JPS63198699A - Peptide having sulfate ester group - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a sulfate ester-containing peptide 'Vc that retains feeding inhibitory properties and is capable of stimulating gallbladder contraction. These peptides are 6-
It has 9 amino acids. However, all of these peptides are structurally different from the following two peptides of similar size that are known to have dietary suppressive properties: Structure: A
sp-Tyr(SOsH)-Met-Gly-Trp
CCK-8 with -Met-Asp-Phe-NHz
and structure: Glp-Gin-Asp-Tyr (SOs
H)-Thr-Gly-Trp-Met-Asp-P
Ceruletide with hi-NH2. The peptides of the invention are not naturally occurring, but rather must be synthesized.

Summary of the Invention The compound of the invention is a peptide of formula (1): where Q is H3H-AsP, H-βAs p, H-DAs
p, H-MeAsP, For, Ac, Suc, de
sQ or R'R'' CHOCO, Y is H, (S)-NH, (R)-R' N or (S)-
R'N, M is MeLDMettMeMet, MetO, Ahx+
DAhx, MeAhx, Leu, MeLeu, Prow
lle, Melle or L7s, G is GlytD
A1a+Pro or Sar, W is TrPMeTr
p or Nal, X is MeLMeMeLMetO,
Ahx, MeAhx+Leu, MeLeu, Ile, M
eIls, Pro or L7s, J is A sp e DA sp * M e A
s p precept is Asn, Fl is (S)-NH, (S)
-R'N or (R)-'R'N, Ft is H* CI, I + B r + F * NO
t + NHt + R' or OR', and Z Nu, , NHR? ]l[NR'R"Thea'J, R1 and R1 are independently H or lower alkyl, R3, R4 and R1 are lower alkyl, Ra is H or lower alkyl, R7 and R1 are lower alkyl and pharmaceutically acceptable salts thereof, provided that: (1) Q is desQ when Y is H; (2) in the same peptide, Q is H-Asp or Ac,
Y is (S)-NI(, and M is Met.

Either MetO, Ahx or Leu, and X is M
Either et, Meto, Ahx or Leu,
G is GIy, DAla or Pro, W is Trp, J is Asp, Fl is (S)-NH,
If 2 is NH, then Fl is not H, (3)
In the same peptide, Q is H3H-βAsp- or F
or, Y is (S')-NH, and M is M e
t * A h X or Leu, G is Gly, W is Trp, X is Met, Ahx or Leu
, if J is Asp, Fl is (S)-NH, and Z>(NH,-C-, then F2 is not H, (4) In the same peptide, Y is H and 1 ), M is Met, X is Met, G is Gly,
W is Trp, J is Asp, and Fl is (S)
-NH and 2 is NH, then Ft is not H, (5) In the same peptide, Q is SuC,
Y is (S)-NH, M is Met, and X is Me
t, G is Gly or DAla, and W is Trp
, J is Asp, and FI is (S)-NH or (
S)-R'N, and if 2 is NH, then F2 is H
Not.

The invention is also a method for producing the peptides of the invention.

The invention also relates to a method for treating obesity and a method for preventing obesity, each of which involves administering the following to a salivary mammal in need of such treatment intraperitoneally, intravenously, intramuscularly, subcutaneously or intranasally. (1) a peptide of the formula (wherein Q is H3H-AsP, H-βAsP, H-DAsP,
H-MeAsp+Forf Ac, Suct desQ
, H-Arg-AsP, Glp-AsP, Glp-Gl
u, Glp-Gln.

Suc-AsP, Glt-AsP, Pht-Asp+R
'C0-A8p+ Boa-AsP, Cbz-AsP
, H-Abut H-A1a+Boc+Cbz, or R
'R'' CHOCO, and Y is (S)-NH, (R
)-R3N or (S)-R3N, M is MeLDMet, MeMet, Meto, Ahx.

DAhx, MeAhx, Leu+MeLeu+Pro+
Ile, Melle, Lys, Thr, Abu+Val
'+Mox, GIy, Phe, Tyr, Kai is Trp, G is G1y+DA1a, Sar, DTrPPro or βAla, W is Trp*MeTrpeNa1. DTrp+Trp(
Me).

Trp(5-F) precept is Trp(6-F) and X is M
eLMeMet, Meto+Ahx, MeAhx.

Leu, MeLeu, I 1 e, MeI 1
e, Prop Lys.

I) Met + Abu or Mox, J is A
sp+DAsp+MeAsp-, βAsp or Asn, Fl is (S)-NH, (S)-R4N, (R)-NH or (R)-R'N, Fl is H+ CI+ I, Br+ FeN0z, N
Ht, R' or OR" and Z NH,, NHR'KaihaNR'R"Thea'),
R1 and R1 are independently H or lower alkyl, R1, R4 and R1 are lower alkyl, R1 is H or lower alkyl, R? , R1 and Ro are lower alkyl) and pharmaceutically acceptable derivatives thereof, provided that (1) Q is desQ when Y is H; (2) in the same L peptide, Q is H-Asp and Y is (S
)-NH, M is Met, X is Met, G is Gly or Pro, W is Trp, J
If is Asp, Fl is (S)-NH, and 2 is NHt, then F2 is not H.

The invention, in its first subgeneric aspect, is defined as compounds of the invention, except as further limited as follows: Q is H-AsP, H-βAsP, H-DAsP, F
or+Ac, Suc, desQ or R' R” CHO
CO: Y is H, (S)-NH or (S)-R3N
;M is MettMeMeteAhx,M
eAhx, LeulMeLeu, He, Melle or Pro; G is Gly or DAla; W is Trp; X is MetoMeMeLAhx, MeAhx+Leu+
MeLeu, I 1 e, Me I 1 e or P
ro; J is Asp; Fl is (S)-NH or (S)-R'N; Ft is H, CI, No, , NH,, R' or OR''; 2 is Nl-1.

The invention further provides, in a second subgeneric aspect, that M is MeMeLM.
eAhx, MeLeu or MeIle and X is M
It is defined as in the case of the first subgenus, except that it is limited to 5 and not eMet, MeAhx, MeLeu, or Melle.

Compounds with increased dietary suppressive activity over a 3 hour feeding period compared to CCK-8 are: Peptides of the formula: where Q is H-βAsp+ForeSuc, desQ or R'
R” CHOCO, Y is H or (S)-NH, M is Met, Ahx, Leu or He, G is G
Iy, W is Trp, X is MettAhxeLeu or Ile, J is A
sp, Fl is (S)-NH precept is (S)-R'N, Ft is H, No, , 'R" or OR", 2 is NH
, R1 and R1 are independently H or lower alkyl, n@, R4, RI and RI are lower alkyl, and pharmaceutically acceptable salts thereof, provided that: ( When 11Y is H, Q is desQ, (2)
In the same peptide, Q is H-βAsp.

For or Ac, Y is (S)-N'H, M
is either Me+Ahx or Leu, and X is Me
t, Ahx or Leu, and Fl is (S)
-NH, then F2 is not H, (3) in the same peptide, Y is H and M is Met,
If X is Met and Fl is (S)-NH,
Fl is not H, (4) In the same peptide, Q is Suc,
Y is (S)-NH, M is Met, and X is Me
t and Fl is (S)-R'N, then Ft is not H.

In an additional subgeneric aspect of the invention, a method of treating obesity or preventing obesity, further comprising any of the compounds of the invention or the compounds disclosed in the first or second general aspect of the invention. limited to administering.

In a closely related invention, the compounds of the invention are (R)-NH
and further in the same peptide, Q is H
-Asp, M and X are Ile, and G is Gly
, J is Asp, Fl is (S)-NH, and 2 is NH, so that the compound of this related invention is of formula (1), where Q is H3H-As p , H-βAs p* H-DA
sp, H-MeAsP, For, Ac+ Suc,
desQ or R' R” CHOCO, Y is (R)-NH, M is M e t + D M e t @ M e M
e t g M e t Og A h x +DA
hx, MeAhx+Leu, MeLeu, PrO.

Ile, Melle or L7m, G is GIy, D
Ala, Pro or Sar, W is TrPMeTr
p or Nal, and X is Met, MeMet, Met
o, Ahx, MeAhx.

Leu, MeLeu+ Ile, Melle, Pro or Lys, J is AsP, DAsP, MeAsp or Asn,
Fl is (S)-NH, (S)-R'N or (R)-R'
N and F! is He CIt I r B r + F v N
Ox e NH* t R' or OR", Z NH,, NI (R ding or Gt NR'R'Thea'
) R1 and R1 are independently K H or lower alkyl, R1, R4 and R1 are lower alkyl, R" is H or lower alkyl, and R7 and R1 are lower alkyl, peptides and drugs (1) In the same peptide, Q is H-Asp;
M and X are Ile, G is 017, and J is As
p, Fl is (S)-NH, and 2 is NH, then F2 can be H.

detailed description definition "Lower alkyl" contains 1 to 6 carbon atoms.

(R) and (S) refer to the absolute configuration of adjacent methine carbons. When Y is (S)-NH, then CI(.

When CHCO is in the L-configuration and Y is (R)-NH, then CHCO is a D-G father. Similarly, when Fl is (S)-NH or (R)-NH, then CH.

F'　CHCO are in the L or D configuration, respectively.

All optically active amino acids are in the L-configuration unless otherwise indicated.

H-AsP, H-βAsp+H-DAsP, H-MeA
sp+H-A r g t H-A bu and H-A
H in la represents hydrogen.

DasQ, which appears when Y is H, means that there is no Q.

R'R'' CHOCO is of the following formula: H1)p(S
O3H) is the following formula: O203H? Each claim directed to a 5 CHCO- compound includes a pharmaceutically acceptable base addition salt of the compound. Base addition salts include both organic and inorganic bases such as ammonia, sodium hydroxide,
Includes those derived from calcium hydroxide, barium hydroxide, tetrabutylammonium hydroxide, ethylamine, diethylamine, triethylamine, etc.

In alternative representations (formula 11 used for brevity), the peptides are also represented according to conventional representation, e.g. H-As p-DTyr (SOs H) -Me t
-Gly-Trp -Me t -As p -Ph
e -NHt is 1 in equation (1), and Q is H-Asp.
, Y is (R)-NH, M is Met,
G is Gay, W is Trp, X is Met, J is Asp, Fl is (S) -NH,
F! represents a compound where is H and 2 is NH.

When amino acids, peptides, protecting groups, active groups, etc. are represented by symbols in this specification and claims, I
Conventional symbols as defined by UPAC and IUB and as used in the art are employed. Examples of symbols are listed below.

Abu --------- ------, 2-aminohexanoic acid A i b -,, ---~----2
-Aminoisobutyric acid A 1 a ----
---Alanine Arg ---------
------Argine A s n -------
-------Asparagine A sp --------
------- Aspartic acid βA sp ---
−−−−−−−−−−1~ Beta aspartic acid B
oc --------------------t-butyloxycarbonyl Cb z -------------
--- Carbobenzoxy C7s (Me) ---
----------S-Methylcysteine DA 1 a
--------------D-alanine DAhx
, ---------------D, 2-aminohexanoic acid DAsp ----------------------D-
Aspartic acid DMet----------------------
--D-Methionine D Ph e ・---------
----------D -7 22-alanine DPh e
-NHI ・------------D-Phenylalanine amide DT r p -------------
D-) Ributofan DTyr---------------------
-------D-Tyrosine E t OCO----
------ Monoethyloxycarbonyl E t P h
e −−−−−−−−−−−−N-ethylphenylalanine E t Ph e−NHt−−−−−−−
N-x tylphenylalanine amide Fmoc --
----------------9-Fluorenylmethyloxycarbonyl F o r ----------------Formyl Gln ・----- −−−−−−−−−−Glutamine G1p-1−−−−−−−−−−−−−Polyglutamine Glu, −−−−−−−−−−−−
--- Glutamic acid G 1 t -------
----------HOOC(CH*)s CO-G
ly. -1～---------Glycine Hi
a ----------------Histidine iBuOCO------1------Imbutyloxycarbonyl I 1 e, --------- ---
--------- Inleucine L e u --------
---1------Royden L 7s ---
−−−−−−−−−−−−−Risine MeAhx −−
1--------------N-Methyl-2-aminohexanoic acid MeAsp----------N-methylasunolagic acid MeLeu---- --------
---N-methylleucineMeIle----
------------N-methylisoleucine MeMe
t ------------------ N-Methylmethionine MeOCO------------ Methyloxycarbonyl MePhe ・----------- −
---N-methylphenylalanineMePhe-NH2
----------, N-Methylphenylalanine amide Met -------------------- Methionine Me t O, -1---------- ---Methionine sulfoxide MeTrp----
------N-α-methyltryptophan MeTyr
N-Methyltyrosine MeTyr (Me
) N,O-dimethyltyrosine MeTyr(M
e) -NHI N, O-dimethyltyrosinamide Mox Metokinin Nal
3-(2-su7tyl)alanine OBt
1-pensotriazolyl ester O
8u Succinimidyloxyester 0tBu t-butyl ester P
he phenylalanine Phe-N
H@ Phenylalanine amide Phe-
NHEt Phenylalanine ethylamide P
he-NHMe Phenyl-methylamide Phe-N(Et)t Phenylalanine diethylamide Phe-N(Me)t
Phenylalanine dimethylamide Phe-OH Phenylalanic acid Phe (4-CI) 5-(4-ri aa7z
2/L/) 7 Lanine Phe (4-Me)-----5-(4-methylphenyl)alanine Ninnine Pro------------------------ ---Proline PrOCO,,,, ---------n
-propyloxycarbonylresin,-
--------------Polystyrene S a r
−−−−−−−−−−−−−〜−−−Monkey; Shin S e
r-----------------Serine S
u c −−−−−−−−−−−−=−−−HOOC(
CHz )t CO-t Bu ---------
------------ t-Butyl Thr・----
−−−−−−−−−−) leonine T r p , --
−−−−−−−−−−−−−−−−)Liptophan Tr
p(5-F)・--------= 5-Fluorotryptophan T r p (6-F) ---------
---, 6-fluorotryptophan T r p (M
e), ----------, 1-methyltryptophan Tyr ----------------
-Tyrosine Tyr -Nru - - - Tyrosinamide Tyr (Me)
0-Methyltyrosine Tyr(Me)-NHz ・---
------0-Methyltyrosinamide Tyr (SO
s H) ・--------0-sulfotyrosine Ty
r(S to H)-former t------0-sulfotyrosinamide V a 1-------------------------- Valine Preferred compounds of the invention are as follows: In the test described in the "Effects of use" column, when administered at 30 μI/kg, food was suppressed by 48-100 S during a 0.5 hour feeding period. (See Table 2 below) At the time of filing this application, the most preferred compounds from the point of view of gallbladder contraction are the following compounds: Hpp(sol
H)-Met-Gly-Trp-Met-As
p-MePhe-NHt.

At the time of filing this application, particularly preferred compounds from the point of view of dietary suppression were found to be effective during a 0.5 hour feeding period when dosed at 15 μI/9 in the test described in the "Efficacy of Use" section below. It suppressed the diet by 20-72 inches. The compound is as follows: H-DAsp-Tyr(So,H)-Met-Guy-
Trp-Met-A8p-Phe-NHtiBuOco
-Tyr (SOs H)-Me t -Gly-T
rp-Me t -As p -Ph e -NHtS
uc-Tyr(SO3H)-Ahx-Gly-Trp-
Ahx-Asp-Phe-NH3H-βAs p-Ty
r (SOs H) -Me t -Gl 7-Tr
p-Me t -As p-MePhe -NH3H-
DAs p-Tyr (SOs H)-Me t-Gl
y-Trp-Met-Asp-MePhe
-Nff*For-Tyr(SO3H)-Met-Gl
y-Trp-Mst-Asp-MePhe-NH.

i BuOCO-Tyr (SOs H)-Me t-
Gly-Tr p-Me t -As p-MePh
e-NH3Hpp(So, H)-Me t-Gly
-Trp-Met-Asp-MePhe-NH.

Prα: o-'ry r (SOs H)-Me t
-Gl F-Trp-Me t -As p-Ph e
-NI(2Etoco-'ry r (SOs H)
-Me t-Gl 7-Trp-Me t -As p
-Ph e -NH.

MeOCO-Tyr (SOs H)-Me t-Gl
)'-Tr p-Me t -As p-Ph e
-MHzH-βAs p-Tyr (Sus H) -
Me t-Gly-Trp-Me t-As p-Ph
e-NHtSu c-Tyr (Sow H)-Me
t-Gly-Tr p-Me t -As p-Ph
e -NHtapp (SOs H)-Me t-G
l y-Trp -Me t-As p-Phe -N
TItH-Asp-Tyr(SOsH)-Leu-
Gly-Trp-Leu-Asp-Phe-NH2Fo
r-Tyr(SO3H)-Met-Gly-Trp-M
et-Asp-Phe-NHISu c-'ry r
(SOm H) -Ahx-Gl 7-Tr p-A
hx-As p-MePh e -NHti BuOC
O-Tyr (Son H) -Ahx-G 1 y
-Trp-Ahx-As p -MePh e -NH
3HPP(SOiH)-Ahx-Gly-Trp-Ah
x-Asp-MePhe-NH.

i BuOCO-Tyr (Son H) -Ahx
-CIy-Tr p -Ahx-As p -Phe
-NB3HpP(SO3H)-Ahx-Gly-Trp
-Ahx-Asp-Phe-Nf(.

Su c -Tyr (Son H) -Me t
-Gly-Trp-Met-Asp-MeP
h e -NH*H”DAs p-Tyr (SOs
H)-I1e-Gly-Trp-I1e-As
p-MePhe-NH2Por-Tyr(SOs
H) -I 1 e -Gly-Trp-I 1 e
-Asp-MePhe -'NH@Suc-Tyr(S
O3H)-Ile-Gly-Trp-Ile-Asp-
MePhe-NHai BuOCO-Tyr (SOs
H) -r 1 e-Gly-Trp-I 1 e-A
sp-MePhe-NH3H-As p-DTyr(S
OsH)-I1e-Gl)'-Trp-I
1 e -As p-MePhe-NH3Hpp(S
on H) -I 1 e -Gly-Trp -I
1 e -As p-M@Phe-NH* compound, E
tOCO-Tyr(SOmH)-Met-Gly-T
rp-Me t -A sp -Ph e -NH4
(L3μg/9) inhibited feeding by 72%.

At the time of filing this application, from a dietary control standpoint, the most preferred compounds are: It suppressed food intake by 50-90%.

The compound is as follows: i BuOCO-Ty
r (SOs H)-Me t-CIy-Trp-Me
t -As p-Ph e -NHaSuc-Tyr
(SO3M)-Ahx-Gly-Trp-Ahx-As
p-Phe-NH.

For-Tyr (SOB H)-Me t-01
7-Trp-Me t-As p-MePh e -N
H4i BuOCO-Tyr (SOs H)-Me
t-Gly-Trp-Me t -As p-MeP
he -NHtHpp(SO3H)-Met-Gly-
Trp-Met-Asp-MePhe-NH.

