SK51194A3 - Peptides - Google Patents

Abstract

Di-, tri- and tetrapeptides in which the last alpha -amino acid is based on aspartic acid and attached to a residue A5 which is H; CF3; -Z1-Z2-Y2 wherein each of Z1 and Z2 independently is a direct bond or an alpha -amino acid residue and Y2 is NH2, C1-4 alkylamino, di-(C1-4 alkyl)amino or a heterocyclic radical attached by a nitrogen to Z2; -CH2-X1-Y3 wherein X1 is O or S and Y3 is heteroaryl; -CH2-Y3; substituted phenyl; ring substituted phenoxymethylene or phenylthiomethylene; ring substituted pyridyloxymethylene; or a radical -CH2-X1-CO-Y4 wherein X1 is O or S and Y4 is trialkylmethyl or substituted phenyl or pyridyl, in free form or in salt form, have pharmacological activity, e.g. IL-1 beta release inhibiting properties.

Description

peptides

Technical field

The invention relates to peptides that are pharmaceutically useful, to methods for their preparation, to pharmaceutical compositions containing them and to the use of these compositions as medicaments.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

R / A, -A2 / NA ₃ -A 4 -A _Xa (I) wherein

R represents a hydrogen atom, an amino protecting group or an optionally substituted benzyloxy group,

Ai is Val, Leu, Ala, clay or three methylsilyl-A1a,

A- represents Phe or Tyr, n represents zero or 1,

A ₃ denotes a direct bond, Val, Leu, Ala, clay, three methylsila y Ala or a divalent radical of formula (a)

In which ring A is optionally substituted by hydroxy or a (C1 -C4) alkoxy group,

Ad represents a direct bond or a divalent radical of formula (b)

-N - CH - CO in which

R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group;

Y 1 represents a residue bonded to the alpha-carbon atom of the alpha amino acid which is optionally protected, the -CH-CHe-N (C 1-6 alkyl) group, and imidazo-1-2-ylmethyl-imidazo benzimidazol-2-yl-methyl, 1H-1,2,4-triazol-3-ylmethyl, pyrazol-3-yl-methyl, indazol-3-yl-methyl or a residue of formula (c) or (d)

(C)

(d) wherein each of R 2 and R □ are nezávisléna are hydrogen, halogen, alkyl of 1 to 4 carbon atoms, _CF3 or trityl, wherein the maximum of one of R 2 and R ₃ is H, and each of R 1 and R 5 is independently hydrogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, CF ₃ , phenyl or halogen, with at most one of R a and R _p is H, or

A ₃ and Ä 4 together form the remainder of formula (aa)

-NH-CH-CO-N-CH-CO

I I I

R _1a R 1 Y i (aa) wherein

Y 1 is as defined above and

R 1 and R 1 _and together are taken together to form - (CH ₂ ) _m where m is 2, 3, 4 or 5, and

1) X represents a divalent radical of formula (e-i)

where

R e represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and

As is hydrogen, CFa, -CH 2 -X 1 -Y 3, wherein

X 1 is O or S and Y 5 is a heteroaryl group, a -CH 2 -Y 3 radical or radicals of formulas (k) to (m)

- CH 2 -X 1 -CO-Ya (k)

or

(M)

R (o) where

Ya is a tri (C _1-4 alkyl) methyl group or a radical of formula

Ring B is pyridyl, .. _ ring C is phenyl or pyridyl, each of the radicals R ₇ and _R are independently alkyl of 1 to 4 carbon atoms, and 1koxyskúp and the C 1 -C 4 alkyl, CF _3, halogen, nitro or cyano, and each of R ₉ , R 10 and R 11 are independently nitro, cyano, CF ₃ , carbamoyl, CO ₃ R 12, -CH = CH-CN or -CH-CHCO ₃ R 13 wherein R ₁₂ is C 1 -C 6 alkyl,

X is also a divalent radical of formula (es)

alkyl alkyl alkyl (e ₂₎ where As is a hydrogen atom, or

2) X represents a divalent radical of formula (f)

(F)

Z z are a

And is a group -Z-AS-Ys, wherein each Z and independently of one another a direct bond or the residue of a-amino acid, and Y is ₌ NHL · C i-1 _{and A} 1 alkyl amino, di (C, N, The alkyl group or a heterocyclic radical attached by a nitrogen atom to Za and / or from the above formulas (k) to (o) as defined above, or OR 13, or NR 13 R 18. wherein R 1a is C 1 -C 12 alkyl optionally substituted with OH or interrupted by oxygen and each of R 1a and R is independently hydrogen, C 1 -C 12 alkyl, C 5 -C 7 cycloalkyl carbon or benzyl, or

3) X represents a divalent radical of formula (g)

(g) and As represents a group -Z1-Z2-Y2 as defined above; or

4) X represents a divalent radical of formulas (h) or (j)

(h) (j) and As are the radicals of formulas (k) to (o), -CH 2 -Y 3 or -CH 2 -X-1-Y 3 as defined above, provided that only one of the groups A ₃ and Ad may be a direct bond when n is zero, and each of Aa and Ad is different from a direct bond when n is 1, and their physiologically hydrolyzable and acceptable esters or amides, in free form, in the form of a salt or in the form of complexes.

Examples of protecting groups in the R substituent are, for example, given in Protective Groups in Organic Synthesis, T.W.

Greene, J. Wiley and Sons NY (1981), 219-287, and are, for example, an acyl group such as an acetyl group, a methoxysuccinyl group, a hydroxysuccinyl group or a benzoyl group optionally substituted on the phenyl ring, for example in para-position with methoxycarbonyl, methoxy or nitro, and 1-alkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl, such as 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl, optionally substituted in the para-position by methoxy, chloromethyl, chloromethyl, n-thio; such as a benzyl group optionally substituted in the para-position by a methoxy group with another, nitro or chlorine, or an arylsulfonyl group such as a phenylsulfonyl group optionally substituted in the para-position by a methyl or methoxy group, or a naphtha group, optionally substituted in the ring, for example with amino or C 1 -C 4 dialkylamino in each of the alkyls.

When R is a substituted benzyloxy group in the ring, it is preferably a benzyloxy group substituted by a hydroxy or alkoxy group having 1 to 4 carbon atoms. A preferred R group is unsubstituted benzyloxy groups.

A preferred halogen atom is a fluorine atom or a chlorine atom

When A3 is a substituted radical of formula (a), this radical is preferably substituted with a C 1 -C 4 alkoxy group, preferably in the para-position to the -c = o group.

A1 is a naturally occurring or commercially available or optical isomer or unnatural, and 1 pha-amino acid is non-natural and 1 pha-amino acid is one and 1 pha-amino acid is not incorporated into the protein of mRNA rules, for example beta-NaI, fluoro-α1α-amino acid, such as fluoroalanine, trimethylsilyl-1 α, or α1α-amino acid, such as

Wn.

H ₂ N - CH-COOH where Πι is an integer from 1 to 6 and n ₂ is an integer from 1 to 12

Protecting groups that may be present in Y 1 are groups that protect the 0, S, or N functional group in the side chain of the amino groups of the alpha-amino acid. N-protecting groups are, for example, those mentioned above for R or a C 3 -C 5 alkyl group such as isopropyl, formyl, sugar moieties such as 1-deoxy-fructosyl or alpha-glucose (1-4) -deoxyfructosyl, d C 3 -C 6 -hydroxyalkyl such as dihydroxypropyl, C 5 -C 7 -cycloalkyl such as cyclohexyl or tropinyl. O- and S-protecting groups for hydroxyl and thiol functional groups are known and are, for example, methyl, tert-butyl or benzyl.

When Y ₂ is a radical heterocyk1 the ears, for example, can be a five or six membered ring such as piperidino, or a pyridinyl group íny1ová 1 ID.

Examples of heteroaryl groups for the substituent Y ₃ include, for example, five-, six- or seven-membered unsaturated heterocyclic radicals containing at least one nitrogen atom and optionally other heteroatoms such as nitrogen, oxygen or sulfur. Preferred Y a is a heteroaryl group containing from 1 to 4 nitrogen atoms, for example pyridyl, triazolyl, tetrazolyl, triazinedionyl.

In ring B of the radical of formula (o), the nitrogen atom may be ortho, meta or para. If ring C in the radical of formula (k) is pyridyl, then it may be 3-, 4- or 5-pyridyl.

The radicals of formulas (ei), (s =), (f), (g) and (j) are derived from Asp and contain one asymmetric carbon atom and the remainder of formula (h) contains two asymmetric carbon atoms so isomerism occurs. Of course, it is to be understood that the present invention encompasses all individual isomeric forms and diastereoisomers, as well as mixtures thereof, for example racemates, unless otherwise indicated.

The remainder of the general formula (e) attached to a substituent which represents a hydrogen atom may exist as in cyclic or non-cyclic form, such as

And 5 form so the equation:

It is understood that when tautomeric forms occur, the present invention encompasses both lactol and oxocarboxylic acid forms, i. although the compounds of formula (I) wherein X is a radical of formula (e) are preferably referred to only as the oxo-carboxylic acid form, it is not to be understood that the invention is limited to the particular nomenclature or graphical representation used for these compounds. Similar considerations also apply to starting compounds exhibiting lactol / oxo-carboxylic acid tautomerism as described above.

The same applies to the remainder of the general formula (h), which may also exist in both linear form and cyclic form, as shown in the following equation:

h ⁺ / -h ₂ 0 base / defect and for compounds of formula I of formula (h) and for the corresponding

containing the remainder of the starting compound.

By physiologically hydrolyzable and acceptable esters or amides is meant esters and amides which are hydrolysable under physiological conditions to alcohols or mines which are themselves physiologically acceptable, i. which are nontoxic at the desired dosage levels.

These esters or amides may be prepared by esterification or amidation of a compound of formula (I) wherein X is a carboxy-containing radical. These esters include esters with an aliphatic or alicyclic alcohol or a polyol containing 1 to 12 carbon atoms. Amides include amides with aliphatic amines, for example, C 1 -C 4 alkylamines, C 1 -C 4 alkoxyalkyl and C 1 -C 4 alkoxy and C 1 -C 4 alkyl, such as beta-methoxyethylamine or aniline.

The compounds of formula I may exist, for example, in free form, in acid salt form, or in the form of complexes. Acid salts may be formed with, for example, organic acids, polymeric acids, and inorganic acids. Such acid salts are, for example, hydrochlorides and acetates. Salts may also be formed with a carboxyl group present in compounds of formula I, for example, alkali metal salts such as sodium or potassium, or further substituted or unsubstituted ammonium salts. For example, complexes are formed from compounds of formula I by addition of an inorganic substance; for example inorganic salts or hydroxides such as Ca- and Zn-salts and / or by the addition of polymeric organic substances.

Hereinafter, the meanings of preferred substituents used either singly or in any combination or subcombination that may be included in compounds of Formula I are given:

R is an amino protecting group or a benzyloxy group, preferably an amino protecting group. Preferably, R is benzyl oxyl when n is zero and A ₃ is a radical of formula (a).

2

2. Each of groups Aa and A-. is different from direct bonding.

. n is nu1 and.

4. A3 is a radical of formula (a) when n is zero.

5. Aa is a direct bond, Val, Leu, Ala, clay or trimethylsilyl-A1.

6. R 1 is a hydrogen atom or a methyl group, preferably a hydrogen atom.

7. Y 1 is a moiety attached to an alpha carbon atom of an alpha amino acid selected from the group consisting of Ala, Leu, His, Phe, Met, Trp, trimethylsilyl-A1, and optionally in the side chain protected by Arg, Orn and Lys, or Y 1 is a radical of formula (c).

8. A ₃ and A ₄ may also together form a radical of formula (aa) if n is zero.

9. m is 2 or 3.

10th X is a residue of of formula (ej and A p is a different than atom hydrogen. 1 1. X is a residue of of formula (G) 1 2. X is a residue of of formula (h) or (J) · 1 3. R 5 is an atom hydrogen or methyl group, with preferably atom

hydrogen.

14. Z 1 in A _s is a residue of a natural alpha-amino acid, preferably an aromatic-heterocyclic alpha-amino acid, especially Pro.

15. In As, the remainder of the natural and 1? -Amino acid, preferably aliphatic and 1? -Amino acid, in particular an aliphatic alpha amino acid containing no other functional groups, most preferably Val.

16. X is a radical of formula (ej), optionally esterified or amidated, and As is a radical of formula (k), (1) or (o).

X is a radical of formula (ej, (h) or (j), optionally esterified or amidated, and A s is -CH 2 -X 1 -Y 3, preferably -CH 2 -S-Y 3 or -CH 2 -Y 3.

3

18. X is a radical of formula (h) or (j), optionally esterified or amidated, and As is a radical of formula (k).

19. X is a radical of formula (j), optionally esterified or amidated, and As is a radical of formula (m).

20. The radical of formula (m) is monosubstituted, preferably in the para position, and more preferably 4-nitrophenyl.

21. All residues and 1 fa-amino acids present except X have the L configuration. X has a D or L configuration.

22. The asymmetric carbon atom in the radical of formula (h) bearing an OH group has an S configuration. Preferably, the asymmetric carbon atom in the radical of formula (j) bearing the group ReR has a configuration.

Also preferred are compounds of formula I wherein n is zero, Aa is a direct bond, Val, Leu, Ala, clay or trimethylsila 1-A 1 a, Αλ is as defined above, or Aa and A ₄ together form a radical of formula (aa) as defined above and

1) X is a radical of formula (ej or (e =), as defined above, and As is a hydrogen atom, or X is a radical of formula (ej a radical of formula (k), (1) or (m) wherein X 1 is O, X is a radical of formula (g) a-A a is -Z 1 -Z 2 -Y 2 as well as or (f) and A a is

2)

3)

4) bo

X is a radical of formula (j) and of general formula (k), (1) or (m), wherein

As is the remainder of everythingX i is 0.

The present invention also relates to a process for the preparation of compounds of the formula I, characterized in that:

a) removes at least one formula I protecting the ac group R of formula I, protecting the aca in the N-terminal protected or adding a compound from the form or group of the compound

(b) converting one compound of formula I into another compound of formula I, or

c) join together by amide bond two peptide fragments, each containing at least one amino acid in protected or unprotected form and one peptide fragment containing a residue of the general formula (ej to (j) as defined above, wherein the peptide fragments are such that by providing a protected or unprotected peptide having the sequence of formula I and optionally removing the protecting group or groups from the compound of formula I in protected form, or

d) for the preparation of compounds of formula I wherein X is a radical of formula (ej or (h) and As is a radical of formula (k), (1) or (o) or -CH-X1-Y3, reacting the compound of formula III

R - / A 1 - A 2 / r, - A 3 - -X 1 - CH 2 -Z and (III) wherein R 1, A 1 to A ₄ and n are as defined above, X 1 is a radical of formula (e-ι) ) or (h) and Za is a leaving group, for example a halogen atom, with the corresponding phenol, thiophenol or HX 1 -pyridine or an acid of the general formula HX 1 -CO-Y? or a functional derivative thereof or with HX 17 Y 3, and

e) for the preparation of a compound of formula I

H Q

(I)

Wherein R, A 1 to As an are as defined above and R ₁₆ is an aliphatic or alicyclic radical having 1 to 12 carbon atoms, oxidizes the compound of formula V

(V) wherein R, A 1 to As, n and R 1 are as defined above, and the compound of formula (I) thus formed is isolated in free or salt form or in complex form.

Processes (a) to (e) may be carried out by methods known in the art.

Removal of the protecting group in step (a) may also include removal of R at the N-terminal group of a compound of formula I. For example, when R is a benzyloxycarbonyl group, this may be removed by hydrogenation in the presence of a catalyst such as palladium.

In accordance with the process of step (b), for example, it is possible to prepare a compound of the formula -. I. wherein X contains a carboxy group, to hydrolyze a compound of formula I, wherein X contains an esterified or amidated carboxy group. This hydrolysis may be carried out by appropriate alkaline or acid hydrolysis, for example in the presence of trifluoroacetic acid.

Further, according to the process of step (b) for the preparation of a compound of formula I wherein X contains an esterified or amidated carboxy group, a (trans) esterified or amidated compound of formula I wherein X contains a carboxy or esterified group may be carboxy.

6

This ester formation or amination may be carried out using methods known in the art, for example by converting a carboxy group to a functional reactive group, for example a corresponding carbonyl halide or anhydride, or using a compound of formula I wherein X is a radical of formula (h) lactone, and reacting such a group with a selected alcohol or amine.

Further, according to the process of step (b) for the preparation of a compound of formula I wherein X is a radical of formula (g), a compound of formula I wherein X is a radical of formula (ej or (ej and A ₅ ) is reacted. a hydrogen atom, with a compound of formula II

H-N-NH-CO-As (II) wherein As is as defined above. This process can be carried out analogously to known methods used to prepare semicarbazones.

A compound of formula I wherein X is a radical of formula (ej) can also be converted by known methods to a compound of formula I wherein X is a radical of formula (es), and vice versa.

The process of step (c) can be carried out by methods known from peptide chemistry. A peptide fragment containing a radical of formula (ej to (j)) is also understood to mean a radical containing a protecting group on the -NR 5 - moiety and correspondingly terminating, for example, As or CH 2 -Za, at the opposite end.

The process of step (d) may be carried out using a Dess-Martin reagent, for example in the presence of a base or a halogen from a silver precipitating salt, or by the Swern oxidation process.

If desired in these reactions, protecting groups can be used for functional groups that do not participate in the reaction. These include, for example, amino protecting groups, carboxy protecting groups, acetal groups, and the like. After completion of the desired reaction, the protecting groups may be removed.

7

Each of the above processes can be carried out using the starting materials in the form of one or more individual optical isomers or mixtures thereof (according to the asymmetric carbon atoms present in the radicals of the formulas (ej to (j) in the meaning of X) or in precursors thereof. Usually, the Salebo R enantiomers are used as starting materials to give compounds of formula I in which the asymentic carbon atom in the radicals of formula (ej to (j) has the S or R configuration).

The starting materials used in steps (d) or (e) of the process according to the invention can be prepared analogously to the process according to step (c).

If the preparation of the starting materials is not mentioned by name, these compounds are known or can be prepared analogously to the known methods used in practice.

The following examples serve to illustrate the present invention in more detail. All temperatures are in ° C.

The following abbreviations are used in the examples:

THF = tetrahydrofuran TFA = trifluoroacetic acid MeOH = methanol The EtOAc = ethyl acetate DCC - dicyclohexy. amorph HOBT - hydroxybenzotriazole FROM = benzyloxycarbones 1 Fmoc = 9-fluorenylmethoxycarbonyl 1 and - amorphous DETAILED DESCRIPTION OF THE INVENTION

Example 1

Z-Val-Met-Asp (OH) -H

Beta-ter c. Butyl 1-methyl-ethyl acetate of Z-N-Met-aspartic acid (1.17 g) was added to CH 2 Cl 2 (150 mL), TFA (15 mL) and water (1 mL) were added and the reaction mixture was added. is stirred at room temperature for 2.5 hours. The solvent was evaporated, toluene was added twice and evaporated again. The crystalline residue was dissolved in water (60 ml) with heating, decanted from the insoluble material and recrystallized at 5 ° C to give the first crop, mp 117 ° C. All mother liquors were combined and chromatographed (SiO 2, acetone / hexane / EtOAc 60/40 / 0.5) to give a second crop of product and the residue was triturated with water.

Example 2

Z-N-Met-Asp (OH) -H semicarbazone

Example 1 (0.27 g, 0.55 mmol) in MeOH (2 mL) was treated with carbazidium HCl (0.6 mL of 1 molar solution) followed by 5 drops of pyridine. The product crystallizes after 10 minutes at room temperature, mp 233-235 ° C.

Example 3

Z-Val-Met-Asp (OH) -H semikarbazonyl-Pro-Val-N _(CH3) 2

Example 1 (0.48 g, 1 mmol) was dissolved in a mixture of MeOH (2 mL), water (0.5 mL) and 3 drops of pyridine. N- (hydrazinocarbonyl) -Pro-Val-N (CH ₃ ) ₃ ( _0.3 g, 1 mmol) was dissolved in MeOH (1 mL), water (2 mL) and 3 drops of 2N HCl. The two solutions are mixed and heated at 40-50 ° C for 2 minutes. The product crystallizes on cooling, m.p. 118-120 ° C.

By repeating the procedure of Example 1, the following compounds were prepared using the corresponding starting compounds;

Example 4

Z-Val-Phe-Asp (OH) -H

Example 5

Z-Val-His-Asp (OH) -H

By repeating the procedure of Example 2 or 3, using the corresponding starting materials made following lowing compounds of formula IA ^Z 3 ^{and A} 4 ^_N

(IA)

C0 ₂ H

where A 3, Aa and As have above importance. example No. A 3 ad and ₅ mp ° C 6 wall Phe H and 7 wall H i s Ή 1 50 8 wall Phe Pro-Val-N _(CH3) 2 126-129 9 wall H i s The 1-V-N _(CH3) 2 10 Ala-Tyr-Val Phe H 205

Example 11 (3S) -3- (Z-valyl-phenylalanyl) -amino-5- (2,6-dimethylbenzoyloxy) -4-oxopentanoic acid

(3S, 4RS) -3- (Z-Val-His) amino-4-hydroxy-5- (2,6-dimethyl-benzoyloxy) -pentanoic acid (0.6 mmol) was treated with Dess-Martin reagent (0.77 mmol) in Cl-kCl (4 mL) for 45 min and then the mixture was filtered. Acetone and 0.5 N NaOH were added and the acetone was evaporated. The remaining crystalline material was washed with water, acidified with 10% tartaric acid and extracted

EtOAc. The combined EtOAc extracts after evaporation gave the tert-butyl ester product as yellow crystals. These were dissolved in CH 2 Cl 2 (4 mL), TFA (4 mL) was added, and the mixture was stirred at room temperature for 15 minutes. The mixture is then evaporated to dryness and chromatographed (SiO = acetone / hexane / EtOAc 60/40/1) to give the desired product as slightly colored crystals.

Example 12

(Z-Valyl-alanyl) - (3R, 4S) -3-Amino-4-hydroxy-5- (2,6-dichloro-benzoyloxy) -pentanoic acid ethyl ester

(Z-Valyl-alanyl) - (3R, 4S) -3-Amino-4,5-dihydroxypentanoic acid ethyl ester and 4-methylaminopyridine are dissolved in pyridine and 2.6 dichlorobenzoyl chloride is added dropwise The reaction mixture was stirred overnight at room temperature, then ice and water were added and the mixture was extracted with AcOEt. The organic layer was washed with water, then with NaCl solution, dried over N and 2 S 0 λ, filtered, evaporated and the crude product chromatographed. The title compound is obtained.

The (3R, 4RS) -trate of the title compound was prepared as follows:

Z-Val-Ala-OH (0.26 mmol), DCC (53 mg, 0.26 mmol) and HOBT.HiO (39 mg, 0.26 mmol) were dissolved in THF / DMF (2 mL / 2 mL). and stirred for 5 minutes followed by the addition of (3S, 4RS) -3-amino-4-hydroxy-5- (2,6-dimethylbenzoyloxy) pentanoic acid tert-butyl ester (87 mg, 0.26 mmol) in THF ( 2 ml). The reaction mixture was stirred at room temperature overnight, then evaporated and chromatographed (SiO 2, EtOAc / MeOH / NH 3 and 95/5 / 0.5) to give the (3S, 4RS) derivative of the title compound.

Example 13

(Z-Valyl-alanyl) - (3R) -3-amino-4-oxo-5- (2,6-dichloro-benzoyloxy) -pentanoic acid ethyl ester

Dimethylsulfoxide in CH 2 Cl 2 was added dropwise at -50 ° C to a solution of oxalic acid in CH 2 Cl 2. After 15 minutes, a solution of the compound of Example 12 in CH 2 Cl 2 is added dropwise and the reaction is stirred for 1 hour while triethylamine is added and stirring is continued for 3 hours at -40 ° C for 1 hour. Water was then added and the reaction mixture was extracted with CH 2 Cl 2. The organic layer was washed with NaHCO 3 solution and NaCl solution, dried over NaXO 4, filtered and evaporated. The residue is chromatographed to give the title compound.

By repeating the procedure of Examples 1 to 3 and 11 to 13, using the corresponding starting compounds, the following compounds of formula IB were prepared

(18) wherein A ₃ , Aa, Rx and Ry have the meanings given below.

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CO CO CO CO 1 - (r-4 i-4 <C <<

cn < I cs / -4 < » CS < I 1 i-4 1 (-4 1 t-4 X X X t-1 T-4 • * 4 • »4 • H R-4 (Ω tn cn «3 1 I 1 > OJ © about 2? • ♦ H »4 R-4 U Gi C-J -H H «Η

<r m \ o i— trs m ir \ ir>

Ή

-P (Λ (0> O here>

rH> 1 + J

P <0

CL cn <0>

H o

'10

P

Cn • H

Ή

ABOUT

X

O '3 o 3 Ό (U r — i tn fO 3' 3 • r — i (0 E> 4 C • n4 3 <U> O '3 i — 1 N

X cz /

the compounds have the R, S configuration in the aspartyl portion

/ alpha / g ^{0 0} = -20.3 c = 1 in MeOH

Example 59

Example 60

[.alpha.] D @ ²⁰ = -21.5 DEG C. = 1.07 MeOH

27 _and Example 61 ^C 6 ^H 5

Example 62

By repeating the procedure of Examples 1 to 3 and 12 to 13 using the corresponding starting compounds, the following compounds of formula IC were prepared.

(IC) where Ä 4, R x and R _y have the meanings given below:

example A. ry Rx * you 63 A 1 a H 2,6-di-1-benzoyl Cl \ _ R, S 9 64 A 1 a C2H5 CO- ^ Q \ Cl R 65 A 1 a t-CuHo 2,6-di-1-benzoyl R, S 66 A 1 a -C2H4-OCH 3 2,6-di-1-benzoyl R, S

Example 67

(3RS) -3- (Z-Valyl-phenylalanyl) amino-4-oxo-6- (p-nitrophenyl) -trans-5-hexenoic acid tert-butyl ester

Tert-butyl (3RS) -3- (Z-valyl-phenylalananyl) -amino-4-oxo-pentanoic acid 5-diethyl phosphonate (0.2 g, 0.29 mmol) was dissolved in THF (15 mL) at temperature Low: 14 ° C. NaOH (25 mg, 0.59 mmol) was added and the mixture was stirred for 10 min, p-nitrobenzaldehyde (0.18 g, 1.1 mmol) in THF (2 mL) was added at 0 ° C and the reaction mixture was stirred for 10 min. is stirred at this temperature for 45 minutes. The reaction mixture is then poured into 5% tartaric acid and extracted with ethyl acetate, the organic phase is dried over Na2SO4, evaporated and the product purified by chromatography. The title compound is obtained.

Example 68

Beta-methyl ester of diethyl acetate in Z-N-Phe-aspartaldehyde

Z-Val-Phe-Asp (OH) -H (0.8 g) was dissolved in MeOH (25 mL) containing 8% HCl, left at room temperature overnight, then evaporated to dryness and the remaining crystals were washed with ether to give the title compound as white crystals, m.p. 168-171 ° C.

The starting compounds are prepared by the following methods:

Example 69

(3S) -3- (Fluorenylmethoxycarbonyl) amino-5-iodo-4-oxo-butanoic acid tert-butyl ester

To tert-butyl (3S) -3- (fluoro-phenylmethoxycarbonyl) -amino-3-carboxybutanoic acid (3.5 g, 8.5 mmol) in THF (60 mL) at -10 ° C was added triethyl amine. n (1.3 mL, 9.6 mmol) followed by ethyl chloroformate (0.92 mL, 9.6 mmol). After 10 minutes, a solution of diazomethane in ether was slowly added and the reaction mixture was stirred at 0-5 ° C for 45 minutes. HCl (2 N) in ether was added at 5-10 ° C until gas evolution ceased. The reaction mixture was evaporated to dryness, taken up in acetone (50 mL), Nal (4 g) was added and stirred at room temperature for 1 hour. Ether (150 ml) was then added and the reaction mixture was filtered and evaporated. The residue is chromatographed (SiOc, EtOAc / hexane) to give the title compound as pale yellow crystals.

Example 70

(3S) -3- (Fluorenylmethoxycarbonyl) amino-5- (2,6-methylbenzoyloxy) -4-oxopentanoic acid tert-butyl ester

(3S) -3- (Fluorenylmethoxycarbonyl) amino-5-iodo-4-oxo-butanoic acid tert-butyl ester (1 g, 1.8 mmol), 2,6-dimethylbenzoic acid (0.5 g, 3.3 mmol) and Dissolve AgOAc (0.6 g, 3.6 mmol) in acetone (25 mL) and heat to boiling for 1 hour. After filtration and evaporation, the crude product chromatog30 is refined (SiO 2, ether / hexane 3/7) to give the title compound.

Example 1 7

(3S) -3- (Fluorenylmethoxycarbonyl) amino-5- (4-nitrophenoxy) -4-oxo-pentanoic acid tert-butyl ester

(3S) -3- (Fluorenylmethoxycarbonyl) amino-5-iodo-4-oxo-butanoic acid tert-butyl ester (1 g, 1.8 mmol), p-nitrophenol (0.5 g, 3.7 mmol) and K = CO ₃ (0.38 g, 2.8 mmol) was heated to boiling in acetone (6 mL) for 30 min, then CH ₃ Cl was added and the organic phase was washed with 2 N NaHCO 3. The combined organic phases were dried, evaporated and chromatographed (SiO ₃ , EtOAc / hexane 2/8) to give the title compound as a yellow oil.

Example 72

(Z-Valyl-alanyl) - (3R, 4S) -3-Amino-4,5-dihydroxypentanoic acid ethyl ester

a) Ethyl (3R, 4S) -3-benzylamino-4,5- (isopropylidenedioxy) pentanoate (Y. Yamada, Tetrahedron Letters 1983, 24, 3009) and 10% Pd / C in ethanol are shaken at 1 ° C. even in a hydrogen atmosphere for 30 minutes. Filtration and evaporation of the reaction mixture gave ethyl (3R, 4S) -3-amino-4,5- (isopropylidenoxy) pentanoate, which was used without further purification.

b) Dissolve Z-Val-Ala-OH in THF, add HOBT.H-O and DCC at 5 ° C. The reaction mixture is stirred for 20 minutes at 5 ° C, followed by addition of diisopropylethylamine and ethyl (3R, 4S) -3-amino-4,5- (isopropylidene dioxy) pentanoate in THF. The reaction mixture was stirred overnight at room temperature, filtered, evaporated and chromatographed. There was obtained ethyl (Z-valylalanyl) - (3R, 4S) -3-amino-4,5- (isopropylidenedioxy) pentanoic acid ethyl ester.

c) Example 74b) was dissolved in AcOH / HaO (75/25) and stirred at 40 ° C for 4 hours. After evaporation, water was added and the mixture was extracted with AcOEt. The combined extracts were washed with water, NaHCO 3 solution, dried over Na 2 SO 4, filtered and evaporated. The title compound is obtained.

The compounds of formula I and their physiologically hydrolyzable and acceptable esters and amides and their pharmaceutically acceptable salts (referred to herein as compounds of the invention) exhibit pharmaceutical activity and are therefore useful as therapeutic agents.

In particular, the compounds of the invention inhibit IL-1 beta secretion as is evident from the following in vitro assay using THP-1 cells and in vivo assay:

a) 900 µl of THP-1 cells (0.5 x 10 ^s cells) along with 100 gamma-terferon / 0.9 ml RPMI 1640 medium (containing 2 mmol L-glutamine and 5% heat-inactivated fetal calf serum) are pipetted into 24 cups of culture dishes. 100 µl of test compound is then added. After 3 hours at 37 ° C in an atmosphere of 5% CO 2/95% air, 10 µl of lipopolysaccharide (500 µg / ml) was added and incubation continued for a further 40 hours. Appropriate controls (with and without stimulus, solvent) are included in the experiment. The media is then removed and clarified by centrifugation at 1000 g for 10 minutes, then 1.0 ml of 0.01% digiotin is added to the wells to lyse the cells which are scraped and scraped off with a rubber spatula and left at room temperature. at 4 ° C for 10 minutes. Immediately thereafter, lactate dehydrogenase measurement is performed and samples are stored at -20 ° C until further determination.

These assays are: IL-1 beta (medium and lysate), TL-6 (medium), TNf-alpha (medium), PGE2 (medium and lysate), lactate dehydrogenase (LDH), and DNA (lysates). IL-1 beta, IL-6 and TNF-alpha assays are determined using commercially available ELISA kits (Cistron), PGE2 is measured using standard RIA and DNA is measured fluorimetrically using DAPI.

In this assay, the compounds of the invention selectively inhibit IL-1 beta release at concentrations from about 0.01 to 100 µM. In contrast, levels of IL-6, TNF-alpha, PGE2, and DNA remain substantially unaffected and compounds are non-toxic because LDH release is unchanged. For example, the compounds of Examples 40 and 50 were determined to have an IC 50 (concentration of compound that inhibits 50% of IL-1beta release) of 1 or 0.1 µM.

b) LPS-horka account

Male Tuttlingen SD rats (150-160 g) are injected with LPS suspension (Sigma, # L-5886, 100 zug / 5 ml glucose solution subcutaneously). Body temperature is measured over a 2 hour period using a thermistor rectal d 1 connected to an ELLAB thermometer. After 4 hours, the test compound is administered orally and after a further 2 hours (6 hours after LPS application) the temperature is again measured. The temperature increase measured in the untreated control is calculated as 100% and is expressed as a percentage of this value in the treated group. ED 50 is the dose causing 50% inhibition of the temperature increase determined in control rats. In this assay, the compounds of the invention inhibit LPS-induced temperature increase at a dose ranging from 0.001 to 0.1 mg / kg orally. For example, it was determined that the compounds of Examples 40 and 50 each had an ED 50 of 0.01 mg / kg orally and the compound of Example 51 had an ED 50 of 0.05 mg / kg orally.

c) Paw edema in rats induced by carrageenan

50FA male rats weighing 150-170 g are used for each group. The test compound is administered orally as a suspension in physiological saline and 0.5% tragacanth 1 hour before the carrageenan injection. Carrageenan (0.1 ml of a 1% suspension in physiological saline) is injected by subpantant injection into one hindpaw. The paw swelling is measured with an Kemper and Amelm anti-phiometer. Control readings are performed immediately after injection and swelling is measured after 3 and 5 hours. The mean readings after 3 and 5 hours are subtracted after reading the control and the values obtained in the treated animals are expressed as a percentage of the values obtained from the untreated controls. The ED 50 value is the dose causing 50% inhibition of carrageenan-induced edema after 3 hours. In this assay, the compounds of the invention significantly inhibit carrageenan-induced edema when administered orally at a dose ranging from 0.02 to 5 mg / kg. For example, the compounds of Examples 40 and 50 were determined to have ED 50 values of 0.2 and 1 mg / kg orally.

The compounds of the invention are therefore useful in the treatment of disorders caused by excessive release of IL-1 beta, for example in various inflammatory conditions and diseases such as tissue calcium depletion, bone and cartilage degenerative processes such as rheumatoid arthritis and osteoarthritis, inflammatory bowel disease, irritable bowel disease, septic shock, psoriasis, asthma, adult respiratory distress syndrome, type I diabetes, osteoporosis of various origins including, for example, climacteric or postmenopausal osteoporosis, as well as osteoporosis due to old age, restraint or trauma, arteriosclerosis and arteriosclerosis.

For the above use, the dosage required will, of course, depend upon the route of administration, the particular condition being treated and the effect desired. However, in general, satisfactory results are obtained using daily dosages ranging from about 0.001 to about 100 mg / kg, preferably from 0.001 to about 10 mg / kg of body weight. Suitable daily dosages for larger mammals, for example humans, are of the order of from about 0.1 mg to about 1 g / day, and the dose can be conveniently used at once, in divided doses two to four times a day, or in slow release form.

Preferably, the compounds of Examples 50 and 51 are.

In accordance with the foregoing, the present invention also relates to:

(a) a method of treating a condition associated with an excess release of IL-1 beta or caused by an excess release of IL-1 beta, for example as described above in a subject in need thereof, the method comprising: administering to a subject to be treated an effective amount of a compound of Formula I, a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof.

b) A compound of formula I, a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament, for example, for use as a condition treating agent as mentioned above.

The compounds of the invention may be administered by any conventional method, particularly nasally, enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, or in the form of suppositories. Single dosage forms contain, for example, from about 25 _of µg to 500 mg of a compound of the invention.

The compounds of the invention may be administered in free form or in the form of a pharmaceutically acceptable salt. These salts can be prepared by conventional methods and exhibit the same activity as the free compounds.

Furthermore, the present invention also relates to:

c) A pharmaceutical composition comprising a compound of formula I, a physiologically hydrolyzable and acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable diluent or carrier. These compositions can be prepared by conventional methods. The compositions may contain up to 99.9% by weight of the active ingredient.

Claims (10)

1) X is a radical of formula (ej or (e ₃ ) as defined in claim 1 and As is a hydrogen atom, or Compounds of formula I R- (A.-Aa) n -Aa-N-X-As (I) wherein R is a hydrogen atom, an amino protecting group or an optionally substituted benzyloxy group, n is zero or 1, A, represents Val, Leu, Ala, clay or three methylsilyl-A1a, A- means Phe or Tyr, A ₃ is a direct bond, Val, Leu, Ala, clay, trimethylsilyl Ala or a divalent radical of formula (a) wherein ring A is optionally substituted with hydroxy or C 1 -C 4 alkoxy, Ad represents a direct bond or a divalent radical of formula (b) -N-CH-CO- (b) II R i Y i in which R 1 represents a hydrogen atom or a C 1 -C 4 alkyl group; Y. represents a moiety bonded to an alpha-carbon atom of an alpha amino acid which is optionally protected, -CH 2 -CH 2 -N (C 1 -alkyl) 2, imidazol-2-ylmethyl, benzimidazol-1-yl; 2-yl-1-methyl, 1H-1,2,4-triazol-3-yl-methyl, pyrazol-3-yl-methyl, indazol-3-yl-methyl or the remainder of the general moiety of formula (c) or (d) (d) in which each of R 5 and R a independently of one another is halogen, alkyl with ka, hydroxy, and alkoxy, CF 3 or one of R hydrogen, C1-C4 uh 1 EXAMPLE 1 -C 4 atäpmami uhtritylová group, ceiling, and R a is a hydrogen atom, and each of R ₄ and R are independently H, alkyl of 1 to 4 carbon atoms, CFA , a phenyl group or a halogen atom, wherein at most one of R ₄ and R 5 'is a hydrogen atom, or / Aa and A-t together form a radical of formula (aa) NH - CH - CO - N - CH - CO R _1a R 1 Y, (aa) wherein Y 1 is as defined above and R 1 and R 1 together taken together form a group - (CH 3 where m is 2, 3, 4 or 5, and X represents a divalent radical of formula (ej where r ₆ means atom H atomam i carbon and A 5 means atom H, X 1 represents O and 1 or S nu, the radical -CH 2 -Y 3 (k) to (m) or an alkyl group of 1 to 4 C F 3, the radical -CH 2 -X 1 -Y 3, wherein and Y 5 represents a heteroaryl group or radicals of the general formulas - CH = -X 1 -CO-Y < (k) or where Y d represents a tri (C 1- ₄ alkyl a1 1) methyl-1 s account or a radical of the formula a pyridyl ring _t Ring C is phenyl or pyridyl, each of the radicals R? and R a are independently C 1 -C 4 alkyl, C 1 -C 4 alkoxy, CF ₃ , halogen, nitro or cyano, and each of Ro, R 10 and R 11 independently of each other is nitro , cyano, CF ₃ , carbamoyl, CO 5 R 18, -CH = CH-CN or -CH = CHCO ₀ R 12, wherein -R 12 is an alkyl group having 1 to 6 carbon atoms, X is also a divalent radical of formula (ej) alkyl alkyl alkyl (e ₂ ) when As is hydrogen, or 2) X is a radical of formula (ej or (f) and As is a radical of formula (k), (1) or (m) as defined in claim 1, wherein X 1 is 0, Compounds of formula I according to claim 1, in which n is zero, Aa is a direct bond, Val, Leu, Ala, clay or three methylsilyl-A1a, _A4 is as defined in claim 1 or As and A λ together form a residue of the general formula ca (aa) as defined in claim 1, and 2) X is a divalent radical of formula (f) and As is -Z 1 -Z ₂ -Ye, wherein each of Z, and Z = is independently a direct bond or an alpha-amino acid residue, and Y 5 is NH 2, C 1- * an alkylamino group, a di (C1-4alkyl) amino group or a heterocyclic radical attached by a nitrogen atom to Z-, or radicals of formulas (k) to (o) as defined above, or OR 13, or NR 11 R 18, wherein R 13 is C 1 -C 12 alkyl optionally substituted by OH or interrupted by oxygen, and each of R 13 and R 18 is independently hydrogen, C 1 -C 12 alkyl, cycloalkyl (C 5 -C 7) or benzyl; or Compounds of formula I according to claim 1, in which n is zero and each of the groups Aa and Aa is other than a direct bond, and their physiologically hydrolyzable and acceptable esters or amides, in free form, in salt form or in the form of dump 1 Exova. 3) X is a radical of formula (g) and As is a group -Z 1 -Z 2 -Y 2 as defined in claim 1, or 3) X is a divalent radical of formula (g) and As is -Z 1 -Z ₂ -Y ₂ as defined above, or Compounds of formula I according to claim 1 or 3, wherein Y 1 is a residue attached to a pha-carbon alpha amino acid atom selected from the group consisting of Ala, Leu, His, Phe, Met, Trp, three methylsilyl-Ala and optionally in the side chain protected Arg, Orn and Lys, or a radical of formula (c), and their physiologically hydrolyzable and acceptable esters or amides, in free form, in salt form or in the form of complexes. 4) X is a radical of formula (j) and As is a radical of formula (k), (1) or (m) as defined in claim 1, wherein X 1 is O, and their physiologically hydrolyzable and acceptable esters or amides, in free form, in salt form or in the form of complexes. 4) X represents a divalent radical of formulas (h) or (j) OH (h) CO ₂ H CHCH '(j) and A ₅ are the radicals of formulas (k) to (o), -CH 2 -Y 3 or -CH 2 -X 1 -Y 3 as defined above, with the proviso that only one of the groups A ₃ and A ₃ -. may be a direct bond when n 'is zero, and each of As and A ₄ is different from a direct bond when n is 1, and their physiologically hydrolyzable and acceptable esters or amides, in free form, in salt form, or in the form of complexes. 5 (ej to (j) as defined in claim 1, wherein the peptide fragments are such that a protected or unprotected peptide having the sequence of the general formula is obtained And optionally removing the protecting group or groups from the compound of formula I in a protected form, and d) for the preparation of compounds of formula I wherein X is a radical of formula (e 1) or (h) and A s is a radical of formula (k), (1) or (o) or -CH 2 -X 1 -Y 3, such as as defined in claim 1, reacting a compound of formula III R- / A, -Aω / n-A3-Aa-X'-CH2-Za (III) wherein R, Ai to Aa and n are as defined in claim 1, X 'is a radical of formula (ej or (h) as defined in claim 1, and Za is a leaving group, with the corresponding phenol, thiophenol or HX 1 -pyridine or with an acid of the formula HX 1 -CO-Y 1 or a functional derivative thereof or with HX 1 -Y 3, wherein X 1, Y ₃ and Y ₄ are as defined in claim 1, or are e) for the preparation of compounds of formula I R- / A (I) wherein R, A 1 to As and n are as defined in claim 1, is an aliphatic or alicyclic radical containing carbon atoms, oxidizes a compound of formula and R 1 g 1 to 12 V ¢ - (V) wherein R, A 1 to As, R 1 are as defined above, and the compound of formula (I) or a physiologically hydrolyzable and acceptable ester or amide thereof is isolated in free or salt or complex form. 5. Compounds of formula I according to claim 1, 3 or 4, wherein X is a radical of formula (ei), (h) or (j), As is other than a hydrogen atom when X is a radical of formula (ej, and their physiologically hydrolyzable and acceptable esters or amides, in free form, in the form of salts or in the form of complexes. 6. (Benzyloxycarbonyl-biphenyl-alanyl) -3R-3-amino-4-oxo-5- (2,6-dichlorobenzoyloxy) pentanoic acid ethyl ester, (Benzyloxycarbonyl-valyl-alanyl) -3R, S-3-amino-4- oxo-5- (2,6-dichlorobenzoyloxy) pentanoic acid, (benzyloxycarbonyl-valyl-alanyl) -3R-3-amino-4oxo-5- (2,6-dichloropyridyl-4-carbonyloxy) pentanoic acid ethyl ester, (Benzyloxycarbonyl-valyl-alanyl) -3R, S-3-amino-4-oxo-5 '(2,6-dichlorobenzoyloxy) pentanoic acid, (Benzyloxycarbonyl-valyl-alanyl) -3R, S-3-amino-4-oxo isopropyl ester -5- (2,6-dichlorobenzoyloxy) pentanoic acid, (benzyloxycarbonyl-valyl-alanyl) -3R, S-3-amino-4-oxo-5- (2,6-dichlorobenzoyloxy) pentanoic acid tert-butyl ester and (benzyloxycarbonyl- valyl-alanyl) -3S-3-amino-4-oxo-5- (2,6-dichlorobenzoyloxy) pentanoic acid in free form, in salt form or in the form of complexes. A process for the preparation of the compounds of the formula I and their physiologically hydrolyzable and acceptable esters and _w- amides as defined in claim 1, characterized in that: (a) removing at least one protecting group from a compound of formula I in protected form, or adding a protecting group R as defined in claim 1 to the N-terminal group of a compound of formula I, or (b) converting one compound of formula I into another compound of formula I, or c) join together by amide bond two peptide fragments, each containing at least one amino acid in protected or unprotected form and one peptide fragment containing a residue of the general formula A compound according to any one of claims 1 to 6 for use as a medicament. A pharmaceutical composition comprising a compound of formula I as defined in claim 1, or a physiologically hydrolyzable and acceptable ester or amide thereof, in free or physiologically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier. 10. A method of treating conditions that are caused by excessive release of IL-1 beta in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula I as defined in claim 1, or a subject thereof. a physiologically hydrolyzable and acceptable ester or amide, or a pharmaceutically acceptable salt thereof.