6-yl-ethyl] -N- (pro-2 -inyl) -ea in 1027 * soeee&gt; $ * nt «fluoro-phenyl) -EB8ter, 0.2 g of 2-eaino-2- (4-fluorophenyl-D-ethanol-trifluoroacetate salt, 0.54 * A mixture of 1 triethylenin, 0.04 g of N-hydroxy-1-benzotoluene and 10 µl of ethyl acetate is stirred for 24 hours at room temperature. The As mixture is evaporated and the residues are purified by flash chromatography on silica gel with increasing polarity of the acetate as hexane. hess with us.

0.19 g of a mixture of the product thus obtained with 5 ml of methanol saturated with anhydrous methanol and 2 [mu] l of methanol for 43 hours was evaporated and the resulting solid was dried under reduced pressure at 60 [deg.] C. for 3 hours. MJ (4-fluoro-phenyl) -2-hydroxy-atij7-P-ZJ^E- (2-Acetyl-4-oxo-J, 4-41H-droquinoline-6-11-methyl) -N- (prop-2-yl) -amino] -T-benzamide (1 , 5 equlw of lene? Water converted to mind any ^ g) we get! op.i 1) -13¾ ·

Spectrum data for B® (CDCl3, 2.33 (³, 3H, GH ^), 317 (t, 1H, CCH), 3.55–3.75 (· · 2H, (¾ H), 4.30 (d, 2H, CggAr),

4.70-4.90 (a, 3H, cyano + OH), 4.95-5.07 (a, 1H, NHCl3), 6.83-7.74 (a, 4H, aromatic), 7.09 (t, 2H, arona), 7.35-7.45 (a,

- 75 2n, srosae), 7,&gt; 2 (d, ui, skew), 7.63 (dd, 1H, drop),

7.96 (d, la, facial), o, 27 (d, In, GChH), 12.15 (broad 8, 1H, iUx) · peak in λmax (♦ Ib) »m / e (M.) 465 · uloBiés based on the formula ^ 28 ^ 25 ^ 4 ^ 5 ^ 1 »5 Bgü» asuBltott * ν »6p, 7 -t» 5.5&gt;, bridge 11.0 plots »Cl 65.5 -, Η» 5, 2%, Bl 11.0 λ.

the 2-attino-2 * (4-fluoro-phenyl) -dimethyl-trixluaracetic acid salt used as starting material is prepared from Wluorophenylglycyl by a procedure analogous to that described in Note (a) to our Table, m.p.

EXAMPLE 19 EXAMPLE 19 Sserlnt jarunil al, but using the corresponding amino instead of 2-aaino * -2- (4-fluorophenyl) -ethanol, is not reported, starting materials are racemic mixtures, Vil. Compounds listed in Table I, which are the first to be obtained. data, roast spectrum, and core spackle * support &amp; spell w «r« cases,

U ^, a, „Süfeimt

UUI-Arg ^ m ..... íwfláffM

<td>x w the line * number of the congregation</td><td></td><td></td><td>í&gt;</td><td>X</td><td>cp · ° c</td><td>«Sticks * note</td>

<td> 1«</td><td> -</td><td>fsull—- ^^u2</td><td>meail-</td><td> 1.5</td><td> 2&gt;4-256</td><td>(the)</td>

<td> 2,</td><td> «·</td><td>5-nitro-ldnxA</td><td>i 2.4 * bri.azoi-5-11-</td><td>u</td><td> 14/-157</td><td>(B)</td>

<td> 5.</td><td>ch₂</td><td>dlaetil-e * * What woman *</td><td>5-nitro * -stops-</td><td></td><td> 255-257</td><td>(C)</td>

<td> 4.</td><td> -</td><td>fanlx- -</td><td>4-ti · eetil »01-2-11-</td><td></td><td> 225-255</td><td>(D)</td>

<td> 5.</td><td>ch₂</td><td>t * rc-butoxl- -</td><td>4-tls eetil »ol * 2 * * yl</td><td> *</td><td> 174-175</td><td>(E)</td>

• · · · «··· ··· • ·

- -

<td>; »Buy eorsafi ©</td><td>THE²</td><td>x² P</td><td>ϊ5</td><td>X</td><td>MEG Op</td>

<td> 6«</td><td>oligo</td><td>bidroxyl -</td><td>4-ethyl-blazol * -2-yl-</td><td></td><td>254-250 (f)</td>

<td colspan="2">7. CHgCH ^</td><td>bldroxil · * -</td><td>3-n-itro-phenyl</td><td> 0,75</td><td>208-213 (g)</td>

(a) The starting material used is (17) -2- [alpha] 11-yl-phenylethyl?

1.5 g of C'0 - (-) - 2- (tert-butoxybenzoxybenzyl-esino) -2-phenyl-ethyl, 2.64 l of triethyl toluene and 5 ml of ethylene chloride under ice-cooling At -0 ° C, 54 µl of sesyl chloride was added dropwise, the mixture was stirred for 2 hours at 5 °, the mixture was stirred and the aqueous solution was diluted with ethyl acetate and dilute aqueous sodium bicarbonate solution. &lt;tb&gt; &lt;sep&gt; mesoate &lt;tb&gt; &lt;sep&gt; mesoate &lt;tb&gt; C, 66g of ndtriunethanethiolate

It is added to a solution of dia 'al diaeti 1 formide and the mixture is stirred for 1 h at room temperature. λ «mixture is evaporated and the residue is purified &amp; purified by chromatography on a gel · using increasing polarity hex &amp; n - ethyl acetate« as eluent ** 1.72 g of solid: - (tert-butoxy-cr.rb? ni 1) - 2- (mttl-ti '-1-phenyl-et11-eraint ke unk.

λr. A solution of the product thus obtained in 40 µl of a 0 ° solution of 1-methylene chloride (1.92 g) was added dropwise with 15 ml of ethylene chloride. Stir the mountain for 1 hour at &lt;Tu ° C, then leave the room iare to Rio tre. «Flutter for 13 hours75» · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -ae washed with tetriazulite-OAU, saturated water · n &amp; ferric hydrogencarbonate solution, and finally with aqueous sodium chloride solution · dried over visuaeaulphate and stored increasing the polarity of the olive oil line using a mixture of nxx &amp; n - ethyl acetate · 1.27 g of solid h- (tert-butoxycarbonyl) -2-iBOsyl-1-phenylethylsmine are obtained · x → a mixture of trifluoroacetic acid (20 ml) and n-ethylene allyl (20 ml) was stirred for 2 hours at room temperature. The reaction uses dinyl formaldehyde instead of oleaginous ethyl acetate · The product is purified by chromatography on silica gel. Polymerization of methyl u-chloride - isopropanol - trifluoroacetic acid mixture as eluent · λ products «, containing 2 equivalents of trifluoroacetic acid, α equivalents of isopropanol · and starting material used is 1- (5-nitrophenyl) - 2- (1,2, d-Triaaul-p-yl-thioethylamine) was prepared as follows (snow) -2- (tert -oxoxy-xylbunylamino) -2- (5-ni trophenyl) s -fe as shown above (aj magjag ^ ztaoeu le irtax according to mesyl chloride &amp; l reagalGotuxu ·

1.14 g of the thus obtained mozila, 1,2,4-triazol-5-yl, 4c g of trityl amide and the dimethylol form are obtained. The mixture was refluxed for 13 hours at 60 ° C and the batch was purified by chromatography on azilic gel.

- 76 srunyu motil'-n-chloride - ethyl acetate was added. 0.5 g h-^f 6-butyl-oxy-1-butyl) -1- (3-trio-phenyl) -2- (1,2,4-trisol-3-yl-thio) -ethyl-eaine is obtained.

0.4 g of the resulting butter and trifluoroacetic acid are stirred for 2 hours at ambient temperature and then evaporated to tip e. The desired starting material is obtained in the form of its trifluoroacetic acid salt. (C) 2- (Dimethyl) starting material -emino) · 1- (5-trifluorophenyl) -ethylamine is prepared as follows by elution of (pho) -S- (tert-butoxycarbonyl) - (3-nitrophenyl) glycine-acetyl and ester 2u. of dimethylamine gas is added to a 10 ml solution of diatyl chloroformate and the mixture was stirred at 10 ng · pigment azo pigment * -&gt; the mixture was evaporated and the residue was purified by chromatography on silica gel · increasing polarity of the killing agent was petroleum ether (fp * &lt;40-6 A) - ethyl acetate mixture · 1.31 g (tert -Butoxy-4-transferrone) - (3-fluoro-8-yl) -glycyl-dimethyl-effluent is obtained.

