[go: up one dir, main page]

WO1993018013A1 - DIPEPTIDE PONTE PAR N,N'-ETHYLENE ET COMPOSE DE DIFFERENTS ACIDES α-AMINES OPTIQUEMENT ACTIFS, ET SON PROCEDE DE PRODUCTION - Google Patents

DIPEPTIDE PONTE PAR N,N'-ETHYLENE ET COMPOSE DE DIFFERENTS ACIDES α-AMINES OPTIQUEMENT ACTIFS, ET SON PROCEDE DE PRODUCTION Download PDF

Info

Publication number
WO1993018013A1
WO1993018013A1 PCT/JP1993/000292 JP9300292W WO9318013A1 WO 1993018013 A1 WO1993018013 A1 WO 1993018013A1 JP 9300292 W JP9300292 W JP 9300292W WO 9318013 A1 WO9318013 A1 WO 9318013A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
cooh
represented
conh
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1993/000292
Other languages
English (en)
Japanese (ja)
Inventor
Yoshitane Kojima
Tetsushi Yamashita
Hidenari Adachi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanyo Fine Co Ltd
Original Assignee
Sanyo Fine Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanyo Fine Co Ltd filed Critical Sanyo Fine Co Ltd
Priority to JP51553493A priority Critical patent/JP3265378B2/ja
Publication of WO1993018013A1 publication Critical patent/WO1993018013A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms

Definitions

  • N, N'-ethylene-bridged dipeptides composed of different optically active a-amino acids and their synthetic methods
  • the present invention relates to a dipeptide derivative having a novel piperazinone ring structure
  • Japanese Patent Application Laid-Open No. 62-196600 discloses a piperazinone derivative of homodipeptide, but does not disclose a piperazinone derivative in which two amino acids are different. It is very unlikely that adjacent amino acids in a protein are the same, and enzymes that specifically cleave between homodipeptides even at cleavage sites such as peptidases Since it is hardly known, the piperazinone derivative disclosed in this publication is difficult to use in the production of peptide analogs. Also, Hlloon et al., Analysis of in vivo Stability, 6 41-644. (1982), and ⁇ . S. Patent No. 4.
  • the present invention relates to a novel and optically active dipeptide having a piperazinone ring structure, which is expected to have its own physiological activity and is useful as a constituent unit of a bioactive peptide analog Intended to produce derivatives
  • the present inventors have conducted intensive studies to achieve the above object, and as a result, linked the amino groups of two different optically active monoamino acids via an ethylene cross-linked chain, and then used an acid catalyst. It has been found that a desired dipeptide derivative having a novel piperazinone ring structure can be produced by cyclization.
  • the present invention provides N, N'-ethylene-crosslinked dipeptides and salts thereof which may have the following protecting groups.
  • R 3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • * represents two asymmetric carbon atoms of this substance
  • R t and R 2 represent the following formula (A): CH 3, one CH (CH 3) 2, - . CH 2 CH (CH3) 2, CH (CH,) CH 2 CH 3, one CH 2 OH, (CH 2) 3 NH-C-NH 2 -CH 2 -HQ), CH 2 H> -OH,
  • N, ⁇ '-ethylene crosslinked dipeptides and salts thereof which may have a protecting group represented by
  • R la and R 2a are represented by the following formula (B): one (CH), NH-C-NHTo s,
  • Groups which may have a substituent such as an alkyl group having 1 to 4 carbon atoms such as a butyl group, a benzyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, and a -chlorobenzyl group.
  • B z 1 represents a benzyl group which may have a substituent such as a benzyl group, a p-methoxybenzyl group, a p-2-trobenzyl group, and a p-chlorobenzyl group.
  • R 3 is the same as above. * And * 'represent the two asymmetric carbons of this material; R lb and R 2b are represented by the following formula (A): CH3, one CH (CH 3 ) 2 , one CH 2 CH (CHj) 2
  • One CH (R 2 ) one COOH, and and R 2 are represented by the following formula (A): .
  • One CH 3 one CH (CH 3) 2, one CH 2 CH (CH 3) 2, one CH (CH NH 3) CH 2 CH 3, - CH 2 OH,
  • CR 4 and R 5 are the same or different and represent a leaving group.
  • General formula (I) characterized by performing a deprotection reaction
  • R 2 may be each having a protecting group and R 2- , or may be R lb and R 2h having no protecting group. Is the favored arbitrary and ⁇ 9, the following formula (A '):
  • R 3 represents a hydrogen atom, a methyl group, Examples thereof include an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group and an n-hexyl group.
  • the protecting group can be easily deprotected by a method and a method generally used in the field of peptide synthesis.
  • monoamino acids that do not form dipeptides include methionine, fenilalanine, tryptophan, lysine, arginine, tyrosine, cystine, aspartic acid, glutamic acid, and the like.
  • 18 types of optically active ⁇ -amidin found in common proteins such as asparagine, glutamine, histidine, alanine, rosin, * lin, leucine, isoleucine, serine, and threonine
  • those having a reactive functional group in the side chain may be used in which the functional group is protected.
  • the ⁇ -amino acid having a protecting group or the ⁇ -amino acid having R 2 as a substituent includes ⁇ -amino acids having a protecting group on a side chain commonly used in the art. The following are preferably used:
  • the (leaving group) is not particularly limited, but may be a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, or one OT os ( ⁇ -toluenesulfonic acid ester), one OM s (medium Examples of such groups include ester groups such as tansulfonic acid ester) and -0Ac (acid ester), which can be eliminated by reacting with an amino group.
  • the salt of the compound of the general formula (I) of the present invention includes p-toluene Inorganic acid salts such as enesulfonic acid, benzenesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, and perchloric acid; organic acid salts such as trifluoroacetic acid, maleic acid, and fumaric acid; or sodium salts and potassium. And alkali metal salts such as salts. These salts can be produced by a conventional method such as dissolving or suspending the compound of the present invention in a solvent, and adding an acid or a base in an equal or excess amount.
  • Preferred correct is a combination of amino acids of the compounds of the present invention, for example
  • a RG- E ( ⁇ ⁇ , S er, P he, A 1 a, H is, M et, L eu, I le, G lu, a sp, G ln, a s, C ys, L ys, V al, shows a T yr, T rp or T hr), L ys- X 0 (X 2 are, S er, P he, a la , His, Met, Leu, Ile, G1u, Asp, Gln, Asn, Cys, Arg, Val, Tyr, Trp or Thr), Xg — L eu (Xo is Ser, P he, A la, His, Met, Arg, I le, G lu, A sp, G ln, A sn, Cys, Lys, Va 1, T yr, T rp or T hr
  • dipeptide derivatives include, but are not limited to, opioid peptides, bone resorption inhibitory peptides, angiotensin (Angiotensin) I and ⁇ , ⁇ ⁇ , bra Dikinin (Bradykinin), BNP, Canolecithinin (Calcitonin), C GRP, CCK, Conotoxin, CNP, Dynorphin, Elafin (E1 affin), ⁇ -Endolphin (fl-Endorphin), 3-endorphin, 7-endorphin (r-En dorphin) endotherin-1 (Endotherin-1), endotherin-1 2 ( Endotherin-2), Endotherin-3 (Endother in-3), Enkephalin (Enkephalin), Demorphin (Dermorp in) Galanin, RGDS, GRGDS, YIGSR, Gastrin ), GRF, GRP, LH-RH, matillin (ttatilin) PTPTH-rp, secretin (Secret
  • a site that is specifically cleaved by an enzyme such as the above-mentioned physiologically active peptide can be replaced with the peptide derivative of the present invention. 5 makes it less susceptible to degradation by peptidases and is useful for increasing its stability in vivo.
  • the dipeptide derivative of the present invention is optically active, it can retain agonist and Z or antagonist activity even when the desired physiologically active peptide or the like is substituted with the derivative. The onset of non-specific toxicity can also be suppressed as compared to the racemic form.
  • the dipeptide derivative (I) of the present invention is produced, for example, as follows.
  • a solvent for the reaction water, a mixed solvent of water and an alcohol, or a mixed solvent of water and acetonitrile, dioxane, tetrahydrofuran or the like is used, and water is preferably used.
  • the reaction temperature is about 60 to 100, and the reaction time is about 3 to 10 hours.
  • the different amino acids are usually used in equimolar amounts, and the compound of the general formula ( ⁇ ) is used in an amount of about 0.5 mole per 1 mole of either amino acid.
  • aqueous sodium hydroxide, hydroxide hydroxide and other metallic hydroxide aqueous solutions, sodium carbonate, sodium carbonate, hydrogencarbonate It is carried out by adding an alkali metal carbonate such as a stream to the solvent, and the amount added is about 1 to 2 times the mole of 1 mole of the total amino acid used. .
  • the mixture may be separated at this point, but is preferably purified after the next cyclization reaction.
  • the desired compound (I) is obtained by subjecting the above three mixtures or the separated and purified condensate of two different amino acids of (1) to a cyclization reaction in the presence of an acid catalyst in a solvent.
  • Solvents include methanol, ethanol, and 1-propanol And alcohols such as 1-butanol.
  • the acid catalyst include p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, concentrated sulfuric acid, hydrochloric acid, and acetic acid.
  • P-toluenesulfonic acid is preferable.
  • the amount of the acid catalyst to be used is about 1 to 3 mol, preferably about 1.5 mol, per 1 mol of the condensate (1) of two kinds of amino acids.
  • the reaction temperature is about 50 to 100, and the reaction time is about 2 to 30 hours.
  • the target dipeptide derivative (I) obtained by the above method is purified by a usual purification method, for example, a method such as column chromatography or recrystallization.
  • the raw amino acid used in the present invention is an optically active R-amino acid or S-amino acid.
  • the dipeptide derivative (I) of the present invention has the following effects.
  • the dipeptide is used as a structural unit of obioid peptide.
  • the macrocyclic peptide having the above-mentioned dipeptide as a structural unit is useful for inclusion of organic and inorganic compounds because it has a structure similar to cyclodextrin, that is, its cavity has a width.
  • it since it is fat-soluble, it can be used as a reagent for various organic synthesis reactions, and is particularly effective for asymmetric reactions.
  • the cyclization of the difficult and low-yield dipeptide derivative proceeds smoothly, and the dipeptide derivative (I) can be obtained in high yield.
  • the cyclization yield is high, which is preferable.
  • side reactions are less when ⁇ -amino acid having an unstable side chain such as methionine is used as a raw material due to mild reaction conditions. Examples
  • R 2 one CH 2 ph (R, R)].
  • p li represents a phenyl group.
  • R 2 -CH 0 CH (CH 3 ) 2 (R, R)] and 2 D '
  • Table 2 shows the elemental analysis values, melting points, and specific rotations (in ethanol, room temperature) of the eight dipeptidoethyl ester hydrochlorides.
  • Table 3 shows the elemental analysis values, melting points, and specific rotations of the hydrochloride of the compound obtained and the 3,5-dinitrobenzol (DNB) form.
  • the specific rotations in Tables 1 to 3 are values measured at room temperature.
  • Table 4 also shows the NMR data of A1a-Trp and Trp-Ala of the present invention.
  • the NMR data of eAla-Trp and eTrp-Ala in Table 4 are all values measured at 30.0 in CDCIn. Also, * indicates an overlapped signal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Dipeptide ponté par N,N'-éthylène et éventuellement protégé, répondant à la formule générale (I), son sel, et son procédé de prodcution. Dans la formule (I), R3 représente -H, -CH3, -CH2CH3, -CH2CH2CH3, ou -CH2CH2CH2CH3; chacun des symboles * et *' représente un atome de carbone asymétrique; et R1 et R2 sont différents l'un de l'autre et chacun représente -CH(CH3)CH2CH3, -CH2OH, (a), (b), (c), -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)OH,- CH2CH2SCH3, -CH2CONH2, -CH2CH2CONH2, -(CH2)4NH2, -CH2COOH, -CH2CH2COOH, -CH2SH, (d) ou (e).
PCT/JP1993/000292 1992-03-10 1993-03-10 DIPEPTIDE PONTE PAR N,N'-ETHYLENE ET COMPOSE DE DIFFERENTS ACIDES α-AMINES OPTIQUEMENT ACTIFS, ET SON PROCEDE DE PRODUCTION Ceased WO1993018013A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP51553493A JP3265378B2 (ja) 1992-03-10 1993-03-10 異種の光学活性なα−アミノ酸からなるＮ，Ｎ´−エチレン架橋したジペプチドおよびそれらの合成法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/51241 1992-03-10
JP5124192 1992-03-10

Publications (1)

Publication Number Publication Date
WO1993018013A1 true WO1993018013A1 (fr) 1993-09-16

Family

ID=12881455

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/000292 Ceased WO1993018013A1 (fr) 1992-03-10 1993-03-10 DIPEPTIDE PONTE PAR N,N'-ETHYLENE ET COMPOSE DE DIFFERENTS ACIDES α-AMINES OPTIQUEMENT ACTIFS, ET SON PROCEDE DE PRODUCTION

Country Status (2)

Country Link
JP (1) JP3265378B2 (fr)
WO (1) WO1993018013A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5120718A (en) * 1991-06-13 1992-06-09 Abbott Laboratories Candida acid protease inhibiting compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5120718A (en) * 1991-06-13 1992-06-09 Abbott Laboratories Candida acid protease inhibiting compounds

Also Published As

Publication number Publication date
JP3265378B2 (ja) 2002-03-11

Similar Documents

Publication Publication Date Title
CN1039125C (zh) 脒基苯丙氨酸衍生物的制备方法
US4535167A (en) Chiral, N-protected, N-substituted α-amino acids
US20060189689A1 (en) Arginine mimetics as factor Xa inhibitors
US12240797B2 (en) Method of preparing a DON prodrug from L-glutamic acid
JPH0355480B2 (fr)
HU201961B (en) Process for producing 2,3-disubstituted isoxazolidines and pharmaceutical compositions comprising same
ES2202625T3 (es) Peptidos.
JPH02292245A (ja) 保護されたアミノ酸及びその製造方法
JP2003508408A (ja) 環状偽ペプチッドの製造方法
WO1999050229A1 (fr) Promedicaments et analogues d'acides gras
WO1993018013A1 (fr) DIPEPTIDE PONTE PAR N,N'-ETHYLENE ET COMPOSE DE DIFFERENTS ACIDES α-AMINES OPTIQUEMENT ACTIFS, ET SON PROCEDE DE PRODUCTION
US6352976B1 (en) Selective inhibitors of MMP-12
HU208838B (en) Method for producing peptones containing aza aminoacides by means of solid-phase synthesis
EP1140854A2 (fr) Procede de synthese de l'acide alpha-hydroxy-beta-amino et de derives amides
EP0948524A1 (fr) Peptides agonistes du recepteur b 2? de la bradykinine
KR890000769B1 (ko) 프롤린 유도체의 제법
JPS58219151A (ja) オリゴペプチドプロドラグ
JPS5828867B2 (ja) 新テトラペプチド誘導体類
Steinmetzer et al. Structure-activity relationships of new NAPAP-analogs
JPWO1993018013A1 (ja) 異種の光学活性なα−アミノ酸からなるＮ，Ｎ´−エチレン架橋したジペプチドおよびそれらの合成法
EP1140984B1 (fr) Inhibiteurs selectifs de mmp-12
US4350628A (en) Preparation of dehydropeptides
JPH11509851A (ja) α−（Ｎ，Ｎ−ジアルキル）−アミノカルボン酸アミドの製法
GB1587809A (en) Synthesis of peptides
EA009980B1 (ru) Новый способ синтеза сложных эфиров n-[(s)-1-карбоксибутил]-(s)-аланина и их применение для синтеза периндоприла

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase