JPH06506941A - CCK analogs containing α-substituted amino acids - Google Patents

Abstract

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

Description

[Detailed description of the invention] CCK analogs containing α-substituted amino acids Background of the invention Drugs that act on central cholecystokinin (CCK) receptors induce satiety Possibly (Schick, Yaksh.

Go, Regulatory Peptides 14:277-291 (1 986)).

C (J peptides include the gastrointestinal tract, endocrine glands and nerves of the peripheral and central nervous systems. are widely (distributed) in various organs of the body; the various biologically active forms are the same. This includes the 33 amino acid hormone and various carcinogens of this peptide. Boxy-terminal fragments [e.g. octapeptide (CCK26-33) and te trapeptide (CCK30-33)] (G, J, Dockra y, Br, father-in-law, Bull, 38 (No, 3): 253-258 ．． 1982).

Various CCK peptides are involved in smooth muscle contraction control, exocrine and endocrine secretion, and sensory secretion. It is thought to be involved in transduction and numerous brain functions. natural peptides Administration has effects on gallbladder contraction, amylase secretion, central neuron excitation, feeding inhibition, and anticonvulsant effects, and other behavioral effects (cholenstokinin dissociation, structural structure and function (“Cholecystokinin: l5olation,” 5structure and Functions”), G, B, J, Glass ed., Raven Press, New York, 1980, 169-221. Page; J, ):, Morley.

Life 5 Sciences, 27:355-368. 1980: Nervous system cholecystokinin (+Cholecystokinin in the Ne rvous 5yst, em"), J, deBell, eroche & G, Edited by J. Dockray, published by Ellis Horwood, Chichester, UK. Rhys, 1984, pp. 110-127).

The presence of high concentrations of CCK peptides in many brain regions also suggests that these peptides (G, J, Dockray, Br, Wed, Bull, 38 (No. 3): 253-258. 1982). most abundant in the brain The most common form of CCK is CCK26-33, but a small amount of CCK30-3 3 also exists (Rehfeld & Gotter! l1an, J, Neu Rochem, 32: 1339-1341 (1979)). central nervous system cc Although the role of K is not clearly understood, it has been shown to be related to feeding control (De lla-Fera & Ba1le, 5science 206: 471-4 73 (1979)).

Currently available appetite suppressants work by increasing energy expenditure (e.g. peripherally (e.g. biguanides) or in other ways (e.g. biguanides). or by exerting central effects on appetite or satiety. That's how it works.

It has recently been shown that patients with fowlphagia have lower than normal plasma CCK levels (Ger et al. acioti et al., New England Journal of Medici ne 319: 683 (1988)). Another role of CCK in erasure is It is to regulate the release of insulin. When administered to mammals, CCK shown to increase insulin levels (Rushakoff et al., J, Cl1 n, Endocrinol.

Metab, 65: 395 (1987)).

The C-terminal fragment of CCK has been shown to act as a CCK receptor antagonist. It was recently reported that it has a function (Jensen et al., Biochem, Biop. hys, ^eta 757: 250 (1983); 5panarkel, J. Biol. Chem. 258:6746 (1983)). Japanese patent application no. No. 70/10506 (Miao et al.) discloses gastrin, which has antigastrin activity. A tetrapeptide derivative of the carboxy-terminal sequence of (L-Trp-L-Lys-L- ^5p-L-Phe-NTo).

Appetite suppressants act centrally, activating the central catecholamine circuit and acting as stimulants. (e.g. amphetamines) or affect serotonergic pathways. (e.g. fenflamin). Other forms of administration include Contains bulking agents that induce a feeling of fullness No. 1090106937 discloses tetrapeptide derivatives as CCK agonists. It shows. This compound may be used in gastrointestinal diseases, central nervous system diseases, and insulin-related diseases. The present invention relates to novel compounds that are CCK ligands, which are: α, α-converted mono-, di-, tri-, tetra-1 or polypeptides of the formula and In the pharmaceutically acceptable formula: R1, R2, R3, R4, R6, R6, R7, R8 , R9, R1, A and n are as defined below.

Co-pending application No. 07/690755 (filed on April 24, 1991) and its Continuation-in-Part Application No. 07/852,086 (Horwell et al., March 20, 1992) Application (incorporated herein by reference) discloses that α-substituted polypeptides Disclosed.

The present invention also provides compounds of formula I together with a pharmaceutically acceptable carrier in unit dosage form. The present invention also relates to a pharmaceutical composition comprising an appetite-suppressing effective amount of a substance.

The present invention further relates to a method of suppressing appetite in a mammal, which includes such treatment. Administering to a mammal in need thereof an amount of the above composition effective to suppress appetite. Including.

The present invention also provides methods for treating gastrointestinal disorders, central nervous system disorders, such as antipsychotics, neurological CNS depressants that can exhibit relaxant, anxiolytic and antispasmodic effects It also relates to

The present invention also relates to methods of inhibiting gastric acid secretion and treating gastrointestinal ulcers.

The invention also addresses the reactions caused by discontinuing drug use or discontinuing alcohol consumption. Inhibits and even enhances the activity of morphine and other opioids in pain treatment Regarding things.

The present invention further provides methods for making compounds of formula I.

The present invention further provides novel intermediates useful in the preparation of compounds of formula I, further The method for preparing this intermediate also shows that Compound 2 is a partial agonist. It shows.

Figure 2 shows that compound 4 is an agonist and compound 5 is a weak agonist. It shows.

Figure 3 shows that compound 6 is an agonist.

Figures 1 to 4 show CCK8 as the agonist reference standard. ing.

detailed description The table below is a comparison of terms used in the description of the present invention.

GABA 4-amitubuconic acid DAY＾　δ-aminovaleric acid ^SP L-aspartic acid PHE L-phenylalanine TRP L-tryptophan 1-800C1-adamantyloxycarbonyl 2-^DOC2-adamantyl Oxycarbonyl Z Benzyloxycarbonyl FMOC9-fluorenylmethoxycarbonyl^ib α-aminoisobutanoic acid PPP Pentafluorophenyl Compounds of the invention are analogs of CCK30-33 and CCK26-33, which contain at least one residue of an α,α-disubstituted amino acid. these compounds are genetically cooperating, in which not all α-substituents are hydrogen at the same time. different from the naturally occurring mammalian peptides that are encoded.

The compounds of the invention are represented by the following formula or a pharmaceutically acceptable salt thereof: In the formula, lit is hydrogen, BOC, 1-^doc, 2-AdocSZ, FMO C, RI2RI3R"5i(C12)Y0CO-(Here, RI2, R13 and and R14 are each independently lower alkyl having 1 to 3 carbon atoms, and m is is an integer from 0 to 3), R”CO- or R”’NHCO- (where R111 is Straight-chain or branched alkyl of 1 to 6 carbons, or 1- or 2-alkyl Damantyl) and: A is bond, Gly, β-ALA, GABA, DAVA, Aib.

NH(CH2), (where p is an integer from 1 to 6), NHCOlMet-Gl y, Tyr-Met-Gly, Asp-Tyr (0503H), Asp-Ty r-Met-cty, Asp-Tyr(OSO3H)-Met-Gly and: R2, R4, R6 and R@ are each independently hydrogen (but not necessarily ), lower alkyl, -CH=CH, , CmiCl, -CH2C11=CH2, -C)+21jcH1-CI, ^r, -CHzOR1-CH20^r, -(C1b)-COJ.

-(CI(2).N(R)2 (where q is an integer from 0 to 3, and R is also hydrogen) or lower alkyl, and Ar is a monocyclic or polycyclic unsubstituted or substituted carboxyl group. or a heteroaromatic or hydroaromatic moiety): R3 is 2- or 3-indolyl, 1- or 2-naphthyl, 2- or is 3-benzochenyl, 2- or 3-benzofuranyl, 2- or 3-y ndacyl or phenyl, both of which contain hydrogen, fluorine, chlorine, and bromine. , iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH having 0 to 3 substituents each independently selected from 2 and 0CF3 Can be done; R5 is lower alkyl, (CH2), 5(C112), CBS (where r is 1 is an integer from 1 to 6, and S is an integer from 0 to 6); n is an integer from 1 to 3. can be; R is -0R1-COOH, tetracyl, triazole, -COOR+6, -C ONR”R (where RI 6 is lower alkyl, RIG and R1+ are as below) as described in ); R9 is selected from R3 above; and R11 are each independently hydrogen, lower alkyl, alkoxycarbonyl , carboxyalkyl, or R111 and R11 taken together , form a ring of 3 to 10 atoms to which nitrogen is attached; RI8 is R1, rn, c o, o, C11CONRIOI? 11 or C0NR"R1'; R2 and R3, R4 and R6, R6 and Rf, R8 and R9 or R1 1 and RIG can also be taken together to form a ring of 3 to 8 atoms. but those atoms are chosen from carbon, nitrogen, oxygen and sulfur.

Preferred compounds of the invention are those of formula I, where R1 is Fw+oc, , Z, Boa, lIemsl(CH*)zOcO-; A is bond, cty, β-A LA, ^ib, ^5p-Tyr-seal et-c1y, ^sp　-Tyr (OSO3 H) -1[et-Gly; R2, R4, R6 and R8 are each independently alkyl of 1 to 3 carbon atoms, carboxy of 1 to 2 carbon atoms alkyl or CH20H; R3 is 3-indacyyl, 3-benzoche 2-benzofuranyl, 3-benzofuranyl or 2-bromo-3-benzo Furanyl; R5 is isobutyl, 5ec-butylethyl, n-propyl or i-propyl And; Ft7 is C0NH,, CONMe2 or 0; R9 is selected from R1. Re: R1 and R1+ are each independently alkyl of 1 to 3 carbon atoms or R11+ and R-th together represent the nitrogen atom bonded to them. form a ring of 4 to 8 atoms containing.

More preferred compounds of the invention have the formula: R1 is hydrogen or BOC; A is a bond or β-AL^; R2, R4, R6 and R8 are each independently CH3 or CI, C02H And: R3 is 3-indolyl, 1-naphthyl or 2-naphthyl; R8 is n-butyl, n-pentyl, (CI, ), SCH3 or (C11) 5CHICH3; R7 is OH, tetrasyl, triazole or C0IH: R9 is phenyl, 1-naphthyl or 2-naphthyl: RIG and R's are each independently hydrogen or CH3, or R+ a and R11 together contain 5 to 6 nitrogen atoms bonded to them; It forms a ring of atoms.

Particularly preferred compounds of the invention are selected from the group consisting of: α-Methyl, Tributophil, One methionyl, One α-Aspartyl, Monophenylalaninamide, α-methyl-D-tryptophyll-L-methionyl -L-α-aspartyl-phenylalaninamide, α-methyl-L-tri Ptophyl-L-methionyl-L-α-aspartyl-phenylalanine Mido, N-Cm, l-dimethylethoxy)-carbonyl]-α-methyl)-L- tryptopyl)-L-methionyl-alpha-aspartyl-phenylara Ninamide, N-[(1,1-dimethylethoxy)-carbonyl]-α-methyl)-DI, Leptophyl-L-methionyl-L-α-aspartyl-cy-phenylalanine Amide, L-tryptophyl-2-methyl-DL-methionyl-α-aspa Rutyl-phenylalaninamide, N-[(1,1-dimethylethquin)- carbonyl]-α-methyl]-D-tryptophyl-L-methionyl-α- Aspartyl-phenylalaninamide, glycyl-α-methyl-D-)ly ptophyll-monomethionyl-L-α-aspartyl-L-phenylalanithio α-Aspartyl-I, -phenylalaninamide, Glycyl-α-methyl-L-)ributophyl-L-methionyl-shi-α-aspa The D and L configurations of compounds of formula I are is possible and within the scope of the present invention.

Preferred compounds are those in which the α-amino acid residue is in the [L] configuration.

The compounds of the present invention can have many chiral centers according to their structure. Ru. The center of asymmetry is the carbon atom bearing the substituent R+ of formula I and R2, R3 of formula I. , R4, R5, R6, R7, R@, R9 and RI7 carbon atoms. I can do it. In particular, the compounds of the invention may be diastereomers, mixtures of diastereomers. or as mixed or individual optical enantiomers. The present invention Contains all forms of compounds such as. Diastereomeric mixtures are typically Obtained as a result of a reaction described in more detail below. The individual diastereomers are , by conventional techniques such as column chromatography or repeated recrystallization. Can be separated from diastereomeric mixtures.

Compounds of the invention include solvates and hydrates as well as pharmaceutically acceptable compounds of formula I. Contains salt.

The term lower alkyl, unless otherwise specified, refers to a straight alkyl group of 1 to 6 carbon atoms. Refers to a chain or a branched alkyl chain.

The term alkoxycarbonyl refers to a carbon group of 1 to 4 carbon atoms.

Preferred pharmaceutically acceptable salts include benzathine, chloroprocaine, choline, di- Ethanolamine, ethylenediamine, meglumine, procaine, aluminum , calcium, lithium, magnesium, potassium, sodium, zinc, diethyl and tromethane.

Particularly preferred pharmaceutically acceptable salts include N-methylglucamine and and sodium, and for bases it is 11-sulfate and trifluoroacetate. Ru.

The individual enantiomers are well known in the art, e.g. optically active compounds and Both are converted into salts and then separated by chromatography or recrystallization. , which can be further separated by reconversion to a non-salt form.

A preferred stereochemistry of the invention is illustrated by the compound of Example 2.

The compounds of the present invention can be prepared by preparing individual substituted α-amino acids using methods well known in the art. [For example, Gross & Mein ``Peptide, that portion'' written by John Hofer (Academic Breath Publishing, New York) The Peptides, ^nalysis.

5ynthesjs, Bjology) is considered in a multi-volume specialized book. (see standard synthesis methods). Individual substituted α-amino acid starting materials are generally is known, but when it is not known it can be synthesized and this technique can be used if desired. It can be synthesized by a method within the technical scope of the technical field (racemic form (DLI-α-methyltripsylate) For the synthesis of tophane methyl ester, M.F. Brafia et al. Heterocyclic Chew+, 17:829 (1980)) thing).

The present invention also includes novel intermediates useful in the manufacture of final products. these intermediates is one or more of the following compounds on a solid phase resin, e.g. Fmoc-11ePh It is e-resin.

Fmoc-MePhe-NH,, Fmoc-Asp(OBu’)-MePhe-NH2, Fmoc-11e t-Asp(OBu')-MePhe-N)12, Fmoc-Trp- ) let-Asp(OBu') -MePhe-NH,, Asp(OBu') -MePhe-NH2, Asp-MePhe-NH2, Fmoc-Met-Asp-MePhe-NH2,11et-Asp( OBu') -MePhe -NH,, 11et-Asp -MePhe -N To.

Trp -Met-Asp(OBu') -11ePhe -NBt, Ftao c-Trp-Met-Asp-MePhe-NH2, Fmoc-MeA sp(OBu')-Phe-NH,, Fmoc-MeAsp-Phe-N H2, Fmoc-Met-MeAsp(OBu’)-Phe-NH2 , Fsoc-Trp-Met-MeAsp(OBu')-Phe-NH,,11 eAsp(OBu')-Phe-NH,, MeAsp-Phe-NBt, Lid et-MeAsp(OBu')-Phe-NO,, Met-MeAsp-Ph e-NO,, Fsoc-11et-11eAsp-Phe-NBt, Fmoc -Trp -Met -MeAsp -Phe -NO,,11ellet-A sp(OBu’)-Phe-NBt, Fmoc-MeMet-Asp(OBu ') -Phe -NBt, Fmoc -MeMet-Asp -Phe -N Bt, 11eMet-Asp-Phe-Nflt, Fmoc-Trp- MeMet-Asp(08u')-Phe-NH2, Ftaoc-Trp- Mailet-Asp-Phe-NBt, Fmoc-MeTrp-Me t-Asp(OBu’)-Phe-NBt, Fmoc-MeTrp-M et-＾5p-Phe-NH2゜Fmoc-Gly-Trp-11et-Asp -11ePhe -NH2, Fmoc-Gly-Trp-Met-Asp(O Bu') MePhe-NBt, Gly-Trp-Net-Asp(OBu')l IePhe-NBt2, Fmoc-Gly-Trp-let-1eAs p-Phe-Nut.

Fmoc -Gly -Trp -Met -11eAsp(OBu') -P he -NHI, Gly-Trp-Met-MeAsp(OBu')-Phe- NBt.

Fmoc-=Gly-Trp-MeMet-Asp-Phe-NH2 , Fmoc-Gly-Trp-MeMet-Asp(OBu')-Ph e -NHz, Gly-Trp-MeMet-Asp(OBu')-Phe-N H,,Fmoc-Gly-11eTrp-11et-^5p-Phe-H1,F vroc -Gly -11eTrp -Met-Asp(OBu') - Phe-NH2, Gly-MeTrp-Met-Asp(OBu') -Phe-NH,, Ftaoc-MeMet-OH.

Fmoc-11eMet-OPFP.

＾5p(OBu’)OH.

FIloc-MeAsp(OBu')On, and Fmoc-1[eA sp(OBu')OPFP0 Ingredients for producing pharmaceutical compositions from the compounds of the invention Active, pharmaceutically acceptable carriers can be solid or liquid.

Solid preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. be caught.

The solid carrier may be one or more substances, which may also be diluted. Also used as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, or tablet disintegrant. It can also act as a coating. In powders, the carrier is a finely divided solid. This is mixed with a finely divided active ingredient. In tablets, the active ingredient is required Mixed in appropriate proportions with carriers with active properties and compressed into desired shape and size be done.

For producing suppository preparations, low-melting waxes such as fatty acid glycerides and (cocoa butter mixture) and then add the active ingredient, e.g. by stirring. disperse in it. This molten homogeneous mixture is then poured into conveniently sized molds. Pour in, cool and solidify.

Powders and tablets preferably contain from 5 to approximately 70% active ingredient. Appropriate responsibility The body contains magnesium carbonate, magnesium stearate, talc, lactose, sucrose, and Cutin, dextrin, starch, tragacanth, methylcellulose, carboxyme These include sodium cellulose, low-temperature melting wax, and cocoa butter.

The term "preparation" includes the active use of the coating material as a carrier to provide the capsule. The capsule contains the active ingredient (along with other carriers). , or other carriers); It is sown. Similarly, cachet is included.

Tablets, powders, cachets and capsules as solid unit dosage forms suitable for oral administration can be used.

Liquid form preparations include solutions, suspensions, and emulsions. Sterile water with active compounds or water-propylene glycol solutions are examples of liquid preparations suitable for parenteral administration. It can be given as follows. Liquid preparations also include polyethylene glycol aqueous solutions It can be formulated as a solution in

Aqueous solutions for oral administration are prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, and salts as desired. It can be manufactured by adding a fixing agent and a swelling agent. Oral aqueous suspension Suspensions contain finely divided active ingredients in viscous substances (e.g. natural and synthetic rubbers, fat, methylcellulose, sodium carboxymethylcellulose) and pharmaceutical technology It can be prepared by dispersing it in water with other suspending agents known in the art.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is They are packaged in unit doses containing appropriate quantities of the active ingredient. The unit dosage form is The package may contain a defined amount of the preparation, e.g. sachet tablets, capsules. , and powders in vials or ampoules. The unit dosage form also includes a capsule. It may be a cell, cachet or tablet itself, or any of these packages. It may also include an appropriate number of.

The biological activity of the compounds of the invention is determined by the binding of the test compound to known CCK receptor sites. We investigated this using an initial screening test that quickly and accurately measures the incidence of cancer. Specific CCK receptors are known to exist in the central nervous system (Flays et al. , Neuropeptides 1. :53-62 (1980); 5atue R et al., 5science 208:11555-56 (1980)).

This screening test tested male CFLP mice weighing between 30g and 40g. The brain cortex obtained from the brain was shredded on ice, weighed, and The resulting suspension was homogenized in S-HCl buffer (pH 74 (0-4°C)). Centrifuge, discard the supernatant, and resuspend the pellet in L. It was washed by centrifugation twice. The final pellet was washed with 130 nM Na KCI of C1, 4, 7nll, 5n M (7) kl g C1, 2, 1nM of EDT^, 5 mg/mL bovine albumin, and pandrasin (0.25 m 20 volumes of 10 nM Hepes buffer [pl+7.2 (23°C) ].

For saturation experiments, a final volume of 500 βl of Hepes incubation buffer (pH 7) was added. , 2), 0.2 to 20 nll of tritium-labeled pentagastrin (Amaji Brain Cortical Membranes were incubated at 23°C for 120 minutes (Cham International, UK). Incubated.

In displacement experiments, increasing concentrations of competitive test compounds (from 10-” to 10-”M ), membranes were incubated with a single concentration (2 nM) (7) of the ligand. So In each case, nonspecific binding was caused by unlabeled octapeptide CCK□-3 ゜ (10-'M).

After incubation, membrane-bound radioactivity was filtered with Whatman GF/B filter. Free radioactivity in the solution was separated by rapid filtration, and then added to a 4 mL water-cooled Washed three times with HCl buffer. Incorporation with tritiated pentagastrin Transfer the filter from the incubated sample to a 4 mL syringe into a polyethylene vial. Add it with a scintillation cocktail and measure radioactivity using liquid scintillation. (Efficacy: 47-52%).

Specific binding to the CCK receptor site is due to the total binding of tritium-labeled pentagastrin. Tritium bound in the presence of io-' octapeptide CCK26-33 from total amount. It is defined as the amount minus the amount of um-labeled pentagastrin.

The saturation curve of specific tritium-labeled pentagastrin binding to mouse cortical membranes was Scatchard's method (Scatchard Ann, New York A cad, Sci, 51:660-72 (1949)) and Hill's method ( Hjll J, Physiol, 40: IV-■ (1910)) were analyzed to obtain the approximate number of maximum binding sites (B-,) and the equilibrium dissociation constant (K,) .

For permutation experiments, suppression curves can be created using a Logitolo-Soto diagram or an iterative curve application compiler. Computer program ^1. L F [T(DeLean, Munson & Redbard, (1978)) and ICi.

and nH (apparent Hill constant) values were obtained. I.C. The value is 50 for specific binding. It was defined as the test compound concentration required to produce % inhibition.

Then, the inhibition constant (K1) of the test compound was calculated using Chcng-Pr ・K−=　IC5o/　1　+　(L)/ K.

Here, [1,] is the concentration of radioactive label and K is the equilibrium dissociation constant.

/M values are shown in Table H for some representative compounds of the invention.

Table ■ Binding to central CCK receptor (2) 5.44 (4,23~7.10) 3 (4) 7.80 (5,56~1 ．． 2.9) 3(5) 9.20 (6,86~], 1.8) 3(6) 30. 40 (26,6-35.5) 3(n) = number of analyzes Electrophysiological data Descriptions and protocols for experiments similar to these can be found in the literature by Hu. ghes, Proc, Natl, Acad, Sci, 87.6728- 6732 (1,990)) and the references cited therein.

Figure 1 shows the amount of C (J8 dose 1 nospocalypse) before and during compound (2). The graph shows the curve for compound (2) and the curve for only compound (2). This curve is from CCK8 to or (2), and represents the total number of action potentials generated during the reaction to (2), and the count ( Y-axis) versus dose (X-axis). The curve of compound (2) is The compound is shown to have partial agonistic properties in this experiment.

-・- is CCK, 2M2 is (2) 100. Mu...... is CCKa+ (2) (1 μM).

Figure 2 shows Bl(-CCK and CCK Figure 4 shows the dose curves of the 4 analogues. Action button generated during reaction The total number of noyals is plotted as counts (Y-axis) versus ligand dose (X-axis). It is. The function (X*^)/(X+8) fits this mark using R3I software. (A-maximum possible response, B-EC of the compound calculated from the curve,.). this Curves (4) and (5) both have agonist-like properties in this experiment. It is shown that. =0= is (5), -Δ- is BH-CCK, ---Moo - is (4), --1-- is (1078,292444*X)/(5,395 304e -03,000X), -1 is (1149,663878X chapter)/(0,0 10686+X), -1111--- is (1100 end X)/(X+ 0.479 53), -1111 is (1100 end X) / (X + 0.014358), ,...110. is (0,5) smoothed CCK, and the phrase is CCK.

The dose-response curves in Figures 3 and 4 are for C(J) and for strong C Before and after bathing CK-8 antagonist PD134308 (4), ( 5) and (6). Total number of action potentials created during the reaction is plotted as counts (Y-axis) versus dose (X-axis).

The curve of the function (X person)/(X + B) can be adjusted to this mark using R31 software. be. These curves show that compounds (4), (5) and (6) It has been shown to have CCK agonist-like properties that are antagonized by antagonists. Ru.

In Figure 3, -・- is CCK, =mu= is (8), -・△- is (6) + PD1 34308, and --1-- is (X book 1126.907666)/(X+ 9.879552), □ is (112:FX)/(X+o, 14062 6), ==c(1127”X)/(X+0.031476).

In Figure 4, --- is CCK, =■; is (5), --- is (4), -- -Bit・−～− is (5) + PD134308, and −1−△−・− is (4 ) + PD134308.

Tables ■ and ■ summarize the four figures.

Table ■ Compound state diagram EC5o/nM (2) Partial agonist 1- (4) Agonist 2 14.0 (5) Weak agonist 2 479.5 (6) Agonist 3 524.0 CCK8 Agonist 1-45.4 This compound was further proven to be an agonist after experiments. In this experiment , these compounds are potent and selective CCK-8 antagonists as described above. reference compound PD134308 (so-called [R-(R*, R chapter)- 4-[[2-[(3-(18-indol-3-yl)-2-methyl-1-ox So-2-[[(tricyclo(3,3,11”)dec-2-yloxy)carbony [amino]-propyl]amino]-1-phenethyl]amino]-4-oxobu (tanic acid).

Table■ Compound graph K, (PD134308)/n1l(4) + reference Compound 4 4.67 (5) + Reference compound 4 3.02 (6) + Riff Reference compound 3 14.4 CCKg + Reference compound -5,4 data Compound (4) is equally effective as CCK 8, and -force ratio compound (6) is slightly lower. Compound (5) has relatively low agonist activity. It is shown that. Compound (2) is a partial agonist.

Compounds of the invention are useful as appetite suppressants based on the tests described below.

Palatable Diet Feeding Assay ay), male adult short-haired Lister rats (loaded) weighing between 200 and 400 g. d.Li5ter rat) were housed one by one and trained to consume preferred food. did. This bait consists of Nestle's sweetened condensed milk, powdered rat chow, and rat feed. It consists of drinking water for drinking water and has a firm consistency when mixed together. Ta. Each rat was given one dose during the light period of the light-dark cycle during the 5-day training period. 20 to 30 g of this recreational feed was fed for 30 minutes per day. The intake of recreational feed is Determined by measuring the weight of the feed container before feeding and after a 30 minute feeding period ( Accuracy limit, 0.1g>. Care was taken to collect and repair spilled feed.

Rats have access to chow and water at all times, except for the 30 minute test period. Can be done.

After the training period, doses for CCK 8 and some representative compounds of the invention Construct response curves (n=8-10 rats/dose level). 1IPer ,. Values (±95% confidence limits) are given for the anorexigenic effects of these compounds. .

When used therapeutically as an appetite suppressant, the compounds of the invention may be used in unit doses of approximately 2 00 to approximately 2800 mg/day.

As agonists, the compounds of the invention have therapeutic use as appetite suppressants and further , as an antagonist, as a drug to treat gastrointestinal diseases, central nervous system diseases, e.g. For example, they exhibit effects such as antipsychotics, sedatives, anxiolytics, and anticonvulsants. It has therapeutic uses as a CNS depressant.

As antagonists, the compounds of the present invention can be used for suppressing gastric acid secretion, suppressing anxiety, and for gastrointestinal Treatment of ulcers, treatment of psychotic behavior, drugs, alcohol, cocaine, benzodiases For prevention of reactions caused by withdrawal of pine, diazepan, or nicotine , and is also expected to have uses in enhancing the effects of morphine for analgesia. Ru.

α-Methyl amino acid-containing CCK analogs are produced by three methods. direction Method A is a solution phase method in which peptides are assembled using standard solution phase protocols. or assembled by standard salt binding, resulting in a fully protected intermediate. , resulting in an aspartate side chain deprotection intermediate. Examples 1 and 2 below describe the method A will be explained in detail.

Peptides can also be produced by method B, which is a solid phase method and here the peptide Tido is constructed on solid phase resin. Treating the resin with ammonia in methanol Alternatively, the appropriately substituted resin can be prepared using 1-lifluoroacetic acid. By direct cleavage with a suitable scavenger to directly generate an amide, This resin is designed to produce a terminal amide. In the latter protocol is DuPont Rapid Amide ■ or Nova Bioche II Novasyn KR[F] is added using a simple foaming device (DuPont resin) or an automatic mixer. It was used in one of the following machines (Nova Biochem Shozo). This method is detailed in Example 3 below. Describe.

The third method (Method C) is a non-solvent method in which an amino component and a pentafluoride the lophenyl esters together at 50 to 100 °C in the absence of solvent. Cook for 20 minutes or more. This method is detailed in Example 4 below.

Male short-haired Lister rats (175-250 g) are housed separately and fasted overnight. (Free water intake). Anesthetized with urethane (1.5 g/kg, IP), natural Intubate the trachea to assist with breathing. Parsons' ``Quantification of drug-induced gastric acid secretion'' Quantative 5 studies of drug-in duced gastric acid 5ecretion”) (University of London Ghosh and Schild's method (G., Ph.D. thesis, 1969). hosb & 5child, “Continuous recording of acid secretion in rats” Continue usrecording of acid 5ecretion in th e rat”, Br, Mu Pharvac, 13:54-61 (1956)) Continuously perfuse the stomach using a modified method. The stomach cavity is connected to the esophagus and body parts. Add 54% (w/v) glucose solution to both needles at a rate of 3 IILZ min. perfusion using This solution is applied using a roller pump (Gilurin, Mini Pulse 2 ( Gilson, Mjnipuls 2)) and the heating coil. Pour inside and bring to 37±1℃. The perfusate is collected through the collection funnel at the bottom and pi-1 electrode connected to a Jenvay pH meter (PlIM6) Pass it through. For online recording of gastric perfusate pH, the output of the ρII meter was Connect to a digital chart recorder.

Pentagastrin was stored as a frozen aliquot of sterile 09% (w/v) Na Dilute to desired concentration with C1. Novel compounds were added to sterile 0.9% ( dilute with NaCl of J/V). lsL/kg through the jugular cannula. A unit dose volume of the drug was administered with 0.15 ml of 0.9% w/v NaCl wash solution. Single intravenous dose. The basal pH is stabilized before starting compound administration. surgery There is typically a 30 minute transition between and the first compound administration.

Compounds of the invention are also effective against pentagastrin at a standard dose of 1 nmol/kg. Therefore, it can also antagonize the stimulation of gastric acid secretion induced by this. The compound is also 1 nano Reduces the amount of gastric acid secreted in response to pentagastrin at mole/kg doses. (initial pentagastrin response 254 μmol/IH''', after compound administration (cumulative The cumulative amount is 1.1 μmol/kg) 128 μmol/11”).For solid compounds, The antagonist is completely reversible in its response to pentagastrin.

Compounds of the invention are also useful as anti-ulcer agents, as discussed below.

Aspirin-induced gastric injury is examined in each group of 10 rats.

All animals are fasted for 24 hours before and during the experiment. The drug or carrier is 45+ g/wL of aspirin in 0.5% carboxymethylcellulose (CMC) Administer 1 mL of phosphorus suspension 10 minutes before oral administration.

Animals are sacrificed 5 hours after aspirin administration and the stomachs are removed and cut open for examination.

Gastric disorders were scored as follows.

Score 1 Small bleeding spot 2 Major bleeding spot 3. Small ulcer 4 Large ulcer 5. Perforated ulcer The mean ulcer score of the saline control group was 12.1 ± 685 (standard deviation). be. Treatment with ranitidine (15 mg/kg, orally) reduced ulcer formation by 7 4%, and the ulcer score was 3.2 ± 2.35 (p compared to control). 0.001), treatment with the compound of the present invention (10 mg/kg, oral administration) The ulcer score was 63±4.14 (p<0.05 compared to control). , ulcer formation was reduced by 48%.

However, the specific dose used will depend on the patient, the severity of the condition being treated, and the compound used. It can be changed according to the activity of the substance. Determining the optimal dose is based on this state of the art. It can be done within.

Compounds of the invention are also effective as anxiolytic agents, as discussed below.

Anxiolytic activity is bright and dark in mice! Dew test (B, J, Jones et al., Br, J , Pharmacol.

93.985-993 (1,988)).

The number of mice was 5, the pretreatment time was 40 min, and the compounds were 0, ], 1, and 10 m It is administered orally at a dose of g/kg.

The device is an open top box with length 45cm, width 27c and height 27ctx, wall J: 20cm. It is divided into a small section (2/5) and a large section (315) by m partition plates. Service The cutting board has a 7.5 x 7.5 cm opening at floor level. The parcel is black; The large section is painted white. The floor of each section is divided into 9cm squares. white section is illuminated by a 100 watt tungsten bulb 17 cm above the box. The black sections are illuminated by similarly placed 60-watt red light bulbs. experiment The room is illuminated with red light.

All experiments are performed between 1300 hours, 0 minutes and 1800 hours, 0 minutes. . By placing each mouse in the center of a white area and allowing it to explore the new environment for 5 minutes. will be tested. The mouse's behavior was videotaped and then recorded. Perform the analysis on video. Measure the following 5 parameters: until entering the black area time, time spent in each section, number of moves between each section, number of transects in each section. number, and the number of times he reared up on his hind legs in each compartment.

In this test, increased time spent in light increases the It is a sensitive measure of the anxiolytic effect, ie it shows a direct proportional relationship. medicine in water or dissolved in saline and administered orally via subcutaneous, intraperitoneal or intragastric needles.

The compound is active by subcutaneous route. Control animals had a measurement time of 5 minutes. Showing 3% crossing into the dark. Mice treated with compound at 1+g/kg (s.c.) It takes 85 crossings to a bright place and only 24 crossings to a dark place, compared to the control. Significant (p<0.01) difference from anxious mice. Diazepan (0,25 mg/kg, ip) has the same effect as the compound in the same experiment.

Compounds of the invention are useful as antipsychotics. The compounds are as described below. to reduce the effects of intra-accumbens amphetamines. will be tested on their ability to

Male Sbragdori (CD) rats of the Platford strain are used. The rat is Housed in groups of 5 at a temperature of 21 ± 2°C, with lighting from 7:00 to 20:00. and a 12 hour light/dark cycle. Rats were fed CR11 diet (Lovesure (L) a1) made by Sure) and water available at any time.

Rats were anesthetized with chloral hydrate (40% g/kg - subcutaneous administration) and their heads were placed in stereotaxic position. (Kopb 5 tereotaxic) Place it in the frame. long term insertion guide crab Stereo held from both sides with Yule (Perspex) holders (consisting of a stainless steel tube (0.65 mm diameter)) for standard stereotaxic surgery. This cannula is implanted using the technique of the nucleus acuben (Ant, 9. 4, Vert, 0.01Lat, 1.6) above 3.5 ■■ Ends or above the central nucleus of the tonsils, Offim (Ant, 5.8, Vert, -1,8, Lat, ±4.5) (atlas of De Groot, 19 It ends at 59). This guide covers stainless steel for the 14 days of recovery. A steel probe (0.3mm in diameter, 0.511II11 protrusion from the tip of the guide) remains open due to

Hold the rat with your hand and remove the probe (intracerebral injection cannula (diameter 0.3) ) and then dispense the drug from the Hamilton syringe, which is connected to the syringe with polyethylene tubing. Pour in 0.5 g of agent over 5 seconds (additional 55 seconds for precipitation). motion Use things only once.

Behavioral experiments were conducted in a quiet room maintained at 22 ± 2°C between 7:30 and 21:30. It will be carried out. Rats are removed from the holding room and allowed 1 hour to acclimate to the new environment.

Locomotor activity was determined using separate partitioned Perspex cages (25 x i5 x 1 5c (height)) (groups of 30 animals lined up in a row). that Each cage has one photovoltaic unit along its long axis at 3.5c from one side. This part is used for e.g. grooming when the animal is in steady state. In fact, it turns out that the false activation count caused by moving your head can be minimized. I know. Light interception is recorded every 5 minutes. At this time, for example, in motor activity For example, non-specific changes such as sedation, lying down, or routine movements, Animals are also observed for the presence of anything that interferes with the recording of motor activity.

The present invention shows the hyperactivity produced by amphetamines injected into the nucleus accumbens of rats. The inhibitory ability of the compound is determined. Bilateral injection of amphetamine into the nucleus accumbens (2H After g), locomotor activity increases, but at the peak of hyperactivity (50-60 counts 1 5 minutes) occurs 20 to 40 minutes after injection.

Compound at 2g/kg or 30mg/kg or 10mg/kg Functions produced by intranucleus accumbens injection of amphetamine when injected intraperitoneally in rats Hyperactivity decreases. This test is known to be useful in predicting antipsychotic activity. Example I N-((1,1-dimethylethoxy)carbonyl]-α-Boc-D-Me Trp -Met-^sp -Phe -N11t (1) DMF (10sL ) of ^5p-Phe-NHz (0.6 g, 2.02 mmol) in diluted Isopropylethylamine (26111 g, 2.02 avol) followed by F moc-methionine pentafluorophenyl ester (Fmoc-Met- 0PFP; 1.10g, 2.05a+mol) and the mixture was left overnight. Stirred. DMF was removed, followed by dilution of the residue with diethyl ether:ethyl acetate (5 : Grind in step 1) and filter the obtained solid. This crude solid, Fmoc -Met-^5p-Phe-N■2 can be used without further purification. Kita (1.22 g, 96%). Repeat the operation to obtain 1.29g of product. I got it.

The solid prepared as above (2,00 g, 3.16 wmol) was added to piperidine. Dissolve in containing DMF (20% to 50% y/v, 16sL) and stir for 20 minutes. Ta. DMF and piperidine were removed and the residue was subsequently triturated with ether to give a white Solid, 1let-^sp-Phe-NIT2 was quantitatively obtained. This too It could be used without further purification.

Free tripeptide (205 g, 0.5 mmol) in DMF (5+L) Suspend and diisopropylethylamine (129 mg, t).

meal) was added. Boc -DL -MeTrp -0PFP (242 i+g, 0.5 mmol) and stirred the mixture until clear (approximately 2 days). Removal of volatiles yielded a light tan residue, which was dissolved in diethyl ether. Trituration with tel:ethyl acetate (1:1) gave an almost white solid. This solid Chromatography (silica gel, 5% M in dichloromethane containing 1% O eOH) to give an off-white solid (279 g, 178%).

NIIR (DMSO-da) δ1.21 and 1.28 (3L 2s), i . 42 and 1.43 (9H, 2S), 1. ．． 99 and 2. Old (38,2s) , 2.24-2.54 (8H, m), 2.81 (IH, dd), 3.11 ( 2H, dm), 4.18-4.4 (3H, m).

4.5 (LH, m), 6.78 (111, br, s), 6.86-7.34 (1], [l, m), 7.47 (11°d), 7.52 and 7.41 (11 (,2br,s), 7.7(IH,br,m), 8.06(LH,br,t ), 8.24 (18, br, d).

FAB-MS (+ve ion) 749 (ll+K), 733 (lI+Na) , 711 (M+H) (-v6 ion) 709 (ml-II) trace analysis; Calculated value of Cs5H4aNsOsS・0.15H20: C, 5g, 03; H , 6, 54; N, 11.60; S, 4.42 Experimental value: C, 58, 1 3, H, 6, 48: N, 11.35; S, 4.40 Similarly, N-[[(1, 1-dimethylethoxy)carbothionyl-μ-α-aspartyl-μm phenyl Alaninamide, Boc-L-a-11eTrp-Net-Asp- Phe-N)I2(2) and N-((1-1-dimethylethoxy)carbonyl I did it.

NMR (2; DMSO-d,) δ1.25 (3H, s), 1.44 (9H, s), 1.83 (2B, m), 2.01 (31, s), 2.38 (2H, m), 2.65 (IH, m), 2.82. (IH.

*), 4.20 (1B, m), 4.33 (II, m), 4.50 (111, i), 6.92-7.47 (12H, m), 7.82 (2H, Im), 8.1 1 (IFI, br, d), 10.91 (IH, s).

NMR (3; DMSO-ds) δ1.29 (3H, s), 1.44 (9H, s), 1.92 (24m), 2.02 (3) 1. s), 2.42 (2Lt), 2 ．． 60 (IH, td), 2.84 (ILdd), 3.13 (211, d), 3. 31 (21 (+ water), 4.19 (Il, l11), 4.36 (11, m), 4.48 (In, n), 6.94-7.24 (12B, Kasu), 7.32 (IH, d).

7.47 (IH, d), 7.84 (1B, br, d), 8.14 (LH, br , d), 8.22 (IH.

br, s), 10.92 (lH, s).

Example 2 In this method, α-methyl-L-tryptophyl-L-Mea-MeTrp-1 1et-^5p-Phe-NH2 (5)) and Nylalaninamide (α-) MeTrp-Met-^5p-Phe-N IT! (6)) was also produced.