To a solution of 0.323 g of this desired solution in Λ 2 ml of a solution of urea in 1 ml of tetrahydrofuran, add 1 ml of 1 molar solution of dlborane in tetrahydrofuran. The mixture is stirred for 1 hour at 0 ° C. molar solution of diborane in tetrahydrofuran was added, ca the mixture was heated to boiling under a stream of water · ..the mixture was allowed to die to anhydrous temperature ·, reduced with 2 ml of 6 h aqueous hydrolyzate by dripping, After boiling for 5 minutes on a boiling rock salt, the mixture is brewed, the residue is seeded between ethyl acetate and water, and the aqueous sodium hydroxide solution is gluted and extracted with tetracetate. . ; ·. the organic phases are combined, washed with water, checked · ············································ milled over ssulfate. éa spit &amp; roljuu. purification of the grit by means of a crude phytoremediation wall on silica gel, eluting with 60 »2 -10.2 teriogsteranyu water - phenol - trifluoroacetic acid © Cases · -, 211 g of the desired starting material is obtained in the gum product Xorxujc. data (m.p. = -2.4-d. j. 2.72 (a, 6H) * 5.46 (broad, 2H), 4,&gt; p (t, 1U), 7.8-3.5 (a, 3U).

(d) the (±) - α- (4-αβ-111-ttezol-2-1-D-benzylene) used as starting material is prepared as follows:

to a -15% solution of g (-) - x * - (nerAryloxy-arbonyl) -phenylglycine in 60 µl of tetrahydrofuran 3_t10 allyl triethyl aslnt, &amp; gt; 2.42 »1 Cl-formic acid isobutyl ester are added · The mixture is stirred for 5 minutes at -10 ° C · Ammonium chloride is introduced into the tunnel under cooling at -5 ° C for 1 hour · Leave the mixture to room temperature and bopurize · «®, dried over water and dried in a tube · 4.42 g of ^ - (bensil-Mi-Carboudii) -x'iftaiL-glyyl-amldat._;.our·

3&gt; 7 g of the thus obtained esid&gt; w ^ 1 pyridine gel was quenched with -5 ° w oxdata, 1, g&gt; 5 ml of l'uoyivryl-oxide 2 · ni-methylene chloride was added to the solution cAapagtw t j3u stir for 1 hour at 0®ν · οη, then quench between ethyl acetate and cold water · Organic l-zll with water and an aqueous solution of sodium chloride, press over supernatant azulfate. and store the remainder of the azilic acid gel, purify my space, and purify the eluate with a 4: 1 by volume mixture of taxane-ethyl acetate in baazoulu · 3 S- (δ-azyloxy-carboxyl) -α-cyano. we get benzyl ozine ·

A mixture of 0.5 g of the thus obtained btonon-III-aine, 78 µl of diethyl-a-ol and 3 cl of dimethyl-XuruumUi at 55 ° C is charged with hydrogen sulfide for 1 hour.

<img file="HUT57739A_D0028.tif" />

and Arc water is added and the mixture is kept at 16 ° C for 16 hours. the precipitate was collected and dissolved in chloroform. dried over a solution of magnesium ion salt and evaporated. A mixture of 4 g of 4- (butylsulfonyloxy) dibutyl-1-glycthioeside is obtained in the form of a mixture of 1.5 g of the resultant tloanide, 2.0 g of chloroacetone, 2 drops of an aqueous solution of saline and 2 hours. The mixture is evaporated and the precipitate is mixed with ethyl-ocobate and water. the organic phase is dried over magnesium azulphate and concentrated by evaporation on a silica gel chromatography, eluting with a 5: 1 mixture of hexane and ethyl acetate in the form of an oily solid, c, 542 g (1 H) -K- (becsi-1). carbenyl) -a- (ostyl-thiazul-2-yl) -benzyl-enlnl *

6.55 6 of the compound thus obtained and 4.2 µl of a 5% (v / v) solution of hydrogen bromide in hydrogen bromide solution for 1 hour were added to the azobacarbon moiety. The mixture is kept at room temperature for 16 hours, then cheetah, and the residue is triturated with diethyl ether * 6,541 g of (;:.) -o- (4-ae ti 1-Usul-2-). il) -bauzyl-ethyldinitrobromide is obtained *

IwiR upektru® «dalai (b ^ u-dg)! 2.45 (s, Ja), 6, - .. 4 (_t 1—), 7.4v (g, 1 · ί), 7.47 (a, 5 ··), 7.6 (m) , 2χ »), 9.14 (broad, 50 · (ej - 2-tert-butoxy-1- (4-acetyl-lasul-2-yl) -ethyl) ethylene used as starting material) was prepared as follows:

To a solution of t, v'-Graz-putyl-Δ-benzalloxycarbonyl-D-xj-azerine 6 x trachydrouron-1x, -15 ° v-cs, 2.4 g of triethyl anion was added. .; 2.21 l of "obu6il-ester" of chloroformate * are added for 5G minutes^SheStir at U and then into the eAgency · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 7&gt; ·, ammonia gas was passed through it during nutta at -5 °. The mixture is left to warm to room temperature and stirred for 1 hour. The mixture is evaporated and the residue is taken up and dried under reduced pressure. 4.91 k of u-tert-butyl-α-benzyl-osbicarbonyl ) A mixture of -A-aaer inoculum * g so obtained, a mixture of 1.65 g of ohaweaeou reagent and nickel ecstonitrile was stirred at reflux temperature for 16 hours. the mixture is evaporated and the residue is purified by chromatography on a silica gel column containing toluene-ethyl acetate n-1,45 g of tert-butyl-1-benzyloxyl-6. rbonil-i-ezerine-thiobid is obtained.

The resulting mixture of thiol, v, 7 µl of chloroacetone, 1.63 ml of 2,6-lutidine and 22 µl of propanol was refluxed for 9 µl. The mixture was refluxed and the residue was ethyl acetate and aq. The organic phase is whitewashed with water, quenched with MgSO4 and sued. the silicate of the regiment is purified by roo &amp; togrefalv, eluting with increasing polarity in hexun - cti.-acetut «Cases · Rubber formidubsti 1.14 g (k. N- (ter-cm-toxyl-orbonyl) -2-tert-butoxy-1- (4-yl-cyanol-α-yl) -ethyl omyl.

· i. ..a ipextruís «delei (ijü. · ..). ? -o ^ u 1.13 (s, yH), 2.34 (d,&gt; d), 5, v ^ uy, 72 (a, ka), 4, -yu (ü, in), 5, ^ 3 (a, 2:), 7.1-7.4 (m, bu).

i ^ y itó'pútt = Git-calu 2v &lt;ial matiXcu-kl-rldool jVwztztG v.Auotuba while stirring and ice, w, 4&gt; yg trln «til-s» ylyl-jod · Stir for ^ minutes at 0 ° υ-οη, then stir at 16 oran ul 5zobeh0 «l &lt;l«. we have enough x2d ml of metauol to burn and burn to the edge. u, 41 g of desired starter saddle in kepunx olive horseradish, 'what's more »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···· ···· ··· ····

- We use 30 font-rich uuxi.ai.

This compound is obtained when it is cleaved. I mix my throat obtained after switching and after filtration with methanol before pre-filtration with trifluoroacetic acid · and then deactivate no fish Fish heap · «. batoxy-1- (4 * -ethyl-thiazol-2-ix) -ethXr-p- ^ o- (2 -a »t 1 1-4- οχ ο -5 ~ / ρ drink 1 oyloxy i- o 111 / -3,4-dihydro-1-na-zulin-6-yl-ethyl) -Improp-4-ynyl) &lt;* euin-4-benzanide and a solution of trifluoro-acetic acid are stirred at room temperature for 2 ·. the case evaporate and purify the morsel of dewaxed crown on silica gel using a mixture of increasing polarity © ethyl n-chloro-ethanol mixture as an oil 0_t636 gl * - ^ '- hÍdraxl-l- (4-6i &amp; aötiL-tridecyl-2-yl) -6tij7^,-p - ^ * (2 '®e * tyl-4-axo - &amp; gt; - / - 1-oxymethyl-ethyl-dihydro-quinolol-6-yl-yl) -o- (prop- 2-xnil) -em in ^ 7 that time ke p unk.

6 »159 g of loo material and 1-oxy-ethyl are removed to space by 1&gt;. _;.l.a., second paragraph, is treated with ammonium-saturated Oauau. &amp; l treated with (g) 3-ealno * 3 - (&gt; · -oitro * pheoyl) -p; While stirring, 1.11 allyl chloride, ojd., 7 g of saloyl-3- (uitrolenyl-D-propic acid) was added. pSX'C 1 ^, - «iv v - vu, —..... y ζ» * w orO. &lt;it «0ΖΌO8110— space-klûteo&gt; 2 verj ..k · ΛιΟ the Mountain you steam. 05 g of Sirlo-3-aaino-3- (3-nitrophenyl) -propylsulfon-methyl-ether_fc·our.

To a solution of 3 µl of the crushed ester with 5 µl of di-di-sturic acid are added 2 µl of triethylalan, 1 µl of 4 g of di-tert-butyl 11-carbonate. &lt;% mixture y oapig room temperature · · te ·· ·· - •••• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ··

- αΧ beat it. c The brain is evaporated and the residue is purified by silica gel chromatography. The eluent used was 5 x 2 volumetric petroleum ether (b.p. 40-60¾) - ethyl acetate · g 5 * (6 'r -Bu6-oxy-xycarbonylamino) -5- (5-nitrophenyl) -propylsulfonate. After stirring to dryness, the ester was stirred at room temperature for 5 minutes at room temperature under stirring to dryness with c, 61b g of adjuvant borohydride and 0.695 g of lithium chloride in 20 l of tetrahydrofuran. then 4 nc_runtil the mixture is evaporated and the slurry is purified by chromatography on silica gel using a volumetric mixture of petroleum ether / ethyl acetate. 0.195 g of 5- (tert-butoxycarbonylamine) -&gt; (5-nitro-fanyl) -propeaol are obtained in the form of a slurry.

LAu spectral data (vi x 1) s 1.4 (a, 9 µ), 1.10 (m, 2 µ), 5.7 / (s, 2x0, 5.4 (s, ii ·), 7.42-7 , 92 (©, 4i.i) · * λ A mixture of the propencl compound thus obtained and 2 ml of trifluoroacetic acid was stirred at room temperature for 2 hours and then crushed to give the desired starting material, which was used without further purification. · «!&gt; · / Üxaübtn Thousands have been described, with this ending, **₄ Instead of 2-amino-2- (4-fluorenylidene) ethenol, the corresponding amides are substituted, unless otherwise stated, &amp; lt; 1 &amp; gt; starting doses are racemic mixtures. · their analytical data, their XiiiR spectra and their mass spectra underestimated the expected structures · 4 · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··

- 32 &amp; U. MUláoJi

<td>Sorting out the compound</td><td> -.2</td><td>X</td><td>M.p.</td><td>Comment</td>

<td> 1.</td><td>4-so ti 1-thia ΛθΙ-2-yl-</td><td> 0</td><td>foam</td><td>(S)</td>

<td> 2.</td><td>1,2,4 - 3 550 ». -J-yl</td><td> 2,5</td><td> 131-14?</td><td>(H)</td>

<td> 5.</td><td>5-oxo-1,2,4-trile-2-yl-5-yl-</td><td> 1</td><td> 15 -165</td><td>(c</td>

The reaction is carried out with di-di-1-sulphuretime instead of ethyl acetate as the solvent in reaction a. —Set Group 1 ©_;This was followed by cooling: 0.22 / crude product, 5 µl of a mixture of 4 µl of rice sodium hydroxide and 5 ml of 1,4-dioxane was stirred for 3 hours at ambient temperature. The mixture was evaporated and the ssl was purified by reverse phase chromatography on silica gel. The cellulose was used in a mixture of 5C: 0.2% v / v of &lt;RTI ID = 0.0&gt; vi-retanol-trifluoroacetic &lt;/RTI&gt; acid. Hsb foraájábtn C_tX2 g of product is obtained, which is 2.6 equivalents of trifluoroacetate.

2- (3-Bydoxoxy-lz * o / 8201-5-11-methylthio) -1- (α-3-ylthiophen-1, 1-2-11) starting oil e y 1-smint í * kö

r. -trÍu »-etGzíd 1.1? · the? · C

-2- (4 ·? Ϊι «ti 1 -t 1zo 1 -2—11) -et · * .n-tlo! t ei.i eaobshősérséLife '«beat. oh enough 0.6 g of 5- (broncho-sa ·, h stirring at its literal temperature: four hours) Oh continue.? e '. &lt;;

The mixture of 33 tor &amp; lt; RTI ID = 0.0 &amp; gt; torahs &amp; lt; / RTI &amp; gt; and 45 volumes / volume of acetic acid hydrogen chloride solution was stirred for&gt; 0 min, azeothermic salt was added dropwise and the precipitate was separated. 94 g of the desired starting material are obtained in the form of a hiarobroffide BORA.

α-Ceebenzyloxycarbonyl-snino) -2- (4-bc-yl-l8wl-2-yl) * etun »thiol, obtained in the above process, is the precious stone

To a solution of 10 / g of cysteine ​​hydrochloride in aliquot of 2 »1 volume of ethanol-water 206 g of triethylamine, m.p. 4 g of 4-setoxybenzyl chloride are added. The mixture was stirred at room temperature for 16 hours, then filtered and filtered to give 107% g of S &lt;* (4-methyl-cis-benzyl) -cisulphate, keeping the filtrate at -10 for 4b for a further 22 hours. , 3 g of cieztein-stalk are precipitated *

126 To a mixture of 10 g of the thus obtained cesium thiol derivative, 525 µl of a 1 N aqueous solution of u &amp; lt; RTI ID = 0.0 &amp; gt; trihydroxy, &amp; lt; / RTI &amp; gt; «Rcngen® be— before the ax-goluse mix the mixture. - react for 2 hours at 15 ° C, store for 1 hour with 2 0 aqueous saline solution._uand the resulting wastewater and ethyl acetate are neglected 4u.zbtc. the organic phase is quenched with water, and the mixture is poured over a .alpha.-R (s) -phalate to obtain a solution of (benzyl) oxy-4-acetylbenzyl) - (4-acetylbenzyl) -.

ni igü- u ^ -pütt 0 í SZ ti ti i í · —u Z uX 'u &lt;AJK., yg 4 ύ pövu — íü ···. To the -5 DEG-bed of reflux olefinic acid and methanol, was added 63 g of triethyl alcohol, followed by 67 g of chloroangesev ethyl ester. the mixture was 1 or «n at u^c\ - ou stir in * rz mixture for 20 minutes «» · aion gas is bubbled in and the mixture kept at 16 ° C for 16 hours. The mixture is filtered, the filtrate is washed with aqueous sodium alumina solution, and the aqueous solution is washed with aqueous sodium chloride solution.

It is dried over -84 silicon sulphate and evaporated to 11^Λ5 There is thus obtained g - (benzyloxybenzyl) -s- (4-methoxyphenyl) cysteine ​​amide.

To a solution of 18.7 g of the eaid compound thus obtained in 200 ml of a solution of 200 ml of acetonitrile, 50.5 g of 2,4-biaz (4-methoxycarbonyl) -1,4 g. dlsulfide (lawesson reagent) was added and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified by chro- tography · 2: 1 toluene-ethyl acetate (19 g) thioalide 4.82 g of 2,6-lutidine are obtained per g of a solution of the thioid compound thus obtained in 140 l of ethanol, then cetane (5.70 g) was added and the mixture was refluxed for 7 µl · purged with a 3: 3 mixture and the residue was purified by cremato-refluxing on ethylene · ethylene chloride - ethyl acetate 9: 1 (v / v). Acetic acid mixture was heated to reflux · 7 6 A; - (benzyloxycarbonyl) -2- (4-ethoxybenzyl-thio) -1- (4-ethyl-thiazol-2-yl) -ethylamine we get·

To a solution of 5.25 g of ethylene thus obtained in 100 µl of trifluoroacetic acid at 0 ° C was added 2.5 µl of enizole followed by 4 g of mercury (II) acetate. The mixture is stirred for 40 minutes at 0 ° C, then evaporated. The residue is dissolved in 200 ml of methanol and the solution is cooled.⁰Cool to C and add 15 µl of 2-mer · to-ethanol · price. mixture for 16 hours at 4^Sheon c. The mixture was filtered and the filtrate was concentrated. the product was purified by chronatogel chromatography on SR silica eluting with increasing amounts of methylene chloride ethyl acetate, 5 g of 2- (benzyloxycarbonyl-1-emino) -2- (4-methyl-thiazol-2-one). 1V-Ethane-Tlol is obtained.

