JPS6289697A - Substituted dipeptide amide - 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 Field of the Invention This invention relates to novel dipeptide amides. In particular, it relates to novel dipeptide derivatives of formula (1) useful as analgesics or antihypertensive agents.

BACKGROUND OF THE INVENTION In 1975, the pentapeptide, methionine enkephalin, was discovered by Hughea et al. (Nature, 25 B, 5
77.1975). This peptide has been found in many brain regions where it may act as a neurotransmitter or neuromodulator in the central nociceptive system. This natural peptide stereospecifically binds to partially purified brain obi-trisesota sites (e.g., Br
adberry et al., Hature, 260.793.1
976]. Although this natural pedicule is highly active in bioassays of hypnotic activity, it exhibits weak and transient analgesic activity when injected directly into the rat brain (e.g., Be
llugi et al., Nature, 260.625.19
76).

To overcome the lack of in ViVO activity, many researchers have made numerous modifications to the methionine cephalin structure. For example, changing the di-standal glycine with a D-amino acid, N-methylating L-tyrosine, substituting 4-phenylalanine with methyl or halo, changing the C-terminal group, etc., and various properties and abilities. enkephalin derivatives have been obtained.

Kin et al. “Peptide Henlistr 7, 1
981 J, 65-70. Protein Research Institute, Osaka (19B
2) is a tripeptide alkylamide such as N-methyltyrosine (D) methionine sulfoxide glycine-methylphenethylamide, (2) and thicine-(D) methionine sulfoxide phenylzolobylamide (3); The synthesis and activity of short chain enkephalin-like peptides were demonstrated.

'Vaurek et al., Peptides 2.303.1
981)'! Enkephalin analog, dipezotide tyrosine-D-alanine-phenylzorozalamik” (
Tyr-(D)Ala-PPA) (4) was disclosed.

When compared to Vabrek's compound, the compound of the present invention has
It has unexpected and surprising properties. The present invention provides novel enkephalin derivatives that exhibit improved analgesic-like activity upon oral and parenteral administration. Additionally, US Pat. No. 4,316,892 relates to methionine enkephalin derivatives useful as analgesics.

(In the formula, R1 is a straight chain or branched lower alkyl, 0002
7 Az * k, hydrogen, 0C02 aryl, 00 O
N is alkyl or aryl, R2 and R3 are hydrogen, lower alkyl, halogeno or Cl-Os alkoxy, R4, R5, R6, R7 are the same or different and represent hydrogen or lower alkyl, and R7 and R1″z (OHa), -8-(OH2)mOH3 (J, m is 0-5, Z k'! C1-2), and RIO is hydrogen, lower alkyl, cyclic, bicyclic, bicyclic or tetracyclic cx
-"10 alkyl, alkylcarboxylalkyl)
X (OH2)nA (A is co2 R11 R
lm is hydrogen or lower alkyl, n is 1 to 4], or HIO is and R9 and RIO together can represent , 1m-substituted phenyl (11 substituents are F%N(CH3)2, CO2R13, ON, OH, heteroaryl, cycloalkyl or substituted cycloalkyl), R12 and R13 are hydrogen or lower alkyl Yes, xl'za%OR%OH2 is absent, Y is (3, OH, OH2 or heteroatom 0, S
, NH, B and D representing phenyl share the 2-position with each other, V represents an asymmetric carbon that can be racemic, 9-form, or L-form, and W represents R4 and R5 are not the same. ,
When the racemic or 9-isomer can take the L-isomer, it shows an asymmetric carbon], and a pharmaceutically acceptable acid addition salt.

Desirable examples of water ratio compounds are: (wherein R1 is cl-c, lower alkyl, hydroxy,
lower alkoxy or substituted or unsubstituted aralkoxy, R2 is hydrogen, halogeno, cl-c4 lower alkyl or lower alkoxy, R3 is hydrogen, 01-
Oa lower alkyl, lower alkoxy, also) @Haol
'C: Ali, R', R', R', R' are the same or different and are hydrogen, lower alkyl, alkenyl or) ial-c6 cycloalkylalkyl,
R7 represents 01-a6 lower alkyl, and when R2 and R3 represent hydrogen or lower alkyl, R4, R6 or R9
at least one of is not hydrogen or R1 is lower alkyl or lower alkyl; branched-chain lower alkoxy-substituted phenyl] and is a pharmaceutically acceptable acid addition salt. All optically active compounds are racemates, pairs of diastereomers, or resolved herastereomers.

Preferred embodiments are compounds having the general formula (wherein each symbol is as defined above, except that R2 and R3 are lower alkyl or norodane) and pharmaceutically acceptable acid addition salts. be.

More desirable are compounds having the general formula (wherein each symbol is as defined above) and pharmaceutically acceptable acid addition salts.

Further preferred embodiments are described in columns.

The present invention is based on the general formula (wherein HL is lower alkoxy or -〇-(OH2)n
-Phenyl (this phenyl group, -No2, -
rIL may be substituted with ON, -NH2, or lower alkyl, n is 1 to 4), RW and R3 are lower alkyl, halogen, lower alkoxy, or R2 and R
One of 3 is hydrogen, the other is lower alkyl, lower alkoxy or halogen, R', R5, R7, R8 and R9 are hydrogen, lower alkyl, lower alkenyl or 't
t-(OHz)m-cycloalkyl (m is 1-4 and cycloalkyl has 3-8 carbon atoms) and R↓0 is -(OH2)p-phenyl (p is 1-4); 4)
, ■ indicates a racemic form or D form, A indicates an asymmetric carbon that can be read as a D form, and W indicates an asymmetric carbon when R7 and R8 are not the same and can indicate a racemic form, a D form, or a D form. ] and pharmaceutically acceptable acidic 710 salts.

In the present invention, R1 is hydroxy, provided that R4, R5,
Compounds in which at least one of R6 or 61 R9 is lower alkyl are also included.

A desirable embodiment of the present invention is a general formula (wherein R2 and R3 are both methyl, hydrogen or chloro, R1 is -0-(C!H2)-phenyl (phenyl is a halogen, -No2, -ON, -NH2 or lower alkyl, and n is 1 to 4) and pharmaceutically acceptable acid addition salts.

A further preferred embodiment is a compound having the general formula where one of R', R5, R6 and R9 is lower alkyl and the other is hydrogen.

Lower alkyl refers to Cl-C6 straight-chain or branched alkyl, such as methyl, ethyl, propyl, inpropyl, butyl, inbutyl, t-butyl, pentyl, hexyl and its isomers.

Lower alkoxy refers to cl-c6 alkoxy,
It has the above lower alkyl moiety. Lower alkenyl is the above lower alkyl spanning one double bond. Optionally substituted phenyl refers to phenyl substituted with one or more specified groups in the oron, meta or para position.

DESCRIPTION OF SPECIFIC EMBODIMENTS The compounds of the present invention and the compounds shown in Examples 1-68 can be prepared by either of two methods shown in Reaction Scheme I Route A and Reaction Scheme II Route B. Many compounds can be prepared by either route, which differs primarily in the reaction order.

Route A in Reaction Diagram I and Route B in Reaction Diagram II show two methods for producing the compounds of the present invention. In the AiC pathway, the blocked amino acid conductor X is reacted with a dialkylamine by mixed anhydride coupling, and the blocking group X is H2
/Pd reduction to obtain amide ■ process. Blocked tyrosine derivative ■Ae is converted into amide by mixed anhydride method■
Let it react with engineering! 4' is obtained, which is separated into thea stereomers and separately blocked to obtain a compound of formula (2).

Reaction Diagram ■ In route B, the ester of the amino acid derivative is coupled with the ester by mixed anhydrous coupling to obtain the ester W. This ester is divided into diastereomers. For example, if XV is a D amino acid derivative,
When AE is a DL tyrosine derivative, %DD and LD diastereomers are obtained. The appropriate dialkylamine is then coupled to the separated diastereomers at <RTIgt;C,</RTI> and the product deblocked to provide a compound of Formula I.

In reaction diagrams I and 2, BOC means t-butoxycarbonyl, and RL -R10 is as defined above. 2 may be BOC or carbobenzoxy or other suitable blocking agent.

Diastereomers are separated by standard techniques such as crystallization or column chromatography.

100 〇Higawa
.

Mountain

[Brief explanation of drawings]

Figure 1 shows route A for the synthesis of substituted dipezotide amides,
Amino acid-amine mixed anhydrous coupling initially involves the mixing
Anhydrous coupling occurs followed by a substituted second amino acid.
. The 11 substituents are as described above. Figure 2 shows route B for the synthesis of 11111L dibepti V amide.
, and the mixed anhydrous coupling of 11-dipezotide was initially
The mixed anhydrous coupling is followed by the amine. The substituents are as described above. Route A In route A, the blocked arbitrary substitution (D)Ala is
Eri N-substituted phenyl-probylamine in mixed anhydride reaction
Coupling with (Compound 1). Mixed anhydrous reaction cup
Pulling compound crab and Z-(D)Ala-OH are compounds■
becomes. 2 is carbobenzoxy or other similar block
Indicates a group. Compound I was deblocked using hydrogen/pd in ethanol.
to obtain compound crab V. Blocked arbitrary permutation (D,
L or more L) Tyrosine (compound 1) is mixed anhydrous.
Depending on the reaction, it is coupled with Compound 1 to form a racemic compound.
Mixtures of shear stereomers that can be separated when using
Compound V, which is a compound, is obtained. Substituted tyrosine (compound EE) is R1 is and 20x,
C1-0, lower alkyl such as methyl, ethyl, n-propylene
lopyl, inpropyl, n-7”chill, cyclozorogyl
Methyl, cyclobutyl, inbutyl or θθC, butyl
, its unsaturated analogous groups, lower alkoxy, substituted or unsubstituted
Substituted aralkoxy examples: evahensyloxy, 1-phenylene
-ethoxy, orne, meta- or para-lower alkyl
Phenylmethoxy, 0-lm-, p-halophenylmeth
Oxygen (halo is like fluorine, chlorine, bromine or iodine)
], 0-1m-1p-substituted phenylmeth
(11m group is nitro, amino, cyano)
and R2 is the above-mentioned 01-04 lower alkyl, lower alkyl
R3 is hydrogen, halodane
, straight chain or branched chain 01-C5 alkyl or lower alkyl
xy and the other substituents listed above.
nothing. Compound V consists of separable diastereomers V and V.
It can be used as a mixture of insects to catch insects. The separation is the result described in Example 5.
It is carried out by crystal ratio or chromatography. Each diaster
Compound shown in G2 after unblocking with Omer HCJ
Get Veeee and Engineering X. Route B In route B, blocked amino e<compound eee
) with optionally substituted (D) alanine-methyl ester
Coupling by a mixed anhydride reaction produces dipeptides (
Compound X) is obtained. The blocked tyrosine derivative is DL
In some cases, the combination of two diastereomers
Represented by thing X. Dividing diastereomers X and X
The fractionated crystal ratio method is used to determine the Saponify each isomer
to obtain the free acid. Each of these free acids is subjected to a mixed anhydride reaction.
Coupled separately with more compound crabs, diastereo
Obtain MaV engineering and VAE. Each of these compounds, HCJ-
Unblock with and the final generation vlJx eeee and engineering
get. Modified Alanine Pathway Another compound of the present invention can be
Replaced with NHOR7R800 (D%L or DL)
Synthesized with alanine. Both Rf and R8 come with R3VC.
As mentioned above, hydrogen, straight chain or branched chain C1-0, lower a
Show Lukiru. Following the manipulation of routes A and B, methyl,
tyl, progyl, butyl, pentyl or hexyl (i1
Modification of alanine to remove asymmetric carbon due to the presence of m group
to produce a compound. There are Rヮ and R8 groups that are not the same
If so, the asymmetric carbon may be retained and may be D, L or DL. The alanine substitutes produced in this series are other
and L amino fR such as leucine, inleucine and
It's phosphorus. Modified route A and B for attaching NHOR7R800
If necessary, the racemic mixture may be added enantiomerically.
This can be avoided by using pure compounds as raw materials. child
The usefulness of these compounds will be obvious to those skilled in the art. The art of using these oppositely pure forms and the division
This results in a mixture of isomers that is difficult to separate. The analgesic activity of the compounds of the present invention is determined by the writhing test.
This is proven by The analgesic activity of the representative compound is Enkef.
alin, tyrosine-(D)-alanine-phenylpropyl
Comparisons were made with those of Ruamide's disclosed analogs. Su River Alpino male mouse (CD-1/HAM/IL
R) was used. Test compound (0,1,d/10y body weight
) 0.025 30 minutes after subcutaneous or gastrointestinal administration
% (W/V) phenyl pen quinone intraperitoneally injected (0
, 1m/body weight 10g). After 5 minutes, move each mouse to a large
Number of rises after placing in a glass beaker for 10 minutes
was measured. The rise involves flexion of the back, extension of the hind legs, and
Consists of strong contractions of the abdominal muscles. By phenylbenzoquinone
Records of the agony caused and the salt water treatment that day
If the average number of writhes performed is less than 1/2, this test
The test compounds were considered to be analgesic. The result is the test
Number of mice in which the compound showed analgesic properties (maybe in 10)
). The number of writhing in the treatment group is unidirectional.
of writhing in the saline-treated control group, as measured by mutational analysis of
If the test compound is significantly lower than the
evaluated. Initial test dose: 10 μ/10 mice
If writhing is suppressed in 6 or more of the animals, additional VO administration
Evaluate the effect of volume and calculate the EDso value using the maximum likelihood function.
I calculated it. ``H-Nalozo'' that isolates or relaxes the scepter.
The ability to displace nθ bonds was evaluated. charr
Obtained from the S.I.J. Barr Institute (Borise, Miami).
Male rat (Cr1: CD(SD)BR) k”:, neck
g (killed by S rearrangement. Purified homogenization of receptor membranes)
The output is based on the method of Chang and Quatreca8a8.
Prepared from the brain (LJ, C!hang and P, 0u
atrecasas, MultipleOpiate
ReCeptOre: znkephalin An
d MorphineBind To Recepto
rs of Different Specifications
Ty. J. Biol Chem, 254.2610-26
18 (1979)). Brain in 10 volumes of 0.32M sucrose
to homogenize and centrifuge twice for 15 minutes at 6.00'OX, F.
Ta. Centrifuge the supernatant fluid for 30 minutes in ao, ooox, p, and then
6. Resuspend in 5 mM) Lith-H (J).
Centrifuged at 000×g. Supernatant liquid is 40.0OOX, 9
It was centrifuged at This resuspended pellet (5mM Tris-HCJ
) was centrifuged twice. Add the final pellet to 2 volumes of 5Q
mM Trix HCJ (pH 7,4) IC Teli
ffi L ta. The homogenate was prepared by the method of Kotzhaki and G111.
Tested for protein wit (R, F, tzhak
i and D, M, G111. A Micro-
Biuret Methoa for Estimat
ingProteins, Anal, Bioch
em, 9.401-410, (19<54)). To couple the test compound to the recedator preparation, Pe
rt and 5n7aer (C, B, Pert and S,
H.
Properties of putter bonds. proc, Natl, ACad
, SC1, 70, 2243-2247.1973)
Measured using a modified method. This resetter test was performed using a final concentration of 1 nM H-NalO.
Performed using XOnθ and 0.5■ protein homogenate.
It was. Levorphanol (I X 'I 0-5M
) was used as a non-binding surrogate. Final concentration of test 1 compound
The degree is 10-5M. The test is 0.05 M)
The test was carried out using acL (pH 7,4). The overall test status is
It was 1.0rnt. The sample was incubated at 25°C for 60 minutes, and then heated using whatman GF/
C. Filter through glass fiber and cool with water-cooled buffer 4-
I rinsed it twice. Air dry the filter at 50°C for 30 minutes.
Ta. After drying, add 10-PO2 to the vial to increase radioactivity.
Sex is count activity 48 tracer analysis Mark
Measured using a liquid scintillation counter. H-Na1OXOne specific binding to Obi-21 triceptor
The concentration of the test compound that suppressed the
It was obtained from a logarithmic plot of the degree-sensitivity curve. Compounds are available in tablets, capsules, gills, powders, granules, and suspensions.
It can be administered orally in the form of a solution. Administer rectally or vaginally in the form of herbal medicine or bougie
You can also do that. Using molds known in medical technology, the eye
The drug may be introduced intraperitoneally, subcutaneously or intramuscularly. general
The preferred mode of administration is oral. Effective, non-toxic compounds are used for treatment. Book
The dosing principle for treatment is to suppress symptoms with the invented compound.
Species, age, weight, notes, and condition of the animal, severity of symptoms
The route of administration of the compound used is determined by various factors.
It will be done. The doctor or veterinarian may administer sedation to limit the severity of the condition.
Effective doses of pain medication can be readily determined. the
In this case, administer a relatively small amount at first and gradually increase the
The dosage will be increased until it is achieved. Compounds of formula I can be prepared as pharmaceutically acceptable acidic 710 salts, e.g.
hydrochloride, hydrobromide, noidroiodide,
sulfate, phosphate, acetate, zolopionate, lactate,
maleate, malate, conolinate, tartrate, etc.
It can be administered as Furthermore, this compound is suitable for
It may also be administered in a hydrated form. Compounds of the invention can be prepared by those skilled in the art (in a number of known ways).
can be manufactured. For example, combine specific amino acids
The reaction order to obtain the compound of formula I is generally less important.
is rx < , in principle a convenient law or maximum yield
Choose by clothes. Also, the selection of active reagents and amino acid or
The conditions for binding pezotide are limited to those described in this specification.
Not done. Peptide intermediates and compounds where possible
, by crystallization method, or by column chromatography method.
Refining plays a role. Additionally, racemic amino acids are used as starting materials.
When used as a quality product, intermediates and finished products are subjected to column chromatography.
Can be separated into diastereomers by roughy
. The matters described herein and the drawings are used to produce the compounds of the present invention.
Two possible methods that can be used to do this are shown below. Total NMR is expressed as ppm from internal TM8 standard.
Proton at 80MHz in DMSO with chemical shift of J
It's magnetic resonance. All optical rotations are in methanol.
be. (Solvent) IJ Zwingha was carried out under reduced pressure at 35° or less.
. Example 1 N-[(1,1-dimethylethoxy]carvnyl]-0
,2,6-dimethyl-DL-tyrosine [1 BOC-2,6-dimethyl fo'/n (3,0 g, 9
．． 100-70 mmol) was prevented from absorbing water in a drying tube.
Dimethylformamide for 17 hours in a round bottom single diameter flask.
(DMF) (5Dent)
(6,8B, 9.48.5 mmol) and potassium carbonate
(5.36 g, 38.8 mmol) and stirred. reaction mixture
The compound was partitioned between water and diethyl ether. Aqueous phase
Wash twice with water, combine the organic fractions, and dehydrate (
MllllO+) L, filter and strip to white solid
did. NMR: J 3.51 and 6.66 with methoxy monomer
One line. 0-Methyl-BO (!-2,6-dimethyltyrosine
Tyl ester (directly from the above reaction, 9.7 mmol, yielded
The rate is quantitative) is dissolved in methanol in a bath of 70-], and in a water bath.
Cooled. HaoH (3.1 g, 77.6 mmol)
Water bath solution (20-) was added. The mixture was stirred for 3 hours. Silica Sly R TLC (1:1 Skelly B
: Ethyl acetate KtOA (according to
Ta. KH8O of water (75+d), (10,6 &, 77.
6 mmol bath solution was added. Strain the mixture to a low volume.
methanol was removed, CH2 (J2 (chloride)
Extracted twice with methylene). organic fractions together
Dehydrated (MgSOt) and stripped through R.
Ta. The density was 2.6&. NMR: Only one methoxy single line at J 5.66. Example 2 0.2.6-dolimethyl-DL-tyrosyl-N-[3-
Phenylpropyl]-D-alaninamide, monohydrochloride o/CH3 Magnetic stirrer, thermometer, dropping funnel (pressure balance
) and a 100 m/3-necked round-bottom flask with a Y-tube.
became. A Y-tube was connected to the N2 population and the drying tube outlet. system
was flushed with N2. 0H2CL2 (0-methyA/-BOC-21 in 30-ton
6-dimethyltyrosine (2.52 g, 7.79 mmol
) was increased by 710. 5A molecular sieve (2, 9, 8-12 mesh)
(Tsushiyu) was released. The reaction mixture was cooled to -15°;
N-methylmorpholine (D-86mt, 7.79 mmol)
710 1 ko. Warming the reaction mixture to +5°
Cooled to -60°. Inbutyl chloroformate (1
, 02 m/, 7.79 mmol). This hula
Immerse the Sco into a water bath (0°) and carry out the reaction at 0° for 60 minutes.
It was. Then immerse the flask in a dry ice/acetone bath.
Soaked and cooled to -70°. N-methylmorpholine (0
, 86 ml, 7.79 mmol), 0H2Cf
D-alanylphenylpropyla in z (10ml)
Midohydrochloride (1,89,9,7,79 mmol) was added dropwise.
and the reaction temperature was maintained at -55° or below. Sole η mouth
After completion, the reaction mixture was warmed to room temperature for 7 JO and then heated for an additional 1.5 JO.
Stir for hours. The reaction mixture was filtered. The filtrate is 0.5
Washed with MxHso. Refresh the generated aqueous layer with rLCH2
Washed with CL2. Combine organic fractions and dehydrate
MgSO3), filter and stir until a stiff foam forms (4,5
1, &) Stripped. This substance is elm silica
It was purified by column chromatography. The syneresis liquid is C
H2Cl2: Ethanol (2B): NH,OHcon
c, (98: 2: 0.1) Tea ivy. The product (4,45,?) was dissolved in glacial acetic acid (50-),
6.8 N H! in dioxane (12d)! processed with J.
. After reacting for 1 hour at room temperature, the mixture is reduced to a syrupy state.
Stripped. Take a bath in this 7° mail
Filter, strip and dilute with diethyl ether.
Both were crushed repeatedly. The generated solid is placed in a vacuum desiccator.
Dehydration gave the product hydrochloride 172 H20. 024H
Elemental analysis of 33N303・HCj l/2H20 (mw
457.02):C63,08:a7.72:H9,1
9:C10,7<S. Actual value 062.95: H7,
37: N 8.92: (j7.79゜[α]=+
29.7°. NMR: Diastereomer mixture has alanylmethyl group (
J O-88, d - J = 7 Hz and Bu 1.16
゜d, J=7tlz), methoxy functional group (, r3.61
8: J 3.6θ days) for two signals and chi
Regarding the Rosyl ring CJ6.508: J6.55 B)
shows 3.5 protons. AJ 3 o, 2,6-drimethyltyrosyl-N-(3-phenyl
Propyl)-D-Alanine Amyr Product of Example 2 800+
+ CHCJ-3 as a vit release agent: Ethanol 2 B
: Using NH40H (Cone, ), Whatm
Column chromatograph with anpartisil 20 column
Offered to Rafi. The first fraction eluted is shown below.
Retained for further chromatography. the next 7 la
The cushion is made of pure substance, dry strung, and 1
Vacuum for 6 hours? After dehydration with a dicator, the free base is 1/,!
(20 was obtained. C24H33N303 ・l/4H20
Theoretical value of (mW416.05) c 69.29: H
8, 12; N 10.0° Actual value 069.30: H
8,45: H9,97° [α]. =-37,8°. N
MR: Alanylmethyl group J 1.21 d , 5 =
7Hz; methoxy, r3. s6s:3.5-diH
/Tyrosine:, I'6.5380 Example 4 0.2.6-)limethyltyrosyl-N-(3-7ale
Derogyl)-D-alanine ami-1HJ3 (see above)
The first fraction for the product preparation of cHcz
3: Ethanol: Use the eluent of NH, 0Hconc.
Applicable to Merck silica columns. Concentrate the first isomer
The mixture was evaporated to dryness to obtain the free base'/4H2o. 024H33
N303 l/4 H2o (mw 416-04)
Theoretical value 069.29; H8,12: N 10.1
0゜Real 411 [Ea69. a2: H8, 31; H9,
88° [α], = 176.2°. NMR: J 1.0
6. d, : Alanylmethylsigna at J=71Jz
Le:f! Methoxy at 1.668; Tiro at J 6.54θ
3.5-diH of syn. f2su5 0-ethyl-2,6-dimethyl-DL-tyrosyl-N-
(3-phenyl)-D-alaninamide, acetate, hydrochloric acid
Salt (4:3:5) Boc-266-dimethyltyrosine (1,5,V,4
．． 85 mmol] to ethyl iodide (3
, 78 g, 24.24 mmol) and potassium carbonate (2,
68.V, 19.59 mmol). generation
The bunny water splitting of Stell was carried out as in Example 1. The mixed anhydrous synthesis of the BOC-protected title compound is as in Example 2.
I went to sea urchin. The Boc-dipezotide amide produced is 1
．． 1.1-) Lichloro2.2.2-Trifluoroethane
and inzolopanol, and elm silica.
Purified by ram chromatography. The purified diastereomeric mixture was prepared as described in Example 2.
The mixture was treated with H(J-dioxane) in glacial acetic acid.
Dissolve in methanol and filter through Celite to remove some methanol.
The capacity was partially reduced by removing the tube. The resulting solution was lyophilized and the compound was expressed as an acetic acid-water solvate.
I got something. c251 (351'J3o3' 1-1/4HCj,
3/4C! H3O02H'/8 Hz0 (mw 518
, 443 Theoretical value C<Sl, 39:H7,68;Na, 11
:(J8.55 Actual value a 61.09: H7,28; N 8.
28:CL 8.54 [α]p=+1 i, sQ, NMR:, ro, ssa
, J=7Hz, I'1.14d, 5=7■2
Nylmethyl signal, 3,5-din of tyrosine
J6.45 A, J, 6.53A; Ethoxy functional group -
0CR2-J3.85 q, I=7H3 knee 0H3
J1.25t, J=7H3゜voice j6 Boa-2,6-dimethyltyrosine (1.5g, 4.
90 mmol) in DMF as described in Example 1.
In the presence of potassium (2,70,9,19,6 mmol)
Improgyl iodide (4.16 g, 24.5 mmol) and
Made it react. After 24 hours, add innorovir iodide to the device.
and 1.25 gx2co3 were added. Another 24 hours
After the reaction, the mixture was treated as described above and the mixture was dissolved in ethyl acetate.
column on Elm silica using hexane eluent.
It was subjected to romatography. NMR of the product shows phenolic inpropyl ether
Restrictive rotation of functional groups Cl O, 981, double at T=7H3
line double, 6 protons). Beauty salon at Jl, 09
Ruin foV! functional signal (double line, J = 7
Hz) indicates free rotation. This substance was administered directly
. Bis-inpropyl ester-ether (1,3y,3
．． 21 mmol) as in Example 1 (Naoa (1,03I
, 25.7 mmol) and Improgyl ether
The free acid (1.0 g) was obtained. The Improgyl ether free acid was prepared as described in Example 2.
The Boa-protected dipeptide amines were treated under anhydrous conditions.
Mido (ether-acid 1.Ol, 2.75 mmol: N-
Methylmorpholine 0.32, d, 2.89 mmol;
Inbutyl chloroformate 0.37d, 2.84 mm
Mol: (D) alanyl phenylprogylamide 0.60
1.2.89 mmol) was obtained. In this case, (D)
With nylphenylpropylamide as the free base, HCj
Used not as salt. Therefore, N-methyl mol
Hollin's second addition 710 was unnecessary. Product 1.
5g was evaporated using methanol-chloroform eluent.
It was subjected to column chromatography using Lucilica. This purification
The two diastereomers are separated by
In-F) and a slow material (In-8) were obtained. Each was used separately in the next step. Dissolve pure Ia-F (494fn?) in glacial acetic acid (5-)
and dioxane/HCj (6,8N, 2 ml
) and processed as in Example 2. The product is 026
H37N303・1-'/8HCL・l/2 Hz0
Isolated as mW 489.62. Theoretical value c63.78: u8.05; Na, 58: C
10,15 Actual value C63,60: H7,95: N 8.35
:C10,93 [αID = +104-2゜Example 7 2.6-dimethyl-(1-methylethyl)tyrosyl
-N-(-3-phenylpropyl)-D-alanine amino
Pure in-5 (440 µg) of Hydrochloride (8:11) 6 was treated in the same manner as in Example 6.
C26H37N303・1-”/B HCL
1-l/B H20 (mw510.00) was obtained. Theoretical value a61.23: a8.03: H8,24; C1
9,56 Actual σ1 [C! 61.50:H8,01:N entered
96 ;C,! 9.20 [α'], =-73,3°NMR: Soil pr methyl J 1.19 d, , T=6
Hz; Alanylmethyl J 1.15 d, J=7H
z0 Example 8 N-((1,1-)*methylethoxy)carbonyl]-
〇-Methyl-L-tyrosyl-N-(6-phenylpropylene)
)-D-alaninamide H3 13oc-L-tyrosine (commercial product, ioy, 35.6
mmol) DMF(150-) as described in Example 1Vc
Medium OH3 (25.3 g, 177.9 mmol) and
treated with 2003 (19.7 g, 142.4 mmol)
I understood. The NMR signal of the product (9,68&) is '3
．． 7 [] (phenolic methyl) and, j3.608 (
methyl ester) and f 6.80 d , J=8
tlz and J7.11d, aromatic protons at J = 8Hz.
Showing Gunar. 0-Methyl-Boa-L-tyrosine methyl ester (
9,68! ! , 65.6 mmol) is NaO as in Example 1.
H (11,411,284-8 mmol). The product was analyzed by NMR on J3/70 days (phenol injection methyl).
Show me the signal. The free acid (8,34,!V, 30.4 mmol) of Example 2
Like, N-methylmorpholine (3,08jJ, 30.
4 mmol), inbutyl chloroformate (4,15
, 9, 30, 4 mmol) and D-alanylphenyl
Zolopyramide (free base, 6.28.9, 30.4 mi)
treated with Rimol). The resulting oil is crystallized as a mixture of diastereomers.
I got the notation encounter. C27H37N305 (mW 483, 61
) [α]D=+63.1° Theory 1 straight c, 67
．． 06; H7,71; H8,69 real song 'I + direct
C! 67.18;H7,84:H8,79NMR
:ome J 3.69 :Aromatic proton/Ty
r:, r6.78d, J=8H2; J”7.13d,
J=8 [(z: Boa methi, J 1,3 Q s
, D-Ala methylbu 1.09, J = 711z
. ]9 0-Methyl-L-tyrosyl-N-(6-phenylzolobysyl)
)-D-alaninamide j 1 hydrochloride H3°/fJ8 (3,9,6・21 mmol) in Example 2
As described, glacial acetic acid (60-ton and 6.8 N Hci-
Treatment with dioxane (8rnt) yielded the desired hydrochloride salt.
Ta. c22a29N3o3・Hcp (mw 419, 9
5) [αII) = 144.90° Theoretical value 062.92:H7,20:N10.01:C
J 8.42 Actual value 062.54:H7,15;N9.78;Cf
8.39 NMR: oMe J 3.71 s; D-a
layte J 1.05 d. J=8Hz. Ga1O N, 0,2.6-tetramethyltyrosyl-N-(3-ph)
enylpropyl)-D-7 lanine 7mide. Hydrochloride (4:5), C, H3 ■ Boa-2,6-cystyltyrosine C0,7ri, 9
．． 2.36 mmol] in 100-DMF in a round bottom flask.
(20,/). Pentane-washed NaH (9,
43 mmol) was added. Attach a drying tube to the flask.
The mixture was stirred. After 30 minutes, methyl iodide (2,34
, @, 16.5 mmol] in 8 mouthfuls. mix for 4 hours
Stir and further add 3 OH (2,2B!J, 16.1mm)
lJ mole] was increased by 710. After another 1.5 hours, NaH (
3.33 mmol) and the mixture was stirred overnight.
. The mixture was partitioned between water and petroleum ether. Wash the aqueous phase with fresh petroleum ether and combine the organic phases.
, dehydrated Mg5O<), filtered and stripped
. The resulting oil was treated with ethyl acetate/5ke11y B as a bath release agent.
was used for column chromatography on EMF silica.
. This material was used directly. 0*N-dimethyl-2,6-cystyltyrosine-
Example of methyl ester (0.66N, 1.88 mmol)
1 no like < NaOH (0,60 &, 15.0617
mol) to give the free acid (0,54,9). N.M.
R: OMθ signal at J 3-668: at J2.59d
N-Mθ signal: Ji, t-bu signal at 28a. N-Me and t-bu signals form a doublet due to restricted rotation.
It is. Each signal collapses into a single line at high temperature (70°)
. 0,N-dimethyl-2,6-cystyltyrosine (0,5
4,9,1,60 mmol) is N-methyl as in Example 2.
Morpholine (0.32!!, 3.20 mmol). Inbutiruku ao home) (0,22,9,1,60
millimoles] and (D) alanyl phenylpropyl amine
treated with hydrochloride. 0.82.9 of the product in ethyl acetate
/Whatman MAG20 using hexane bath release agent
It was subjected to column chromatography on silica. Splitting the two diastereomers, the first (in-F)
, the first isomer and the later (in-8), the last isomer
I got a sex body. This early isomer (In-F, 0.1311) was prepared as in Example 2.
Dioxane (2.5mj) in ice vinegar! (10m) and 6.
Treated with 8N HtJ. Dissolve the produced solids in water,
Filtration through Celite and lyophilization gave the product. C25H35NzOzl-”/4H(J・H2O(mw
439, i7) Theoretical value 061.39:H7,
88: N8.59; ci9.06 Actual value 061.50; H746; N 8.43
:'49.36 α)9 = -73,3°NMR: OMeJ 3.59 s; N-ue J
5.04m; D-Ala methyl J 1-15d,
J=7Hz. Shio: 11 fJ, 0, 2, 6-tetramethyltyrosyl-N
-(3-phenylpropyl)-D-alanine amino♂. 1 Hydrochloride Example 10 The slow phase difference of C-in-8,0,18#) is Example 2
glacial acetic acid (IDmt) and 6.8 N MCI -
Treated with dioxane (2°5-). The resulting solids are treated with an aqueous solution.
Dissolved in tanol. Reduce volume of solution and lyophilize
I let it happen. The generated solid is dissolved/suspended in methylene chloride VC6.
I let it happen. Diluted with ether and filtered the mixture.
. Concentrate and solidify liquid g, dry in a vacuum desiccator, and separate.
I left it overnight for my child. Generation 911 f'L N i[
20) C25H35N303 ・HCL ・Yo/2
H2O (mW471.04). Theoretical value C63,75:n7.92:Na,92;C2
0.53 Actual value 063.85:H7,73:Na, 81:C
20,71 [α]=+94°NMR: aMo J 3.66 s: NMe
f 3.01 d, y = 6Hz: D-Al
aMethi k 10-89 d, J=7Hz. Example 12 N,2.6-)-tyrosyl-N-(3-phenylpropyl
)-DL-tyrosyl-N-(3-7enylpropyl)
-D-alaninamide, monohydrochloride H H2CHOL Boa -2,6-dimethyltyrosine (5,0,9,1
6.2 mmol) was dissolved in DMF (100 ml).
, K2CO3 (6.69 g, 48.5 mmol)
Ta. The mixture was stirred under a drying tube in a 250-mL single-headed round-bottomed flask.
Ta. Odor 1hibenzyl (11,1,9,64,6 mmol
) and the mixture was stirred for 24 hours. Even more odor fhibe
200 mmol (5,46,9,61,9 mmol)
3 (3,4jl, 8 mouthfuls of 24.6 mmol, and more
Stirred for 24 hours. The mixture was then partitioned between water and ether.
did. The aqueous phase was washed with ether. Combine the organic phases;
Dehydrated (MgSOa) L, filtered and strung
, an oil was obtained. Shake this oil with petroleum ether
Ta. This mixture was seeded and rapidly crystallized. N.M.
R: Benzol proton (4 protons L/a, 99s, total
Aromatic integration 12 zoa tons. 0-benzyl-Boa-2,6-dimethyltyrosinpe
Dyl ester (1,73,V, 3.53 mmol)
D in a 100-peach flask protected with a drying tube.
Sodium hydride (7,06 mm) in MF (22,1)
mol, rinsed with petroleum ether]. After 15 minutes, CH3 (2.51 g, 17.7 mmol)
I spoke eight times. After 2.5 hours, the reaction mixture was reduced to 0.5 N
KH8O. diluted to 150i and extracted the reaction mixture three times with ether.
did. The organic fractions were combined and dehydrated (MgSOa
) L, filtered, stripped, oil (2,27
, 9) were obtained. This oil was dissolved in ethyl acetate/methylene chloride.
Column chromatography on Elm silica with lye eluent
flooded the country. The isolated insect extract is O-benzo-N-methyl-
]3oc-2,6-dimethyltyrosine methyl ester
: CH2CHCO20H3 菟CH3-N-CoC(CH3)3. NMR: 002Me j' 3,65 s, QC! H
2φf5.03 (2 protons), J containing 35 (5,7 protons)
Roton), N-M13 f2-55 s %BOC-Me
Chill chiral, doublet J1.30゜This ester (0,85
, 9,2,06 mmol] as in Example 1.
0,669,16,5 mmol) Teva water splitting site. N
MR: 0OH2φ) s, o 1, J 7.35:N
-Me J 2.59 s: BOC-methyl asymmetric J
1.27゜0-benzyl-N-methyl-Boc-2
16-dimethyltyrosine (0.70 g, 1.69 mmol
N-methylmorpholine (0,
18,9,1,78 mmol), inbutyl chlorophor
(0,211,1,75 mmol) and D-a
Ranylphenylpropylamide (free base, 0.367
,? , 1.78 mmol 5. The produced oil is converted into acetic acid.
Use ethyl/methylene chloride bath release agent to
It was subjected to column chromatography using a liquid crystal solution. Change the generated substances
4u chromatography using hexane/ethyl acetate eluent.
It was processed using Ronplate (centrifugal thick layer chromatography).
. The product mixture of thea stereomers (0,45 & ) is 2
Palladium black (0
,0451 in THF (30 ml).
provided. D still another palladium black (0,045,?)
Yes, it was applied for 65 hours under the same conditions. Filter the product mixture
and stripping to obtain a solid, ethanol: 0H
Column chromatography on Elm silica with 2Cj2 bath release agent
Served for fi. The first compound that appears is unchanged
N-methyl-Boa-216-dimethyl (D
L) Tyrosyl-(D) Alanylphenylfurohylamide
Met. This was retained for unblocking. next generation
The compound is the expected 〇-hypothesis protected product: N-methyl-Bo
a-2,6-dimethyl(DI,)-tyrosyl-CD
) was alanyl phenylzorobilamir. This shea
The stereomer mixture is ethanol: 0H2CL22.
5: 97.5 to 5.5: 94.5 gradient bathing
Another column chromatography using elm silica
provided. The first σ compound (in-F) and the second compound (
In-8) is unblocked separately as in Examples 16 and 14.
Ta. 0-benzyl-N-methyl-Boa-2M 6-di,
I-1-l(DL)-tyrosyl-(D)-alanyl
Phenylpropylamide was dissolved in dioxane (1-) for 24 hours.
Treated with methanol (1,5 m) and 6.8 N HCJ between
did. The mixture was evaporated with nitrogen steam to aqueous methanol.
Dissolved. Filter the bath liquid through Whatman 5 Q filter paper.
, reduce the nitrogen flow volume and lyophilize. The product is C31
H3C51H3・HCJ, 3/4 H2O (mW 5
51, 64). Theoretical value 067-50: H7,58: N7.62:
(J6.43 smile side cabinet G67.44: H7,41SN7.47:
C16,69 [α], = +51.8°NMR: Penzylmethylene J4.958%f5.038
, alanylmethyl J 1.16 d , J= 7H2
: J O, 88d, y=7Hz. Alternatively, 0-benzyl-N-methyl-BOC-2,6
-dimethyl(DL)-tyrosyl-(D)-dimethylphene
Nilzologylamide was purified by column chromatography.
was divided into its component diastereomers. Each diastereomer
is meta as described for diastereomeric mixtures.
Treated with HCJ in nol/dioxane. product (separate
) corresponds to O-benzyl-N-methyl-2,6-silane.
Methyl-tyrosyl(D)-dinylphenylzorogyl
This is Amir. (D-D) 03H3gN303 ・H
CJ (!nW 538-13) Theoretical value: 069.
19:H7,19:N7.81:C16,59 Actual value: 069.50:H7,52:N7.92:
C10,66 NMR: Alanylmethyl J 1.18d, J=7E
IzsN-methyl J 2.51 , benzylmethylene J
4.95, [α]. = -62,3゜(L,D) 031H3gN303・HCJ (mW
538, 13) Theoretical value: (D, D) Actual value for Ic: 069.07:H7,58:N7.90:
C10,78 NMR: Alanylmethyl J O,86d, J=7
11z, N-methyl/2.50, benzylmethylenej
s, o 3, [α] n = +95.5° Example 1! I N, 2,6-drimethyltyrosyl-N-(6-phenyl
propyl)-D-alanine amyl', 1 salt! Salt H Example 12 (7) N-methyl-Bcc-216-simethyl
Tyrosyl (D)-alanylphenylpropylamide (
(F) as described in Example 2 in methanol-HCJ,/di
Treated with oxane. However, methanol-HCJ,/di
Since methanol was not used after oxane removal,
No volume reduction was necessary before lyophilization. raw ri5t
q Nazuha 024H35N303- HCf・1-1/4 H2O
(mw 470.53) Theoretical value: c61.26:
H7,82: N8.93 lol Measured value: (!61.11:
H7,46: N8.87 [α]. =-si, o. NMR: Alanylmethyl 1.18d, J=7h. Example j14 N,2.6-)limethyltyrosyl-N-(3-phenyl
propyl)-D-alanine aminov, salt e salt (4:5) H %J 12 Q) N-methyl-Boa-2,/,-di
Methyltyrosyl-(D)-alanylphenylzorovira
Mido (InS) was prepared using methanol-HCl as described in Example 2.
/treated with dioxane. The product is 024H33N30
3 ・1-'/B HCL-H2O (mW 47 [
3-58) Theory clay: 061.26:H7,74:N
8.93: CJ, 8.46 actual measurement: c61.23; a7.4D; N8.88:
(J8.83 [α] = +1120 NMR: (D) Alanylmethyl J O,90d,
J=7Hz Example 15 2.6-dimethyl-DL-tyrosyl-Nα-methyl-N
-(3-phenylzoa-gyl)-D-alanine amyl, 1
Hydrochloride H Carsaben 1'kr Shi(Z) -(D)-Alania
(22,3y, 100 mmoln to THF' (500
m) was commonly understood. Methyl iodide (114 & 800ml
mol) was added to DΩ and the mixture was cooled to -5°. Hydrogen ratio
Thorium (300 mmol, 50% suspension in mineral oil)
) was added over 1 hour. temperature for another hour+
It was maintained at 10°. Add 30 rows of THF and mix.
The mixture was stirred at room temperature for 68 hours. Ethyl acetate (500d
) was added to the reaction mixture, followed by H2O (10 m ).
I got 7JO. Concentrate this mixture and partition between water and ether
did. The aqueous layer was washed twice with ether and the organic fraction
were combined and rinsed with saturated aqueous NaHCO3. aqueous
Fractions were combined. Then remove the organic layer and add water
The pH of the sexual layer was adjusted to 4 with a citric acid bath. acidic aqueous flux
The solution was extracted with vinegar fllx chill. organic fraction
Wash twice with 5% Na2!9203 IJ solution and once with water.
It was. The organic fraction was dehydrated (MgSO4) and filtered.
Filter and strip to obtain oil (22,2,9)
Ta. Crystallize with ethyl acetate/5kelly B mixture
I did it. NMR (cDcz3): N-M13 J 2.8
9 days, alanylmethyl J 1.43, [α]D (eta
Nord) = +24.5°. N-methyl-z, -(D)alanine (7,12!I. 3060 mmol) was added to N-methyl molybdenum as described in column 2.
Luforin (3,04,9,30,0 mmol), Inbu
Chloroformate (4,10, @, 60.0 mm
] and 3-phenylpropylamine (4,06 g,
30.0 mmol] to obtain 9.87 g of pale yellow oil.
Ta. This oil was diluted with 10% Pa/a in methanol at 25°
Hydrogen ratio with catalyst (60p131 H2,) L, filtered/concentrated
Deprotected N-methyl-(D
)-alanyl-phenylpropylamide was obtained. N-1f Ru(D)-alanylphenylpropyl 7 ml
'(2,88,V, 13.05 mmIJmol))-! F
(D)-Alanylphenylated mixed anhydrous synthesis described in J2
Replaced with lusoloviramide. Boc-216-shime
Tyltyrosine (4,00 &, 13.05 mmol) and i
(3,58 &, 26.1 mm)
Using 2 moles of moruin butyl chloroformate, this
2 moles of act as a protecting group for the free phenol] and
of N-methylmorpholine (2.64 g,
26.1 mmol)
I reacted. The final amide synthesis of the mixed anhydride is performed at 25°.
I did it for one night. After the procedure described in Example 2, this material was chromatographed.
I used it as is. ○-Imbutoxycarbonyl-Boc-2,6-(D
, L)-dimethyltyrosyl-N-methyl-(D)-a
Ranylphenylzorobilami) F(6,71,li')
Dissolved in methanol (100m), K2O03 (1,
98!9) and stirred for 4 hours. Concentrate the mixture to 0H2
Cj2 and 0.5 N KISO. organic layer
Q, 5 N KISO. I extracted two. Each washed aqueous layer has a new 0H2CJ2
Backwashed with. Combine the organic fractions
, saturated NaHco3 (backwash, e.g. CH2
Washed three times with Cl2), washed with saturated brine, and dehydrated (with N
a2s04 followed by Ca5O4) L, filtered and strained
Ripping was performed to obtain an oily substance (5,50,9). this oil
Using an ethyl acetate/salt ratio methylene bath remover, remove the
Diastere was subjected to column chromatography on Lucilica.
The omer mixture (3,47&) was isolated. This oil was ground with a 5ke11yB/techtel mixture and foamed.
A product of 3.18 # was obtained. This foam (3.03 g) was prepared using glacial acetic acid (2.0 g) as described in Example 2.
4 m) and 6.2 N H”,!/dioxane (9.6 m
1) to obtain the desired 2,6-dimethyl(D,L)-thi
Rosyl-N-methyl-(D)-alanylphenylpropyl
Ruamide hydrochloride was obtained. C24H33N303・HCJ, l/4 H2O(m
W a 52.51) Theoretical value: 063.70:
H7,69:N9.29:(J7.83 Actual value: c63.45:H7,60:N9.10:
CJ, 7.70 [α]D= +36-30, NMR: DMSOα
N-methyl partially hidden in /2.58: alanylmethy
J0.97d, J=7Hz. Example 16 2.6-dimethyl-DL-tyrosyl-N-methyl-N-
(3-phenylpropyl)-D-alaninamide 1 salt
Acid salt z -(D) -7Raniy (10-01,44,8mi
As described in Example 2, N-methylmorphol
(4.54 J, 44.8 mmol), inbutylchloride
loformate (6,12,?, 44.3 mmol) and
and N-methyl-ro-phenylpropylamine C6,69
1,44,8 mmol] in methylene chloride to form an oil.
(14,5, V) was obtained. -g(4,07,9) of this oil using 5% pd/c catalyst.
9 times in THF and subjected to hydrogen ratio (60ps1H2)
, deprotected (D)alanyl-N-methyl-3-phenylated
Lupropylamide (2,50,9) was obtained. Boc-216-dimethyltyrosine (6,54y, 1
1.5 mmol) and N-methylmorpholine (1,16,
9,11,5 mmol) in DMF (16 ml) and salt.
The reaction was carried out in a mixture of methylene chloride (13 m/liter).
12, stirred for 30 minutes and cooled to -500 f.
Also inbutyl chloroformate (1,565+, 11.
5 mmol) was placed in 8 mouthfuls, and the temperature was raised to -10°. reaction
The mixture was recooled to -500 and (D)-alanyl-N-
Methyl-3-phenylpropylamide (a small amount of aH2c
2.50.9) was added during t2. Bring the mixture to room temperature VC71
The mixture was heated to 0 and stirred for 3 hours. The reaction was carried out as in Example 2 and the foam
5.10,? I got it. Resuspend this foam in 0H2C22
filtered and stripped to obtain oil (4,0,?)
Ta. Use methanol/chloroform bath remover to remove this oil.
It was subjected to column chromatography on silica. this life
The product is a BOC-protected diastereomer (2,40&)
It was a mixture. A portion of this mixture (0,5D, u) was heated at 25° for 20 hours.
Dioxane (20 m/) and 6.8 N HCI/zooxane
San (2,88). This mixture is
Pound to obtain foam, crush with ether three times, 78°,
Decommissioning at 0.01 tOrr for 2 hours using Abdelhalden equipment.
I watered it. The product was the desired hydrochloride l/2H20
. 024H35N303・HCJ,・”/2 N20 (
m”457,02) Theoretical case: C63,08:
C7,72:N9.19;C27,76 Around actual measurement: (1!63.07:N7.47:N8.9
6:C13,16 [α] = +21.2°, NMRN-methyl: /
2.79 t collapses to 2.82 d at 60°;
Nylmethyl f1.12m, JQ, 31m: These are 60
Double line collapses at °. These are probably alanyl and phenylp
Attributable to the limited rotation due to the reaction of the ropylamide methyl functional group.
due to Example 17 2.6-dichloro-4-chloromethylanilin H2C
1 Zochloroaninol 53.8 & (333 mmol 1 nmol),
@HC! 34Qfn1 and 67% formaldehy r5
2.5-(1,72 Mh) was heated at 500 to 710 heat overnight.
Ta. The reaction mixture was diluted with water and brine and extracted twice with ether.
did. Combine the ether phases and add water, saturated 1JalcO3
, washed with saturated brine, dehydrated with Mg804, concentrated,
Tsuf (56#) was obtained. 250. g/min to hexane
Two re-bathed σ〕Normal phase silica cartridge
Waters 500σ] Chromatography results
, 2El of white solid was obtained. aBH,ocJ3 (mW225.50) Theoretical power:
aA2.61:N39.61:C:J47.17 disaster
fllNi: 039.61 :N2.79; Tomoe
50.34 Example 18 Diethyl(acetylamino)In(2,6-dichloro-
4-methoxyphenyl)mer/-le]-solonondio
EtCH2C(Co2Et)2 HNC! 0OH3 Under ArO, 3.4g (137 mmA/ ) Without Ha
I solved the water EtoHVcfg, and it was 32.3. V (147
Add 7JO of millimorne diethyl acetamyl malonate.
, and refluxed for 1 hour. The product of Example 17, 27.9#(
124 mmol) was added to 710 mL and refluxed overnight. reaction mixture
Stripping things, 1 of 400: I CHC
j3/H20 and the organic phase was heated with N20, saturated Ha(J
, dried over MgSO4 and concentrated to a solid (43
, 9) were obtained. This is divided into two normal phase silica columns.
Chromatographed on Watere 500 at 25
〇-Bath with 25% ethyl acetate/toluene for 7 minutes, m,
p, 153.5-156.4° solid 26.7 gulls were obtained
Ta. C17H21NO6CJ-2 (mw a 06-27
) Theory fiii: C! 50.26;N5.21:N
3.45: (J17.45 Jitsuma j1 shift: C50,33: H5,12:
N 3.38: Two 7.79 Example 19 2.6-dichloro-DL-tyrosine, ium salt H OH2CHCO2H NN2.HCl 70 with nate 710! I! 1 (PJl 8) 23.
9 (56,6 mmol), K2O0350 & (36
2 mmol) and phenylselenol 45 g (2
85 mmol) in 200 ml DMF overnight under N2
It refluxed. The reaction mixture was diluted with 11 N20 and ether
Extracted with . The aqueous phase was acidified with HCj and saturated NaC
Extracted with 1.1% liquid solution, dried over MgSO4, and concentrated to an oil (
371) was obtained. This oil was shaken with 150 m 5kal17 B and the supernatant
The liquid is 10 D at aH2ct□ before the oil is crystallized.
Decanted 3x to give solid N-acetylamino acid 11
．． 5.9 was obtained. Then this compound wo160d6N
Hct Qi was refluxed overnight, cooled, filtered, and crystallized at 9.91.
I got it. 09H1ONO3 (J3 (mw 286, 55)
Theoretical value: H37,72:H3,53:N4.89:
cz37.12 Actual value: H37,63: H3,45: H4,83:
Cj36.20 Example 2O N-C(1,1-dimethylethoxy)carzanyl]-2
．． 6-DichloroDL-tyrosine H OH2-OH(!02H HNOOO(OH3)3 9.9 g (4,00 mmol) of the product of Example 19 was dissolved in 25
vt) 12o, pH 9 with 10% NaOH,
5 to give a final volume of 100-. t-Buoa
(100-) and (Boc2)o 14.5 & (64
Pour 8 mouthfuls of (mmol) and maintain - to 9.5 with 10% NaOH.
I held it. - to 13 and the reaction mixture to 50° 710
@L, O (BOC12 was saponified. The reaction mixture was cooled.
IM KH8O. and extracted with ethyl acetate. organic phase
Extracted with saturated brine, dried over MgSO4 and concentrated. The residue was subjected to crystallization using 0H2J2 to obtain 8.5I crystals. 0x4H1yNOsCJ2 (mW 3 5 0,
19) Theoretical value: 048.02:H4,89
:N4. OO: cz20.25 Actual value: H47,36; H4,64; N3.75;
Cl2O,53 Example 21 N-((1,1-dimethylethoxy)carvinyl]-2
,6-dichloro-DL-tyrosyl-N-(3-phenyl
Propyl)-D-alanine amide 20 product 7,
F (20,0 mi 13 hol) under nitrogen for 2.02. ! i'
(20-Omi')mol)y-Memorpho+)ytW
60 w 0H2Cj2, -30″CIC?'
it B L, 2.73.9 (20.0 mmol) i
7JO of butyl chloroformate was added. 15 minutes later, D
-alanylphenylpropylamide 5# (24 mmol
) and brought the temperature to -20°C before sledding. reaction mixture
The mixture was stirred at room temperature overnight. The reaction mixture was reduced to 500 dEt.
Diluted with OAC, IM KH8O, saturated NaHcO
3. Extracted with saturated NatJ and dried with MgMO. bath
The solution was concentrated to obtain foam with a CI of 0.9. two normas
Waters 500 on Lunar Phase Silica Column
chromatographed at 1.6% mass at 250 fnt/min.
eluted by tanol/CHCl3 and migrated quickly.
1.3 g of isomer A and 1.1 g of slower migrating isomer B were obtained.
. 0211H33N305Cj2 (m W 538.4
7). Theoretical value of isomer A: 058.00:H6,18;
N 7.80: fJl 3.17 Actual value: C! 57.82:H6,13:H7,68
:Cjl3.21 [α'), = -1,9° Theory of isomer B [E: C! 58.00:H6,18
:N 7.80 :Cjl 3.17 Actual f111 value: 057.87:H6,06:H7,
62: Cj 1! 1.25 [α]. = +6.6゜ga22 2.6-dichlorotyrosyl-N-(3-phenylzolopi
)-D-alaninamide monohydrochloride? 121 isomers
A 1.3.9 (2.40 mmol) with 8-glacial acetic acid
8rn16JHCJ! ,/dissolved in dioxane. this
After that, the solution was concentrated to a small volume and the ether was dissolved at 710 t.
, filtered. 0.90 g, C21H26CJ-3N
303・1/2H20 (mW483.82) Theoretical value: c52.13; a5.64: N8.69:
C,! 21.98 Real i! ! +11 shift: a51.94: a5.33: N
8.62; IJ, 21.63 [α], --57O NMRAla methyl J = 1.18 J = 6
Hz Tyr(ph-H) δ = 6.80 Example 23 2.6-dichlorotyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride ○H Isomer B of Example 21 was described with respect to Isomer A of Example 22.
The title compound was obtained in the same manner as above. C'21H26C13N303°1/2H20 theoretical value:
(Same as column 22) Actual value: 052.03; H5,58:N8.40C
j21.17 [α), = +53. <SO NMRALa (OH3)/ 1.00111pm (
J = 6 Hz) T7r(Ph-H] δ = 6.
85 Example 24 2.4.6-tIJ-1-l-L-phenylalanyl
-N-(3-phenylpropyl)-D-alaninamide
, monohydrochloride/HCl 2.4.6-drimethylpenzyl chloride (200,
9,1,19 mol) of diethylacetoacetate as in Example 18.
Sodium salt of midomalonate (274,V, 1.31
Mormalonate: 30.1 y, 1.31 molnatri
2.4.6-drimethyl-N-acetate
Leu α-carpoxyethylene was added. Reflux was continued for 18 hours. Added 710 g of water (11 liters to 710 liters and briefly started refluxing. Reaction mixture.
Cooled things down. The product was crystallized, crushed, and then cooled with INH.
Washed with Cf, acetone and ether. recombined from water
,2゜4.6-)limethylphenylalanine 6B,! 9
I got it. 2.4.6-17methylphenylalanine (62g,
254 mmol] of di-tert-butyl dicarbonate as in Example 20.
bonate (581,2 mmol) and Boc
-2m 4 m 6-drimethylphenylalanine 6
4g is 4. BOC-2,4,6-drimethylphenylalanine (7
-87 &, 25.6 mmol) as described in Example 2.
-methylmorpholine (2,58,9,25,6 mmol
), inbutyl chloroform) (3,55,9,25
, 6 mmol] and (D)-alanylphenylpropyl
Ruamide (free base, 6.OI!, 25.6 mmol)
Processed with. This product mixture is ethanol/methylene chloride.
Volacyl silica neutral strength ram chromatography using
Offered to Rafi. Two diastereomers were resolved. The first isomer (2.23g) coming out of the column is shown in Example 2.
Glacial acetic acid (40m) and 6.8NHCl/zo
Treated with oxane (7.5m) to achieve the desired 2. d, 6-
) Limethyl-(L)-phenylalanyl-(D)-7
Ranil phenyl derovir ami pwoi. 024H33N302・HCl (mW 432, mouth 2
), [α] = +115.70 Theoretical value: a66.72: H7, 93: N9.73 disaster
Oki H Nao: 066.25:H7, 85:N9.
61NMR (CD30D): d-methyl/2.2
28; Alanylmethyl J0.98d. Example 25 2.4.6-toIJ methylphenylalanyl-N-(3
-Phenylpropyl)-D-7 lanin amide monohydrochloride.
isomer (3.63 g) in ice vinegar as described in Example 24.
acid (50 m) and 6.8 N HCJ,/dioxane (1
3, d) to obtain the desired 2.4.6-drimethyl-
(D)-phenylalanyl-(D)-alanylphenyl
Propylamide was obtained. C24H33N302・HCJ1/4 H2O (mW
436-52) [α]: = -74,7° Theoretical value: c66, C3:H7,97; s9.63 actual
Measured value: 066.19:H7,96;N9.61NM
RA (Co30D): 4-methylbu2.12:
Alanylmethyl f1.27 d Example 26 N-[(1,1-dimethylethoxy)carmenyl]-2
,6-dimethyl-〇-(3-phenylpropyl)-DL
O-benzyl-BOC-2, prepared as in 12,
6-dimethyltyrosine benzyl ester (511,0,
21 mmol] ff NaoH (3
, 27jj, 31.7 Cl mmol) and expressed as
The compound was obtained. NMR: f 4.99 s (2p
roton) and benzyl methylene. Example 27 2.6-dimethyl-(3-phenylpropyl)-L
-Tyrosyl-N-(3-phenylpropyl)-D-ara
Ninamide, monohydrochloride 0-benzyl-Boc-2,6-dimethyltyrosine (
3,50, u, 8.77 mmol) as described in Example 2.
, N-methylmorpholine (0,93 &, 9.21 mmol)
), inbutyl chloroformate (1,23y, 9
．． 04 mmol) and D-alanylphenylzolobi
treated with Ruamide (1,90 @, 9.04 mmol)
Ta. The product was evaporated with methanol/chloroform as eluent.
Column chromatography on boracyl silica using the mixed solution.
Submitted to graphics. Two substances, early isomers (in-F
] and the late isomer (in-8) were isolated. The isomer that migrates first (the first to exit from the In-F column)
1 g) in dioxane (3-) as described in Example 2.
treated with aqueous acetic acid (10 m/) and 6.8 N HCJ.
. The resulting solid was dissolved in aqueous methanol, filtered, and lyophilized.
Drying gave the title compound. 03oH3,N503-HC'J・”/4 N20 (
m” 537-62) Theoretical value: c67.02;
a7.41: N7.82: tJ 6.59 real filli: C67,03: a7.12:
N 8.21: Cl 6.84 [α] = +115.7 NMR: Penzylmethylene: J 5.038;
Nylmethyl f O,83d , J = 71 (z Example 28 2.6-dimethyl-〇-(3-phenylpropyl) ~D
-Tyrosyl-N-(3-phenylpropyl)-D-ara
Slowly migrating isomer of ninamide, hydrochloride Example 27 (in which exits the column late)
-8,1&) is described for the In-F compound of Example 27.
The compound c30H37"3o3 j 1- l/s HCj・'
/2 N20 (mw 537.67) was obtained. Theoretical value: c67.02; N7.33: N7.82:
(J7.42 actual measurement value: 066.84:N7.14:N7.98:
(J7.15 [α].=-69,7 NMR: Benzylmethylene: f4.95s;
Chill J 1.14 d, J = 7flz voice 129 N-4(1,1-dimethylethoxy)carbonyl]-2
,6-dimethyl-DL-tyrosine, methyl ester OH CH2CHCO2CH3 HNCOC(OH3) 3 Thermometer, dropping funnel, and N2 population and drying tube outlet.
methanol (250tnt) equipped with Y-tube
The 11!6-necked flask was cooled to -70°. Add thionyl chloride (3B, 711,325 mmol) dropwise
and the reaction temperature was maintained below -60°. Addition is complete
After that, the mixture was warmed to 0°. Add 710 g of Boc-2m 6-dimethyltyrosine (40#. 162 mmol) and cool the mixture at room temperature under N2.
It was stirred overnight. Filter the reaction mixture to remove traces of solids
and strip it to get the oil and combine it with ether.
It was crushed and left to stand. Let the oil solidify overnight and then
Drying in a vacuum at 60° gave the title compound. NMR:Me
Toxy/3.45 s, aromatic ring J 6,44 s
For 6.5-zoHO this product (40y, 154 mi
N-
Methylmorpholine (15,!1M, 16.94-115
4 mmol) was added and the mixture was stirred under nitrogen for 40 minutes. Di-t-butyl dicarbonate (!13.61 y,!
+ 5.42 m, 154 mmol) and the mixture
Stir overnight. Wash the mixture twice with water and dehydrate (MgSO+) L, S)
I did an IJ trip. Grind the residue and filter with hexane.
, the indicated mixture was obtained. NMR: Methoxy/3.50 days, Boc-methyl J1
35θ. Example 30 0-((4-cyanophenyl)methyl]-N-((1,
1-dimethylethoxy)carbonyl]-2,6-cymethy
Lu DL-Tyrosine CH2-CH-002H HNCoC(CH3)3 Mapping suspension of NaH/oil (27.3 mmol)
Weigh it into a 11 round bottom flask fitted with a gunnet stirrer.
Ta. Wash this suspension with hexane to remove inorganic oil.
and immediately charge TI (F (200m) into the flask.
did. Boa-2m 6-dimethyltyrosine methyl ester
Stell 1J29.8. V. 24.8 mmol) was added and a drying tube was inserted. blend
was stirred for 2 hours, and α-promo p-tolnitrile (5,
24&, 26.8 mmol) and the mixture was brought to room temperature.
Stir overnight at warm temperature. Thin layer chromatography (2:l5kelly
B: Ethyl acetate]. starting material still present
Lifting platform, NaH dispersion (l/2 mol) and alkylation
Vat amount of agent [l/2 molar amount] was added, and the reaction was kept at room temperature for another 24 hours.
I did it. Pour the mixture into water (1,21,0H2(
Rapid extraction was performed 6 times using J2. Combine the organic fractions
, dehydrated (MgSO4) L, stripped and produced
(o-(p-cyanohensyl)-poc-2,6-cy
methyltyrosine methyl ester), which is described in Example 1.
As posted. Direct 710 water splitting with NaOH gave the title compound. NMR: Benzylmethylene/5.10 B: Tyroshi
Le aromatic tlcf o) yJ 6.60 s; Ben
The diaromatic proton is centered at J7.65. Example 61 o-((4-chlorophenyl)methyl]-N-((1,
1-dimethylethoxy)carbonyl]-2,6-cymethy
DL-tyrosine 0H20HO02H HN(!00(OH3)3 riu60 α-bromo-1)-) 4-chloronitrile
Replacement with lobenzyl chloride gave the title compound.
. NMR: /<ndylmethylene J 5.008: Chiro
Syl aromatic proton 16.608: benzyl aromatic proton
All tons are / 7.408゜Example'52 N-(1,1-dimethylethoxy)carbonyl]-2,
6-Simethyl-〇-[(2-methylphenyl)methyl)
-DL-Tyrosine 0H20HO02H HNOOO(OH3). α-promo p-)lunitrile of Example 30
Filling with 0-xylene gave compound No. 1.
. NMR: Benzylmethylene J4.958: Tyrosylmethylene
Group J2.25B: Penzylmethyl group J2.30B
. Example 33 N-[1,1-dimethylethoxy]carbonyl]-2,
6-dimethyl-o-((4-nitro7enyl)methyl]
-DL-Tyrosine 0H20HC! 02H HNC! 00(OH3)3 11ffiJ 30 α-promotolnitrile was converted into p-nitrile
[1 conversion with tropentulpromide gave the title compound]
. NMR: Benzylmethylene J5,13e: Tyrosyl aroma
Group proton J6.65B: benzyl proton F7.60
B, J=81 (z and / 8-20 d-J"
8 Hz. Example 34 N-[:(1,1-dimethylethoxy]carbonyl]-
0-CC4-70-phenyl)methyl]-2゜6-zome
Chiru DL-Tyrosine f:! H20HOO2H aNcoc(CH3)3 I fJ30 α-promotolnitrile was converted to 4-fluorobendi
Replaced with rubromide to obtain the compound shown in 1.NMR
: Penzylmethylene J 5.008 : Tyrosyl aroma
Group proton J6.6os: benzyl aromatic proton is /
Focus on 7.25. Example 35 N-((1,1-SP methylnidoxin carbonyl)-
2,6-dimethyl-o-((4-methylphenyl)methy
]-DL-tyrosine ca2caao2H HNGOO(OH3)3
Substitution with silene gave the title compound. Example 36 N-((1,1-dimethylethoxy)carbonyl]-O
-[(4-(1,1-dimethylethyl)phenyl)methylene
]-2,6-dimethyl-DL-tyrosine CH20HCOQH HNOOO(CH3)3
Substitution with dilbromide gave the title compound. Example 37 o-[(A-chlorophenyllamethyl)-2,<S-di
/f Rutyrosyl+N-(3-phenylpropyl)-D-
When exposed to the mixed anhydrous condensation of alanine esteramide, monohydrochloride Example 2, 0-methyl-BOC-
Instead of 2,6-dimethyltyrosine, the product of Example 31 was treated
After treatment, a mixture of diastereomers was obtained, which was added to the column column.
Divided by chromatography. Each diastereomer
Treated with dioxane/HCJ,/glacial acetic acid as described in Example 2.
Two diastereomers of the title compound were obtained. Sha1j68 2.6-dimethyl-04(2-methylphenyl)methyl
]Tyrosyl-N-(3-phenylpropyl)-D-ara
When exposed to mixed anhydrous condensation of Ninami-11 hydrochloride Example 2, 0-methyl-”OC
-2+ 6- Production of Example 32 instead of dimethyltyrosine
After treatment, a mixture of diastereomers is obtained, which is
Separate by column chromatography. Each diaster
Add omer to dioxane/HCI/ice vinegar as described in Example 2.
Treatment with acid produces two diastereomers of the compound shown in 1.
I got it. Packed into L and D diastereomers: 031H39N303 ・HCf3/4 H20(In
W 551, 6 a)] Theory 1 (ii: 067
．． 50:H7,58:H7,62; (J6.43 actual value: c67, s2:a7.27:H7,81;
Cl-6,62 [α)D= + 108.40. NMR: Jg,
Alanyl methyl signal at B 5 a, J = 8 [1
z, 0-methyl signal for pencil group: J2.
24s. World 139 2,6-dimethyl-o-((4-nitrophenyl)methy)
]Tyrosyl-N-(3-7enylprogyl)-D-a
When exposed to mixed anhydrous condensation of laninami-11 hydrochloride H2 IFIJ 2, 0-methyl
-BOC-2#6-dimethyltyrosine in place of Example 33
In the product, after the manipulation, a mixture of diastereomers is obtained, which
This is separated by column chromatography. Then each
The diastereomers were diastereomerized as described in fPIJ 2 K.
After treatment with xane/HCJ,/glacial acetic acid, 2 of the indicated compound
Two diastereomers were obtained. [α] = -27.9 (D, D) and +72.7° (L,
D)/methanol. (D, D): 03oH36N, 05
・H(Jl, yo/4 H20(mW59 1
．． 63) Theory area: 060.90:H6, 52:H9
, 47: Cl5.99 Actual value: c60.58; a6.36: H9,46:
Cl6.27 NMR: Alanylmethyl f 1.28 d (L, D)
030H36N405 ・11/4 HCl, 11/
2H20 (mW 605.25) Theory II: 059.53:H6,70;H9,26
:Cl7.32 Actual value: c59.13:a6.36:H9,d5:
V7.27 NMR: Alanylmethyl, 10.95dl1vl140 o-C(d-70lophenyl)methyl)-2,(S-di
Methyltyrosyl-N-(3-phenylprogyl)-D-
When subjected to mixed anhydrous condensation of alaninamide, monohydrochloride Example 2, 0-methyl-Boa
-Product of Example 64 instead of 2,6-dimethyltyrosine
Now, after the operation, we obtain a mixture of diastereomers, which is
It was separated by column chromatography. Each diastereomer
- with dioxane/HCJ,/glacial acetic acid as described in Example 2.
Process to obtain two diastereomers of the compound shown in 1.
Ta. [α]=-64,20 and +94.0°/methanol. Example 41 2.6-dimethyl-〇-((4-methylphenyl)methyl
] Tyrosyl-N-(3-phenylpropyl)-D-a
When subjected to mixed anhydrous condensation of laninamide, monohydrochloride Example 2, 0-methyl-BoC
-2,6-dimethyltyrosine instead of the product of Ga35.
After the operation, a mixture of diastereomers is obtained, which is applied to the column.
It was resolved by chromatography. Then each diaster
Omer as described in gAU2 GeoΦsan/vJ,/ice
Treatment with acetic acid separates the two diastereomers of the listed compound.
Obtained. Example 42 0-C(4-(1,1-dimethylethyl)phenyl)methane
]-2,6-dimethyltyrosyl-N-(3-phenyl)
luzolopyr)-D-alaninamide v. 1 hydrochloride H2 When subjected to the mixed anhydrous condensation of Example 2, 0-methyl-Boa
-Product of Example 36 instead of 2,6-dimethyltyrosine
Now, after the operation, we get mixed diastereomers and color them.
It was resolved by mucochromatography. Each diastereomer
dioxane/H(J/ice vinegar) as described in Example 2.
Treatment with acid yields two diastereomers of the title compound.
Ta. (D, D): 0s4H45NzO3・HCJ-V2
H20 (mW 589, 22) theoretical value: a69.
31:H8-04:H7,13; (J16.02 actual value: a68.98;H7,55:H7,23;
C10,42 NMR: Alanylmethyl J1.15d [α] = -50,0° (LD): C34H45N303'H (J''/2
H20 (mw589, 22) theoretical value: (D,
Same actual value as D): 069.25:H7, 93H7, 36:f
:j6.14 NMR: Alanylmethyl, rO,8d [α] = +102.4° Example 43 0-((4-cyanophenyl)methyl)-2,6-di'
f Rutyrosyl-N-(3-phenylpropyl)-D-a
When subjected to mixed anhydrous condensation of Laninamide, monohydrochloride Example 2, 0-methyl-Boc
-Product of Example 30 instead of 2,6-dimethyltyrosine
After the operation, we will obtain mixed diastereomers, which will be applied to the column.
It was separated by chromatography. Each diastereomer
- with dioxane/HCJ,/glacial acetic acid as described in Example 2.
Work-up provided two diastereomers of compound 1. [α] = -74.4° and +90.2°/methanol. (D, D): C! 31H36N403・1'/B
HCI ・l/2 H20 (mW562.69) Theoretical value: c66.17:H6,83:H9,96:
C27,09 Actual value: cs5.80: a6.67: H9,84:
CJ6.86 NMR: Alanine methyl group: J1.16d (L, D
): C! 31H36N403-HCJ, -l/4
H20 (mW553, 62) Theoretical value: 067.2
6:! 16.83:N10.12':Y6.40 Actual value: 066.96:H6,96:N10.09
; CJ6.59 NMR: Alanine methyl group: J O, 81d. Example 44 0-((4-aminophenyl)methyl]-2,6-cyme
Tyltyrosyl N-(3-phenylpropyl)-6-7
)-alaninamide 1 hydrochloride jM2 The title compound of Example 39 was dissolved in water in the presence of pd/a in methanol.
It can be processed directly. The mixture was filtered and concentrated to low volume. Living
The product was triturated with ether and dried to give the title compound. [α] D Aero 00/methanol (D, D). C30H3111N403 ・HCJl/2 H20(
mW 548-13) Theoretical value: 065.74:H
7,36:N10.22:CJ,6.47 Actual 1filJ value: c65.94; a7.09:H9
, 91; CJ6.55 NMR: alanylmethyl group f1.16d. Example 45 2R-((cyclozologylmethyl)amino)-N-(3
-phenylpropyl)propanamiP(D)-alanyl
Phenylzolobilamide (0,82S&, 4.
0 0 mmol], NaHCO3 (
1,00 &, 1.20 mmol), bromomethylsic
lopropane (0.64 g, 4.74 mmol) and 1
A mixture of 0-ethanol (2B) was refluxed for 8 hours with stirring.
It was hot. The reaction mixture was partitioned between ethyl acetate and water. organic
Separate the phases and Na280. I was dehydrated. Remove solvent under reduced pressure
Column chromatography of the refined oil using a Boracyl column
Purified by 5/96-8/0-2'',
Eluted with M5eOH/0HCj3/NH4OH
. NMR: (ODCJ3) Shift (D) Ala f
1.2 Bd. J = 91 (z 0 cyclopropylmethyl; fO ~ 0.25, complex
x, 2aJ0.30-0.65, complex, 2
H; JD, 65-1.00, Complex, 1a:
d of Jd, J2. sq, Jl=3.5 [IZ, J2=
81b. A sample of the above product was dissolved in methanol and 2-propanol
Tens of H
Ta. Add anhydrous ether to the turbidity point and bring the mixture to 00
Cooled. The solid produced is filtered and decompressed under vacuum under an inert atmosphere.
I watered it. J = 9 Hz, cyclozolopylmethyl: fO62
0~0.70, AH, Complex: JO, 80~1
．． 30.1H, complex; 2.4-2.9.2H
Concealment. 016H24N20・H (Theoretical elemental analysis value of J:
c64,74;H8,49:H9,44:Cjll,9
4 Actual measurement value: 064.63:H8,37:H9,44:
(J12.11 Example 46 N-[(1,1-dimer F-lethoxy)carbonyl]
-2,6-dimethyl-DL-tyrosyl-Nα-(cyclo
propylmethyl)-N-(3-phenylprogyl)-D
- The title compound of alanine amyl flJ 45 is the mixed anhydride described in Example 2.
(D) alanyl phenyl progylamide)
did. Boc-2,6-dimethyltyrosine (2,97
, S', 9.60 mmol], inbutylchlorophos
-Mate (1,31#, 9.60 mlJ mol) Oh! BiN
-Methyl-morpholine (0,98,9,9,60 mmol
] and reacted. Dimethylformamide is a solvent
It was replaced with methylene chloride. The reaction mixture was prepared as in Example 2.
The foam (4, 4, 9) produced by the sea urchin treatment is treated with Merck silica.
Purified by column chromatography of
The solution was bathed with methylene chloride. 2.6-dimethyl-DL-tyrosyl-Nα-(cyclop
(3-phenylpropyl)-N-(3-phenylpropyl)-D-
Alaninamine V.1 Hydrochloride H Product of Example 46 (0-51,9,0-924 mmol)
with glacial acetic acid (5-) and 6.2NHC as described in Example 2.
J-/dioxane (1,367) to obtain the desired 2
．． 6-dimethyl(D,L)-tyrosyl-N-cyclopro
Gylmethyl-CD)-dinylphenylpropylamide
The hydrochloride was obtained. 027H37N303-H(J・↓/2H20(mw
497.08) Calculated value: C65,24:H7,91
:H8,45:C10,13 Actual value: 065.19:H7,73;H8,42:
cz7.20 [α] = +13.6°. NMR: Ccvct3)
Cyclopropyl: JO~J1.0 complex, 5H
; Partially hidden by 2,6-dimethyl group (tyrosine)
J2.252H shifts to I”C23 and 1.413H
do. Column 48 N-((1,1-dimethylethoxy)carbonyl]-N
-(2-propenyl)-D-alanine allyl iodide (6,
72, F, 40.0 mmol) is iodine f-himethyl and Bo
a-(D)-alanine (1,89 g, 10.0 mm
) is substituted for Z-(D)alanine in the reaction in column 15.
did. These were combined with sodium hydride (30.0 mmol,
50% suspension in mineral oil) and THF (30ml
) was reacted. Using the operation process of Example 15, 2.2
An oil of 7.9 was obtained. NMR: (CD(43)alanylmethyl J1.45:
N Allyl J 3.70-4.0O12H; 4.95-5
．． 30.2H; [α] Methanol = 43.3'0゜Example
49 1.1-dimethylethyl-[IR-methyl-2-okyne
-2-[(3-phenylderobirunamino]ethyl](
2-propenyl) carbamate N-7/l/-BO
(!-(D)-Alanine (Example 48) (9,58#, 41
．． 8 mmol) as described in Example 2, N-methyl mol
Holin (4,27,V, 41.8 mmol), Inbu
Chil chloroformate (5,71, !II, 41.8 mi
] and 6-phenylpropylamine (5,65
, V, 41.8 mmol) and pale oil 38.8
3 I got &. NMR (CD'J3): Alanylmethyl J 1.35
: N-allyl; J 3.7 0 ~ 6.
90, 2H; 4.95 to 5.30.2H: 5
．． 50-6. I Q: I Hl:α〕methanol
=126.3°. Example 5O N-(3-phenylzolopyl)-2R-(2-propenylate)
Ruamino)-propanamide (r!4) The product of Example 49 (13.83 g, 39.9 mmol)
6-2 with glacial acetic acid (100 m) as described in fI12.
Treated with N HCI/dioxane (58,711yg)
and the desired N-allyl-D-alanylphenylzolopi
Ruamide hydrochloride was obtained. Dissolve this in a small amount of water and
Treated with NaHCO2 and no alkali injection. It was then converted into a base by extraction with methylene chloride. The extract was dehydrated with Na2SO4 and the solvent was removed under reduced pressure.
, flame-colored oil 8.98. I got u. AJ51 2.61”Tyltyrosyl-N-(3-phenylzolopyl
)-Na-(2-zorobenyl)-D-alaninamide V H H2 N-allyl-(D)-alanylphenylprogylamide
(5,00, V, 20.3 mmol) C as described in Example 2 & C
(D)-alanyl-phenyl in mixed anhydrous synthesis
Replaced with propyl amyl. That fjt Boa -2
,6-dimethyl-tyrosine (6,28,@, 20.3
mmol) and inbutyl chloroformate (2,77y
, 20.3 mmol]. dimethyl formua
Mido was replaced with 0H2Cj2 as a solvent. reaction mixture
was treated as in Example 2, and the resulting oil (ICL62#) was
Purified by column chromatography against lumsilica
and eluted with 3-5 methanol/methylene chloride.
Split the stereomers. NMR: (ODCJ3)yneF'-(D)alanyl
Methyl J1.26.6HN-alkyl, but3.50-3
．． 80.2H: 4.80~5.25, 2H: 5.25~
5.75H0 Then each diastereomer was mixed with dioxane (HCj) and ice.
Treatment with acetic acid (as in Example 2) removes the two dimethylamino acids of the title compound.
Astereomers were obtained. Example 52 N((1,1-dimethylethoxy]carbonyl]-2,
6-dimethyltyrosyl-N-(6-phenylsologyl)-Na-(2-zorobenyl)-D-arani
N-amide 0H N-allyl-(D)-alanylphenylzorobylamide
(5,00,9,20,3 mmol) as described in Example 2
(D)-alanyl-phenylzolo in mixed anhydrous synthesis
Replaced with pyramide. Boa -2,6-shime
Tyrutyrosine (6, 28, 9, 20, 3 mol),
N-methylmorpholine (2,05ji. 20.6 mmol) and indityl chloroformate
(2,77#, 20.3 mmol). Dimethylformamide is used as a solvent for 0H2 (alternative to J2).
did. The reaction mixture was worked up as in Example 2 and the product oil (10
, 62g) was subjected to column chromatography on elm silica.
3-5% methanol/methylene chloride
The diastereomers were separated. NMR: 1st isomer from (aDcz3) column:
(D) -alanyl mail, ro, 4a, t, h
1. oo ~1.50 (rotamer) 3H:N-allyl
(Propenyl)/3.50-3.80 $2 H: 4
．． 80-5.25.2H: 5.25-5.75.1 2nd isomer from HO NMR (CDC4) column: D-ara
Nylmethyl J 1.00-1.50 (o-tamer)
3H: N-allyl (zorobenyl) 3.50-3.80
．． 2H:4.80-5.21.2)1:5.25-5.
75 1H. Example 53 H 1.00 g of the early migrating isomer of Example 52 as described in Example 2.
, glacial acetic acid, (6m) and 6.2 N HfJ/dioxa
(2,7 m) to obtain the desired (D) -2,6-
di) f-rutyrosyl N-(3-phenyldecour-Nα
-(2-7'Lopuel)-D-alaninamide hydrochloride
Obtained. 026H35N303・H(J・”/2 H2O(]n
W 4 B 3 , 05 ) Theoretical value: (:!64.
65:H7,72;N8.70;(J7.34 Actual value: 06449:H7,61;Na-74:C
J, 7.45 [α] = −48,6O NMR: (DMSOd,)in? -(D)-Alani
Methyl J0.47+1.13 (Rotamer)%3H
:N-allyl (propenyl)/4.50-5.50.2
H; 5.25-5.85, IHo late moving 7 lactations were treated as above and L, D
The isomer was obtained. 026H35N303・HCJ”/2 H2O(m W
483-05) Theoretical value: c64.65; a7-
72: Na, 70; Cj 7.34 Actual value: Cj64-87: H7,5+! S:Na,
60:C17,66 [α]D=+117.9O NMR: (D) Alanylmethyl j=1.06d Example 54 3-phenylpropyl 4-EC2,6-dimethyl-4-
(phenylmethoxy)phenyl)methyl:]-]5-o
Kin-2-phenyl-3-oxa ψ lysine xylene
2,6-dimethyltyrosine hydrochloride (20,0#) in water
It was dissolved in 11. -8.5 (10% 1JaOH water bath solution
Pencil chloroformate (14,3II
) were added to some of them. -I in water 9% NaOH 12 hours 7
It was maintained at ~8. The reaction mixture was then acidified (conc. H(J
)l, extracted with ethyl acetate. Saturation of the aqueous layer with NaCj
The mixture was combined and extracted three times with ethyl acetate. Combine the π machine fractions and dehydrate (Na2SO4)
L, filtered and stripped to give an oil. This oil is
Trituration with ether/hexane gave a solid. Powder this solid
Mortar and pestle), 420.11
Dry overnight at 0 torr. The generated N-carboben 1xy(Z)-2,6-di
Methyltyrosine (IFl, a portion of 43.7 mmol)
Dissolved in DMF 200- and benzyl at room temperature for 16 hours.
Bromide (29.9M, 20.Oat, 174.7M)
Rimol] and potassium carbonate (1s, i, !i+, 131
．． 1'13 mol). Dilute the reaction mixture with water 1,7
1 and extracted twice with 0H2CJ2. organic frac
Combine the sections and dehydrate CMgBO4) L, Ill.
The oil was obtained by filtering and stripping. This oil is ethyl acetate
Column chromatography on silica del using hexane/hexane eluent.
It was subjected to matography. The main insects taken are N-Z-2, 6-1
'Methyltyrosine benzyl ester. this substance
(11.1 g, 22.5 mmol) is directly added in the next step.
I heard from you. Sodium hydride in mineral oil (28.2 mmol)
Wash the suspension with petroleum ether and dilute with DMF (20
0rnl). N-Z-2,6-dimethylthi
I got 7JO from Rosin Penzyl Ester. 1
After stirring for 0 minutes, Penzilde O? Ido (3,20ta
Immediately chop 4-601゜26.9 mm IJmol)
added. The mixture was stirred for 16 hours and processed as above.
The dibenzylated product 13,9' was obtained. The generated O-benzyl-N-z-2,6-dimethyltyro
Synbenzyl ester is 51C, methano, as described in Example 1.
Hydrolyzed to the free acid with sodium hydroxide, 0-base
Njiru-N-'Z-2,6-dimethyltyrosine 12.1
．． I got a 9. This acid (12 g, 27.7 mmol) was
Filled the 5-person molecular sieve (8-12 sieves)
500-round bottom single class flask with Knoxley extractor
I put it in. 1.1.1-Trichrominita in this flask
N (350-), Penzaldehy? C5, 62m1゜5
．． 86.9.5.54 mmol) and toluene-sulfur
Hon-I N20 (5-271, 27.7 mmol
] was charged. Place this flask in an oil bath (temperature 120°C).
) and the mixture was refluxed for 16 hours. Then mix the reaction
The mixture was cooled and washed with saturated NaHOO3. that water book
was rewashed twice with aH2CJ, 2. all organic flax
Combine the sections, dehydrate (MgSOa), filter, and rinse.
Trig the silica with ethyl acetate/hexane eluent.
It was then subjected to Erycolumn chromatography. Notation f hi compound
was isolated as a solid, washed with ethanol and purified with ether.
I washed it with NMR diaromatic proton J 4.21 m%
Benzyl Zek f 4.99
). Integration shows three benzyl (idene) groups
. Example 55 3-phenylpropyl 4-[[2,6-cymethyl-4-
(phenylmethoxy)-phenyl]methyl]-4-methy
Ru-5-okino 2-fer-3-oxadelidifuka
Lupoxylate magnetic stirrer, thermometer, dropping funnel, Y-tube
500-maru equipped with (connected to N2 population and drying pipe outlet)
Charge the bottom flask with anhydrous THII' (150 tons).
, cooled to −60° (dry ice bath). hexamethi
Ludisladen potassium toluene solution (0,653M,
21.0m, Carrerie - chemical company, American
I got it all. The solution was cooled to -70° and the table of Example 54
Tap (10
0ml)! Drop the liquid rapidly and keep the reaction temperature below -62°.
I kept it. Stir the mixture in the cold bath for 30 minutes, then remove the cold bath.
Excluding A. Stir for another 30 minutes at room temperature and raise the reaction temperature to -12°.
Ta. Re-immerse in a cold bath at the reaction temperature and return the temperature to -700.
Ta. Iodide fikC1,05d, 2.40g. 16.9 mmol) was added immediately, and after another 10 minutes,
I removed the cold bath. Warm the reaction mixture to room temperature and remove the cold bath.
After 3 hours, the mixture was exposed to N20 (200-), 0.
5 NKH8O, (50@g), saturated saline (200t
Rt), and z-TkC200rd). water
Wash the Shuso with ether, combine the organic fractions,
Dehydrated (MgSO4) L, filtered and stripped
and obtained oil. The oil was extracted using ethyl acetate/hexane eluent.
was subjected to silica del column chromatography and expressed as
I got a compound. NMR: f 2.71 α methyl group in A,
6 protons. Example 56 α,2,6-drimethyl-4-(phenylmethoxy)-
α-[[(phenylmethoxinecarbonyl]amino]be
The title compound (2,42, V) of Zenepropanoic acid Example 55 was mixed with
cz2: Dissolved in methanol 5-, methanolic Na
oa (IN, 100 m). stirring
After 3 hours of stirring, the mixture was concentrated to 75- and diluted to 500- with water.
Diluted and extracted twice with ether to remove acidic impurities.
. The aqueous phase was acidified with 0.5 N KH80, OH2
Extracted four times with C22. Combine the aH2cz2 fractions.
Drain, dehydrate (MgSO4), filter, and strip.
The title compound (1,7!1M) was obtained. NMR:
α methyl group/f2-75゜Example 57 α, 2.6-)limethyl-N=[(phenylmethoxy)
carbonyl)-0-(3-phenylpropyl]tyrosyl
-N-(3-phenylprogyl)alaninamide The compound described in Example 56 was mixed under anhydrous conditions as described in column 2.
Reacted with 2-protected dipezotide amide (acid 1.75
& , 3.91 mmol: N-methylmorpholine skin
42.9, 4.11 mmol; inbutyl chlorophor
mate 0.53m, 4.03 mmol: (D)-arani
Luphenylpropylamide o, ss, y. 4.11 mmol) was obtained. Product 2.32 & eta
Nor: Methyl t,-butyl ether: Ammonium hydroxide
Silica del column chromatography using chromium eluent
It was served to Split the two diastereomers and
Bioisomers and late developmental isomers were obtained. Example 58 α,2.6-)limethyl D-tyrosyl-N-(3-phene
Nilbrovir]-D-Alaninamide H Example 570 The notation isomer (1, DI) which occurs more rapidly
710 at hydrogen pressure 6Opθ1 for 17 hours at room temperature in methanol
Water split. Filter the mixture to remove the catalyst and refilter.
It was then stripped to remove fine particles. Dissolve the residue in ethanol/water/methanol, filter,
Reduce the volume with a stream of nitrogen and lyophilize to give the title compound, D,
The D-isomer was obtained. NMR: α-methyl group/two rho
About the theme J2.11 and 2.25:No1.21
d is alanylmethyl, J=7H2゜[α]D=-2
3.2°. 024H33N303'work/4H20(m,
w416.05). Theoretical value: 069.29:H8, 12:N10.10
Actual value: C! 69.24:H8,11;H9,81
Mo59 α,2,6-trimethyl-L-tyrosyl-N-(6-
phenylpropyl)-D-alanine amide Example 560 and more
The slowly occurring notational isomer is treated as described in Example 57.
The title compound, L and D isomers were obtained. NMR: f 1.10 d, J=7 [11Z, [
α〕9=+90.1°. c2. a33N3o3 (mw 4 1 1.54
) Theory file: c70.04; a8-08:N
IC1,21 actual value: (!70.41:H7,95
:N10.21 Example 60 Glue-sedator binding properties and biological properties of the following 16 compounds of the present invention
The quality of
The results are shown in Table 1. Standard screening for rising tests
The dose was 10 nq/hs-C0 and p,o. Ogi
The standard screening dose for the ate binding test is 10-5 molar
1 2 2.9x1F7 Activity Activity 3 4.2x
1o-7 activity Activity 4 7.5X10-8 activity Activity 5 1.
3X10””7 Active Inactive 6
4.7xi13-a Inactive Inactive
11 6, lX1O-' Active Active 9 Inactive
Sex Activity Activity 12 3.6XID-' Activity Activity 13
1.8X10-'g! Inactive T
a14 1.4x10-7 activity
Inactive 15 6-OXlo-” Active Active 16
3.0X10"-7 active inactive 23 L6x1
0-' Activity Activity 25 2.0X10-b
g a inert 27 3.6X10-7
Oily Active 28 2.2x10-8 Active Active
Gender b = activity means the effect of the following Suf 1)-ningyoga
do. (10~/kliI).

Claims (91)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is lower alkoxy or -O-(CH_2
)_n-phenyl (this phenyl is a halogen, -NO_
2, may be substituted with -CN, -NH_2 or lower alkyl, n is 1 to 4), and R^2 and R^3 represent lower alkyl, halogen, lower alkoxy, or R^2 or one of R^3 is hydrogen and the other is lower alkyl lower alkoxy or halogen; R^4, R
^5, R^6 are hydrogen, lower alkyl, lower akenyl, or -(CH_2)_m-cycloalkyl (however, m is 1 to
4 and cycloalkyl has 3 to 8 carbon atoms), R^1^0 is -(CH_2)_p-phenyl (p is 1 to 4), and V is racemic or Indicates an asymmetric carbon that can be in the D or L form, and W can represent a racemic form or a D or L form in which R^7 and R^8 are present, but
When they are not the same, it indicates an asymmetric carbon, and R^1 is R^4, R^
5, when at least one of R^6 or R^9 is lower alkyl, it may be hydroxy] and pharmaceutically acceptable acid addition salts thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is lower alkoxy or -O-(CH_2
)_n-phenyl, phenyl is halogen, -NO
_2, -CN, -NH_2 or lower alkyl may be substituted, n is 1 to 4, R^4, R^5 and R^
6 is hydrogen or lower alkyl), the compound according to claim 1, its acid addition salt and its optical isomer. (3) O-ethyl-2,6-dimethyltyrosyl-N-(
3-phenylpropyl)-D-alaninamide, and its acetate or hydrochloride. (4) 2,6-dimethyl-O-(1-methylethyl)-
The compound according to claim 2, which is tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (5) N,O,2,6-tetramethyltyrosyl-N-(
The compound according to claim 2, which is 3-phenylpropyl)-D-alaninamide hydrochloride. (6) N,O,2,6-tetramethyltyrosyl-N-(
3-Phenylpropyl)-L-alaninamide hydrochloride. (7) The compound according to claim 2, which is N,2,6-trimethyl-O-(phenylmethyl)-tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (8) The compound according to claim 2, which is 2,6-dimethyl-O-(phenylmethyl)-tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (9) O-{(4-chlorophenyl)methyl}-2,6
-dimethyltyrosyl-N-(3-phenylpropyl)-
Claim 2, which is D-alaninamide hydrochloride
Compounds described in Section. (10) 2,6-dimethyl-O-{(2-methylphenyl)methyl]tyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride, the compound according to claim 2. (11) 2,6-dimethyl-O-[(4-nitrophenyl)methyl]tyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride, the compound according to claim 2. (12) O-[(4-fluorophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride, the compound according to claim 2. (13) 2,6-dimethyl-O-[(4-methylphenyl)methyl)tyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride, the compound according to claim 2. (14) O-[[4-(1,1-dimethylethyl)phenyl]methyl]-2,6-dimethyltyrosyl-N-(3
-Phenylpropyl)-D-alaninamide hydrochloride. (15) O-[(4-cyanophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
-D-alaninamide hydrochloride, the compound according to claim 2. (16) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, one of R^4, R^5, R^6 and R^9 is lower alkyl, and the others are hydrogen, patent A compound according to claim 1. (17) N,2,6-trimethyltyrosyl-N-(3-
17. The compound according to claim 16, which is (phenylpropyl)-D-alaninamide hydrochloride. (18) The compound according to claim 16, which is 2,6-dimethyl-DL-tyrosyl-Nα-methyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (19) 2,6-dimethyl-DL-tyrosyl-N-(3
-Phenylpropyl)-D-alaninamide hydrochloride. (20) α,2,6-trimethyl-D-tyrosyl-N-
17. The compound according to claim 16, which is (3-phenylpropyl)-D-alaninamide. (21) α,2,6-trimethyl-L-tyrosyl-N-
17. The compound according to claim 16, which is (3-phenylpropyl)-D-alaninamide. (22) Compounds and pharmaceutically acceptable acid addition salts having the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^6 is 2-propenyl or cyclopropylmethyl). (23) 2,6-dimethyl-DL-tyrosyl-N^α-
23. The compound according to claim 22, which is (cyclopropylmethyl)-N-(3-phenylpropyl)-O-alaninamide hydrochloride. (24) The compound according to claim 22, which is 2,6-dimethyltyrosyl-N-(3-phenylpropyl-Nα-[2-propenyl]-D-alaninamide hydrochloride. (25) The compound according to claim 1, which is 2,6-dichlorotyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (26) 2,4,6-trimethylphenylalanyl-N
-(3-phenylpropyl)-D-alaninamide hydrochloride. (27) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is straight or branched lower alkyl, OCO
_2 alkyl, hydrogen, OCO_2 aryl, OCON alkyl or aryl, R^2 and R^3 are hydrogen, lower alkyl, halogen or alkoxy having 1 to 6 carbons, R^4, R^5, R ^6, R^7 and R
^9 is the same or different and is hydrogen or lower alkyl,
R^7 and R^8 are ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, q and p are 0 to 5), and R^8 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (m is 0-5, z is 0-5
2), and R^1^0 is hydrogen, lower alkyl, cyclic, bicyclic, tricyclic or tetracyclic C_1-C_1_0 alkyl, alkyl alkylcarboxylate or (CH_2)_
nA (A is CO_2R^1^1, R^1^1 is hydrogen or lower alkyl, and n is 1 to 4), or R^1^0 is ▲ where the mathematical formula, chemical formula, table, etc. There is▼, n
is 1 to 4, and both R^9 and R^1^0 may be ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and n
is 1 to 4, or R^1^0 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and B and D are phenyl, substituted phenyl (
Substituents are F, N(CH_3)_2, CO_2R^1^3
, CN, OH, heteroaryl, cycloalkyl or substituted cycloalkyl), R^1^2 and R^1^3 are hydrogen or lower alkyl, and x is C, C
H and CH_2 are absent, Y is C, CH, CH_2 or a heteroatom O, S, NH, B and D representing phenyl share the 2-position with each other, and V is racemic or D-form. or an asymmetric carbon which can have an L-form, and W represents an asymmetric carbon when R_4 and R_5 are not the same and can represent a racemic form, a D-form, or an L-form) and pharmaceutically acceptable compounds. Acid addition salts. (28) R_1 is C_1-C_4 lower alkyl, hydroxy, lower alkoxy, or substituted or unsubstituted aralkoxy, and R_2 is hydrogen, halogen, C_1-C_
4 lower alkyl or lower alkoxy, R_3 is hydrogen, C_1-C_6 lower alkyl, lower alkoxy or halogen, R_4 and R_5, R_6, R_8 and R_9 are the same or different, hydrogen, lower alkyl, alkenyl or C_1-C_6 cycloalkylalkyl, R^7 is C_1-C_6 lower alkyl, R_
When 2 and R_3 are hydrogen or lower alkyl, R^4,
At least one of R^6 or R^9 is not hydrogen, or R^1 is lower alkyl, lower alkoxy, or substituted or unsubstituted aralkoxy, and Ar is phenyl or substituted phenyl (one or more C_1-C_6 lower alkyl, substituted with one or more amino, hydroxy, halogen, nitro or C_1-C_6 lower branched alkoxy), and the optically active compound is a racemate, a pair of diastereomers, or a split diastereomer, the patent A compound according to claim 27. (29) The compound according to claim 28, wherein R^2 and R^3 are lower alkyl or halogen. (30) The compound according to claim 29, wherein R^2 and R^3 are both lower alkyl or halogen. (31) The compound according to claim 30, wherein R^1 is lower alkyl. (32) The compound according to claim 30, wherein R^1 is hydroxyl. (33) The compound according to claim 30, wherein R^1 is lower alkyl. (34) The compound according to claim 30, wherein R^1 is substituted or unsubstituted aralkoxy. (35) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is straight or branched lower alkyl, OCO
_2 alkyl, hydrogen, OCO_2 aryl, OCON alkyl or aryl, R^2 and R^3 are hydrogen, lower alkyl, halogen or C_1-C_6 alkoxy, R^4, R^5, R^6, R ^7 and R^8 are the same or different and represent hydrogen or lower alkyl, R^7
and R^8 are ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, q and p are 0 to 5), and R^8 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, l, m is 0-5, z is 0-2), and R^1^0 is hydrogen, lower alkyl, cyclic, bicyclic, tricyclic or tetracyclic C_1-C_
1_0 alkyl, alkylcarboxylalkyl or (
CH_2)_nA(A is CO_2R^1^1, R
^1^1 is hydrogen or lower alkyl, n is 1 to 4), and R^1^0 is ▲There is a mathematical formula, chemical formula, table, etc.▼ (n is 1 to 4) , or R^9 and R^1
^0 may also be ▲a mathematical formula, chemical formula, table, etc.▼ (n is 1 to 4), or R^1
^0 has ▲mathematical formulas, chemical formulas, tables, etc.▼ (B and D are phenyl, substituted phenyl (substituents are F, N (
CH_3)_2, CO_2R^1^3, CN, OH, heteroaryl, cycloalkyl or substituted cycloalkyl), R^1^2 and R^1^3 are hydrogen or lower alkyl, is C, CH, CH_2 or none, and Y is C, CH, CH_2 or a heteroatom O
, S, NH, or phenyl, B and D share the 2-position with each other, and V is a racemic body, a D body, or a L body.
W indicates an asymmetric carbon that can take the form of a racemic form, a D form, or an L form) and a pharmaceutically acceptable acid. Added salt. (36) R_1 is C_1-C_4 lower alkyl, hydroxy, lower alkoxy, or substituted or unsubstituted aralkoxy, and R_2 is hydrogen, halogen, C_1-C
_4 is lower alkyl or lower alkoxy, R_3 is hydrogen, C_1-C_6 lower alkyl, lower alkoxy or halogen, R_4 and R_5, R_6, R_8 and R_9 are the same or different, hydrogen, lower alkyl, alkenyl or C_1-C_6 is cycloalkylalkyl, R_7 represents C_1-C_6 lower alkyl, and R_2 and R_3 are hydrogen or lower alkyl;
At least one of ^4, R^6 or R^9 is not hydrogen or R^1 is lower alkyl, lower alkoxy or substituted or unsubstituted aralkoxy, and Ar is phenyl or substituted phenyl (one or more C_1 -C_6 lower alkyl, one or more amino, hydroxy, halogen,
36. The compound according to claim 35, wherein the optically active compound is a racemate, a pair of diastereomers, or a resolved diastereomer. (37) The compound according to claim 36, wherein R^2 and R^3 are lower alkyl or halogen. (38) The compound according to claim 37, wherein R^2 and R^3 are both lower alkyl or halogen. (39) The compound according to claim 38, wherein R^1 is lower alkyl. (40) The compound according to claim 38, wherein R^1 is hydroxy. (41) The compound according to claim 38, wherein R^1 is lower alkyl. (42) The compound according to claim 38, wherein R^1 is substituted or unsubstituted aralkoxy. (43) The compound according to claim 38, which is 2,4,6-trimethyl-L-phenylalanyl-N-(3-phenylpropyl)-D-alaninamide monohydrochloride. (44) 2,4,6-trimethylphenylalanyl-N
-(3-phenylpropyl)-D-alaninamide 1
39. A compound according to claim 39, which is a hydrochloride salt. (45) N,2,6-trimethyltyrosyl-N-(3-
41. The compound according to claim 40, which is (phenylpropyl)-D-alaninamide monohydrochloride. (46) N,2,6-trimethyltyrosyl-N-(3-
41. The compound according to claim 40, which is (phenylpropyl)-D-alaninamide hydrochloride. (47) 2,6-dimethyl-DL-tyrosyl-N^α-
41. The compound according to claim 40, which is methyl-N-(3-phenylpropyl)-D-alaninamide monohydrochloride. (48) 2,6-dichlorotyrosyl-N-(3-phenylpropyl)-D-alaninamide monohydrochloride,
A compound according to claim 40. (49) 2,6-dimethyl-DL-tyrosyl-N^α-
41. The compound according to claim 40, which is (cyclopropylmethyl)-N-(3-phenylpropyl)-D-alaninamide monohydrochloride. (50) The compound according to claim 40, which is 2,6-dimethyltyrosyl-N-(3-phenylpropyl)-N^α-(2-propenyl)-D-alaninamide. (51) O,2,6-trimethyl-DL-tyrosyl-N
-(3-phenylpropyl)-D-alaninamide 1
42. The compound according to claim 41, which is a hydrochloride salt. (52) O,2,6-trimethyltyrosyl-N-(3-
42. The compound according to claim 41, which is (phenylpropyl)-D-alanine amide. (53) The compound according to claim 41, which is O-ethyl-2,6-dimethyl-DL-tyrosyl-N-(3-phenylpropyl)-D-alaninamide acetate/hydrochloride. (54) 2,6-dimethyl-O-(1-methylethyl)
42. The compound of claim 41, which is tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (55) 2,6-dimethyl-O-(1-methylethyl)
42. The compound of claim 41, which is tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (56) N-[(1,1-dimethylethoxy)carbonyl]-O-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide, described in claim 41 compound. (57) O-methyl-L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide monohydrochloride,
A compound according to claim 41. (58) N,O,2,6-tetramethyltyrosyl-N-
42. The compound of claim 41, which is (3-phenylpropyl)-D-alaninamide hydrochloride. (59) N,O,2,6-tetramethyltyrosyl-N-
42. The compound according to claim 41, which is (3-phenylpropyl)-D-alaninamide monohydrochloride. (60) N,2,6-trimethyl-O-(phenylmethyl)-DL-tyrosyl-N-(3-phenylpropyl)
-D-alaninamide monohydrochloride, the compound according to claim 42. (61) 2,6-dimethyl-O-(phenylmethyl)-
Claim 42, which is L-tyrosyl-N-(3-phenylpropyl)-D-alaninamide monohydrochloride.
Compounds described in Section. (62) 2,6-dimethyl-O-(phenylmethyl)-
43. The compound of claim 42, which is D-tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (63)O-[(4-chlorophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
43. The compound according to claim 42, which is -D-alaninamide monohydrochloride. (64) 2,6-dimethyl-O-[(2-methylphenyl)methyl]tyrosyl-N-(3-phenylpropyl)
43. The compound according to claim 42, which is -D-alaninamide monohydrochloride. (65) 2,6-dimethyl-O-[(4-nitrophenyl)methyl]tyrosyl-N-(3-phenylpropyl)
-D-alaninamide monohydrochloride, the compound according to claim 42. (66)O-[(4-fluorophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
43. The compound according to claim 42, which is -D-alaninamide monohydrochloride. (67) 2,6-dimethyl-O-[(4-methylphenyl)methyl]tyrosyl-N-(3-phenylpropyl)
-D-alaninamide monohydrochloride, the compound according to claim 42. (68) O-[(4-(1,1-dimethylethyl)phenyl)methyl]-2,6-dimethyltyrosyl-N-(3
-Phenylpropyl)-D-alaninamide monohydrochloride. (69)O-[(4-cyanophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
-D-alaninamide monohydrochloride, the compound according to claim 42. (70) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is lower alkoxy or -O-(CH_2
)_n-phenyl (However, this phenyl is a halogen, -
may be substituted with NO_2, -CN, -NH_2, or lower alkyl, n is 1 to 4), and R^2
and R^3 represent lower alkyl, halogen, lower alkoxy, or one of R^2 or R^3 is hydrogen,
The other is lower alkyl, lower alkoxy or halogen, R^4, R^5, R^7, R^8 and R^9 are hydrogen or lower alkyl, and R^6 is hydrogen, lower alkyl, lower alkenyl. or -(CH_2)_m-cycloalkyl (m is 1 to 4, cycloalkyl has 3 to 4 carbon atoms)
8) and R^1^0 is -(CH_2)_p
- phenyl (p is 1 to 4), V is racemic or D
Indicates an asymmetric carbon that can take the form of body or L form, and W is R^7
and R^8 are not the same, racemic, D or L
When it can take a body, it shows an asymmetric carbon, R^1 is R^4, R
and pharmaceutically acceptable acid addition salts. (71) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is lower alkoxy or -O-(CH_2
)_n-phenyl, and this phenyl is a halogen, -
May be substituted with NO_2, -CN, -NH_2 or lower alkyl, n is 1 to 4, R^4, R^3
and R^6 is hydrogen or lower alkyl) and pharmaceutically acceptable acid addition salts and optical isomers. (72) O-ethyl-2,6-dimethyltyrosyl-N-
72. The compound according to claim 71, which is (3-phenylpropyl)-D-alaninamide and an acetate or hydrochloride. (73) 2,6-dimethyl-O-(1-methylethyl)
72. The compound of claim 71, which is tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (74) N,O,2,6-tetramethyltyrosyl-N-
72. The compound of claim 71, which is (3-phenylpropyl)-D-alaninamide hydrochloride. (75) N,O,2,6-tetramethyltyrosyl-N-
72. The compound of claim 71, which is (3-phenylpropyl)-D-alaninamide hydrochloride. (76) N,2,6-trimethyl-O-(phenylmethyl)-tyrosyl-N-(3-phenylpropyl)-D-
72. The compound of claim 71, which is alaninamide hydrochloride. (77) 2,6-dimethyl-O-(phenylmethyl)-
72. The compound of claim 71, which is tyrosyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (78)O-[(4-chlorophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (79) 2,6-dimethyl-O-[(2-methylphenyl)methyl]tyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (80) 2,6-dimethyl-O-[(4-nitrophenyl)methyl]tyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (81)O-[(4-fluorophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (82) 2,6-dimethyl-O-[(4-methylphenyl)methyl]tyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (83) O-[[4-(1,1-dimethylethyl)phenyl]methyl]-2,6-dimethyltyrosyl-N-(3
-Phenylpropyl)-D-alaninamide hydrochloride. (84)O-[(4-cyanophenyl)methyl]-2,
6-dimethyltyrosyl-N-(3-phenylpropyl)
72. The compound of claim 71, which is -D-alaninamide hydrochloride. (85) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, one of R^4, R^5, R^6 and R^9 is lower alkyl, and the other is hydrogen) The compound according to claim 70, which has. (86) N,2,6-trimethyltyrosyl-N-(3-
86. The compound of claim 85, which is (phenylpropyl)-D-alaninamide hydrochloride. (87) The compound according to claim 85, which is 2,6-dimethyl-DL-tyrosyl-Nα-methyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (88) The compound according to claim 85, which is 2,6-dimethyl-DL-tyrosyl-N-methyl-N-(3-phenylpropyl)-D-alaninamide hydrochloride. (89) α,2,6-trimethyl-D-tyrosyl-N-
86. The compound of claim 85 which is (3-phenylpropyl)-D-alaninamide. (90) α,2,6-trimethyl-L-tyrosyl-N-
86. The compound of claim 85 which is (3-phenylpropyl)-D-alaninamide. (91) General formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