PrOCO-Tyr (SOs H,)-Me t -
G1)'-Trp-Met-Asp-Ph
e -NHtSuc-T)'r (SOI H)-Me
t-Gl 7-Trp-Me t-As p-Ph
e -HlltSu c-Tyr (SOs H)-A
hx-Gl)'-Trp-Ahx-Asp-M
ePh e -NHti BuOCO-Tyr (So
nH)-Ahx-Gly-Trp-Ahx-As
p -MePh e -NH3Hpp(SO3H)-A
hx-Gly-Trp-Ahx-Asp-MePhe-
NHti BuOCO-Tr r (SOs H)-A
hx-G 1 y-Tr p -Ahx-As p-P
h e to Hpp (Son H)-Ahx-Gly”T
rp-Ahx-Asp-Phe-M(.

Su c -'ryr (SOs H)-Me t-G
lF-Trp-Met-Asp-MePh
e-NH.

For-Tyr (Son H)-I 1 e-GI
y-Trp-I 1 e-Asp-MePhe-NH2
For-Tyr(5O3H)-I1e-Gly-T
rp-I1e-As p-MePhe-Nt (.

i BuOCO-Tyr(SOs H)-I 1 e-
Gly-Trp-I1e-Asp-MePhe
-NH.

Hpp(sos H)-I 1 e-Gly-Trp-
I1e-Asp-MePhe-NH.

Compound, Suc-Tyr(SO3H)-Ile-Gly
-Trp-Ile-Asp-MePhe-N& is 3μ!
1 in 9 suppressed food intake by 90 g during a 3-hour feeding period.

The novel sul7ate ester bebutides of the present invention and their novel intermediates can be prepared by methods known in the art, for example by coupling individual amino acids on a stepwise basis on homologous resins. Alternatively, it can be prepared by attaching amino acid groups onto a solid phase resin to yield the desired peptidyl resin intermediate.

Such addition, as is known, converts the amino group of an amino acid or a group of an amino acid, such as the t-butyloxycarbonyl (BOC) i into a 9-fluorenylmethyloxycarbonyl (Fmoe) derivative. and then protect the carboxyl group of the amino acid or the group of the amino acid with its 1-hydroxybenzotriazole ()LOBt)
This is achieved by converting it into an N-hydroxysuccinimide (HO8u) ester derivative and activating it. This 5-protection-activated intermediate is then converted into an amino acid-
resin or a peptidyl-resin with free amine groups, thus elongating the peptide chain to form a compound of formula 2 (Pg
is a peptidyl-resin with a suitable protecting group, such as Boa or Fmoc.

(2) The phenolic OH group in the hole is removed using a normal sulfating agent.
For example, it is converted to a sulfate ester using a sulfur trioxide pyridine complex. More specifically, for example, peptidyl-resins of formula 2 may be combined with dimethylformamide (DMF),
The sulfate ester-containing peptides of the invention are prepared by suspending them in pyridine or a similar solvent and adding about a 10-40 molar excess of the sulfur trioxide pyridine complex to give a sulfated peptidyl-resin of formula 3: Since the terminal-product is a C-terminal amide, the chemical bond linking the peptide chain to the resin must be such that its cleavage by a suitable reagent readily yields the amide. Due to the lability of the sulfate ester group to strong acids (e.g., fluid hydrogen fluoride), the peptidyl-resin bond is more sensitive to weaker acids (e.g., brief treatment with trifluoroacetic acid, TFA) and/or It may be cleavable by any nuclear reagent (eg, ammonia, amine, hydroxyl, alkoxide). Among suitable resin derivatives, mention may be made of oxymethyl-polystyrene, 4-(oxymethylphenyl) (CHt ) HCO-aminomethyl-polystyrene (n=os-s) and 4-(oxymethylphenyl)oxymethyl-polystyrene. be able to. Similarly substituted polyacrylamide resins are equally well suited as the polystyrene-based resins mentioned above. For the purposes of the present invention, a-(oxymethylphenyl)CH,CO-aminoethyl-polystyrene [referred to herein as 4-(oxymethylphenyl)acetamidomethylpolystyrene or OCHt-Pam-resin] Best suited for producing peptide amides. That is, the present invention provides sulfated peptidyl -OCHI-Paw- of formula (4)
A method of synthesizing a resin, where the resin is polystyrene (the term "polystyrene" includes copolymers with small amounts, usually 1 ts, of unsaturated supermers such as divinylpenze) is described.

When forming the peptide sequences of the present invention, the amine function can be replaced by commonly used amino protecting groups such as Boc, F.
moc, (4-methoxybenzyl)oxycarbonyl,
It can be protected with 2-nitrophenylsul7denyl or the like. Boe and Fmoc protecting groups are preferred. Carboxyl and hydroxyl protecting groups include methyl, t-butyl (t
Bu), benzyl, 4-methoxybenzyl, etc.

The tBu group is preferred.

The amino acids defined by the Fl and F groups of formula 4 can be attached to the OCH, -Pam- resin in several ways. (a) For example, a Boa protected-phenylalanine (where Fl is (S)-Nu and F! is H) is combined with a suitable 4-(bromomethyl)-phenylacetate ester (e.g. phenacyl ester). Reaction and further processing to give Boa-Phe-(4-oxymethylphenyl)acetic acid, which was coupled to aminomethyl-polystyrene to give Boc-Phe-(4-
(oxymethylphenyl)acetamidomethylpolystyrene (Boa-Phe-OCHt-Pam-resin). (b) Alternatively, 4-(bromomethyl)phenylacetic acid is coupled to aminomethylpolystyrene to give 4-(bromomethyl)phenyl7cetamidomethylbolystyrene (BrCHl-Pan-resin), which can be converted into Boa-Phe- It can be reacted with a cesium salt of OH to form a Boc-Phe-OCHI-Pam-resin.

Among suitable activating groups, groups which make the acid function of the amine ester more active, such as acid chlorides, mixed and symmetrical anhydrides, carbodiimides (e.g. dicyclohexylcarbodiimide, DCC) and active esters (e.g. , H.O.
Bt, HO3u, 2- or 4-ditrophenol, 2,
4.5-) reaction product with dichlorophenol). The use of esters of DCC, HOBt and HO8u is particularly preferred from the standpoint of yield, low by-products and, as a result, ease of purification.

2.30 For Boc and/or tBu removal, treatment with dilute TFA (dichloromethane, 50% in DCM), for Fmoc removal, diluted piperidine (20% in DMF), to name a few. A sulfated peptidyl resin of formula (5) is obtained by treatment with .

The sulfate ester-containing peptide of Formula 1 can be obtained by cleaving the peptidyl-OCHl-Pam-resin bond in (5) with an appropriate reagent. C-terminal sulfated peptide amides are derived, for example, by treating a sulfated peptidyl resin of formula (5) with a methanolic solution of ammonia, an alkylamine, or a dialkylamine.

An automatic peptide synthesizer (5ynthesizer) was used for solid phase synthesis of the sulfated peptide amide of the present invention. The protocols for coupling to aminomethyl-resin or peptidyl-0CH2-Pam-resin (1 mmole of available nitrogen), deimaging, sulfation, cleavage and product purification are shown in Table 1.

Table 1. Protocol for in-phase synthesis of sulfated peptide amides (1 mmol scale). Each process volume is 50 -, unless otherwise indicated. All washing steps are repeated three times. Abbreviation: DCC, dicyclohexylcarbodiimide; D
CM, dichloromethane; DIEA, N,N-diisopropylethylamine; DMF, dimethylformamide; H
OBt, 1-hydroxybenzotriazole; TFA,
) Lifluoroacetic acid.

Table 1 1 DCM wash 1 min 2 Step 3.5
Alternatively, go to line 8 < -1----3 protected amino acids (or protected dibebutyl preactivation for 2-15 hours,
The FHOBt-coupled and preactivated (0 °C, 1 h between pulls) mixture of HOBt (45 m'L, DCCI mole), and DCC (3 mmol) was prepared in 1:4 DMF,/DCM. Add to 4 Step 10.16.21 or 25 line < -1-
--- 5 protected amino acids (or protected dipebuti, in situ activation 2-15 hours, 3 mmol and aOBt (ts
t, DCc'/mmol) to 1:2DMF/DCM
Add to HOBt cup 30-, then DCCC5
Add bring msol) to DCM2o-6 2-Proper tool cleaning 1
Minute 7 Go to Step 4 < -1----8 Active ester or anhydride (5m non-DC
C/2-15 hours) with DCM, DMF or this
Add to mixture of HOBt active et al. Sexualized coupling 9 Go to step 4 < -----
m-10DCM cleaning 1 minute 11 49
: 1 : 5oTFA/aniso-Boc and 3
Treat with 0 min Lu/DCM tBu removal 12
DCM cleaning 1 minute 161: 19
Treat with DIEA/DCM Neutralize 1 min 14 DCM Wash 1 min 15 Step 1.
16. Go to 21 or 26 -11111 1tSDMF Wash 1 min Treat with 171:4 piperidy/DMF Remove Fmoc 3 min Treat with 181:4 piperidy7/DMF Remove Frnoc 7 min 19DMF Wash 1 Minute 20 Go to step 15 < ---------21 DM
F Wash 1 minute 221:2 pyridine/D
MF wash 1 min 25 sulfur trioxide pyridine complex (40 sulfated 20-24 h mmol)
Add to 1:2 pyridine/DMF 60Wt24 DMF wash 1 minute 25 Go to step 4 < -----126 Methanol wash 1 minute 27
Ammonia saturation (-20℃) meta resin cleavage 2-5
Nitol or 20 timethanolic amine (250 g) 28 methanol Washing 1
Isolate the a-condensed P solution from steps 27-28.
-m-binding 60 Amberlite XAD-2 (low purified
-1-M&Haas, 2.5 X 60crrL.

methanol gradient α1M in ammonia), trisacrylic MDEAE (LKB incoborated, 2,5 x 47an, ammonium bicarbonate gradient), and/or P-40 0DS-1 (Whatman, melon 8 x 50 cHL% ammonium acetate). The residue is chromatographed on a column of methanol gradient (2%).

The sulfate ester containing the peptide of formula (1) thus prepared can be desalted and purified by conventional methods. For example, the product can be converted to Trisacryk (
Trisacr71) M DEAE, DE
Ion exchange chromatography using AE-cellulose etc., Sephadex ('5ephadex) L H
-20, partition chromatography using Sephadex G-25, etc., Amberlite (Amber is te)
X A D-2,0DS-Reversed phase chromatography using silica gel etc., normal phase chromatography using silica gel etc., or high performance liquid chromatography (H
PLC).

Similar procedures in which the reaction is carried out without solid phase components (resins) are well known for the time being and are well suited for large scale production. (See, eg, US Pat. No. 892,726) Effect of use The peptide of the present invention has the ability to suppress dietary activity in mammals, and as a result, it has an effect of use in the prevention and treatment of obesity. Dietary suppression activity can be demonstrated in rats as follows: male Spragg-Dawley (
Sprague-Davrley) rat (weight 50
0-3509) individually in the basket and 12 hours of light,
Animals are kept on a dark cycle and trained to be fed for 3 hours during the dark cycle for at least 14 days and withheld food for 21 hours preceding that 3 hour period. On research day
Rats were given saline (control) or test compound (dissolved in saline; usually 13 to 50 doses of test compound per 1 kg weight).
(at a concentration of 0 micrograms) is administered intraperitoneally. Food is introduced 10 minutes after administration of saline or test compound. A test compound is considered active if the test group consumes significantly less food than the saline control during a feeding period that ends either 0.5 hours or 3 hours after food is given. . Table 2 lists the results for CCK-8 and various compounds of the invention. For example, the dietary suppression obtained with CCK-8 (first row of Table 2) was 70% for the hour feeding period and 25% for the 3 hour period.

Table 2 Hpp(SO3H)-Met-Gly-Trp-Met
-Asp-Phe-NH! 99-75Ph a -Nl
MuHpp(SO3H)-Met-GIy-Trp-Pro
-Asp-Phe-NH,4B-IAHpp(SO3H
)-Pro-Gly-Trp-Pro-Asp-Phe
-NHt25-IAHl)p(SO3H)-Ahx
-Gly-Trp-Ahx-ABp-Phe-NHt
100-99P11 e -Nl island Hpp(SO3H)-Ile-Gly-Trp-Ile
-Asp-Phe3NH,87-a5IA means "inactive".

*-50μF! Inhibition of <10 at 9 to 1: The numbers shown reflect the inhibition at 9 to 300 μg/dose.

NT means "not tested".

A preferred method of administering the above-mentioned peptide, which is suitable for intraperitoneal, intravenous, intramuscular, subcutaneous or intranasal administration, to a mammal in need of obesity treatment or prevention is to administer 1 kg of body weight per day.
The dosage is approximately 5 μg to 3 mg per dose, and the entire amount may be administered at one time or divided into 2 to 4 doses. The dosage may vary depending on the needs of the patient and the compound used.

The peptides of the invention have the ability to stimulate contraction of the mammalian gallbladder. Therefore, they also have utility as diagnostic aids in X-ray examinations of the gallbladder. The use of biliary constrictors as diagnostic aids is an established medical practice.

EXAMPLES Hereinafter, the present invention will be explained in more detail based on examples. Examples 1-18 illustrate the synthesis of intermediates. Examples 19-33 illustrate the synthesis of compounds of the invention or compounds described above as compounds useful in the treatment and prevention of obesity. The following examples are merely illustrative of the invention and do not limit it in any way.

Peptide synthesis was carried out using aminomethyl resin (this resin had a styrene:divinylbenzene ratio of 9), unless otherwise specified.
9:1 copolymer) was used to start.

Reactions were performed at room temperature unless otherwise noted.

Unless otherwise noted, washing steps were performed three times using 50 specified solvents.

Example 1 N-hydroxysuccinimide (Ho5u, 49.2 a, t,
dicyclohexylamine (DCH
A) Salt was added little by little. After stirring the resulting suspension overnight, the precipitated DCHA hydrochloride was removed and washed with chloroform. Dilute the concentrated solution (approx. 50 -) and washing solution with 400 - ethyl acetate (EtOAc), add 10 g (citric acid (4 x 100 -), prine (2 x 100 mg), 10
% sodium bicarbonate (5×10 o−) and brine (axlooi), then dried (magnesium sulfate), filtered, and concentrated to about 100−.

When diluted with ether and precipitated with hexane, m
p 1BuOcO-O8u28, 6g (
A yield of 62 cm) was obtained.

Example 2 D-tyrosine (1,811) was mixed with 10-N-sodium hydroxide in water and tetrahydrofuran (T
HF) dissolved in 50-. With rapid stirring, solid 9-fluorenylmethylsuccinimidyl carbonate (37 g of Fmoc-O8us) was added. The suspension was adjusted to pH 7 with N sodium hydroxide and stirred overnight. Solid citric acid (3g) was added followed by EtOAc
Added 60 d. The EtOAc layer was collected, washed with 10% citric acid, brine, and dried (magnesium sulfate). The light tan syrup obtained by evaporation of the EtOAc solution was crystallized from dichloromethane (DCM) and mp
49 g of Fmoc-DTyr-OH at 178-181°C
I got it.

Example 5 Fmoc-Tyr-0H Following the procedure of Example 2 except that L-tyrosine (9.06 g) was used instead of D-tyrosine, Fmoc-T)'r- OH111L 49 was obtained.

Example 4 N-methyltyrosine (1,951
), but following the procedure of Example 2, mp 152-1
Fmoc-UeTyr-OH1, 22p at 58°C was obtained.

Example 5 Acetic acid Boc-MePhe-OH (2 o 93 y) and 4-(
phenacylethyl bromomethyl)phenylacetate (353
Potassium fluoride dihydrate (1&2s11) was added to a solution of 2g) in acetonitrile (1ooo-). The suspension was stirred overnight, filtered, and the P solution was evaporated to dryness. The residue Boa-MeP, he-(4-oxymethylphenyl)acetic acid 7-enacyl ester was converted to 85 thiacetic acid (1200 m)
and treated with zinc dust (128 g) and stirred for 2-4 hours.

The filtered reaction mixture was concentrated to about 400 ml of water and about 32 ml of water.
The oil obtained by diluting with 00- was dissolved in EtOAClC,
Treatment with DCHA yielded the D CHA salt of the title compound 41.
51 g was obtained. mp 120-122℃.

Example 6 Boc-EtPhe instead of Boa-MePhe-OH acetate
Boc-EtPhe -(4-oxymethy/l/ 7
5.69 g of DCHA salt of acetic acid was obtained. m
p137-141°C.

Example 7 Boc-Phe (4-CI)-(4-oxymethyl B
Boc-Phe (4-
Following the procedure of Example 5, but using 2,5 g' of Boc-Phe(4-CI)-(4-oxymethylphenyl)acetic acid, 544 g of the free base of Boc-Phe(4-CI)-(4-oxymethylphenyl)acetic acid were obtained.

Example 8 Boa-Tyr (M
e) Boa-Tyr(Me)-(4-oxymethy/17
7, Znyl) 1.839 of the free base of the vinegar layer was obtained. m
p 64-67°C.

Example 9 Fmoc-'r instead of Boa-MePhe-OH
7Fmoc-Tyr(tBu) following the procedure of Example 5 except using r(tBu)-OH(6-86,!9)
-(4-Oxydimethylphenyl)acetic acid free base 4°8
8g was obtained. mp1?2-195℃.

Example 10 Fmoc-Met-OH (14,879), HO
Fmoc-Me
t-O8u was prepared in situ. The precipitated dicyclohexylurea (DCU) was removed by filtration and the THF solution was dissolved in a pre-cooled solution of 40-N-sodium hydroxide.
-Asp(OtBu)-0H in 10:1 water/THF (
22o-) solution. After stirring the reaction mixture overnight at room temperature, solid citric acid (20 g) was dissolved in EtOAc.
(60 (ld)) was added. The EtOAc layer was separated, washed with 10 citric acid, brine, and dried (magnesium sulfate). The residue obtained by evaporating the EtOAc solution was dissolved in EtOAc 200 x lt. Dissolve, DCHA
(7.84 mg) of the DCHA salt of the desired compound.
7.939 was precipitated. mp159-162°C.

Example 11 Boc-Phe-(4-oxymethylphenyl)acetic acid (
0,83,9,2 mmol/L/), 1-hydroxybenzotriazole (HOBtlo, a6g, 3 mmol)
and DCC (141 g, 2 mm/I/) at 4:
Dissolved in IDCM/DMF50- and stirred at 0°C for 1 hour. Aminomethyl-resin (1.54 g, 1 mmol available nitrogen) was added to the filtered reaction mixture (precipitated DCU removed).
and shaken for 2 to 15 hours. Product Boc-
The Phe-OCHI-Pam-resin was isolated by filtration and processed according to Table 1 (steps 10-14) to give the desired free base H-Phe-OCH.

-Pan- resin was obtained.

Example 12 H-MePhe-OCHI-Pam-resin aminomethyl-resin (1,34,9,1 mmol available nitrogen), 1
:3 DMF/DCM (40m') Boc-MePh
e-(4-oxymethy#7en=v)acetic acid [from its DCHA salt (Example 5) 1.82 g, 3 mmol] and HOBt (α699.4.5 mmol)
Then DCC (0,629,3 mm/L) in DCM2O was added and the resulting suspension was shaken for 2-15 hours. Desired compound Boc-MePbe-OCH@-P
The am-resin was isolated by filtration, washed with 2-propanol and DCM, and processed according to Table 1 (steps 10-14) to give the desired free base H-MePhe-OCH, -Pam.
-Resin obtained.

Example 15 Boa-MePhe-(4-oxymethylphenyl)'
Boa-EtPhe-(4-oxymethylphenyl)acetic acid [its DCHA salt (Example 6)] 1.87.9 in place of acetic acid
, 3 mmol] was followed to obtain H-EtPhe-OCH,-Pam-resin.

Example 14 Boc-Phe-(4-CI)-(4-oxymethy/L/7 x 2A/)acetic acid was replaced with
4-oxymethylphenyl)acetic acid co,90,! i
H-Ph e (4-Cl ) -0CH! following the procedure of Example 11 except using i+, 2 mmol, Example 7). -P
am-resin was used.

Example 15 Boc-Phe(4-NOx)-OH(j, 59 g
) was dissolved in 70 timethanol (MeOH) 10°, and the pH was adjusted to 7 by adding N-cesium hydrogen carbonate.

The solution was blown to dryness and the residue was evaporated three more times with additional DMF. The obtained dried Boc-P
he(4-Now)-OH cesium salt in DMF60-
and shaken overnight with BrCHt-Pam-resin (1 meq. of Br). Desired product Boa-P
The ho(4-No!)-0CHI-Pam-resin was isolated by filtration, washed with DCM and shown in Table 1 (steps 10-1).
4) to obtain the desired free base H-Phe (4-N
Ox)-0CHz-Pam-resin was obtained.

Example 16 Boc-Phe-(4-oxymethylphenyl)acetic acid was replaced with Boa-Tyr(Me)-(4-oxymethylphenyl)acetic acid (0,879,2-, Limol, Example 8). H-Tyr(Me)-0 according to the procedure of Example 11
CH! -Pam-resin was obtained.

Example 17 Fmoc-Tyr(tBu)-(4-oxymethylphenyl)acetic acid (1,82 g, 3 mmol, Example 9), 1-hydroxybeni/citriazole (HOBt.

0,691i, 4.5 mmol) and DCC (α62
1.3 mmol) to 4: I DCM/DMF 5
0- and stirred at 0°C for 1 hour. Amitumedel resin (1,5
4 g, 1 mmol available nitrogen) was suspended and assisted for 2-15 hours. Product F, moc-Tyr(tBu)-0
The CHx-Pam-resin was isolated by filtration and processed according to Table 1 (steps 16-20) to give the desired free base H-Tyr.
(tBu)-0CHt-Pam-resin was obtained.

Example 18 Boc-Me instead of Boa-Phe(Nt)-OH
H-Me following the procedure of Example 15 except using Tyr(Me)-OH (from 1.47 g of its DCHA salt)
Tyr(Me)-0CHI-Pam-resin was obtained.

Example 19 Fm in H-Phe-OCHI-Pan-resin (Example 11)
oc-Asp(OtBu)-0H, Fmoc-Met-
OH, Fmoc-Trp-OH, Fmoc-Guy-O
H.

Fmoc-Met-OH%Fmoc-Try-
OH (Example 3) and Fmoc-DAsp(OtBu)-
0H sequentially, Table 1 (coupling steps 3-4 then Fm
Coupling according to oc removal steps 16 to 20) and F
moc-DAsp(OtBu)-Tyr-Met-Gl
:t'-Trp-Met-Asp(OtBu)-Phe
-OCH, -Pam- resin was obtained. This is shown in Table 1 (Step 2
1-25, steps 10-20 followed by steps 26-29 with ammonia, deprotection and resin separation to give the title compound. This was purified by chromatography on Trisaeryl M DEAE according to Table 1 (Step 30) to obtain ammonium*198 of the title compound.
Got the cape. Asp 2.11 in amino acid analysis after acid digestion
(2), Tyr 1.04 (1), Met2, O
y (2), Gly 1. o 5(1) and Phe
1.04(1) was shown. The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 1050CF, -'. TLC (here, 6:
Chromatography of the title compound on Merck silica gel thin layer plates in a 5:1:1 chloroform-methanol-acetic acid-water system) Rf value α35
゜Example 20 F to H-Phe-OCHt-Pam-resin (Example, 11)
moc-Asp(OtBu)-0H, Fmoc-Met
-OH.

Fmoc-Trp-OTT, Fmoc-Gly-OHl
Fmoc-Met-OH and Fmoc-T3'r(t
Bu)-OH was coupled sequentially according to Table 1 (coupling steps 5-7 then Fom removal steps 16-20) to give H-Tyr(tBu)-Met-Gly-Trp-
Msp(OtBu)-Phe-OCHg-Pam-resin was obtained. To this, 1BuOc according to Table 1 (Steps 8-9)
iBuOC by coupling o-O8u (Example 1)
O-Tyr(tBu)-Met-Gly-Trp-Me
t-Asp(OtBu)-Phe-OCH, -Pam-
Resin was obtained. This is shown in Table 1 (Steps 10-15, Steps 21-
25 followed by debinding with ammonia according to steps 26-29), sulfation and resin separation to give the title compound. This was added to Ambertte according to Table 1 (Step 5O).
Sequential purification by chromatography on XAD-2, Trisacryl M DEAE and P-400DS-5 afforded the ammonium salt 206 of the title compound.

Amino acid analysis after acid digestion showed Asp 1.06 (1),
Tyr 1. o am, Met2.04(2), Gly
1.06(1) and Phel, 04(1) were shown. In the infrared absorption spectrum, it is 1050c! ! L-”
A strong peak characteristic of sulfuric acid esters was observed. T
LC Rf value Q, 56° Example 21 Fm in H-Phe-OCHI-Pam-resin (Example 11)
oc-Asp(OtBu)-OH, Emoc-Met-
Oh.

Fmoc-Trp-OH, Fmoc-Gly-OH%F
moc-Met-OH, Fmoc-DTyr-OH (Example 2) and Boa-Asp(OtBu)-OH sequentially;
Boa-Asp
(OtBu)-DTyr-Met-Gly-Trp-M
et-Asp(OtBu)-Phe-OCHI-Pam
-Resin obtained. This is shown in Table 1 (Steps 21 to 25, Step 1
0-15 then sulfated with ammonia according to steps 26-29), deprotected and resin separated to give the title compound. This was added to Trsacryl according to Table 1 (Step 30).
Purification on M DEAE with glue o"v Togelafy gave the ammonium salt 2414 of the title compound. Amino acid analysis after acid digestion revealed that A8p2-14 (2), Tyr 1.
06 (1), Met2.12 (2), Glyα95 (
1), Phe[L98(1) and NHa i,
S O(2) was shown.

The infrared absorption spectrum showed a strong peak characteristic of sulfuric esters at 101050c.

TLC Rf value CL32゜Example 22 Fm in H-Phe-OCH, -Pam-resin (Example 11)
oc-Asp(OtBu)-OH, Fmoc-Met-
Oh.

Fmoc-Trp-OH, Fmoc-Gly-OH,
Fmoc-DMet-OH, Fmoc-Ty
r-OH (Example 3) and Boa-Asp(OtBu)
-OH sequentially, Table 1 (coupling steps 3-4 then F
Boa-Asp(OtBu)-Tyr-DMet-CI by coupling according to moc removal steps 16-20)
y-Trp-Met-AsP(OtBu)-Phe-O
CHt-Pam-resin was obtained. This is shown in Table 1 (Step 21
~25, steps 10-15 then step 2 with ammonia
6-29), the title compound was obtained by sulfation, deprotection, and resin separation. This is determined according to Table 1 (Step 30) i.
Purification on acryl M DEAE with off-thorn fluorophore afforded the ammonium salt of the title compound, 219+19. Asp2.07 (2) in amino acid analysis after acid digestion
, Tyr 1.02 fl), Met 2.11 (2
), Guy (L95(1), Phe 1.11 (IJ
and NH31,51(2) were shown. The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 1050cIrL-'. TL (1) Rf value o, 37° Example 23 Fm in H-Phe-OCHt-Pam-resin (Example 11)
oc-Asp(OtBu)-0H1Fmoc-Met-
Oh.

Fmoc-Trp-OH, Fmoc-Gly-OH, F
moc-DAhy -OH, Fmoc -Tyr-
OH (Example 3) and Boa-Asp(OtBu)-0H
Table 1 (coupling steps 3-4 then Fmoc
Boa is coupled according to removal steps 16 to 20).
-Asp(OtBu)-Tyr-DAhx-Gly-T
rp-Met-Asp(OtBu)-Phe-OCHt
-Pam-resin was obtained. This is shown in Table 1 (Steps 21-25
, steps 10-15 followed by steps 26-2 with ammonia
Sulfation, deprotection and resin separation according to 9) gave the title compound. This was prepared using Tris according to Table 1 (Step 30).
The ammonium salt of the title compound, 24E19, was obtained by gelatinization on acryl M DEAE. Amino acid analysis after acid digestion revealed that A8p2.11(2), T
yr 1.05 (1), Ahx Q, 97 (1)
, Gly 0.99 (1), Met 1.07 (1
) and Phe i, 07 fl) were shown. The infrared absorption spectrum showed a strong peak characteristic of sulfuric esters at 105 ocm-1. R of TLC
f value Q,! +4゜Example 24 H-Ph e -0CHt -P JLm-Resin (Example 1
1) with Fmoc-Asp(OtBu)-0I (, Fmo
c-Met-OH.

Fmoc-Trp-OH, Fmoc-8ar-OHlF
moc-Me t-OH, Fmoc -T'l r-
OH (Example 3) and Boc-Asp(OtBu)-OH
are sequentially coupled according to Boa-1 (coupling steps 3-4 and then Fmoc removal steps 16-20) to obtain Boa-
Asp(OtBu)-Tyr-Met-8ar-Tr
p-Met-Asp(OtBu)-Phe-OCHz
-Pan- resin was obtained. This is shown in Table 1 (Steps 21 to 25,
Steps 10-15 then steps 26-29 with ammonia
Sulfation, deprotection and resin separation according to ) gave the title compound. This is done according to Table 1 (Step 30).
Purified by chromatography on cryl M DEAE! ! Ammonium salt 24019 of the compound was obtained.

Amino acid analysis after acid digestion revealed AIpl, 93(2), Ty
r (L 97(1), Met2-00(2), 58r
1.03 (1), Phe 1.02 (1) and NH
m 1.54 (2) was shown. The infrared absorption spectrum showed a strong peak specific to sulfuric esters at 1050 rho1. TLC Rf value 0.32゜Example ≦H-Phe-OCHz-Pam-resin (Example 11) in Table 1
(Coupling steps 3 to 4 followed by Fmoc removal step 1
Fmoc-Asp(OtBu)-0H according to 6-20)
, Fmoc-Met-Ko, Fmoc-MeTrp-OH
, Fmoc-Gly-OH, Fmoc-Met-OHl
Fmoc-Tyr (tBu)-0)! , and Fmoc
Fmoc-Asp (OtBu) -Tyr (tB
u) -Met-Gly-MeTrp-Met-Asp
(OtBu)-Phe-OCH2-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25
, steps 16-20 then steps 26-29 using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was purified on Trisacryl MDEAE according to Table 1 (step 30). Purification by chromatography yields the ammonium salt of the title compound 310
mg was obtained. Amino acid analysis following acid digestion gave the following results + Asp 2.03 (2), Tyr 1
．． 02 (1), Metl, 95 (2), Glyo,
93 (1), and Phe 1.01. (1),
The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC's R2
Value 0.35゜Example 26 H-As-Tr(SOJ)-Met-Gl-Na
l-Met-As-Phe-NH2H-Phe-QC
) 12-Pam-resin (Example 11) as Fmoc-Asp(OtBu)-0H, Fmoc-M according to Table 1 (Coupling steps 3-4 then Fmoc removal steps 16-20)
et-OHlFmoc-Nal-Ko, Fmoc-Gl
y-OH, Fmoc-Met-OH, Fmoc-Tyr
-Oll (Example 3), and Boa-Asp (OtB
u) Bo'c-Asp by sequential coupling with -OH
(OtBu) -Tyr-Met-Gly-Nal-
Met-Asp (OtBu)-Phe-OCt(*-
A Pam-resin was produced, which was described in Table 1 (Steps 21 to 25,
Steps 10-15 followed by steps 26-29 using ammonia), deprotection and resin separation to produce the title compound, which was purified using Tris according to Table 1 (step 30).
Purification by chromatography on acryl M DEAE gave 260 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 1.97 (2), Tyr O,91 (
1), Met 2.13 (2), Gly 1.
09 (1), Na10.76, and Phe L,
14 (1) - Infrared absorption spectrum is 1050 cm
''' I showed a strong peak characteristic of sulfate ester. TLC Rt value 0.38°) 1-Phe-OCHz
-Pam- resin (Example 11) was prepared according to Table 1 (coupling steps 3-4 followed by Fmoc removal steps 16-20).
oc-DAsp (OtBu)-Kano, Fmoc-Met
-OHlFmoc-Trp-OH,Fmoc-Gly-
OH, Fmoc-Met-OH, Fmoc-Tyr-O
H (Example 3), and Boa-Asp (OtBu) by sequential coupling with Boa-Asp (OtBu)-lobes.
-Tyr-Met-Gly-Trp-Met-DAs
p (OtBu)-Phe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 21-25, Steps 1o-1
5 then sulfated, deprotected and resin separated according to steps 26-29 using ammonia to produce the title compound,
This was mixed with Trisacryl according to Table 1 (Step 30).
Purification by chromatography on M DEAE gave 121 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp.
2.03 (2), Tyr O, 98 (1), Met
2.05 (1), Gly 1.07 (+), and Phel, 08 (+). The infrared absorption spectrum is
A strong peak characteristic of sulfuric acid ester was observed at 1050 cm-'. TLC Rf value 0.43°H-Phe-OCHz-Pam-resin (Example 11) is shown in Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asn-OH, Fmoc-M
et-Kano, Fmoc-Trp-DH, Fmoc-Gl
y-Kano, Fmoc-Met-OH, Fmoc-Tyr (
tau)-0)1, and Fmoc-Asp(OtBu
Fmoc-Asp by sequential coupling with J-OH
(OtBu) -Tyr (tBu) -Met-Gl
y-Trp-Met-Asn-Phe-OC)lz-P
am-resin was produced, and this was shown in Table 1 (Steps 10 to 15,
Steps 21-25, steps 16-20, then steps 26-29
, using ammonia), sulfation, deprotection and resin separation to produce the title compound, which was prepared in Table 1 (
Purification by sequential chromatography on Trisacryl M DEAE and P-400DS-3 according to step 30) afforded 30 m, g of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.02 (2), Tyr 1.03.
(1), Metl, 93(2), Gly 1.01
(L) and Phe 1.01 (1), the infrared absorption spectrum showed a strong peak characteristic of sulfate ester at 1050 cm6'. TLC Rt value 0.
43° di) 1-MePhe-OCHz-Pam-resin (Example 12)
Fmoc-Met-Asp (Ot
Bu)-0H (free base of Example 1o, Fmoc-Trp
-0)1. Fmoc-Gly-DH, Fmoc-Met
-OH, Fmoc-Tyr(tBu)-0)1, and F
Fmoc-Asp (OtBu) -Tyr(
tBu)-Met-Gly-Trp-Met-Asp(
OtBu)-MePhe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25,
Steps 16-20 followed by Steps 26-29 using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was treated with Trisacryl M DEAE and P- according to Table 1 (Step 30). 400DS
Successive purification by chromatography on -3 yielded 243 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp2.14
(2), Tyr 1.02 (1), Met 2.0
4 (2), Glyl, 07 (1), and NH31,8
7(1). The infrared absorption spectrum is 105105O'
showed a strong peak characteristic of sulfate esters. T
LC R2 value 0.37 °h) 1-MeTyr (Me)-0CH2-Pam-resin (Example 18)
Fmoc-Met-A according to oc removal steps 16-20)
sp(OtBu)-08 (free base of Example 1o), Fmo
c-Trp-OH,Fmoc-Gly-OHlFmoc
-Met-0)1. Fmoc-Tyr (7 Bud-O
H, and Fmoc-Asp (OtBu)-OH to form Fmoc-Asp (OtBu)-
Tyr (tBu)-Met-Gly-Tyrp-Met
-Asp (OtBu) -MeTyr (Me) ”O
A CHz-Pam-resin was produced, which was described in Table 1 (Step 10
-15, Steps 21-25, Steps 16-2o, then Steps 26-29, using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was prepared in Table 1 (Steps Trisacryl M according to 30)
Purification by sequential chromatography on DEAE and P-400O3-3 gave the ammonium salt of the title compound 10
0 mg was obtained. Amino acid analysis following acid digestion gave the following results: Asp 2.06 (2), Tyr
1.06 (1), Met 1.98 (2), and GI
y 1.05 (1). The infrared absorption spectrum is 1
It showed a strong peak characteristic of sulfuric acid ester at 050 cm''. 4 then Fm
Fmoc-Asp(O
tBu)-0)1, Fmoc-Met-OH,Fm
oc-Trp-OH, Fmoc-Gly-OH, Fmo
c-Met-OH, Fmoc-Tyr(tBu)-0H
1 and Fmoc-Asp (OtBu)-T by sequential coupling with Fmoc-Asp (OtBu)-T
yr(7Bu)M-Met-Gly-Trp-Met-
Asp (OtBu)-Phe (4-NO2)-OC
)1. -Pam-resin was produced, and this was shown in Table 1 (Step 10
~15, Steps 21-25, Steps 16-20, then Steps 26-29, using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was prepared in Table 1 (Steps Trisacryl M according to 30)
Purification by sequential chromatography on DEAE and P-4000S-3 gave the ammonium salt of the title compound 12.
8 mg was obtained. Amino acid analysis following acid digestion gave the following results: Asp C98 (2LTyr1.05
(1), Met 1.92 (2), and Glyl
, 05 (1), the infrared absorption spectrum is 1051
A strong peak characteristic of sulfuric acid ester was observed at 05O'. Rr of TLC (tllo, 37゜salmon yu) 1-Aszr 5O3) 1-Met-Gl -Tr
-Met-As -Phe 4-2r H-, Phe (4-CI)-0CH2-Pam- resin (Example 14) in Table 1 (coupling steps 3-4 then Fm
Fmoc-Asp(O
tBu)-0H, Fmoc-Met-OH, Fmoc-
Trp-OH, Fmoc-Gly-011, Fmoc-
Met-0)1. Fmoc-Tyr(tBu)-08
, and Fmoc-Asp (OtBu)-T by sequential coupling with Fmoc-Asp (OtBu)-T
yr(tBu)-Met-Gly-Trp-Met-A
sp (OtBu) -Phe (4-CI) -OC
Hz-Pam-resin was produced, and this was shown in Table 1 (steps 10 to 10).
15, steps 21-25, steps 16-20, then step 2
6-29 using ammonia), sulfation, deprotection and resin separation to produce the title compound, which was purified using Trisacryl M 0 according to Table 1 (Step 30).
Purification by sequential chromatography on EAE and P-400O3-3 gave the ammonium salt of the title compound 299m
I got g. Amino acid analysis following acid digestion gave the following results: Asp1.85(2), Tyrl, 02
(1), Met 1.78 (2), and atyo
, 92(1). Infrared absorption spectrum is 1050cm
-1 showed a strong peak specific to sulfuric esters. TLC Rt value 0.36゜H-Asp-Tyr (SOs)l) -Met-Gl
y-Trp-Met-Asp-Phe (4-NCh)
-NHz (64 mg, Example 31) in 85% acetic acid (20
ml) and treated with zinc dust (69 mg) with stirring. After 30 minutes, the filtered reaction mixture was evaporated to dryness and the residue was converted to P-4000S-3 according to Table 1 (Step 30).
Chromatography above gave 30 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results + Asp 1.92 (
2L Tyr O, 98 (1), Met 187 (2
), and Gly 1.00 (1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC R2 value 0.35° H2 H-Tyr (Me)-0CH2-Pam-resin (Example 1
6) to Fmoc-Asp (OtBu
)-01(,,Fmoc-Met-Kano,Fmoc-Tr
p-0)1. Fmoc-Gly-OH, Fmoc-Me
t-0)1. Fmoc-Tyr(tBu)-0H and Fmoc-Asp(OtBu)-014 were sequentially coupled to produce Fmoc-Asp(OtBu)-
Tyr(tau)-Met-Gly-Trp-Me
t-Asp (OtBu) -Tyr (Me)OCH
2-Pam-resin was produced, and this was shown in Table 1 (Step 10~
15, Steps 21-25, Steps X6-20, then Step 2
6-29 using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was purified using Trisacryl M according to Table 1 (Step 30).
Purification by sequential chromatography on DEAE and P-400DS-3 gave the ammonium salt of the title compound 313.
mg was obtained. Amino acid analysis following acid digestion gave the following results: Asp 2.05(2), Tyrl.
98 (1), Met 1.88 (2), and Gl
yl, 09 (1). The infrared absorption spectrum is 10
A strong peak characteristic of sulfuric acid ester was observed at 5105O'. TLC (7) Re value o, 38°
Fmoc-Asp (OtBu)-Yo, Fmoc-Met-01 (, Fmoc-Trp-O
H%Fmoc-Gly-OHlFmoc-Met-Ko,
Fmoc-Tyr (tBu)-0)1. and Fmoc
-Asp (OtBu) - Fmoc-Asp (OtBu) -Tyr (tBu
)-Met-Gly-Trp-Met-Asp (Ot
Bu) -Phe-OCHz-Pam-resin is produced;
This is shown in Table 1 (Steps 10-15, Steps 21-25, Steps 16-20, then Steps 26-29, using ammonia)
Deprotection, sulfation, deprotection and resin separation according to Table 1 (Step 30) produced the title compound, which was converted to Trisacryl MDEAE, Trisacryl
Purification by sequential chromatography on M DEAE and P-400DS-3 gave 196 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Aspl, 99 (2), Ty
rl, OO (1), Met 1.98 (2),
The infrared absorption spectra of Glyl, 00(1), and Phe 1.01 showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC Rt value 0
．． 47°H-Phe-OCL-Pam-resin (Example 11) was prepared in Table 1 (
Coupling steps 3-4 followed by Fmoc removal step 16-
20) according to Fmoc-Asp (OtBu)-Yo,
Fmoc-Met-Kano, Fmoc-Trp-OH,F
moc-Gly-OH, Fmoc-Met- Kano, Fmo
c-Tyr-OH (Example 3), and Boc-Asp (O
Boc-As by sequential coupling with tBu)-OH
p (OtBu) -Tyr-Met-Gly-Trp
-Met-Asp (OtBu)-Phe-OCHz-
A Pam-resin was produced, which was described in Table 1 (Steps 21 to 25,
Steps 10-15 followed by steps 26-29 using ammonia), deprotection and resin separation to produce the title compound, which was purified using Tris according to Table 1 (step 30).
Purification by sequential chromatography on acryl M DEAE and P-400DS-3 gave 180 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 1.99 (
2), TyrO184(1), Met 2.0 3
(2), Gly 1.0 1(1), Pheo
, 97 and N1 (3L, 14° infrared absorption spectrum showed a strong peak characteristic of sulfate ester at 105105O'. TLC R2 value 0.49° H-Phe-OCH2-Pam-resin (Example 11) Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asp(OtBu)-0H,
Fmoc-Met-OH, Fmoc-Trp-OH, F
moc-Gly-Kano, Fmoc-Met-OHlFmo
c-Tyr(tBu)-Ko, and Fmoa-Asp
Fmoc by sequential coupling with (OtBu)-OH
-Asp (OtBu) -Tyr (tau) -Me
t-Gly-Trp-Met-Asp (OtBu)
-Phe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25, Steps 16-2
0, then deprotected according to steps 26-29 using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was purified using Tris according to Table 1 (step 30).
Purification by sequential chromatography on acrylM DEAE and P-400DS-3 gave 100 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.02 (2
), Tyrl, 01 (1), Met 1.97 (2
), Gly O,99(1), and Phe 1.01
(1), The infrared absorption spectrum is 105105
O' showed a strong peak characteristic of sulfuric esters. TLC R2 value 0.35°H-Phe-QC)It-
Pam-resin (Example 11) was prepared in Table 1 (Coupling step 3~
4 Then Fmoc according to Fmoc removal steps 16-20)
-Asp(OtBu)-0H, Fmoc-Met-OH
, Fmoc-Trp-0)1. Fmoc-Gly-Kano,
Fmoc-Met-01 (, Fmoc-Tyr (tB
ul-Ko, and Fmoc-Asp (OtBu)-ON
Fmoc-Asp (OtB
u) -Tyr(tBu)-Met-Gly-Trp
-Met-Asp (OtBu)-Phe-OCHz-
Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 5).
Steps 21-25, steps 16-20, then steps 26-2
9 using ammonia), sulfated, deprotected and resin separated to produce the title compound, which is shown in Table 1.
Trisacryl MDEAE according to (Step 30)
and chromatography on P-400DS-3 to obtain 102 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp2.16 (2), Tyrl, 03 (1), Met 1.92.
(2), Gly 1.00(1), and Phe 1
．． 09 (1), infrared absorption spectrum is 1050c
Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asp(OtBu)-0H,
Fmoc-Met-OH, Fmoc-Trp-OH, F
moc-Gly-Kano, Fmoc-Met-OHlFmo
c-DTyr-OH (Example 2), and Boc-DAsp
Boc by sequential coupling with (OtBu) -OH
-DAsp (OtBu) -DTyr-Met-Gl
y-Trp-Met-Asp (07Bu)-Phe-
OCHz-Pam-resin was produced, which was shown in Table 1 (Step 1
Fmoc-βAsp-DTyr-Met-Gly-
Trp-Met-Asp-Phe-OCHz-Pam-
A resin was obtained, and the resin was summarized in Table 1 (Steps 21 to 25, Step 10).
-15 then sulfated, deprotected and resin separated according to steps 26-29 (using ammonia) to produce the title compound, which was treated with Trisacryl according to Table 1 (step 30).
Purification by sequential chromatography on M DEAE and P-400DS-3 gave 121 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: +Asp1.94(2), Tyr 1
．． 02 (1), Met 1.91 (2), Gly
1.11(1) and Phe 1.01(1), the infrared absorption spectra showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rf value 0.37° diH-Phe-OCHz-Pam-resin (Example 11) is shown in Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asp(OtBu)-0H,
Fmoc-Met-0)1. Fmoc-Trp-O
H, Fmoc-Gly-OH, Fmoc-Met-OH
lFmoc-DTyr-OH (Example 2), and Fmoc-
Fmoc-DAsp (OtBu) -DTyr- by sequential coupling with DAsp (OtBu) -OH
Met-Gly-Trp-Met-Asp (OtBu
) -Phe-OCH2-Pam- resin was produced, and the resin was prepared in Table 1 (Steps 1o to 15, Steps 21 to 25, Step 1
6-20 then deprotected according to Steps 26-29 (using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was treated with Tr according to Table 1 (Step 30).
Purification by sequential chromatography on isacrylM DEAE and P-4000S-3 gave 100 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.08
(2), Tyrl, 06(1), Met 1.83 (
2), Gly 1.05(1), and Phelo 4
(1), the infrared absorption spectrum is 1050cm''
showed a strong peak characteristic of sulfate esters. T
Rt value of LC 0.24°Example L soil H-Phe-OCHz-Pan-resin (Example 11) Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asp(OtBu)-0H,
Fmoc-Met-OH, Fmoc-Trp-OH, F
Sequential coupling with moc-Gly-OH, Fmoc-Met-OH, and Fmoc-DTyr-OH (Example 2) produced 11-DTyr-Met-Gly-Trp-M.
et-Asp (OtBu)-Phe-OCH2-Pa
m-resin was prepared and coupled with succinic anhydride (0.6 g, 6 mmol in DMF) according to Table 1 (steps 8-9) to give Suc-DTyr-Met-Gly-T.
rp-Met-Asp (OtBu)-Phe-OCH
z-'Pam-resin was obtained, and the resin was subjected to Table 1 (Steps 10 to 1).
5, steps 21-25, then steps 26-29, using ammonia), sulfated, deprotected and resin separated to produce the title compound, which was synthesized in Table 1 (step 30).
) according to Trisacryl M DEAE and P-4
Successive purification by chromatography on 00DS-3 yielded 290 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp.
1.08 (2), Tyrl, 04 (1), Met
1.70 (2), Gly 1.14 (1), and Phe 1.03 (1), the infrared absorption spectra showed a strong peak at 105105 O' that is characteristic of sulfate esters. Rt value of TLC 0.51°
r -Ile-As -Phe-N)lxH-Phe-
OCHz-Pam-resin (Example 11) was processed into Fmoc-Asp (OtBu)-Ko, Fmoc- according to Table 1 (coupling steps 3-4 then Fmoc removal steps 16-20)
Ile-OHlFmoc-Trp-OH, Fmoc-G
ly- Kano, Fmoc-Ile -OH, Fmoc-Ty
r(tBu)-OH, and Fn+oc-Asp (Ot
Fmoc-As by sequential coupling with Bu)-OH
p (OtBu) -Tyr (tBu) -1ie-G
ly-Trp-Ile-Asp (OtBu)-Phe
-OCL-Pam-911 fat was produced, and this was shown in Table 1 (
Deprotection according to steps 10-15, steps 21-25, steps 16-20 and steps 26-29 using ammonia),
Sulfation, deprotection and resin separation produced the title compound, which was converted to Amber according to Table 1 (Step 30).
Purification by sequential chromatography on XAD-2, Trisacryl M DEAE and P-400DS-3 gave 370 mg of the ammonium salt of the title compound.

Amino acid analysis following acid digestion gave the following results:
Asp2.05 (2), Tyrl, ○O (1), Met
1.95 (2), Gly 1. O0(1),
and Phe L, OO (1), the infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC Rr value 0.33°H-Phe-OCL-Pam-resin (Example 11) in Table 1
(Coupling steps 3-4 followed by Fmoc removal step 16)
~20) Fmoc-Asp (OtBu)-Ko,
Fmoc-Lys(Back-OH, Fmoc-Tr
p-Ko, Fmoc-Gly-OH, Fmoc-Lys (
Boc) -OH, Fmoc-Tyr(tBu)-OH
1 and Fmoc-Asp(OtBu)-OH by sequential coupling with Fmoc-Asp(OtBu)-Ty
r (tau) -Lys (Boc) -Gly-T
rp--Lys (Boc) -Asp (OtBu)
-Pha-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25, Steps 16-2
Deprotection, sulfation, deprotection and resin separation according to Steps 26-29 (using ammonia) to produce the title compound, which was converted to Amber according to Table 1 (Step 30) using Amber te XAD-2, Trisacryl MDEAE and chromatography on P-400DS-3 to obtain 61 mg of the ammonium salt of the title compound.

Amino acid analysis following acid digestion gave the following results:
Asp 1.98 (2), Tyrl, 01 (1),
Lys 2.00 (2), Gly O,99 (1
1, and Phel, 02 (1), the infrared absorption spectra showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC Rt value 0.10° Example 44 NH2 H-Phe-OCL-Pam according to Table 1 (coupling steps 5-7 followed by Fmoc removal steps 16-20)
- Sequential Fmoc-Asp(OtBu) on resin (Example 11)
-OH, Fmoc-Met -OR, Fmoc-Trp
-OL Fmoc-DAla-OH1 and Fmoc
-Me t-OH is coupled to H-Met-
DAla-Trp-Met-Asp(OtBu)-Ph
e-OCffi-Pam-resin, and Hp p -O8u was coupled to this according to Table 1 (Steps 8-9) to obtain Hpp-Met-DAla-Trp-Met-As.
p(OtBu)-Ph e-OC-Pam-resin, which was deprotected, sulfated and cleaved from the resin according to Table 1 (steps 10-15, steps 21-25, followed by steps 26-29 with ammonia). to give the title compound,
This is shown in Table 1 (Step 30) K Therefore Trisacrylic M DE
Purification by sequential chromatography on AE and P-400DS-5 afforded the ammonium salt of the title compound. Amino acid analysis after acid decomposition is Asp 1.0
2(1), Met 1.97(2), Alaa, q
a (1), and Phs 1. OS (1) was given. The infrared absorption spectrum showed a typical strong peak of sulfate esters at 1050 (141!).TL
CRfQ, 52 Example 45 Ph e -NH2 H-Phe-OCRl-Pam according to Table 1 (coupling steps 5-7 followed by Fmoc removal steps 16-20)
- Sequential Fmoc-Asp(OtBu) on resin (Example 11)
-OH%Fmoc-Ahx-OR, Fmoc-Trp-
OH, Fmoc-Gly-OH, Fmoc-Ahx-O
H, and Fmoc-Tyr(tBu)-0H are coupled to form H-Trp(tBu)-Ahx-Gly-T
rp-Ahx-Asp(OtBu)-Phe-OC)!
, -Pam- resin, to which was coupled anhydrous amber (16 g, 6. mol, in DMF) according to Table 1 (steps 8-9) to produce Suc-Tyr(tBu)-Ahx-
Gly-Trp-Ahx-Asp(OtBu)-Phe
-OCL-Pam- resin, which is shown in Table 1 (Steps 10-
15, steps 21-25, then step 2 with ammonia
6-29), sulfated and cleaved from the resin to give the title compound, which was converted to Amberlite XAD-2, Trisacryl M D according to Table 1 (Step 30).
Purified by sequential chromatography on EAE and P-400DS-5 to give the ammonium salt of the title compound 240M
gave g. Amino acid analysis after acid decomposition is A11l)
1.01 (1), TyrQ, 95 (1), Ahx
2.10 (2), Gly 1.06 (1), and P
he(L 88 (11) was given. The infrared absorption spectrum showed a typical strong peak of sulfate esters at 1050α. TLCRfo, 36 Example 46 Table 1 (Coupling steps 5-7 followed by Fmoc removal step 16 ~20) H-MePhe-OCL-Pa
Fmoc-Met-Asp (
OtBu)-0H (Example 10), Fmoc-Trp-OH
.

Fmoc-Gly-OH, Fmoc-Met-OH, F
moc-Tyr(tBu)-OH, and Boc-βAs
Coupling p(OtBu)-OH to form Boa-β
Asp(OtBu)-Tyr(tBu)-Met-Gl
y-Trp-Met-Asp(OtBu)-MePhe
-OCHl -Pam -resin, which was deprotected according to Table 1 (Steps 10-15) Ic and coupled with Fmoc-O8u (1,11) according to Table 1 (Steps 8-9) to obtain Fmoc- βAsp-Tyr-Met
-Gly-Tr p -Me t -As p -Me
Ph e -OCH, -Pam- resin, which is shown in Table 1
Sulfation, deprotection and cleavage from the resin according to (steps 21-25, steps 16-20, then steps 26-29 with ammonia) to give the title compound, which is shown in Table 1 (
Purification by sequential chromatography on Amberlite XAD-2,) Lyacryl MDEAE and P-400DS-3 according to step 30) gave the ammonium salt of the title compound 7219. Amino acid analysis after acid digestion is A.
sp-2. o3(2), Trp 1.05(1), Me
tl, 85 (2), and Gly 1.10 (1). Infrared absorption spectrum is 1050cI! L-1 showed a typical strong peak of sulfuric acid ester. T.L.
CRf 0.53 Example 47 H-MePhe-OCL-Pa according to Table 1 (coupling steps 3-4 followed by Fmoc removal steps 16-20)
Fmoe-Met-Asp (
OtBu)-0H (Example 10), Fmoc-Trp-OR
.

Fmoc-GLy-OHlFmoc-Met-OH,F
moc-Trp(tBu)-OH, and Fmoc-DA
Fmoc by coupling sp(OtBu)-0H
-DAsp(OtBu)-Trp(tBu)-Me t
-Gly-Trp-Met-Asp-(OtBu)-
MePhe-OCH,-Pam-resin, which is shown in Table 1
Deprotection and sulfation according to (steps 10-15, steps 21-25, then steps 26-29 with ammonia),
Deprotection and cleavage from the resin afforded the title compound, which was converted into Trisacryl M DEAE according to Table 1 (Step 50).
and P-400DS-3 by sequential chromatography to give the ammonium salt of the title compound. Amino acid analysis after acid digestion is Asp 2-01
(2), Tyr 1. o 1 (1), Me t 1.
91 (21), and Gly t 07(1).

The infrared absorption spectrum showed a typical strong peak of sulfate esters at 1050α. TLCRfα35 Example 48 MePhe-NH2 H-MePh e -OCHx according to Table 1 (coupling steps 5-7 followed by Fmoc removal steps 16-20)
-Pam-resin (Example 12) sequentially with Fmoc-Met-A
sp(OtBu)-OH (Example 10), Fmoc-Tr
p-OH.

Fmoc-Gly-OH, and Fmoc-Met
-OH is coupled to Fmoc -Me t-G
ly-Trp-Met-Asp(OtBu)-MeP
he -OCHl-Pam-resin, which was deprotected according to Table 1 (Steps 10-20) and coupled with For-Tyr-OH to it (Table 1 (Steps 5-7)) to form For- Tyr-Met-Gly-Trp-
Met-Asp-MePhe-OC%-Pam-resin, which was sulfated and cleaved from the resin according to Table 1 (steps 21-25, then steps 26-29 with ammonia) to give the title compound, which was 1 (Step 30)
According to Amberlite XAD-2, Trisacryl MD
Purification by sequential chromatography on EAE and p-400DS-3 gave 78 kg of the ammonium salt of the title compound. Amino acid analysis after acid digestion is Asp 1.0
2 (1), Tyr 1. o 1 (1), Met
1.95 (2), and Gly 1.02 (1). The infrared absorption spectrum showed a typical strong peak of sulfate esters at 1050α-1. TLCRf
0.45 Ushioka mutually beaten H-MePhe'-OCf12-Pam-resin (Example 12
) in Table 1 (coupling steps 5-7 and then Fmo
Fmoc-Met-A according to c removal steps 16-20)
sp (OtBu)-Ko (Example 10), Fmoc-Trp
-OH, Fmoc-Gly-Ko, Fmoc-Met-Ko and Fmoc-Tyr (tBu)-Ko (sequentially coupled with) I-Tyr (tBu) -Met-
Gly-Trp-Met-Asp(OtBu)-MeP
he-OCHz-Pam-resin was produced and shown in Table 1 (
1BuOco-O3u (Example 1) according to steps 8-9)
Coupling with 1BuOco-Tyr (tB
u) -Met-Gly-Trp-Met-Asp (
OtBu)-MePhe-OCHz-Pam-resin was prepared, which was deprotected according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29, using ammonia), sulfated and separated from the resin. to prepare the title compound, which was mixed with Amber according to Table 1 (Step 30).
was purified by sequential chromatography on te XAD-2, TrisacrylMDEAE and P-400DS-3 to give 302 mg of the ammonium salt of the title compound.
I got it. Amino acid analysis following acid digestion gave the following results: Asp 1.03 (1), Tyr 1.
02 (1), Met 1.91 (2), and G
lyl, 04 (1). The infrared absorption spectrum is 1
05105O' showed a strong peak characteristic of sulfuric esters. TLC Rr value 0.67゜h H-MePhe-QC) 12-Pam-resin (Example 12)
Table 1 (coupling steps 3-4 and then Fmoc
According to removal steps 16-20) Fmoc-Met-A
sp (OtBu) -0H (Example 10), Fmoc-T
rp-OH, Fmoc-Gly-Kano, Fmoc-Met
-OH,Fmoc-DTyr(tBu)-0)1. and Fmoc-Asp(OtBu)-OH by sequential coupling with Fmoc-Asp(OtBu)-DT.
yr (tBu) -Met-Gly-Trp-Met
-Asp (OtBu)-MePhe-OCL-Pam
- Produce a resin, which is shown in Table 1 (Steps IO-15, Steps 21-25, Steps 16-20 and then Steps 26-29)
, using ammonia), sulfated, deprotected and separated from the resin to produce the title compound, which was purified using Trisacryl M according to Table 1 (Step 30).
Purification by sequential chromatography on DEAE and P-4000S-3 gave 29 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.02 (2), T
yr 0.97 (1), Met 1.93 (2)
, and Gly 1.07 (1). The infrared absorption spectrum showed a strong peak at 1050105O, which is characteristic of sulfuric esters. TLC Rf value 0.28°11-MePhe-QC)I2-Pam-resin (Example 12
) in Table 1 (coupling steps 3-4 and then Fmo
According to c removal steps 16-20) Fmoc-Met-
Asp(OtBu)-0H (Example 10), Fmoc-
Trp-OH, Fmoc-Gly-0)1. and Fmo
c-Met-OH) I-
Met-Gly-Trp-Met-Asp (OtBu
)-MePhe-QC)lx-Pan+-resin was prepared and coupled with 3-(4-hydroxyphenyl)propionic acid N-hydroxysuccinimide ester ()Ipp-OSu) according to Table 1 (steps 8-9). Let Hpp-Met-G ly-Trp-Met-As
p(OtBu)-MePha-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 15, Steps 21 to
25 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was converted to T according to Table 1 (step 30).
risacryl M DEAE and P-400O3-
Purification by sequential chromatography on 3 ml yielded 170 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Aspl
, 02(1), Met 1.97(2), and Gl
y 1.01 (1). The infrared absorption spectrum is 105
A strong peak characteristic of sulfuric esters was observed at 105O'. TLCORf value 0.58° H-MePhe-OCL-Pam-resin (Example 12) was converted into Fmoc-Met-Asp according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20)
(OtBu) -0ff (Example 10), Fmoc-Trp
-0)1. Fmoc-DAla-OH and Fmoc-
(by sequential coupling with Met-OH) I-Me
t-DAla-Trp-Met-Asp (OtBu)
-MePhe-OCHa-Pam- resin was prepared and coupled with Hpp-OSu according to Table 1 (steps 8-9) to Hpp-Met-DAla-Trp-M
et-Asp (OtBu)-MePhe-OCHz-
Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 15).
, steps 21-25 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which is summarized in Table 1 (step 30).
According to Amber te XAD-2, Trisac
Purification by sequential chromatography on Ryl M DEAE and P-400DS-3 gave 84 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results for two Asp 0.99 (
1), Met 194 (2), and Ala 1.08
(1), the infrared absorption spectrum is 105105O
' showed a strong peak characteristic of sulfate esters.

TLC Rt value 0.49゜GodandanPrOCO-Tr(SO311)-Met-Gl-
Tr -Met-As -Phe-NHzH-Phe-
QC) It-Pam-resin (Example 11) in Table 1 (Coupling steps 5-7 and then Fmoc removal steps 16-2
Fmoc-Asp(OtBu)-0) according to 0)1.
Fmoc-Met-OH, Fmoc-Trp-OH,
H-Tyr-(tBu)-Met-Gl was prepared by sequential coupling with Fmoc-Gly-OH, Fmoc-Met-OH, and Fmoc-Tyr (tau)-OH.
y-Trp-Met-Asp (OtBu)-Phe-
An OCHz-Pam-resin was produced, which was shown in Table 1 (Step 8
~9) according to PrOCO-OSu (melting point 31~34
°C, coupled with PrOCO-Tyr (tB
u)-Met-Gly-Trp-Met-Asp (O
tBu)-Phe-OCL-Pam-resin was prepared and deprotected according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29, using ammonia),
Sulfation and separation from the resin produced the title compound, which was then converted to Amber according to Table 1 (Step 30).
was purified by sequential chromatography on TE XAD-2 and P-400DS-3 to give 270 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 1.01
(1), Tyrl, 03(1), Met 1.87
(2), Gly 1.02 (1), and Phel,
06(]). The infrared absorption spectrum is 1050cm-'
showed a strong peak characteristic of sulfate esters. T
LC R2 value 0.45°) 1-Phe-OCH2-Pam-resin (Example 11) in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
-08, Fmoc-Met-OH, Fmoc-Trp-
OH, Fmoc-Gly-OH, Fmoc-Met-O
H, and Fmoc-Tyr (tau)-OH to form H-Tyr-(tBu)-Me.
t-Gly-Trp-Met-Asp (OtBu)-
Phe-OCH2-Pam-resin was produced and shown in Table 1.
(Steps 8-9) to couple EtOCO-OSu (melting point 52-54.5 °C, prepared according to the method of Example 1 except that isobutyl chloroformate was replaced with ethyl chloroformate) to produce EtOCO-T
yr (tBu)-Met-Gly-Trp-Met-
Asp (OtBu)-Phe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 1° to 15, Step 21
~25 and then Steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was then purified according to Table 1 (Step 30) to Amber te XAD-2 and P -400D
Purification by continuous chromatography on S-3 gave 300 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: As
pl, 02 (1), Tyr 1.01 (1), Me
t 1.91 (2), Gly 1.02 (1)
, and Phe 104 (1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 105105O'. TLC Rt value 0.44゜Salmon j H-Phe-OCHz-Pam-resin (Example 11) Table 1
Fmoc-Asp(OtBu) according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
-0H, Fmoc-Met-Ko, Fmoc-Trp-Ko, Fmoc-Gly-OH, Fmoc-Met-DH,
and Fmoc-Tyr (tau)-OH to form H-Tyr-(tBu)-Met-
(ily-Trp-Met-Asp (OtBu)-P
he-OCH2-Pam-resin was produced and shown in Table 1.
(Steps 8-9) according to MeOCO-OSu (melting point 8
7-89° C., MeOCO-Tyr
(tBu)-Met-Gly-Trp-Met-Asp
(OtBu) 7Phe-QC)I2-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-
25 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was then converted into Amber te XAD-2 and P- according to Table 1 (step 30). 400OS
Continuous loft graph on -3. Purification with E yielded 270 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: As
p 1.04 (1), Tyrl, 05 (1), Me
t 1.82 (2), Gly 1.03 (1)
, and Phel, 06(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 105105O'. The title compound with a TLC Re value of 0.44° has been previously prepared ([DigestiveD 1se
ases) J, Vol. 15 (1970), No. 149-
156 pages). H-Phe-OCHz-Pam-resin (Example 1.1) was treated with Fmoc-As according to Table 1 (coupling steps 3-4 and then Fmoc removal steps 16-2o)
p(OtBu)-OH,Fmoc-Met-OH,F
moc-Trp-OH, Fmoc-Gly-OHlFm
oc-Met-Ko, Fmoc-Tyr-OH (Example 3),
and Boc-βAsp-(OtBu)-Off by sequential coupling with Boc-βAsp(OtBu)
-Tyr-Met-Gly-Trp-Met-Asp(
OtBu)-Phe-OCI (2-Pam-resin was prepared which was sulfated, deprotected and purified from the resin according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29, using ammonia). Separation produces the title compound, which is purified by Trisa according to Table 1 (Step 30).
Purification by chromatography on cryl M DEAE gave 283 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.03 (2), Tyr O,94 (
1), Met 2.08 (2), Gly O, 99
(1), and PheO, 96(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric esters at 1050 cm-'. TLC Rt value 0.52° The title compound has been previously prepared (U.S. Patent No. 3.
839,315 and 3.705.140). )
I-Phe-QC)1. -Pan- resin (Example 11) was prepared according to Table 1 (coupling steps 3-4 and then Fmoc removal steps 16-20) with Fmoc-Asp (OtBu
) -OHlFmoc-Met- Kano, Fmoc-Trp
-0)1. Fmoc-Gly-OH, Fmoc-Me
Boc-Tyr-Met-Gly-Tr by sequential coupling with t-OH, and U Boc-Tyr-OH
p-Met-Asp (OtBu)-Phe-OCHa
-Pan- resin was produced, and this was shown in Table 1 (Steps 21 to 2
5, steps 10-15 and then steps 26-29, using ammonia) to produce the title compound, which was prepared in Table 1 (step 30).
) to give 240 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 1.05 (1)
, Tyr 1.04 (1,), Met 2.10
(2), Gny 1.07 (1), and Phel,
08 (1), infrared absorption spectrum is 10510
A strong peak characteristic of sulfuric acid ester was observed at 5O'. TLC R2 value 0.55° The title compound has been previously prepared (European Patent Application Publication No. 0.107,860), ) l-Ph
e-QC)1. -Pan-resin (Example 11) in Table 1 (Coupling steps 3-4 and then Fmoc removal step 16)
~20) Fmoc-Asp(OtBu)-0
H, Fmoc-Met-OH, Fmoc-Trp-0)
1. Fmoc-Gly-OH, Fmoc-Met-O
H1 and Fmoc-Tyr-0)1 (Example 3) to generate H-Tyr-Met-Gly-T
rp-Met-Asp (OtBu)-Phe-OC
Hz-Pam-resin was produced, and this was shown in Table 1 (Steps 8-9).
) to form Suc-Tyr-Met-G ly-Trp-Met by coupling with succinic anhydride in DMF according to
-Asp(OtBu)-Phe-OCL-Pam-resin was produced, and this was shown in Table 1 (Steps 21 to 25, Step 10).
-15 and then steps 26-29 using ammonia), deprotected and separated from the resin to produce the title compound, which was chromatographed on Trisacryl M DEAE according to Table 1 (step 30). Purify the ammonium salt of the title compound 246
mg was obtained. Amino acid analysis following acid digestion gave the following results: Asp 1.03 (1), Tyro
, 95 (1), Met 2.08 (2), Glyo
, 98(1), and Pheo, 96(1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rt value 0,54
゜The title compound has been previously prepared ('Int.

J, Peptide Protein Re5g, Vol. 16 (1980), pp. 402-411), )l
-Phe-OCL-Pam-Resin C Example 11) in Table 1 (
Coupling steps 3-4 and then Fmoc removal step 1
Fmoc-Asp(OtBu)-0 according to 6-20)
8, Fmoc-Met-Ko, Fmoc-Trp-OH,
Fmoc-Gly-Of (and Fmoc-Met-D
H-Met-Gly-
Trp-Met-Asp(OtBu)-Phe-OCH
t-Pam-resin was produced and this was shown in Table 1 (Steps 8-9)
Hpp-Met-Gly-Trp-Met-Asp by coupling with Ipp-O3u (in DMF according to
(OtBu)-Phe-QC)lx-Pam-resin was prepared, which was sulfated and deprotected according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29, using ammonia) and the resin to prepare the title compound, which was purified by Trisa according to Table 1 (Step 30).
Purification by chromatography on cryl M DEAE gave 65 mg of the ammonium salt of the title compound.

Amino acid analysis following acid digestion gave the following results:
Asp1.04 (1), Met 2.04 (2),
Guy 0.95 (1), and Phe 1.00
(1). The infrared absorption spectrum is 1050 crn-
' showed a strong peak characteristic of sulfate esters.

TLC Rr value 0.47.

The title compound has been previously prepared (U.S. Pat.
No. 892,726). H-Phe-OCH, -Pam-
The resin (Example 11) was treated with Fmoc according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20).
-Asp(OtBu)-0H, Fmoc-Met-OH
,Fmoc-Trp-Of(,Fmoc-Gly-OH
, Fmoc-Ahx-OH, Fmoc-Tyr(tBu
)-0H.

and Fmoc-Asp(OtBu)-by sequentially coupling with Fmoc-Asp(OtBu)-
Tyr(tBu)-Ahx-Gly-Trp-Me
t-Asp (OtBu)-Phe-QC)Iz-Pa
An m-resin was produced, which was prepared in Table 1 (Steps 10-15, Steps 21-25, Steps 16-20 and then Steps 26-29).
, using ammonia), sulfated, deprotected and separated from the resin to produce the title compound, which was treated with 1M 7risacry according to Table 1 (Step 30).
Purification by sequential chromatography on DEAE and R-40DS-3 gave 188 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Aspl, 97(2), Tyr O
, 99 (1), Ahx 1.06 (+), Glyl
, 07(1), Met O, 93(1), and Phe
O, 98(1). The infrared absorption spectrum is 10510
A strong peak characteristic of sulfuric acid ester was observed at 5O'. The compound with a TLC Re value of 0.57° has been previously prepared (U.S. Pat. No. 3,
No. 892,726). H-Phe-OCH, -Pan-
The resin (Example 11) was treated with Fmoc according to Table 1 (coupling steps 3-4 and then Fmoc removal steps 16-20).
-Asp(OtBu)-0H, Fmoc-Met-OH
, Fmoc-DTrp-OHlFmoc-Gly-OH
, Fmoc-Met-OH, Fmoc-Tyr-0)1
(Example 3), and sequentially coupled with Boc-Asp (OtBu)-lobes to form Boc-Asp fOt
Bu) -Tyr-Met-Gly-DTrp-Met
-Asp (OtBu)-Phe-QC)Ia-Pam
- preparing a resin, which is sulfated, deprotected and separated from the resin according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29, using ammonia) to produce the title compound; This was purified by chromatography on Trisacryl IA I)EAE according to Table 1 (Step 30) to yield 314 mg of the ammonium salt of the title compound. From amino acid analysis following acid digestion,
The following results were obtained: Asp 2.07 (2),
Tyrl, 01 (1), Met 2.01 (2),
Gly 1.06 (1), and Phe 0.98
(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 1050 cm''.TL
A compound with an Rt value of 0.30° for C has been previously prepared (US Pat. No. 3,892,726). H-Phe
-OCHz-Pan- resin (Example 11) in Table 1 (Coupling steps 3-4 and then Fmoc removal steps 16-2
Fmoc-Asp(OtBu)-0H,F according to 0)
moc-Ahx-OH, Fmoc-Trp-OH, Fm
oc-Gly-OH, Fmoc-Met-0)1. F
moc-Tyr-OH (Example 3), and Boc-Asp
By sequentially coupling with (OtBu)-OH, Bo
a-Asp (OtBu) -Tyr-Met-Gly
-Trp-Ahx-Asp(OtBu)-Phe-OC
Ha-Pan-resin was produced, and this was shown in Table 1 (steps 21 to 21).
25, steps 10-15 and then steps 26-29, using ammonia) to produce the title compound, which was purified on Trisacryl M DEAE according to Table 1 (step 30). chromatography to obtain 87 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results + Asp 2.11 (2
), Tyr 1.00 (1), Met 1.11
(1), Gly 1.02 (1), Ahxl, 0
4(1), and Phe O, 99(1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC R2 value 0.23゜Godanyu H-As -Tr 5O3H-Met-Gl
-Tr-Met-As-DPhe-NH2 The title compound has been previously prepared (U.S. Pat. No. 3,8
No. 92,726) * H-DPhe-QC) I2-P
am-resin (this is )I-Phe-OCHt-Pa
Boc-MeP in Example 5 in a similar manner as m-resin
From Boc-1)Phe-(4-oxydimethylphenyl)acetic acid obtained by replacing he-OH with Boa-DPhe-OH, Boc-Phe-(4-oxydimethylphenyl)acetic acid was converted into Boc-DPhe- (4-
(oxymethylphenyl) produced by replacing acetic acid)
Table 1 (coupling steps 3-4 and then Fmoc
Fmoc-Asp (O
tBu)-Yo, Fmoc-Met-0)1. Fmoc
-Trp-OH, Fmoc-Gly-OH, Fmoc-
Boa-Asp (OtBu) -Tyr by sequential coupling with Met-OH, Fmoc-Tyr-OH (Example 3), and Boa-Asp (OtBu)-OH
-Met-Gly-Trp-Met-Asp (OtB
u) -DPhe-OCHz-Pam-resin was prepared which was sulfated, deprotected and separated from the resin according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29 using ammonia). to prepare the title compound, which was treated with Trisacry according to Table 1 (Step 30).
Purification by chromatography on 1 M DEAE gave 141 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: A
sp 1.97 (2), Tyro, 98 (1), M
et 2.03 (2), Glyl, 09 (1)
, and Phe 1.05 (1). The infrared absorption spectrum showed a strong peak at 1050 cm''1 that is characteristic of sulfuric esters. TLC Rt value 0.32° The title compound has been previously prepared (rNobel
Symp, J, Volume 16 (Front, Ga5t
rointest, Harm.

Res, ) (19, 73), pp. 41-56). H
-Phe-OCHz-Pam-resin (Example 11) in Table 1
Fmoc-Asp (OtBu) according to (coupling steps 3-4 and then Fmoc removal steps 16-20)
- Kano, Fmoc-MetO-OHlFmoc-Trp-
OH, Fmoc-Gly-OH, Fmoc-MetO-
OH, Fmoc-Tyr-QH (Example 3), and Boc-
Boc-Asp (OtBu) -Tyr-Met by sequential coupling with Asp (OtBu)-OH
O-Gly-TrpJetO-Asp (OtBu)
-Phe-QC)Iz-Pan-Producing resin1. This was sulfated according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29, using ammonia),
Deprotection and separation from the resin produced the title compound, which was treated with Trisacryl according to Table 1 (Step 30).
Purification by chromatography on M DEAE gave 162 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: As
p2.09 (2), Tyr 1.00 (1),
Meto 1.83 (2), Gly 1.08 (
1), and Phe 1.08 (1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. The title compound with a TLC Rf value of 0.14° has been previously prepared (U.S. Pat. No. 3,
No. 892,726). H-Phe-QC)Iz-Pam
- Resin (Example 11) was prepared with Fmo according to Table 1 (coupling steps 3-4 and then Fmoc removal steps 16-20).
c-Asp(OtBu)-08, Fmoc-Ahx-O
H, Fmoc-Trp-0)1. Fmoc-Gly-O
H, Fmoc-Ahx-OH, Fmoc-Tyr-0)
1 (Example 3), and Boc-Asp (OtBu)-
Boa-Asp (
OtBu) -Tyr-Ahx-Gly-Trp-Ah
x-Asp(OtBu)-Phe-OCHz-Pam-
A resin was produced, and the results were shown in Table 1 (Steps 21 to 25, Step 10).
-15 and then Steps 26-29, using ammonia), deprotected and separated from the resin to produce the title compound, which was converted to T according to Table 1 (Step 30).
Purified by chromatography on risacryl M DEAE to give 94 mg of the ammonium salt of the title compound.
I got it. Amino acid analysis following acid digestion gave the following results: Asp 2.18 (2), Tyrl, 0
6 (1), Ahx 2.01 (2), Gly 1.
10(1), and PheO, 94(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric esters at 1050 cm-'. TLC R2 value 0.3
2° The title compound has been previously prepared (Digestive Diseases, Vol. 15 (1970), Vol. 1).
(pp. 49-156). H-Phe-OCH2-Pam-resin (Example 11) was converted into Fmoc-
Asp (OtBu) - Kano, Fmoc - Lsu - OHl
Fmoc-Trp-0)1. Fmoc-Gly = Kano,
Fmoc-Leu-0)1. Fmoc-Tyr (t
Bu)-OH, and Fmoc-Asp(OtBu)-
Fmoc-Asp (
07Bu) -Tyr (tBu)-Leu-Gly-
Trp-Leu-Asp (OtBu) -Phe-O
A CHz-Pam-resin was produced, which was described in Table 1 (Step 10
-15, steps 21-25, steps 16-20 and then steps 26-29, using ammonia), sulfated, deprotected and separated from the resin to produce the title compound, which is shown in Table 1 Amber according to (step 30)
te XAD-2, Trisacryl M DEA
Purified by sequential chromatography on E and P-400DS-3 to give the ammonium salt of the title compound 150
mg was obtained. Amino acid analysis following acid digestion gave the following results: Asp 2.02 (2), TyrO
, 99 (1), Leu 2.02 (2), Gly
O, 98(1), and Pheo, 98(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 1050 cm''. TLC Rr value 0.3
5° The title compound has been previously prepared (U.S. Pat. No. 3,7
05.140), H-Phe-OCHz-Pa
m-resin (Example 11) in Table 1 (Coupling steps 3-4
and then Fm according to Fmoc removal steps 16-20)
oc-85p(OtBu)-OH% Fmoc-Met
-DH,Fmoc-Trp-0)1゜Fmoc-Gly
-OH, and Fmoc-Met-OH to sequentially couple H-Met-Gly-Trp-Met-A.
sp (OtBu) -Phe-OClh-Pam- resin was prepared and deprotected according to Table 1 (Steps 1-15) to obtain H-Met-Gly-Trp-Met-As.
p-Phe-OCHt-Pam-resin was prepared and coupled with For-Tyr-OH according to Table 1 (steps 3-4) to form For-Tyr-Met-Gly-
Trp-Met-Asp-Phe-0(:Hz-Pam
- Preparing a resin, which is sulfated and separated from the resin according to Table 1 (Steps 21-25 and then Steps 26-29, using ammonia) to produce the title compound, which is prepared according to Table 1 (Step 30). Trisacryl M
Purification by sequential chromatography on DEAE and P-400 [15-3] gave 30 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion yielded the following results: two Asp1.00 (1), Met 1
．． 98(2), GIyl, 07(1), and Phe
l, O○ (1). The infrared absorption spectrum is 1051
A strong peak characteristic of sulfuric acid ester was observed at 05O'. TLC R2 value 0.37°H-Phe-OCH2
-Pam- resin (Example 11) was prepared according to Table 1 (coupling steps 3-4 and then Fmoc removal steps 16-20) as Fmoc-Asp(OtBu)-0H, Fmoc-M
et-〇11, Fmoc-Trp-OH, Fmoc-G
ly-Kano, Fmoc-MetO-OH, Fmoc-Ty
r-0)1 (Example 3), and Boc-Asp (OtB
u) Boc-A by sequential coupling with -OH
sp (OtBu) -Tyr-MetO-Gly-T
rp-Met-Asp (OtBu)-Phe-OC
Hz-Pam-resin was produced, and this was shown in Table 1 (steps 21 to 21).
25, steps 10-15 and then steps 26-29, using ammonia) to produce the title compound, which was sulfated, deprotected and separated from the resin according to Table 1 (step 3).
Purification by chromatography on Trfsacryl M DEAE according to 0) gave 230 mg of the ammonium salt of the title compound. The infrared absorption spectrum is 1
05105O' showed a strong peak characteristic of sulfuric esters. The title compound with TLC R1 value of 0.26° has been previously prepared ([Peptide (P
eptides) 1984 J, (1984), pp. 383-385). )I-Phe-QC)12-Pa
m-resin (Example 11) in Table 1 (Coupling steps 3-4
and then Fm according to Fmoc removal steps 16-20)
oc-Asp(OtBu)-〇)1. Fmoc-Me
t-0)1. Fmoc-Trp-OHlFmoc-D
Ala-Kano, Fmoc-Met-OH, Fmoc-Ty
r-0)1 (Example 3), and Boa-Asp (GtB
u) Boc-As by sequential coupling with -OH
p (OtBu) -Tyr-Met-DA Ia-T
rp-Met-Asp (OtBu)-Phe-QC)
Iz-Pam-resin was produced, and this was prepared according to Table 1 (steps 21 to 21).
25, steps 10-15 and then steps 26-29, using ammonia) to produce the title compound, which was purified according to Table 1 (step 30) with Trisacryl M DEAE and Amber. was purified by sequential chromatography on te XAD-2 to give the ammonium salt of the title compound 1
40 mg was obtained.

Amino acid analysis following acid digestion gave the following results:
Asp 1.93 (2), Tyr O,94 (
1), Metl, 81(2), Ala 0.97 (
1), and Pheo, 95(1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rt value 0.34°H-Phe-OCHz-Pam-resin (Example 11) in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 3-4 and then Fmoc removal steps 16-20)
-0H, Fmoc-DMet-Kano, Fmoc-Trp-
OH, Fmoc-Gly-Kano, Fmoc-Met-OH
lFmoc-Tyr-0)1 (Example 3), and Boc
Boc-Asp (OtBu) -Tyr by sequential coupling with -Asp (0-tBu) -0)1
-Met-Gly-Trp-DMet-Asp (Ot
Bu) -Phe-OCHz-Pam-resin is produced;
This was sulfated, deprotected and separated from the resin according to Table 1 (Steps 21-25, Steps 10-15 and then Steps 26-29, using ammonia) to produce the title compound, which was prepared in Table 1 (Steps Trisacr according to 30)
Purification by chromatography on yl M DEAE gave 368 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results:
Aspl, 90(2), Tyr O, 99(1), Me
t 1.97' (2), Gly O, 92 (1), and Phe O, 98 (1). The infrared absorption spectrum is
A strong peak characteristic of sulfuric esters was observed at 105105O'. TLC Re value 0.31°H-Phe-OCH2-Pan-resin (Example 11) in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 3-4 and then Fmoc removal steps 16-20)
-0H, Fmoc-Meto-OH, Fmoc-Trp
-08% Fmoc-Gly-OH, Fmoc-Met
-OHlFmoc-Tyr-OH (Example 3), and Boc
Boa-Asp (OtBu) -Tyr-M by sequential coupling with -Asp (OtBu) -OH
et-Gly-Trp-MetO-Asp (OtBu
) -Phe-OCH2-Pam- resin was prepared, which was sulfated according to Table 1 (steps 21-25, steps 10-15 and then steps 26-29, using ammonia),
Deprotection and separation from the resin produced the title compound, which was purified by Trisacrylation according to Table 1 (Step 30).
Purification by chromatography on 1 M DEAE gave 126 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results + A
sp2.03(2), Tyr O,96(1), Met
o, 98 (]), any 1.10 (1), Met
o 0.97 (1), and PheO,96 (+).

The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC's R2
Value 0.29° (H-Phe (4-Me)-QC) -Of(
In Example 11, Boc-Phe (4-Me)-(4-oxydimethylphenyl)acetic acid obtained by replacing
he-(4-oxymethylphenyl)acetic acid with Boc-P
he (4-Me)-(4-oxymethylphenyl)acetic acid) was prepared by replacing Fmoc-Asp(OtBu)-OH according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20). ,Fmoc-
Met-OH, Fmoc-Trp-OH, Fmoc-G
ly-Kano, Fmoc-Met-Kano, Fmoc-Tyr
(tBu)-OH2 and Fmoc-Asp (OtBu
)-DH to form Fmoc-As.
p (OtBu)-Tyr (tBu)-Met-Gl
y-Trp-Met-Asp (OtBu) -Phe
(4-Me)-0CL-Pan-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25, Step 16
-20 and then Steps 26-29 using ammonia), sulfated, deprotected and separated from the resin to produce the title compound, which was prepared in Table 1 (Step 30
) according to Amber teXAD-2, Trisac
Purification by sequential chromatography on Ryl M DEAE and P-400DS-3 gave 420 mg of the ammonium salt of the title compound.

Amino acid analysis following acid digestion gave the following results:
Asp 2.02 f2), Tyr 1. OO[
1), Metl, 91+21, Gly i, o 6
(1), and Phe (4-Metl, 12+11° infrared absorption spectrum showed a strong peak characteristic of sulfate esters at 1050 cm-'. TLC Rt
Value 0.44.

H-Tyr(tBu)-0CHz-Pam-resin (which was prepared by converting Boc-MePhe-OH to Fm in Example 5 in a similar manner to the H-Phe-OCHz-Pam-resin).
Boc-Phe-(4
-oxydimethylphenyl)acetic acid with Fmoc-Tyr (
■ produced by replacing tBul-(4-oxydimethylphenyl)acetic acid with Fmo according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20)
c-Asp(OtBul-OH, Fmoc-Met-O
H,Fmoc-Trp-OHlFmoc-Gly-OH
, Fmoc-Met-DH, Fmoc-Tyr-OH (
Example 3), and Boc-Asp (OtBu) by sequential coupling with Boa-Asp (OtBu)-OH.
) -Tyr-Met-Gly-Trp-Met-As
p (OtBu) -Tyr (tBu) -0CHz-
A Pam-resin was produced, which was described in Table 1 (Steps 21 to 25,
Sulfated, deprotected and separated from the resin according to steps 10-15 and then steps 26-29 using ammonia) to produce the title compound, which was converted into Amber te XAD-2 according to Table 1 (step 30). Trisacr
Purification by sequential chromatography on yl M DEAE and P-400DS-3 gave 42 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp 2.09 (
2), Tyr 2.16(2), Met 1.66
(2), and Gly 1.09 (], ). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC R2 value 0.2
9°H-Phe-OCHz-Pam-resin (Example 11) in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
-0H, Fmoc-Pr.

- Kano, Fmoc-Trp- Kano, Fmoc-Gly-OH
, and sequentially coupled with Fmoc-Met-lo) I-Met-Gly-Trp-Pro-Asp
(,OtBu)-Phe-OCH2-Pam-resin was prepared and coupled with 1lpp-O3u in DMF according to Table 1 (steps 8-9) to form Hpp-Met.
-Gly-Trp-Pr.

-Asp (OtBu)-Phe-OCHz-Pam-
A resin was produced, and the results were shown in Table 1 (Steps 10 to 15, Step 21).
-25 and then steps 26-29, using ammonia), sulfated and separated from the resin to produce the title compound, which was converted to A according to Table 1 (step 30).
amber is te XAD-2, Trisacryl M
Purification by sequential chromatography on DEAE and P-400DS-3 gave 70 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Met 1.01 (1), G
Iy L, 04 (1), Pro 0.97 (1),
Asp L, 04(1), and PheO, 94(1).

The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rf
Value 0.51°) 1-Phe-OCHz-Pam-resin (Example 11) is shown in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
-Of(, Fmoc-Pr.

-OH, Fmoc-Trp-OH, Fmoc-Gly-
0)1. and Fmoc-Pro-OH) I-Pro-Gly-Trp-Pro-
Asp (OtBu)-Phe-'OCHz-Pam-
Produce a resin and DM it according to Table 1 (Steps 8-9)
1 (coupled with pp-O3u) Ipp in F
-Pro-Gly-Trp-Pr.

-Asp (OtBu)-Phe-OCHz-Pam-
A resin was produced, and the results were shown in Table 1 (Steps 10 to 15, Step 21).
~25 and then Steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (Step 30) to Amber te XAD-2, Trisacryl
MDEAE and sequential chromatography on P-400DS-3 gave 480 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Pro 2.02 (2)
, GIy 1.05 (1), Asp 1.00 (1
), and Phe O,93(1), the infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC R2 value o, 44°t (-MePhe-OCHz-Pam-resin (Example 12)
Table 1 (coupling steps 5-7 and then Fmoc
Fmoc-Ahx-As according to removal steps 16-20)
p (OtBu) - Kano (Fmoc-Me in Example 10
produced by replacing t-OH with Fmoc-Ahx-0), Fmoc-Trp-OH, Fmoc-Gl
y-OH, Fmoc-Ahx-DH, and Fmoc-T
Sequential coupling with yr (tau)-OH yields 1(-Tyr (tBu) -Ahx-Gly-Trp
-Ahx-Asp (OtBu)-MePhe-QC)
! , -Pam-resin was produced, and this was shown in Table 1 (Step 8~
Suc-Tyr (tBu)-Ahx-Gly-Tr was prepared by coupling with succinic anhydride in DMF according to 9).
p-Ahx-Asp (OtBu) -MePhe-O
CHz-Pam-resin was produced, and this was shown in Table 1 (Step 1
0-15, steps 21-25 and then steps 26-29,
Deprotection using ammonia), sulfation and separation from the resin produced the title compound, which was summarized in Table 1 (
According to step 30) Amber is te XAD-2, T
risacryl M DEAE and P-400DS-
Purification by continuous chromatography on 3 ml yielded 100 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: TyrO
, 97(+), Gly 1.00 (1), and As
pl, 00(1). The infrared absorption spectrum is 1051
A strong peak characteristic of sulfuric acid ester was observed at 05O'. TLC Rt value 0.46° H-MePhe-OCHt-Pam-resin (Example 12) was converted into Fmoc-Ahx-Asp according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20).
(OtBu) -0H (Fmoc-M in Example 1○
et-01 (produced by replacing Fmoc-Ahx-OH), Fmoc-Trp-OH, Fmoc-Gl
y-OH, Fmoc-Ahx-0)1 and Fmoc-T
H-Tyr (tBu) -Ahx-Gly-Trp by sequential coupling with yr (tBu) -OH
-Ahx-Asp (OtBu)-MePhe-OCH
z-Pan-resin was produced, which was shown in Table 1 (Steps 8-9)
1BuOco-OSu in DMF according to Example 1
) to form 1BuOcO-Tyr (tB
u) -Ahx-G 1y-Trp-Ahx-Asp
(OtBu)-MePhe-OCH2-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-2).
5 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (step 30) with Am
ber was purified by sequential chromatography on te XAD-2 and P-400O3-3 to give the ammonium salt of the title compound, 29'Omg. The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rf value 0.54
゜1-1-MePhe-QC) 12-Pan-resin (Example 1
2) in Table 1 (coupling steps 5-7 and then Fm
Fmoc-Ahx- according to oc removal steps 16-20)
Asp (OtBu) -OH (Fmo in Example 10
produced by replacing c-Met-OH with Fmoc-Ahx-OH), Fmoc-Trp-OH, Fmoc-
H-Ahx-Gly-Trp-Ah by sequential coupling with Gly-OH1 and Fmoc-Ahx-DH
x-Asp (OtBu) -MePhe-OCFI2
-Pam-resin was prepared and coupled with Hl)p-OSu in DMF according to Table 1 (steps 8-9) to produce Hpp-Ahx-Gly-Trp-Ahx-Asp.
(OtBu) -MePhe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 15, Steps 21 to 2).
5 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (step 30) with Amb.
er iste XAD-2, Trisacryl MD
Purification by sequential chromatography on EAE and P-400DS-3 gave the ammonium salt of the title compound 9.
1 mg was obtained. Amino acid analysis following acid digestion gave the following results: +Ahxl, 92(2), Gly 1.
03(1), and Aspl, 05(1). The infrared absorption spectrum showed a strong peak characteristic of sulfate ester at 105105O', and the TLC R2 value was 0.4.
0°H-Phe-OCHz-Pam-resin (Example 11) in Table 1
Fmoc-Asp(OtBu) according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
-0H, Fmoc-Ahx-OH, Fmoc-Trp-
OH, Fmoc-Gly-OH, Fmoc-Ahx-D
H-Tyr (tBu) − by sequential coupling with Hl and Fmoc-Tyr (tBu) −0ft.
Ahx-Gly-Trp-Ahx-Asp (OtBu
)-Phe-OCH2-Pam-resin was prepared and treated with 1BuOcO in DMF according to Table 1 (steps 8-9).
-OSu (Example 1) and coupled with 1BuOc
O-Tyr (tBu) -Ahx-Gly-Trp-
Ahx-Asp (OtBu)-Phe-OCHz-P
An am-resin was prepared, which was deprotected according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29, using ammonia), sulfated and separated from the resin to produce the title compound. , according to Table 1 (Step 30), Amber te XAD-2 and P-400DS
Purification by continuous chromatography on -3 gave 800 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyr
O, 90(1), Ahxl, 84(2), Gly 1
．． 12 (1), Asp 1.12 (1) and P
heO,92(1), infrared absorption spectrum is 1050
cm showed a strong peak characteristic of sulfate esters. TLC R2 value 0.58°t(-Phe-OCt(z-Pam-Resin (Example 11)) was treated with Fmoc-Asp(OtBu
)-0H, Fmoc-Ahx-Ko, Fmoc-Trp-
0)1. Fmoc-Gly-OH, and Fmoc-A
H-Ahx-G by continuously coupling with hx-ko
ly-Trp-Ahx-Asp (OtBu)-Phe
-OCL-Pan- resin was produced, and this was shown in Table 1 (Step 8
Hpp-Ahx-Gly-Trp-Ahx-A by coupling with Hpp-OSu in DMF according to ~9)
sp (OtBu)-Phe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 15, Steps 21 to 2).
5 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (step 30) with Am
ber was purified by sequential chromatography on te XAD-2 and P-400O3-3 to yield 450 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Ahxl, 92
[2), Gly 1.01 (1), Asp 1
．． 10(1) and Phe O,97[+), the infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC R1 value 0.
47° The title compound has been previously prepared (Peptides 1984 J (1984
), pp. 373-378). H-Phe-OCHz-
Pam-Resin C Example 11) in Table 1 (Coupling Step 3
-4 and then Fmoc removal steps 16-20) Fmoc-Met-Asp (OtBu) -OH (Example 10), Fmac-Trp-OH, Fmoc-DAla
-OH, FmocJet-OH, and Fmoc-Tyr
(7Bu)-0) by sequentially coupling with 1
(-Tyr (tBu) -Met-DAIa-Trp
-Met-Asp (OtBu)-Phe-OCHz-
Pam-1' (produce fat, which is shown in Table 1 (Steps 8 to 9)
) by coupling with succinic anhydride in DMF according to Suc-Tyr (tBu)-Met-DAla-Tr
p-Met-Asp (OtBu) -Phe-OCH
z-Pam-resin was produced 1, which was shown in Table 1 (Step 10
~15, steps 21-25 and then steps 26-29, using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (step 30) with Trisacryl M DEAE and Purification by continuous chromatography on a P-400DS-3 gave 110 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyr 1.02 (1), MetL93 (
2), Ala 1.00 (1), Asp 1.05
(1) and Phe 1.01 (1), the infrared absorption spectra showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC R value 0,
38°) 1-Phe-OCHz-Pam-resin (Example 11
) in Table 1 (coupling steps 5-7 and then Fmo
Fmocile-As according to c removal steps 16-20)
p(OtBu)-0H (Fmoc-Me in Example 1o
produced by replacing t-OH with Fmoc-Ile-OH), Fmoc-Trp-OH, Fmoc-Gly-
0) 1, and sequentially coupled with Fmoc-Ile-OH to form H-Ile-Gly-Trp-Ile-A.
sp (OtBu) -Phe-OCHz-Pam-resin was prepared and deprotected according to Table 1 (Steps l○ to 15) to obtain H-Ile-Gly-Trp-I 1e-A.
sp-Phe-QC)12-Pam-resin was prepared and treated with For-Tyr-O according to Table 1 (steps 3-4).
For-Tyr-Ile-Gl by coupling with H
y-Trp-Ile-Asp-Phe-OCHz-Pa
An m-resin is prepared which is sulfated and separated from the resin according to Table 1 (Steps 21-25 and then Steps 26-29, using ammonia) to produce the title compound, which is prepared according to Table 1 (Step 30). According to Amber te
Purification by sequential chromatography on AD-2 and P-400DS-3 gave 200 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: TyrO,98(1), Ile
1.94 (2), Gly 1.00 (1), A
sp 1.09 (1), and Phe O,98 (1
). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rt value 0.59°H-Phe-OCHz-Pam-resin (Example 11) in Table 1
Fmoc-Ile-Asp(O
tBu)-08 (produced by replacing Fmoc-Met-Ko with Fmoc-Ile-Ko in Example 10), F
moc-Trp-OH, Fmoc-Gly-Oft, F
moc-Ile-OH1 and Fmoc-Tyr (tB
u) H-Tyr by sequential coupling with -OH
(tBu) -I 1e-Gly-Trp-Ile-A
sp (OtBu)-Phe-OCH2-Pam-resin was prepared and treated with DMF according to Table 1 (steps 8-9).
Coupled with succinic anhydride in Suc-Tyr
(tBu) -I Ie-Gly-Trp-Ile-A
sp (OtBu)-Phe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-
25 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound, which was purified according to Table 1 (step 30) with Am
ber was purified by sequential chromatography on TE XAD-2 and P-400DS-3 to yield 300 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyr 1.0
0 (1), Ile 2.07 (2), Gly
0.97 (1), Asp 0.97 (1), and Pheo, 99 (1). The infrared absorption spectrum is 10
A strong peak characteristic of sulfuric acid ester was observed at 5105O'. TLC Rt value 0,42 °f (-Phe-OCH3-Pam-resin (Example 11)
(OtBu) - Kano (Fmoc-Met in Example 10)
-OH is replaced with Fmoc-Ile-OH), Fmoc-Trp-OHlFmoc-G ly-
OHlFmoc-Ile-Ko, and Fmoc-Tyr
(tBu)-H-Ty by continuous coupling
r (tau)-Ile-Gly-Trp-Ile-A
sp (OtBu)-Phe-OCH3-Pam-resin was prepared and coupled with 1BuOc0-O3u in DMF according to Table 1 (steps 8-9) to give 1Bu
Oco-Tyr (tBu)-Ile-Gly-Trp
-Ile-Asp (OtBu)-Phe-OCHz-
Pam-resin was produced, and this was shown in Table 1 (Steps 10 to 15,
Deprotection, sulfation and separation from the resin according to steps 21-25 and then steps 26-29 using ammonia) to produce the title compound, which was converted to Amber te XAD-2 and P-4000
Purification by continuous chromatography on S-3 gave 390 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Ty
r 1.07 (1), Ile 2.21 (2)
, Gly 1.04 (1), Asp 1.00
(1) and Phel, 03(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 1050 cm6'. TLCORr value 0.61° H-Phe-QC) (z-Pan-resin (Example 11)
(OtBu) - Kano (Fmoc-Met in Example 10)
-OH replaced with Fmoc-I 1e-0), Fmoc-Trp-Ko, Fmoc-Gly-D
H-Tie-Gly-Trp-Ile-Asp by sequential coupling with Hl and Fmoc-Ile-DH
(OtBu) -Phe-OCHz-Pam- resin was prepared and coupled with Hpp-O3u in DMF according to Table 1 (steps 8-9) to form Hpp-Ile.
-Gly-Trp-Tle-Asp (OtBu) -
Phe-OCHz-Pam-resin was produced and shown in Table 1.
(Steps 10-15, steps 21-25 and then step 2
Deprotection, sulfation, and separation from the resin according to Amber te
Purification by sequential chromatography on AD-2 and P-400DS-3 gave 280 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Ile 2.04 (2), G
lyo, 99(1), Asp O, 98(1) and Ph
e O, 99(1). The infrared absorption spectrum is 105
A strong peak characteristic of sulfuric esters was observed at 105O'. TLC Rf value 0.52゜Takumi Danko's title compound has been previously produced ["Peptide 1
984J, (Proceedings of the 18th European Peptide Scissibodium Conference, edited by U. Ragnarsso, Almqvistand Wikse International)
Ill International Publishing (1985)), pp. 373-378]. H-MePhe-OC)
The Iz-Pam-resin (Example 12) was converted into Fmoc-Met-Asp (OtBu)-Ko(
Example 10), Fmoc-Trp-Ko, Fmoc-Gl
y-OH, Fmoc-Met=Kano, and Fmoc-Ty
r (tau)-OH)
i-Tyr (tBu) -Met-Gly-Trp-
Met-Asp (OtBu) -MePhe-OCH
z-Pam-resin was produced and this was shown in Table 1 (Steps 8-9)
S by coupling with succinic anhydride in DMF according to
uc-Tyr(tBu)-Met-Gly-Trp
-Met-Asp(OtBu)-MePhe-QC)I
t-Pam-resin was produced, and this was shown in Table 1 (Step 10~
15, steps 21-25 and then steps 26-29, using ammonia) to produce the title compound, which was converted into Amber te XAD- according to Table 1 (step 30), sulfated and separated from the resin. 2 and P-
Purification by continuous chromatography on a 400DS-3 gave 170 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyrl, 02(1), Met 1.94, (2
), Gty 1.09 (1), Asp 1.00
(1) and MePhe 1.02 (1), the infrared absorption spectra showed a strong peak at 105105O' that is characteristic of sulfate esters. TLC R2 value 0,
58゜''h H-MePhe-QC)Iz-Pam-Resin (Example 12)
Table 1 (coupling steps 5-7 and then Fmoc
According to removal step 16-2o) Fmoc-Ile-A
sp (OtBu) - Kano (Fmoc-M in Example 10
produced by replacing et-OH with Fmoc-Ile-014), Fmoc-Trp-OH, Fmoc-Gl
y-OH, Fmoc-Tie-OH, Fmoc-Tyr
(tBu)-0)! and Fmoc-DAsp (OtB
Fmoc- by sequential coupling with u)-0)1
DAsp (OtBu) -Tyr (tBu) -I
le-Gly-Trp-I 1e-Asp(OtBu)
-MePhe-QC) 12-Pam-resin was produced, and this was shown in Table 1 (Steps io to 15, Steps 21 to 25, Step 1
6-20 and then steps 26-29, using ammonia)
Deprotection, sulfation, deprotection and separation from the resin according to Table 1 (Step 3
0) according to Amber te XAD-2 and P-4
Purification by continuous chromatography on a 00DS-3 gave 30 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results:
Asp 1.96 (2), Tyro, 97 (1),
Ile 1.92 (2), Gly O, 98 (1
) and MePhel, 18(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 105105O'. TLC Rt value 0.36°H -MePhe-OCHz-Pam-resin (Example 12) was converted into Fmoc-1ie-Asp according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20).
(OtBu) -0H (Fmoc-Me in example IQ
produced by replacing t-OH with Fmoc-Ile-0)1), Fmoc-Trp-OH, Fmoc-Guy
-0)1 and Fmoc-ll5-OH to sequentially couple H-Ile-Gly-dirp-I l5-
Asp (OtBu) -MePhe-0(, Hz-P
am-resin was prepared and deprotected according to Table 1 (steps 10-15) to yield H-Ile-Gly-Trp-Ile.
-Asp-MePhe-OCHz-Pam-resin was prepared and treated with F according to Table 1 (coupling steps 3-4).
For-Ty by coupling with or-Tyr-OH
r-rle-Gly-Trp・-Ile-Asp-Me
A Phe-(tcHz-Pam-resin was prepared, which was sulfated and separated from the resin according to Table 1 (steps 21-25 and then steps 26-29, using ammonia) to produce the title compound, which was 1 (step 30)
Purification by continuous chromatography on -3 gave 90 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyr
1.04 (1), Hel, 95 (2), Guy O
, 97(1), Asp 1.01(1) and MeP
hel, 03(1). The infrared absorption spectrum is 105
At 0 cm, a strong peak characteristic of sulfuric esters was observed. TLC Rr value 0.60°1 (-MePhe-OCH2-Pan-resin (Example 12) in Table 1
Fmoc-Ile-Asp ( according to (coupling steps 5-7 and then Fmoc removal steps 16-20)
OtBu) -0)1 (Fmoc-Me in Example 10
produced by replacing t-OH with Fmoc-I 1e-OH), Fmoc-Trp-OH, Fmoc-Gly
-OH, Fmoc-Ile-OH and Fmoc-Tyr
(tBu)-OH and H-
Tyr (tBu) -Ile-Gly-Trp-IL
e-Asp (OtBu)-MePhe-OCHz-P
am-resin was prepared and coupled with succinic anhydride in DMF according to Table 1 (steps 8-9) to obtain Suc-
Tyr (tBu)-Ile-Gly-Trp-Ile
-Asp (OtBu)-MePhe-OCHz-Pa
An m-resin is prepared which is deprotected according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29 using ammonia), sulfated and separated from the resin to produce the title compound. , according to Table 1 (Step 30)
Purification by continuous chromatography on -3 gave 130 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Tyr
0.94 (1), Ile 1.92 (2),
Gly 1.04 (1), Asp 1.09 (
1), and MePhel, 00 (1). The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters. TLC Rt value 0.37゜h H-MePhe-0(:Hz-Pam-resin (Example 12)
Table 1 (coupling steps 5-7 and then Fmoc
According to removal steps 16-20) Fmoc-Ile-A
sp (OtBu) -0H (Fmoc in Example 10
-Met-Ko is replaced with Fmoc-Ile-OH), Fmoc-Trp-Ko, Fmoc-Gly
-OH, Fmoc-11g-Kano and Fmoc-Tyr
H-T by sequential coupling with (tBu)-OH
yr (tau)-Ile-Gly-Trp-Ile-
Asp(OtBu)-MePhe-QC:Hz-Pa
m-resin was prepared and coupled with 1BuOcO-O3u (Example 1) in DMF according to Table 1 (steps 8-9) to give iBuOCO-Tyr (tBu)-Ile
-Gly-Trp-Ile-Asp (OtBu)-M
An ePhe-OCH7-Pan-resin was prepared which was deprotected according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29, using ammonia), sulfated and separated from the resin to yield the title Prepare the compound and convert it to Amber te XA according to Table 1 (Step 30)
Purification by sequential chromatography on D-2 and P-400DS-3 gave the ammonium salt of the title compound 5.
0 mg was obtained. Amino acid analysis following acid digestion gave the following results: Tyrl, 00 (+,), Ile
1.92 (2), Gly 1.02 (1),
Asp 1.03 (1) and MePhe 1.03
(1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 105105O'. T.L.C.
R2 value of 0.74゜Godanyu H-As -DT r 5O3H-Ile-Gl -T
r -Ice-As -MePhe-H-MePhe-OCHz-Pam-resin (Example 12) according to Table 1 (coupling steps 5-7 and then Fmoc removal steps 16-20)
p (OtBu) - Kano (Fmoc-Me in Example 10
t-0)1 by replacing Fmoc-I 1e-OH), Fmoc-Trp-Of (, Fmoc-G
ly-OH, Fmoc-Ile-OH, Fmoc-DT
yr(tBu)-0H, and Fmoc-Asp(Ot
Fmoc- by sequential coupling with Bu)-OH
Asp (OtBu) -DTyr (tBu) -Il
e-Gly-Trp-Ile-Asp(OtBu)-M
ePhe-OCHz-Pam-resin was produced, and this was shown in Table 1 (Steps 10-15, Steps 21-25, Steps 16-2
0 and then deprotected according to Steps 26-29, using ammonia), sulfated, deprotected and separated from the resin to produce the title compound, which was converted into Amber te XAD-2 according to Table 1 (Step 30). and P-400DS
Purification by continuous chromatography on -3 gave 200 mg of the ammonium salt of the title compound. Amino acid analysis following acid digestion gave the following results: Asp.
2.08 (2), Tyrl, 01 (1), is e
1.94 (2), Gly O,98 (1), and M
ePhe 0.99 (1). The infrared absorption spectrum showed a strong peak characteristic of sulfuric ester at 105105O'. TLC Rf value 0.38°H-MeP
he-OCftz-Pan-resin (Example 12) is shown in Table 1 (
Coupling steps 5-7 and then Fmoc removal step 1
Fmoc-I 1e-Asp (O
tBu)-Koh (Fmoc-Met-OH in Example 10
produced by replacing Fmoc-1ie-OH),
Sequentially coupled with Fmoc-Trp-Ko, Fmoc-Gly-OH1 and Fmoc-Ile-0)1)! -Ile-Gly-Trp-Ile-Asp (
OtBu)-MePhe-OCHz-Pam-resin was prepared and was converted to Ipp according to Table 1 (steps 8-9).
- Hpp-Ile-Gly by coupling with O3u
-Trp'-Ile-Asp (OtBu)-MePh
e-OCHz-Pam-resin was produced and shown in Table 1 (
Steps 10-15, steps 21-25 and then steps 26-
29, using ammonia), sulfated and separated from the resin to produce the title compound, which was converted into Amber te XAD-2 according to Table 1 (Step 30).
and purified by continuous chromatography on P-4000S-3 to give 70 mg of the ammonium salt of the title compound.
I got it. Amino acid analysis following acid digestion gave the following results: e 1.94 (2), GIy 1.0
1(1), Asp 1.02(1), and MePh
e 1.04 (1).

The infrared absorption spectrum showed a strong peak at 105105O' that is characteristic of sulfuric esters.

TLC R2 value 0.63° Procedural amendment February 2, 1986

Claims (1)

[Claims] 1. General formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (Here, Q is H, H-Asp, H-βAsp, H-DAsp, H
-MeAsp, For, Ac, Suc, desQ, or R^1R^2CHOCO, Y is H, (S)-NH, (R)-R^SN, or (S)
-R^SN, M is Met, DMet, MeMet, Me
tO, Ahx, DAhx, MeAhx, Leu, MeL
eu, Pro, He, MeIle or Lys, G is Gly, DAIa, Pro or Sar, W is Trp
, MeTrp or Nal, X is Met, MeMet, MetO, Ahx, MeAh
x, Leu, MeLeu, Ile, MeIle, Pro
, or Lys, J is Asp, DAsp, MeAsp, or Asn, F^
1 is (S)-NH, (S)-R^4N, or (R)-R
^4N, F^2 is H, Cl, I, Br, F, NO_2,
NH_2, R^5, or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
, R^2 are each independently H or lower alkyl, R^3,
R^4, R^5 are lower alkyl, R^6 is H or a lower alkyl group, and R^7, R^8 are lower alkyl groups) and their pharmaceutically acceptable salts (however, ( 1) Q is desQ when Y is H, (2) F^2 is when Q is H-As in the same peptide
p or Ac, Y is (S)-NH, M is Met, Met
O, Ahx or Leu, X is Met, Me
tO, either Ahx or Leu, G is Gly, D
Ala or Pro, w is Trp, J is Asp, F^1
is (S)-NH and Z is NH_2, then it is not H, and (3) F^2 is if Q is H, H- in the same peptide.
βAsp or For, Y is (S)-NH, M is Met
, Ahx or Leu, G is Gly, W is Trp, X is Met, Ahx or Leu, J is Asp, F^1 is (
S) -NH, and if Z is NH_2, then it is not H, (4) F^2 is, if in the same peptide, Y is H, M is Met, X is Met, G is Gly, W is Trp , J is A
sp, F^1 is (S)-NH, and Z is NH_2, and (5) F^2 is not H, if Q is Suc in the same peptide.
, Y is (S)-NH, M is Met, X is Met, G is G
ly or DAl, W is Trp, J is Asp, F^1 is (S)-NH or (S)-R^4N, and Z is NH_
If it is 2, it is not H). 2, Q is H, H-Asp, H-βAsp, H-DAsp
, For, Ac, Snc, desQ, or R^1R^2
CHOCO; Y is H, (S)-NH or (S)-R^3
N; M is Met, MeMet, Ahx, MeAhx, L
eu, MeLeu, He, MeIle or Pro;G
is Gly or DAla; W is Trp; X is Met, MeMet, Ahx, MeAhx, Leu
, MeLeu, He, MeIle or Pro; J is A
sp; F^1 is (S)-NH or (S)-R^4N; F^2 is H, Cl, NO_2, NH_2, R^5 or OR^6;
The peptide according to claim 1, wherein and Z are NH_2. 3. M is Met, DMet, MetO, Ahx, DAh
x, Leu, Pro, He or Lys, X is Met,
MetO, Ahx, Leu, He, Pro or Lys
The peptide according to claim 1, which is 4, M is Met, DMet, MetO, Ahx, DAh
The peptide according to claim 1, which is x, Leu, Pro, He or Lys. 5, H-DAsp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is ly-Trp-Met-Asp-Phe-NH_2. 6, iBuOCO-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is ly-Trp-Met-Asp-Phe-NH_2. 7, H-Asp-DTyr(SO_3H)-Met-G
The peptide according to claim 1, which is 1y-Trp-Met-Asp-Pbe-NH_2. 8, H-Asp-Tyr(SO_3H)-DMet-G
The peptide according to claim 1, which is ly-Trp-Met-Asp-Phe-NH_2. 9, H-Asp-Tyr(SO_3H)-DAhx-G
The peptide according to claim 1, which is ly-Trp-Met-Asp-Phe-NH_2. 10, H-Asp-Tyr(SO_3H)-Met-S
The peptide according to claim 1, which is ar-Trp-Met-Asp-Phe-NH_2. 11, H-Asp-Tyr(SO_3H)-Met-G
ly-MeTrp-Met-Asp-Phe-NH_2
The peptide according to claim 1, which is 12, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is ly-Trp-Met-DAsp-Phe-NH_2. 13, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is ly-Trp-Met-Asn-Phe-NH_2. 14, H-Asp-Tyr(SO_3H)-Met-G
ly-Trp-Met-Asp-MePhe-NH_2
The peptide according to claim 1, which is 15, H-Asp-Tyr(SO_3H)-Met-G
ly-Trp-Met-Asp-MeTyr(Me)-
The peptide according to claim 1, which is NH_2. 16, H-Asp-Tyr(SO_3H)-Met-G
ly-Trp-Met-Asp-Phe(4-NO_2
)-NH_2. The peptide according to claim 1, which is -NH_2. 17, H-Asp-Tyr(SO_3H)-Met-G
ly-Trp-Met-Asp-Phe(4-CI)-
The peptide according to claim 1, which is NH_2. 18, H-Asp-Tyr(SO_3H)-Met-G
Iy-Trp-Met-Asp-Phe(4-NH_2
)-NH_2. The peptide according to claim 1, which is -NH_2. 19, H-Asp-Tyr(SO_3H)-Met-G
Iy-Trp-Met-Asp-Tyr(Me)-NH
The peptide according to claim 1, which is _2. 20, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Phe-NHMe. 21, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Phe-NHEt. 22, H-Asp-Tyr(SO_3H)-Met-G
Iy-Trp-Met-Asp-Phe-N(Me)_
2. The peptide according to claim 1, which is 23, H-Asp-Tyr(SO_3H)-Met-G
Iy-Trp-Met-Asp-Phe-N(Et)_
2. The peptide according to claim 1, which is 24, H-βAsp-DTyr(SO_3H)-Met
-GIy-Trp-Met-Asp-Phe-NH_2
The peptide according to claim 1, which is 25, H-DAsp-DTyr(SO_3H)-Met
-GIy-Trp-Met-AsP-Phe-NH_2
The peptide according to claim 1, which is 26, Suc-DTyr(SO_3H)-Met-GI
The peptide according to claim 1, which is y-Trp-Met-Asp-Phe-NH_2. 27, H-Asp-Tyr(SO_3H)-Ile-G
The peptide according to claim 1, which is Iy-Trp-Ile-Asp-Phe-NH_2. 28, H-Asp-Tyr(SO_3H)-Lys-G
The peptide according to claim 1, which is Iy-Trp-Lys-AsP-Phe-NH_2. 29, H-DAsp-Tyr(SO_3H)-Met-
GIy-Trp-Met-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 30, H-Asp-DTyr(SO_3H)-Met-
GIy-Trp-Met-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 31, Hpp(SO_3H)-Met-GIy-Trp
-Met-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Met-Asp-MePhe-NH_2. 32, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Nal-Met-Asp-Phe-NH_2. 33, Hpp(SO_3H)-Met-DAla-Tr
The peptide according to claim 1, which is p-Met-Asp-Phe-NH_2. 34, Suc-Tyr (SO_3H)-Ahx-GIy
-Trp-Ahx-Asp-Phe-NH_2 peptide according to claim 1. 35, Q is H, H-Asp, H-βAsp, H-DAs
p, H-MeAsp, For, Ac, Suc, desQ
, or R^1R^2CHOCO, Y is H, (S)-NH, (R)-R^3N, or (S)
-R^3N, M is Met, DMet, MeMet, Me
tO, Ahx, DAhx, MeAhx, Leu, MeL
eu, Pro, He, MeIle or Lys, G is GIy, Pro or Sar, W is Trp, MeTrp or Nal, X is Met, MeMet, MetO, Ahx, MeAh
x, Leu, MeLeu, Ile, MeIle, Pro
, or Lys, J is Asp, DAsp, MeAsP, or Asn, F^
1 is (S)-NH, (S)-R^4N, or (R)-R
^4N, F^2 is H, CI, I, Br, F, NO_2,
NH_2, R^5 or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
and R^2 is independently H or a lower alkyl group, R^3,
R^4 and R^5 are lower alkyl groups, R^6 is H or a lower alkyl group, and R^7 and R^8 are lower alkyl groups, and the peptide according to claim 1 and its pharmaceutical use Acceptable salts (provided that (1) Q is desQ when Y is H, (2) F^2 is desQ if Q is H-As in the same peptide.
P, or Ac, Y is (S)-NH, M is Met, Me
tO, either Ahx or Leu, X is Met, M
Either etO, Ahx or Leu, G is GIy or Pro, J is Asp, F^1 is (S)-NH and Z
If is NH_2, then it is not H, and (3) F^2 is, if in the same peptide, Q is H, H-βAsp or For,
Y is (S)-NH, M is Met, Ahx or Leu,
G is GIy, W is Trp, X is Met, Ahx or L
eu, J is Asp, F^1 is (S)-NH, and Z is N
If it is H_2, it is not H. (4) F^2 is if Y is H, M is Met, X is Met, G is GIy, W is Trp, and J is A
sp, F^1 is (S)-NH, and Z is NH_2, and (5) F^2 is not H, if Q is Suc in the same peptide.
, Y is (S)-NH, M is Met, X is Met, G is G
Iy, W is Trp, J is Asp, F^1 is (S)-NH
or (S)-R^4N, and if Z is NH_2, then H
(not). 36, Q is H, H-Asp, H-βAsp, H-DAs
p, For, Ac, Suc, desQ, or R^1R^
2CHOCO; Y is H, (S)-NH, or (S)-R
^3N; M is Met, MeMet, Ahx, MeAhx
, Leu, MeLeu, He, MeIle or Pro
; G is GIy; W is TrP; X is Met, MeMet, Ahx, MeAhx, Leu
, MeLeu, He, MeIle or Pro, J is A
sP, F^1 is (S)-NH, or (S)-R^4N, F^2
is H, Cl, NO_2, NH_2, R^5 or OR^
6. The peptide according to claim 2, wherein Z is NH_2. 37, H-βAsp-Tyr(SO_3H)-Met-
GIy-Trp-Met-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 38, For-Tyr (SO_3H)-Met-GIy
-Trp-Met-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Trp-Met-Asp-MePhe-NH_2. 39, iBuOCO-Tyr(SO_3H)-Met-
GIy-Trp-Met-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 40, Hpp(SO_3H)-Met-DAIa-Tr
The peptide according to claim 1, which is p-Met-Asp-MePhe-NH_2. 41, PrOCO-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Phe-NH_2. 42, EtOCO-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Phe-NH_2. 43, MeOCO-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Phe-NH_2. 44, H-Asp-Tyr(SO_3H)-Met-G
Iy-Trp-Met-Asp-Phe-(4-Me)
-NH_2. The peptide according to claim 1, which is -NH_2. 45, H-Asp-Tyr(SO_3H)-Met-G
The peptide according to claim 1, which is Iy-Trp-Met-Asp-Tyr-NH_2. 46, Hpp(SO_3H)-Met-GIy-Trp
-Pro-Asp-Phs-NH_2. The peptide according to claim 1, which is -Pro-Asp-Phs-NH_2. 47, Hpp(SO_3H)-Pro-GIy-Trp
-Pro-Asp-Phe-NH_2. The peptide according to claim 1, which is -Pro-Asp-Phe-NH_2. 48, Suc-Tyr (SO_3H)-Ahx-GIy
-Trp-Ahx-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Trp-Ahx-Asp-MePhe-NH_2. 49, iBuOCO-Tyr(SO_3H)-Ahx-
GIy-Trp-Ahx-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 50, Hpp(SO_3H)-Ahx-GIy-Trp
-Ahx-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Ahx-Asp-MePhe-NH_2. 51, iBuOCO-Tyr(SO_3H)-Ahx-
The peptide according to claim 1, which is GIy-Trp-Ahx-Asp-Phe-NH_2. 52, Hpp(SO_3H)-Ahx-GIy-Trp
-Ahx-Asp-Phe-NH_2. The peptide according to claim 1, which is -Ahx-Asp-Phe-NH_2. 53, For-Tyr (SO_3H)-Ile-GIy
-Trp-Ile-Asp-Phe-NH_2. The peptide according to claim 1, which is -Trp-Ile-Asp-Phe-NH_2. 54, Suc-Tyr (SO_3H)-Ile-GIy
-Trp-Ile-Asp-Phe-NH_2. The peptide according to claim 1, which is -Trp-Ile-Asp-Phe-NH_2. 55, iBuOCO-Tyr(SO_3H)-Iie-
The peptide according to claim 1, which is GIy-Trp-Ile-Asp-Phe-NH_2. 56, Hpp(SO_3H)-Ile-GIy-Trp
-Ile-Asp-Phe-NH_2. The peptide according to claim 1, which is -Ile-Asp-Phe-NH_2. 57, H-DAsp-Tyr(SO_3H)-Ile-
GIy-Trp-Ile-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 58, For-Tyr (SO_3H)-Ile-GIy
-Trp-Ile-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Trp-Ile-Asp-MePhe-NH_2. 59, Suc-Tyr (SO_3H)-Ile-GIy
-Trp-Ile-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Trp-Ile-Asp-MePhe-NH_2. 60, iBuOCO-Tyr(SO_3H)-Ile-
GIy-Trp-Ile-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 61, Hpp(SO_3H)-Ile-GIy-Trp
-Ile-Asp-MePhe-NH_2. The peptide according to claim 1, which is -Ile-Asp-MePhe-NH_2. 62, H-Asp-DTyr(SO_3H)-Ile-
GIy-Trp-Ile-Asp-MePhe-NH_
2. The peptide according to claim 1, which is 63. General formulas▲Mathematical formulas, chemical formulas, tables, etc.▼ (Here, Q is H-βAsp, For, Suc, desQ
, or R^1R^2CHOCO, Y is H or (S)-NH, M is Met, Ahx, Leu, or He, G is GIy
W is Trp, X is Met, Ahx, Leu, or Ile, J is Asp
, F^1 is (S)-NH or (S)-R^4N, F^2 is H, NO_2, R^5, and OR^6, Z is NH_2 R^1 and R^2 are independently H or lower alkyl group, R^
3, R^4, R^5, R^6 are lower alkyl groups) and pharmaceutically acceptable salts thereof (provided that (1) Q is desQ when Y is H; (2)
F^2 is if Q is H-βAsp in the same peptide,
For, or AC, Y is (S)-NH, M is Met,
Either Ahx or Leu, X is Met, Ahx
or Leu, and if F^1 is (S)-NH, it is not H, and (3) F^2 is, if in the same peptide, Y is H, M is Met, X is Met, and F^1 is (
S)-NH, not H, (4) F^2, if in the same peptide Q is Suc, Y is (S)-NH, M is Met, X is Met, and F^1 If is (S)-R^4N, then it is not H). 64. The peptide according to claim 63, wherein Q is iBuOCO. 65. The peptide of claim 63, wherein Q is Suc. 66. The peptide of claim 63, wherein Q is For. 67, General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Q is H, H-Asp, H-βAsp, H-DAsp, H
-MeAsp, For, Ac, Suc, desQ, or R^1R^2CHOCO, Y is (R)-NH, M is Met, DMet, MeMet, MetO, Ahx
, DAhx, MeAhx, Leu, MeLeu, Pro
, Ile, MeIle or Lys, G is Gly, DAIa, Pro or Sar, W is Trp
, MeTrp or Nal, X is Met, MeMet, MetO, Ahx, MeAh
x, Leu, MeLeu, Ile, MeIle, Pro
, or Lys, J is AsP, DAsp, MeAsp, or Asn, F^
1 is (S)-NH, (S)-R^4N, or (R)-R
^4N, F^2 is H, CI, I, Br, F, NO_2,
NH_2, R^5, or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
, R^2 is independently H or lower alkyl group, R^3, R
^4 and R^5 are lower alkyl groups, R^6 is H or lower alkyl groups, R^7 and R^8 are lower alkyl groups) and pharmaceutically acceptable salts (with the exception of (1) F ^2 means that Q is H-Asp, M and X are Ile, and G in the same peptide.
is GIy, J is Asp, F^1 is (S)-NH, and Z
is not H when is HN_2). 68, The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, Q is H, H-Asp, H-βAsp, H-DA
sp, H-MeAsp, For, Ac, Suc, des
Q, H-Arg-Asp, GIp-Asp, GIp-G
Iu, GIp-GIn, Suc-Asp, GIt-As
p, Pht-Asp, R^9CO-AsP, Boc-A
sP, Cbz-Asp, H-Abu, H-AIa, Bo
c, Cbz, or R^1R^2CHOCO, Y is H, (
S)-NH, (R)-R^3N, or (S)-R^3N
, M is Met, DMet, MeMet, MetO, Ah
x, DAhx, MeAhx, Leu, MeLeu, Pr
o, Ile, MeIle, Lys, Thr, Abu, V
al, Mox, GIy, Phe, Tyr, or Trp, G is GIy, DAIa, Sar, DTrp, Pro, or βAIa, W is Trp, MeTrp, NaI, DTrp, Trp (
Me), Trp(5-F), or Trp(6-F), X
is Met, MeMet, MetO, Ahx, MeAhx
,Leu,MeLeu,Ile,MeIle,Pro,
Lys, DMet, Abu, or Mox, J is Asp, DAsp, MeAsp, βAsp, or A
sn, F^1 is (S)-NH, (S)-R^4N, (R
)-NH, or (R)-R^4N, F^2 is H, CI, I, Br, F, NO_2, NH_2
, R^3, or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
and R^2 is independently H or a lower alkyl group, R^3,
R^4 and R^5 are lower alkyl groups, and R^7 and R^8
, R^9 is a lower alkyl group), and an obesity treatment agent containing an effective amount of a pharmaceutically acceptable salt thereof (provided that (1) Q is desQ when Y is H;
2) F^2 is the same peptide in which Q is H-Asp, Y is (S)-NH, M is Met, X is Met, G is GIy or Pro, W is Trp, J is Asp, F^1 ga (S)
-NH, and not H when Z is NH_2). 69, General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (Here, Q is H, H-Asp, H-βAsp, H-D
Asp, H-MeAsp, For, Ac, Suc, de
sQ, H-Arg-Asp, GIp-Asp, GIp-
GIu, GIp-GIn, Suc-Asp, GIt-A
sp, Pht-Asp, R^9CO-Asp, Boc-
Asp, Cbz-Asp, H-Abu, H-AIa, B
oc, Cbz, or R^1R^2CHOCO, Y is H,
(S)-NH, (R)-R^3N, or (S)-R^3
N, M are Met, DMet, MeMet, MetO, A
hx, DAhx, MeAhx, Leu, MeLeu, P
ro, Ile, MeIle, Lys, Thr, Abu,
VaI, Mox, GIy, Phe, Tyr, or Trp
, G is GIy, DAIa, Sar, DTrp, Pro or βAIa, W is Trp, MeTrp, Nal, DTrp, Trp (
Me), Trp(5-F), or Trp(6-F), X
is Met, MeMet, MetO, Ahx, MeAhx
,Leu,MeLeu,Ile,MeIle,Pro,
Lys, DMet, Abu, or Mox, J is Asp, DAsp, MeAsp, βAsp, or A
snF^1 is (S)-NH, (S)-R^4N, (R)
-NH, or (R)-R^4N, F^2 is H, CI, I, Br, F, NO_2, NH_2
, R^5, or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
, R^2 is independently H or lower alkyl group, R^3, R
^4, R^5 are lower alkyl groups, R^6 is H or lower alkyl groups, R^7, R^8, R^9 are lower alkyl groups), and the peptide and its pharmaceutically acceptable salts (provided that (1) Q is desQ when Y is H, and (2) F^2 is Q in the same peptide).
is H-AsP, Y is (S)-NH, M is Met, and X is M
et, G is GIy or Pro, W is Trp, J is As
When p, F^1 is (S)-NH and Z is NH_2, H
(not). 70, General formulas▲Mathematical formulas, chemical formulas, tables, etc.▼ (Here, Q is H-βAsp, For, Suc, desQ
, or R^1R^2CHOCO, Y is H or (S)-NH, M is Met, Ahx, Leu, or He, G is GIy
, W is Trp, X is Met, Ahx, Leu, or He, J is Asp
, F^1 is (S)-NH or (S)-R^4N, F^2 is H, NO_2, R^5, or OR^6, Z is NH_2 R^1, R^2 are independently H or lower alkyl group, R^
3, R^4, R^5, R^6 are lower alkyl groups) and pharmaceutically acceptable salts thereof (provided that (1) Q is desQ when Y is H; (2)
F^2 is if Q is H-βAsp in the same peptide,
For, or Ac, Y is (S)-NH, M is Met,
Either Ahx or Leu, where X is Me, Ahx
or Leu, and if F^1 is (S)-NH, it is not H, and (3) F^2 is, if in the same peptide, Y is H, M is Met, X is Met, and F^1 is (
S)-NH, not H, (4) F^2, if in the same peptide Q is Suc, Y is (S)-NH, M is Met, X is Met, and F^1 is (S)-R^4N, not H). 71, General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Q is H, H-Asp, H-βAsp, H-DAsp, H
-MeAsp, For, Ac, Suc, desQ, or R^1R^2CHOCO, Y is (R)-NH, M is Met, DMet, MeMet, MetO, Ahx
, DAhx, MeAhx, Leu, MeLeu, Pro
, Ile, MeIle or Lys, G is GIy, DAIa, Pro or Sar, W is Trp
, MeTrp or NaI, X is Met, MeMet, MetO, Ahx, MeAh
x, Leu, MeLeu, Ile, MeIle, Pro
, or Lys, J is Asp, DAsp, MeAsp, or Asn, F^
1 is (S)-NH, (S)-R^4N, or (R)-R
^4N, F^2 is H, CI, I, Br, F, NO_2,
NH_2, R^5, or OR^6, Z is NH_2, NHR^7 or NR^7R^8, R^1
, R^2 is independently H or lower alkyl group, R^3, R
^4 and R^5 are lower alkyl groups, R^6 is H or lower alkyl groups, R^7 and R^8 are lower alkyl groups) and pharmaceutically acceptable salts (with the exception of (1) F ^2 means that Q is H-Asp, M and X are Ile, and G in the same peptide.
is GIy, J is Asp, F^1 is (S)-NH, and Z
is HN_2, but not H). 72. Add the required protected amino acids or protected oligopeptides in sequence (with deprotection after each addition) to the aminoacyl resin of the formula ▲ Mathematical formula, chemical formula, table, etc. ▼ to form the formula ▲ Mathematical formula, chemical formula, A method for producing the compound according to claim 1, which comprises a solid-phase method of producing a protected peptide resin represented by ▼, sulfating it, deprotecting it, and treating it with a methanolic amine. 73, Add the required protected amino acid or protected oligopeptide to the aminoacylamide represented by the formula ▲ Mathematical formula, chemical formula, table, etc. (with deprotection after each addition), and form the formula ▲ Mathematical formula, chemical formula , Tables, etc. ▼ A method for producing a compound according to claim 1, which comprises producing a protected peptide amide represented by ▼, and sulfating and deprotecting the same.