, starting material 5- (bromomethyl):

• · • · ··· ··· · · • « « · · · · ···· ···· ··· ·· ··

- -3- (tert-butyl-1-ylcylsilyloxy) isoxysol is prepared in the following manner:

9.9 g of 3-hydroxy-5 * -ethyloxyloxox (e. Che, Hars, Juli * 1277/1966 / casein), 5 g of 3-pore-lithium oleacals, and 2 µl of methylene chloride. To 3 ° G * 18 was added 11.1 g of tricbylalan, followed by 1 x dg of tert-butyl dlaatylsilyl chloride, and the mixture was stirred for 5 hours at 3 ° C, and the slurry was purified by silica gel chromato- graphy using petroleum ether (fp, 5 4-gA) - methylene chloride (1: 1), Oil phosphorus 16.2 gp * (tert-butyldialyl-azyloxy) -5-ae 1 * oxoxylated 11 images ·

Thus, a mixture of 14.3 d of wpotb compound, lv, lgg, 3-dibromo-5,3-di &amp; eethylhydt-utoin, 1 g of azo-bis (isubutyronitrile) and 1 slurry of tri-fluoride in 16 articles xt at reflux was used. »RcljUK. -wash-ll-ll, and this hair stake is cleaned with a chromabograx'ii ^ made on a permissive basis, ^ lualúszrkunt áeauetbec jwöiIJm-Kiorluot, -; &lt;-. sznalunü. 3.97 g of 5- (bromo-methyl) -3- (tert-bus t-butyl) are quenched with tile 1-v. solubilization in reaction instead of ethyl acetate d 1 □ € c 11—9 &lt;· u - * u »1 u u tn« this n &amp; xunk *

2- (3-Hydroxyisoxy-z-l-y-1x-ua) 1-iu; -1- (1,2, d-trimethyl-ziol-1) -e111-amine used in the clinical formula was used as f '. For the purification of the fatty acids, azzfc-1 is prepared by treating 2- (bacyl) oxy-carboxylic acid-2- (1,2,4-tri8Zol-5-yl) -ecane-thiol with xosgc. * (bromo-1-ethyl) -3- (tert-butyl-duTi-c2-xyloxy, iso-xyl) &amp; lt; 1 &amp; gt; - (benzyloxycarbonyl-2-yl) -2- (1,2,4- Crifesol-3-yl) -ethanethyl is prepared as follows:

X. · · · · · · · • · ··· the·· · * • · · · · · · *··· ···· ··· ·· ··

7&gt; α- (beusil-uxi-Maybanyl) -K- (4-tolecoxyl-umemail) • In a solution of cis-tel n-amld yuo mi pix'luinuel, 4q g of fossil or yl Chlorine is added dropwise. the mixture was stirred at room temperature for 2 hours at 0 ° C, x 4 days for 4 hours at room temperature and stirred for 4 hours at room temperature for stirring. The pyridine was evaporated and the residue was partitioned between ethyl acetate and yoga. Servo - Fusion 2 The aqueous salt is washed with water, dried over Khtgnosium azulphate and evaporated. 4y g of oily substance are obtained.

2u g So slurry thermos, 2.6 g ethanol, 2u ml aubilium chloride or T ml of ethyl ether u.v. For 15 minutes, hydrogen chloride vapor was added and the mixture was stirred for 2 minutes at &gt;C and then After stirring for 1 h, the mixture was evaporated and the residue was partitioned between a slurry of a saturated aqueous solution of potassium terbonate and ethereal diethyl ether. the organic phase was discarded and evaporated over magnesium sulfate. 22 g of ozllurdY2- (beuzyl-OA1-kerbonyl-omino) -5- (a-toxin-bsnail-bio) -proploalylate is obtained in the form of a solution of 40 ml of ethanol in 40 ml of ethanol to obtain 6, - triethyl omine is added followed by 2.4 gf orail-hiur. r bed for 4 hours at room temperature} Stir then for 4 hours^c· The mixture is evaporated and the oats are purified by purification with a crude crystalline crystal · Increasing polarity as a starting material Cetylene Chloride - Methane &lt;x -guniu b ηάόζο ^ ΐαη * · ρ, ρ g Yellow enyaÓ U w lV j, UUá · .2. i_Defend. Worn termite is dissolved in 4 «ml of volumetric solution and the solution is refluxed with 2.5 uranium in a continuous stream» solution for 16 h »4^uo o o stored · xxultured precipitate, dl g; .-. {teu 3 -yloxy-1. 10 -bromoyl) -2- (4-methoxyl-benzylthiyl) · · · · · · ··· ·· &lt;«♦ · · · · · · · · · · · · · · · · ···

- rz -1- (1,2,4- ^ 1 »ζο1-3 · ί1) * · &amp; 11 · 0» 1η0 «apunk ·

2.3 g of the product obtained are added to a solution of 0 ml of trifluoroacetic tea in 1 ml of alalone, followed by 1.91 g of hlgaliyl (II) -eucetate for 3 minutes;^üStir v, then evaporate to r. the residue is dissolved in 5o littermates in females, the solution ee is cooled to 0% and&gt; ml ml of 2-m-naphthoethanol is added nozzu · b mixtures for 1 hour^ŰStir at Q and then for 2 hours at rabbit ssobs. The mixture is filtered and the filtrate is spared * and the serum is formed by the catheter-phosphatophile on the member III, increasing in polarity as the closure is mixed with methylene chloride / methanol * 1.5. g 2- (binsil-ozl-consoleU-emino) -2- (l_t2,4-trisyl-3-yl) -ethane-t-10 is obtained. (C) The product is cryoprecipitated on reverse phase chelated silica gel with a decreasing polarity of the eluent aetenol-vn. - use trifluoroacetic acid flies · product contains 1 water of etvlvataiae, trifluoroacetate of α eaviv &amp; lons · 2- (3-hydroxyis * qxiii ui-5-ix-iaa txi- Taste- [1- (p-odo-1,4-triazol-3-yl)] -minine was prepared as described above (a, xx), with 8calcarboxylate. of large .k- (6-benzyloxy-pyridylamine) -1- (5-hydroxy-5H-triazol-3-yl) -ethanol was reacted with 5- (bromoethyl) -3-. - (tert-butyl-propyl-a * 1X10 -XXX; -tazazoX13X-2- (banyl; yloxycarbonyl) -alkyl; -2- (5-oxo-1, 4, 4-carboxylic acid). P-iXi-preference is prepared on the stone stick. ·:

4.02 g of ethyl 2- (beyloxy-thia-alanyl-atino) -3- (4-thaethoxybenzyl-bio) -propionic acid are dissolved in 20 ml of ethanol at 0, 4 g, by auction. trieiii.-aaius, then 2, uo g of tíCil-k.rbo— is added, © the soft of βλ © is stirred for 6 hours at oob temperature— «· · · · · · · · · · · · · · · · ·

.... "··· ··· ·· ·" - ANCESTOR ·"

..2USóü x- z i'i, on 7 goods stored at 4 ° .., - cn. The slurry was evaporated, and the crude chromatographs were purified on a silica gel gel. , .Lual. nsv ~. ': set polylate setil ^ n-chloride · a / U-nol clsgysk. 3.9 g of yellow hsbot hsta4kj * lgv of product obtained are kept at 2.3 g at 15G. The resulting product is purified by chromato-tographase on an angiol and a gel, using as a secondary substance p.o.-pituitary petroleum ether (m.p. 4-C0 ° C) -Ityl acetate. . · Foam in the form of a foam, 34 g of ..- (bt; n311-oxy-2erboniL) -2- (4-oxoxybenzylthio) -1- (3-oxo-1,2,4-triethyl) 1-3-11) -e11 L-nxint ta? Pnn.

