HUT54492A - Process for producing lysyl oxidase inhibitors and pharmaceutical compositions comprising the inhibitors - Google Patents

Abstract

Halogenated alkylamine derivs of formulae (Ia) and (Ib) and pharmaceutically acceptable salts are new where X=Y=Cl or Br; or X or Y=H and the other Cl or Br; R1 = H or 1-4C alkyl; A=-(CH2)m-CHR2-(CH2)n-, -(CH2)p-D-(CH2)q-or -(CH2)r-CH=CH-(CH2)s-; R2=H, Me or Et; m,n = 0-16; (m+n)=max 17; D = 0 or S; p = 0-16; q = 1-16; (p+q) = max 17; r = 0-16; s = 1-16; (r+s)= max 16; and R = Me. - The use is claimed of (Ia) or (Ib) or salt for prepn of a medicament for treating diseases and conditions associated with abnormal deposition of collagen, or for inhibiting lysyl oxidase, where the definitions are extended as follows, X=Y=F, Cl or Br; or X or Y = H and the other = F, Cl or Br; and R = Me, Ph (opt substd by 1 or 2 of 1-5C alkyl, 1-5C alkoxy, 0H, Cl, Br, F, I, CF3, N02, 1-5C alkylcarbonyl, benzoyl or Ph), 1- or 2-naphthyl, 1-, 2- or 3- indenyl, 1-, 2- or 9-fluorenyl, 1-, 2- or 3-piperidinyl, 2- or 3-pyrrolyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-indolyl, 2- or 3-thianaphthalenyl or 2- or 3-benzofuranyl. - Prod is claimed comprising penicillamine and (Ia) or (Ib) (with extended definitions) or salt, as a combined prepn for simultaneous, separate or sequential use as above.

Description

Collagen is Mr, Inak, Bone, Cartilage and Protein of Logfépfc of Knitwear, Aoloka of Collagen *

• ·

• 2 · leaks can be described by the alpha-clavicle wall-stepping, back-to-back structure, each collagen molecule has a circular arc of 300 na hoaazu and a circle of 1.5 na. in the aole of your end na ·• tanai · paptidsk you have naval groups · • that prakurzer pro-alpha lenes for the tor ·! MS · driven paptide asiathesia to the left of the flbroblasase. «Zak a pro» al * a «lones are formed first of all by intracellularly triple-soluble procollagen aolacules, then the proline and lysine groups are hydroxylated, then glycosylated, the secretion tarene on the procallagene • olecules after collagen, it is organized into rocks and then reats, the strength of collagen both within and between the fibers · between the different lysine groups · is determined by the kareate binder · the cortex-linked tree · the oleate step · the lysine and hydroxylzine group daxamination of the axtracolluler with lysyl oxide, thus forming · hydroxy groups · These highly reactive ·· oaa · anthers form the karate bonds, the amount and type of the caraestes vary greatly, with the formation of different types of tissue · blocking the formation of karate bonds, then aa more belts *

- 3 * thin loez to emeok on aogfelolt easily elongated · fisásoe vulture would ask to quit for lack of capable colleague crosslinks, watch out for thlare-uanloe syndrome in marfan toc indroena in conditions characterized by the problem of collagen metabolism and in diseases such as differential fibrotic conditions such as tgdö fibrosis and prolimotiv vitreo retinopathy in surgical wounds; inhibitors are known, for example, m penicillmmln ee · bota-eminoprep · milk nitrile (öapn). known as BAHw, gall bile <l * laccioan prevents the sniffer band * because it can block 11 · zil exidase. Both peniolllamlnt · and 8APN ·! have been studied extensively in your stomachs and people · how they work in conditions characterized by abnormal collagen deposition · presenters of ezabmtol · have discovered that certain halogenated allylemines inhibit the function of o lysine oxidase to you · are useful for abnormal collagen In the treatment of diseased diseases and diseases

• «• · ·

The compound of Formula I or IX is ··

X-C-Y II

R-C-ChgMMRj

X-C-Y

II

II • In which

X ye mean ·· exonee ye Anything can be: • damage to fluorine · get out of one of the hydrocarbonsMCto · * or x of the sky in Y · · ye · other fluorine * get out of one of the breo · • tOM | judge ·· hydrogen ·· buy 1-4 eaene · * • ancient elkeperté mean ·· ·

I (CHj) can be derived from bepert by the formula of formula # 2, meaning # 2 represents ·· hydrogen ··, «« a bridge group or • a bridge group, and the value of one year is equal to two times, so * ♦ · should not be greater than 17 ·> 9 - ••• where o is the value of the current sulfur · p · y · 16 Today's total ·· q value · 1 yo 19 · · Provided · tip · * η should not be less than 17 years • (CMg) _r -CM-CH- (CHg) _s ••• • value is 1 ye to 16 yrs all of this is * y 16 hands all this ·· with this condition * the r * e value of the tip * may be greater than 16 ye · k · · · · · · · · · · · · · · · · · · · · · eeepert the hands of those who made it

1 * 9 years ago elkileeepert · 1 * 5 years ago ·· elke «i * eeepert · hierezi-eeepert · out · bre ·· fiver chemical · triflver-ethyl · nitr ·· 1-5 years · · zeeev elkile * kerbenyl · Beesel! chemical phenyl eeeperti

What is the meaning of ·· 1 * buy 2-eeftll · 1- · 2 * buy 1 * «iMtenlli 1 ·· 2 · buy 9-flverenl! 2 «chemical 3-plperléinili 2 · chemical 1 * red111 2» chemical * 2 non chemical

1-furanyl 2 * chemical> * lMeUl | 2 * buy MieeeftUenUi • · · *

«G α»

2 · or SMMnzofuranyl «sepert ι or an acceptable salt thereof.

Λ UAÜKitU ttMlIXM, AUríM as A «vsl denotes the value groups marked · Heifer example -GM ^ _f - (CHjJj-.

<Χ | 8 · (Ο ^) ₂ ·, -CHjjOÍCKjJj- and «at« GM ^ | ·· AS * <· »alkenylsubstituted alkyl * alkcfojoséo means straight-chain alkylated alkU * coopcrt« Examples of carbonyl-lower alkyl groups astyl · »ethyl» n »propyl _# isopropyl · n * tnityl« isobutyl, tero-isttyl, and fwpestyl moiety · as * ι · 5 alkene * osskclephee means straight chain branched al · kCKlM & euport · to 1 · 5 carbon atoms examples include setesl »etesl» n-propoxy, isopropoxyl »n-butOM1, isobutos and n * pentesl, the term s * 1-5 carbonyl otososee alkylcarbonyl * joloétéco alnd straight aldogase carbonyl carbonyl cooper acotll, propionll and rwbutirll group »

In the case of the azeocarbs, it is obvious that the compounds of formula 1 have one or two double bonds, so it is possible for the goosetrlal isomerism, for example, in the saccapath of the allilaain · and if present in the ssapsrt alsfl * »

- For compounds of formula 7, the prefixes "(£ j ^w éa" (1) will be used in the usual manner · to denote the storeocele of the cotyledon * If a nucleus is given «ttorookoal · then • it may be derived from certain isomers · eind may be · In compounds where x and Y are represented by one fluorine · Exposed to a bromine atom · The other is a hydrogen atom, these are preferred by the patentee, in which the balogenetom cysteine is present in the lead to the * K or · α · κ group compared to the compounds of the present invention, all of them are sold in the form of free beige salts, eav additive salts are simply more convenient to use, and in practice, the amount used in the barley form is more than the amount used in the sabod base. * Pharmaceutically acceptable acid · • Addition salts ** is a term used in any natostatic · 1 is applied to the organic or eaer · vstlon eav * addleione salt of the parent compound of formula (II) · examples of the corresponding salt · inorganic acids are the hydra · chloride · hydrebroald · sulfurea and phosphorous acid and the metallic acid oats as well as the sodium monofosregate · and my caramel »hydrogen» osulphate · characteristic organic constituents of the corresponding salts mono · dl óo tri *

• β · carboxylic acids * Examples of such ·· * aoat «av _t glltealaav * t« j ·· * »· ζ010 ·· ν * aalon ·· ** b» ro «tyánkéaav * glutar · acid * phonor · ** nalaneav * berki ·· * »cltroa ·· ** aazkar» b & n ·· * »« aleln ·· * »hldroxi-« sX «ln ·· ** benzoa ·· ** hldroxi · • at ···· *» phenyl · ·· tea * · cinnamon ·· * · salami · · * <· 2 * • f «noxl * b« nz ···· * · Hey ·· «« gfelold «wes · * able« «« rvo · •• Blind · Sulferoic Acids * alike a «t ^ trozulfoncav edge · 2» hldroxb »« tansulfone ·· ** tz »kinds aind hydrated ·« ind JOtyogébon vlaaant · # able to see in your forehead * You can set «tocksdanderd« with odeMers · 1ά «for example» get • exabad bizeté water or w * »s« in alcohol * solution * or ··· in Aegel solutes * aaoly cakes ·· ** z «used eava, isolate with evaporate solution * or the free base organ ·· in solvent ·· gelled * aeely eeet the a directly precipitates · Or · «can be obtained with a solution concentrator * the present invention is * * rintl« «» · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · crystals ·· materials * are soluble in water kVariously hydrophilic organ ··· the wedge for the zabod base phosphor has a melting point and a soluble branch, which are examples of the 1 general ·· formula Jellas

2-isobvtil «S ~ flttor ·» chloro »or bromo ** allila« ilni 2 * lzopropi.l * 3 * f luor · »out or br * allllaaln ι • · · · · · ··· ·· · · · · · · · ·

2- (9-octadonoyl) -3-fluoro-chloro or bromo-allUMH-2- (1-netll-S-butan-11) -3-fluoro, chloro or bromoall * amine}

2- (4-aetH-2-butoneH) -3 * fluoro-chloro or bromo

2-aa «k-butyl-3 * fluer * chloro or bromo-allHsain | 2-butyl * 3-fluoro, chloro, or bromoallyl allain 2-oxo-H-3-fluoro-chloro, or bromo-allyl Hsain> 2-hopt11-3-fluoro · chloro · or bromo allylanin> 2-otoxlaotyl-3-fluoro ·· chloro · or bromoallyl allyl 2-thloatllaot11-3-brotherly · chloro · or bromoallyl allyl 2-fanll-3-fluoro · chloro · or bromoallyl allyl 2- (2-Methyl-fanyl) * 3-fluoro-chloro or bromo-allyl 2- (3-ethoxyl-fanyl) -3-fluoro-chloro or bromo-allyl | 2- (4-AethoxyphenH) -3-fluoro-chloro-or bromo-allyl 2- (2,3-dinatxxi above) -3-fluoro-chloro or bromo-allyl)

2- (Bv4-dl «otoxt-above) -3-fluoro-chloro, or bromoallyl allyl

2- (2.9-Dlaotoxyphenyl} -3-fluoro, chloro, or bromo-allylanin

2- (2-E-dlnatll fontl) -3-fluoro ·. chlorine ·, or bromo-all llaalm

• w ·

2- (3 «4-dlaat« xl-fanil) -3 * fluoro- · chloro · v * gy brom · * - · 1111 ·· 1η »

2- (3 _f S -dl »stexl * fanyl) -1-flMr-chloro * or bromo * -allallaaln;

2- (2-bXdroxy-f «all)« 3- * la «r- · chloro. or bro · -

- • llllaaln;

2- (3-hydroxyphenyl} -3 fanll «F _t · chloro or bróa- • llilesin;

2- (x-hydroxyphenyl-3-fluoro, chloro or bromo)

- • ·· in 1111;

2- (2 * 3-Dihydroalanyl) -3-fluoro-chloro or bromo-allyl Hasin;

2- (2,4-dihydroxy * fanyl) -3 * flt »ar ·· chloro * or bromo * allyls;

