AU2885292A - Peptides inhibiting il-1 beta release - Google Patents
Peptides inhibiting il-1 beta releaseInfo
- Publication number
- AU2885292A AU2885292A AU28852/92A AU2885292A AU2885292A AU 2885292 A AU2885292 A AU 2885292A AU 28852/92 A AU28852/92 A AU 28852/92A AU 2885292 A AU2885292 A AU 2885292A AU 2885292 A AU2885292 A AU 2885292A
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- Prior art keywords
- formula
- radical
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- amino
- alkyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/545—IL-1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06052—Val-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Description
PEPTIDES INHIBITING IL-1 BETA RELEASE
The present invention relates to peptides having pharmaceutical utility, processes for their production, pharmaceutical compo-sitions comprising them and their use as pharmaceuticals.
More particularly the present invention provides a compound of formula I
R-[A1-A2]n-A3-A4-X-A5 (I) wherein
R is hydrogen, an amino protecting group or optionally ring substituted benzyloxy
A1 is Val, Leu, Ala, lie or trimethylsilyl-Ala
A2 is Phe or Tyr,
n is 0 or 1,
A3 is a direct bond, Val, Leu, Ala, lie, trimethylsilyl-Ala or a divalent radical of formula (a)
vherein ring A is optionally substituted by hydroxy or
C1-4alkoxy,
is a direct bond or a divalent radical of formula (b)
wherein R1 is hydrogen or C1-4alkyl, and
Y1 is the residue attaching to the α-carbon atom of an α-amino acid and optionally protected, -CH2-CH2-N(C1-4alkyl)2, imidazol-2-yl-methyl, benzimidazol-2-yl-methyl, 1H-1,2,4-triazol-3-yl- methyl, pyrazol-3-yl-methyl, indazol-3-yl-methyl or a radical of formula (c) or (d)
or
wherein
each of R2 and R3, independently, is hydrogen,
halogen, C1-4alkyl, CF3 or trityl, at most one of R2 and R3 being H, and
each of R4 and R5 independently is hydrogen,
C1-4alkyl, hydroxy, C1-4alkoxy, CF3, phenyl or halogen, at most one of R4 and R5 being H, or A3 and A4 form together a radical of formula (aa)
wherein Y1 is as defined above and R1 and R1a form together
-(CH2)m- wherein m is 2, 3, 4 or 5, and
1) X is a divalent radical of formula (e1)
wherein R6 is H or C1-4 alkyl,
and A5 is hydrogen; CF3; a radical -Z1-Z2-Y2 wherein each of Z1 and Z2 independently is a direct bond or an α-amino acid residue and Y2 is NH2 , C1-4alkylamino, di-(C1-4alkyl)amino or a heterocyclic radical attached by a nitrogen to Z2; a radical -CH2-X1-Y3 wherein X1 is O or S and Y3 is heteroaryl; a radical -CH2-Y3; or a radical of formulae (k) to (m)
or
wherein
Y4 is tri-(C1-4alkyl)methyl or a residue ring B is pyridyl,
- ring C is phenyl or pyridyl,
each of R7 and R8 independently is C1-4alkyl, C1-4alkoxy,
CF3, halogen, nitro or cyano, and
each of R9, R10 and R11 independently is nitro, cyano,
CF3, carbamoyl, CO2R12, -CH=CH-CN or -CH=CHCO2R12 wherein
R12 is C1-6alkyl,
X being also a divalent radical of formula (e2)
when A5 is H, or
2) X is a divalent radical of formula (f) ,
and A5 is -Z1-Z2-Y2 or a radical of formulae (k) to (o) as defined above, or OR13 or NR14R15 wherein R13 is C1-12al- kyl optionally substituted by OH or interrupted by 0 and each of R14 and R15 is independently hydrogen, C1-12al- kyl, C5-7cycloalkyl or benzyl, or
3) X is a divalent radical of formula (g)
and A5 is -Z1-Z2-Y2 as defined above, or
4) X is a divalent radical of formula (h) or (j)
and A5 is a radical of formulae (k) to (o), -CH2-Y3 or
-CH2-X1-Y3 as defined above, with the provisos that
only one of A3 and A4 can be a direct bond when n is 0, and each of A3 and A4 is other than a direct bond when n is 1. and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes.
Examples of protecting groups as R are e.g. disclosed in "Protective Groups in Organic Synthesis", T. W. Greene, J.Wiley & Sons NY (1981), 219-287, for example acyl such as acetyl, methoxysuccinyl, hydroxysuccinyl or benzoyl optionally substituted on the phenyl ring with e.g. p-methoxycarbonyl, p-methoxy or p-nitro; alkoxycarbonyl such as t-butyloxycarbonyl; arylmetho¬xycarbonyl such as 9-fluorenylmethoxycarbonyl or benzyloxy carbonyl optionally substituted on the phenyl ring with p-methoxy, p-nitro, p-chloro or m-phenyl; arylmethyl such as benzyl optionally ring substituted with p-methoxy, p-nitro or p-chloro; or arylsulfonyl such as phenylsulfonyl optionally ring substituted
with p-methyl or p-methoxy, or naphthylsulfonyl optionally ring substituted with e.g. amino or di(C1-4alkyl)amino.
When R is ring substituted benzyloxy, it is preferably benzyloxy substituted with hydroxy or C1-4alkoxy. Preferably R is
unsubstituted benzyloxy.
Halogen is preferably fluorine or chlorine.
When A3 is a substituted radical of formula (a) it is preferably substituted by C1-4alkoxy, preferably in para to -C=O.