413 g of a.sp.t.sp./sp.sub.1 ml of trifluoroacetic acid-concentrated solution of 16 ml of anisole are added, followed by 32 g of mercury (11) -C. The mixture was stirred at rt for 1 h and evaporated. for the remainder 1 sl of the learned food »1 2-mercap * to-etn-nAt, oo tz e1-igyct 1 hour Y at room temperature kovsrjüfi. &lt;.z vl.g ^ ct is pierced, and the experiment is bepled in lead · purifiers are cleaned with a crude drip reflux done on a silile rege, this ammunition is i.vekvo flaritasu ha ti 1.-na loride-methanol mixtures are called · &lt;. , 3 gk '- (benzyloxycarbonyl omido) -2- (5' '-oxo-1,2,4-tr 1') c 1-3-yl} -ct-n-1. unk ·, μ / τΛ, .In, faliig.

p- / n- (2,7-in. tyl-4-cx: -5- / i. iv.) oxy: ethyl. . '·. Ir.-tl -u.t'l) - -. · Ϊ́1.-ο: ·' .ί: ^ - ό € ηζοβ. ·? · Ν- (₄· &lt;Ι: ηΐ &amp; «· 1L ·. 1; -i iu. .-.- rl c 1 .. »after 1 -.ι ··! · 'c. ·. wrote'. 1 '-z rir.t lx: / lr&gt; .— x - (&gt; - ui iirc-i. -R.1.1) -öt ·' η iái r &lt;. '·· ^. Uv tuu&gt;., &amp; ..- JC s'. · ·. tt out · ttór.gut iehs &lt;lt_wu. ' . ··; ivA Al-cu i-setil protected c co_tExterminator. p / T -. (&lt;_#7—^! i. xⁱ&lt;? ti 1-4—. áo— '·, -r—— ili. ΓΟ'άΙχΛ '. · .. 1 ·^í. — I l — i- '111) - -'. 0 t - 1 — a &amp; i - ^, ^ 7-1 - / ^ - 111.02 ^^ 1-1- (3-111 ti'v-fenii). -eti ^ T-bonzhaidot U \ unk 7y. · — five 'HazZv «isis 1 (a tartat k *, 2&gt; skvivaleiu vxZőt oa ... ; p-4-? - (2,7-dimethyl-4-axo-3- / pivyloxl-uxl-av? / 3,4-dibydro-quinazoline as starting material? -6-yl-acetyl-methyl-methyl-t-beuzoessv-pentofluorophenyl-ester is prepared as follows: g G- (maleoethyl) -2,7-di-ethyl-3- (piyloxyloxy) &lt;tll&gt; &lt; -3,4-dihydro-quinazolin-4-one, 5.4 g of methylmethylamino) benzoic acid, 5 g of 2,6-lutidine, 5 A mixture of sodium iodide (mg) and dimethylformamide (175 mL) was stirred at 6 ° C for 26 hours. The mixture was cooled and diethyl ether and water brine was added. the organic layer was washed with an aqueous solution of nutrient chloride, dried over anhydrous sulfate and evaporated to give 16.6 g of helvunybams as a solid which was used for further purification on the wall.

To a solution of the product thus obtained in ® 1 with diacetate is added 13.6 g of pentafluorobenzene under ice-cooling and 16.5 g of alicycloesylcarbodiimide. the mixture is stirred at room temperature for 4 hours · the mixture is sued and the residue is purified by chromatography on z.silica gel · Aluulooarkuot '^, ριί, ρ volume of chloroform - wahanol mixture is obtained. solids solids dl; ethyl ether · lp, i &gt;&gt; £ »z-ct initial sink ·

P- / JU-1 zK-rum-α-s * t il-α-uxo-p * / 'pivaloyloxy 1-ae 111 / -, 4-tha uro-k i uú zuii uo i 1 - ae t (1) (pro-p-yl) -phenyl (b-benzoic acid) -phenyl-phenyl) -phenyl ester as described in the example 2-amino-2- (3-fluorophenyl) - After reacting with eu-nollsl, the product is pivalolated with 1-oxyethyl groups, the product is then decanted * p »- ~ - (- uruK-2-methyl 1-4-oxo), '+ -dibiaro-fiber. -6-11-me ti 1) -. * - (pr op-2- 90 -iniD-aai ng7^d 1-1- (3-n 11 r o-i en 11) -j 7-b φ this aid yields 61-oe of our image (the thermos contain 0.25 equivalents of water) | 221-232%.

m of starting material used were p-Ea-(7-bromo-4- -0x0-5- / plvalo-11-o * -methyl) -3,4-dlH-dichloro-zolin-6-yl-thi 1) --- (Prop-2-ynyl) -nyl-N-benzoate (pentafluorophenyl) ester is prepared as follows:

5.6 g of 7-bromo-6- (bromophenyl) -2-ethyl-5- (pivaloyloxymethyl) -3,4-diahydroquinazolin-4-one, 3.6 g of ter- butyl p- (prop-2-ynyl) - &amp; lt; / RTI &amp; gt; benzoate, 1.3 g of xylcarbonate and 266 l of diacetylacetamide are stirred at 6% or more by volume. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. &gt; ·. the organic phase is triturated with water, over MgS04 and stored. The residue was purified by chromatography on a silica gel column eluting with increasing polarity hexane - ethyl acetate. 3.5 g of solid are obtained.

5.5 8 A mixture of the crude compound, 50 µl of trifluoroacetic acid, 260 ml of ethyl ethyl chloride was stirred for 1 hour. The slurry was evaporated and the residue was triturated with diethyl ether. Ultrasonic distillate bean form 3.3 g of p - [(7-bromo-2-ylethyl-4-oxo-5- / pivoyloxy] -ethyl] -3,4-dihydro-k. z 01 i ub-11 -:;. til) (pro-p-2-ynyl) -a mi n ^ 7-be to oe se ve t is obtained.

The product thus obtained was mixed with 30 ml of ethyl acetate n-chloride and 2.0 g of penyl fluorophenol, followed by 3.2 g of dictclohexyl-xrodiodylBiaec sduni, and the mixture was stirred for 3 hours. brewed tec |, fz * flies are sued, and the residue is purified by falsification of silica fume with natalog, .ilual condom * 91

5% v / v toluene / ethyl acetate 2.55 8 white solid starting material is obtained.

? -Bromo-6- (bromo-α-ethyl) -2-thiophene-4-dihydroquinazole-4-one used in the above-mentioned rela? &lt;5 g of 3-bromo-4-cetyleniline were prepared as follows_t 400 el eeAtsev and 400 el diethylether with ice cooling and vigorous stirring 3? The precipitate was collected and washed with dtothylether. The precipitate was washed with dethyl ether and saturated aqueous sodium bicarbonate solution. the deer phase was washed with water Botsuk, dried over Na2SO4 and sued. The B8j 3d was purified by chromatography on silica gel eluting with toluene. 20 g 2,5-dibromo-4-netll-a ni Unt top.

To a solution of the aniline compound so prepared in 200 µl of acylacetate was added 3.5 g of catacetic acid anhydride followed by 6.55 µl of cat acid and the mixture was stirred for 3 days at room temperature. The mixture was concentrated and 200 µl of diethyl ether was added to the sera. The supernatant precipitate was collected and washed with diethyl ether. 16 g of 2,5-dibromo-4-cetylacetenilide «

A mixture of 14.5 g of the thus-obtained acetenylide compound, 6.35 g of copper (l) · -cyanide and 200 µl of B-Msatllpyrrolidin-2-one was stirred for 40 minutes at 150 ° C. The mixture was allowed to cool and Dilute aq. aqueous hydrochloric acid in 600 volumes of water. The precipitate was collected, dissolved in water and dissolved in 1 liter of acetylene chloride. The solution was dried over magnesium sulfate and the solvent was evaporated. and the residue was triturated with ethyl acetic acid. To a solution of 9.8 g of 5-bromo-2-cyano-4-methyl-eetanediamine in 15 µl of ethanol was added to a solution of the resulting acetanilide in 20 µl of ethanol. aqueous hydrogen peroxide (v / v) and a solution of 4 g of sodium hydroxide in 40 L of water are added * the mixture is carefully heated to 55 ° C, the reaction is heated and the heating bath is removed briefly · The mixture is stirred for 4 hours 55 And keep it at room temperature, and dilute aqueous saline solution were added · The bulk of the stanol was shoveled, ή the resulting precipitate was collected and dried to give 7.9 g of 7-bromo-2,6-dimethyl-, 4-dihydro-kinesolin-4 *

A solution of 1.9 g of sodium hydride (60% by weight mineral oil in oil dispersion) in 20 ml of diacetylsulfoxide in 60 ml of dimethylsulphoxide was added with stirring. Stir at room temperature for 1 hour · Add 9.4 g of a solution of chloromethyl pivalate in 20 ml of diethylsulfoxide, stir at room temperature for 16 hours · pour the mixture into dilute aqueous saline and ice, extracted with ethyl acetate · The organic phase is dried over magnesium sulfate and evaporated · The precipitate is triturated with hexane and diethyl ether, 6.3 g of 7-bromo-2,6-divalent-3- (cf. aloe-1-oxy). ae tyl) -3,4-dihydroquinazolin-4-one is obtained ·

A mixture of As is obtained, 3.2 g of N-bromo-succinimide, 0.1 g of benzyl peroxide and 300 ml of chloroform is refluxed for 6 hours, the As is evaporated and the residue is purified by chromatography on silica gel with 9: 1 as an eluant. volume ratio of toluene / ethyl acetate · 6.5 g of 7-br-6m-6- (bromoethyl) -2-methyl-3- (pivaloyloxyethyl) -3,4-dihydro-clnoline; We get 4 on · · ·

- 93 ·

24th Repeat the procedure described in Example 1 and Example 1, paragraph 1, and repeat the procedure for eating (-) - (2R) -2- »nno-2-phenyl-otanol as 2- (d-eaenobenzyl) -2 1-Methyl-1,3-dioxolane is used and the reaction mixture is stirred for 2 hours at 2 ° C.

A mixture of 0.9 g of this material, 7 µl of 1 N aqueous sodium hydroxide solution and 35 µl of ethanol was stirred for 4.5 hours at room temperature. The mixture is evaporated to dryness. The sera is added with 30 ml of water and the mixture is acidified to pH 6 with glacial acetic acid. The precipitate is collected, washed with water and dried. 0.23 g of the product thus obtained, 2.5. ml of acaton is kept at 45 ° C for 3 hours · The mixture is evaporated and the shreds are triturated with water · The solid is washed with water, and dried under reduced pressure · 0.12 g of p - [4- (2-tobyl-4-ozo-3,4-dihydro-quinazolin-6-yl-ethyl) -M-prop-2-ynyl] -axy-7-: .- (2-Oxo-1 * € enl 1-propyl) benzide (product contains 3.5 equivalents of water) | op. »164-169 ° 0 ·

OR spectral data (DKGO-dg) »2.0, lo (?, 5H, 0?)_?), 2.55 (s, 5H, CH3), 3.21 (broad a, 1H, chen), 4.33 (fibrous β, 2H, CH3), 4.82 (a, 2H, CH3), 5, 66 (d, IB, Cf fcc), 6.84 and 7.78 (a, 411, aromatic), 7.28-7.47 (? 5H, facial), 7.70-7.89 (a). , 2H, stream), 8.05 (δ, 1 → aromatic), 8.68 (d, 1H, CON CON).

xdmegspaktrua coucsértéto (+ iAB) »m / e (P + l) 479 · Analysis by ^c29^B26^K4⁰&gt; · 5.5 Hgu formula »calcd» Cj 64, JS, Hs 5.9%, Ν »1.4 4 found» Ct 64.5 Hl 5.6%, Si 1.5 h ·

The 2- (α-eanobenzoyl) -2-ethyl-1,3-dioxolane used as starting material is prepared as follows.

15.1 g phenylglycine, 100 ml acetic anhydride and 1G0 ml • · ·

until the gas evolution ceases, the mixture is pulverized, the residue is added 300 ml of toluene and the resulting mixture is concentrated to 200 ml of aq. hydrochloric acid solution and Reflux for 4 hours · The mixture is evaporated and the sera recrystallized from ethanol · 9.19 g of l-aaino-1-phenylpropau-2-one hydrochloride kpanki op * t 204-207¾ ·

A mixture of the product thus obtained, 3.4 l of ethylene glycol, 12 g of p-toluenesulfonic acid and 500 l of toluene, is heated under reflux for 3 hours under a Sean-Otark water separator, and the precipitate is collected.

11.7 g of crude starting material are obtained in the form of a salt of p-toluenesulfonic acid.

Nuclear Magnetic Resonance Spectrum adstal (n₆) t 1.09 (a, 30), 2.29 (s, 3d), 4.02 (a, 4Γ), 4.43 (a, IB), 7.12 (d, 21% 7.4) -7.6 (a, 7H), 3.33 (broad s, Jh) ·

In the same manner as in Example 24, «2- (η-« η1ηο-4-chloro-beu211j-) is substituted for 2 - («- aino-benzenesulfonyl) -2-ethyl-1,3-dioxolane. 2-set) -1.3-41 xolin are used. N- (X- (4-Chlorophenyl) -2-oxopropyl) -p- [N- (2-ethyl] -4-oxo-3,4-dibydro-pentazoline-11-yl-ethyl). -l- (prop-2-ynyl) -aaln_&lt;p7-benzanide (4 equivalents of water is stored) is obtained at from 10 DEG to 19 DEG-19 DEG C.

The 2- (o-ialno-4-chlorobenzyl) -2-ethyl-1,3-dloxolane used as starting material was prepared as described in Example 23, except that: o-Anino-4-chloro-phenylacetic acid is used in place of phenylglycine · The desired starting material is prepared in the form of its p-toluene-sulfonic acid salt • 95 bon sputum with a 47 6 · Spectrum (D ^-dg), l, Go (a, 5i), 2.29 (a, 3E), 5.95-4.06 (®, 4i), 4.56 (a, lh), 7.10 (d, 2a), 7.44 -7.6υ (m, 6H), 8.55 (s, 5H).

Example 26

1.08 g of N- (2-ethyl-4-oxo-5- (pivololloxymethyl) -3,4-dihydro-quinazolin-6-yl) -yl- (prop-2- inyl) -alkyl-7-benzoic acid N- (ponteflaor-Rhenyl) -ethers, 0.56 g of (4 g, 5 g) - (O-5-omino) -2,2-diethyl-4-phenyl-1,5-g. a mixture of dioxane, 1.2 µl trio-methylamine, 065 g N-hydroxybenzotriazole and 50 µl ethyl acetate was stirred at ozobic temperature for 72 hours. The mixture was evaporated and 0 residue was triturated with hexane to give a white solid. wash with food ·

A mixture of this worn material, 15 µl of a 2 ft aqueous azo solution and 15 µl of target was maintained at 65% for 5 hours. The mixture was evaporated and the residue was partitioned between otylacetate and water. The organic phase was dried over Na2SO4 and The residue is purified by chromatography on an azilegel gel using increasingly polar mixtures of methylene chloride and ethanol as eluant to give 54 g of a solid.

To a supernatant solution of 5 ml of ethanol in ethanol, 20 ml of ethanol saturated with anhydrous gas are removed and the mixture is stirred at room temperature for 48 hours. The mixture is evaporated and the residue is triturated with diethyl ether. 1S, 23) -1,8-Dihydroxy-1-phenyl-pro-2-yl-7β- (2-ethyl-4-oxo-5,4-dilaidro-quinazolin-6-yl) yl ) -i- (prop-2-ynyl) * ®^the 7-Benzenide is obtained (product contains 25 equivalents of water) m.p. 210-212% · tR &amp; lt; + &amp; gt;

C = CH), 2.57 (·, 5 → h CHj), δ, δ -5.92 (m, 2H, C ^H), 4.17 (d, 2H, HHjCl), 4, 55 U, 1H, ΚΕΰφ, 4.76 (s, 2H, CH2 N), 5.11 (d,

III, Gjytti), 6.8 * 7.65 (?, 48, aroma), 7.20-7.48 (m, 5 &amp; amp; aromatic), 7.70 * 7.85 (?, 2H, erao), 8.15 (d, 1H, aroma).

XuB6 £, peak value of spectraB (+ o): s / e (1 + 1) 497 «

<img file="HUT57739A_D0029.tif" />

calculated for G 69.5 H1 5.7 and 11.2 M found Cl 69.4 L, H 5.5 L, B11.4 L.

27th Example p-££ - (2,7-O-1? - 111-4-oxo-5 * / piv® lo-1-cu lset! 1? -3,4 * di hydroquins »olin-6 * yl * Methyl) -1- (prop-2-ynyl) -ammongg in 7A as described in Example A (A) - (5-nitro-9-yl) -glycine-1-methylsulfonyl-R tuiu responded to you. 11- / 2,7-dlaet 11-4 * oxo-5,4-dihydroxy-1-n-6 * 11 -methyl-1 H -proph-2-yn-1-amine ) In an oil (22 * n-trophenyl) -glycine-h- (not sulfonyl) -aa (product containing 4.5 equivalents of water) 22% of hosastmal op. 242 °. (diethyl ether rubbed with utu).

0.5 g of N - (4-oxo-2 * / pivaloyl-η 5 -5,4-dihydro-quinazol-6-yl) -atyl) -α- (prop-2-ynyl) -emine₁N-Benzoyl - (pent 3-fluorophenyl) ester, 0.2 g of 2-alkoxo-2- (5-nitrophenyl) -otoluene trifluoroacetic acid salt, 0.41 ml of triethylamine and 10 ml After stirring for 48 hours at room temperature, the di-di-1-sulfoxide mixture was concentrated, and the pellets were purified by chromatography on silica gel using ethyl acetate as the eluent. 0.55 gives 6 pale yellow oil.

A mixture of the product thus obtained and 2 L of aqueous sodium hydroxide solution was stirred at room temperature for 16 hours. The reaction mixture was evaporated and the residue was purified by reverse-phase chromatography on silica gel. excellent polarity as a scavenger: methanol - water - trifluoroacetic acid &lt;. flies, the resulting solid was reduced to p.l.5 by addition of 5 µl of wax and the mixture of the mixture. The mixture was filtered and the solid was washed with water, vinegar and diethyl ether. 0.12 g of p- [4- (2-aalno-4-oxo-3,4-dihydro-ethylsulfanyl-6-yl-ae] -11) -O- (pr j; -2-IndiD-eaii ^ -yl); N -hydroxy -1- (3-nitrophenyl) was added to the oil (containing 8 equivalents of sodium chloride) at 236-240 ° C.

KUií; upektrun data (βόον-αθ) * j, io (s, 1H, csjj), 3.65-3.75 (a, 2H, C C óH), 4.3 · (broad s, 2á_f chg / .r), 4.71 (s, 28, g «₂10, 5.08-5.18 (a, 18 »qyui), 6.84 and 7.78 (a, 4H, aromatic), 7.25 (d, In, aromatic), 7.55-7.67 (η »2Π, aromatic), 7.78-7 * 9'0 (a * 2H, aromatic), 8.09 (d, XH, aromatic), 8.26 (wide a, III, aromatic), 8, 52 (d. Á, C ^ «ak ak ak ak ak ak ak ak ak ak: alapján alapján 141 141 141 141 141 141 141 141 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^: ó 15 * 0; »| found: vi 58.2 -α, Ixi 4.1&gt; = ·, JSi 14.6, α used as starting material for ρ-Τ-((4-oxo-2- / pivaloyl anino / -5,4-dlydro) -insinol-6-yl-2-ethyl) -N- (prop-2-ynyl) -phenyl-benzoeave (pentafluorophenyl) -ester is prepared as follows: g 6- (bromo-ethyl) -4-oxo-2 - (pivalol-alpha) -3,4-dihydro-quinazoline (J. Therm. Chem. 12). 128J / 1975 /), 12 g of p- (prop-2-ynyl) -amino-benzo [t-tert-butyl] ethyl ester (Compound No. 239,362), 4.87 g of 2, A mixture of 6-lutidine, 0.25-8 sodium iodide, and dinethyl ether was maintained at 5 ° for 10 hours. As solvent

98 were evaporated and the granules were triturated with 10 * 1 volumes of ethyl acetate / methylene chloride and the resulting solid oil was extracted with ethyl acetate. 15.18 g of p - [(4-oxo-2-yl) -1-en-1-yl] -5,4-dl-hydroquinolazin-6-one. 11-ae (111) -N- (prop-2-yl) -amino] -7-^,benzoic acid tert-butyl ester.

A mixture of 3.5 g of the resultant compound, 15 ml of trifluoroacetic acid / Ipw al mephelic acid chloride is stirred for 4 hours at room temperature. The mixture was evaporated and 5 residues triturated with 4 x 1 volume of diethyl ether / ethyl acetate · the supernatant was washed with diethyl ether · 7.1 g of p - [4- (4-oxo-2- / piveloyl-8-amino) / * 5 »4-dlhydro-quinazoline ~ 6-ll-me 111) -Mprop-2-1 ni 1) -a ski-7-beuz oe sa ve tk» peak · spectrum edatat '1 ^ 53- ^) t 1, 25 (·, 9H, C C), 5.21 (t, 1H, G &amp;O), 4.55 (broad, 2H, 1 H, C), 4.79 U, 2H, Hg), 6.8 -7.3 (12, 4H, aromatic?, 7.49 (1H, m, aromatic), 7 »7θ (1H, □, erotBis), 7.95 (1H, d, aromatic) ·

The resulting benzoic acid derivative B-S2, 2.25 g of pentefluorophenol, 2.11 g of trlethylsine, 48 ml of ethyl acetate in 45 ml of di-ethylsulfide was added to 1.95 g of dicyclohexylcarbodiold. a solution of dimethylsulfoxide was added. The mixture is stirred for 2 days with 2 g of room-shaker teas · The mixture is evaporated and the crude is taken on silica gel^&lt;5fcfe The polarization was performed using hexane - ethyl acetate blankets of increasing polarity. 1.22 g of the desired starting material is obtained in the form of a white bet.

0.05 g of p- [4- (2-methyl-4-oxo-5,4-dihydro-quinazoline-6-11-me111) -A- (pro-p-2-ynyl) -mino] -K- T— (5-tro tro 1) -2—

Cl, 2.4 »triez01-5-yl^wFor a solution of 0.5 ml of dinethylfenonide in 0.01 g of a-chloro-perbenzoic acid (60%), · · · ···

- 99 ml of thiazide-type salt (0.5 g) of a dilute solution of the phosphatic acid solution is added dropwise and the mixture is stirred for 3 hours at 320 ml of salt. The mixture was evaporated and the crude residue was purified on crudeosephalic oil. Polyethyl chloride - methanol · acetic acid, growing in polarities as a result of falling rain. 0.046 g of pZ ^ (2-wetyl-4-oxo-3,4-dihydro-chloro-3011n-6-yl-1-yl) -4- (pro-pS-inyl) -N- [4- (3-yl) methyl] -N -phenyl) -2- (1,2,4 »-trisao-3-11-11-83uIXinyl) -ethyl-7-benzamide (eq. water, 1.2 eq. plan and 0.2 eq. diethyl ether in t ); mp 182-193 ° C.

KK3 spectrum transducer (Dddd-d6) t 2.34 (a, 3H, CH2), 3.03 (a, u,, 3.73-4, · Ό (® ·, 2ΰ, C »^)¹-¹-), 4,&gt; 4 (e, 2Ii, H. J ^ gC-G),

4.79 (s, 2H, atCH₂: 0, 5.30-5.45 (a, III, C&gt; H), $ 7.8 (a, 26, aromatic), 7.52-8, oo (a, 5H, aromatic). 8.01 (a, 14, sroaaaa), 3.14 (a, IU)_S Eauau), $ 3.2 (e, 1Π, srosds), 3.73 and 3.31 (2a, 1H, Erosa), 9.0 (a, X4 »···. *

Mass (+ FG.B) peak mass spectra (? # 1) 611.

Sleaaéa ® c_x elepjaam aananototti C 55.5 H1 5.1 g, 4s 15.6 d; total I Cl 55.2%, Hl 4.7 Á, 41 15.2% ££ z ·. 1g p-£ T- (2-aet 11-4-0XO-3,4-dihydro-indole-6-ylmethyl) -4- (pro p-2-in 11). · N-ZT * (3-d &amp; lt; c &amp; gt; 1) -2- (1,2,4-triesol-4'-yl-t'cO-ethyl-t'-beazamide, 2 ml of dimethylformamide) ®, a solution of α-cl6r-parbonzoic acid (purity of 60 d-oc) in 1L of diacetylformamide was added dropwise and stirred for 3 hours at room temperature. To the mixture was added 0.04 g of a-ul per-hour benzoic acid and the mixture was heated at room temperature for 3 hours. the bones are evaporated and the gift is reversed phase, this illtogol crore, rs £ ulv &amp; ttoatitit, · decreasing polio as a coolant. A mixture of tenol - water - trillouracetic acid was used. The λ-topped fractions were further purified on ethyl acetate using chromium-to-silica gel, using an increasing amount of polyvinyl alcohol, using a mixture of ethyl-n-fluoride-methanol-acetic acid · 056 g ρ - ^, Γ- (2-αβ til-4-oxo-3). , 4-Dihydro-quinazulin-6-yl-methyl) -prop-2-ynyl) -emino-5 ', 5'-5'-phenyl-2-enyl) -2- (1,2,4- tri (zol-3-yl-azulonyl) et al

of benzoic acid (volume * 1.2 equivalents of acetic acid and 1.4 equivalents of trifluoroacetic acid tartrate) | mp 24 ° -251 ° C.

hkit spectral data (DMwv-γ g) δ 2.32 (a,&gt; H, µl),

3.17 (a, lü, C ^ olii), 3.7'3 (n, iii, · 4.06 (a,

4.31 (β, 2H, auxig), 4.77 (s, 2H, Cxig), 5.5-5.63 U, 1H, 1CH), 6.65 and 7.67 (a, 41i, aromatic). , 7.5-7.6? (a, 34, arozo, 7.97 (β »14), 3, o6 (d, 14, reporting), 3.21 (a, III, aromatic), 9.04 (d, 14, Cuito), 12 , Arc (wide 3, IH, chin) · loskgspetoram peak (+ * '^ 5) sm / e (· ♦!) 627 · • essence 3 ^ 30 ^ 26 ^ 8 ^ 6 ^ * ΟΉ ^ νΟΉ · 1.4 The formula is based on the formula: vi 49.2 x, uL 3.3 Ai 13, l found Cl 49.5 ~, 4 «5.0 M, in 12.9% ·

31 · example

1.28 g of p-1T- (2,7-di®-ethyl-4-oxo-3- (pentyl-Dxi-motyl) -5,4-thiourea-Kiazol-6-yl). prvp-2-ynyl) -7-benzoic acid, peutofluorophenyl ester from the corresponding benzoic acid derivative and _tveg prepared from entolluoro-1'-enol according to Example 9 9 starting material_wovernight, v, 73 g of 10-nitrophenyl) -2- (1,2,4-trisol-3-ylthi &amp; lt; / RTI &amp; gt; ethylamine-trifluoro-acetic acid salt, 2.02 g of triethyltin per year in 15 ml of diethyl ethyl -azuixoxide ^ is beaten for 10 hours to aububiomycrs «n to • · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

The mixture was evaporated and the residue was purified by chromatography on silica gel. The increasing polarity of our cleaving slurry was followed by extraction with ethyl acetate - isopropanol to give 0.474 g of oily ®.

A mixture of the material thus obtained and ethanol saturated with 15 ml of ammonia gas was stirred at room temperature for 24 hours, and the brains were evaporated and the residue was triturated with Ser. 0.382 g of p-Z, N- (2,7-diacetyl-4-oxo-3,4-dihydro-quinazolin-6-yl-ethyl) -α- (pro-p-2-ynyl) -amine. - T- (3-nitrophenyl) -2- (1,2,4 * tri-thiol-3-ylthio) -thio-7-benzylate is obtained (contents of 1 equivalent of water) | mp 219-236^ü8.

m spectral data (D 6 S -d 2 H 2.30 J 2.43 (2a, 6xi), 3.16 (1 H) t 3'45-3.70 (a, 2H), 4.26 (s, 2H), 4 , 66 (a, 2H), 5.49 (a, lri), 6.3-8.3 (n, eu), 3.45 (aze, 1H), 3.9 (a, 1H).

principal time spectrum eanesvalue (* xaB) ig / e (141) 609 ·

Memories of the ^ 51 ^ 28 ^ 8 ^ 4³ · ^{i £}2^Ű Calculating the Formula Formula δi Cl 59'4 ^, Hl 4.8 a, Bolt 17.9 -4 finds Cl 59.9 A, Hl 5'3 bar 18.1 .v.

52nd example

0.14 g of N - (2,7-dinotyl-4 * oxo-3 '- 4-dihydro-quinazolin-6-ylmethyl) -1- (prop-2-ynyl) -α, 7'H- T- (3-yl-trophenyl) -2- (1,2,4-triaeol-3-ylthio) -ethX7-benzamide was prepared as described in Example 29 with eserine 0.066 g of n-chloroporobenzoic acid (6 _{/ I}of purity) is reacted · The crude product is purified by chrometrographal chromatography on rewrs phase silica gel, eluting with 50% v / v of a mixture of netanol / water / trixluoroacetic acid. mixtures are used · 0.074 g · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 12 - {4 - [(2'-7-di-6-yl-4-oxy-5,4-tetrahydro-quinazolin-6-yl-ethyl) -4- (prop-2-ynyl) -min] -h- T- (5-trinophenyl) -2- (1,2,4-triazol-5-yl) -vinyl] -ethylbenzamide was obtained (0.75 equivalent of water and 7 equivalents of trifluoro). -acetoavst-containing) · spectral data (Ιλ4Λ-α $) ι 201 and 2.45 (2e, 6h), 5 * 19 (a, 1K), 5.65-4.0 (m, 2H), 4.2 $ (a, 2H), 4.68 (a, 2n), 50 and 5.6 (2a, 13), 7.6-00 (m,)),,, € and 80 (2s, 13) ·. ^ 51 ^ 28 ^ 8 ^ 5 ^ * 6.75 ^ 2^υ C = 54.2 -, 3: 4.2 fis 150 M found: C: 54.6%, il: 4.6, h, 15.4.

2AA ».26íMjlfi

0.15 δ p-4 * - (20-Dimethyl-4-oxo-5,4-dibydro-quinine-quin-6-ylmethyl) -1 * - (pro-2-ynyl) -amine 7 * N- [4- (5-trophenyl) -2- (1,2,4-triazol-5-H-thimethyl) ethyl] benzide is prepared as described in Example 50. In Example 1a, the slurry was reacted with u, 142 g of m-chloro-parbansoic acid (6% purity) for 6 hours. The crude termus was purified by chromatography on an insect on Xuzisu silica gel, eluting with 551.4 / to, 2 tériog®tsranyu methanol. - water-trifluoroacetic acid mixture · 0.065 β- [4- (2,7-diethyl-4-oxo-5,4-dihydro-quinazolin-6-ylmethyl) -O- ( prop-2-lnyl) -aaina7 * -λ- £ Ϊ- (5-ni tr o-Ce n 11) -2- (1, 2,4-Triazol-5-yl-1-sulfonyl 1) -N-benzamide is obtained in the form of the product, 75 equivalents of water and 7 equivalents of triXluoroacetic acid. ud ^): 2.5j and 2.44 (2s, 63), 5.19 (δ, 1 * 0, 5.6-4, u (m, 26), 4.27 (a, 2H), 4.69 (· , 23), 5.62 (β, 1M), 6.8-00 (a, self), 8.77 (s, 1H), o, 84 (d, 16).

Tütog Spectrum c ^ ucs TteK® (♦ ixb) 1 m / e (r + 1) 641 · • «• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··

The compound of formula (1) and / or

1-5 Pharmacologically Available Drug Formulations Containing Dropable Drugs of the Invention The following examples are provided for the composition of the present invention.

.._;fíktö3 (th.-ur. Quality) hr oaz would ask for 11 oz at riue

Maize starch (5 wt / vol · ob pulp) IZegnéz i us s tea rut (b&gt; MU &amp; líW active ingredient hoctose (ah «our · Quality)

Ro as kame 11 óa-ná tr iua

t. u tor ics ke® and ny it

Ρϋ11 (vinyl pyrrolidoo) (&gt; m / v% by weight) &amp; aguÓ3iua-3öte &amp; rut

Lettose (rh. .4ur «quality) hro str 1 se zr, tr lua corn hard ItÖ (5 wt / vol ·.-Oe paste)

Megnésiua-ssteerát

Hetóeuyeg

Lectose (rh · our. Olcőeégü) scars iua-azte c-rat

100 mg / teblatta

182,75

12,0«

2,25“

3.0 mg / tablet

225,75

6,0«

15,0

2,25“

3,0

1.0 µg / tablet

93,25

4,0 *

0,75

1.0 µg / capsule

48, 5 * '

1»5

agent

5.0 working hours / ter. % • · • · ··

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IC4

1 µl of an aqueous solution of nutriamine hydroxide&gt; 1 N or 2 volumes (up to pu 7.6). was (ethyl-gly-1 (h «4o))

15, - square £ / terf. %

4 »&gt; w / v ·% injection for injection Int a water ad Ioo l &amp; volume

Sodium xylacetate (B1-quality) o, lh aqueous sodium hydroxide solution, water for injection, 1.0 w / v. %

3.6% w / v *%

15.0 space · / volume *% ed ΙΟ. λ

U) L-BK / al .., ¾ ^ ....... Uh injection:

<td>detóeaysg</td><td> ^.1</td><td>lake Mg / volume ·%</td>

<td>-ncrius-shred (3 quality)</td><td> 2,26</td><td>w / v. €</td>

<td>Cltrossav</td><td>, 3o</td><td>w / v. %</td>

<td> ol-ethyl-giitol (A «4uj)</td><td> 3,5</td><td>w / v. %</td>

<td>Injection c ·. for horses the lka lse is water</td><td>ed lo; 1 »</td><td></td>

- fsntl put together a bunch of medicine for your medicine: ological methods · Wanted eescbsa at^cFor example, an enteric coating such as a cell Loz-scetec-X'Tel would be applied to a vinotin.