In these latter three examples, the final residue used was the appropriate F that resulted in the protected tetrapeptide. (2) It was an OC-α-MeTrp activated ester. The tetrapeptide is in DMF. The protecting group was removed by treatment with piperidine. This completely deprotected Tetrapeptide (4-6) was obtained. RP-HPLC (lIecN l'1x Each peptide was purified by NMR (4; D20) δ 1.73 (3B, s), 1.85 (2H, q), 2.04 (3H, s), 2.34C2H, t), 2.66 (211, qd), 3.07 (2H, qd ), 3.41 (2t1.s).

4.34 (11, t), 4.54 (2H, m), 7.14 (Hf, t), 7.21. -7.37 (9H.

閤), 7.48-7.56 (2R, dd).

NMR (5:, D20) δ1.54 (31'1.s), 1.78 (2H, + a), 1.97 (3) 1. s), 2°54 (2H, a+), 2.93-3. 28 (6H, a+), 4.13 (18, t), 4.42 (In.

t), 4.45 (IH, m), 7.13-7.36 (8H, m), 7.5 1 (IH, d), 8.18 (IFl, d).

NIIR (6; 020) δ1.73 (3H, s), 1.85 (211, m) , 1.94 and 2.03 (3H, 2s), 2.34 (IH, t), 2.7 4. (2+(, a), 3.06 (2H, qd).

3.40 (2B, abq), 4. Old and 4.34 (IH, 2t), 4.60 ( 28, m).

7.1], -7,48 (Ion, @), 7.53 (2H, t).

The following compounds were produced as described above for Method A.

Glycyl-α-methyl-D-1 ribtophyll-L-menamide Glycyl-α-methyl-DL-tryptophyl-L-glycyl-α-methyl-L -1-Lyptophyllu L-Me Trp-31et-^sp-Animals-11ePhe- NHz・CF3CO2H, and Trp-Met-DL-MeAsp-Ph e -NHz.CF3CO2)10 These can also be produced in the examples below.

Example 3 Nova Biochem 4170 automatic peptide synthesizer and Biopl Fmoc amino acid pentafluorophenyl or DH The peptide was constructed from the C-terminus with Bt ester and +10Bt catalyst. each remainder Groups were added in a 5-fold excess to ensure rapid and complete unification.

At a scale of 0,095 mmol, peptide (4) was cleaved from the resin by TF^^ (94% TF^, 5% anisole, 1% ethanedithiol), it was isolated with a yield of 46%. (2 hours, room temperature) (32 mg).

In HPLC (C18, 20-80% MeCN-H20 + 0.1% TF^), >90% purity as a 1:1 mixture of diastereomers (detected by 25411) It was shown that

NMR (D, 0) δ103 (3H, s), 1.69 (2+1.m), 1.91 (2)1. m).

1, 95 (311, s), 2.59 (2H, m), 3.09 (21, m), 3.38 (2H, m).

4.31 (18, m), 4.51 (2H, n+), 7.1.7-7.37 ( 1011, w+), 7.52 (LH.

d), 7.68 (Hl, d), 10.94 (IH, s). When prepared by liquid phase method The same was true for both cases.

L-α-1lleTrp-Net- identical in all respects to that prepared above Asp-Phe-NHz (4) was similarly prepared.

Example 4 Trp-Met-^sp-MePhe NHz・CFsCOJ (8) Fs oc　-Asp(OBu’)　-DL　-MePhe　-NH2MePhe　 NHz (90 mg, 0.5 mmol) and Fmoc-Asp (OBu’) A mixture of OPfp (290mg, 0.5a+5ol) was dissolved in the minimum amount of ethyl acetate. Immediately evaporate the solvent. After heating the resulting viscous part in a boiling water bath for 2 hours Cooling. The resulting resin was triturated with diethyl ether and the product was then precipitated. The yield was 159I1g (56%). Further chromatography of the ether wash The product could be obtained by graphing.

Ftaac -Met -Asp(OBu') -DL -MePhe -NH 2 The dipeptide (900++g, 1.58mmol) was added at 20% in DMF. N-protection was performed using piperidine for 20 minutes, followed by complete removal of the solvent.

The residue was triturated repeatedly with n-hexane to give the free aminodipeptide (293-g, 0.84 sulfur mol) was produced. In addition, Fwoc-11et-OPfp (450 11 g 10.84 s ol), followed by the addition of a minimum amount of ethyl acetate to obtain a clear solution. Obtained.

The solvent was immediately removed and the resulting viscous oil was heated in a 65°C water bath for 45 minutes. Living The purified resin was triturated with diethyl ether to obtain the protected tripeptide (418 g178 %) was obtained.

Fmoc -Trp -Met -Asp(OBu') -DL -11e Phe -NHffi the above tripeptide (300s+g, 0.43 discussion o1 ) was N-deprotected using 20% piperidine in DMF for 20 minutes. Remove solvent The residue was triturated with n-hexane to give the free tripeptide (19811 g, 0 ．． 41sol) was obtained. In addition, Fwoc -Trp -0Pfp (243 mg, 0.41 s ol) and enough ethyl acetate to obtain a clear solution. . The solvent was immediately removed and the resulting mixture was heated at 65° C. for 15 minutes. Remove the residue Trituration with thyl ether gave a white solid (283 mg, 78%).

Trp -11et -Asp -DL -MePhe -NHl・CF3C0 tH(8) the above tetrapeptide with 20% piperidine in DMF for 20 min. N-deprotection followed by removal of solvent and trituration of the residue with n-hexane to remove free amino acids. Notetrapeptide was produced. This was combined with thioanisole and ethanedithiol ( 100-25hL/mmol and 50-100IIL/mmol), followed by and treated with 95% TFA aqueous solution (3-5 mL/■■01) for 5 minutes.

- remove the volatile components and triturate the residue with diethyl ether to obtain a white solid, This was purified using Preparative 11PLc.

Fmoc-one animal ^5p (OBu') -Phe -NR2Fmoc -DL -MeAsp(OBu’)OPfp (1,46g, 2.47m@ol) and II Phe Ntlt (θ, 41 g, 2.5 smol) in the minimum amount of ethyl acetate to produce a clear solution and the solvent was immediately removed.

The mixture was subsequently heated to 100° C. for 1 hour and further cooled.

The residue was triturated with diethyl ether to give the protected dipeptide (993 mg, 71%). I got it.

Fmoc -11et -DL -MeAsp(OBu') -Phe -N H.

The dipeptide (571 mg, 1.0-■ol) was protected by the N-hypothesis as described above. Ta. After trituration with n-hexane, the residue was purified with Fmoc-11et-OPfp (3 50s+g, 0.65s■ol) and enough ethyl acetate to dissolve . The solvent was immediately removed and the residue was subsequently heated at 65° C. for 4 hours. diethyl ether The residue was triturated with a gel to give the protected tripeptide (210 g, 146%). Sara The product can be separated from the ether wash by chromatography. came.

OFmoc -Trp -Met -OL -11eAsp(OBu') -Phe -N8m The above tripeptide (400 mg, Q, 57+mol) As mentioned above, the N- theory was protected. After trituration of the residue with n-hexane 258a+g The product was isolated. This 20011g (0,42iwaol) and Fmo Sufficient ethyl acetate for c-Trp-OPfp (246 mg, 0.42 gmol) and dissolved it. The solvent was immediately removed and the residue was heated at 65° C. for 20 minutes.

The resulting mixture was triturated with diethyl ether to obtain the protected tetrapeptide (28 3 mg, 77%).

Trp-Violet-MeAsp-Phe-NH2-CF3CO2H (9) above The tetrapeptide was treated like this tetrapeptide to obtain (8), which was then treated with ether. After the final trituration (9) was obtained.

0.001 0.010 0.100 1.000 10.000CCK concentration ( uM) Continuation of front page (51) [nt, C1,5 identification symbol Internal reference number C07K 5108 7106 Z 8318-4H // CO7K 99:00 I

Claims (16)

[Claims] 1. A compound of the following formula or a pharmaceutically acceptable salt thereof: ▲The mathematical formula, chemical formula, table, etc. There is▼I During the ceremony, R1 is hydrogen, BOC, 1-Adoc, 2-Adoc, Z, FMOC, R12R 13R14Si(CH2)mOCO- (where R12, R13 and R14 are each independently lower alkyl of 1 to 3 carbon atoms, where m is an integer from 0 to 3. number), R15CO- or R15NHCO- (where R15 is 1 to 6 carbons) straight-chain or branched alkyl or 1- or 2-adamantyl atoms); A is bond, Gly, β-ALA, GABA, DAVA, Aib, NH (CH2 )p (where p is an integer from 1 to 6), NHCO, Met-Gly, Tyr- Met-Gly, or Asp-Tyr-Met-Gly, Asp-Tyr(O SO3H)-Met-Gly; R2, R4, R6 and R8 are each independently hydrogen (but not necessarily all hydrogen at the same time), low -CH=CH2, C=CH, -CH2-CH=CH2, -CH2C ≡CH, -CH2Ar, -CH2OR, -CH2OAr, -(CH2)qCO2 R, -(CH2)qN(R)2 (where q is an integer from 0 to 3, R is hydrogen or or lower alkyl, and Ar is a monocyclic or polycyclic unsubstituted or substituted or a heteroaromatic or hydroaromatic moiety); R3 is 2- or 3-indolyl, 1- or 2-naphthyl, 2- or is 3-benzothienyl, 2- or 3-benzofuranyl, 2- or 3-y ndazoyl or phenyl, both of which contain hydrogen, fluorine, chlorine, bromine, and iodine. Uron, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH2 and OCF3, each having 0 to 3 substituents independently selected from OCF3. tree; R5 is straight chain or branched lower alkyl having 1 to 6 carbon atoms, (CH2)r S(CH2)sCH3 (where r is an integer from 1 to 6, s is an integer from 0 to 6 is an integer); n is an integer from 1 to 3; R7 is -OH, -COOH, tetrazole, triazol, -COOR18, -C ONR10R11 (where R18 is lower alkyl and R10 and R11 are R9 is selected from R3 above; R17 has ▲mathematical formula, chemical formula, table, etc.▼, CH2OR18 or H (here R10 and R11 each independently represent hydrogen, lower alkyl, or alkoxycarboxylic Bonyl, carboxyalkyl, or R10 and R11 taken together Together with the nitrogen to which they are bonded, they form a ring of 3 to 10 atoms, and this ring is containing atoms selected from carbon, nitrogen, oxygen, and sulfur); R18 is R1, CH2CO2H, CH2CONR10R11 or CONR10 R11; R2 and R3, R4 and R5, R6 and R7, R8 and R9 or R9 and R10 may be taken together to form a ring of 3 to 8 atoms, and these atoms The children are selected from carbon, nitrogen, oxygen and sulfur. 2. R1 is Fmoc, Z, Boc or Me3Si(CH2)2OCO2H the law of nature; A is a bond, Gly, β-ALA, Asp-Tyr-Met-Gly; R2, R4, R6 and R8 are each independently an alkyl group of 1 to 3 carbon atoms; R, carboxyalkyl of 1 to 2 carbon atoms or CH2OH; is 3-indazolyl, 3-benzothienyl, 2-benzofuranyl, 3-benzof ranyl or 2-bromo-3-benzofuranyl; R5 is isobutyl, sec-butylethyl, n-propyl or i-propyl can be; R7 is CONH2, CONME2 or OH; R9 is selected from R8; R17 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Here, R10 and R11 are each independent and alkyl of 1 to 3 carbon atoms, or R10 and R11 taken together to form a ring of 4 to 8 atoms containing the nitrogen to which they are attached). A compound according to claim 1. 3. R1 is hydrogen or BOC; A is a bond or β-ALA; R2, R4, R6 and R8 are each independently CH3 or CH2CO2H can be; R3 is 3-indolyl, 1-naphthyl or 2-naphthyl; R5 is n-butyl, n-pentyl, (CH2)2SCH3 or (CH2)2S CH2CH3; R7 is OH, tetrazole, triazole or CO2H; R9 is phenyl, 1-naphthyl or 2-naphthyl; R17 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R10 and R11 are each independently hydrogen, CH3 or R10 and R11 together, a claim that they form a ring of 5 to 6 atoms containing the nitrogen to which they are attached) A compound according to item 1. 4. α-Methyl-DL-tributophil-L-methionyl-L-α-asparty A compound that is L-L-phenylalanine amide. 5. α-Methyl-D-tributophyl-L-methionyl-L-α-aspartyl - A compound that is L-phenylalanine amide. 6. α-Methyl-L-tryptophyl-L-methionyl-L-α-aspartyl - A compound that is L-phenylalanine amide. 7. N-[[(1,1-dimethylethoxy)carbonyl]-α-methyl]-L- [Tryptophyl]-L-methionyl-L-α-aspartyl-L-phenylara A compound that is a ninamide. 8. N-[(1,1-dimethylethoxy)carbonyl]-α-methyl-DL-t Leptophyl-L-methionyl-L-α-aspartyl-L-phenylalanine A compound that is an amide. 9. L-tryptophyl-2-methyl-DL-methionyl-L-α-asparty A compound that is L-L-phenylalanine amide. 10. N-[(1,1-dimethylethoxy)carbonyl]-α-methyl-D-t Leptophyl-L-methionyl-L-α-aspartyl-L-phenylalanine A compound that is an amide. 11. Glycyl-α-methyl-D-tryptophyl-L-methionyl-L-α- A compound that is aspartyl-L-phenylalanine amide. 12. Glycyl-α-methyl-DL-tryptophyl-L-methionyl-L-α -A compound that is aspartyl-L-phenylalanine amide. 13. Glycyl-α-methyl-L-tryptophyl-L-methionyl-L-α- A compound that is aspartyl-L-phenylalanine amide. 14. an amount of a compound according to claim 1 effective to suppress appetite in a mammal; and A pharmaceutical composition comprising a pharmaceutically acceptable carrier. 15. from administering an appetite suppressing effective amount of a compound according to claim 1 to a mammal. A method of suppressing appetite in mammals. 16. Compounds selected from: