UA73349C2 - A method for the preparation of substituted acetals of aspartic acid (variants) and intermediary compounds - Google Patents

Abstract

Disclosed is a method for producing compounds being useful as prodrugs of caspase inhibitor, of the formula (I), wherein R1 is not necessarily substituted group selected of aliphatic group, aralalkyl group, heterocycloalkyl or aryl group, and R2 is preferably P2-P4 û caspase inhibitor component. Key intermediary compounds comprise azylodactones (III) and (VIII).

Description

Description of the invention

The present invention relates to a method of synthesis of substituted acetals of aspartic acid. The method is useful 2 for the production of biologically active compounds, in particular, defined caspase inhibitors or prodrugs based on them, such as inhibitors of interleukin-1p-converting enzyme ("CE").

Caspases are a family of cysteine protease enzymes that are key mediators in signaling pathways for apoptosis and cell elimination (Ppogpregu, Spet. VioiI., 1998, 5, K9U7-K103). Apoptosis, or programmed cell death, is the primary mechanism by which organisms eliminate unwanted cells. Dysregulation of apoptosis, or excessive apoptosis, or its lack occurs in a number of diseases, such as cancer, acute inflammatory and autoimmune disorders, and some neurodegenerative disorders (see in general Zsiepse, 1998, 281, 1283-1312; Eiv ei aiI ., App. Chem. Sci. Viol., 1991, 7, 663). Caspase-1, the first caspase identified, is also known as interleukin-1 D-converting enzyme ("CE"). Caspase-1 converts the precursor of interleukin-1β -CrRIS-18") into an anti-inflammatory active form by specific cleavage of ri!/-18 between Avr-116 and AlIa-117. In addition to caspase-1, there are also eleven other known human caspases, which are classified in families based on their biological function.

A number of useful caspase inhibitors have been reported that contain the aldehyde component of aspartic acid, which exists in equilibrium with its cyclic hemiacetal form, as shown below:

M n y

Gee! on de Ko represents another part of the caspase inhibitor molecule. Hemiacetal-based orally available prodrugs of these inhibitors have been developed, having the acetal structure 1, where C is alkyl or aralkyl, as illustrated by d) 2. ISE inhibitor 2 prodrugs, which are developed as a treatment for rheumatoid arthritis (see

US Patent 5,716,929). c) (22) biy o : yiv) sn M «y zon de: ba; so n O-vi n o 1 2 o

The process for the production of prodrugs based on the peptide caspase inhibitor of formula 1, where K 4 is benzyl and the amino acid sequence As-U-M-A, was described by Spartap. (Wioga. Med. Speth. Gay. 1992, 2 (6), 613). However, this way has significant inconveniences, especially if it is desired to obtain chiral compounds. For example, the process requires expensive starting material and chromatographic separation of diastereomers (see the discussion in the publication of PCT application UUO/9903852).

Not so long ago, a shorter process was described for the production of compounds of formula 1, where K 4 is ethyl C with (PCT patent application, publication UUO/9903852). The process involves the co-addition of an aralkylamine to » alkoxyfuranone 3 to give the diastereomeric compounds 4 as shown below:

Kz t u

Yes, yes - 2

Zoya, I UM - ОХ с poto o oto o oboto tkhi Kk o z 4 5,8-5 iz , , , , , , , where Kz is an alkyl group having from one to four carbon atoms, and K. neobov necessarily substituted aryl

Ge) group. Diastereomers 4, or their additive salts, according to reports, can be separated by crystallization.

The aralkyl group on the amine can then be removed by hydrogenolysis to give 5, a useful synthetic intermediate for making caspase inhibitors. One limitation of this approach lies in the hydrogenolysis conditions used to remove KzKASN-, when K is benzyl. Under such conditions K; will also be removed.

It would be desirable to have a technology for the synthesis of caspase inhibitors based on aspartic acid acetals or (F) prodrugs based on them, which is suitable for large-scale production and overcomes the above-mentioned disadvantages or otherwise improves the synthesis in comparison with the methods used.

This invention provides a process for the manufacture of a compound of formula I: 60 y

Sshcha;

Kk

HK

65 where VK! - an optionally substituted group selected from an aliphatic group, an aralkyl group, a heterocyclylalkyl group or an aryl group, and KB? - an organic radical. The process is especially useful for obtaining compounds I, where в2 is Ро-Р. caspase inhibitor component or part thereof.

Some compounds of formula I! are prodrugs based on caspase inhibitors, in particular, ISE inhibitors. IN? - preferably any component which, being attached to another part of the molecule of formula I, provides such an inhibitor.

Parts B, in particular, are referred to in the prior art as P 5, Rz or Ru. components or sites. These Ru designations are references to the amino acid sequence adjacent to the aspartyl cleavage site of the specified caspase substrate. Ri refers to the aspartyl residue of the substrate when caspase-induced cleavage occurs on the native substrate. When designing new, non-peptide caspase inhibitors, the Ru designation is often left to indicate which part of the amino acid sequence has been replaced by a non-peptide component. As used herein, the term "P 2-P." component refers either to the amino acid sequence described above or to a chemical component known to replace such a sequence to become a caspase substrate, and in particular an ISE substrate.

Examples of Ro-R. components that are non-peptide, described in US Patent 5,919,790 (AiPep eii aiI.); 5,874,424 (Vaispeog ei ai.); 5,847,135 (Vetiv ei ai.); 5,43,904 (Vetiv ei aiYi.); 5,756,466 (Vetiv ei ai.); 5,7116,929 (Vetiv ei ai.); 5,656,627 (Vetiv ei a); UMO 99/36426 (UUagpeg-atreg); OoMe ei ai., 9. Mea.

Spet., 40, 1941 (1997); MO 98/10778 (Odyp); UUO 98/11109 (Odyp); UMO 98/11129 (Idyp) and UMO 98/16502 (UUagpeg

And atbegi), all of which are incorporated into this application by reference.

One method of this method for making I, referred to herein as Method A, includes the following steps: (a) providing butenolactone of formula II: c) and,

O- tt s de V! is as described above; Ho) (B) treatment of II with azide M--U, where U is hydrogen, a silyl group or a counterion, to create azidolactone I: o to 2

M

07-x, - (c) transformation of III into aminolactone IM or iminophosphorane M: me) 9) c) so uv, o; - RAM no

O-B' tiu or O-k y, and (a) coupling IM or M with K?СООН or its chemically active equivalent to obtain I. It will be clear that "group B? can be chosen from any organic radical that is stable under coupling reaction conditions such as those described here. Mostly HF? - is a Ro-, Ro-Ra- or Ro-Ra-Ru- component. 8 c Unless otherwise discussed, the following definitions will be used here. The terms "lactone" and "furanone" can be used interchangeably, as will be understood by those skilled in the art. The term "aliphatic" as used herein refers to linear, branched, or cyclic C 41 -C 4" hydrocarbons that are fully saturated or contain one or more units of unsaturation. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl" and "alkoxy" when used alone or as part of a larger compound refer to both straight and branched chains containing from one to twelve carbon atoms. The terms "alkenyl" and "alkynyl", used alone or as part of a larger component, include both straight and branched chains containing from two to twelve carbon atoms. The term "aryl," used alone or as part of a larger compound, such as in "aralkyl," refers to aromatic ring groups having from five to fourteen members, such as phenyl, benzyl, 1-naphthyl, 2- naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic groups or heteroaryl groups such as 2-furanyl, 3-furanyl, M-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, d- isoxazolyl, B-isoxazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 29 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrrolyl, 3-pyrrolyl , 2-pyridyl,

HF) 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiadiazolyl, 5-thiadiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, b5-tetrazolyl, 2-triazolyl, b5B-triazolyl, 2-thienyl, or 3-thienyl. The term "aryl ring" also refers to rings that are optionally substituted. Aryl groups also include fused polycyclic aromatic ring systems in which the carbocyclic aromatic ring or heteroaryl ring 60 is fused to one or more other rings. Examples include tetrahydronaphthyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, isoindolyl, acridinyl, benzoisoxazolyl, and the like. Also within the scope of the term "aryl" as used herein is a group in which one or more isocyclic aromatic rings and/or heteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclic ring, such as idanes or tetrahydrobenzopianes. The term "heterocyclic group" refers to saturated and unsaturated monocyclic or polycyclic ring systems containing one or more heteroatoms and ring sizes from three to eight, such as piperidinyl, piperazinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, etc. .

An aliphatic, alkyl, aryl, heterocyclic or isocyclic group may contain one or more substituents. Substituents are selected from those that will be stable under the reaction conditions of this process, as should be well known to those skilled in the art. Examples of substituents include halogen, -K, -KO, -OH, protected

OH (acyloxy type), phenyl (RY), substituted RY, -ORI, substituted -ORAY, -MO», -SM, -MNK, -M(K)», -MNSOK, -MNOSOMNnk, -MKSOMNEK, MNSOM(K )", -MASOM(K)", -"МКСОК, -МНСОМК, -МКСОоК, -СооК, -СОК, -SOMNK, -СомМ(кК)", -5(0)2E, -ZVOMN", -(О )K, -5ZO2MNE, -5024(K)2, -"MNO(O)2o, MAB(O)"K, o, -5, -MMNE, MMK", -M-OK, 70 hMMNSOK, -MMASOK, "ММНСОо", "ММАСОоК, ММНЗО"оК, "ММАЗО"К, or MK where K is an optionally substituted aliphatic, aryl or aralkyl group.

Substitutable nitrogen on the heterocyclic nucleus may be optionally substituted. Suitable substituents on nitrogen include K, SOK, 5(O2), and SOZH, where K is an aliphatic group or a substituted aliphatic group.

Unless otherwise discussed, the structures depicted here are assumed to include all stereochemical 7/5 forms of the structure, i.e., K and 5 configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the considered compounds are included in the scope of the invention. Unless otherwise stated, the structures depicted herein are intended to include compounds differing only in the presence of one or more isotopically enriched elements. For example, compounds having the structure in question, except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by carbon enriched with "ЗС-" or "С" are included in the scope of the present invention.

Butenolactone II is quite accessible and inexpensive. Preferred B" groups include methyl, ethyl, propyl, 2-propyl, butyl, pentyl, (hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, phenylbutyl, (4)-menthyl, (1)-menthyl, 1-dadamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 3-tetrahydrofuranyl, benzyl, A-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, CM 4-methylbenzyl, 4-( 2-propyl)benzyl and 4-trifluoromethylbenzyl. The most preferred groups B" include ethyl and benzyl. o

Azidolactone III can be obtained by conjugation or Michael addition of group M" to I! according to the methods generally known from the prior art for similar compounds (see 5. ). MiPeg ei ai., 1999, Ogog. Hack, 1 (7), 1107). For example, I can be obtained by adding II to a premixed solution of M4-U and an acid catalyst in a suitable solvent followed by the addition of a Lewis base. b» The azide can be any nucleophilic azide that is suitable from the point of view of the prior art. "

Examples of such azides include alkali or alkaline earth salts of azide such as MaMz or HyMaz, tetraalkylammonium azide, azidotrialkyl-, azidotriallyl-, azidoalkylaryl- or azidodialkylarylsilanes such as trimethylsilyl azide, (ze) triphenylsilyl azide or diphenylmethylsilyl azide, or azidotrialkyltins such as azidotrimethyl or with azidotributyltin.

When Ma4-U is a three-substituted silylazide of the trimethylsilylazide type, the following conditions and reagents can be used. Suitable acid catalysts include carboxylic acids such as formic acid, acetic acid, propionic acid, and benzoic acid, and halogenated carboxylic acids such as trifluoroacetic and trichloroacetic acids and Lewis acids of the type BE5.OEB, aluminum trichloride, zinc chloride, and titanium trichloride. Acetic acid and БЕ5.ОЕБ are the best acids. Suitable solvents include ethereal solvents such as tetrahydrofuran, OME, diethyl ether, methyl tert-butyl ketone or dioxane; aromatic hydrocarbons of type C with benzene, toluene or xylene; halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane or dichloroethane. The best solvent is dichloromethane. The presence of a Lewis base is necessary only in a catalytic amount. Suitable Lewis bases include aliphatic tertiary amines such as triethylamine, diisopropylamine, 1,8-diazabicyclo(|5.4.0)undec-7-ene (OB), 1,5-diazabicyclo(4.3.onone-5--ene (OBM ); heteroaromatic bases such as M-alkyl imidazole (which may be bonded to the resin) or pyridine. The preferred base is OBO. The reaction can

Sh- to be carried out at a temperature in the range from about 02 to 1002C, preferably from about 02 to 402C, and most preferably - from about 202 to 402C. The concentration of II will be in the range of 0.01M to 10M, preferably about 0.1 to 1.0M. The amounts of Ma-X reagent such as trimethylsilyl azide and Lewis acid will be for each

Mami generally ranges from about 1.0 to 10 equivalents per HER equivalent. t» 50 The above-mentioned conditions and reagents for the conversion of II to III may vary depending on the nature of M 5-U.

When M43-M is an azide, where the counterion is an alkaline earth metal such as lithium, sodium, barium, or calcium, the following conditions and reagents can be used. The amount of azide will again range from about 1.0 to 10.0 equivalents. The reaction temperature will be as described for trimethylsilyl azide. Suitable acids include formic acid, acetic acid, benzoic acid, and buffered acids such as tetrabutylammonium 99 bisulfate, ammonium chloride, ammonium acetate, and ammonium formic acid. The best acids are acetic acid,

HF) tetrabutylammonium bisulfate and ammonium chloride. The amount of acid will generally range from about 1.0 tons to about 10.0 equivalents. Suitable solvents include aprotic organic solvents such as acetone, M-methylpyrrolidone, methyl ethyl ketone, tetrahydrofuran (THE), dioxane, dimethoxyethane (OME), dimethylformamide (OMERE), and the halogenated hydrocarbons described above. 60 When Ma3-U is NMz, it is preferable to use an excess of azide, generally from about 5 to 25 equivalents of azide per equivalent of butenolactone I (see I akssptiraiii ei aiYi., 1997, Teiapedgop IGekf., 38 (14), 2551).

Only a catalytic amount of base is required, generally in the range of about 0.01 to 0.25 equivalents, preferably at least about 0.10 equivalents. Suitable bases include tertiary amine bases such as triethylamine, diisopropylamine. OVO, OVM, or aromatic M-heterocycles such as pyridine, alkylpyridines, and M-alkylimidazole (which may be resin bound), preferably triethylamine. Suitable solvents include aromatic hydrocarbons such as benzene, toluene or xylene. Toluene is preferred. The reaction temperature will generally range from about 202C to about 1102C, preferably from about 702 to about 9096.

When M3-U is EBAYIM3, it is preferred to use about 1.0 to 3.0 equivalents of azide per equivalent of butenolactone II. (Spypo, ei ai)., 1998, You. Kogeap Spet. Zos, 9, 269). Suitable solvents include aprotic organic solvents such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, hexane, benzene and toluene, which is a preferred solvent. The reaction temperature will range from about -202C to about 402C, preferably from about 202C to about 402C.

Azidolactone I can be transformed into the corresponding aminolactone IM by hydrogenation or reaction with 70. triphenylphosphine. Hydrogenation is more suitable when K' is a group that is resistant to hydrogenation conditions, such as an alkyl group. You can use standard hydrogenation conditions, such as the use of hydrogen gas under a pressure of 1-4 atmospheres. Alternatively, hydrogen can be produced by known methods. For example, such as the formation of ammonium formic acid under the conditions of a phase transition.

Azidolactones II containing benzylic and other groups that are not resistant to hydrogenation can be reduced to aminolactone III with triphenylphosphine by the well-known Staudinger reaction. Similar reducing agents include trimethyl-, triethyl-, or tributylphosphine, or an alkyl diphenylphosphinite such as methyl or ethyldiphenylphosphinite. Suitable solvents for this reduction include aqueous organic solvents such as TNE, dioxane, acetonitrile, acetone, and OME containing from about 195 to 5095 water, preferably from about 595 to 1095 water. The best organic solvent is TNE. The reaction temperature can be in the range of about 02C to about 602C, preferably between about 202C and about 40260.

Alternatively, azidolactone III can be treated with triphenylphosphine or a similar reducing agent under anhydrous conditions to give iminophosphorane MU, which is a useful intermediate: o a; 0 » earth (o)

oh

Therefore, one embodiment of Method A is implemented through an intermediate compound MU, and another embodiment of Method A is implemented through an intermediate compound IM. (at)

Aminolactone IM obtained as described above can be used with or without separation from the reaction mixture. Desired caspase inhibitor I prodrugs are obtained with IM by adding the appropriate Ro, Ro-P3, or Ro-P. component t

Conjugation of IM with such a component can be carried out using a suitable carboxylic acid or its co-reactive equivalent under standard conditions for the formation of an amide bond or coupling. A typical coupling reaction includes a suitable solvent, IM at a concentration ranging from about 0.01 to 10M, preferably from about 0.1 to 1.0M, the necessary carboxylic acid, a base, and a peptide coupling reagent. h-

If the IM is used without separation, the coupling can be carried out directly in the solvent of the reaction mixture, which was used in the preparation of the IM, or in another solvent. To this reaction mixture the required carboxylic acid can be added and the reaction maintained at a temperature in the range of about 0°C to 100°C, preferably between about 20°C and 40°C. from about 02 to 602C, preferably between about 202 to 4026. t s The base is typically a tertiary amine base such as triethylamine, diisopropylethylamine, M-methylmorpholine, OVO, "» OBM, M-methylimidazole, preferably triethylamine or diisopropylethylamine. The amount of base used ," in general, up to about 20 equivalents per IM equivalent, preferably at least about 3 equivalents of base.

Examples of peptide bond reagents include OSS (dicyclohexylcarbodiimide), BIS (diisopropylcarbodiimide) 45, di-p-toluenecarbodiimide, BOR (1-benzotriazolediethylphosphate-1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide), -ES (1-( 3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride), cyanuric fluoride, cyanuric chloride, TEREN co (tetramethylfluoroformamide hexafluorophosphonate), ORPA (diphenyl phosphorazidate), BvVOR (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), nvt and (O-benzotriazole -i-yl-M,M,M',M'-tetramethyluronium hexafluorophosphate), two of them 20 (O-benzotriazol-i-yl-M,M,M',M'-tetramethyluronium hexafluorophosphate), no) (O- (M-succinimidyl)-M,M,M',M'-tetramethyluronium tetrafluoroborate), NATO with (M-Kdimethylamino)-1-H-1,2,3-triazolo|4,5,6|-pyridine-1 -ylmethylene|-M-methylmethane-ammonium hexafluorophosphate

M-oxide), BOR-SI (bis(2-oxo-3-oxazolidinyl) phosphine chloride), RUVOR ((1-H-1,2,3-benzotriazol-1-yloxy)-tris(pyrrolidino) phosphonium tetrafluoro- phosphate), BP (bromotris 29 (dimethylamino) phosphonium hexafluorophosphate), OERVT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(ZH)-one),

GF! RUVHOR (bromotris (pyrrolidino) phosphonium hexafluorophosphate). EOS, NOAT, VOR-SI and RUVHOR are the best peptide bond reagents. The amount of peptide bond reagent ranges from about 1.0 to about 10.0 equivalents. Optional reagents that can be used in the amide bond formation reaction include OMAR (4-dimethylaminopyridine) or active ether reagents such as NOVvVtT 60 (1-hydroxybenzotriazole), NOAT (hydroxyazabenzotriazole), NOBi (hydroxysuccinimide), HOM ( endo-M-hydroxy-5-norbornene-2,3-dicarboxamide), in amounts ranging from about 1.0 to about 10.0 equivalents.

Alternatively, it is possible to treat either IM or M with a chemically active equivalent of a carboxylic acid, such as Р.о-, Ро-Ра- or Ро-Ра-Р.-С (хО)Х, where С(-О)Х is a group , which is more chemically active than COOH in the coupling reaction. Examples of the -C(-O)X group include groups where X is SI, ER, OS(O)K (K is an aliphatic or aryl group),

ZN, ZK, 5Ag or ZeAg. When the intermediate compound is M and not IM, it is preferred that an acid fluoride (X is E) be used in the coupling reaction. Suitable conditions for using these reactive equivalents are known from the prior art.

A number of chemical groups are known, which can be used as P 3-R- part of ISE or caspase inhibitor prodrugs.

Examples of such groups Pz-Pho- are shown in Table 1 as part of P.-Pz-Pho-component.

And Ge) o o still at 2 70 o.g

Table 1. R.i-RU-R.»- Groups in AA. h

Ra Da r. |: her Paradise (SNgdp

I am with S

O Av, No Ge a y se a do she kh Sh

M Ra» M. iAdo

R. - Y o -

Я о ем 5 т сч в в ж (8) 5 A, -Uy h-uk y ts

S / He and AA. (at)

Ra". M g

Ra- M - N o ay Re - t t Ad" "v « h a 3 so so ko 2 M - sn -

Y Zh Mch Rem g

M

Ra. Mshi Ry-k 76 yo

And Gee! n " 3 k 1 y - (sne )p iy s Ra-nm 8 R. ikh h" ny "MN che Ra-m y y shchi (in) Ge! n ОО АХА; sh a o -I -uk v ve |: A - s He ve U laz M that Re. Mykh (95) t M Rak Mik) yo t no o sh»

R a x iChe) where n - from 0 to 3; AA refers to the side chain of an amino acid; X - M, 0, 5, 50, 50", SNE, SE", c(v3u,

S-O or FEMALES; A - O, 5 or H"; M - M or CH; K - hydrogen, C.4.42 an alkyl group, an aryl group or a heteroaryl group, and the K groups are optionally replaced by an ion or a halogen; VK Z is alkyl having from one to six

Gee! carbon atoms; and CO is hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkyloxy, amino, phenyl, phenoxy, hydroxy, alkoxycarbonyl, carboxyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylcarbonylamino, where alkylcarbonylalkylamino, alkylamino, dialkylamino, aminosulfonyl or cyano group; and K5 and B" are independently chosen from

VU, aryl, heteroaryl, (C1-12 alkyl) aryl, (C4-12) benzocycloalkyl or (C1-42 alkyl) heteroaryl. 60 The best groups R.-Ra-Ro- are shown in Table 2.

Table 2. The best groups R.-Raz-R»- b5 more. and em My Rez uiM ben and pu i - a-1 і-1 . : Ms

IS

: 8 to R. Her M and R, ek Re M em M ge) no no se-2 e-3 se-4 (c)

Kk sn m

Re Rem M M.

Come on Rem,

H se-5 s-b a-1i o o s

M dream

In o BB (8) c. Re. shi sho si Ge) Y o Resn a-2 e-1 zh-1 F

Ya-y ns o « no M sn jo y

Re M Ran M M z y; h- M her and Re-M to t so

Ha! Sn N shcha h-1 p-1 1-1 o, o « m Z

Fi, M I s y m M Re M ; Ra ve nu ;" M -- yoshe 3-1 k-1 1-1 -I o pe v e o i m v i Ra u - z o sund (Che) 1-2 shshch-1 t-z (F. ko 60 65

IS

! and

Ra. M Y M, 2 Y on | 7 Ra. M (2) R M M Y "r --kt n o o oe-i o-2 o-3

Osn yh M- - y Wei NIC "she

SNz NN o n 8) in-i «-1 k-1

NM. 20 Va

R

M-8. KI

Rak x A 5 no shg-2 p-1 seI where B5 is optionally substituted benzyl, as described below, or 2-indanyl, and the Ri component is represented by K-T-, where o

K-T is K-SO, KOS-O, EMNO-O, KS(O) S-O or KO". The best K of the P group are shown in Table 3.

Table 3. Best B group R. Geo)

Gee) - -

From sn - 2 o SU and s E « 100 101 102 103 104 - s a SI s. in"

THAT IS IS si si s SI SI 105 106 107 108 109 -I (95) in» SU CKU with DO e E NU Kk; but us (Che) 110 111 112 113 114

On Nz si o -- no yuyu NhM no o nom a

E SN» SN» Si 115 vo 116 117 119 120 b5 nd Su ? I'm sorry. in

Ge) o; 121 122 123 124 about | I in s n DY Na av

Z Z o. he Not g 125 126 127 128

E or OME chan si

M | M | - M "

OMe OMe si 129 130 131 132 133 -- o so

N r M. Nam Ge N cm - I sa n o 134 135 136 137 138 o . about her

M M

» (HA a OO s h 139 140 141 142 143 so

Ge) : He be Me 7 m.

Si-cho Alkyl Z Y SI Y - M M. 2 2 M

Ha) 144 145 146 147 148 «

Kk - there is oh Ge! 5. s OO ss so r 4 "with re M M (ozh 7 p 149 150 151 152 153 - M. I "E S . M with SO SYU (in) o 154 155 156 157 t" si nin o" ev: nu S polo t

NC) 158 1559 160

IF) Most preferably, if K-T- is K-CO, where K is 1-naphthyl, 2-naphthyl, 1-isoquinolinyl or

But 5 where positions C and 5 in K are independently and optionally substituted by halogen, preferably chlorine, or C..3 alkyl, and position 4 is optionally substituted by amino, acetamido, hydroxy or methoxy.

The best groups R.-Ra-Ro- are shown in Table 4. b5

Table 4. The best groups of R.-RURo -

Uh in; iv

NM r ve M o "ZhK i Ky t ia no a-ia і-1а і-1і5 t sho" ke "АХ "х n о і o і a-іа h-1a h-2a 20 ky ev nm Kk і secondary school

N

25 o o o-g2a s-ta e-iia (o) o vu M (22) 30 9 « s-vba de K, according to Table 3, - one of the following groups: 100, 105, 107, 108, 114 . connected in series. For example, Boc-protected proline (pyrrolidine-alpha-carboxylic acid) can be attached to IM to give MI. and "c)

M

40 va, o, s 0 No o-vk ts Ui y?

After removing the Bos, P z or Pa3-P group. components can be attached by alkylating or acylating the nitrogen of pyrrolidine-alpha-carboxylic acid. about (in)

V gyu cho o s M di M b-v i (4av,58)-Iita (45,58)-IIII iz 50 o Ge) o ra. head of the university n oO-k! N ba

Ia Ib

F)

GI I (c) o 2 - g o bo i a n O-v! N o-k!

Yes, yes

The reaction of M 5-X on racemic II generally gives the anti-isomers Ša and Shb shown above. They can be transformed by this process into anti-products Ia and IB. In many cases 2? will be a chiral fragment and Ia and

IBs will be diastereomeric. Chromatography and/or crystallization can be used to separate the diastereomers, depending on the nature of K' and B. Epimerization of both Ia and IB gives syn isomers Is or Id, respectively. The epimerization reaction is performed in the presence of a protonic acid or a Lewis acid (French Patent Application 97/08932). Suitable Lewis acids include ferric chloride, titanium tetrachloride, boron trichloride, boron trifluoride and stannous tetrachloride, and suitable protonic acids include organic acids such as methanesulfonic acid, trifluoroacetic acid and paratoluenesulfonic acid and inorganic acids such as hydrochloric acid and sulfuric acid.

Another method of this process for the production of compound I is carried out through butenolactone MII, where X is chlorine, bromine or iodine:

And Ge g? h

OV U.

The best starting butenolactone MI! is bromofuranone (Х - ВХ), which can be obtained by Ezsobag ei a|!., Ap.

Otsit., 1971,. 67, 43. This process, referred to herein as Method B, includes the steps: (a) provision of butenolactone MII: (c) t Ж» x

O-Ki Uti, where is V! as described above, and X is chlorine, bromine or iodine; (B) treatment of MI with azide M4-U, where U is a silyl group or counterion, to form azidobutenolactone MI: c

Ge oh y; m

UiIiYi; (o) (c) conversion of MI into aminobutenolactone ХХ or iminophosphoran ХХ: « ) о со ув; /8;

M Re

On b-v' tk o or RoREM b-v kh: co - (4) combination of either ХХ or ХХ with В-СООН or its chemically active equivalent to obtain Х: )

X /e. "

Kk M

НН о-нх, и - ин (е) reduction of the double bond of the furan ring in X to obtain I. К2СООН is an organic radical, ;» mainly P»-, Ro-Rz-, or Ro-P. carboxylic acid.

It will be apparent that steps 6-4 of the aforementioned Method B method are analogous to the steps previously described for

Method A, and can be performed in a similar way. - And also within the framework of this invention, another embodiment of the reaction of the amine bond THEM to obtain | carried out by acylation of anion IX using a reactive equivalent of a carboxylic acid, such as P 5-, Po-Ra-, or o Ro-Ra-P.-C (50) X, where C(-O) X is as described above. Their anion is first obtained by treating them in a solvent with any suitable base. Examples of solvents that can be used include ether 50 solvents such as TNE, OME, dioxane, diethyl ether, methyl tert-butyl ether; aromatic hydrocarbons, such as benzene, toluene, xylene; halogenated hydrocarbons, such as dichloromethane, carbon tetrachloride, dichloroethane;

Ge) or other organic solvents such as acetonitrile. Preferred solvents include TNE, UOME, toluene, or dichloromethane. Suitable bases for producing the anion include organic bases such as alkali metal hydride, alkali metal tert-butoxide, alkyl or aryl lithium such as methyl- or butyl-phenyllithium; an alkali metal amide such as lithium, sodium, or potassium bis(trimethylsilyl) amide, diisopropylamide, or tetramethylpiperidine.

Preferred bases include lithium bis(trimethylsilyl)amide, lithium diisopropylamide, or lithium tetramethylpiperidine.

F) The IH anion is treated with a carboxylic acid equivalent at the reaction temperature, which can range from about -782C to 1202C, preferably between about 02C and 6020C.

Azidobutenolactone MI can be obtained from MI by replacing its X substituent with azide. For the MIIA reaction, where its substituent X is bromine, MI! preferably treated with an alkaline or alkaline earth salt of azide, such as Mamz or GiMz. A silyl azide (M43-U, where U is the above-described silyl group) can be used in the presence of a fluorine reagent such as tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, sodium fluoride, or the like to produce a nucleophilic azide anion. Suitable solvents include aprotic organic solvents such as acetone, MMP, MEK, TNE, OME and dioxane, and halogenated hydrocarbons such as chloroform, b5 carbon tetrachloride, dichloromethane and dichloroethane. The reaction proceeds at a temperature in the range of about 02C to 1002C, preferably between about 202C and 4026C.

Reduction of the double bond of the furanone ring in X to obtain I can be carried out with the help of a hydride reducing agent, in particular, borohydride. Examples of such borohydrides include sodium or lithium borohydride, sodium or lithium triacetoxyborohydride, sodium or lithium cyanoborohydride, tetrabutylammonium cyanoborohydride, sodium or lithium trialkylborohydride, preferably sodium cyanoborohydride. Typically, the reaction mixture is adjusted to be weakly acidic, preferably with a pH between 3.0 and 6.0, with acids such as NH,

HBg, acetic acid, formic acid, trifluoroacetic acid, VEz.OEB, aluminum trichloride, zinc chloride or titanium tetrachloride. Optionally, the reaction can be buffered with 1.0-5.0 equivalents of sodium acetate. Optionally, the reaction can be catalyzed by adding 1-595 SosSi o/polukorin, 2psSi", 70. or 1-2 equivalents of chlorotrimethylsilane. Such chiral hydride reductants as K- or 5-AIripe Nuagide F (lithium B-isopinocampheyl-9-bora-bicyclo|3.3.1|nonyl hydride) are known for carrying out asymmetric reduction.

To get | reduction of the ring double bond in X can also be performed. This is useful when K is resistant to hydrogenation conditions, such as when B is an alkyl. Typical hydrogenation conditions include hydrogen gas under a pressure in the range of about 1 to 100 atmospheres, preferably about 15 to 70 atmospheres, and the presence of catalyst 75 in an amount of about 0.1 to 0.5 equivalents per equivalent of X. Suitable catalysts include Pa /С, РАД(ОН)2, РО, РІС, РІІУ2, mainly РІС or Ra/С. Suitable solvents include ethyl acetate, alcohols such as methanol, ethyl alcohol, isopropyl alcohol, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as TNE, OME, dioxane, preferably ethyl alcohol or TNE. When B is alkyl or aralkyl, such as benzyl, a rhodium(I) or ruthenium(II) catalyst is preferred for stereoselective reduction. Such a catalyst is obtained by the reaction of a metal in the form of one of its various complexes with chiral forms of ligands, such as methyl- or ethyl-PSHRNOH (1,1-bis-2,5-dialkylphospholano)benzene, OIOR (2,3-0-isopropylidene- 2,3-dihydroxy-1,4-bis(diphenylphosphino)butane), VIMAR (2,2'-bis(idiphenylphosphino)-1,1-binaphthyl), SNIKARNOBZ (bis(diphenylphosphino)butane), VRRM (M-Y-butoxy -carbonyl-2--diphenylphosphino)methyl-4-(diphenylphosphino)pyrrolidine), VRRREA c | (M/M-dimethyl-1-I(1",2-bis(diphenylphosphino) ferrocenyl|ethylamine-, OESRNOZ (M-benzyl-3,4-bis(diphenylphosphino) o pyrrolidine) or alkyl - BRE (bisphospholanoethane). Many other suitable ligands are known from the prior art.The preferred catalysts are 1,2-bis(2,5-dialkylphospholano)benzene(cyclooctadiene)rhodium (I) trifluoromethanesulfonate, where alkyl is a straight or branched chain alkyl group with 1- 8 carbon atoms, optionally substituted with an aromatic hydrocarbon of the phenyl type. The use of the (KK) isomer of these ligands (o) will lead to the (5)-configuration of the A-amino carbon in the product, and the use of the (5, 5) isomer will lead to the (K) " configurations. Suitable solvents include ethyl acetate, alcohols such as methanol, ethyl alcohol or isopropyl alcohol, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as TNE, OME or sodium dioxane. The preferred solvents are toluene or methanol. Reaction concentration X will typically range from about 0.01 M to 1.0 M, preferably from about 0.1 M to 1.0 M. Of course, the reaction temperature is in the range from about 02C to 602C, preferably from about 202C to 402C. (For the use of rhodium catalysts, see: - b. 2py, 27. Spep, Kh. 2papo; U. Ogd. Spet. (1999) 64, 6907-6910; M. 9. Vytk, 9U.. AyPep, MU. R .Kieztap; 9. Ateg.

Spent os, (1998), 120, 657-663; M.). Vigk, 9U.E. Reavieg, MU.A. Mydepi, K.I. Nagiom/; U. Ateg. Spent boss, (1993), 115, 10125-10138; For the use of ruthenium catalysts, see: 9U.M. Vhom/p, M. Koze, R.I. Kpidii, AM/iepapa; "

Hey! Tgtam Spit Rouse-Wavs, (1995), 114, 242-251; M.5arygi, M. OppiKki, M. Odazamjaga, T. Takanavzni, M. Ospiaa; Temapedgoop en. (1992), 33, 5783-5786; M. Mashtseoii, M. Vedpeno, A. Zoshimapii; . MoiIescshiag Saiiaiuviv A: - from Spetis! 140 (1999) 131-137). "» The above-mentioned Method B describes the sequence in which aminobutenolactone ХХ is first connected with P, or Rukh " by a component of caspase and then the ring double bond is restored. Alternatively, recovery and coupling can be performed in reverse order (Method C). Method C of this process includes the following stages: (a) provision of butenolactone MIA: - and c) (95) /e; x mni OK ut, 1 1 y y i od: where K' is as described above, and X is chlorine, bromine or iodine;

Ge) (5) treatment of MII with M-U azide, where U is a silyl group or counterion, to form MIP azidobutenolactone: iv) ro

M o Ov ut;

HF (c) conversion of MIIA into aminobutenolactone IX: c) 60 /e;

NOM

About them; (4) restoration of the ring double bond in IH to obtain amino lactone IM: b5 c) y; nm 2 O-K tu; and (is) the combination of IM with the organic acid КВ2СООН or its chemically active equivalent to obtain I, where

В?СООН - mainly Rо»о-, Rо-Ра-, or Rо-Р4 carboxylic acid. In Method C, stages (a) - (c) are the same as in Method B, and stages (a) and (e) are the same as the corresponding stages in Method A. Therefore, Method C with respect to the corresponding 70 stages can be done in the same way.

The scope of this invention includes certain intermediates described herein that are useful in the manufacture of caspase inhibitors and corresponding prodrugs. Therefore, one of the aspects of this invention relates to the compounds of the formulas

AI MT: o (c) demo

Mu b-v! m B. vi

ІиІ чУИииІ where VK! selected from an optionally substituted aliphatic group, an aralkyl group, or an aryl group. Examples

B include methyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, phenylbutyl, (ad)-methyl, (1)- methyl, 1-adamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 3-tetrahydrofuranyl, benzyl,

A-methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-(2-propyl)benzyl or 4-trifluoromethylbenzyl. high school

Especially useful are I and MI, where B is benzyl or C is alkyl, such as ethyl. at

Other aspects of this invention relate to compounds of the formulas o o no; /9; iy

Ku b-r: or ER: U gy chI

In Kk x, so de VK! is selected from an optionally substituted aliphatic group, an aralkyl group or an aryl group, and, in particular, from E! groups described above.

In order that this invention may be better understood, the following are manufacturing examples. These examples are provided for illustration purposes only and should not be construed as limiting the scope of the invention.

Examples of synthesis

Example 1. Production of 4-azido-5-ethoxy-dihydrofuran-2-one (I, B'-EVO «

This procedure was performed similarly to that described in Yu. .). Skegip, and ai/ Ogu. Heck (1999), 1, 1107-1109, Acetic acid (18.1 ml, 0.32 mmol) was added to a solution of azidotrimethylsilane (25.8 ml, 0.32 mmol) in dichloromethane (400 ml) at room temperature under nitrogen, and the reaction proceeded with stirring for 20 min. 5-ethoxy-5H-furan-2-one (II, 2'-EU (8.10 g, 0.06 mmol) was added dropwise, then 1,8-diazobicyclo

I5.4.01Y undec-7-ene (1.9ml, O0.01Zmmol). The reaction mixture was stirred for 24 hours, then washed with sodium bicarbonate, dried with sodium sulfate and evaporated. Purification by flash chromatography (5iO»5) eluting with 1:9 ethyl acetate:hexane gave 4-azido-5-ethoxy-dihydrofuran-2-one (7.85g, yield 7395) as a colorless oil. them TN-NMR (BOOMHCc, SOSIz) 5 5.17 (p, 1H), 4.00 (dd, 9U-7.0, 1.0Hz, 1H), 3.71 (m., 1H), 3, 49 (m., 1H), 2.77 (95) (dd, 9U-17.0, 6.0Hz, 1H), 2.32 (dd, U-8.0, 2.2Hz, 1H), 1 .08 (t, U-7.1HzC, 1.5H), 1.07 (t, U-7.1Gu, 1.5H) ppt. with a method similar to that described above, except that starting with 5-benzyloxy-5H-furan-2-one (I,

B'-Bp), 4-azido-5-benzyloxy-dichlorofuran-2-one (I, K'-Bp) was prepared as a solid substance, pi 1.62 g (yield 7296). (Che) TN-NMR (BO00MHz, SOSIi) 5 7.19 (d., BN), 5.25 (s, 1H), 4.71 (d, U-11.5Hz, 1H), 4.48 ( d, U-11.4Hz, 1H), 4.07 (dd, U-6.9, 0.9Hz, 1H), 2.82 (ddd, 9U-18.1, 7.1, 1.0Gu, 1H), 2.36 (ddd, U-18.1, 4.3, 1.4Hutz, 1H) ppt.

Example 2. Production of 4-((triphenylphosphoranylidene)-amino|-5-ethoxy-dihydrofuran-2-one (M, K-EO

A solution of 4-azido-5-ethoxy-dihydrofuran-2-one (0.05g, 0.29mmol) and triphenylphosphine (0.078g, 0.29mmol) in otoluene (ml) was stirred at room temperature under nitrogen for 5 hours. The solvent was evaporated to give 4-Ctriphenylphosphoranylidene)amino|-5-ethoxy-dihydrofuran-2-one (0.12g, yield 10095) as a yellowish, milky solid.

TN-NMR (BOOMHCts, SOSIz) 5 7.50 (d., 6H), 7.40 (m., ZN), 7.33 (m., 6H), 5.08 (d, U-31HC, 1H ), 3.63 (m., 60 1H), 3.23 (m., 1H), 2.50 (dd, 9-17.1, 5.9Hz, 1H), 2.27 (dd, 92171, 5.9Hz, 1H), 0.91 (t, 9-7.0Hz, ЗН) ррт.

Example C. Production of tert-butyl ether (2k)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (I K-EO

Method 1. From 4-azido-5-ethoxy-dihydrofuran-2-one through hydrogenation:

A mixture of 4-azido-5-ethoxy-dihydrofuran-2-one (1.06g, b.2mmol), 1 bo (5)-pyrrolidine-1,2-dicarboxylic acid tert-butyl ether (1.33g, b.2mmol ), and 1095 palladium on carbon (0.50 g) in ethyl acetate,

pre-degassed with the help of M" (50 ml), was stirred in a hydrogen atmosphere at a pressure of Tatm at room temperature for 1 hour. The mixture was diluted with dichloromethane, filtered (celite) and evaporated. The crude mixture was dissolved in dichloromethane (100 mL), treated with diisopropylethylamine (5.4 mL, 30 mmol), ES (1.48 g, 7.7 mmol) and NOVT (1.04 g, 7.71 mmol) and stirred at room temperature under nitrogen for 24 hours The reaction mixture was diluted with ethyl acetate, washed with 1095 sodium bisulfate, saturated sodium bicarbonate and brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (502) eluting with 1:1 ethyl acetate:hexanes gave tert-butyl ether (K)-2-(2-ethoxy-5-oxo-tetrahydrofuran-z3-ylcarbamoyl)-pyrrolidin-1-carboxylic acid 11, 19g, output 5690) in the form of 70 very viscous, pale yellow oil.

TN-NMR (500 MHz, SOSIv) 5 7.61 (ssh, 0.6H), 5.29 (s, 0.6H), 5.25 (ush s, 0AN), 4.29 (ush, 1.2H ), 4.20 (Ush s,

O.8H), 3.78 (m., 1H), 3.57 (m., 1H), 3.34 (ush, 1.4H), 3.25 (ush, 0.6H), 2.94 (ear dd, 9U-14.9, 3.8Hz, 1H), 2.31 (dd, 9U-18.0, 1.4Hz, 1H), 2.1-2.3 (ear 1H), 1, 82 (ush c, 1H), 1.39 (c, 9H), 1.17 (m., ZN) ppt. MS (EZ w): t/e-343 (M'-H).

Method 2. From 4-triphenylphosphoranylylene)amino|-5-ethoxy-dihydrofuran-2-one:

A solution of 1-tert-butyl ether (5)-pyrrolidine-1,2-dicarboxylic acid (0.11 g, 0.5 mmol), diisopropylethylamine (0.18 ml, 1.0 mmol) and tetramethylfluoro-formamidine hexafluorophosphate (TEREN) (0.13Hg,

0,bmmol) in dichloromethane (3 ml) was stirred at room temperature under nitrogen for 3 hours. A solution of 4-triphenylphosphoranylidene)amino|-5-ethoxy-dihydrofuran-2-one (0.20g, 0.5mmol) in dichloromethane (3ml) was added and the mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with 1095 sodium bisulfate, saturated sodium bicarbonate and brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (505) eluting with 1:11 ethyl acetate:hexanes gave (K)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ether ( 0.11g, output 6595) in the form of a very viscous, pale yellow oil.

Method C. From the tert-butyl ether of (K)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (X, BK'-EYUO through o hydrogenation:

To a solution of tert-butyl ether (2)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (X, BK"-EU (0.09 g, . diethyl-phospholano)benzyl-(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (5-15mg) The reactor was sealed and filled with hydrogen under pressure (950 psig bbatm) and left at room i) temperature for 2 days The solvent was evaporated and the residue was purified by flash chromatography (502) eluting with 1.5:98.5 methanol:dichloromethane to give tert-butyl ether

Zo (K)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (0.092 g, square yield) in v. in the form of a colorless oil. Chiral NRI C (SpigaIrak-AO column, eluting with 1:9 ethanol:hexanes): isomer IB - 35.490, isomer Ia - 564905, (mixture of isomers and Is) - 8.290.

TN-NMR (BOOMHCz, SOSIz) 5 7.60 (ssh s, 0.25Н), 7.40 (ush s, 025Н), 6.5 (ush m., 025Н), 5.38 (d, U- 5Hz, « 0О.5Н), 5.27 (s, 0.5Н), 4.65 (ush, 0.5Н), 4.20 (ush m., 1.5Н), 3.85 (m., 0.5Н), 3.77 (m., 0.5Н), 3.57 (m., 1Н), - 70 330 (m., 2Н), 2.95 (m., 0.5Н), 2 ... -1Hz, 1.5N), 1.15 (t, U-7Hz, 1.5N) ppt. ; Example 4. Production of tert-butyl ether (2k)-2-(2-benzyloxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (I, B'-Bp)

A solution of tert-butyl ether (5)-pyrrolidine-1-carboxylic acid (0.13g, 0.bmmol), - 15 4-azido-5-benzyloxy-dihydrofuran-2-one (0.14g, 0.1bmmol) and triphenylphosphine ( 0.28g, 1.0mmol) in tetrahydrofuran (bml) and water (5 drops) were stirred under nitrogen for 0.5 hours at room temperature and 2 (95) hours at 6523. The reaction mixture was cooled to room temperature, treated with diisopropylethylamine with (0 .52ml, 5.0mol), ES (0.15g, 0.75mmol), and NOVT (0.10g, 0.75mmol) and stirred at room temperature under nitrogen for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with 1095 ml of sodium bisulfate, saturated sodium bicarbonate, brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (505) eluting with 2:3 ethyl acetate:hexanes gave (K)-2-(2-benzyloxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidin-1-carboxylic acid tert-butyl ether ( 0.12g, output 4995) In the form of a viscous resin. "H-NMR (50O0MHz, SOSIz) 6 7.63 (ssh d, 9U-7.6Hz, 0.7H), 7.28 (m., 5H), 6.50 (ush, 0.ZN), vv 9.3 (ush c, 0.5Н), 5.33 (с, 0.5Н), 4.77 (d, U-11.6ГЦ, 1Н), 4.56 (dd, U-11.6, 3.7Hz, 1H), 4.37 (ush s, 1H), 4.18 (ush s, 1H), 3.32 (ush s, 14H), 3.24 (ush s, 06H), 2.97 (ush d, 9U-11.6Hz, 1), 2.35 (dd, 9U-181, 1.7HzC, iF) -1H), 2.1-2.3 (ush, 1H), 1.81 ( уш с, ЗН), 1.58 (с, 9Н) ppt. MS (E5 zhk): m/e-405 (M.N). ka Tert-butyl ether (2k)-2-(2) was prepared in a similar way -ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (I, K'-EU (0.07g, yield 60 190).

Example 5. Production of 4-bromo-5-ethoxy-5H-furan-2-one (MII, B7-E)

This procedure was performed similarly to the one described in S. Ezsobag, et al., App. Ocit. (1971), 67, 43-57.). A solution of bromine (4.05 ml, 78.2 mmol) in carbon tetrachloride (25 ml). The reaction mixture was stirred for 1 hour at 02С, then for 2 hours at room temperature. The solvents were removed under reduced pressure and after a short period of time the residue was distilled in vacuo (ca.

Oh, 5mm). The fraction collected at 10020-1202C gave 4-bromo-5-ethoxy-5H-furan-2-one (13.2g, yield 8290) as a yellow oil. 7H-NMR (500 MGu, SOSI") 5 6.24 (p, 1H), 5.63 (s, 1H), 3.71 (m., 1H), 3.63 (m., 1H), 1, 14 (t, 9-7 1Hz, ZN) ppt.

Example 6. Production of 4-azido-5-ethoxy-5H-furan-2-one (MI, B'-EO

A mixture of 4-bromo-5-ethoxy-5H-furan-2-one (2.07 g, 10.0 mmol) and sodium azide (0.66 g, 10.2 mmol) in dimethylformamide (LOml) was stirred at room temperature under nitrogen for 24 hours . The reaction mixture was diluted with ethyl acetate, washed with 09C water and brine, dried with sodium sulfate and evaporated. 70 Purification by flash chromatography (SO 5) eluting with 1:29 ethyl acetate:hexanes gave 4-azido-5-ethoxy-5H-furan-2-one (1.04 g, yield 6295) as a pale yellow oil.

TN-NMR (500 MGu, SOSI") 5 5.83 (p, 1H), 5.63 (s, 1H), 3.99 (m., 1H), 3.88 (m., 1H), 1, 35 (t, U-71Hz, ZN) ppt.

Example 7. Production of 4-amino-5-ethoxy-5H-furan-2-one (IX, K7-E) 75 Method 1. Through hydrogenation:

A mixture of 4-azido-5-ethoxy-5H-furan-2-one (0.62g, 3.67mmol) and 1095 palladium on activated carbon (0.91g) in deoxygenated ethyl acetate (20ml) was stirred in a hydrogen atmosphere under a pressure of Tatm 24 hours The reaction mixture was filtered (celite) and evaporated to give 4-amino-5-ethoxy-5H-furan-2-one (0.53g, yield 100905) as a yellow oil. "H-NMR (B5О0МГЦС, СОСІІ) 5 5.60 (s, 1H), 4.85 (ush s, 2H), 4.81 (s, 1), 3.81 (m., yin), 3, 67 (m., 1H), 1.22 (t, 9-7 1Hz, ZN) ppt.

Method 2. Using the Staundinger reaction:

A mixture of 4-azido-5-ethoxy-5H-furan-2-one (0.10g, 0.59ummol) and triphenylphosphine (0.15g, 00.59mmol) in tetrahydrofuran (ml) and water (0.5ml) was stirred for 20 hours at room temperature, then 3 days at 659 under nitrogen. The reaction mixture was diluted with dichloromethane, washed with water, dried with sodium sulfate and evaporated to give 4-amino-5-ethoxy-5H-furan-2-one in a mixture with triphenylphosphine oxide (0.25g, yield at 10096).

Example 8. Production of 4-((triphenylphosphoranylidene)amino|-5-ethoxy-5H-furan-2-one (XI, B7-E)

A solution of 4-azido-5-ethoxy-5H-furan-2-one (0.17 g, 1.0 mmol) and triphenylphosphine (0.26 g, 1.0 mmol) in toluene F) (bml) was stirred at room temperature under nitrogen for 1 hour, then heated at 60-70 for 8 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with sodium bisulfate, sodium bicarbonate and brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (FL) eluting with 1:1 ethyl acetate:hexanes gave 4-[triphenylphosphoranylidene]amino|-5-ethoxy-5H-furan-2-one (0.18 g, yield 4595) as a yellowish solid .

TN-NMR (BO0MHCc, SOSIv) 5 7.73 (sh. 6H), 7.65 (m., ЗН), 7.55 (m., 6H), 5.58 (s, 1H), 4.33 (c, 1H), 3.81 in. (m., 1H), 3.64 (s, 1H), 1.27 (t, 9-7, 1Hz, ZN) ppt. MS (E5 I) t/e-404 (M.N).

Example 9. Production of tert-butyl ether (2)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (X, K-EO)

Method 1. Due to the conditions of the peptide interaction: C 50 Solution of 4-amino-5-ethoxy-5H-furan-2-one (0.04g, 0O.ZOmmol), (5)-pyrrolidine-1,2-dicarboxylic acid, 1 with tert-butyl ether (0.07 g, 0.0 mmol), diisopropylethylamine (0.12 ml, 0.0 mmol) and

Iz» O-benzotriazol-yl-M,M,M',M'-tetramethyluronium hexafluorophosphate (HVT) (0.14 g, 0.3 mmol) in dichloromethane (3 ml) was stirred for 24 hours, evaporated, re-dissolved in 1-methyl-pyrrolidinone (Zml) and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with 1095 sodium bisulfate, saturated sodium bicarbonate and brine, dried with sodium sulfate and evaporated. Purification by two flash - and chromatography (50 5) eluting with 4:6b, then 35:65 ethyl acetate:'hexanes gave tert-butyl ether oz (K)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran -3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (0.009g, yield 990) in the form of a film. o TN-NMR (5O00MHz, SOSI»v) 5 10.2 (ssh s, 0.7Н), 10.1 (ush s, 0.3Н), 6.21 (ush s, 0.7Н), 6, 17 (sh s, 0.3H), 5.68 t. 50 (sh, 0.7H), 5.60 (sh s, 0.3H), 4.38 (sh s, 1H), 3.85 ( m., 1H), 3.72 (m., 1H), 3.25-3.45 (m., 2H), 2.53 (ush d, c 12.5Hz, 0.7H), 2.1 (ush, 0, ZN), 1.87 (ush m., ZN), 1.44 (c, 9H), 1.21 (M., ZN) pp.

MS (EZ zhk): t/e-341 (M.N).

Method 2 (A). Due to the formation of anion/(acylation:

A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.6b4ml, (F) 0.b4mmol). The reaction mixture was stirred for an hour at 09Sb. A solution of 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ether (0.20g, 0.77mmol) in tetrahydrofuran (3ml) was added dropwise. The reaction mixture was stirred for 16 hours at room temperature. The mixture was diluted with ethyl acetate, washed with 10956 sodium bisulfate, saturated sodium bicarbonate and brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (ZO 5) eluting with 35:65 ethyl acetate:hexanes gave tert-butyl ether (K)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidin-1- of carboxylic acid (0.05 g, yield 26965).

The parent 4-amino-5-ethoxy-5H-furan-2-one (0.03 g, yield 36905) was also isolated. 65 Method 2 (B). Due to anion formation/acylation:

To a solution of 4-amino-5-ethoxy-5H-furan-2-one tert-butyl ether (0.05 g, 0.5 ppm) and

Sodium tert-butoxide (0.05g, 0.49mmol) was added to 2-fluorocarbonyl-pyrrolidine-1-carboxylic acid (0.09g, 0.42mmol) in tetrahydrofuran (bml) at room temperature under nitrogen. The reaction mixture was stirred for 1 hour with heating in a reflux flask. After cooling, the mixture was diluted with ethyl acetate, washed with 1096 potassium bisulfate, saturated sodium bicarbonate brine, dried with sodium sulfate and evaporated. Purification by flash chromatography (5iO5) eluting with 4:b ethyl acetate:'hexanes gave tert-butyl ether (K)-2-(2-ethoxy-5-oxo-2,5-dihydro-furan-3-ylcarbamoyl)- of pyrrolidine-1-carboxylic acid (0.075 g, yield 6395). The original 4-amino-5-ethoxy-5H-furan-2-one (0.016 g, yield 32905) was also isolated.

Example 10. Production of tert-butyl ether (k)-2-(oK, 70.33)-2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl|-pyrrolidine-1-carboxylic acid (MI, 2'-EV

A mixture of 4-amino-5-ethoxy-5H-furan-2-one (0.13g, 0.75mmol), 1-tert-butyl ether (5)-pyrrolidine-1, 2-dicarboxylic acid (0.16g, 0 .75 mmol) and a few crystals of the Sopdo Kay indicator in ethyl alcohol (5 ml) was treated with sodium cyanoborohydride (0.06 bg, F0.900 mmol), followed by the dropwise addition of 4AM NOI in dioxane to obtain and retain a bluish color (urNH). The reaction mixture was stirred for 2 hours, filtered (Celite) and evaporated. The residue was dissolved in dichloromethane (5ml), treated with diisopropylethylamine (0.52ml, 3.0mmol), EOS (0.18g, 0.94mmol) and NOVT (0.13g, 0.94mmol) and stirred at room temperature under nitrogen for 20 hours . The reaction mixture was diluted with ethyl acetate, washed with 1090 sodium bisulfate, saturated sodium bicarbonate and brine, dried with sodium sulfate and evaporated.

Purification by flash chromatography (ZO 5) eluting with 1:11 ethyl acetate:hexanes gave a 4:1 mixture (according to 7"H-YAMe) of tert-butyl ether (k)-2-(2K, 35)-2-ethoxy- 5-oxo-tetrahydrofuran-3-ylcarbamoyl|-pyrrolidine-1-carboxylic acid and tert-butyl ether (k)-2-(25,35)-2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl|-pyrrolidine -1-carboxylic acid (0.06bg, yield 2390) in the form of a colorless oil.

TN-NMR (5O00MHz, SOSIv) 5 7.60 (ssh, 0.15Н), 7.44 (ush s, 0.5Н), 6.51 (0.35Н), 5.38 (d, 9-5 ,3Hz, 0.8H), 5.29. DC SM 259 (s, 02H), 4.5 (ush m. 08H), 4.1-4.3 (ush m. 1.2H), 3.84 (m. 08H), 3.78 (m. . (ush m., 0.8), 2.34 (dd, 9U-17.2, 104Hz, 0.8H), 1.9-2.3 (ush 1.7H), 1.83 (ush s, 2.5Н), 1.39 (c, 9Н), 1.19 (m., ЗН) ppt.

This product, (K)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ether, was also isolated as a mixture of Me stereoisomers (0.030g, yield 1195) in the form of a colorless oil. "t

Example 11. Production of 1-(2-(4-amino-3-chloro-benzoylamino)-3,3-dimethylbutyryl|pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide me )

Stage A. Benzyl sulfur with 11-(2-(2-Ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-carbonyl|-2,2-dimethyl-propyl)-carboxylic acid 39 -

To a solution of tert-butyl ether (2k)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid (X, B'-EХО (014g,

0.41 mmol) ("H-NMR shows the ratio of epimers « 8:2 syn-anti) and dimethylpyridine (0.48 ml, 4.1 mmol) in « dichloromethane (5 ml) at room temperature under nitrogen was added dropwise with 70 trimethylsilyl trifluoromethanesulfonate (0.48 mL, 2.4 mmol). The reaction mixture was stirred for 0.5 h, then treated with saturated sodium bicarbonate, extracted with three parts of dichloromethane, dried (sodium sulfate), and evaporated. To the crude intermediate was added 2 -benzyloxycarbonylamino-3,3-dimethylbutyric acid (0.12g, 0.045mmol) in dichloromethane (5ml), EOS (0.10g, 0.5mmol) and NOVT (0.07g, 0.51mmol). The resulting mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was diluted with ethyl acetate, washed with 1095 g of potassium bisulfate, saturated sodium bicarbonate and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (505) eluting with 1:11 ethyl acetate:hexanes gave ( 95) 311-(2-(2-ethoxy-5-oxo-tetra-hydrofuran-3-yl. carbamoyl)-pyrrolidine- 1-carbonyl|-2,2-dimethyl-propyl)carboxylic acid benzyl ether (0.12 g, yield 59905) in the form of a white foam.

TN-NMR (BO0MHZc, SOSIi) 5 7.43 (ssh d, 9-7.7Hz, 1H), 7.28 (s, BN), 5.40 (m., 2H), 5.02 (AB k , uU-1211, ve З1.0Hz, 2H), 4.55 (m., 2H), 4.29 (d, 9U-9.6Hz, 1H), 4.23 (m., 02H), 3, 85 (m., 0.8H), 3.73 (m., 1H), 3.58 (m.,

He) 2H), 2.90 (m., 0.2H), 2.74 (dd, 9U-17.0, 8.4Hz, 0.8H), 2.30 (m., 2H), 2, 05 (m., 1H), 1.90 (m., 1H), 1.80 (m., 1H), 1.20 (t, 9U-7.0 c, 2.4H), 1.15 ( t, U-1.0Hz, 0.6H), 0.93 (s, 9H) ppt. 7H-NMR shows the presence of epimers in the amount of "- 8:2 syn:anti. And S/M5 (EZ-yuK): t/e-490.14 (MAN)

Stage B. 1-(2-(4-amino-3-chloro-benzoylamino)-3,3-dimethylbutyryl|pyrrolidine-2-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide and F) Benzyl ether solution of 11-(2-(2-ethoxy-5-oxo-tetrahydrofuran-3-yl cocarbamoyl)-pyrrolidine-1-carbonyl|-2,2-dimethylpropyl)icarboxylic acid (0.12g, 0.24mmol) in ethyl alcohol (ml) was treated with 1095 palladium hydroxide on carbon (0.05 g), stirred in a hydrogen atmosphere at atmospheric pressure for 4 hours, filtered through celite and evaporated. The crude intermediate was dissolved in dichloromethane (5 mL) and treated with 4-amino-3-chlorobenzoic acid (0.04 g, 0.2 mmol), EC (0.06 bg, 0.29 mmol) (4-diisopropylethylamine (0.1 mL, 0.7 mmol) ) and stirred at room temperature under nitrogen for 20 hours.

The reaction mixture was diluted with ethyl acetate, washed with 1095 potassium bisulfate, saturated sodium bicarbonate and brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (5iO5) eluting with ethyl acetate:hexanes gave 1-(2-(4-amino-3-chloro-benzoyl-amino)-3,3-dimethylbutyryl|pyrrolidine-2-carboxylic acid

(2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide (0.08 g, yield 62905) in the form of a colorless film. 1H-NMR (5О0О0МГЦц, СОСИв) 5 7.67 (5, 9U-2.0HzЦ, 1Н), 7.50 (m., 0.2Н), 7.44 (dd, uU-8.4, 2, 0Hz, 1.0H), 7.33 (d, -8.0Hz, 0.8H), 6.69 (d, U-8.4Hz, 71H), 6.55 (d, 9U-9.2Hz , 71H), 5.39 (d, 9U-5.2Hz, 0.8H), 5.29 (s, 0.2H), 4.79 (d, uU-9.4Hz, 1H), 4.62 (m., 08H), 4.50 (m., 7.0), 4.25 (m., 02H), 3.83 (m., 08H), 3.77 (m., 02H), 3 .62 (m., 08H), 3.55 (m., 0.2), 2.92 (m., 0.2H), 2.76 (dd, 9U-17.2, 8.4Hz, 08H ), 2.30 (m., 2H), 2.05 (m., 1H), 1.93 (m., 1.0H), 1.85 (m., 1H), 1.22 (t, 9-7 1HzC, 2.4H), 1.16 (t, U-71Hz, 0.6H), 1.00 (s, 9H) ppt. "H-NMR shows the presence of epimers in the ratio "- 8:2 synant.

While we have described a number of embodiments of the present invention, it is understood that our basic examples may be modified to implement other embodiments that utilize the compounds and methods of the present invention. Therefore, it should be understood that the scope of this invention should be determined according to the attached claims, and not according to the specific embodiments that were presented as an example.

Claims (34)

/5 Formula of the invention 1. The method of obtaining the compound of formula I: as follows; tm N o-k! where VK' is an optionally substituted group selected from an aliphatic group, an aralkyl group, a heterocyclylalkyl group or an aryl group, and B? - an organic radical, in which: o (a) preparation of butenolactone of formula I: Ge) II; with F « O-v! (B) treatment of the compound of formula I with azide Ma-U, where MU is hydrogen, a silyl group or a counterion, to obtain the azidolactone of formula II: co PI; o and - where M (c) is the transformation of the compound of the formula PI into aminolactone of the formula IM or iminophosphorane of the formula M: c) c or (o) and I» to it (c) o) - 7 NM Cream O-v! bro! (65) M U; o (4) interaction of a compound of the formula IM or M with K2СООН or with a reactive compound equivalent to it, with "" 20 obtaining a compound of the formula |. c 2. The method according to claim 1, in which 2 is a fragment of R.-Ra-R" - a caspase inhibitor or its part. 3. The method according to claim 2, in which B? - fragment Ru-Ra-P" - caspase inhibitor, and where the said fragment represents one of the following groups: Ф) име) 60 b5 AD, in Adz OH R y M 1 R y (I (SN am U vek em v n Н n 9) AA» Ge! g) a s A» Az ra H r M (SNa)a : M Sho Rad M . and A» di No No a e E v? 5 A x- Hmm M Ra. M M AD» M M M t No 2 H , s chCh i o A» (2) Vo Zh tA SN ; M Gr tenakh " /-x tsi Ra M M (ze) Ra M RAM do yo MN (9) (ze) no m. 3 k 1 v " (sno )p y v ! Ra. U-8 | g - NM Ra. M Rah M s i MN Z M na o No A "z IF) 4 p t p o t 5 (95) 5 7 -UK vo e Ak v / i95) M ZH Kk i: Az k-k s" - M Райох Мн Te) с т no Рче ГФ) where n - from 0 to З; AA refers to the side chain of an amino acid; X - M, 0, 5, ZO, 505, SNE, Сg», с( в3y, 7 С-О or SAMOK; A - O, 5 or H»; M - M or CH; K - hydrogen, C..42 alkyl group, aryl group or heteroaryl group, and the EC groups are optionally substituted; KZ - alkyl having from one to six carbon atoms; and KZ - in hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkyloxy, amino, phenyl, phenoxy, hydroxy, alkoxycarbonyl, carboxyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylcarbonylamino, alkylcarbonylalkylamino, alkylamino, dialkylamino, aminosulfonyl or cyano group; and 25 and B" are independently selected from Y, aryl, heteroaryl, (C.412alkyl)aryl, (C4.12)benzocycloalkyl or (C.12alkyl)heteroaryl. 4. The method according to claim 3, in which EC? - fragment P.-Ra-P" of a caspase inhibitor, and where the said fragment is one of the following groups: N Vo - | - am Mokh v ha M y N Ge! 2 N o Y o a-1 i-1 I : se-1 70 E SNU as Renu den venu (o) N o) o s-2 s-3 s-4 VK in | o SN M y Rem" yk M M se Ru/- o Go "MM M, (o) s-5 s-6 a-1 Ge) zo " so 10) o Go) "sn M. t o m ' M ге; nН o be o) « 70 а-2 е-1 ж-1 7 с з я-и нас о nНб M «СНз - 0 в сх, M з (95) cho lem - vi ne s N o o sv but there are 70 h-1 in-1 and-1 (Che) F) what is 65 TV, about M s and i? 7 And; Raz M. N Ra. M ve o em -- "Scho No 7 3-1 k-1 1-1 M. 5 8 i, r u Rak u M n o N ) (o) 1-2 tpt-1 t-2 s E ' o y Rem M Y Me N t | But Ra. M b) Ba -t No « No 1 so o- o-2 - o-3 so m. 5OSNz So her and; Rom M Ra krech SN i o ni o s khz» r-i h-1 k-1 NM 2-0 -I R OO M- Yam M R. m N / y syu M o o N o sh» te) K-? where VZ is optionally substituted benzyl or 2-indanyl, and R. is a component represented by K-1-, where K-T is K-SO, KkOS-O, EMNOS-O, KS(O)C- Oh or BO". where 5. The method according to claim 4, in which K2 is a R.-Ra-Ro fragment, in which the R. part is selected from B-SO, KOS-O, EMNO-O, KS(О0)С-О or KBO", and K - one of the following groups: bo b5 sos So su su y si E 100 101 102 103 104 si si si 7 us Yake; but NM ko si si SI si si 105 106 107 108 109 and DU SU new no t no yo 110 111 112 113 114 sch ns ns si zvu o) in. - uv Y i no E SNz SNz s b Zo 115 116 117 119 120 - so so i- « - s z -I d) d) iz 50 s (F) t bo 65 they and NM om Z; NM ns. in o o 121 122 123 124 o g Zh NM. o SNz Nas M o, on SI 125 126 127 128 E » cha 7OMe zny so o Sg OMe OMe SI 129 130 131 132 133 s o o Ge") so " (o) Y me) nom n-K ryk 7 si on me) for 134 135 136 137 138 - " - -- M s z" 139 170 141 142 143 - I o o o trip 50 s F) about 65 : U X y: U Sta Ali o S s s M "o M (o); 144 145 146 147 148 be ss so "Us / Jew M K 2 7 shchi 149 150 151 152 153 "sb so is and I I her o) 154 155 156 157 s o SI X 0 2 No M Myto y / N si t 158 159 160 o 6. The method according to claim 5, in which B? - a fragment of R.-Ra-Ro, selected from one of the following groups: о ч- « ши с з -И (95) (95) из 50 иЧе) Ф) име) 60 б5 There is A vv; - "ut Ky o v v v me a n o o o 70 a-1a і-1a і-15 her ХУ Хм Хм вОНМ В7СНМ І ВН І (o) Ge) (8) a-1a h-1іia h-2a se и | s" (o) o o "A u i c) o No o-2a c-7a c-1ia b " Ge) c) in Fo for KON M 6) s-ba de K - one of the following groups: "70 s si Z ia S khz" y; but NM 100 si SI SI 45 . - 105 107 108 2) Su No SI o n ZH iz 0 y ns SN s (Che) - 114 117 119 126 - and . (c) ts M o -- o NM 139 170 si 141 bo 136 7. The method according to claim 2, in which B is methyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, or phenylbutyl, (a)-menthyl, ()-menthyl, 1-adamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 3-tetrahydrofuranyl, benzyl, t -methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-(2-propyl)benzyl or 4-trifluoromethylbenzyl. 8. The method according to claim 2, in which B is ethyl or optionally substituted benzyl. 9, The method according to claim 8, in which B is ethyl or benzyl. 10. The method according to claims 1 or 2, in which Ma3-X is selected from GiMz, Mamz, TM5-Ma5, NMaz or ESAIM z. 11. The method according to claims 1 or 2, which is carried out by obtaining an intermediate aminolactone compound of the formula IM. 12. The method according to claims 1 or 2, which is carried out by obtaining an intermediate iminophosphorane compound of the formula U. 13. The method of obtaining the compound of formula I: 70 (o) What iv) c) more, n O-v! 1 ! ! ! . ! . where K' is an optionally substituted group selected from an aliphatic group, an aralkyl group, a heterocyclylalkyl group or an aryl group, and K2 is an organic radical in which: (a) the preparation of butenolactone of the formula MIII: g) "MI Y о х О -k! where X is chlorine, bromine or iodine; c (B) treatment of the compound of the formula MI with azide Ma-M, where M is a silyl group or counterion, with the production of azidobutenolactone of the formula MIP: Ge) MI; (22) uv; M Ж -рв1 Кк со (c) conversion of the compound of the formula MI into the aminobutenolactone of the formula IX or the iminophosphorane of the formula XI: r HF) or (is! ХИ; ча у; Го НМ ЕзРеМ « О-к О-к их - с | шк Х Y "z (4) the interaction of a compound of the formula IX or Xy with K-COOH or its reactive equivalent to obtain a compound of the formula X: Ge! Xy t i) F АХ с y; (e) reduction of the double bond of the furan ring of the compound of formula X to obtain the compound of formula I. 14. The method according to claim 13, in which B? - the R.-Ra-R" fragment of the caspase inhibitor or its part. 15. The method according to claim 14, in which K2 is a Ru-Ra-R»o fragment of a caspase inhibitor, where the mentioned fragment belongs to one of the following groups: Ф) име) 60 б5 AD, 6 AAZ Okh r Shkh laz V r z TSI (SNo)p am z Reno M v NO dd N No 2 (c) a s A» Aj M (SNodv x M Sho Rachm M AA; Rai-k no Ry -- ne no M 5 a e E 5 A. 5 -uy h- ld k ? Hey yu-ye/ Kha m Ra M M. Al Ra. M 4 M Z - yo a M -- no AA Ry-m o NN o 2 n 9 v i s (8) A Vo -k her tena" / M F /A ! Ra M - their " Ra. M a R-M o) M N (in) so No 3 Kk 1 so m in i - (sna )in ХУ ! Ra. U-8 | Mr. NM Ra. M R, M and MN Z More "(c) Gee! About AA, shi t p o s 2" and in 7 -UK in K A 6 M Y AA, M- Kk with Me - I ih M.X r r M Raz o M M no t kh no (95) і" 50 r and E where n - from 0 to Z; AA refers to the side chain of an amino acid; X - M, 0, 5, ZO, 505, SNE, Sg", c(v3y, c C-O or SAMOK; A - O, 5 or H", M - M or CH; K - hydrogen, S.. 42 is an alkyl group, an aryl group or a heteroaryl group, and the EC groups are optionally substituted; KZ - alkyl having from one to six carbon atoms; and KZ - hydrogen, halo, alkyl, alkoxy, haloalkyl, haloalkyl, amino, phenyl, phenoxy, hydroxy, alkoxycarbonyl, carboxyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkylcarbonylamino, alkylcarbonylalkylamino, HF) alkylamino, dialkylamino, aminosulfonyl or cyano group; and 25 and B" are independently selected from Y, aryl, heteroaryl, 7(C 1-4 alkyl)aryl, (C 4-12 )benzocycloalkyl or (C 1-12 alkyl)heteroaryl. 16. The method according to claim 15, in which K2 is a fragment of Р.-Ра-Р» - a caspase inhibitor, where the said fragment is one of the following groups: б5 N GU and lem Mi Rem and E o) Na o a-i i-1i . : si 70 E CH as Remesh vein N Ge) N Ge) io) s-2 s-3 s-4 E (6) IS . SNU M sch 1 y Rem rec M tsi i no o Re-m U n e-5 s-6 a-1i o " (o) o) so M m" so i (o ' R.- R,- "What But "M o a-2 e-1 x-1 « - - I-I pas her i? but - what else? Ra. H l M M. iSna Re M She r RA-M do t -i N o o Sna no 0 o h-1 v-1 i-1 (95) them (Che) (F. kobo 65 t, o M F ; in 2nd in Rem M M N Rem M. em to 9) But that 3-1 k-1 1-1 M 5 5 Ra M u Ra o n o Re- m n N Ge) (c) 1-2 pcs-1 t-2 se E ' o xx Ra m M | M. N t | and Ra M F zo M -7 na - no Ge) o-1 - - o-2 o-3 s - 5OSNZ M- M Ra M Rah I SN h СНz M M - nN o N o s h" v-1 "- 1 k-1 NhM Khe) -I o M- RK M Re. MY Y 7 5, o iz Ge) (3; k-2 p-1 99 where B9 is optionally substituted benzyl or 2-indanyl, and R. is a component represented by K-1-, where K-T is K -SO, F! KkOS-O, EMNOS-O, KS(O)S-O or BO". 17. The method according to claim 16, in which 2 is РА-Ра-Р» - a component, where the R part is selected from K-СО, KOS-О, KMNO-О, KС(О0)С-О or KBO». and K is one of the following groups: bo b5 I sleep SI and sos so su su and SI E 100 101 102 103 104 si si si Oh that vod voi "y si s s si 105 106 107 108 109 and SO OS vo us ti no No 110 111 112 113 114 ns og s oi sch НО о - ой но Go) ON | si E SNU SNz IF 115 116 117 119 120 o zo « so so yich- « - s z -And (95) (95) ride (Che) (F) ko 60 65 Oh OK cha ne c) No o 121 122 123 124 " ii - o sn nem to o on SI 125 126 127 128 E ke OMe g si g si o Su -M M M ii OMe OoMe SI 129 130 131 132 133 s (o) yo so y (c) nom N b" what po si " 134 135 136 137 138 s so im M i m | 7 EE rya M 139 140 141 142 143 « - with : with" -And (95) (95) ride (Che) Ф) ko bo b5 also 03 C C, o M "o M (o) 144 145 146 147 148 M Sat" ss co "Us / lada 7 K " 41/ 4/ 149 150 151 152 153 c) M, | ry is F. r - xY M M y 154 155 1565 157 s shchi oz 75 (8) o) F) vozhevvonn. si (22) 158 159 160 M 18. The method according to claim 17, in which B? - fragment R.-Ra-R" -, selected from one of the following groups: со со m. « ши с з -И (95) (95) из 50 иЧе) Ф) име) 60 b5 у/че З Н t , "ut by o! in vo M t In! o Go) a-1a й-1a й-1й5 10 o vi U M vo rr, XX ml kONM NM Osn Her l g Y a-1a h-ia h-2a 20 with X A i Y o schrn ob uchy vi lm o (c) N Ge! n o o-2a s-ta s-1a (22) 30 A V i M so o so 35 se-ba i-de K - one of the following groups: C si si « - Sh voshvoshei "with 100 SI SI Si " 105 107 108 45 ns SI o with more. YES D Fo to to nom ns M s SN» si a "114 126 1 117 119 iChe) Zo i . a in 139 15750 i nM a o si 141 ime) 136 60 19. The method according to claim 14, in which B is methyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, phenylbutyl, ( a)-menthyl, ()-menthyl, 1-adamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 3-tetrahydrofuranyl, benzyl, -- -methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl , 65 4-(2-propyl)benzyl or 4-trifluoromethylbenzyl. 20. The method according to claim 14, in which B! - ethyl or optionally substituted benzyl. 21. The method according to claim 20, in which B! - ethyl or benzyl. 22. The method according to claims 13 or 14, in which M3-U is selected from GiMaz, MaMz, TM5-Mz or ESAIMz. 23. The method according to claims 13 or 14, which is carried out through the amino lactone of formula IX. 24. The method according to claims 13 or 14, which is carried out using iminophosphorane of formula XI. 25. The method of obtaining the compound of formula I: c) What 10) iv) still n O-c! where B' is an optionally substituted group selected from an aliphatic group, an aralkyl group, a heterocyclylalkyl group or an aryl group, and B2 is an organic radical, in which: (a) preparation of butenolactone of the formula MII: o "MI /; X O -v! where X is chlorine, bromine or iodine; (B) treatment of the compound of the formula Mi with azide Ma-Zh, where M is a silyl group or counterion, with the production of azidobutenolactone of the formula MIP: o UT o re; Mu F O-vi " (c) conversion of the compound of the formula MI into the aminobutenolactone of the formula IX: (4) reduction of the double bond of the compound of the formula IX to obtain the aminobutenolactone of the formula IX: » o nm Oo-k! (e) interaction of the compound of the formula IM with K2СООН or with a reactive compound equivalent to it, to obtain the compound of the formula |. 2) 26. The method according to claim 25, in which 2 is the P.-Ra-P" fragment of the caspase inhibitor or its part. 27. A compound of formula I or МY: Щ» с о (о; М Z ur ko M, UP, vo where B" is selected from an optionally substituted aliphatic group, an aralkyl group or an aryl group. 28. The compound according to claim 27, in which K 1. is methyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, phenylbutyl , (a)-menthyl, ()-menthyl, 1-adamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 3-tetrahydrofuranyl, benzyl, -- -methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4 -methylbenzyl, 65 4-(2-propyl)benzyl or 4-trifluoromethylbenzyl. 29. The compound according to claim 27, in which B! - ethyl or optionally substituted benzyl. 30. The compound according to claim 29, in which B is ethyl or benzyl. 31. Compound of formula M or XI: Gee! M or (F) XI, o /; CREAM CREAM. OK! OK! where VE! selected from an optionally substituted aliphatic group, an aralkyl group, or an aryl group. 32. The compound according to claim 31, in which K 1. is methyl, ethyl, propyl, 2-propyl, butyl, pentyl, hexyl, 4-methylpentyl, 2-methylpropyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenylethyl, phenylpropyl, phenylbutyl , (a)-menthyl, ()-menthyl, 1-adamantyl, 2-adamantyl, 1-indanyl, 2-indanyl, bornyl, 193-tetrahydrofuranyl, benzyl, -- -methylbenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-(2-propyl)benzyl or 4-trifluoromethylbenzyl. 33. The compound according to claim 31, in which B is ethyl or optionally substituted benzyl. 34. The compound according to claim 33, in which B is ethyl or benzyl. shu, , , shu. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 7, 15.07.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. со (22) « со со i - - with . and? -I (95) (95) iz 50 iChe) F) ime) 60 b5