CN1094730A - Peptides - Google Patents

Abstract

Dipeptides, tripeptides and tetrapeptides having pharmacological activity such as IL-1β release inhibitory, in free form or in salt form, wherein the last α-amino acid is based on aspartic acid and carries a residue A ₅ , It is H; CF ₃ ; -Z ₁ -Z ₂ -Y ₂ , wherein each of Z ₁ and Z ₂ is a direct bond or an α-amino acid residue, and Y ₂ is NH ₂ , C _1-4 alkylamino, two (C _1-4 alkyl) amino or a heterocyclic group connected to Z ₂ via nitrogen; -CH ₂ -X ₁ -Y ₃ , wherein X ₁ is oxygen or sulfur, and Y ₃ is heteroaryl; -CH ₂ -Y ₃ ; Substituted phenyl; Ring substituted phenoxymethylene or phenylthiomethylene; Ring substituted pyridyloxymethylene; Or -CH ₂ -X ₁ -CO-Y ₄ groups, where X ₁ is oxygen or sulfur, Y ₄ is trialkylmethyl or substituted phenyl or pyridyl.

Description

The present invention relates to pharmaceutically practicable peptides, methods for their production, pharmaceutical compositions composed of them and their use in pharmacy. More specifically, the present invention provides a compound of chemical formula I

in

R is hydrogen, an amino protecting group, or optionally substituted benzyloxy on the ring;

_A is valine, leucine, alanine, isoleucine or trimethylsilyl-alanine,

A ₂ is phenylalanine or tyrosine,

n is 0 or 1,

_A3 is a direct bond, valine, leucine, alanine, isoleucine, trimethylsilyl-alanine, or a divalent group of chemical formula (a)

Among them, hydroxyl or C _1-4 alkoxy can optionally be substituted on ring A, and A ₄ is a direct bond or a divalent group of chemical formula (b)

wherein R ₁ is hydrogen or C _1-4 alkyl, and

Y ₁ is an optionally protected residue attached to the α-carbon atom of an α-amino acid, -CH ₂ -CH ₂ -N(C _1-2 alkyl) ₂ , imidazol-2-yl-methyl, Benzimidazol-2-ylmethyl, 1H-1,2,4-triazol-3-yl-methyl, pyrazol-3-ylmethyl, indazol-3-yl-methyl or chemical formula (c ) or (d) group

in

R ₂ and R ₃ are independently hydrogen, halogen, C _1-4 alkyl, CF ₃ or trityl, at most one of R ₂ and R ₃ is H, and R ₄ and R ₅ are independently is hydrogen, C _1-4 alkyl, hydroxyl, C _1-4 alkoxy, CF ₃ , phenyl or halogen, at most one of R ₄ and R ₅ is H, or A ₃ and A ₄ together Form a group of formula (aa)

wherein Y ₁ is as defined above, and R ₁ and R _1a together form -(CH ₂ )m-, wherein m is 2, 3, 4 or 5, and

1) X is a divalent group of chemical formula (e ₁ )

Wherein _R is H is C _1-4 alkyl,

And A ₅ is hydrogen; CF ₃ ; -Z ₁ -Z ₂ -Y ₂ group, wherein Z ₁ and Z ₂ are each independently a direct bond or -α-amino acid residue, and Y ₂ is NH ₂ , C _1-4 alkylamino, di(C _1-4 alkyl)amino, or a heterocyclic group connected to Z ₂ via nitrogen; -CH ₂ -X ₁ -Y ₃ group, wherein X ₁ is O (oxygen ) or S (sulfur) and Y ₃ is a heteroaryl group; a -CH ₂ -Y ₃ group; or a group of formulas (k) to (m)

in

Y ₄ is tri(C _1-4 alkyl)methyl, or the residue

Ring B is pyridyl,

C ring is phenyl or pyridyl,

R ₇ and R ₈ are independently C _1-4 alkyl,

C _1-4 alkoxy, CF ₃ , halogen, nitro or cyano, and

R ₉ , R ₁₀ and R ₁₁ are independently nitro, cyano, CF ₃ , carbamoyl, CO ₂ R ₁₂ , -CH=CH-CN or -CH=CHCO ₂ R ₁₂ ,

Wherein R ₁₂ is C _1-6 alkyl,

X can also be a divalent group of chemical formula (e ₂ )

At this time A ₅ is H, or

2) X is a divalent group of chemical formula (f)

And A ₅ is -Z ₁ -Z ₂ -Y ₂ as defined above, or a group in formulas (k) to (o), or OR ₁₃ or NR ₁₄ R ₁₅ , wherein R ₁₃ may be C _1-12 alkyl optionally substituted by OH or interrupted by O (oxygen), and R ₁₄ and R ₁₅ are independently hydrogen, C _1-12 alkyl, C _6-7 cycloalkyl or benzene methyl, or

3) X is a divalent group of chemical formula (g)

and A ₅ is -Z ₁ -Z ₂ -Y ₂ as defined above, or

4) X is a divalent group of chemical formula (h) or (j)

and _A is a group of formulas (k) to (o) as defined above,

-CH ₃ -Y ₃ or -CH ₂ -X ₁ -Y ₃ ,

The additional condition is that when n is 0, only one of _A3 and _A4 can be a direct bond, and when n is 1, neither _A3 nor _A4 is a direct bond;

And the physiologically hydrolyzable and acceptable esters or amides of the compound exist in the form of free form, salt form or complex.

Examples of protecting groups such as R are, for example, disclosed in "Protective Groups in Organic Synthesis", TW Greene, J. Wiley and Sons NY (1981), 219-287, e.g. Acyl, like acetyl, methoxysuccinyl, hydroxysuccinyl, or benzoyl which may optionally be substituted on the benzene ring with, for example, p-methoxycarbonyl, p-methoxy or p-nitro; alkyl Oxycarbonyl, such as tert-butoxycarbonyl; Arylmethoxycarbonyl, such as 9-fluorenylmethoxycarbonyl, or optionally on the benzene ring with p-methoxy, p-nitro, p-chloro or meta Benzyloxy substituted with -phenyl; arylmethyl, such as benzyl optionally substituted with p-methoxy, p-nitro or p-chloro on the ring; or arylsulfone Acyl, such as phenylsulfonyl which may optionally be substituted with p-methyl, p-methoxy on the ring, or may be optionally substituted with e.g. amino or di(C _1-4 alkyl)amino on the ring to substituted naphthylsulfonyl.

When R is a benzyloxy group substituted on the ring, it is preferably a benzyloxy group substituted by a hydroxyl group or a C _1-4 alkoxy group, and preferably R is an unsubstituted benzyloxy group.

The halogen is preferably fluorine or chlorine.

When A ₃ is a substituted group of formula (a), it is preferably substituted with C _1-4 alkoxy, most preferably at the para position of -C=0.

By α-amino acid is meant a naturally occurring or commercially available or unnatural α-amino acid, or an optical isomer thereof. Unnatural α-amino acids are amino acids that cannot be incorporated into proteins under the command of mRNA, such as β-Nal, fluoro-α-amino acids, such as fluoroalanine, trimethylsilyl- Alanine, or such as

α-amino acids such as, wherein n is an integer from 1 to 6, and n ₂ is an integer from 1 to 12.

Protecting groups which may be present on _Y1 are groups which protect the O (oxygen), S (sulfur) or N (nitrogen) functionality on the side bonded amino group of the α-amino acid. The N-protecting group is, for example: R as disclosed above, or C _3-5 alkyl such as isopropyl, formyl, such as 1-deoxy-fructosyl or α-glucosyl (1-4 )-sugar residues such as deoxy-fructosyl, dihydroxy C _3-6 alkyl such as dihydroxypropyl, C _5-7 cycloalkane such as cyclohexyl or tropinyl base. O- and S-protecting groups for hydroxy or thiol functionality are known and may be, for example: methyl, tert-butyl or benzyl.

When Y ₂ is a heterocyclic group, it may be, for example, a 5- or 6-membered ring, such as piperidino or pyrrolidino.

Examples of heterocyclic aromatic groups as _Y include, for example: 5, 6 or 7-membered unsaturated heterocyclic group. Preferred _Y3 is a heteroaryl group containing from 1 to 4 nitrogen atoms, such as pyridyl, triazolyl, tetrazolyl, triazin-dionyl.

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

Groups (e ₁ ), (e ₂ ), (f), (g) and (j) are derived from aspartic acid and contain an asymmetric carbon atom, while group (h) contains two asymmetric Symmetrical carbon atoms, and thus cause optical isomerism. It is self-evident that, unless stated otherwise, the invention includes all individual isomeric forms and diastereoisomers and mixtures, eg racemates.

The group of formula (e ₁ ) attached to A ₅ is hydrogen, which can exist in cyclic and acyclic forms, for example:

It must be understood that where tautomeric forms occur, the invention encompasses both the ortho-hydroxylide and the oxo-carboxylic acid forms, that is, although for convenience the compound of formula I is referred to as the compound of formula ( _e1 ) The group X is defined only as the oxo-carboxylic acid form, but the invention is not to be construed as being limited to any extent by the specific nomenclature or graphic depiction used. The same reasoning applies as described hereinafter with respect to starting materials exhibiting the ortho-hydroxylide/oxo-carboxylic acid interconversion phenomenon.

The same reasoning applies to the group of formula (h), which can exist in both chain and cyclic forms, as follows:

It also applies to compounds of formula I containing a group of formula (h) and to the corresponding starting materials.

The term "physiologically hydrolyzable and acceptable esters or amides" means esters or amides that are hydrolyzed under physiological conditions to yield their own physiologically acceptable alcohols or amines Class, which means that the ester or amide is non-toxic at the desired dosage level.

Such esters or amides can be obtained by means of esterification or amidation, respectively, of compounds of formula I in which X is a group bearing a carboxyl group. Such esters include esters with aliphatic or cycloaliphatic alcohols, or polyols having 1 to 12 carbon atoms. Such amides include C _1-4 alkoxy C _1-4 alkylamines with aliphatic amines such as C _1-4 alkylamines, such as β-methoxy-ethylamines, or amides with anilines.

The compounds of formula I may exist, for example, in free form, in the form of acid addition salts, or in the form of complexes thereof. Acid addition salts may be formed, for example, with organic, polymeric or inorganic acids. Such acid addition salt forms include, for example, hydrochlorides and acetates. Salt forms may also include those obtainable from the carboxylic acid group of the compound of formula I, for example alkali metal salts such as sodium or potassium, or substituted or unsubstituted ammonium salts. The formation of complexes, for example: the compound of chemical formula I can be added to inorganic substances, for example: added to inorganic salts or hydroxides, such as calcium and zinc salts, and/or used It undergoes addition to polymeric organic substances.

Among the compounds of formula I, those defined below are preferred individually, or in any combination or subcombination:

1. R is an amino protecting group or benzyloxy, preferably an amino protecting group. When n is 0 and _A3 is a group of formula (a), R is preferably benzyloxy.

2. Neither A ₃ nor A ₄ are direct bonds.

3. n is 0.

4. When n is 0, A ₃ is a group of chemical formula (a).

5. _A3 is a direct bond, valine, leucine, alanine, isoleucine or trimethylsilylalanine.

6. R ₁ is hydrogen or methyl, preferably hydrogen.

_7. Y is a residue attached to the α-carbon atom of an α-amino acid selected from the group consisting of alanine, leucine, histidine, phenylalanine, methionine, tryptophan, Trimethylsilylalanine, and optionally branched protected arginine, ornithine and lysine, or Y ₁ is a group of chemical formula (c).

8. When n is 0, A ₃ and A ₄ can also form a group of chemical formula (aa) together.

9. m is 2 or 3.

10. X is a group of formula (e ₁ ), and A ₅ is not hydrogen.

11. X is the group of chemical formula (g).

12. X is a group of chemical formula (h) or (j).

13. _R6 is hydrogen or methyl, preferably hydrogen.

14. _Z1 in _R5 is the residue of a natural α-amino acid, preferably an aromatic/heterocyclic α-amino acid residue, especially proline.

15. Z ₂ in A ₅ is a residue of a natural α-amino acid, preferably an aliphatic α-amino acid, especially an aliphatic α-amino acid without other functional groups, preferably valine.

16. X is a group of formula (e) which may optionally be esterified or amidated, and _A is a group of formula (k), (l) or (o).

17. X is a group of formula (e ₁ ), (h) or (j) which may optionally be esterified or amidated, and A ₅ is -CH ₂ -X ₁ -Y ₃ , preferably -CH ₂ -SY ₃ or -CH ₂ -Y ₃ .

18. X is a group of formula (h) which may optionally be esterified or amidated, and A ₅ is (k).

19. X is a group of formula (j) which may optionally be esterified or amidated, and _A5 is a group of formula (m).

20. The group of chemical formula (m) is monosubstituted, preferably at the para position, preferably 4-nitrophenyl.

21. Except for X, all occurrences of α-amino acid residues have the L-configuration. X has a D- or L-configuration.

22. The asymmetric carbon bearing the OH group on (j) has configuration S. Preferably on (j) its asymmetric carbon with _R6 has configuration R.

In a series of specific embodiments, the present invention also provides compounds of formula I, wherein

n is 0, _A3 is a direct bond, valine, leucine, alanine, isoleucine or trimethylsilylalanine, _A4 is as defined above, or _A3 together with _A form a group of formula (aa) as defined above, and

i) X is a group of formula (e ₁ ) or (e ₂ ) as defined above, and A ₅ is hydrogen, or

ii) X is a group of formula (e ₁ ) or (f), and A ₅ is -Z ₁ -Z ₂ -Y ₂ as defined above or a group of formula (k), (l) wherein X ₁ is 0 ) or (m) group.

iii) X is a group of formula (g) and A ₅ is -Z ₁ -Z ₂ -Y ₂ , or

iv) X is a group of formula (j) and A ₅ is a group of formula (k), (l) or (m) wherein X ₁ is 0.

The present invention also provides the method for preparing the compound of chemical formula I, and its process comprises:

(a) remove at least one protecting group from the compound of formula I in the protected state, or add a protecting group R to the N-terminal group of the compound of formula I; or

(b) converting a compound of formula I into another compound of formula I; or

(c) coupling together by means of an amide bond two peptide fragments each containing at least one amino acid in a protected or unprotected state and one peptide fragment having formula (e ₁ ) as defined above to a group in (j), so that these protected or unprotected peptide fragments have a sequence consistent with the compound of formula I shown above, if desired, from the compound of formula I in the protected state On the compound, remove one or more protecting groups; or

(d) For the preparation of a group in which X is formula (e ₁ ) or (h), and A ₅ is formula (k), (l) or (o), or -CH ₂ -X ₁ -Y ₃ The compound of chemical formula I, the compound of chemical formula III

R-[A ₁ -A ₂ ] _n -A ₃ -A ₄ -X′-CH ₂ -Z _a (Ⅲ)

Wherein R, A ₁ to A ₄ and n are as defined above, X' is a group of chemical formula (e ₁ ) or (h), and Z _a is a leaving group, for example: halogen,

with the corresponding phenol, thiophenol or hydroxypyridine, or an acid of formula HX ₁ -CO-Y or a functional derivative thereof or HX ₁ -Y ₃ ; or

(e) For the preparation of compounds of formula I

Wherein R, A ₁ to A ₅ and n are as defined above, and R ₁₆ is -C _1-12 aliphatic or alicyclic residue, the compound of chemical formula V is oxidized

wherein R, A ₁ to A ₅ , n and R ₁₆ are as defined above,

The compound of formula I is then recovered, thus obtaining the product in free or salt form, or in the form of a complex.

The above methods (a) to (e) can be carried out according to standard techniques well known in the art.

In method (a), the removal of the protecting group may also include the removal of R at the N-terminal group of the compound of formula I. For example, when R is benzyloxycarbonyl, this group can be removed by means of hydrogenation in the presence of, for example, a palladium catalyst.

According to method (b), for example, to prepare a compound of formula I wherein X contains a carboxyl group, a compound of formula I wherein X contains an esterified or amidated carboxylic acid may be hydrolyzed. Such hydrolysis may be accomplished by treatment with a suitable base, or by hydrolysis with an acid, for example, in the presence of trifluoroacetic acid.

Further, according to method (b), in order to prepare a compound of formula I wherein X contains an esterified or amidated carboxyl group, a compound of formula I wherein X contains a carboxyl group or an esterified carboxyl group can be (transferred)ester oxidization or amidation. Such ester formation or amidation can be accomplished using any technique known in the art, such as converting the carboxyl group into a functional reactive group such as a corresponding carbonyl halide or anhydride, or utilizing A compound of formula I wherein X is a group of formula (h) in the lactone form and reacting such a group with a selected alcohol or amine.

According to more specific embodiments of method (b), in order to prepare a compound of formula I wherein X is a group of formula (g), wherein X is a group of formula (e ₁ ) or (e ₂ ), and A ₅ is the reaction of the compound of the chemical formula I for H with the compound of the chemical formula II

H ₂ N-NH-CO-A ₅ (Ⅱ)

Wherein A ₅ is as defined above. This can be accomplished in a manner similar to techniques known for the preparation of semicarbazones (semicarbazones).

Compounds of formula I in which X is a group of formula (e ₁ ) can also be converted into compounds of formula I in which X is a group of formula (e ₂ ), and vice versa, according to known techniques.

Method (c) can be carried out by means of techniques known in the art of peptide chemistry. The peptide fragment containing one of the groups of formulas (e ₁ ) to (j) also means that the group itself has a protecting group on the -NR ₆ - moiety, and also has a suitable terminal group, for example: A ₅ or CH ₂ -Za.

Method (d) is conveniently carried out using the Dess-Martin reagent, e.g. in the presence of a base or a silver salt of a precipitated halogen, or following the Swern oxidation procedure.

In these reactions, a protecting group may be used if necessary so that a functional group does not participate in the reaction. These protecting groups may be, for example, amino protecting groups, carboxyl protecting groups, acetal groups and the like. These protecting groups can be removed after the desired reaction is complete.

Each of the above methods can be carried out using any one of the starting materials in the form _of individual optical isomers, or starting materials in the form of a mixture [involving the presence of as of X, or an asymmetric carbon occurring in the precursor of such a group]. A convenient way is to use starting materials such as S- or R-enantiomers to prepare compounds of formula I, wherein the asymmetric carbon on the group of formulas (e ₁ ) to (j) has the S or R configuration respectively .

The starting material used in method (d) or (e) can be prepared in a similar manner to method (c). The preparation of starting materials is not particularly described herein, and these compounds are known in the art or can be prepared by methods well known in the art.

The following examples illustrate the invention. All temperatures are in degrees Celsius (°C).

Use the following abbreviations:

THF = Tetrahydrofuran

TFA = trifluoroacetic acid

Me OH = Methanol

EtOAc = ethyl acetate

DCC = Dicyclohexylcarbodiimide

HOBT = hydroxybenzotriazole

Z = benzyloxycarbonyl

r.t. = room temperature

Fmoc＝9-fluorenylmethoxycarbonyl

a = amorphous (non-crystalline)

Example 1: Z-Valine-Methionine-Aspartic Acid(OH)-H (Z-Val-Met-Asp(OH)-H)

Take Z _- valine-methionine-aspartic anhydride dimethyl acetal-β-tert-butyl ester (1.17 g) in _CH2Cl2 (150 ml), add TFA (15 ml) and water (1 ml) and 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 heated water (60ml), the supernatant decanted from some insoluble material and crystallized at 5° to give the first crop: m.p. 117°. All mother liquors were collected and chromatographed ( _SiO₂ , acetone/hexane/EtOAc 60/40/0.5) to give a second crop which was crystallized by trituration with water.

Example 2: Z-valine-methionine-aspartic acid (OH)-semicarbazone

The compound of Example 1 (0.27 g, 0.55 mmol) in MeOH (2 ml) was mixed with semicarbazone, HCl (0.6 ml of a 1M solution) and 5 drops of pyridine were added. The product crystallizes after 10 minutes at room temperature: mp 233 to 235°.

Example 3: Z-Valine-Methionine-Aspartic Acid (OH)-H Semicarbazone-Proline-Valine-N(CH)

The compound of 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. And N-(hydrazinocarbonyl)-proline-valine-N(CH ₃ ) ₂ (0.3 g, 1 mmol) was dissolved in MeOH (1 mL), water (2 mL) and 3 drops of 2N HCl. The two solutions were combined and warmed at 40° to 50° for 2 minutes. Cooling causes the product to crystallize: melting point 118° to 120°.

Repeat the steps of Example 1 and use the corresponding starting materials to prepare the following compounds:

Example 4: Z-Valine-Phenylalanine-Aspartic Acid (OH)-H

Example 5: Z-valine-histidine-aspartic acid (OH)-H

By repeating the steps of Examples 2 and 3 respectively, using the corresponding starting materials, the compound of the following chemical formula (IA) can be prepared.

Wherein A ₃ , A ₄ and A ₅ are defined as follows.

Example A3 A4 A5 Melting point ℃

6 Valine Phenylalanine H a

7 Valine Histidine H 150

8 Valine Phenylalanine Proline-Vale 126-129

Acid-N(CH ₃ ) ₂

9 Valine Histidine Proline-Valine

Acid-N(CH ₃ ) ₂

10 Alanine-Phenylalanine H 205

Tyrosine-

Valine

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

(3S,4RS)-3-(Z-valine-histidine)amino-4-hydroxy-5-(2,6-dimethylbenzoyloxy)pentanoic acid tert-butyl ester (0.6 mM mol) in _CH2Cl2 ( _4ml ) with Deess-Martin reagent (0.77mmol) for 45 minutes and filtered. Then acetone and 0.5N NaOH were added and the acetone was evaporated off. The residual crystalline material was washed with water, acidified by adding 10% tartaric acid, and extracted with EtOAc. Evaporation of the combined EtOAc extracts gave the product tert-butyl ester as yellow crystals. These were dissolved in _CH2Cl2 (4ml), TFA (4ml) was added and the _mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to dryness and chromatographed ( _SiO₂ , acetone/hexane/EtOAc 60/40/1) to give a slightly colored crystalline product.

Example 12: (Z-valyl-alanyl)-(3R,4S)-3-amino-4-hydroxy-5-(2,6-dichlorobenzoyloxy)

Dissolve ethyl (Z-valyl-alanyl)-(3R,4S)-3-amino-4,5-dihydroxypentanoate and 4-dimethylaminopyridine in pyridine and add dropwise to 2 , 6-dichlorobenzoyl chloride. The reaction mixture was stirred at room temperature overnight, then ice and water were added and the mixture was extracted with AcOEt. The organic layer was _washed with water and then with NaCl solution, the water was removed with _Na2SO4 , filtered and evaporated, and the crude product was chromatographed to give the title product.

Derivatives of the title compound (3R, 4RS) can be prepared as follows:

Dissolve Z-valine-alanine-OH (0.26 mmol), DCC (53 mg, 0.26 mmol) and HOBT·H ₂ O (39 mg, 0.26 mmol) in THF/DMF (2 mL/ 2 ml) and stirred for 5 minutes, then added (3R,4RS)-3-amino-4-hydroxy-5-(2,6-dimethylbenzoyloxy) in THF (2 ml) tert-Butyl valerate (87 mg, 0.26 mmol). The reaction mixture was stirred at room temperature overnight, evaporated and chromatographed ( _SiO2 , EtOAc/MeOH/ _NH3 95/5/0.5) to give the (3R,4RS) title compound.

Example 13: Ethyl (Z-valyl-alanyl)-(3R)-3-amino-4-oxo-5-(2,6-dichlorobenzoyloxy)pentanoate

Dimethylsulfoxide in _CH2Cl2 was _added dropwise to the solution of oxalyl chloride in _CH2Cl2 at -50 °C _. After 15 minutes _, a solution of the compound of Example 12 in _CH2Cl2 was added dropwise and the reaction mixture was stirred at -40°C for 1 hour. Triethylamine was added and stirring was continued for 3 hours at room temperature. _Water was then added and the reaction mixture was extracted with _CH2Cl2 . The organic layer was washed with _NaHCO3 solution, then with NaCl solution, dried over _Na2SO4 , filtered and evaporated _. Chromatography of the residue yielded the title compound.

Repeat the steps of examples 1 to 3 and 11 to 13, using the corresponding starting material, the compound of the following chemical formula IB can be prepared

Wherein A ₃ , A ₄ , R _x and R _y are as defined below.

Example A ₃ A ₄ Ry Rx [α] ²⁰ _D c(MeOH)

or melting point ℃[2]

14 Valine Phenylalanine H 2,6-Ditoluoyl

15 Valine Histidine H 2,6-Ditoluoyl

16 Valine Histidine H p-Nitrophenyl

17 Valine Histidine H H a[2]

(1-trityl)

18 Valine Histidine H 2,6-Dichlorobenzoyl

19 Valine Histidine H 2,6-bis(trifluoromethyl)-benzoyl

20 Valine Histidine H 2,6-Dinitrobenzoyl

21 Valine Histidine H 2,6-bis(trifluoromethyl)benzoyl

(2-CF ₃ )

22 Valine Tryptophan H 2,6-bis(trifluoromethyl)benzoyl

23 trimethyl histidine H 2,6-dichlorobenzoyl

Silicone

Oxyalkyl-

Alanine

H 2,6-二氯苯甲酰基twenty four

H 2,6-dichlorobenzoyl

25 Alanine- Phenylalanine H H H a[2]

Tyrosine -

Valine

26 D-Valine Histidine H 2,6-Dichlorobenzoyl-39.2°1.21

27 Valine Arginine H 2,6-Dichlorobenzoyl

28 valine histidine C ₂ H ₅ 2,6-dichlorobenzoyl-26.7°1.02

29 Valine Histidine H -18.0°0.97

-19.0°0.9630 Valine Histidine H

-19.0°0.96

H 2,6-二氯苯甲酰基31

H 2,6-dichlorobenzoyl

32 Valine Ornithine H 2,6-Dichlorobenzoyl

33 Valine Lysine H 2,6-Dichlorobenzoyl

34 Valine Alanine H 2,6-Dichlorobenzoyl

35 Valine Histidine H H Pivaloyl

36 Valine Histidine IsoC ₄ H ₉ 2,6-Dichlorobenzoyl**

37 valine histidine n-C ₁₀ H ₂₁ 2,6-dichlorobenzoyl**

38 Valine Histidine Benzyl 2,6-Dichlorobenzoyl ＊＊

39 valine histidine CH ₂ CH ₂ OH 2,6-dichlorobenzoyl**

40 Valine Alanine C ₂ H ₅ 2,6-Dichlorobenzoyl**

41 Valine Leucine H 2,6-Dichlorobenzoyl

42 Valine Histidine H 2,6-Dichlorobenzoyl

43 Valine Histidine H 2,6-Dichlorobenzoyl

(2-CF ₃ )

44 valine histidine C ₂ H ₅ pivaloyl**

45 Valine Histidine H 2,6-Dichlorobenzoyl ＊

46 Valine Lysine H 2,6-Dichlorobenzoyl

(N ^ε -iC ₃ H ₇ )

47 Valine Lysine C ₂ H ₅ 2,6-Dichlorobenzoyl**

(N ^ε -iC ₃ H ₇ )

48 Valine Alanine H 2,6-Dichlorobenzoyl ＊＊

49 Valine alanine tertiary C ₄ H ₉ 2,6-dichlorobenzoyl**

50 Valine Alanine C ₂ H ₅ 2,6-Dichlorobenzoyl*

51 Valine Alanine C ₂ H ₅

52 trimethylhistidine C ₂ H ₅ 2,6-dichlorobenzoyl

Silane

C₂H₅2,6－二氯苯甲酰基 ＊＊53

C ₂ H ₅ 2,6-Dichlorobenzoyl**

54 Valine Alanine IsoC ₃ H ₇ **

55 trimethylalanine tertiary C ₄ H ₉ 2,6-dichlorobenzoyl

Silane

base-propane

amino acid

56 Trimethylalanine H 2,6-dichlorobenzoyl

Silane

base-propane

amino acid

57 trimethylalanine C ₂ H ₅ 2,6-dichlorobenzoyl

Silane

base-propane

amino acid

*These compounds have the following configuration at the aspartyl moiety:

**These compounds have the R,S configuration at the aspartyl moiety.

Example 58:

Z-histidine-aspartic acid

[α] ²⁰ _D = -20.3° c = 1 in MeOH

Example 59:

Fmoc-Valine-Histidine-Aspartic Acid

Example 60:

组氨酸-天门冬氨酸

Histidine-Aspartate

[α] ²⁰ _D = -21.5° c = 1.07 MeOH

Example 61:

组氨酸-天门冬氨酸

Histidine-Aspartate

Example 62:

缬氨酸-丙氨酸-天门冬氨酸

Valine-Alanine-Aspartic Acid

Repeat the steps of examples 1 to 3 and 12 to 13, and use the corresponding starting material to prepare the compound of the following chemical formula IC

Z-valine-A ₄

wherein A ₃ , R _x and R _y are as defined below.

example A Ry Rx *

63 Alanine H 2,6-Dichlorobenzoyl R,S

64 Alanine C ₂ H ₅ R

65 Alanine tertiary C ₄ H ₉ 2,6-dichlorobenzoyl R,S

66 Alanine-C ₂ H ₄ -OCH ₃ 2,6-Dichlorobenzoyl R,S

Example 67: (3RS)-3-(Z-Valyl-phenylalanyl)amino-4-oxo-6-(p-nitrophenyl-trans-hex-5-enoic acid tert-butyl ester

(3RS)-3-(Z-Valyl-phenylalanyl)amino-4-oxo-pentanoic acid tert-butyl ester-5-diethylphosphonate (0.2 g, 0.29 mM) in 5 Dissolve in THF (15 ml) at °C. NaH (25 mg, 0.59 mM) was added, and the mixture was stirred for 10 minutes. p-Nitrobenzaldehyde (0.18 g, 1.1 mM) in THF (2 ml) was added at 0°C and the reaction mixture was stirred at this temperature for 45 minutes. The reaction mixture was poured into 5% tartaric acid, extracted with ethyl acetate, the organic phase was dried over NaSO, evaporated, and purified by chromatography to yield the title compound.

Example 68: Z-Valine-Phenylalanine-Aspartaldehyde Dimethyl Acetal-β-Methyl Ester

Z-valine-phenylalanine-aspartate(OH)-H (0.8 g) was dissolved in 8% HCl in MeOH (25 ml), left at room temperature overnight and evaporated to dryness, The residual crystals were washed with diethyl ether to obtain the title compound as white crystals. Melting point 168 to 171°.

The starting material can be prepared as follows:

Example 69: (3S)-3-(Fluorenylmethoxycarbonyl)amino-5-iodo-4-oxobutanoic acid tert-butyl ester

Triethylamine (1.3 ml, 9.6 mmol) was added to tert-butyl (3S)-3-(fluorenylmethoxycarbonyl)amino-3-carboxy-butyrate in THF (60 ml) at -10° ester (3.5 g, 8.5 mmol), followed by ethyl chloroformate (0.92 ml, 9.6 mmol). After 10 minutes a solution of diazomethane in ether was added slowly at 0-5°C and the reaction mixture was stirred for 45 minutes. HCl in ether (2N) was added at 5-10° until gas evolution ceased. The reaction mixture was evaporated to dryness, taken up in acetone (50ml), added NaI (4g), and stirred at room temperature for 1 hour. Further diethyl ether (150ml) was added and the reaction mixture was filtered and evaporated. Chromatography ( _SiO₂ , EtOAc/hexane) of the residue yielded the title compound as pale yellow crystals.

Example 70: (3S)-tert-butyl 3-(fluorenylmethoxycarbonyl)amino-5(2,6-dimethylbenzoyloxy)-4-oxopentanoate

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) were dissolved in acetone (25 mL) and refluxed for 1 hour. After filtration and evaporation, the crude product was chromatographed ( _SiO₂ , ether/hexane 3/7) to yield the title compound.

Example 71: (3S)-3-(Fluorenylmethoxycarbonyl)amino-5(4-nitrophenoxy)-4-oxopentyl tert-butyl ester

3S-3-(fluorenylmethoxycarbonyl)amino-5-iodo-4-oxobutanoic acid tert-butyl ester (1 g, 1.8 mmol), p-nitrophenol (0.5 g, 3.7 mmol) and K ₂ CO ₃ (0.38 g, 2.8 mmol) was refluxed in acetone (6 ml) for 30 minutes, CH ₂ Cl ₂ was added and the organic phase was washed with 2N NaHCO ₃ . The combined organic phases were dried, evaporated and chromatographed (SiO, EtOAC/hexane 2/8) to yield the title product as a yellow oil.

Example 72: (Z-Valyl-alanyl)-(3R,4S)-3-amino-4,5-dihydroxypentanoic acid ethyl ester

a) At room temperature, ethyl (3R,4S)-3-benzylamino-4,5-(isopropylidenedioxy)pentanoate (Y.Yamada, Tetrahedron Letters 1983, 24, 3009) and 10% palladium (Pd)/carbon (C) in ethanol, under H ₂ , shake for 30 minutes. The reaction mixture was filtered and evaporated to give ethyl (3R,4S)-3-amino-4,5-(isopropylidenedioxy)pentanoate which was used without further purification.

b) Z-valine-alanine-OH was dissolved in THF, and HOBT·H ₂ O and DCC were added at 5°C. After stirring at 5°C for 20 minutes, diisopropylethylamine and ethyl (3R,4S)-3-amino-4,5-(isopropylidenedioxy)pentanoate in TFH were added. The reaction mixture was stirred overnight at room temperature, filtered, evaporated, and chromatographed to yield (Z-valyl-alanyl)-(3R,4S)-3-amino-4,5-(iso Propyl dioxy) valerate ethyl ester.

c) Compound 74b) was dissolved in AcOH/ _H2O (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, _NaHCO3 solution, _NaCl solution, dried over _Na2SO4 , filtered and evaporated to yield the title compound.

These compounds of formula I, their physiologically hydrolyzable and acceptable esters and amides, and their pharmaceutically acceptable salts (hereinafter referred to as compounds of the present invention) exhibit pharmaceutical activity , and are therefore effective as medicines.

Particularly as shown in the following in vitro test using THP-1 cells and in vivo test methods, the compound of the present invention inhibits IL-1β secretion.

a) Mix 900 microliters of THP-1 cells (0.5× ¹⁰⁶ cells) with 100 units of γ-interferon/0.9 milliliters of RPMI 1640 medium (containing 2 mML-glutamine and 5% heat-inactivated fetal bovine serum ) into a 24-well culture dish with a pipette. Then 100 microliters of the test compound was added. After three hours at 37°C in 5% _CO₂ /95% air, 10 µl of lipopolysaccharide (500 µg/ml) was added and the incubation was continued for 40 hours. Also include appropriate control groups (with and without stimulus, solvent). Remove the culture medium, centrifuge at 1000g for 10 minutes to clarify the culture medium, add 1.0 ml digitonin (0.01%) to the wells for lysis, scrape loose with a rubber policeman, and place at 4°C Leave for 10 minutes. Lactate dehydrogenase assays were then performed immediately, and samples were stored at -20°C until other assays could be performed. These assays are: IL-1β (broth and lysates), IL-6 (broth), TNF-α (broth), PGE2 (broth and lysates), lactate dehydrogenase (LDH) and DNA (lysate). IL-1β, IL-6, and TNF-2 were measured using commercially available ELISA kits (Cistorn), _PFE2 was measured using standard RIA, and DNA was fluorometrically measured using DAPI.

In this assay, compounds of the invention selectively inhibit the release of IL-1[beta] at concentrations ranging from about 0.01 to 100 [mu]M. In contrast, IL-6, TNF-[alpha], _PGE2 and DNA levels remained essentially unchanged, and these compounds were nontoxic due to unchanged release of LDH. For example, the compounds of Examples 40 and 50 have been determined to have _IC50 values (the concentration of compound that inhibits IL-1β release by 50%) of 1 and 0.1 µM, respectively.

b) LPS-fever

Male Tuttlingen SD mice (150 to 160 g) were injected with LPS-suspension (Sigma, Cat. L-5886; 100 µg/5 ml glucose solution/kg, subcutaneously). After 2 hours, body temperature was measured using a thermistor rectal probe connected to an ELLAB telemetry thermometer. After 4 hours, the test compound was orally administered, and 2 hours later (6 hours after the injection of LPS), the body temperature was measured again. The temperature increase obtained in the untreated control group was taken as 100%, while the temperature increase in the treated group was expressed as a percentage of this value. _ED50 is the dose that causes 50% inhibition of the measured increase in temperature in control mice. In this test, the compound of the present invention inhibited the increase in temperature caused by LPS when administered in a dose ranging from 0.001 to 0.1 mg/kg orally. For example: the compounds of Examples 40 and 50 have been determined to have a _DE50 value of 0.01 mg/kg orally administered, and the compound of Example 51 has an _ED50 value of 0.05 mg/kg orally administered.

c) Carrageen causes foot edema in mice

50FA male mice weighing 150 to 170 g were used in each group. Test compounds were given orally as a suspension in saline/0.5% tragacanth gum 1 hour prior to carrageenan injection. Carrageenan (0.1 ml of a 1% suspension in saline) was injected into one hind paw by subplantar injection. Swelling of the feet was measured with an antiphlogometer according to Kemper and Amel. Control readings were taken immediately after injection and swelling was measured 3 and 5 hours later. The 3 and 5 hour readings were averaged after subtracting the t control readings. Values obtained from treated animals are expressed as a percentage of values obtained from untreated animals. The _ED50 is the dose that produces 50% inhibition of carrageen-induced swelling after 3 hours. In this test method, the compound of the present invention significantly inhibited carrageen-induced swelling when orally administered at a dose ranging from 0.02 to 5 mg/kg. For example, the compounds of Examples 40 and 50 have been determined to have _DE50 values of 0.2 and 1 mg/kg orally, respectively.

Accordingly, the compounds of the present invention are effective for the treatment of disorders of etiology involving or involving excessive IL-1[beta] release. For example: a wide variety of inflammatory conditions and diseases such as depletion of tissue calcium, degenerative processes in bone and cartilage such as rheumatoid arthritis and osteoarthritis, inflammatory bowel disease, allergic bowel disease, septic shock , Psoriasis, Asthma, Adult Breathing Syndrome, Diabetes Type I, Osteoporosis of various causes, including: such as menopausal or postmenopausal osteoporosis and Osteoporosis caused by Alzheimer's disease.

For the above uses the required dosage will of course vary depending upon the mode of administration, the particular condition to be treated and the effect desired. In general, however, satisfactory results will be achieved at a daily dosage rate of from about 0.001 to about 100 mg/kg animal body weight, preferably 0.001 to about 10 mg/kg animal body weight. For larger mammals, such as humans, suitable daily dosage ratios are from about 0.1 mg to about 1 g/day in one dose, in divided doses 2 to 4 times/day, or in delayed release the form.

Compounds of Examples 50 and 51 are preferred.

According to the foregoing, the present invention also provides:

a) A method of treating an etiological disorder involving or involving excessive IL-1β release, such as that described above in a patient in need of such treatment, which method comprises administering to said patient an effective amount of formula I Compounds, their physiologically hydrolyzable and acceptable esters or amides, or their pharmaceutically acceptable salts;

b) Compounds of formula I, their physiologically hydrolyzable and acceptable esters and amides, or pharmaceutically acceptable salts thereof, for example as disclosed above for use as medicines, for example: as preparations use.

The compounds of the present invention can be administered by any convenient route, specifically nasal, enteral, 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. Unit dosage forms include, for example, from about 25 micrograms to 500 milligrams of a compound of the invention.

The compounds of the present invention can be administered in free form or in the form of pharmaceutically acceptable salts. Such salts can be prepared conventionally and exhibit the same level of activity as the free compounds.

The present invention further provides:

c) A pharmaceutical composition comprising a compound of formula I, its physiologically hydrolyzable and acceptable ester or amide, or a pharmaceutically acceptable salt thereof, as defined above, and pharmaceutically Such acceptable diluents or carriers together. Such compositions can be manufactured by conventional methods. They may contain up to 99.9% by weight of active ingredient.

Claims (9)

1, a kind of compound of chemical formula I

Wherein

R is that hydrogen, amino protecting group or optional ring are gone up substituted phenmethyl.

N is 0 or 1,

A ₁Be Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl-L-Ala,

A ₂Be phenylalanine or tyrosine,

A ₃Be a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine, trimethyl silyl-L-Ala, or the divalent group of chemical formula (a)

Wherein the A ring is optional can be by hydroxyl or C _1-4Alkoxyl group replaces, A ₄It is the divalent group of a direct key or chemical formula (b).

R wherein ₁Be hydrogen or C _1-4Alkyl, and

Y ₁Be the residue on the alpha-carbon atom that is connected a-amino acid, and optional can be protected ,-CH ₂-CH ₂-N (C _1-2Alkyl), imidazoles-2-base-methyl, benzimidazolyl-2 radicals-ylmethyl, 1H-1,2,4-triazole-3-base-methyl, pyridin-3-yl-methyl, indazole-3-base-methyl or chemical formula (c) or group (d)

Wherein

R ₂And R ₃Be hydrogen, halogen, C independently respectively _1-4Alkyl, CF ₃Or trityl, R ₂And R ₃In have one to be H at most, and R ₄And R ₅Be hydrogen, C independently respectively _1-4Alkyl, hydroxyl, C _1-4Alkoxyl group, CF ₃, phenyl or halogen, R ₄And R ₅In have one to be H at most,

Or A ₃And A ₄Form the group of a chemical formula (aa) together

Y wherein ₁Be definition as mentioned, and R ₁And R _1aFormation-(CH together ₂) _m-, wherein m is 2,3,4 or 5, and

I) X is a chemical formula (e ₁) divalent group

R wherein ₆Be H or C _1-4Alkyl,

And A ₅Be hydrogen; CF ₃Group-Z ₁-Z ₂-Y ₂, Z wherein ₁And Z ₂Be respectively a direct key or an a-amino acid residue independently, and Y ₂Be NH ₂, C _1-4Alkylamino, two (C _1-4Alkyl) amino or through nitrogen-atoms and Z ₂The heterocyclic radical that connects; Group-CH ₂-X ₁Y ₃, X wherein ₁Be O (oxygen) or S (sulphur), and Y ₃Be assorted aromatic base; Group-CH ₂-Y ₃Or chemical formula (k) arrives the group in (m).

Wherein

Y ₄Be three (C _1-4Alkyl) methyl or residue

The B ring is pyridyl,

The C ring is phenyl or pyridyl,

R ₇And R ₈C is C respectively independently _1-4Alkyl,

C _1-4Alkoxyl group, CF ₃, halogen, nitro or cyano group, and R ₉, R ₁₀And R ₁₁Be nitro, cyano group, CF independently respectively ₃, carbamyl, CO ₂R ₁₂,-CH=CH=CN or-CH=CHCO ₂R ₁₂, R wherein ₁₂Be C _1-6Alkyl,

X also can be chemical formula (e ₂) divalent group

This moment A ₅Be H, perhaps

Ii) X is the divalent group of chemical formula (f)

And A ₅For as hereinbefore defined-Z ₁-Z ₂-Y ₂Or the group of chemical formula (K) in (0), or OR ₁₃Or NR ₁₄R ₁₅, R wherein ₁₃Be any C that selects available OH replacement or interrupt with O (oxygen) _1-12Alkyl, and R ₁₄And R ₁₅Be hydrogen, C independently respectively _1-12Alkyl, C _5-7Cycloalkyl or phenmethyl, perhaps

Iii) X is the divalent group of chemical formula (g)

And A ₅For definition as indicated above-Z ₁-Z ₂-Y ₂, perhaps

Iv) X is chemical formula (h) or divalent group (j)

And A ₅Be as hereinbefore defined chemization (k) group in (O) ,-CH ₃-Y ₃Or-CH ₂-X ₁-Y ₃,

Collateral condition is

When n is 0, A ₃With A ₄In have only one to can be direct key, and when n is 1, A ₃With A ₄It or not direct key.

With and physiology on hydrolyzable and ester class or the amides accepted, and exist with free form, salt form or with the form of mixture.

2, according to the compound of the chemical formula I of claim 1, wherein n is 0, and A is a direct key, Xie Ansuan, leucine, L-Ala, Isoleucine or trimethyl silyl-L-Ala, A ₄As the definition of claim 1, or A ₃With A ₄Form group together as the defined chemical formula of claim 1 (aa), and

ⅰ) X is as the defined chemical formula (e of claim 1 ₁) or (e ₂) group, and A is H, perhaps

ⅱ) X is chemical formula (e ₁) or group (f), and A ₅For as claim 1 defined-Z ₁-Z ₂-Y ₂, or as the defined chemical formula of claim 1 (k), (l) or group (m), wherein X ₁Be O(oxygen),

ⅲ) as claim 1 definition, X is the group of chemical formula (g), and A ₅For-Z ₁-Z ₂-Y ₂, perhaps

ⅳ) as the definition of claim 1, X is the group of chemical formula (j), and A ₅Be chemical formula (k), (l) or group (m), wherein X ₁Be O(oxygen).

With and physiology on hydrolyzable and acceptable esters or amides, and

With free form, salt form, or exist with the form of mixture.

3, according to the compound of the chemical formula I of claim 1, wherein n is 0, and A ₃With A ₄Be not direct key, with and physiology on hydrolyzable and acceptable esters or amides, and with free form, with salt form, or exist with the form of mixture.

4, according to the compound of the chemical formula I of claim 1 or 3, Y wherein ₁Be the residue on the alpha-carbon atom that is connected a-amino acid; described amino acid is selected from L-Ala, leucine, Histidine, phenylalanine, methionine(Met), tryptophane, trimethyl silyl-L-Ala; and it is optional with the shielded arginine of side chain, ornithine and the Methionin or the group of chemical formula (c); and hydrolyzable and acceptable esters or amides on the physiology; and with free form, salt form, or exist with the form of mixture.

5, according to the compound of the chemical formula I of claim 1, wherein X is chemical formula (e ₁), (h) or group (j), when X is (e ₁) time, A ₅Be H, and hydrolyzable and acceptable esters or amides on the physiology, and with free form, salt form, or exist with the form of mixture.

6, with free form, salt form or exist: (benzene methoxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2 with the form of mixture, 6-dichloro-benzoyl oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R-3-amino-4-oxo-5-(2,6-dichloropyridine base-4-ketonic oxygen base) Valeric acid ethylester, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) valeric acid, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) isopropyl isovalerate, (benzene methoxycarbonyl-valyl-alanyl)-3R, S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) the valeric acid tert-butyl ester, and (benzene methoxycarbonyl-valyl-alanyl)-3S-3-amino-4-oxo-5-(2,6-dichloro-benzoyl oxygen base) valeric acid.

7, a kind of preparation is as the method for hydrolyzable on chemical formula I compound claimed in claim 1 and the physiology thereof and acceptable esters and amides, and its step comprises

(a) from the compound of the chemical formula I of guard mode, remove at least one protecting group, or, add one as the defined protecting group R of claim 1 at the N end group group place of the compound of chemical formula I; Or

(b) a kind of compound of chemical formula I is transformed into the compound of another kind of chemical formula I; Or

(c) by amido linkage two peptide fragment are coupled at together, they contain at least one amino acid under protected or not protected state respectively, and have a peptide fragment to contain as defined in claim 1 chemical formula (e ₁) arrive a group in (j), and make the such peptide fragment of protected or not protected peptide that obtains have the sequence consistent with the compound of chemical formula I, if need, can remove one or more protecting groups from the compound of the chemical formula I guard mode; Or

(d) X is chemical formula (e in the claim 1 in order to prepare wherein ₁) or group (h), and A ₅Be chemical formula (k), (l) or group (o), or-CH ₂-X ₁-Y ₃The compound of chemical formula I, with the compound of chemical formula III.

Wherein R, A ₁To A ₄And the definition of n such as claim 1, X ' is as the defined chemical formula (e of claim 1 ₁) or group (h), and Z _aIt is a leavings group

With a corresponding phenol, thiophenol or pyridone or chemical formula HX ₁-CO-Y ₄Acid or its functional derivatives or HX ₁-Y ₃, X wherein ₁, Y ₃And Y ₄Be as the definition in the claim 1, react; Or

(e) in order to prepare the compound of chemical formula I

Wherein R, A ₁To A ₅Be as defined in claim 1, and R ₁₆For-C _1-12Aliphatics or alicyclic residue are with the compound oxidation of chemical formula V

R wherein, A ₁To A ₅, n and R ₁₆System and reclaims the compound of chemical formula I as hereinbefore defined, or hydrolyzable and acceptable esters or amides on its physiology, thereby obtains with free or salt form, or the product that exists with the form of mixture.

8, a kind of compound among the claim 1-6 is used to prepare the purposes of medicine.

9, a kind of composition pharmaceutically, the compound that comprises chemical formula I as defined in claim 1, or hydrolyzable and acceptable esters or amides on its physiology that exists with the salt form that can accept on free form or the physiology, and pharmaceutically for this reason and acceptable diluent or carrier.