JPS60136554A - Enkephalinase inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to enkepbal 1n
asc) inhibitors, and more particularly to novel mercaptoalkanoyl and acylmercaptolkanoyl compounds having enkephalinase inhibitory activity and useful as analgesics, as well as pharmaceutically acceptable salts thereof.

Structure and effects of the invention The novel compound of the present invention is represented by the following formula [IJ.

1 [In the formula, -Ill is hydrogen or R5-C-11 111 1 1I l1 1 (1゜n is an integer from 1 to 15 - 1) is an integer from 1 to 4, 111 is 0 or an integer from j to 4, (6 is lower alkyl having 1 to 4 carbon atoms - 1 to 4 carbon atoms (
7-) Lower alkoxy-lower alkylthio having 1 to 4 carbon atoms, hydroxyl-+3r-F-ami2-Nl
l-lower alkyl (1 to 4 carbon atoms) --N (lower alkyl) 2 (lower alkyl has 1 to 4 carbon atoms = + or l-U fluoromenalium r) an integer from 1 to 3 (however -R6 or Hydroxy-methyl-methoxy-C1 or 1
Only in the case of z, 1" is from 1) - 1 (1o is hydrogen, lower alkyl, cycloalkyl or phenyl - R]-] is hydrogen - lower alkyl, lower alkoxy or phenyl, and 1 (7 and R8 are each independently and combined with hydrogen and a lower atom, the formula: It forms a ring] Words used to define various symbols 1 - What is "lower alkyl"?
It refers to a straight or branched hydrocarbon group having 7 or less carbon atoms, such as methyl-ethyl-propyl, isopropyl, in-butyl-butyl-t-butyl, pentyl, impentyl, and the like. Preferred lower alkyls have 4 or fewer carbon atoms, with methyl and ethyl being most preferred. Similarly, the phrases "1-lower alkoxy" and "1-lower alkylthio" - refer to where such alkyl is attached to oxygen or sulfur.

The term "1-cycloalkyl" refers to a saturated ring having 3 to 7 carbon atoms, and cyclopentyl-cyclohexyl and cycloheptyl are preferred.

Formula: (el12)Pfl=-(C112)■, indicating that it is combined with the prefix and the child.

U.S. Pat. No. 4,401.677 to Greenbelv et al. discloses that various mercaptoalkanoyl alpha-amino acids are useful as analgesics based on their enkephalinase inhibitory activity.

U.S. Pat. No. 4,053,651 to Onodetsutei et al. discloses that various mercaptoalkanoyl and acylmercaptoalkanoyl alpha amino acids are useful as antihypertensive agents based on their angiotensin-converting enzyme inhibitory activity.

Loukies et al. 0:) i' Na Lure J (2
Volume 88-1980 1.1 +4.286-288)
-Thiorphan (r11iorl citya+i)-i.e. ['(+3.l,)-3-mercapto-2-benzylpropanoyl"J-resinka in vitro at nanomolar concentrations, and also for intravenous or systemic administration. It has been disclosed that it is an inhibitor of enkephalinase in vivo after one animal.

European patent application ffr 3 s 7 of Roukies et al.
It is well established that various α-amino acid derivatives, including -mercaptoalkanoyl and acylmercaptoalkanoyl derivatives, exhibit enkephalinase inhibitory activity.

7 Muho/L/Dora(7,) l-Biochcmic
al and 13io1) physicalResea
rch Comm, J (Volume 109, Teeth 4-1982-
1303-1309) discloses that various substituted N-carboxymethyl dipeptides (including those having a terminal β-alanine group) have enkephalinase inhibitory activity.

European Patent Application No. 54862 to Berger et al.
Enkephalinase inhibitory peptides of the formula:

l-Biocllcmistry of Kutsushi, 17 N et al.
J (Volume 16, No. 025. 1977-5484-54
(page 91) discloses various carboxyalkanoyl and mercaptoalkamylamino acids as angiotensin-converting enzyme inhibitors, and these compounds have the formula: It
s-((tears 2) 2.-c knee Nishi C112) 2-C
I was beaten by OOII.

4 Nonotein et al.'s U, 5, 6;! j permission number 4235
885 and 4297275 have the formula: (II1 is 0 or an integer from 1 to 9, R3 includes hydrogen -
mercaptoalkanoyl and acylnorcaffeinated 01-alcamose (CO, agcnasc) inhibitors are disclosed.

→ノ”/Dean et al. U, S, Patent No. 43271.1.
No. 1 has a set: R, -5-CD2-CIl-C-Ni1-(C112)
,, -C-R4 (1 and 4 are hydrogen-alkyl or aryl, ■ is 1 to 20 II<number- and 1ζ3 is 3 carbon atoms
Mammalian collagenase inhibitors are disclosed comprising mercaptoalkanoyl and acylmerhbutoalkanoyl compounds of ~8 alkyl-cycloalkyl-aryl or arylalkyl having 3 to 7 carbon atoms.

The compound of the present invention of formula [1] can be obtained by acylating an amino compound of the formula: 1(30 11) 112N-C1l-(C112), -C-R41 with an acid of the formula or a chemical equivalent thereof. One can be manufactured. By the above acylation, acylmercaptoalkanoyl compounds of the formula [D, where 1 is R5-C-] are obtained. When these acylmercaptoalkanoyl compounds are treated with '7i'+ hydrolysis, , R, or hydrogen, the corresponding mercaptoalkanoyl compound of formula 1J is followed.

This acylation reaction can be carried out in the presence of a coupling agent (such as dicyclohexylcarbodiimide) - or by combining the acid of formula CIIIJ with its mixture jH (hydrate monosymmetric anhydride, acid/Slide active ester formation). Alternatively, it can be activated using Woodward's reagent, i.e., n-ethylene 1-quinecarbonyl-2-ethoxy-1,2-dihydroquinolino. Test i1 of the acylation method.
For Houben-Wei/l/'i 1McL
boclcn clcr 0rganiscl+eo
Cbcm1e''(~'of, XV-Part 11-1
Preferably, acid halides of the formula L, +113 (especially acid halides) are used.

The product of formula 1, where 1ζ is hydrogen-1, 4, or lower alkoxy, or each substitution], is a compound of formula LJ, where R1 is hydrogen, or 4 or hydroxy, It can be prepared by selective kenation in the presence of dicyclohexylcarbodiimide and dimedylaminopyridine after treatment with a suitable alcohol.

The formula [1] 5 o)/1-substitute is 1 (1 or hydrogen - C = Iζ4 or hydroxy). It can be produced by acylation with a halide.

It can be produced by using an amino compound of formula [■] having an amide group at the position. Also R7 and 1
(If 8 is hydrogen - the formula I (4 is lower alkoxy) as a carbonic acid ester - the acylation reaction can be completed using the old intermediate - the acyl mercaftalkanoyl amino acid with a methanolic solution of mmonium A compound of formula L' II J in which both R7 and II8 are □
or hydrogen, can be obtained.

Formula C where 1o0 1 1'-4 is -0-Cll-0-C-Rll
The ester product of I'lJ can be prepared by using an amino compound of formula 1111 with an ester group in place in the reaction. In addition, the product of the formula [■] where R4 or Hi1 Dorokin-1ζ□ is R5-C- is expressed by the formula:
J functional group) can be treated with a compound of molar f1; Next, the R5-C- group is removed by selective saponification to obtain a product in which □ is hydrogen.

Amine intermediates of formula [ll] are known in the art and can be prepared from known α-amino acids by the 1-Jo method of Ondetsutei et al.
Urnal ofλ4edicinal Chetni
stry j (Volume 13, Yang 7-19.75-761
-Sequential tuning according to move 1 to 4 (pages 763) (5uc
cessive bomologation).

Acyl mercaptocarboxylic acid intermediates of formula Cll1i'J have been described in various patent documents and references.
(e.g. U, S of Onterati et al. [Patent Nos. 4,053,651 and 4,105,776, and Sandeen's U, S, Patent Nos. 4,235,885 and 432]
(See No. 7111).

Preferred compounds of the formula C1,] are hydrogen), 1 11 11 (m is 1 or 2- and R6 is methyl-methquine-(
・/-1'-amino)-nitro or hydroxy) +
'11+ to 1 (2 or pencil-1 (3) hydrogen, straight chain or branched chain with 1 to 4 carbon atoms 1 + 1 11 (01 is 1 or 2, and 116 is methyl, methoxy-CI, methyl, hydroxyamino Mataha Nitro), 1(
4 is hydroxy, methoxy-Nl12 or 1910 4 straight-chain or branched lower alkyl or cyclohexyl, and R11 is straight-chain or branched lower alkyl having 1 to 4 carbon atoms), especially l It is a compound in which n is an integer of 1 to 9, particularly 3 to 6.

The compound of formula [■] has one or two asymmetric centers (I (two asymmetric centers if 3 is other than hydrogen). Therefore, the compound of formula [1] exists in a stereoform or a racemic mixture thereof. All of these forms can be used in the process of the invention. In the above-mentioned syntheses, one starting compound can be used in the form of a racemic mixture or as a single isomer.

Compounds of formula CI in which 4 is hydroxy form basic salts with various inorganic or organic bases. formula〔
Pharmaceutically acceptable salts of the compounds of J] are useful in the method of the invention. Such pharmaceutically acceptable salts include alkali metal salts such as sodium or potassium - alkaline earth metal salts such as calcium or magnesium - and salts derived from amino acids such as arginine, lysine and the like. Such salts are prepared by reacting the acid form of the compound (i.e., 4 is hydroxy) with a base that provides an equivalent amount of a given basic ion in the medium or aqueous medium in which the salt is precipitated, followed by lyophilization.・ In addition, the compound of formula [J] having -amine group has each J+
Forms acid addition salts with inorganic and organic acids of li. Such pharmaceutically acceptable salts include - for example, hydrohalides (hydrochlorides, bromates, etc.), sulfates, phosphates,
Nitrate, aryl sulfone-1 salt (camphor sulfone-1
-Salt-Benzenesulfone-1・Salt-Toluenosulfonate salt) -Citrate -Ascorbate -Maleate, fumarate, vermoate (pa+noate)
, acetate, tartrate-salicylate), etc. It is often convenient to form monoacid salts of such compounds or to precipitate them in a medium in which they do not dissolve. These bases also form quaternary ammonium salts with quaternizing agents, which may be used in pharmaceutical applications in a 1:'1 ratio, such as lower alkyl halides (methyl chloride-odor). Examples include methyl chloride-ethyl chloride), lower argyl sulfates (methyl sulfate-ethyl sulfate, etc.)-monocyclic aryl (lower alkyl) halides, and sulfates (pendyl chloride-benodylsulfedonato). Formation of this quaternary ammonium salt is accomplished by reacting a base with an alkyl halide misulfate or the like.

When administered to mammals, the compound of formula [■] is useful as an analgesic based on its enkephalinase inhibitory activity. The scope of the present invention is not limited to any particular theory or mechanism of action; Met
) and (i, cu”)-enkephalin (-J'y
r-Gly-Gly-Pbc-1-eu)
i;
Vol.-December 1975-577△ 579)], and these sedative peptides are also linked to specific peptides (enkephalinase, which is presumed to be located specifically at nerve terminals in the brain from which enkephalins are released).
be functionally inactivated by cleavage of the Gly''-Plte' peptide bond by 1-Malfroy et al.
January 523-526)] was proposed. Specific inhibitors of this enkephalinase From brain slices to endogenous enkephalinase 1-5cienc
e J (212 Tame, June 1981, 1153-11
(see p. 55)], Nail (no 11'+i in mice reversed by surface antagonists); see Loukies et al.

By prolonging the natural analgesic action of the drug released from the peripheral and central regions, other medicinal effects, such as antitussive or antidiarrheal activity, are brought about.

In this way, the compound of the present invention 1-]J or its pharmaceutical 1
1'1 By pouring a composition containing one or a mixture of salts capable of responding to 1-j, one mouthful of milk is obtained! The bitterness of the luJ host is despised. Approximately 0.1 = 100 nry
/ throughout the body (Ky) /1, j, etc. "preferably about 1 to 2
The desired analgesic activity is achieved by single administration or preferably by 2 to 4 divided daily administrations, subject to the basal t11 of 5IIIv/body. Town 111j of the present invention
The drug composition is preferably administered intraperitoneally, but parenteral administration such as subcutaneous injection may also be used.

In particular, the compound [1] of the present invention also has a strong enkephalinase inhibitory activity, but it is more effective as an angiotensin converting enzyme inhibitor than the corresponding α-amino acid compound described in the patent documents of Ondetsutei et al. and Greenberg et al. It was found that the activity was much lower. Therefore, by administering the compound of the present invention (C1), a selective analgesic effect, which was not possible with conventional σ-amino acid compounds, can be obtained.

The compound of the present invention (1) can be administered in the form of tablets, capsules, or elixirs for oral administration, or in the form of a sterile solution or suspension for parenteral administration. It can be used as an enkephalinase inhibitor to reduce bitterness. Compound of the present invention [1] or one or a mixture of physiologically acceptable salts about 1.0 to 5
00 my is formulated in unit dosage form as required by acceptable pharmaceutical practice with a physiologically acceptable vehicle-carrier-excipients, binders-preservatives-stabilizers-flavoring agents, etc. The dosage of the active ingredients in these single or combination preparations is determined so as to obtain an appropriate dosage within the range specified in the table below.

Specific examples of adjuvants that can be mixed into tablets, capsules, etc. include the following. Namely, a binder such as cornstarch or seratin, an excipient such as dicalcium phosphate, and a disintegrant such as cornstarch, potato starch, or alginic acid.
Moisturizing agents such as magnesium stearate - Flavoring agents such as sucrose, lactose or zatukarin - Peppermint - Flavoring agents such as Toryokuura or Cherryura. Unit dosage forms or capsules may contain, in addition to the materials mentioned above, a liquid carrier such as a fatty oil. Various other substances may also be present as coatings or otherwise to form the physical form of the unit dosage form.

For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain one active compound, sucrose as a flavoring agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

Sterile injectable compositions are prepared in accordance with normal pharmaceutical practice by incorporating the active substance in a suitable vehicle such as water for injection, naturally occurring vegetable oils (Komaura coconut oil, peanut oil, cottonseed oil, etc.) or synthetic fatty vehicles (oleic acid, etc.). ethyl, etc.)
They can be blended by dissolving or suspending them. Further, a buffer, a preservative, an antioxidant, etc. can be mixed as necessary.

The following examples are merely illustrative of the invention. In the example sentence, 1
AlX degree unit is °C.

Example 1 (1) Preparation of -3-[[:2-(mercaptomethyl)-1-o-t-7-3-phenylpropyl]amino]furopanoic acid -(Acetylthio)methyl J-x-oxo-3-phenylpropyl]Production of amino J propanoic acid ethyl ester
<Acetylthio)methyl]-3-phenylpropanoic acid 0
．． 95! (4,0 mmol) of ethyl ether 8 m
1 solution in a drying tube, chloride oxa') JLtO, 37m
(4,2 mmol) and then carefully treated with catalytic dimethylformamide (3 drops). Chamber this mixture? Stir for 1 hour and concentrate under reduced pressure to 1". 5N11 of tetrahydrofuran is added to the residue to drive off some remaining oxalyl chloride.

The two layers (yellow and green) of the liquid residue were diluted with 5 J of methylene chloride.
and decant the soluble portion into a dropwise M1 container. This solution was mixed with 10% methylene chloride under a nitrogen atmosphere. β-alanine ethyl ester hydrochloride 0.61' (4,069
mol) and diisopropylethylamine 1.46 nJ (
8.38 mmol) in a cold (ice/methanol) mixture over 10 minutes. After stirring for 3 hours, the resulting slurry IJ- is filtered and concentrated. The residue was diluted with 50% ethyl acetate.
treated with mIV, filtered again and the ρ solution was treated with 1096 potassium hydrogen sulfate, water, saturated sodium bicarbonate and 5096
Wash with brine (30 rrl each), dry over sodium sulfate and concentrate under reduced pressure. A viscous yellow oily residue 1.201 silica gel (23 <) ~ 1 lO0 mesh) 80! Column-1-, hexane/acetone (7:
2) for elution and purification. Fraction containing the desired product (
TLC C) were combined and concentrated as a clear, almost colorless oil to give <-1-) ethyl -3-[[2-[(acetylthio)methylrho-1-oic acid di-3-phenylfurohyl]amino]fropanoate. 1.04 fI of ester is obtained.

l], (±)-3-((2-(mercaptomethyl)-1
- Preparation of oxo-3-phenylpropyl]amine]propanoic acid: 1.01' of the product obtained in section a above (3.02 mmol of methanol 6+lt solution was chilled on ice/methanol), and this was carried out under nitrogen atmosphere. 1N sodium hydroxide 1-1J 6
．． Add 35 ml over 15 minutes. The mixture was stirred for 3 hours while warming to room temperature (LC indicates incomplete reaction), then 1N sodium hydroxide was added.
Add 1 at a time. After stirring the chamber for an additional 3 hours, the mixture was concentrated to about 1/2 volume in vacuo, and the residue was diluted with 50% water.
ml and 30 ml of ethyl acetate.

The aqueous layer was washed with 30+l of ethethyl v'1 acid, and then purified with concentrated hydrochloric acid.
I I about 2 to key 1! ijL, 11f and ethyl acetate (
20rnlX 3 times) Draw 1"4. Combine these organic layers and add water and saline (30 + 117, respectively)
-C washing, sodium sulfate l) ram drying and concentration under reduced pressure 1ζ as a white solid (±)-:3-LC2(mercaptomethyl)-1-oxo-3-phenylpropylJamine]propanoic acid o, 71y was tll. Melting point 76-82℃
. I' I-C (silica gel 7, toluene/acetic acid (4:
]) 1 (f-o, 37: Small speck at 0.07.

)1L Pilgrimage Analysis, Ci 311□7N03S, JI
Calculated value: C, 58,409fi; It, 6.4], 96:
N.

5.24%; S, 11.9996, Actual value: C, 58,17!16: [1,6,3496;
N.

515%: S+11.8596° Example 2 Production of (±)-4-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]butanoic acid Ni a, 4-aminobutanoic acid methyl ester hydrochloric acid Preparation of the salt 4-Aminobutanoic acid 4. In methanol under nitrogen atmosphere. ], 2! To a cold (-10°C) 41 suspension of (40 mmol) was added 5.86 m of thiol chloride.
l (80,0 mmol) at a reaction temperature of -5 to -10°C.
Add dropwise with mechanical stirring at a rate that maintains the temperature. Add this mixture to room temperature for 7 hours. Stir overnight at rL/l and reduce to r3 under reduced pressure. The off-white crystalline residue was treated with ethyl ether (twice) and dried under reduced pressure to give 4-aminobutanoic acid methyl ester hydrochloride 625 as an almost white solid.
get g. Melting point 1], 8.5-122°C (softens at 90°C).

+3. (1-)-4-C[2-((acetylthio)methyl]-1-oxo-3-phenylpropyl]amino”
Preparation of methyl butanoic acid ester Under a nitrogen atmosphere, (above) -2-((acetylthio)methyl J-: Add 0.95 g (4.0 mmol) of 3-phenylpropanoic acid to a solution of 8d in ethyl ether. This mixture was carefully treated with dimethylborumamide catalyst i'ri: (3 drops),
Stir for 1 hour at room temperature.

After concentration under reduced pressure], the residue was diluted with tetrahydrofuran 10
rnl, and again remove excess 17i of oxalyl chloride and concentrate to 1i. (47 The resulting residue was diluted with methylene chloride, 5
d and transfer the soluble portion to a dropping funnel. This solution,
4-Aminobutane methyl ester hydrochloride 0.68y (
44 mmol) and diisopropylethylamine 1.6
A cold (-5 DEG C.) solution of 10 ml (9.0 mmol) of methylene chloride is added dropwise over a period of 10 minutes with stirring under a nitrogen atmosphere. After cooling and stirring for 3 hours, the supporting color solution was concentrated in vacuo. The residue was diluted with acetic acid (-fiv (
i (l ml to remove diisopropylethylamine hydrochloride/lI, 1096 potassium hydrogen sulfate,
Wash sequentially with water, 50% saturated sodium bicarbonate and 5096 saline (30- each). The organic layer is dried over 1-1 J of sulfuric acid to yield 1.34 g of a light brown solid.

This solid was adsorbed onto a small amount of silica gel (230 to 400 mesh) and loaded onto a similar silica 801 column. Elution with hexane/acetone (5:2) yielded (4: )-4-[[2-[:(acetylthio)methyl]-]-oxo-3-phenylpropyl] as a white solid.
1.09 g of amino]butanoic acid methyl ester is obtained. Melting point: 81-82°C.

(, (±)-4,-[(2-(mercaptomethyl)-1
-Production of t-j-so-3-phenylpropyl 37mi/]butanoic acidNitrogen atmosphere-de, 0.6 g (1,
8 mmol) in 5 ml of methanol and placed in an ice bath at 41 ml.
Let it cool down. Add 5.4 liters of 1N sodium hydroxide to this solution.
ml (3 equivalents) is added dropwise over 10 minutes. The mixture is stirred in the cold for 3 hours and concentrated under reduced pressure to about 1/2 volume.

The residue was diluted with 40 ml of water and diluted with 1 form (1
5mJl! Wash twice) and adjust to 1) 11 to 15 with hydrochloric acid. The cloudy white color (white) was diluted with ethyl acetate (1
, 5ml x 3 times). These extracts were combined, washed with water and brine (15 yJ' each), dried over sodium sulfate, and concentrated to form a white solid (()-
s-([2-(mercapto7tyl)-1-oxo-3-
0.48 g of phenylpropyl]amino]butanoic acid was obtained. Melting point: 94.5-101°C. TLC (on silica gel, benzene/acetic acid (4:1)) -0,41° elemental analysis, calculated as C□411 t 9 N 03S: C, 59,76%; II, 6.81% :,N,4
゜98%:S; 11.4oq6, Actual value: C, 59,8196; II, 6.8196;
N, 4°96%; S, 11.3796° Example 3 (S)-3-((2-(mercaptomethyl)-1-oxo-3-phenylpropyl) aminocobenzenebutanoic acid (isomer A) Preparation of i1. Preparation of (S)-4-phenyl-3'= (((phenylmethoxy)carbonyl)amino/)butanoic acid methyl ester. Preparation of its mixed anhydride using isobutyl chloroformate in ethyl ether. The method of Penke et al.
Helvetica Kimi Chikara Acta (11elv.

Ch i +t+ Acta) Volume 53 1057
-Page 1061 (1970)], (S)-
(3-siacy2-oxo-1-(phenylmethyl)propyl)carbamic acid phenylmethyl ester is obtained.

1.09 (4.7 mmol) silver benzoate are mixed with 10 ml of triethylamine and filtered. A portion of the ρ solution (approximately 0.5 ynl) was added to the above diazo compound 2.01C6,2
mmol) of methanol 207. Add to Il solution. Dregs release occurs and the mixture becomes dark in color. Foaming has stopped (
After about 10 minutes), pour the mixture into the river with silver benzoate solution (about 0.5
ml') and stir for 30 minutes. The mixture was treated with activated carbon, filtered through d-'i and jl+! under reduced pressure. : Shrinks to obtain a dark tar-like residue. Flori
(S'il) (ethyl ether eluent) to give (S)-4-phenyl-3-(((phenylmethquin)carbonyl J amino]bucunoic acid methyl ester 1. Obtain 65g.

+3. (S)-4-Phenyl-3-L((S)-4-phenyl-3-L((
phenylmethoxy)carbonyl]amino]butanoic acid methyl ester 1.649 (5.0 mmol)
-1-luenesulfonic acid hydrate o, 95! (1,0
30 ml of 95% ethanol solution of [1;) was added to 109
6 palladium/activated carbon catalyst 10071r"j. The mixture was stirred under hydrogen pressure for 1.5 hours and
Filter and concentrate to obtain an off-white residue. 141 crystallizes from acetonyl) as needle-shaped white crystals.
s > -: 3-amino-4-phenylbutanoic acid methyl ester/I) -toluenesulfonic acid JjA 1.4
Get 497. Melting point 168.5-170.5'Co (αJ,
, +7°0° (C=1.05 in methanol).

C, (S)-34(2-[(acetylthio)methyl]-
Preparation of 1-oxo-3-phenylpropyl]amine]benzenebutanoic acid methyl ester (isomer A) (±)-2-((acetylthio)methyl)-3-phenylpropanoic acid 0.92 IC3,9 under a neat argon atmosphere 30 ml of ethyl ether P(j'lf
Add oxalyl chloride (11th grade) to k. This solution was carefully treated with dimethylformamide (2 drops) and
Stir for 5 minutes. The mixture is concentrated under reduced pressure and the residue is dissolved in 5 ml of methylene chloride. Under an argon atmosphere, (S
)-3-amino-4-phenylbutanoic acid methyl ester/I)-1-luenesulfonate 1.4113.84
mmol) and diisopropylethylamine 1.35 ml
(7.75 mmol) in 20 ml of cold (ice/methanol) solution of methylene chloride, add 1 -1- methylene chloride solution.
Drip over 0 minutes. The mixture is warmed to room temperature and stirred for 3 hours before aJ III. The residue was diluted with 5096 saturated hydrogen carbonate, 100 ml of saturated hydrogen carbonate, and ethyl acetate (30,
+7×3). Combine the organic layers and add water, 1O9
6 Potassium hydrogen sulfate and saline (50nf each)
Wash with water, dry over sodium sulfate, and concentrate to obtain 57 g of yellow flakes (slowly crystallizing). This oil was applied to a 160 g column of silica gel (230-400 g), pre-absorbed with a similar solica solution (I+'-), and eluted with 2696 ethyl chloride/Ishiura ether. IP < Fractions containing only the migrating isomer are combined and elastically contracted to produce (S)-3-112- as a white crystalline solid.
0.7026 g of 1c acedelthio)methyl]-JAxo3-phenylpropyl]amine]bennanobbutuic acid methyl ester (isomer Δ)? 1). Melting point: 87-885°C o Cd] 1. -7
75° (Cro J Holm, c=o, 96).

d, (S)-2-L [2-(mercaptomethyl)-
Preparation of 1,--4gyso-:3-phenylpropyl]amino 1 to 7-zenfucnoic acid (isomer Δ). , 85 mmol) in methanol was added dropwise with 1.87 d (2,2/17) of 1N sodium hydroxide over 10 minutes.After 2 hours, 1N of thorium hydroxide was added to 2 ml of methanol solution.
．． 7. Remove the mixture and treat the mixture with enough methanol to dissolve the precipitate. After stirring for 7 hours at room temperature, the methanol is evaporated off under reduced pressure. The residue was diluted with water and treated with 2N sodium hydroxide to dissolve the solids,
Ethyl acetate (30rnl x 2) then hexa7
(30 nJ). Water layer with concentrated hydrochloric acid 1) ■1 approx.
．． 0 and extracted with ethyl acetate (20, meX 3 times). The organic layers were combined and diluted with water and brine (30% each
rn1. ), dried over 1-1J ml of sulfuric acid, and concentrated under reduced pressure to give (S)-3-[(2-(mercaptomethyl)-1-oxo-3-phenylpropyl J amine]) as a white solid. Obtained 0.231 ml of benzenebutanoic acid (isomer A), melting point 149~], 51.5°C. [αJ, +4
0. :3° [C=1.00 in methanol). l"
I-C (silica gel 1), benzene/acetic acid (7: ),
) R, +140° Elemental analysis, C: 20 +I23 No a S, calculated value: C, 67,2096: II, 6.49
%; N, 3°9296; S, 8.97%; Actual value: C, 66,8696; II, 6.45%
;N13.9:<”6: S, 8.71 Q6
.

Example 4 Preparation of (S)-3-((2-(mercaptomethyl)-1-oxo-3-phenylpropyl)amine)benzenophthanoic acid (isomer 13) N.D., (S)-3-4 (2-
Preparation of [(acetylthio))tyl]-]-]oxo3-phenylpropylamino]henzenbuta/acid methyl esters 1 to 1) Example 3 was concentrated and treated according to Example 3 (Section 1) to give (S)-3-[2-[(acetylthio)methyl]-1-oxy;3-phenylpropyl]amino]benze as a white solid. Amphitanic acid methyl ester (isomer n
) o67g. Melting point 93.

6 5-95℃0 "α] -155.4° (chloro, -1=
l) C-1. , 0 0 ).

1, +. (S) Production of -3-shi[2-(merca, ptomethyl)i-1-t-7-3-phenylproyl]benzenebutanoic acid (isomers 1 to 1) under argon atmosphere , the product of section a above 0.35ii
'(0.85 mmol) of Nukunor 3++dJ solution was added to this while stirring, sodium hydroxide Oi02! /(3
An aqueous solution of 2096 methanol (equivalent to 1.5 ηf) was added dropwise over 15 minutes. After stirring for 6 hours in chamber 1711□, the reaction was incomplete (TLC), so 1J of sulfur hydroxide (1N) was added to the mixture.
Introducing 0.85+++7 ml of sodium hydroxide aqueous solution,
Keep in a cool place (refrigerator) - overnight. The next day, the methanol was removed under reduced pressure and the residue was partitioned between 40 ml of water and 25 J. x 2 of ethyl chloride. The aqueous layer was adjusted to about 1.0 l with concentrated hydrochloric acid, and diluted with ethyl acetate (2).
0+l+7! x 3 times) Extract.

These extracts were combined and diluted with water and saline (30% each).
m1. ), dried over sodium sulfate and concentrated in vacuo to give (s)-3-(
(2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]benzenozotane I￥2 (isomer n
) 0.3oF was obtained. Melting point: 148 to 150℃
.

[α]26-289° (in methanol, C-=l, Q7
).

1) 1' L C (silica gel), benzene/acetic acid (7
: ], )) Rf -0,34゜Element 5) Analysis, c2o1123No3s, calculated value: c, 67.2oq6: II, 6゜4996:N
.

3.9296: S, 8.9796, Actual value:
Cl66.9596; It, 6.5396;
N.

3.82%; S, 8.82%.

Example 5 < jy ) -5-([2-(mercaptomethyl)-
Preparation of 3.5-aminovaleric acid methyl ester hydrochloride 2.34 g (2.34 g) of 5-aminovaleric acid in 25 nJ of methanol
In a cold suspension of thionyl chloride (2.93 mmol)
ml (40 mmol) at the reaction temperature of -5 to -10°C.
Add dropwise with stirring at such a rate that Bj is maintained at . After the dropwise addition of thionyl chloride is complete, the mixture is stirred overnight in room 1 flA]. Put the mixture under vacuum! The shrunken white crystals are treated twice with ether to obtain 2.68 g of 5-aminovaleric acid methyl ester hydrochloride as a white solid. Melting point 132-137°C (softens at 86°C).

b, (±)-5-([2-C(acetylthio)methyl]-1-oxy-3-phenylpropyl]amino]pentanoic acid methyl ester production (±)-2-((acetylthio)methyl)-3- Phenylpropane 1!112
1.19 g (5 mmol) of ethyl ether in 10 ml.
Add oxalyl chloride 0°45ml (5.2mm) to the solution.
mol). Pour this mixture, ffl and M! lt
Treat with a medium amount of dimethylformamide (3 drops) and stir for 1 hour at room temperature. The mixture was concentrated under reduced pressure and the oily product was dissolved in tetrahydrofuran.

ml and concentrated in vacuo. The residue was dissolved in 6 ml of methylene chloride and mixed with 5-aminovaleric acid methyl ester hydrochloride (0.91 mol) (5.4 mmol) and diisopropyl. ethylamine 1.96ml (11
11 ml of methylene chloride (-25 mmol)
°C) solution dropwise with stirring for 10 min.

After stirring for 2.5 hours in a cold place (-5℃), the mixture was heated to room temperature 11.
．． Allow to rise and stir overnight. The next day, the mixture was concentrated in a vacuum, the residue was taken up in 60ml of ethyl acetate, and diisopropylethylamine hydrochloride was removed. The p solution is washed sequentially with 1096 potassium bisulfate, water, 5096 saturated sodium bicarbonate and 5096 saline (20i4×3 times each). 1~ sulfuric acid the organic layer
Drying and reduction for 1 km gives 1.49 g of a very light yellow oil. This oily substance is mixed with silica gel (230~
(400 mesh)' applied to a 11.5 fI column and eluted with hexane/acetone (5':2) to give (±)-5-[[2-[(acetylthio)methyl]- as an anhydrous oil.
1.41 g of 1-oxo-3-phenylpropyl]amino]penotanoic acid methyl ester are obtained.

C6(]ni)-! 5-[(2-(mercaptomethyl)-
Preparation of 1-oxo-3-phenylpropyl acetic acid noropentanoic acid Under a nitrogen atmosphere, 1.20 g (3°41 mmol) of the product of item 1) in methanol 13 nlI! a Solution (
Water bath), 1N sodium hydroxide 12.9□4 (3,8
) was added dropwise over 10 minutes. The mixture was stirred at 0° C. for 10 minutes, allowed to rise to 77° C. and stirred for 3 hours. Concentrate this mixture to 1 & 1 upper and lower halves. Dilute the residue with 40 ml of water, wash with chloroporm (2x20x), and adjust the pH to about 1.5 with hydrochloric acid. The white color obtained! v!,, the turbid liquid is extracted with ethyl acetate (15+++7!×3 times).
The extracts were combined and diluted with water and saline (20 ml each).
), dried over sodium sulfate, and concentrated to obtain 082 g of a white wax-like solid. The solid was dissolved in 119 ethyl acid, filtered and concentrated, and the residue was treated with ether.
(-"=')-5-L[2-(mercaptomethyl)-1-oxo-3-phenylpropylcoamino"pentanoic acid was obtained as a white solid. Melting point 78-79°C. T1. , C
(R of silica gel-1-1 henzene/acetic acid (4:1) (
==0.30 (Itsuzuka Tlink is recognized)
.

Elemental analysis, calculated value as C□5■I2□N03S:
C, 60, 9996; II, 7. L796:N.

4.74%; S, 10.85%, actual value: C, 60,8096; II, 7.1596: N
.

4.629+i:S, 10.7396°Example 6 Preparation of (1-)-6-[(2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amine]hexa/acid::1. Preparation of 6-aminocarbohydrate methyl ester hydrochloride 6-aminocarbronol 1122 in 25ml methanol
．． 2.93 ml (40 mmol) of thionyl chloride was added to a suspension of 7 Add thionyl chloride;
Stir for a while. The mixture was concentrated in vacuo and the white solid obtained was treated twice with ether to give 6- as a white solid.
Ami7cabronoic acid methyl ester hydrochloride 3.53V is obtained.

Melting point: 1.14-18°C (softens above 109°C).

1), (j2)-6-[2-[:(acetalthio)methyl'-1-oxoco3-phenylpropyl]amino J
Production of hexanoic acid methyl ester (±)-2-((
Acetylthio)methyl)-3-phenylpropanoic acid 1-
, 19 f/ (5 mmol) of ethyl ether/l/
10 Add oxalyl chloride to n4J6 solution. .

Add 45〃z no C5,2 mmol). The mixture is carefully treated with catalytic dimethylpolamide (3 drops) and stirred for one period in room 7:iA. The mixture was concentrated to a reduced volume and the resulting oil was diluted with 10% of tetrahydrofuran.
ml and concentrated again under reduced pressure. The residue was dissolved in 6 n, l of methylene chloride and mixed with 0.98 g (54 mmol) of 6-aminocaproic acid methyl ester hydrochloride and 19 g (11,
, 25 mmol) of methylene chloride, 117 nl of cold (-5°C
) Stir and add dropwise to the moxibustion mixture for 1.0 minutes. After stirring in the cold (~5°C) for 25 hours, the mixture is allowed to warm to room temperature and stirred for 2 hours. The mixture was concentrated in a vacuum and the residue was dissolved in 60+yJ ethyl acetate.
to remove diisopropylethylamine hydrochloride. The ρ solution was sequentially treated with 10% potassium hydrogen sulfate, water, 5096 saturated sodium hydrogen carbonate and 5096 saline (2 on each, 1 x 3 times). Yes (
The layers were dried over sodium sulfate and concentrated to give (±)-6-[t2-((acetylthio)methyl J-1-oxo:3-phenylbutylene) as a slightly yellow solid.
1 pill] Amino J hexanoic acid methyl ester 1.64g
get. Melting point: 50-54"U <: 39°C or higher - sintering).

(, (1)-6-(L2-(mercaptomethyl)-1-
146 g of oxo-3-phenylzo, 146g product of the production of vircoamino acid
(399 mmol) of methanol (12 rnl cold melt bath), 1N hydroxide, 1.2 rnl, r
/' (:J) 1i) was added dropwise at 1 (σσ for 3 minutes). The mixture was stirred at O'C for 10 minutes and then heated to room temperature.
+A ni warm 0) wo it'l, 311fi between 1
[Stir. The mixture is reduced and compressed to half Nj.

The residue was diluted with 40 ml of water and diluted with chloroform (20 ml).
III/' ? 4
The white suspension was diluted with ethyl acetate (1.5 ml
3 times) Extract. These extracts were combined, diluted with 6 t of water and saline (20 ml each), and diluted with 1 J of sulfuric acid.
The mixture was dried over a vacuum and concentrated to give 1.23 g of a colorless oil. This oil was applied to an 80 g column of silica gel (<230-400 mesh) and dissolved in 20% acetic acid/toluene. (Obtains colored parts o, 99!).
The above was chromatographed again and eluted with 1596 acetic acid/toluene to yield 75 g of a colorless oil. 1. Jru.

This material was applied to a 5ilicAR・((-4sil/\\ column) and eluted with chloroform by gradual addition of ethyl acetate (10-4096+!I ethyl acetate).
0.67 g of white solid is obtained. This solid was treated with hexane/ether to give (I: )-6-[[
456 g of 2-(mercaptomethyl)-1-oxo-3-phenylpropyl was obtained. R (-(J) of melting point 58-60"Co"'Ic (silica-1-, toluene/xylic acid (4:i)).

26 (slight tilling is observed).

Elemental analysis, C□61123N03S, 0.18f120
, calculated value: c, 6]. 4696;11,7.53
06:N.

4, 4 896; S, 1 0.2 596, actual value: C, 61, 46%: 11, 7.47%; N.

4.4096: S, l 0.1496゜Example 7 (''2)-5[[2-(mercaptomethyl)-1,-1
Preparation of -1-7-3-phenylpropyl]amino]pentanoic acid methyl ester under nitrogen atmosphere (±)-5-[(2-[(acetylthio)methyl]-1-oxo-3-phenylbutylene) Amino]pentanoic acid methyl ester 9:35' (5.5 mmol) is dissolved in methanol 10n+7! and cooled in a water bath.To this solution is added 1N sodium hydroxide 55+l+7!
(1.0 equivalent: I;) is added i16 over 10 minutes. The mixture was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature until 1 liter and stirred for 1 hour. This mixture is depressurized and
Concentrate to half volume, dilute the residue with 20 ml of water and extract with ethyl acetate (3x15*+AX). The organic layers were combined and washed with water and brine (15 mi each);
Dry with sodium sulfate and concentrate to give 1.68p colorless oil.
get. The oil was applied to a approximately 125 g column of Nlcrtk silica gel (230-240 mesh) and eluted with hexane/acetone (5;3) as a white solid (±)-5-([2- (Mercaptomethyl)
1.34 g of -1-oxo-3-phenylpropyl]amino]pentanoic acid methyl ester was obtained. Melting point 39-41
1ζ[-0.29 (slight tilling is observed) of 01" L C (silica gel"-ohexane/acetate) (5:3)).

Elemental analysis, calculated value as C□61 1 z 3N 0 :3 5: C , 6 2. 1 1 96;
Ll, 7. 4 9%;N.

4,5396: S, 10.3696: Sl
l, 10.6996, real 4111 value: (:, 61.
86%:ll, 7.5496:N.

4, 50%: S, 10.2196; Sll, 10.62
%.

Example 8 (±)-7-([2-((acetylthio)methyl J-1
-Production of oxo-3-phenylpropyl]amino]heptanoic acid methyl ester a. Preparation of 7-amitzhebutanoic acid methyl ester hydrochloride (1:1) 7-amine in methanol 30-/I ¥21.8!
/ (J2.4 mmol) of cold 'j''!'' fl: '4 solution with thionyl chloride 1, -8 1-rni (2 4.8
mmol) is stirred at a rate such that the reaction temperature is maintained between -5 and -10°C. After adding all of the thionyl chloride, the mixture is in the chamber. Allow to warm up and stir overnight. The mixture was concentrated to a volume of 11. The resulting white solid was treated twice with ether to form a white solid containing 7-aminoheptanoic acid methyl ester salt (1:1)
2.38! Get V. Melting point 132-134℃ (1 1
Sintered at 8'C or higher).

b, (=+=)-7-LL2-((acetylthio)methyl J-1-oxo-3-phenylpropyl]amino J
Preparation of hebutanoic acid methyl ester 3-acetylthio-2-benocylpropanoic acid 1.

83! /(7.0 mmol) of ethyl ether (15
ml' solution, add 0.0% oxalyl chloride. 6 7ml
(7.69 mmol) is added. This mixture is carefully treated with catalytic dimethylformamide (2M) and stirred in a chamber/tube. The mixture is concentrated in vacuo and the resulting oil is The product was dissolved in 15 ml of tetrahydrofuran and concentrated again under reduced pressure. The residue was dissolved in 15 Tnl of methylene chloride, and this was dissolved in 7-amizhebutanoic acid methyl ester hydrochloride (
1:1) 1.50y (7.0 mmol) and 2.68 rnl (15.38 mmol) of diisopropylethylamine in 15 ml of cold (-5°C) methylene chloride is added dropwise over 10 min at 712 E12. Cold place (-
After stirring for 2.5 hours at 5° C., the mixture is allowed to warm to room temperature and stirred overnight. The mixture was concentrated to a volume of 1” and
The residue was taken up in ethyl acetate and diimpropylethylamine hydrochloride was removed. I5 solution with 10% potassium hydrogen sulfate, water, 596 saturated hydrogen carbonate) IJum, water and 5096 saline (3 o, +7!x, respectively)
3 times) Next wash. The organic layer was dried over sodium sulfate and concentrated to obtain 2.60 g of a white solid. This isomer was fractionated and crystallized from hexane/ethyl acetate as a white solid (±)-7-C (2-[ (acetylthio)
Methyl]-1-ogiso-3-phenylpropyl]ami7
] 248 g of heptanoic acid methyl ester was obtained. Melting point 8
'4~85℃ (J-te sintering above 51℃). l'Lc
(Silica gel 1-1 ethyl citrate/hexane (2:1))
0) R (-0,45° elemental analysis, C: 201129 N O, i S, 1?1 Cod t1 direct: C, 63,3096; II,
7.7096; N.

:(, fi 996: S, 8.45%, actual value:
C,63,0196:II,7.5796:N.

:3.5], “6: S, 8.40?6.

Example 9 (1: ) -7-(1:2-<mercaptomethyl)-■-oxo-3-phenylpropyl"aminoloheptanoic acid production ni(+)-7-cl:2-acetylthio)methyl 1 -1
-oxo-3-phenylpropylloamino 1-hebutanoic acid methyl ester (1.6 Fl (4,3,: 1 mol) was dissolved in 20 ml of methanol (11) and cooled in a water bath in a nitrogen poison atmosphere. This solution 1.3 ml of 1N thorium hydroxide (approx.
: Allow to warm to +A and stir for 3 hours.

The mixture was concentrated in vacuo to remove all 118' of methanol. The residue was diluted with 40 ml of water and diluted with chloroporm (2
0ffdX twice), and the aqueous part was adjusted to pH approximately 1.0 with concentrated hydrochloric acid.
Key n1j to 5. The resulting white kake 7i! Extract the '5 solution with ethyl acetate (15 mA! x 3 times). The combined extracts are washed with water and brine (20 ml each), dried over sodium sulfate, and concentrated to give 132 g of a white solid. Approximately 90 g of Merck silica gel (230-400 mesh) was added to the solid, and toluene/acetic acid (7
:l) to obtain 1.1.4 g of a white solid. This material was applied to a silica gel (3IIICAR/CC-4) column and eluted with chloroform and O to which ethyl acetate (10-5596 dichloromethane) was gradually added and used as an eluent. As a solid (Jni>-
7-((2-(mercaptomethyl)-1-oxo-3-
Phenylpropyl] amino J heptanoic acid 1.05 g? ! # Ta.

Melting point: 71-73°C (sintered at 65°C or higher). -r r-
c: (R of benzene/acetic acid (4:1) on silica gel (
==Q, 36 (trace at 0,27).

Elemental analysis, calculated as C□71125N03S: 63.13%; II, 7.79%; N.

4.3096:S, 9.9]! %: Sll, 10.22
%, actual value: C, 63,3696: II, 7.9196
:N.

4.2196: S, 9.57%: Sll, 9.89%.

Example 10 (+)-7-[:[2-(mercaptomethyl)-1-
Preparation of oxo-3-phenylpropyl]amine]hebutanoic acid methyl ester a: - (di-7-((2-[(acetylthio)methyl]-1
1.43 g (3.77 mmol) of oxo-3-phenylpropyl]amino J hebutanoic acid methyl ester was dissolved in 30 ml of methanol while heating, and the mixture was heated under a nitrogen atmosphere.
Cool in an ice bath. To this solution, 3°77 iJ (equivalent to 1-0) of 1N thorium hydroxide (11) was added dropwise over a period of 0 minutes. The mixture is stirred 1α for 10 minutes at 0° C. and then allowed to warm to room temperature for 1 hour. The entire amount of methanol was removed from the mixture under reduced pressure and the mixture was condensed. The residue was diluted with 20 ml of water and diluted with ethyl acetate (15 ml
3 times) Extract. These E1 layers were combined, washed with water and brine (15 I each), dried over sodium sulfate, and concentrated to yield 1.2 cr of a white solid! get. The solid is dissolved in 25 ml of a mixture of methanol:water (1:1) and adjusted to pl+approx. 1.0 with concentrated hydrochloric acid. There is no zinc powder in this solution.
．． 080 g are added and the mixture is stirred at room temperature for 30 minutes.

The residual zinc powder is removed by F, and all 17j of methanol in the r liquid is removed and concentrated. The residue is diluted with 20 rnl of water and extracted with ethyl acetate (3 times 25,n1). These organic layers were combined, washed with 5% sodium bicarbonate, water and brine (2x20JX each), dried over sodium sulfate,
Concentrate to white solid 1.2:3! fold. This substance is mixed with Merck silica gel (230-400 meth 7-1) 5
Purified by flattening chromatography and eluting with ethyl acetate to give a white solid, 0.9
Get 809. The solid was dissolved in methanol, filtered through a cellulose microfilter, and concentrated in vacuo to yield (4-)-7-[2-(mercaptomedel)-1-oxo-3-phenylpropyl]amine]. Hebutanoic acid methyl ester was obtained. Melting point 68-70°C oT1. R of C (silica gel 1-1 Hensen/acid resistance (4:1)) (= 0.
44.

Elemental analysis, calculated value as C□s f'l 2□N03S: C, 64,0696:11, 8.06%; N.

4.1596; S, 9.50%; S11,
9.8 o96, actual value: C, 64, 33%: Il, 8
．． 14%:N.

3.999δ:S, 9.4596:Sll, 9.79
%.

Example 1 ■ (1) Preparation of -8-4[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]octanoic acid Ni a, 8-aminooctanoic acid methyl ester hydrochloride (1:
Production of 1)-1 methanol 25 me 1118-aminooctanoic acid 3
．． 18! Thionyl chloride 2,9: (ml (40 mmol)) was added dropwise to a cold suspended solution of (20 mmol) without stirring at a speed such that the reaction temperature was maintained at -5 to -]0'C. After adding all 16 drops of thionyl chloride, the mixture was allowed to warm to room temperature and stirred overnight.The mixture was concentrated in vacuo and the resulting white solid was treated twice with ether.
Obtain 3.98 fl of 8-amine octanoic acid methyl ester hydrochloride (1:1) as a white solid. Melting point 130-13
2℃.

b, (±)-8=((2-[(acetylthio)methyl"
Production of -1-oxo-3-phenylzolopyl]amine]octanoic acid methyl ester: -3-acetylthio-2
- ethyl ether of 1°19 g (5 mmol) of benzylpropanoic acid 10++11! Oxalyl chloride 0.45++17 to melt! (5.2 mmol) is added. This mixture is carefully treated with catalyzed dimethylformamide (3 drops) and stirred at room temperature for 1 hour. The mixture is concentrated under reduced pressure and the resulting oil is concentrated in tetrahydrofuran LO.
Dissolve in MJIE and reconcentrate in MJIE. This residue was dissolved in 6 ml of methylene chloride, and 1.06 g (5 ml) of 8-aminooctanoic acid methyl ester hydrochloride (1:l)
, 1 mmol) and diisopropylethylamine ■, 96
□, 1V (11°25 mmol) methylene chloride 11+
dropwise into the cold (-5° C.) solution with stirring over a period of 10 minutes. After stirring for 2.5 hours in the cold (-5°C), the mixture is allowed to warm to room temperature and is stirred overnight. The mixture was concentrated in vacuo, the residue was taken up in 60ml of ethyl acetate, and diisopropylethylamine hydrochloride was extracted.

The ρ solution was mixed with 10% potassium hydrogen sulfate, water, 596 saturated sodium bicarbonate, water and 50% saline (20+ each).
++7! 3 times).

The organic layer was dried with thorium sulfate and concentrated to a bright yellow solid.
2. Get oig. The solid was dissolved in ethyl acetate and blotted onto a small ft. This material was passed through a similar silica column (approximately 125 g) and dissolved in hexane/ethyl acetate (1:1).
LL L, white solid χ (±)-8-1:(2-[(
Acetylthio)methyl]-1-oxo-3-phenylpropyl” aminocooctanoic acid methyl ester 1.69g
get. Melting point 44-45'C6 (', (1-)-8-CC2-(mercaptomethyl)-
Production of 1-oxo-3-phenylpropyl[amino/]octanoic acid under nitrogen atmosphere, methyl ester product 1 of item 1)
．． 691 (4.3 mmol) in 13 ml of methanol
Dissolve in water bath and cool. To this solution, 13 ml (approximately 1 piece) of 1N thorium hydroxide is added dropwise over 10 minutes. The mixture is stirred at 0° C. for 10 minutes, allowed to warm to room temperature, and stirred for 4 hours. This solution is flushed with argon and stored at -rt in a refrigerator (a white precipitate forms after stirring for about 3.5 hours).

Methanol is added and the solution is concentrated under reduced pressure to remove all the methanol. The residue was diluted with 40 □J of water, washed with chloroform (2 times 20+++/X), and the aqueous portion was adjusted to about 1.5 with concentrated hydrochloric acid. The resulting white breath fluid is extracted with ethyl acetate (15+ulXa times). These extracts were combined, washed with water and brine (20 ml each), dried over 1-1 J UNO of sulfuric acid, and concentrated to give a white solid 0.7'20. get. The chloroform layer of J.Kenhachi is 1N.
Re-extract with sodium hydroxide (15d x 2). The aqueous layer was acidified, combined with the previous acidified layer and added with ethyl acetate (
20ml x 2) Okegawa. These extracts were washed with water and brine, dried, concentrated, and a white solid of 0.3
8 (obtain l.

The two portions of solid were combined to yield 1.1.Oq of (±)-8-[(2-(mercabutomethyl)-1-oxo-3-phenylp II-bil]amino]octanoic acid. Melting point 8J~ 8
; 3°C (sintering at 68°C or higher). 19-0.4 of i' L C (silica gel I-, pensene/acid resistance (4:1))
2° elemental analysis, C18■127NO3S, 31 glue value: C, cr4. o6x: ++, 8. o6%:N.

4.1.596: S, 9.5096: SI
I, 9,8096, Actual value: C, (53,7shi6
:+1.7.5ioo;N.

4.1296: S, 91896: Sll
, 9,6696゜Actual h1 Example 12 (top) -11-L (2-(mercaptomethyl)-1
-Production of oxo-3-phenylpropyl]amino]undecanoic acid 1.11-Aminoundecanoic acid methyl nisder hydrochloride (
]:]) Preparation: - 11-aminoundecanoic acid 8 in 50 ml of 9/-
05 g (40 mmol) of thionyl chloride (5.84i < 80 mmol) was added to the reaction/7A'IM
Add dropwise with stirring at a rate such that I is maintained at ~-10°C. After adding the thionyl chloride dropwise, the mixture is allowed to warm to room temperature. The white precipitated product was dissolved by further adding 50 ml of methanol to this mixture,
Stir overnight (Q) at room temperature. The mixture was concentrated under reduced pressure and the resulting white solid was treated twice with ether to give Jl-aminoundecanoic acid methyl ester hydrochloride (1:1) 7.26.
Get V. Melting point 155-158°C.

1), (-2)-] ]-[t2-4 (acetylthio)
Preparation of methyl]-■-ox2:3-phenylpropyl]amino]undecanoic acid methyl ester [ethyl ether of 3-acetylthio-2-benzylpropanoic acid 1437 (6 mmol)], O, nl solution, subxalyl chloride 0 Add .54 ml (6.2 mmol).

The mixture is poured, treated with dimethylformamide (3 drops) of catalyst 1d and stirred for 1 hour in chamber A.

The mixture is concentrated under reduced pressure and the resulting oil is dissolved in 10J of tetrahydrofuran and concentrated under reduced pressure.

Dissolve this residue in 6 ml of methylene chloride and add 11
-Aminoundecanoic acid methyl ester hydrochloride (1:])
11.61 g (6.4 mmol) of diisopropylethylamine and 2.23 ml (128 mmol) of diisopropylethylamine in methylene chloride], added dropwise to a cold (-5°C) solution of l(v) over 10 minutes with stirring.Cold. Place(-5”C)-(2,
51LIllil After stirring 1fl, the mixture is in the chamber l:u'+
Allow to rise to 114 degrees and stir overnight. The mixture is concentrated to a volume of 1.degree., the residue is taken up in 1.00+r+l of ethyl acetate, and the diisopropylethylamine hydrochloride is removed. d1 liquid I O966A: oxyhydrogen) J Liut., water,
59+; Sodium bicarbonate, water and 5096 meals 1'
Next wash with f, i' + water (each, 30 mfx 3 times).

a (7 gaseous layers were dried with thorium oxide, 7F condensed, and a light yellow solid (-+-)-], 1.- [[
2-[(acetinose1)methyl, l-1,--txo-3-phenylpropyl'amine, lunodeca71'1
Tsumedel Nisdel 25g? Do 1. Melting point 64-66℃
.

(', (1)-] 1-C(2-(mercaptomethyl)
-1-1xo-3-phenyldi1]pyru d-amino 1/
Preparation of decanoic acid Nitrogen', j; Surroundings, 1-Note 1) methyl ester product 2.5! (5,74 mm-6/l/) of methanol 25. Dissolve in mt and cool in a water bath. Add 23d (approximately 3 equivalents) of 1N thorium hydroxide (i)) to this solution for 10 minutes.
Drop 71 u per minute (sodium hydroxide total: 1:
(The solution becomes cloudy after addition.) Heat the mixture at 0°C for 10 minutes, and then heat the mixture in the chamber. Allow it to warm up to nf; 3:1 (old J
Stir. Concentrate under reduced pressure to remove all methanol from the mixture. The residue is diluted with 40 ml of water and extracted with 10 ml of chloroform (20 m/x 2 times). The chloroform layer is extracted with 1 J of N hydroxide (20 m, 1. x 2 times). Combine 1 volume of the aqueous extract and add concentrated hydrochloric acid 1)
11 to about 15) 14. The resulting white suspension is extracted with ethyl acetate (4-0 J x 3 times). These extracts were combined and diluted with water and saline (4.0 + i% each).
), dried over Ar, sodium chloride, and concentrated to give 209 g of the egg yolk solid. E crystals. Therefore, dissolve this material in ethyl acetate and obtain ]IJ hge/l/(5ilic AR
・CG-4) Sucking on the small instep? f and apply it to a similar silica-based filler I.

RJI form and ethyl acetate was gradually added to it (
10-4O96ethyl acetate) was dissolved as an eluent to give (-)-tl-((2-(mercaptomethyl)-■-oxy-3-phenylpropyl J amino)/decano f!1121 as a white solid. -777 was obtained, melting point 10.
4-105°C o Tl, R of C (silica gel-1-, beno7ane/vinegar!! [& (4:1)) = 0.51° elemental content (
B, 02□ [133N0:3S, calculated value: C, 6
6,4596:II, 8.7696:N.

3.69%+S, 8.459b: SII, B, 7I9, Actual value: 66.1296: II, 8
．． 7596:N.

3,659b: S* 8.4596: S II
, 8.6796° Example 13 < + )-5-(C2-(mercaptomethyl)-1-
Preparation of oxo-3-phenylp[cobyl]amine]pentamide;1. Preparation of 5-CC(1,1-dimethylethoxy)carbonyl J amine] pennotanoic acid a: -5-aminopenconic acid 293 g (25 mmol) in 1-butanol:water (2:1) 7.5+nI! Add solution (remol). Furthermore, 9 ml of [-butanol:water (2:l) was added and dissolved, and then C-L-butyl dicarbonate 6, Of (
'27.5 mmol) is added in several portions over 1 hour. Add 5 ml of (-butol) to the mixture and stir the thick white slurry for 3.5 days.
Dilute with rrt and extract with hexane (15y, 3x4I). Potassium hydrogen sulfate 3.5. f (water 25 m
Make acidic with l).

The product was diluted with ethyl acetate (25++7X once, 15 m
1 x 2), washed with water and brine, extracted with sodium sulfate I
Dry and evaporate to form a colorless sheet (gradually crystallizes)
Obtain 5.38 g. This was treated with hexane-ethyl ether to give a white crystalline solid with 4.2 cc of 5-cc(x,t-dimethylethoxy)carbonyl]amine]penotanoic acid.
Get 9f/. Melting point: 47-50.5°C.

1) Production of -5-[[(1,1-dimethylethoxy)carbonyl]amino]pentamide 5-(((1,1-
dimethylethoxy)carbonyl]amino J pentanoic acid 2
．． 61! 12 mmol) and N-methylmorborea 1
．． 32 ml (12 mmol) of tetrahydrofuran 1
5+++fu! Add 1. isobutyl chloroformate to the solution (-15°C). ．． 55 ml (12 mmol) is added dropwise over about 5 minutes while stirring vigorously (η) and maintaining the reaction temperature at -25 to -15°C. The mixture is stirred for 12 minutes and a methanol solution of 71k (0°C 10 ml (saturated at room temperature) are added dropwise over a period of 30 minutes at approximately -15 DEG C. The mixture is stirred in the cold for 30 minutes (16 minutes, allowed to warm to room temperature, and stirred overnight). Dilute the i-liquid “Bezei White Town” with water,
Remove the organic solvent and concentrate to 150 ml of ethyl acetate.
Extract with ml. The ethyl acetate solution was washed with water, 10% potassium hydrogen sulfate, water and brine, dried over sodium sulfate and evaporated to give a white solid product 1. , 54 g is obtained. 1W1; point 135-1385°C.

Since the recovery rate was low, the first aqueous extract was concentrated to half a volume and diluted with ethyl acetate (75L++7!X once, 25.,!
, x 3 times). Add acid-resistant ethyl solution to water (10ml 1X
2 times) and saline solution C10mAX 2 times), dried over sodium sulfate, and concentrated to give 0.56 g of white solid (total amount'
2.1 g of product) are obtained. A small amount of the total amount of the product is recrystallized from ethyl acetate to obtain pure 5-([(1,1-dimethylethquin)carbonyl]amino]pentamide. Melting point: 138-1.40°C.

Preparation of (,5-aminopentamide hydrochloride (1:1)) tR to 20 ml of 1.3N hydrogen chloride in n'1 acid.
The solution was left in a room at 111°N for 45 minutes. The solvent is evaporated under reduced pressure and the curved residue is treated with cold ethyl ether to give a hard gum. Approximately 2 ml of methanol was added to the product and the product was triturated, and the fine white powder was collected to give 5-aminopentamide hydrochloride (L:1) 1.18
get g.

d, (±)-5-[2-[(acetylthio)methyl]-
Production of 1-oxo 3-phenylpropyl J amino]pentamide: 1:3-acetylthio-2-benozylpropanoic acid 1°4
:3! (6 mmol) and oxychloride → Noryl O,5
8 ml (6,6 mmol) of ethyl ether 121n
Add 1 drop of trimethylformamide to the l solution. The mixture is stirred between the ribs at room temperature and reduced to elasticity. The residue is dissolved in 5-1.0 ml of tetrahydrofuran in two portions, the final traces of oxalyl chloride (-11) are removed by evaporation, and the pressure is reduced with a vacuum pump for 10 minutes.
7.5 ml of methylene chloride solution of J.
6 mmol) and inoglobylethylamine 2.09 n1
1 (1.2 mmol) in a solution of 15 ml of methylene chloride,
1 drop over 1 hour at 5-10°C. The mixture is stirred in the cold for 1 hour, allowed to warm to room temperature, and stirred for 2 hours. The solvent was evaporated and the υ-1 residue was dissolved in ethyl acetate 200
Dissolved in mlI, water, 596 sodium bicarbonate, water,
1096 potassium hydrogen sulfate, water and brine (approximately 20 ml x 2 times each), dried over sodium sulfate, and concentrated in vacuo to yield 144 g of a white solid. 1
do. Crystallized twice from ethyl acetate-hexane, (±)
-5-((2-1:(acetylthio)methyl)-1-oxo-3-phenylpropyl]amine]bentami+;o
, s6g? 4 Ru.

c, (±)-5-[:[2-(mercaptomethyl)-1
-Production of oxo-3-phenylpropyl]amine]pentamide (±)-5-([2-[(acetylthio)methyl]-1
-Oxo-3-phenylpropyl]amino]pentamide 0.851 (2,5:3 mmol) in methanol 5.
, l solution (0-5°C), add 2.5 liters of 1N sodium hydroxide.
3n+7! (1 portion) is added dropwise over 5 minutes. Remove the water bath and stir the mixture for 1.5 hours. Most of the methanol was evaporated and the residue was diluted with approximately 7 ml of water and diluted with 1N
Adjust to H)ll 7.0 with hydrochloric acid.

The separated isomer was dissolved in ethyl acetate (10 ml, then 20+I
+7! x 3 times)-C extraction. The Ariiso extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to leave a white solid residue of 0.75 f! get. Melting point"12~12
2℃. iTG crystallized once from methanol-water and melting point],
Turn the material between 22.5 and 125°C. This solid h I:
J: Sorikakeru (5ilic ALCC-4), which is concentrated by combining 11 irl and packed with clonoporum.
The column is old. This column was first run in chloroporm at 10%
(±)-5-[[2-(mercaptomethyl)- 0.50 g of 1-oxo-;3-phenylpropylcoamino]pe7tamide was obtained. Melting point 127~
128.5℃ol-1, R(-0,25
(weak tilling).

Elemental analysis, (7□5' 122 N202 S,
Total cod 1 (1 white 'C+ 6 1.1 9 96;
H, 7,5396; N.

9.5]96:S, 10.8996:Sfl, 11.2
396, actual value: C, 60,8896; II, 7.64
96:N.

9.2896;S, 10.8396:Sfl,
11.11%.

Examples 14-45 Using the amino compound shown in column 1 above and the carboxylic acid shown in Q. Obtained. This compound was hydrolyzed to obtain the mercaptoalkanoyl compounds shown in column 1V (the symbols in each formula are shown in Table 1).

■ Column 1 (3゜112N -C11-(CH2), -C-R4R5
- to -5-C112-CIl -C-011111 column] V column Gl-r+ ω N M Ma - 12 Gl M ω 6 To ω Ma n c 1 Mah +"+ Cao N's I:l ? N I ′FI FI Q I:l ” ψ ma.

−〇平0=〒; to lx I+l In the cases of Examples 14 to 35.38 and 43 to 45, the hydrolysis of the acylcaptoalkanoyl Δ ester shown in column 1 (compounds where 4 is hydroxy) or the corresponding mercaptoalkanoylcarboxylic ester (i.e. 1 (compounds where 4 is JI [column (Table 1)
It is effective depending on the conditions in which any one of the ester groups (ester groups shown in 1) is used. The hydroxy protecting group of Example 33 and the amino protecting group shown in Example 45 can be removed following completion of the reaction.

Example 46 (:'-) -5-(1: Preparation of 2-(mercaptomethyl)--1-4xo-3-phenylpropyl]amino]pentanoic acid thorium salt (2-(mercaptomethyl)-1-
Oxo-3-phenylpropyl]amino]pentane l!
[&(I mmol) is dissolved in 50 ml of water.

Add 2 (Lt) of 0.1N aqueous solution of sodium bicarbonate to this, and freeze-dry this aqueous solution. Dissolve this in 1° of water and apply it to a Sephadex chromatography gel G-10 column (5 cm x 60 cm). Elute with water.

Fractions containing the desired product were combined and lyophilized to yield (±)−
5-[(2-(mercaptomethyl)-1-oxo-3-
Phenylpropyl]amino]pentanoic acid sodium salt was obtained.

Example 47 From the following ingredients, per tablet (,!2) -5-(
[2-(Mercaptomethyl)-]-]oxo3phenylpropyl]ami/]pentanoic acid 100 m! ? 1000 tablets containing the following are prepared according to the manufacturing method described below.

Ingredients: (±)-5-([:2-(mercaptomenal)-1-oxo-3-phenylzo[hupyl]amino"pentanoic acid 1
00g, cornstarch 5oy.

7.5g gelatin.

Avicel (Avice!-Microcrystalline cell r'-su) 25
y, 2.5 g of magnesium stearate.

Nanao (±)-5-([2-(mercaptomethyl)-1,
-Jxo-3-phenylpropyl]amino]pentanoic acid and corn starch are mixed with an aqueous gelatin solution.

The mixture was dried and pulverized to produce a fine powder.
become The granules are mixed with Avicel and then magnesium stearate. This mixture was compressed in a tablet crimper to formulate 1000 sintering agents containing 10 Q 1ny of active ingredient per tablet.

Tablets were prepared in the same manner using the compounds of Examples 1 to 4 and 6 to 45 as active ingredients.

'l skin rl'i, l trace! Self-individual E.R.N.K. & Zands, Inc. 1st person B ``Rishiko 111 1 other person Continuing from page 1 ■Int, CI,' Identification code Internal reference number 0 Inventor Methyl・A-onde American stand [Tsutei]
Tsukuken Sark Noro New Chassis, Flinstone, Hemlole 7man

Claims (1)

[Claims] 1. Formula - 1, where -R1 is hydrogen or R5-C-+1 11 1.1 -10 +1 is an integer from 1 to 15 - 1) is an integer from 1 to 4 - III is O or an integer of 1 to 4 - (6 is lower alkyl having 1 to 4 carbon atoms, lower alkoxy having 1 to 4 carbon atoms, lower alkylthio-hydroxy-Cz-Br-1'-amino having 1 to 4 carbon atoms, N11 -lower alkyl (1 to 4 carbon atoms), -N (lower alkyl) 2 (lower alkyl has 1 to 4 carbon atoms) -21, or trifluoromethyl -r is an integer from 1 to 3 (provided that -1 ( 1 is hydrogen-lower alkyl, cycloalkyl or phenyl, "11 is hydrogen, lower alkyl-lower alkoxy or phenyl- and R7 and R8 is each independently combined with hydrogen-lower atom to form the formula: ((1 is O or 1, A is C11-R9-oxygen or N
-R9 and O.1ζ9 form a ring (hydrogen or lower alkyl having 1 to 4 carbon atoms), or a pharmaceutically acceptable salt thereof. 0 0 1 1 amount 11 1 1I 11 I11 is 1 or 2- R6 is methoxy) b-methoxy-Cz-F-hydroxy ~ nitro or amino- R4 is hydroxy-methoxy, -Ni12 or -0-
C1l-C)-C-4(11, ■(□. is hydrogen, straight chain or branched eQ having 1 to 4 carbon atoms)
The compound according to item 1 above, wherein lower alkyl or cyclohexyl-R1□ is a straight chain or branched button lower alkyl having 1 to 4 carbon atoms, and n is an integer of j to 9. 3,! 1) The compound according to Item 1 or 2 of Item 1J, wherein 1 is an integer of 3 to 6. 4, n h) The compound according to item 1 or 2 above, which is 1. n, where 5n is 2; the compound according to Section J or Section 2; The compound according to item 1 or 2 above, wherein 611 is 3. 7. The compound according to item 1 or item 2 above, wherein n is 4. 9, n according to the above item 1 or 2, wherein B, n is 5;
The compound according to item 1 or 2 above, which is 6. The compound according to item 1 or 2 above, wherein IQ and rl are 9. 11. The compound according to any one of items 1 to 10 above, wherein 111ζ1 is hydrogen. 12, the first term to the first term in which R1 is lI3CC-
A compound according to any one of item 0. 13. The compound according to any one of the above items 1 to 12, wherein R2 is benzyl. 141ζ3 or hydrogen, the compound according to any one of items 1 to 13 above. 15, l (the compound according to any one of the above items 1 to 13, in which 3 is benzyl; 16°1 (the compound according to any one of the above items 1 to 13, in which 4 is hydroxy)
A compound according to any one of paragraphs. 17.1 (Compound according to any one of paragraphs 1 to 15 above, wherein 4 is methoxy. 18, Iζ47)) N l '. The compound according to any one of items 1 to 15 above. 19, Formula-1 [In the formula, ko is hydrogen or 1L5C- 1 111 R3 is hydrogen, lower alkyl, -(C1l.) 1.1 peg) 1 ■11 i (I O 11 is an integer from 1 to 15 - P is an integer of 1 to 4; m is 0 or an integer of 1 to 4; R6 is lower alkyl having 1 to 4 carbon atoms; lower alkoxy having 1 to 4 carbon atoms; - Br- F-amitsu-
Nll - lower alkyl (1 to 4 carbon atoms) - N (lower alkyl) 2 (lower alkyl 1 to 4) - ditromata is trifluoro) t-thyl - l is an integer of 1 to 3 (however,
Rc, or hydro: V-cy, methyl, methoxy:/-CI!
or 17 only +6 or 1) - I ( is hydrogen, lower alkyl-cycloalkyl0 or phenyl, technique is hydrogen-lower alkyl-mono-lower alkoxy or phenyl, and 7 and 8 are respectively independently hydrogen-4A class a1+
ij together with the formula: (q is 0 or 1, A is CLI -R9-oxygen or N
I'-9, and 1 (where 9 is hydrogen or lower alkyl having J to 4 carbon atoms) forming a ring J or a pharmaceutically acceptable salt thereof as an active ingredient. One-place sedative for animals.