2- (2 _', 5-dihydroxyphenyl) -3 * fluoro-chloro or bromo-allylene;

2- (2.6-dihydrexl-fanyl) -3-fluoro-chloro or bromo-allyl;

2- (3,4-dlhydrexl-phenyl) -3 * fl «idr- · chloro- · or brto- • 1111 ·· In;

2- (3 «S« dlhidrexl-fanll> -3-flaer- · chloro or bromo »· - • lilMln;

2-fanil-3 * 3-difluoro ₍ dichloro-or dibromo-amine);

2 * (2-Mtaxi «fanyl) -3« 3 * difluoro, dichloro or dl *

-brá-allilM in ι • · · • «

2 * (2 * «ataxlfaall)» 3 »3 * dlfliMr ·· dlchlor ·» or dl · bréa «allilaalni

2 * (4 * aataxifanll) * 3 «3« dlfliiar * ₉ dlkldr · »or dlbré ·· • 1111 ·· in i

2 * (2 * 3 ^ 1Mitaxl «fanll)« 3 »3 *» dlfluar ·· dlklér »·· or dlbróa-ellllMln i

2 «(2» 4 ^ 1 * ataxl «fanll) * 3 _t 3Mflflvar ·» dlkldr ·· or d IbrdaMill ÜM In i

2 * (2 »S * dlaataxl» fanll) «3 ₍ 3 * dlfliiar · * dlkldr ·, or dribble« «allilaaini

2 · (2 «βΜΐ1 ·· ΐ · χ1 · # · η11) * 3,3« dlf luor *. dlchlor · * or dlbréeKHill llMln i

2 «(3 * 4 * dlnataxi * fanll)» 3 * 3 * dlfl4ter ·· dikldr · * or dlbróa «» «lllla» ln i

2 * (3 »5 * dlaataxl» fanU) * 3 «3 * dlfliiar ·· dlkldr» «or d ibró« * all 11 ·· In>

2 »(3» bldraxl * fanll) * 3 »3 * diflaar ·· dlchloro ·· or dibro« «all11 ·· in>

2 »(3» hydrexi »f * nil)« 3 «>» difluor ·· dichlor · or dl · bréa ~ allila «lnj

2 »(4« hldraxi »f« nll) «3» 3 * dlfluar ·· dlloro ·· or dl * bro ··· !! Ha · in i

2 »(2» 3 <»dibldraxi« fanll) «3.3 * dlfluar ·· dlchloro ·· or dibro» * allllaain i • ···· · ······················································································

2- (2 · 4-43ΐ * 14 ^ χΑ »ίηηΗ) -3» 3 »41flaar- · tflachlor * · or dibro-allllaain ι

2 * (2 _t S * 41iil4raxl * faiiU) * 3 »3 * 41flaer * · old chlorine * · or dlbróa-all Haaln ι

2- (2,6-dlhydrexyphenyl) -3 »3- <Hfltiar-« dichloro, or 4iter * all Um in ι

2- (3,4-Dihydraxl-phenyl) -3β-difluoro, dihydrochloride, or 4bromo * allHain

2- (3 _t 5 * dlhldrexl * feail) * 3 «3 * dlfltfor * · dichloro- or 4 ibroa Hsain ι

2-benxU-3 * fluoro-chloro or bromo-allHalliis 2 * fanetH * 3 * flwer * · chloro * »or bromo-allHaaini 2- (2-ethoxy-benzyl) -3-fluoro-chloro · or bro-allHaalni

2 «0-aetcxl-banzH) -3-fluoro * · chloro» · or bromoallallic

2 * (4 * aatexl * benxH) «3 * flaar« · chlorine * · or bromine * «allHaalni

2- (2,3-benxH 4iaetaxl *) "3" fluar-, chlorine _or Break • allHaaln »

2- (2,4-dmatexl-fanH) -3-fluoro, chloro * or bromoallalla)

2- (2,5-dlnatexyphenH) »3« fluoro ·· chloro * · or bromoallyl

2 * (2 »6 * 41aetaxi« ftanaH) «3 * flifor * · chlorine * · or bréa • allHaaini • 15 ·« ·· · ·············································································· · • · ·

2 * (3 «4 * dlaatexl * banxll) * 3 * flaar * · up ·· buy bre» · • aUUaalna

2 * (3 »b * dla« tOMl * b »nxil) * 5 * fluar ·· matures · or bre · * •• 1111 ·· ina

2 * (2 * hldrexl * baiixil) * 3 * fliaar ·· up ·· or bre ·· • allllMina

2 »(3 * hldroxl * b« nxll) «3» flttar ·· up »or bre · * -> • 1111 ·· in i

2 * (4 * hldroxl * baiwilé * 3 * fllaor cler »· or bre · * •• UH ·· ifi a

2 * (2 _t Mihidroxl * b »nail) * 3 * flaar * · rises * · or bre · * -all 11 ·· in;

2- (2 _t 4-dlhldr «xl-b« nxll) -3-fluoro- ₍ mature * · or bre · * * • 1111 ·· in i

2 «(2 _t 5 * élhldraxl * banzyl) * 3 * fluor * _t equals * · or bre · * • all11 ·· ini

2 * (2, é * elhldroxi * b «nxll) -3 * fluorine ·· out * or or br» »•« 1111 Mini

2 * (3 «4 * dlhidr» xl * b »nzll) * 3 * flu« r * · up * or bre · * • all llm in t

2 * (3 _a 5 * dlhldroxi * b «naU) * 3 * flyor ·· up · * or bre · * • allHa · in a

2 * b «nzll * 3» l * edge fluer * · edge halter * · or ebraff * allll * • sleep

2 * (2 * a «texl * b» n * il) * 3 «5 * edgeflttar ·· breeze * · or dl · bréaallllaalna ····

- 14 2- (3 * ethoxyl-benxH) -3,3-dlflw «r- _t dlcler * · or dlbróa-allHealn»

2 * (4 * aeta * l »beviaH)» 3 »l * difIvar ·, diclar ·· or spotted * -allHaaini

2 * (2 ₉ 3 ^ 1seidxá * baraíU) * 3 _t Ml * lsor * · dlklér-. or -dlbrós-alilasln »

2 * (2 _> 4-dlMtexl * befutH) * 3,3 * diILltter- · dlklér-. or • Dib-allHsaln i

2 * (2 «S * diMtejil * lMMKU) * 3« 3 * dlfltMr * · dlklár ·· or • dibrós-all Hasin i

2 * (2 »6 * diaotexi * tosn * H) * 3» 3 * difl «ior * · dlklár-» or -dlbrás-allylln i

2- (3,5-Diacetoxyl-benzyl) -3,3-dichlorofluorophenyl or dibasic allylminin

2- (2-HldrcxlbenxH) -3,3-dinoro-, dichloro, or dibromo-alllasin »

2 * (3 * bidrexl * benxU) * 3 _> 3 «^ lfliiar * _> dichloro- or di · bromo in the in

2 * (4 * hi4r0xl * beiuEU) * 3t3 * difliier * _t dlklár ·· or dl * bróa * allllasini

2- (2,3-dlhydrexi-benxll) -3,3-dtfIvar * · dlklar ·· sgy dlbréa * allHasln i

2 * (2.4-dlhidrexl-bansH) -3,3-difluoro *, dichloro or dibromoallllallni · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ····· · · · · · · · · · · ···

-182 * (2 «b» olddroxl »bonxyl)« 3,3 * dtfluoro »· dlchloro or dlbróa» allllaatnι

Of 2- (2,6 »lead-trixl-baryl)» 3 _t 3 * of lead, dichloro or dibromo |

2- (3 -? - 4-thidroxyl * boftxyl) «3 _? 3» dlfluoro- dichloro »or dibromoallallaalm

2 »(3« 4ylhydroM «boaall)» 3 »3-difluoro» · dlchloro · or dtbróra all

2 »fanaxl» aetll-3 * fluoro, chloro, or bromo * alliloalm

2- (d- «atoxl-f-noxl-ethyl) -3-fluoro-chloro * or bromo» allyl * int

2 * (2 «ó» dlaatexi * phonoxl «aotll) * 3 * fliM» r * · chlorine »· or bromo-allylMin>

2- (2, O »dlaatexl * fanoxyl-atyl) -3-fluoro, chloro» or bromoallala »

2 »(3 • 4» aotilone «dioxy» phonyloxyethyl) »3-fluoro. Mlóf or bora-allllani

2- (3-hydroxy-phanoxyoxyethyl) -3-fluoro, chloro or bromo-al If

2- (4 »hydroxy» feaoxi »aotll)» 3 »fluorine» · chlorine »· or bromo-all 11 ·· ini • · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ··· ······ · · ··················································································································································································································································· · Bremen allÜMini

2 * (2 »4 * éihWroxl * faiwxi-« atll) * 3-flttar · »up ** or toré * alltlaai * u

2 * (2 * aatil * fanoxl * Mtll) * l * flver * · up * or tor »» allila «ilni

2 * (2 «to * faiiexlMMtll) * l * flvar * · to * or tor» »« • llllMlni

2 * (4 * clere * fonaxl * aetll) *> * fliier ·· matures * · or bréa • • allilaaint

2- (4 * trlfl «ter * aotü * faAéxl *« otll) * 3 * fIvar * · up · or bre »» allilaalA)

2 · (tla * fanexl-e «tll * a · fiver ·,« up * or bréa * «• llilaalAi

2 * (4 * aataxl * tia * faftaxl * aetll) »3 * flttar * · up * or * fer *» to die

2 »{2 _t 4 * éiaeteMl * thia * fanexl * aetll) * 1 * brother ·, rises * · or bré-allllMilni

2 * (2,4 »eifer * tie * fafiaxl * Mtll) * l * tléer _w · com * * or • toréa * allHaaini 2 * (4 * hiéroxl * tie * f« nexl * eetll) * 3 * fluer ·, worth * · or bra «die

2 * (1 * éaftll * exl * eatll) * 3 * flver * · up * or tor * * • allllaa & i », éa

2- (2-naphthyloxyethyl) -3-fluoro, chloro * or bromoalloyl |

At: »the formula of the alien is preferable to those who are presently late» aeelyokbon * one year or one of the chlorine or brateate of the present · one of the two substances of the present invention for esoleol, the production of flakes has been announced »e.g. in the descriptor (dated June 12, 1984), the 2,182,818 oorezáau in Szabsdalal announcement (published by iggg »February 5), vol. 4 edo 007 seroséau by Aaorlkal Bgyoeél - llaaek in Ezolabala llra7 όπ), As in these publications, it is easy to obtain analogous methods for composing tufts of late slate in these publications.

and the conditions according to the present invention are diseases and conditions associated with these collagen oetebollzooe defects »e. g. are capable of inhibiting the enzyme lllzyl oxidation · The present invention claims that the 18 strains are characterized by the presence of lysll «axidex ectlite * in exemplary exemplary formulas · the active ingredient of the active ingredient varies according to the limits of its inflammation. elkel * • that dog unit · the time of the treatment · the age of the patient treated * the age and maturity of the patient treated, valealnt of this treated disorder and the age of maturity · the dose of ektlv administered «api oeezaennyegeé usually ranges from 5 * 900 sq. It may contain one or more thousand or more times a day · The active compounds of formula I are a herbal drug * herbal, gel, and / or lotion for acai * orally, parenterally, or topically · for patient with collagen derivative of Mr eb * Norselie · local ointment is considered to be advantageous, · in the case of intrauterine ebnereélie lerédée, where practicable it may be practicable, in the locus, · where leeleele or topazée edagelée is not possible, ozleztéa oaagalté should be of short duration only, days, and the patient must be severely harmed * in terms of the structure of his injury benefits ·

The X formula of life ·· combines with • dageléee penloillasin, a substance for chance, tip • essence · »hcexable abneralia pen · ** gene-deflected yelleaxatt batage-burns in the treatment of ailments, but aaelyrele le laeert» -exldx barrier divergent aaaaa eMMtédlk, bloodthirsty • girl ·· AzAX formula buy ·! weekly intake of penetilla with penieillaaln adeine-adegalée «tetta bloody • let« keda! dozeláe eeetén ée ex-dosed pe * nleHl! ·· in eefmylelege burns ex cdagolée childbirth dependent hands ·! ex Xi »» formula of compound and penieUleaía aleeeoayabb dose start »and eat« without dose »and doxlgekgt should be converted to methane. mountain reach this coffee fishes · Αχ X general ·· formula buy ·! penileillin penneyillacin ayeiehexexen openedxexact ash »for example isi-winter liSOOtál, hyllvdnvalá» tip at the edge of X ··· formula! basically · in the presence of penile lacin, • in life, “afterwards, you can add“ lime ”cetene · chemicals so you can use it as a liquid manure, for example Juk» pepex, pills , solution, ezu suspension, or «aulaié foraáabaa · one thousand one-déxle forae may be a capexula» aaely may be necca-keaeny or soft-coated xealetln-tipueu · aaely may contain for example wallolactives »substances» lubricants »ée

- 10 · lactose * azaeharose «calclua · charcoal 6e corn · • coa. the benefits of the present invention are ozorized by the losses of the present invention can be viewed with tablets, pages, pops, teas, * esaeharose, and corncrops *, * with * dyes *, etc. * mountain eegiteek folkbait · • food * folate after boade * on-duty potato ^ keao · opener, alginaaw * corn * koaényit6vela guor «gu · ski * lingonberries * chances this spike * that jovlteo féte léte · Soak up · adhering its substance to the tabletting device * for example talkuaaal * eztoarinée or aag · looking · * calcium »or clnk * iterate * · intimate * coloring substances and isoelite substances * that their function * improve pills estonian property 6a to make it more acceptable for the patient • to contain your sitad in liquid dispensing tournaments · to dilute eagle-doping excipients with dilute minerals * such as water and alcohols * that is, e * tan * benzyl * alcohols and * polyethylene alcohols healing agent * azo-suspending agent or azo-suspending agent * · ··················· *

with or without the addition of a eoulgoelé substance ·· The compounds of the present invention may be administered via the porenteral route, i.e. solutions of liquids or liquids such as water, alveolate, water · dextrose, similar oily solutions such as alcohol · such as atanol, isopropanol or hydroxyethyl alcohol, glycodes, brain-propylene glycol or poly-glycol glycol-glycals, aren't you int a 2 * 2-dleetil ·! _t 3-Dlexolan-4-Eetanol «»> ethers, * Polyethylene · glycol 400, one «oil, one zaireev, so zeireev-ether or zolic acid-gllooride, or a sesylated zeireav-glioaride added or well« brain medicine acceptable active ingredient, t-shirt oil, or soap detergent, azo-pendant materials such as pectin, carbaors, aotylcellulose, hydroxypropyl ethyl ethyl cellulose or corboxinate, cellulose or auxiliary substance and a pharmaceutically acceptable adjuvant,

Oils for use in jelly feathers of the Jelon Horsetail Azores can be of petroleum, animal, vegetable, or ezetietic origin, such as walnut oil, rose oil, olive oil, cottonseed oil, corn oil, olive oil, petroleum * · 9 · fatty acids for cakes, oleic acid, azartaric acid to lseostoarinoic acid · Mgololate zoireav ethers include, for example, to etU-elate to isapropyl-alrlskate · suitable salts for rock drops are alkali metal, ammonium, and tranetate salts, suitable for use as dotorgonooks in non-toxic detergents, such as dimethyl dialkyl-amenum lum-dusted alkyl alkyl pyridinium helogonides to alkylMln-OM moieties, , for example, alkyl, aryl to olefin parenthetics, alkyl, olefin, ether and onogloboride decoy to sulfo-succinate noaionoe dotorgones, e.g. n Scold, sairoav alkanolemidok to polttMiotilén-polypropylene copolymers> aafotor detargoncák, for example, alkyl-beta-onlnoprepianátok to 2-alkyl-imldaxolln kvsterner ammonium salts, mixtures · valaaint the present invention ezerinti *** pe ⁿ * · * rally kéezltoényck tipikuean 0, 1-0 e * of the active ingredient in a solution in tartrate · The preservative thousands may be used as buffers · Allow or discolorate the injectable liquid, such formulations should contain a non-inhaled fololactic agent. -17 stone. On such compartments, the WallOlotoktlv materials contain a large amount of eu. the topotoxicant may be the ogyctoponoaoic substance with the font ML0, or it may be two or more of the desired MLös.

- Mixture of 21 HLB-containing materials * Typical surface-active materials used in post-office handles include the eeeport of pelethylene-thousandserbltene zeirtav eters, e.g. kendoncáclée are produced there ·

The calendula of the present invention is preferably administered topically for use in treating a disease or condition described by abnormal deposition of a colleague in the skin. Any of the above liquid formulations, including gels and ointments, may be formulated with a moisturizing cream. , toppers, gels, gels, gels, after-shave, cosmetics, and the like · Usually, a composition of the present invention for topical use contains 0.01 to 9 g of compound of formula 1 ·

1. »«! «»

UKUsauucuUsMtijamUuafc

The lysyl oxidase preparation is prepared from bovine aorta using m, «« lliim intact h, h, xagen CAnal «Blochoa ·, 149, 430-437 (1BB9) 1 and HH · kagan ae» A _e 8ullivan • ·· · · · · · • 24 · tMethede m feneynclegy. 637 * 650 (1222) 3 halves · pre-fed • thousands of millet freneen to win this enzyme · * * survive on a day 4 · θ · η convert · experiment to raise aesthetize to live 90 minutes a year * (2 »5 volumes of buffer 19 · 2 lbs» «feez · fetal 1« »phenylphenyl * fliterM / g a year), to which 0.19 M NeCl was added,« overnight · silver pellet was fluted (20 min, 11,000 xg) «Eee flies with heeegenlelé edges are eaten with peffer ♦ 0.19 m with Ned *, eeek buffer» ejd buffered with 1M kerbesld, 1 H in kerbesld * mixed with a mixture • mixed with a mixture fillets are buffered ♦ in 4 m kerbesld, mixed for 19 veins, • centrifuged, lllzll-exide is added * handwashed, this year is buffered, + 4 h are left to stir, kéteze we rinse, rinse the llzll «exideous extracts,

The water thee nedezer r, C, TreekMntél ée nun * quadruple bought CAnel · Sleehe · ,, 111. 136 * 142 (1992) 1 · Every single urine dictates two ee years, from the beginning one ee 0.2 eM beta * e »Lne * prc * pienltrllt (BAPW), · • edges · reeled for Meltéee • dunk SAPM · 0.19 ·! llzll * exldé «prcperétuaet, 0,1 ·!

29 · carboaldehyde (4H), buffer (v, 91 µl, 200 µM friendly, pH · 8 * 2), hoaovanllllnoav (0.02 µl, 90 HM · solution) and teraoxide (0 µl, Slgao IX) tipuou, at a concentration of 9 µg / al protein) is incubated in 2 liters · 59 ° C * in a textexe, 0.1 el (190 ah) of caviar is added and the incubated water is added * Ida 99 ° oo continue to cartilage. The mixture made into tortolaxa is then placed in ice, and then the eeozoo is oaebe, auolylk noa tartalaezza is added, 8APN is added, and the fluoroezoonolé is used to make cerebellar (gore *, 10a, 0, for 8APN * minutes, this is the enzyme octlvi · téo a value, For the larval * oxidase-transformed cadaverine burns, the standard larynx is consequently zaseed, 8AHi «t is added * poroxide was added to the codaver, and after 10 reactions, the reaction changed to an east-hand fluoroezconclo * change.

with this sddsxer, the lysyl * oxidase barrier activity is expressed in terms of IG ^ g (barrier compound concentration), that is to say, the concentration of lysyl * oxidase barrier is determined as follows: • ·

- 26 mines are covered in Table 1 »

Table 1 _f <UjUiUmABSM-Uillsía4ÍM mili «ktivit *.»

Test compound (M) (6) · 2 · (4 * fluerfanet11) -3 * fIvar * -all Hsain 1x10 ¹⁰ (&) · 2 · ί3 «* ΜΙμtaxi alanyl * propyl) * 3 * 1x10 ^1U -fluorral! Hsain («) * £ * (tlo * fanexl * aatil) -flaar * • allH * eain 1x10 ¹⁰ (6) -2-f anil-3-f luar-ail Has in 1x1lT9 (X) -2- (3,4-Chloro-phenoxyethyl) -3- 1x10® * * Flw0r allilaam (X) «2« (2 * tienH) * 3 «flyor» ell Hsain 1Χ10-® (£) * 2 »iaebu 1Η-3-f liMr-all llaa in 1x1 © ® (6) -2-undcyl * 3 * fluoro-allHaain 1x10 ⁷ (6) * 2 «(3,4» ΰ1 · ο <6χ1 · ίηη11) «3 · * 1ΰ0Γ«> IxlO * ⁷ -allllaaln (t) -N-at 11-2- (3 «áMllaa taxi * fanH) -3 * 1x10® ) »2 * fanatH * 3 * c klar-allHaain ......................—— 1xW ^ö (g) «2 * izebutH * 3 * chloro-allHaaln HLI. . . . 1x10 ' ItJrgrfMiU t-Mtr-iimMin ................................  ...

• · ·

Claims (3)

1- »2« or $ * piperldiayl · 2 * or 3-pyrrolyl, 1-, 2- or 3-indonyl *, 1-, 2- or 9-fluoronyl · 1. A process for the preparation of compounds of formula X or IX, wherein the compounds of formula XX or XV are the same and each can be fluorine, radiolabel, or x to one of its histogens. fluorine, chlorine or bromo means aotileooport »phenyl or substituted phenyl ceoport, a substituent one or two of the following groups, 1 to 5 ozenato-toluene-alkoxy, 1-9 ozenotoaic acid-alkoxy group» hydroxy-Coopert · ray » brad, fluorine, iodine, trifluoro • cetyl · nitro-cooper, 1-5 isozoate alkyl • carbonyl ceoport benzene or fanyl oeoport or jolontéoo 1- or 2-naphthyl cooper> 2 * A process for the preparation of compound s as claimed in claim 1, wherein Rj is hydrogen, notyl or ethyl and 9 is the same as nint salt. 3. A process according to claim 1, wherein w is of formula C and s is a reaction or hydrolytic reaction with hydrazine. 4. A process according to claim 1, characterized in that the alcohol of formula V_ or VI is treated with armed reeds to elute the hydroxyl group to prairar alcohols, wherein x * y and R are the staples in claim 1. with the proviso »that if one of x ye y is fluorine * chlorine is bronchoate then their women may have hydrogen ··. The edge of claim 4, wherein the alcohol is converted into an old alcohol. The following water is converted to the general formula VZ1X, where X »Y and R are the same as in claim 1 *. we are »on the condition» that if X vs Y is ·· fluorine »chlorine or bromoeto · * their aes cannot be hydrogenated · and e is B · · · narrowininime oeeport * ftel * Mid or • leled · group · hexMotlene * tetronnonlun group or 1 * 4 this week elkllkerboxenlno group and this restart is then treated to a female · · Here - 30 nalointdo, succinyldo or ftallsldo groups, hexaethylene tetraazonium groups or so 1 * 4 carbon atoms and alkylcarboxazino groups for conversion into prairie · Process according to claim 5, wherein the salt is Jolié s) B is a succinaldehyde, phthalidea or MlolMido group, and the conversion of the cleaved group to an osino group is accomplished by hydrazolphioe reaction or by hydrolysis with a strong acid; b) Converting 8 of its meaning into a hexinoethylenetrotenyl group and an as ealitstt group into an osino group; obsession c) 0 Meaning · Convert 1-4 ozenatoaozaaa alkylcarboxaaino group and esterified group to aaino group with high acid hldrollzlaool · The boronolyl process according to claims 3 to 8, wherein x is fluoro, y is hydrogen, R is 3,4-diiodoxyphenyl, and R is hydrogen * and olefinic torso (£) -2 • ( 3 *, 4 * -di (otaxi above) -3-fluoroallyl allyl. • 31st 8 · · · exit IX or X may even ·· formula vegyOlet elééllitóetra eaelyben · X · Y _t R is the same as sending the ·· Reports Int AaIT ex igénypeotban aeghetóroztunk · 1 wherein the tip off · R · reception means not ·· · non · * · Dl · chemical tri · hydroxy phenyl group and if one of X or Y is fluorine · escapes * or bromoate · then the atelic acid may be hydrogen ··· «2 mean ·· hydroxy * eeoport · characterized by · tip 4 XX or XXX in general ·· Formula chemical · In which X · Y, R and e are the same as those defined in claim 1 and denoted by Rd · · · · · · · · · · · · · · · · · · · · · 9 · The process of claim 8, wherein the reduction is carried out with a diisobutyl "aluainiua" hydride. 10 · walked · · in patients ebnoretlie collagen deposited · eal Characteristic diseases and conditionsexacted ·· ozone Characterized · that active ingredient of formula I of formula XX is administered to the patient · aaely xylophenic and ye meaning ·· · Chlorine or bromoMatoa or x ye Y is represented by one of hydrogen · • te ·· and neiteik is fluorine «chlorine or bromoate> means ·· hydrogen atom or 1 · 4 ezenatoao · alkyl · -oesport 1« 1 • · · · * meaning ·· divalent ceoport, · - (CKJ.-MCCHj), edged by ··· in which Rg represents · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · n may not · be greater than 17 - (O-ÍCHg CHgJ ^) ^ In which ΰ is · oxygen or sulfur, p is 0 ye to 16 ye, y is q is 1 y to 16, provided that ♦ n is not more than 17 ye - (ΟΗ ^ -οΗ-οΗ-ί ^) * Where · has a value of 1 ye 16 ye this value has a value of O ye 16 ye ·, provided that r * e may not be more than 16 yo denotes · ethyl group · phenyl or substituted phenyl-eepert, · replaces one or two of the following eepert with 1 * 6 ethylene-ethyl-1-, • zenatoaee-blue-eper, hydroxy-eepert, chromium, fluorine, iodoethane, trlfluoroethyl ·, nltro-ceoport, 1-6 yenMezaau elkll-kerbenll-eepert, benzyl or phenyl-ceoport chemical ···· - 33 R jol «n · · 1- or 2-n» phtiloaoporti 1 ·· 2 · or 3-Indyl, 1, 2, or 3-fluorophenyl, 1-, 2-, or 3-piperidinyl, 2- or 3-pyrrolyl, 2- or 3-Thienyl, 2- or 3-furanyl, 2- or 3-indalyl, 2- or 3-tetanaphthyl Ilon 11-, or 2- or 3-bonzofvr · nll-cocporti or a pharmaceutically acceptable salt thereof · 1I, the ly. The oxerin base of claim 1, wherein x and> 'are each chloro or bromo, or X intact Y is one of chloro or bromo and the remainder are hydrogen, 12 «Aloe according to Claim 10 or 11, characterized in that R represents the above or one thousand or twice substituted phenylcarboxylates, the alkyl radicals containing 1-5 carbon atoms, the alkoxy radicals having 1-5 carbon atoms, hydroxy *. , chloro, bromo, fluoro, iodo, trifluoromethyl, nitro, 1-5 xenethomezamyl alkylcarbonyl, benzene or phenylceoport, 13, A process according to any one of claims 10 or 11, characterized in that R is a motilceaport · and A, if present ν · η then the following bivalent eeoports are brain · ^R 2 ···· ···· · · • 34 • in the case of Rg, it is · Hldrogenatoa, Katii or «tllceoport, and from the n beds of the κ valaalnt, it is 0 0a 16, provided that ♦ n is allowed to be greater than 17 - (CK ^ -D in CH ^ aaely is oxygen or sulfur tea »p value 0 · ag 16 ez »» »értéke 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 The oleaginous oil of claim 10 or 11, wherein the R is a group of A * if present, the following bivalent ooports are selected. in aaely Rg · · hldrogenat * catatile or atylcooport »aé value · o éo 16 agée azéa» value · zeros · aloe oalant ·· oxygenate or sulfur tea »p value O éa 16 agée this» q value · 1 . ···· ································································································ · 19 A process according to claim 11 wherein the deer is R, wherein R is phenyl-ethoxyphenyl, di-taxi-phenyl · hydroxyphenyl · · dihydroxyphenyl, chlorophenyl · or dichlorophenyl eooport . 10. A process according to claim 19, wherein the group A is or is not a group The meaning is -othylene or -SGH ₂ - or -OCi ^ Method 17 for inhibiting the enzyme lysyl oxidase in a patient having a nose need, characterized by the effective amount of the compound of formula X or IX that is administered to the patient. In aaoly, X and Y are the same and each may be fluoro *. chlorine or bromine · orx and Y have one hydrogen atom and the other fluorine, chlorine or bromine atom » R j is hydrogen or a C 1-4 alkyl group selected from the group consisting of the general formula "2" in which * 2 is hydrogen, a metal compound otyl and a and n independently of the bis, provided that that the value of ♦ n is greater than 17 for my females 1 · · · · · ♦ · ··· ··· - 36 - (CH ₂ ) _p- u- (GH ₂ ) _q ••• o Its oxygen or sulfur ·· p value · 0 ya 16 knit 1 ghee q value is 1 y 16 yg · . that the value of ♦ n can be no · greater than 17, eh - (CHG) _r -CH = CH- (CHG) _f aaolyben ogéoz word e is between 16 · Eo i. éo r is 0 og 16 for ogose ·, provided that r ♦ e Bea can be greater than 16] y R is aotileeoport · phenyl. or substituted phonyl-gooper · the substituent is one or two of the following groups} 1-5 cyanoateo-elkll groups. C 1-5 alkoxy. hldroxl-cooport · chlorine * bromo. fluorine, iodate ·. trifluoro-1,1'-nitro-cooper, 1-5-azoateo alkylcarbonyl-ceopor. bonzole or phenyl group: or R is 1- or 2-naphthyl-eeport. 1 ". 2- or 3Indenil ·. 1-, 2- or 9-fluorenyl. 1-, 2-, or 3-piperidine-112- or 3-pyrreltyl-2- or 3-dimethyl-2- or 3-furanyl. 2 or 3-indolyl, 2- or 3-thianaphthylenyl or 2- or 3-benzofursnylceoportium or a pharmaceutically acceptable salt thereof. • 37 · 18. Claim 47 «s« rlntl «Arya ·« zzal Jeli · * hzv «that X and« Y communicate one of the half-bought Brems ··· and they eat their hydrogen ··· 19 A claim according to claim 17 or claim 18, wherein R is phenyl or brain or phenyl substituted by two thousand. the substituent 1 * S · ζθη · ιο · βζ0 · ν alkyl * · 1 * 5 azenatoatzému • Icoxy-hlde «xl * oeoport, chlorine · bromine, fluorine, Jead atom, tri * fluorine · · · til *, nitro *, 1 * 5 ζ4ηοο · ·· · υ ζ8 alkylcarbonyl _t * benzoyl or phenyl-ceoport. Method according to any one of claims 17 «or 18«, characterized in that R represents ethyl ethyl, and A, if present, · the following bivalent ports • FAQs • R ₂ - (CMgJ ^ -Cn-ÍCHg) ^ • MlylNn Rg represents ······································································ square hours Subm measure minutinyl-free. value must not be greater than 17 * in the mother 0 Report ·· oxygen or sulfur · *, p value · 0 II 2 «é géax ax, g value é 1 e 18 eg - 38 with this · conditional ·! * That ♦ n must not be greater than 17 · 21 * The process of any one of claims 17 «or 18 · is characterized by * the value of R * · mmyl-ceoport if present, then one of the following bivalent eoopers ·« ₂ • < ^CM 2> «* ^CH < ^CM 2 ^ • is a hydrogen atom of Rg, an integer of 0 · 16, the value of · methyl or ethyl *, n is zero, and • (£ ** 2 p · ^ ^ 20 where D is xylene or sulfur) * p has a value of 0 from 16 ye · * q has a value of 1. 22 · An oil of claim 18 · characterized by * a R is phenyl · * ethoxyphenyl »dimethoxyphenyl, hydroxyphenyl * dihydroxyphenyl, Jtlor, phenyl or dlklor il-oeo po rt · 23 · A process according to claim 22, characterized in that # this cooper is either absent or represents A as a motile, or -SCHg- or -OCHg-ceopor, 24 Diseases associated with sufficiently abnormal deposition in patients with conditions and conditions, suggesting * how much inhibitory activity of panleillamln lysyl exidase is · · · · · · · · · · · · · · · · · · · · · · · · · · · • · * ··· · * 99 »1 - the addition of a salt of the compound of formula I or IX is administered to the patient *, wherein x and y are the same in active ingredient, fluorine, chlorine or bromine, or x and Y represent one of hydrogen, chlorine or fluorine; bróastoa; R 4 is hydrogen or alkyl of 1 to 4 ozene atoms groups A is a bivalent radical * selected from the group consisting of * 2 in which Rg is a hydrogen atom, a methyl or a methyl group, a and n are independently 0-16, provided that ♦ n cannot be 17 bigger, - (CH ₂ ) _p -ü- (CH ₂ ) _q aaelybon o is oxygen or sulfur, p is an integer from 0 to 16, and q is an integer from 1 to 16, with the proviso that ♦ n non &Gt; 17 (CH2 -CH-CMCH2S) 40 · In this case, the value of e · 1 · 18 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ♦ · may not be more than 16 reports · ethyl ethyl, phenyl or substitute phenyl. the substituent one or two of this sheaf * from the hand group * 1 * 5 azenetoeo * elcylceopor, 1 * 5 carbon · atorase alkoxy, hicroxyceopor, chlorine, brec · fluorine, iodoetoa, trlfluor «til ** nitro * group . 1 * 5 benzene-aza-alkylcarbonyl, benzene or phenyl * or 1-or 2-naphthylceopor, 1-, 2-or · 3-inden11. 1, 2 or 9-fluorenyl, 1, 2 or 3-piperidinyl, 2 or 3-pyrrolo, 2 or 3-tri11, 2 or 2- or S-thienyl · »2- or 3-furanyl · · 2- or 3-indolyl- »2 · or 3-tanaftonyl · or 2- or 3-bonzofuranyl-ooeport »• · · · - 28 signs · hydrogen · * ·· or 1 · 4 · ζ8η · * ··· ζ0βυ • Xkll-ceeportt j «X« n * éa ^ bivalentO ••• lawsuit, · maybe ·· pictureXotö oaoportpél oálewrtv ·. aao! yb «n Report · hldregénatea,« ethyl or o * iXa «, the value of« n »depends on your age« tX «iX O y · 16, • zzaX af! that the value of ♦ n may not be 17 · η61 greater than • aelybsn 0 iolone ·· oxygen chemicals, p 16 is an integer «zéa and 4 is an integer between 1 and 16, provided that ♦ n is a value greater than 17» • aely · is a value between 1 and 1 ogéas asa = 0 and 16 ngéaz the ancestor, with the patch !! !!, let r * e non be shot at more than 16 or ± Jolö formula, Ion treat reeds to ozukelninld, aaXsiniaido or ftéXiald · eaeportot prlaer aaino ο · οραΓ ** 0 aXekltottk · 3-fluorenyl, 2 · or 3-Indo-111, 2 · or 3-tannaphthylenyl, or 2 · or 3-tonsofuranyl * ceoport i or a pharmaceutically acceptable salt thereof ·