By α-amino acid is meant a naturally occurring or commercially available or non natural α-amino acid or an optical isomer thereof. A non natural α-amino acid is an α-amino acid which is not incorporated into a protein under mRNA direction, e.g. β-Nal, a fluoro-α-amino acid such as fluoroalanine, trimethylsilyl-Ala or an α-amino acid such as
wherein n1 is an integer from 1 to 6 and n2 is an integer from 1 to 12.
Protecting groups which may be present in Y1 are groups which protect the O, S or N functionality in the side chain amino groups of an α-amino acid. N-protectiπg groups are e.g. as disclosed above for R, or C3-5alkyl such as isopropyl, formyl, a sugar residue such as 1-deoxy-fructosyl or α-glucosyl(1-4)-
deoxyfructosyl, dihydroxy-C3-6alkyl such as dihydroxypropyl, C5-7 cycloalkyl such as cyclohexyl or tropinyl. O- and
S-protecting groups for hydroxy and thiol functionalities are known and may be e.g. methyl, t.-butyl or benzyl.
When Y2 is a heterocyclic radical, it may be e.g. a 5 or 6 membered ring, e.g. piperidino or pyrrolidinyl.
Examples of heteroaryl as Y3 include e.g. 5-, 6- or 7-membered unsaturated heterocyclic radicals, comprising at least one nitrogen and optionally further heteroatoms such as N, O or S. Preferably Y3 is heteroaryl comprising from 1 to 4 nitrogen atoms, e.g. pyridyl, triazolyl, tetrazolyl, triazin-dionyl.
In ring B of radical (o), the nitrogen atom may be in o-, m- or para. When ring C in radical (k) is pyridyl, it may be 3-, 4- or 5-pyridyl.
Radicals (e1), (e2), (f), (g) and (j) are derived from Asp and comprise one asymetric carbon atom and radical (h) comprises two asymetric carbon atoms and accordingly they lead to optical isomerism. It will be understood that the present invention includes all individual isomeric forms and diastereoisomers as well as mixtures, e.g. racemates, unless otherwise stated.
Radical of formula (e1) attached to A5 which is hydrogen may exist in both cyclic as well as in non-cyclic form e.g. as follows:
It is to be understood that where tautomeric forms occur, the present invention embraces both lactol and oxo-carboxylic acid forms, i.e. although compounds of formula I wherein X is a radical of formula (e1) are defined for convenience by reference to the oxo-carboxylic acid form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphic representation employed. Similar considerations apply in relation to starting materials exhibiting lactol/oxo-carboxylic acid tautomerism as hereinafter described.
The same considerations also apply to radical of formula (h) which may exist in both linear and cyclic form as follows:
and to compounds of formula I comprising a radical of formula (h) and to the corresponding starting materials.
By the term "physiologically-hydrolysable and -acceptable esters or amides" are meant esters and amides which are hydrolysable under physiological conditions to yield alcohols or amines which are themselves physiologically acceptable, i.e. which are non-toxic at the desired dosage levels.
Such esters or amides are obtained by esterification or
amidation, respectively, of a compound of formula I wherein X is a radical bearing a carboxy group. Such esters include esters with an aliphatic or alicyclic alcohol or polyol having 1 to 12 carbon atoms. Such amides include amides with aliphatic amines, e.g. C1-4alkyl amine, C1-4alkoxy-C1-4alkyl amine such as
β-methoxy-ethyl amine, or aniline.
The compounds of formula I may exist e.g. in free form, acid addition salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. Salt forms may also include those obtainable with the carboxylic group present in compounds of formula I, e.g. alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts. Complexes are e.g. formed from compounds of formula I on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca-and Zn-salts, and/or an addition of polymeric organic substances.
In the compounds of formula I, the following significances are preferred either individually or in any combination or sub-combination:
1. R is an amino protecting group or benzyloxy, preferably an amino protecting group. R is preferably benzyloxy when n is 0 and A3 is a radical of formula (a).
2. Each of A3 and A4 are other than a direct bond.
3. n is 0.
4. A3 is a radical of formula (a) when n is 0.
5. A3 is a direct bond, Val, Leu, Ala, lie or trimethylsily-Ala.
6. R1 is hydrogen or methyl, preferably hydrogen.
7. Y1 is the residue attaching to the α-carbon atom of an α-amino acid selected from Ala, Leu, His, Phe, Met, Trp,
trimethylsilyl-Ala and optionally side chain protected Arg, Orn and Lys, or Y1 is a radical of formula (c).
8. A3 and A4 may also form together a radical of formula (aa) when n is O.
9. m is 2 or 3.
10. X is a radical of formula (e1) and A5 is other than H.
11. X is a radical of formula (g).
12. X is a radical of formula (h) or (j).
13. R6 is hydrogen or methyl, preferahly hydrogen.
14. Z1 in A5 is the residue of a natural α-amino acid, preferably of an aromatic/heterocyclic α-amino acid, particularly Pro.
15. Z2 in A5 is the residue of a natural α-amino acid, preferably an aliphatic α-amino acid, particularly an aliphatic α-amino acid without further functional group, most preferably Val.
16. X is a radical of formula (e1) optionally esterified or
amidated and A5 is a radical of formula (k), (1) or (o).
17. X is a radical of formula (e1), (h) or j(j) optionally esterified or amidated and A5 is -CH2-X1-Y3, preferably
-CH2-S-Y3, or -CH2-Y3.
18. X is a radical of formula (h) or (j) optionally esterified or amidated and A5 is (k.).
19. X is a radical of formula (j) optionally esterified or
amidated and A5 is a radical of formula (m).
20. Radical of formula (m) is monosubstituted, preferably in
para, more preferably it is 4-nitrophenyl.
21. All α-amino acid residues present except X have the L
configuration. X has the D or L configuration.
22. The asymetric carbon in (h) bearing the OH group has the
configuration S. Preferably the asymetric carbon in (j) bearing R6 has the configuration R.
In a series of specific embodiments, the present invention also provides a compound of formula I wherein
n is 0, A3 is a direct bond, Val, Leu, Ala, lie or trimethylsilyl-Ala, A4 is as defined above, or A3 and A4 form together a radical of formula (aa) as defined above, and
i) X is a radical of formula (e1) or (e2) as defined above and
A5 is H, or
ii) X is a radical of formula (e1) or (f) and A5 is -Z1-Z2-Y2 as defined above or a radical of formula (k), (l) or (m) wherein
X1 is 0,
iii)X is a radical of formula (g) and A5 is -Z1-Z2-Y2, or iv) X is a radical of formula (j) and A5 is a radical of formula
(k), (l) or (m) wherein X1 is 0.
The present invention also provides a process for the production of a compound of formula I, which process comprises: a) removing at least one protecting group from a compound of formula I in protected form or adding a protecting group R at 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) coupling together by an amide bond two peptide fragments,
each of which contains at least one amino acid in protected or unprotected form and one peptide fragment containing a radical of formula (e1) to (j) as defined above, the peptide fragments being such that a protected or unprotected peptide having the sequence according to formula I above is obtained and, if necessary, removing the protecting group or groups from a compound of formula I in protected form; or d) for the production of a compound of formula I wherein X is a radical of formula (e1) or (h) and A5 is a radical of formula (k), (l) or (o) or -CH2-X1-Y3, reacting a compound of formula III
R-[A1-A2]n-A3-A4-X'-CH2-Za (III) wherein R, A1 to A4 and n are as defined above, X' is a radical of formula (e1) or (h), and Za is a leaving group, e.g. halogen, with a corresponding phenol, thiophenol or HX1-pyridine or an acid of formula HX1-CO-Y4 or a functional derivative thereof or HX1-Y3; or e) for the production of a compound of formula I
wherein R, A1 to A5 and n are as defined above and R16 is a C1-12 aliphatic or alicyclic residue, oxidizing a compound of formula V
wherein R, A1 to A5, n and R1 6 are as defined above, and recovering a compound of formula I thus obtained in free or salt form or in the form of a complex.
Processes (a) to (e) above may be carried out in accordance with standard techniques known in the art.
The removal of a protecting group in process step (a) may also include the removal of R on the N-terminal group of a compound of formula I. For example, when R is benzyloxy carbonyl, this group may be removed by hydrogenation in the presence of a catalyst, e.g. Pd.
In accordance with process step (b) for example, for the production of a compound of formula I wherein X comprises a carboxy group, a compound of formula I wherein X comprises an esterified or amidated carboxy group may be hydrolysed. Suchhydrolysis may be effected by treatment with an appropriate alkali or by acid hydrolysis, for example in the presence of trifluoroacetic acid.
Furthermore, in accordance with process step (b), for the production of a compound of formula I wherein X comprises an esterified or amidated carboxy group, a compound of formula I wherein X comprises a carboxy group or an esterified caboxy group may be (trans) esterified or amidated. Such ester formation or amidation may be carried out using any of the techniques known in the art, for example converting the carboxy group in a functional
reactive group, e.g. a corresponding carbonyl halide or anhydri- de, or using a compound of formula I wherein X is a radical of formula (h) in the lactone form, and reacting such group with the selected alcohol or amine.
In accordance with a further embodiment of process step (b), for the production 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 (e1) or (e2) and A5 is H may be reacted with a compound of formula II
H2N-NH-CO-A5 (II) wherein A5 is as defined above. This process may be carried out in analogy to the known techniques used for the preparation of semi carbazones.
A compound of formula I wherein X is a radical of formula (e1) may also be converted in accordance with known techniques into a compound of formula I wherein X is a radical of formula (e2) and vice versa.
Process step (c) may be carried out by the techniques known in the art of peptide chemistry. By peptide fragment comprising a radical of formula (e1) to (j) is also meant the radical itself bearing a protecting group on the -NR6- moiety and an appropriate ending, e.g. A5 or CH2-Za, on the other end.
Process step (d) may conveniently be effected using a Dess-Martin reagent, e.g. in the presence of a base or a halogen-precipita-ting silver salt, or according to the Swern oxidation procedures.
Where desired, in these reactions, protecting groups may be used for functional groups which do not participate in the reaction.
These may be e.g. amino protecting groups, carboxy protecting groups, acetal groups etc. When the desired reaction is complete, the protecting groups may then be removed.
Each of the above processes may be carried out using starting materials in the form of one or other of the individual optical isomers or in the form of mixtures [relating to the asymetric carbons present in radicals of formulae (e1) to (j) as X or in such a radical precursor]. Conveniently the starting materials are used as S- or R-enantiomers to produce a compound of formula I wherein the asymetric carbon in radicals of formulae (ei) to (j) has the S or R configuration, respectively.
The starting materials used in process steps (d) or (e) may be prepared in analogy with process step (c).
Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known and practiced in the art.
The following examples are illustrative of the invention. All temperatures are in °C.
The following abbreviations are used:
THF = tetrahydrofuran
TFA = trifluoroacetic acid
MeOH = methanol
EtOAc = ethyl acetate
DCC = dicyclohexylcarbodiimide
HOBT = hydroxybenzotriazole
Z = benzyloxycarbonyl
r.t. = room temperature
Fmoc = 9-fluorenylmethoxycarbonyl
a = amorph
EXAMPLE Is Z-Val-Het-Asp (OH) -H
Z-Val-Met-Aspartic aldehyde dimethyl acetal-β-tert. butyl ester (1.17 g) is taken up in CH2Cl2 (150 ml), TFA (15 ml) and water (1 ml) added and stirred for 2,5 hrs at r.t. The solvent is evaporated, toluene added twice and evaporated again. The crystalline residue is dissolved in water (60 ml) upon heating, decanted from some undissolved material and crystallized at 5 °, affording the first crop of the product: m.p. 117 °. All mother liquors are collected and chromatographed (SiO2, acetone/hexane/- EtOAc 60/40/0.5) to give a second crop of product, crystallizing upon trituration with water.
EXAMPLE 2: Z-Val-Met-Asp(OH)-H Semicarbazone
Compound of Example 1 (0.27 g, 0.55 mmol) in MeOH (2 ml) is combined with semicarbazide, HCl (0.6 ml of 1 molar solution), then 5 drops of pyridine are added. The product crystallizes after 10 min. at r.t.ϊ m.p. 233 - 235 °.
EXAMPLE 3: Z-Val-Met-Asp(OH)-H semicarbazonyl-Pro-Val-N(CH3)2
Compound of Example 1 (0.48 g, 1 mmol) is dissolved in a mixture of MeOH (2 ml) water (0.5 ml) and 3 drops of pyridine.
N-(hydrazinocarbonyl)-Pro-Val-N(CH3)2 (0.3 g, 1 mmol) is
dissolved in MeOH (1 ml), water (2 ml) and 3 drops of 2N HCl. Both solutions are combined and warmed for 2 min. at 40 - 50 °. The product crystallizes upon cooling: m.p. 118 - 120 °.
By repeating the procedure of Example 1, using the corresponding starting materials, following compounds may be prepared:
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 respectively, using the corresponding starting materials, following compounds of formula IA
wherein A3, A4 and A5 are as defined below, may be prepared.
Example A3 A4 A5 M.P.°C
6 Val Phe H a
7 Val His H 150
8 Val Phe Pro-Val-N(CH3)2 126-129
9 Val His Pro-Val-N(CH3)2
10 Ala-Tyr-Val Phe H 205
EXAMPLE 11: (3S)-3-(Z-valyl-phenylalanyl)-amino-5-(2,6-dimethyl benzoyloxy)-4-oxo pentanoic acid
(3S,4RS)-3-(Z-Val-His)amino-4-hydroxy-5-(2,6-dimethylbenzoyloxy) pentanoic acid tert. -butyl ester (0.6 mmol) is treated with Dess-Martin reagent (0.77 mmol) in CH2Cl2 (4 ml) for 45 min. and filtered. Aceton and 0.5 N NaOH are then added and aceton is evaporated. The residual crystalline material is washed with H2O, acidified with 10 % tartaric acid and extracted with EtOAc. The combined EtOAc extracts affords after evaporation the tert. butyl ester of the product as yellow crystals. These are dissolved in CH2Cl2 (4 ml), TFA (4 ml) is added and the mixture is stirred at r.t. for 15 min. The mixture is evaporated to dryness and chromatographed (SiO2, aceton/hexane/EtOAc 60/40/1) affording the product as slightly colored crystals.
EXAMPLE 12: (Z-valyl-alanyl)-(3R,4S)-3-amino-4-hydroxy-5- (2,6-dichlorbenzoyloxy)
(Z-valyl-alanyl)-3R,4S)-3-amino-4,5-dihydroxy pentanoic acid ethyl ester and 4-dimethylaminopyridine are dissolved in pyridine and 2,6-dichlorobenzoyl chloride is added dropwise. The reaction mixture is stirred overnight at room temperature, then ice and water are added and the mixture is extracted with AcOEt. The organic layer is washed with water, then with NaCl solution, dried over Na2SO4, filtered, evaporated, and the crude product is chromatographed to give the title compound.
The (3R,4RS) derivative of the title compound may be prepared as follows:
Z-Val-Ala-OH (0.26 mmol), DCC (53 mg, 0.26 mmol) and HOBT.H2O (39 mg, 0.26 mmol) are dissolved in THF/DMF (2 ml/2 ml) and stirred for 5 min., before (3S,4RS)-3-amino-4-hydroxy-5(2,6- dimethylbenzoyloxy)-pentanoic acid tert.butyl ester (87 mg, 0.26 mmol) in THF (2 ml) is added. The reaction mixture is stirred overnight at r.t., evaporated and chromatographed (SiO2, EtOAc/MeOH/NH3 95/5/0.5) to afford the (3R,4RS) title compound.
EXAMPLE 13; (Z-valyl-alanyl)-(3R)-3-amino-4-oxo-5-(2,6-dichloro- benzoyloxy) pentanoic acid ethyl ester
Dimethylsulfoxide in CH2Cl2 is added dropwise to a solution of oxalyl chloride in CH2Cl2 at -50°C. After 15 min., a solution of compound of Example 12 in CH2Cl2 is added dropwise and the reaction mixture stirred for 1 hour at -40ºC. Triethylamine is added and stirring is continued for 3 hours at room temperature. Water is then added and the reaction mixture extracted with
CH2Cl2. The organic layer is washed with NaHCO3 solution and
NaCl solution, dried over Na2SO4, filtered and evaporated. The residue is chromatographed yielding the title compound.
By repeating the procedure of Examples 1-3 and 11 to 13, using the corresponding starting materials, following compounds of formula IB
wherein A3, A4, Rx and Ry are as defined below, may be prepared.
EXAMPLE 58:
EXAMPLE 59:
EXAMfLE 60:
EXAMPLE 61:
EXAMPLE 62:
By repeating the procedure of Examples 1-3 and 12-13 and using the corresponding starting materials, following compounds of formula IC
wherein A3 , Rx and Ry are as defined below, may be prepared
EXAMPLE 67: (3RS)-3-(Z-valyl-phenylalany1)amino-4-oxo-6- (p-nitrophenyl)-transhex-5-enoic acid tert.butyl
(3RS)-3-(Z-Valyl-phenylalanyl)amino-4-oxo-pentanoic acid tert. butyl ester-5-diethylphosphonate (0.2 g, 0.29 mM) is dissolved in THF (15 ml) at 5°C. NaH (25 mg, 0.59 mM) is added and the mixture stirred for 10 min. p-Nitrobenzaldehyde (0.18 g, 1.1 mM) in THF (2 ml) is added at 0ºC and the reaction mixture stirred for 45 min. at this temperature. The reaction mixture is poored on 5 % tartaric acid, extracted with ethyl acetate, the organic phases dried over Na2SO4, evaporated and the product purified by chromatography yielding the title compound.
EXAMPLE 68: Z-Val-Phe-Aspartic aldehyde dimethyl acetal-β-methyl ester
Z-Val-Phe-Asp(OH)-H (0.8 g) is dissolved in MeOH (25 ml) containing 8% HCl, left at r.t. over night, evaporated to dryness and the residual crystals washed with ether, providing the title compound as white crystals. M.p.: 168 - 171 °.
Starting materials may be prepared as follows:
EXAMPLE 69: (3S)-3-(Fluorenylmethoxycarbonyl)amino-5-iodo-4-oxo butanoic acid tert.butyl ester
Triethylamine (1.3 ml, 9.6 mmol), followed be ethylchloroformiate (0.92 ml, 9.6 mmol) are added to (3S)-3-(fluorenylmethoxycarbo-nyl)amino-3-carboxy-butanoic acid tert. butyl ester (3.5 g, 8.5 mmol) in THF (60 ml) at - 10 °. After 10 min., a solution of dia-zomethane in ether is added slowly, and the reaction mixture stirred for 45 min. at 0 - 5 °. HCl (2N) in ether is added at 5 -10 ° until gas evolution has ceased. The reaction mixture is eva-porated to dryness, taken up in acetone (50 ml) Nal (4 g) added
and stirred for 1 hr at r.t. Ether (150 ml) is added, the reaction mixture filtered and evaporated. The residue is chromatographed (SiO2, EtOAc/hexane), yielding the title compound as slightly yellow crystals.
EXAMPLE 70: (3S)-3-(Fluorenylmethoxycarbonyl)amino-5(2,6- difflethylbenzoyloxy)-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), 2,6-dimethylbenzoic acid (0.5 g, 3.3 mmol) and AgOAc (0.6 g, 3.6 mmol) are dissolved in acetone (25 ml) and refluxed for 1 hr. After filtration and evaporation the crude product is chromatographed (SiO2,
ether/hexane 3/7) yielding the title compound.
EXAMPLE 71: (3S)-3-Fluorenylmethoxycarbonyl)amino-5(4- nitrophenoxy)-4-oxo pentanoic acid tert.butyl ester
3S-3-(Fluorenylmethoxycarbonyl)aminσ-5-iodo-4-oxo-butanoic acid tert.butyl ester (1 g, 1.8 mmol), p-nitrophenol (0.5 g, 3.7 mmol) and K2CO3 (0.38 g, 2.8 mmol) are refluxed in acetone (6 ml) for 30 min., CH2Cl2 added and the organic phase washed with 2N
NaHCO3. The combined organic phases are dried, evaporated and chromatographed (SiO2, EtOAc/hexane 2/8), yielding the title compound as a yellow oil.
EXAMPLE 72: (Z-valyl-alanyl)-(3R,4S)-3-aaino-4,5-dihydroxy
pentanoic acid ethyl ester a) Ethyl (3R,4S)-3-benzylamino-4,5-(isopropylidenedioxy)
pentanoate (Y. Yamada, Tetrahedron Leters 1983, 24, 3009) and 10% Pd/C in ethanol are shaken at r.t. for 30 mn under H2.
Filtration and evaporation of the reaction mixture give ethyl (3R,4S)-3-amino-4,5-(isopropylidenedioxy)pentanoate which is used without further purification. b) Z-Val-Ala-OH is dissolved in THF, HOBTH2O and DCC are added at 5°C. After stirring for 20 min. at 5°C, diisopropylethylamine and ethyl (3R,4S)-3-amino-4,5-(isopropylidenedioxy)pentanoate in THF are added. Reaction mixture is stirred overnight at room temperature, filtered, evapored and chromatographed to afford (Z-valyl-alanyl)-(3R,4S)-3-amino-4,5-(isopropylidenedioxy)pentanoic acid ethyl ester. c) Compound 74 b) is dissolved in AcOH/H2O (75/25) and stirred at 40°C for 4 hours. After evaporation, water is added and the mixture is extracted with AcOEt. The combined extracts are washed with water, NaHCO3 solution, NaCl solution, dried over Na2SO4, filtered and evaporated, yielding the title compound.
The compounds of formula I their physiologically-hydrolysable and -acceptable esters and amides and their pharmaceutically
acceptable salts (hereinafter referred to as compounds of the invention) exhibit pharmaceutical activity and are, therefore, useful as pharmaceuticals.
In particular, the compounds of the invention inhibit IL-1β secretion as indicated in the following in vitro test using THP-1 cells and in vivo test methods: a) 900 μl THP-1 cells (0.5 × 106 cells) together with 100 U
γ-interferon/0.9 ml RPMI 1640 medium (containing 2 mM
L-glutamine and 5 % heat-inactivated foetal calf serum) are pipetted into 24 well culture plates. 100 μl of the compound to be tested are then added. After 3 hours at 37 ° C in 5 % CO2/95 % air, 10 μl lipopolysaccharide 500 μg/ml is added and
the incubation continued for a further 40 hours. Appropriate controls (with and without stimulus, solvent) ar also included. The media are then removed and clarified by centrifugation at 1000 g for 10 min. 1.0 ml digitonin 0.01 % is added to the wells to lyse the cells which are loosened by scraping with a rubber policeman and left at 4 ° C for 10 min. Lactate dehydrogenase measurements are then performed immediately and the samples stored at - 20 ° C until the other determinations can be made. The assays are: IL-1β (medium and lysate), IL-6 (medium), TNF-α (medium), PGE2 (medium and lysate), lactate dehydrogenase (LDH) and DNA (lysates). IL-1β, IL-6 and TNF-α assays are determined using commercially available ELISA kits (Cistron), PGE2 is measured using a standard RIA and DNA fluorimetrically using DAPI.
In this test, the compounds of the invention selectively inhibit IL-1β release in concentrations from about 0.01 to 100 μM. In contrast IL-6, TNF-α, PGE2 and DNA levels remain substantially unaffected, and the compounds are non-toxic, since LDH release is unchanged. It has for example been determined that compounds of examples 40 and 50 have an IC50 value (concentration of compound which inhibits to 50% the release of IL-1β) of 1 and 0.1 μM respectively. LPS-Fever
A LPS-suspension (Sigma, No. L-5886; 100μg/5ml glucose solution/kg s.c.) is injected in male Tuttlingen SD rats
(150-160g). 2 hours later the body temperature is measured using a thermistor rectal probe connected to an ELLAB tele-thermometer. After 4 hours the test compound is administered p.o. 2 hours later (6 hrs after LPS administration) the temperature is measured again. The temperature increment shown by the untreated controls is taken as 100% and that in
the treated group is expressed as a percentage of this value. The ED50 is the dose causing a 50% inhibition of the temperature increase determined in the control rats. In this test compounds of the invention inhibit the LPS-induced temperature increase when administered at a dosage in the range of from 0.001 to 0.1 mg/kg p.o. It has for example been determined that compounds of examples 40 and 50 have each an ED50 value of 0.01 mg/kg p.o. and compound of example 51 an ED50 value of 0.05 mg/kg p.o. Carrageenan-Induced Paw Edema in the Rat
50FA male rats, 150-170g body weight, are used for each group. The test compound is administered orally as a suspension in physiological saline/0.5% tragacanth 1 hour prior to the carrageenan injection. Carrageenan (0.1ml of a 1% suspension in physiological saline) is given by subplantar injection into one hind paw. The swelling of the paw is measured by means of an antiphlogometer according to Kemper & Amelm. A control reading is taken immediately after the injection, and the swelling is measured after 3 and 5 hrs. The mean value of the 3- and 5-hour reading is taken after deduction of the control reading, the values obtained from the treated animals are expressed as a percentage of the value obtained from non-treated controls. The ED50 is the dose causing a 50% inhibition of the carrageenan-induced swelling after 3 hrs. In this test method compounds of the invention inhibit significantly the carrageenen-induced swelling when administered p.o. at a dosage in the range of from 0.02 to 5 mg/kg. It has for example been determined that compound of example 40 and 50 have an ED50 value of 0.2 and 1 mg/kg p.o. respectively.
Compounds of the invention are therefore useful for the treatment of disorders with an aetiology associated with or comprising excessive IL-1β release, e.g. in a wide variety of inflammatory states and diseases, for example tissus calcium depletion, degenerative processes in bone and cartilage, e.g. rheumatoid arthritis and osteoarthritis, inflammatory bowel disease, irritable bowel disease, septic shock, psoriasis, asthma, adult respiratory distress syndrome, diabetes type I, osteoporosis of various genesis including e.g. climacteric or post-menopausal osteoporosis as well as osteoporosis consequential to old age, immobilization or trauma, arteriosclerosis and Alzheimer disease.
For the above uses the required dosage will of course vary depen¬ding on the mode of administration, the particular condition to be treated and the effect desired. In general however, satisfactory results are achieved at daily dosage rates of from about 0.001 to about 100 mg/kg, preferably 0.001 to about 10 mg/kg animal body weight. Suitable daily dosage rates for larger mammals, for example humans, are of the order of from about 0.1 mg to about 1 g/day, conveniently administered once, in divided dosages 2 to 4 x/day, or in sustained release form.
Compounds of Examples 50 and 51 are preferred.
In accordance with the foregoing the present invention also provides: a) A method for the treatment of disorders with an aetiology
associated with or comprising excessive IL-1β release, e.g. as indicated above in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof;
b) A compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical, for example for use as an agent, e.g. in the method as disclosed above.
The compounds of the invention may be administered by any con¬ventional route, in particular nasally, enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally e.g. in the form of injectable solutions or suspensions or in a suppository form. Unit dosage forms contain, for example from about 25 μg to 500 mg of a compound of the invention.
The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form. Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds.
Furthermore the present invention also provides:
c) A pharmaceutical composition comprising a compound of formula I, a physiologically-hydrolysable and -acceptable ester or amide thereof or a pharmaceutically acceptable salt thereof, as hereinbefore defined, together with a pharmaceutically acceptable diluent or carrier therefor. Such compositions may be manufactured in conventional manner. They may comprise up to 99.9% by weight of active ingredient.
Claims (1)
1. A compound of formula I
wherein
R is hydrogen, an amino protecting group or optionally ring substituted benzyloxy
n is 0 or 1,
A1 is Val, Leu, Ala, Ile or trimethylsilyl-Ala
A2 is Phe or Tyr,
A3 is a direct bond, Val, Leu, Ala, lle, trimethylsilyl-Ala or a divalent radical of formula (a)
wherein ring A is optionally substituted by hydroxy or C1-4alkoxy,
A4 is a direct bond or a divalent radical of formula (b) wherein R1 is hydrogen or C1-4 alkyl, and
Y1 is the residue attaching to the α-carbon atom of an α-amino acid and optionally protected, -CH2-CH2-N(C1-4alkyl)2, imidazol-2-yl-methyl, benzimidazol-2-yl-methyl, 1H-1,2,4-triazol-3-yl- methyl, pyrazol-3-yl-methyl, indazol-3-yl-methyl or a radical of formula (c) or (d) or
wherein
each of R2 and R3, independently, is hydrogen,
halogen, C1-4alkyl, CF3 or trityl, at most one of R2 and R3 being H, and
each of R4 and R5 independently is hydrogen, C1-4alkyl, hydroxy, C1-4 alkoxy, CF3, phenyl or halogen, at most one of R4 and R5 being H, or A3 and A4 form together a radical of formula (aa)
wherein Y1 is as defined above and R1 and R1a form toge- ther -(CH2)m- wherein m is 2, 3, 4 or 5, and i) X is a divalent radical of formula (e1)
wherein R6 is H or C1-4alkyl,
and A5 is hydrogen; CF3; a radical -Z1-Z2-Y2 wherein each of Z1 and Z2 independently is a direct bond or an α-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; a radical -CH2-X1-Y3 wherein X1 is O or S and Y3 is heteroaryl; a radical -CH2-Y3 ; or a radical of formulae (k.) to (m)
-CH2-X1-CO-Y4
(k)
wherein
Y4 is tri-(C1-4alkyl)methyl or a residue ring B is pyridyl,
ring C is phenyl or pyridyl,
each of R7 and R8 independently is C1-4alkyl,
C1-4alkoxy, CF3, halogen, nitro or cyano, and each of R9, R10 and R11 independently is nitro, cyano,
CF3, carbamoyl, CO2R12, -CH=CH-CN or -CH=CHCO2R12 wherein R12 is C1-6alkyl, being also a divalent radical of formula (e2) when A5 is H, or
ii) X is a divalent radical of formula (f),
and A5 is -Z1-Z2-Y2 or a radical of formulae (k) to (o) as defined above, or OR13 or NR14R15 wherein R13 is C1-12alkyl optionally substituted by OH or interrupted by 0 and each of R14 and R15 is independently hydrogen, C1-12 alkyl, C5-7cycloalkyl or benzyl, or iii) X is a divalent radical of formula (g)
and A5 is -Z1-Z2-Y2 as defined above, or
iv) X is a divalent radical of formula (h) or (j)
and A5 is a radical of formulae (k) to (o), -CH2-Y3 or
-CH2-X1-Y3 as defined above, with the provisos that
only one of A3 and A4 can be a direct bond when n is 0, and each of A3 and A4 is other than a direct bond when n is 1. and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes. A compound of formula I according to claim 1, wherein n is 0, A3 is a direct bond, Val, Leu, Ala, lie or trimethylsilyl-Ala, A4 is as defined in claim 1, or A3 and A4 form together a radical of formula (aa) as defined in claim 1, and i) X is a radical of formula (e1) or (e2) as defined in
claim 1 and A5 is H, or
ii) X is a radical of formula (e1) or (f) and A5 is
-Z1-Z2-Y2 as defined in claim 1 or a radical of formula
(k), (l) or (m) as defined in claim 1 wherein X1 is 0, iii) X is a radical of formula (g) and A5 is -Z1-Z2-Y2 as
defined in claim 1, or
iv) X is a radical of formula (j) and A5 is a radical of
formula (k), (l) or (m) as defined in claim 1 wherein X1 is 0. and the physiologically-hydrolysable and -acceptable esters or amides thereof,
in free form, in salt form or in the form of complexes. A compound of formula I according to claim 1 wherein n is 0 and each of A3 and A4 are other than a direct bond, and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes. A compound of formula I according to claim 1 or 3 wherein Y1 is the residue attaching to the α-carbon atom of an α-amino acid selected from Ala, Leu, His, Phe, Met, Trp, trimethyl-silyl-Ala and optionally side chain protected Arg, Orn and Lys, or a radical of formula (c), and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes. A compound of formula I according to claim 1, 3 or 4 wherein X is a radical of formula (e1), (h) or (j), A5 being other than H when X is (e1), and the physiologically-hydrolysable and -acceptable esters or amides thereof, in free form, in salt form or in the form of complexes. (Benzyloxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2,6-di chlorobenzoyloxy) pentanoic acid ethyl ester, (benzyloxycarbonyl-valyl-alanyl)-3R,S-3-amino-4-oxo-5-(2,6-dichloro benzoyloxy) pentanoic acid ethyl ester, (benzyloxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2,6-dichloro-pyridyl-4-carbonyloxy) pentanoic acid ethyl ester, (benzyloxycarbonyl-valyl-alanyl)-3R,S-3-amino-4-oxo-5-(2,6-dichlorobenzoyl oxy) pentanoic acid, (benzyloxycarbonyl-valyl-alanyl)-3R,S-3-amino-4-oxo-5-(2,6-dichlorobenzoyloxy) pentanoic acid isopropyl ester, (benzyloxycarbonyl-valyl-alanyl)-3R,S-3- amino-4-oxo-5-(2,6-dichlorobenzoyloxy) pentanoic acid t.-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 producing a compound of formula I and the physiologically-hydrolysable and -acceptable esters and amides thereof, as defined in claim 1, which process comprises 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 at 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) coupling together by an amide bond two peptide fragments, each of which contains at least one amino acid in protected or unprotected form and one peptide fragment containing a radical of formula (e1) to (j) as defined in claim 1, the peptide fragments being such that a protected or unprotected peptide having the sequence according to formula I above is obtained and, if necessary, removing the protecting group or groups from a compound of formula I in protected form; or d) for the production of a compound of formula I wherein X is a radical of formula (ei) or (h) and A5 is a radical of formula (k), (l) or (o) or -CH2-X1-Y3 as defined in claim 1, reacting a compound of formula III
R-[A1-A2]n-A3-A4-X'-CH2-Za (III) wherein R, A1 to A4 and n are as defined in claim 1, X' is a radical of formula (e1) or (h) as defined in claim 1, and Za is a leaving group,
with a corresponding phenol, thiophenol or HX1 -pyridine or an acid of formula HX1-CO-Y4 or a functional derivative thereof or HX1-Y3 wherein X1, Y3 and Y4 are as defined in claim 1; or e) for the production of a compound of formula I
wherein R, A1 to A5 and n are as defined in claim 1 and R16 is a C1-12 aliphatic or alicyclic residue, oxidizing a compound of formula V
wherein R, A1 to A5, n and R16 are as defined above, and recovering a compound of formula I or a physiologically-hydrolysable and -acceptable ester or amide thereof thus obtained in free or salt form or in the form of a complex. A compound according to any one of claims 1 to 6 for use as a pharmaceutical. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a physiologically-hydrolysable and -acceptable ester or amide thereof, in free form or in physiologically acceptable salt form, together with a pharmaceutically acceptable diluent or carrier therefor. A method for the treatment of disorders with an aetiology associated with or comprising excessive IL-1β release, in a subject in need thereof, which method comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1, a physiologically-hydrolysable and -acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof.
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GB919123326A GB9123326D0 (en) | 1991-11-04 | 1991-11-04 | Improvements in or relating to organic compounds |
GB9123326 | 1991-11-04 |
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EP (1) | EP0611375A1 (en) |
JP (1) | JPH07500828A (en) |
AU (1) | AU2885292A (en) |
CA (1) | CA2116653A1 (en) |
CZ (1) | CZ106794A3 (en) |
FI (1) | FI942061A (en) |
GB (1) | GB9123326D0 (en) |
HU (1) | HUT68200A (en) |
IL (1) | IL103612A0 (en) |
MX (1) | MX9206306A (en) |
NO (1) | NO941629L (en) |
NZ (1) | NZ244985A (en) |
PT (1) | PT101027A (en) |
SK (1) | SK51194A3 (en) |
WO (1) | WO1993009135A1 (en) |
ZA (1) | ZA928511B (en) |
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-
1991
- 1991-11-04 GB GB919123326A patent/GB9123326D0/en active Pending
-
1992
- 1992-10-29 WO PCT/EP1992/002472 patent/WO1993009135A1/en not_active Application Discontinuation
- 1992-10-29 JP JP5508146A patent/JPH07500828A/en active Pending
- 1992-10-29 CZ CZ941067A patent/CZ106794A3/en unknown
- 1992-10-29 HU HU9401303A patent/HUT68200A/en active IP Right Revival
- 1992-10-29 AU AU28852/92A patent/AU2885292A/en not_active Abandoned
- 1992-10-29 SK SK511-94A patent/SK51194A3/en unknown
- 1992-10-29 CA CA002116653A patent/CA2116653A1/en not_active Abandoned
- 1992-10-29 EP EP92922580A patent/EP0611375A1/en not_active Withdrawn
- 1992-11-02 NZ NZ244985A patent/NZ244985A/en unknown
- 1992-11-02 IL IL103612A patent/IL103612A0/en unknown
- 1992-11-02 PT PT101027A patent/PT101027A/en not_active Application Discontinuation
- 1992-11-03 MX MX9206306A patent/MX9206306A/en unknown
- 1992-11-04 ZA ZA928511A patent/ZA928511B/en unknown
-
1994
- 1994-05-03 NO NO941629A patent/NO941629L/en unknown
- 1994-05-04 FI FI942061A patent/FI942061A/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU685447B2 (en) * | 1993-06-04 | 1998-01-22 | Vertex Pharmaceuticals Incorporated | Peptidic phosphinyloxymethyl ketones as interleukin-1beta- converting enzyme inhibitors |
Also Published As
Publication number | Publication date |
---|---|
SK51194A3 (en) | 1995-02-08 |
NO941629L (en) | 1994-07-04 |
CZ106794A3 (en) | 1994-12-15 |
HU9401303D0 (en) | 1994-08-29 |
JPH07500828A (en) | 1995-01-26 |
HUT68200A (en) | 1995-05-29 |
WO1993009135A1 (en) | 1993-05-13 |
GB9123326D0 (en) | 1991-12-18 |
NO941629D0 (en) | 1994-05-03 |
EP0611375A1 (en) | 1994-08-24 |
FI942061A0 (en) | 1994-05-04 |
MX9206306A (en) | 1993-05-01 |
CA2116653A1 (en) | 1993-05-13 |
ZA928511B (en) | 1994-05-04 |
NZ244985A (en) | 1995-06-27 |
IL103612A0 (en) | 1993-04-04 |
PT101027A (en) | 1994-02-28 |
FI942061A (en) | 1994-05-04 |
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