JPH04504716A - Peptides with a novel polar N-terminal group - 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] Background of the invention of peptides having a novel polar N-terminal group The present invention provides novel compounds. More specifically, the present invention provides novel peptide Provide analogues. More specifically, the present invention provides a renin substrate (angiothelial 10. L Contains an uncuttable transitional state insert corresponding to the 1st position. and a novel polar group at the N-terminus of the peptide. . These peptides can be used as renin inhibitors and as retroviral protea It is useful as an inhibitor of enzymes. Renin inhibitors can cause renin-dependent hypertension and hemophilia. of renin-dependent hyperaldosteronism, and other renin-dependent cardiovascular disorders. Useful in diagnosis and control. Retroviral proteins such as HIV-I butyase Rotease inhibitors can be used to treat rotease disorders such as human acquired immunodeficiency syndrome (AIDS). Useful in treating diseases caused by viruses.

Renin is known for its N-terminal sequence in horse substrates, e.g. (L, T, Skeggs et al,) Mental Medicine (J, Expert, Med,), 106.439 (19 As found by (57): It is an endobeptidase that specifically cleaves a specific peptide bond of

A human renin substrate has recently been developed by D. Kesbury etal,), Biochemical and Biophysical Research Communications (Biochem, Biophys, R es, Comm, ), 99.1311 (1981). They have completely different arrangements. it is: Lenin -Val-11e-His-lB It can be expressed as Ru.

Renin cleaves angiotensinogen to produce angiotensin■, which is Converted to angiotensin H, an excellent pressor agent. Multiple angiotensin I conversions It is known that enzyme inhibitors are useful in treating hypertension. It also inhibits renin. Harmful agents are useful in the treatment of hypertension.

A large number of renin-inhibiting peptides have been disclosed. Thus, U.S. Patent No. 442 4207; European Published Applications 45665, 104041; and 156322 No. 825,250, filed Feb. 3, 1986; discloses certain peptides with dipeptides at positions 10 and 11 containing bonds; ing. A number of statin derivatives that are said to be renin inhibitors have been disclosed. Ru. For example, European Published Application Nos. 77028; 81783; 114993; 15 No. 6319, and No. 156321: and U.S. Patent No. 4,478,826: No. 4 See No. 470971; No. 4479941; and No. 4485099. Also, Terminal disulfide rings have been disclosed in renin inhibiting peptides. For example, See Patent Nos. 4477440 and 4477441. 10.11 of renin substrates Aromatic and aliphatic amino acid residues at positions US Pat. No. 4,478,827 and and No. 4455303. U.S. Patent No. 4,485,099 and European published applications 156320 and 156318 disclose C-terminal amides 1 It is shown. European Publication Nos. 111266 and 77027 contain certain Tet Lapeptides are disclosed. Furthermore, European Published Application No. 118223 is 10- 11 The peptide chain is a carbon chain or a carbon-nitrogen chain of 1 to 4 atoms. Disclosed are certain engineered renin-inhibiting peptide analogs. In addition, Holladay et al. Synthesis of ketomethylene/peptide isosteres Hydroxyethylene and KemoethyleneDipe ptide l5osteres) J, Tetrahedron Letters (Tet) rahedron Letters), Volume 24, Issue 41, Pages 4401-4404 , 1983, and the steric restriction disclosed in the aforementioned U.S. Pat. No. 4,424,207. Preparation of “ketomethylene” and “hydroxyethylene” dipeptide isosteric functional groups disclose various intermediates in the process.

In addition, published European applications 45161 and 53017 describe angiotensin modification. Amide derivatives useful as inhibitors of convertases are disclosed.

Certain dipeptides and tripeptides are described in US Pat. No. 4,514,322: No. 4510085; and No. 4548926 and European Published Application No. 1287 No. 62; No. 152255; and No. 181110. Pepusta Renin inhibitors derived from pepstatin are disclosed in US Pat. No. 4,481,192. Disclosed in the issue.

Retroinverso bond modification at positions 10-11 is U.S. Patent No. 4,560,505, European Published Application No. 1 '27234 and No. 127235. Induction of isosteric bond substitution at positions 10-11 Conductors are published in European published applications 143746 and 144290; and 1986 No. 8,339, filed Feb. 27, 2003. 11- Isosteric bond modifications at positions 12 and 12-13 are described in European Published Application No. 179352. Disclosed in the issue. Certain peptides containing 2-substituted statin analogs A similar type is disclosed in European Published Application No. 157409. 3-aminodeoxystatin Certain peptides containing Ru. Containing 1-amino-2-hydroxybutane derivatives at positions 10-11 Species of peptides are disclosed in European Published Application No. 172346. 10th-11th place Certain peptides containing 1-amine-2-hydroxypropane derivatives is disclosed in European Publication No. 172347. A containing N-terminal amide type 1 Certain peptides are disclosed in U.S. Patent Application No. 844,716 filed March 27, 1986. Disclosed in the issue. Certain peptides containing dino\lostatin are 198 Disclosed in PCT Application No. 000713, filed April 7, 2006.

European Published Application Nos. 156322, 114993: and 118223: and No. 798,459, filed November 15, 1985; U.S. Patent Application No. 8,252,510 filed February 3, filed February 27, 1986 US Patent Application No. 833,993; Application No. 844716 discloses hydroxamic acids or esters at the C-terminus. I'm doing it.

Shori p dish show P'CT patent application filed January 27, 989, PCT/U S8910 No. 0247 has various polar end groups at the N-terminus and/or C-terminus. Discloses renin inhibiting peptides.

U.S. Patent Application No. 4,613,676 discloses that a hydrogen or acyl N-terminus and a transition state site are Certain substituted 5-amino-4-hydroxybars with two amino acid residues between Discloses leryl derivatives. Hydroxy-substituted alkyl and etherified sugars A wide class of acyl substituents are disclosed, including moieties.

International application No. PCT/EP87100593 (International Publication No. PCT/EP87100593 dated April 21, 1988) Publication No. 88102756) is a poly(type of sugar) in peptides other than renin inhibitors. It is expected to incorporate the following types.

U.S. Pat. No. 4,729,985 discloses, for example, (tris-hydroxy)-(t-butyl containing a protecting group with a molecular weight of less than 500, including butyluriedo Discloses renin inhibitors.

US Pat. No. 4,668,770 discloses a renin inhibitor having a polyhydroxy group at the C-terminus. Comprehensive disclosure of harmful tripeptides.

British patent application GB2200115-A (published 27 July 1988) discloses renin inhibitors having a sugar moiety at the N-terminus linked via a linkage; ing.

Summary of the invention In particular, the present invention corresponds to positions 10 and 11 of the renin substrate (anchiotensinogen). has a non-cleavable metastatic insert, and has a formula at the N-terminus: b　＞　HtNc　cCH3)　--1c)HO,C-1 d) (H, N) (HO, C) CH-5 or e) (HO), P (0) O-; herein, n is inclusively 0 to 5]. .

These peptides can be used as renin inhibitors and retroviral proteases. is useful as an inhibitor of

"Renin inhibitory peptide" is a peptide that can inhibit the renin enzyme in mammalian metabolism. three or more amino acid residues by a peptide or pseudopeptide bond means a compound that has

"Uncleavable transitional state insert" means a transition state insert that cannot be cut.

Various such transition state inserts corresponding to the 10.11-position of the renin substrate are Publications in the art, including those disclosed in the following documents, which are hereby incorporated by reference: It is knowledge.

US Patent No. 4424207 (Szelke): European Patent No. 10 No. 4041A (Szelke): European Patent Application No. 144290A (Ciba Geigy AC); European Patent 0156322 No. (Merck); European Patent No. 161-588A (Me rck)): European Patent No. 0172347 (Abbott); State Patent No. L72-346-A (Abbott); European Patent No. No. 156-318 (Merck): European Patent No. 157-409 (Merck) Merck): European Patent No. 152-255 (Sankyo) kyo)): and U.S. Patent No. 4,548,926 (Sankyo )): and No. 904,149 filed September 5, 1986: March 2, 1986 No. 844,716, filed April 7, 1986; CT Application No. ○00713; filed on November 22, 1986, U.S. Patent Application No. 94 No. 5340: and U.S. Patent Application No. 825,250 filed February 3, 1986. ; and A. Svartenstein, B. Carpino, F. Myake and Bi Bi Hiskins (A, 5paltenstein, F, Miyake and P, B.

Hyskins), Tetrahedron Letters ), 27:2095 (1986); M NisφBernatowicz (D, H,’ Rich and M, S, Bernatowicz), Journal on Median Chemistry ( J, Med, Chem, ), 25 Near 91. (1982): O Jar (R oger), Journal on Median Chemistry (J, Med, Chem, ), 28: 1062 (1985); D.M. Gritsuk et al. (D, M, G11ck et al), Biochemistry try), 21:3746 (1982); D x Ichi Rich (D, H , Rich), Biochemistry, 24':31 65 (1985); R.L. Johnson, Journal on Median Chemistry (J, Med, Chem, ), 25:605 (19B2): R. L. Johnson and Kay Be. Rushobor (R, L, Johnson and K, Verschove r), Journal of Medicinal Chemistry (J, Med, Ch. ein, ), 26:1457 (1983); R.L. Johnson (R. , L. Johnson), Journal on Median Chemistry ( J, Med, Chem), 27:1351 (1984); Bartlett et al., Journal O. American Chemical Society (J, Am, Chem, 5oc ), 106: 4282 (1984): and peptides synthesis, structure and Functions (Peptides: 5 synthesis, 5 structure and 　Function) [V. J, Hruby; D.

H, Rich)] 8th American Peptide Symposium (8th American Peptide Symposium) an Peptide Sym, ), Pierre Chemical Company (Pier ceChemical Company, Rockford ), ■, 511-20; pp. 587-590 (1983).

"Polyhydroxy-substituted-alkyl group" means a bond or an amide, or an 3 to 9 molecules linked to the C-terminus of the renin-inhibiting peptide by a ster bond cyclic or acyclic carbon atoms and 2 to 8 hydroxyl substituents means a branched or unbranched alkyl derivative of the formula. These polyhydrides A roxy-substituted-alkyl group is an amino acid on the polyhydroxy-substituted-alkyl group. or force, brine, at the C-terminus of the renin-inhibiting peptide by a hydroxyl substituent. sugars and other linear or branched polyhydroxy-substituted-alkyl derivatives Including the body. ``Words bonded directly through carbon or nitrogen are polyhydrocarbons. It is intended to exclude the use of an ether linkage between the xy substituent and the peptide. Appropriate Examples of amino-substituted polyhydroxy-substituted-alkyl derivatives include aminodesoxyalkyl derivatives. Doses and aminodesoxyketoses, cyclic or reduced derivatives thereof, 2 ．． 3-dihydroxy-2-(hydroxymethyl)propylamine, 2-hydroxy C-1,1-bis(hydroxymethyl)ethylamine, 3-hydroxy-2,2 -bis(hydroxymethyl)propylamine, 3-amino-1,2-propanedi ol, 2-amino-1,3-propanediol, 4-hydroxy-3,3-bi (hydroxymethyl)butylamine, and 2,3,4-trihydroquine butylamine. amines. Polyhydroxy-substituted-alkyl with appropriate carboxylic acid substitutions Examples of derivatives are onic acids such as gluconic acid and glucuronic acid; uronic acid, glyceric acid, 3-hibitroxy-2,2-bis(hydroxymethyl ) Acetic acid, 4-hydroxy-3,3-bis(hydroxymethyl)butyric acid, 2,3.4 - includes trihydroxybutyric acid. Examples of suitable aldehyde or ketone substituted sugars is an aldo which can be directly condensed to the C-terminus of the renin-inhibiting peptide by esterification. -ses and ketoses. Incorporation of sugars into peptides with free amines This and other reactions suitable for Disclosed in the issue.

"Derivatives" of amino acids are those commonly used in the renin inhibitors described in the above reference. refers to a well-known amino acid derivative.

Examples of peptides of the invention are represented by Formula I. In formula I, 1 of the renin substrate The non-cleavable transition state insert corresponding to the 0.11-position is El. -F +1 It will be done.

The present invention provides novel peptides having a polar functional group at the N-terminus. Below N - Terminal groups are preferred: γ-glutamic acid, β-valine and phosphoric acid. These pages Putido has increased aqueous solubility and improved ADDME properties (e.g. absorption and secretion).

As will be apparent to those skilled in the art, the peptides of the invention contain conflation around an asymmetric carbon atom. Depending on the formulation, diastereomeric forms can occur. All Such diastereomeric forms are included within the scope of this invention. Preferably, The stereochemistry of amino acids corresponds to that of naturally occurring amino acids.

Renin-inhibiting peptides usually have a protecting group at the C-terminus. These safeguards Protecting groups are known in the polypeptide art. Examples of these protecting groups are given below. these Any of the protecting groups are suitable for the renin-inhibiting peptides of the invention.

Examples of pharmaceutically acceptable acid addition salts are: acetate, adipate, alkinate, as Partate, Benzoate, Benzene Sulfonate, Hydrogen Sulfate, Butyrate, Que phosphate, camphorate, camphor sulfonate, cyclopentanepropion acid salt, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycol Lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate , lactate, maleate, methanesulfonic acid L2-phthalenesulfonate, Nicotinate, oxalate, balmate, pectate, peroxosulfate, 3 - phenylpropionate, picrate, pivalate, propionate, Huccinate, tartrate, thiocyanate, p-toluenesulfonate, and Includes decanoate.

The carbon atom content of various hydrocarbon-containing groups is determined by the minimum and maximum carbon atoms in the group. Indicated by a prefix indicating a large number. That is, the prefix (Ct CJ) comprehensively , represents a group having an integer "i" to an integer "j" number of carbon atoms. (C□-C ,) Alkyl refers inclusively to alkyl of from 4 to 4 carbon atoms, or methyl ethyl, propyl, butyl and their isomeric forms. C, -C, cyclic amino represents a monocyclic group containing one nitrogen atom and 4 to 7 carbon atoms.

Includes alkyl-substituted cycloalkyls containing up to a total of 10 carbon atoms Examples of (CJ-C,,)cycloalkyl are cyclopropyl, 2-methylcyclopropyl Lopyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propyl Pylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclo Hexyl, cyclohbutyl, cyclooctyl, cyclononyl, cyclodecyl and It is an isomeric form of

Examples of aryl are phenyl, naphthyl, (0-1m-1 or p-)tolyl, (o -1m-1 or p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o -Tolyl, 5-ethyl-m-)lyl, (0-1m-1 or p-)propylphenyl Nyl, 2-propyl-(0-1m-1 or p-)tolyl, 4-isopropyl- 2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4-12, 3,6 or p-)fluorophenyl, (o-1m-1 or p-1-lifluor phenyl, 4-fluoro-2,5-xylyl, (2゜4-12,5- 12, 6-13, 4-1 or 3. 5-) difluorophenyl, (o-1m- 1 or p-)chlorophenyl, 2-chloro-p-1-lyl, (3-14-15 - or 6-) chloro-〇-tolyl, 4-chloro-2-propylphenyl, 2- Impropyl-4-10lophenyl, 4-chloro-3-fluorophenyl, (3 - or 4-) chloro-2-fluorophenyl, (o-1m-1 or p-)l -lifluoro-methylphenyl, (o-1m-1 or p-)ethoxyphenyl , (4- or 5-)chloro-2-methoxy-phenyl, and 2,4-dichloro ro(5- or 6-)methylphenyl and the like are included.

Examples of -Het are: 2-13-1 or 4-pyridyl, imidazolyl, indolyl N 1n-formyl-indolyl N t"-C, -C, alkyl-C (0) - Ia t’ IJ le, 1. 2. 4-t1j7 zolyl, 2-14-1 or S-pyrimidinyl, 2- or 3-chenyl, piperinyl, pyryl, pyro Linyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazo Linyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxa Silyl, oxazolidinyl, inoxasilyl, inoxazolidinyl, morpho linyl, thiazolyl, thiazolidinyl, inthiazolyl, inthiazolidinyl, Quinolinyl, Isoquinolinyl, Benzimidazolyl, Benzothiazolyl, Benz Includes oxacylyl, furyl, chenyl, and benzothenyl. these Each of the groups may be substituted as described above.

As generally understood by those skilled in the art of organic chemistry, Heterocycle, as defined herein, refers to dicyclic rings through oxygen or sulfur or within the ring. It would not be bonded through the nitrogen that becomes part of the heavy bond.

Halo means halogen (fluoro, chloro, bromo, matahyotho) or trifluoro. It is lomethyl.

Examples of pharmaceutically acceptable cations are: pharmacologically acceptable metal cations, ammonia cations, amine cations, or quaternary ammonium cations.

Cationic forms of other metals, such as aluminum, zinc, and iron, are also within the scope of this invention. Particularly preferred metal cations are alkali metals, e.g. thium, sodium, and potassium, and alkaline earth metals, e.g. It is derived from nesium and calcium. Pharmacologically acceptable aminka Thiones are derived from primary, secondary, or tertiary amines.

The novel peptides herein include natural amino acid residues and synthetic amino acid residues. Contains both. These residues are standard amino acid residues unless otherwise noted. Abbreviations (e.g. ItJPAC-IUB joint commission on by) Chemical Nomenclature (Joint Comm1sion on B iochemical Nomenclature) (JCBN), “A Nomenclature and representation of amino acids and peptides (Nom-enclat ure and Symbolism for Am1no Ac1ds an d Peptides): , Nylobian Journal on Biochemistry See Story (Eur, JBiochem,), l 38.9 (1984) ).

The peptides of the invention can be used to advantageously reduce the concentration of active circulating renin. It is also useful in treating medical diseases. An example of such a disease is renin-dependent hypertension. hypertension, hypertension being treated with another anti-platelet pressure agent and/or diuretic, hemorrhagic heart failure, renin-dependent hyperaldosteronism, angina, and post-myocardial infarction , including other renin-dependent cardiovascular and ocular disorders. Renin-Angioten The syn system appears to be responsible for maintaining intracellular homeostasis. clinical and ex Verimental Hypertension (C1inical andExperim) ental Hypertension), 86.1739-1742 (19 84), see discussion on page 1740.

The peptides of the invention preferably inhibit renin for the purpose of positively influencing blood pressure. It is administered orally to humans to carry out this procedure. For this purpose, the compounds may be 0.1 mg to 100 mg per kg, administered 1 to 4 times daily. other throws Equivalent doses of the given route can also be used. For example, renin-related hypertension and high Ludosteronism is treated by administering 0.5 to 50 mg of the compound per kg of body weight per day. It is effectively treated by administration of Regram.

The exact dose depends on the patient's age, weight, and symptoms as well as the frequency and route of administration. Ru. Such variations are within the skill of the practitioner or can be readily determined.

The peptides of the invention can be prepared from free bases by methods well known in the art. Pharmaceuticals, both those that can be produced and those in which the acid has a pharmacologically acceptable conjugate base It can be in the form of any of the above acceptable salts.

Conventional dosage forms and means for administering renin inhibitory compounds can be used. , which is described, for example, in U.S. Pat. No. 4,424,207, referenced herein. Listed for. Similarly, the amounts disclosed in U.S. Pat. No. 4,424,207 are This is an example applicable to the compounds of the invention.

The peptides of the present invention are preferably administered in the form of pharmacologically acceptable acid addition salts. Administered by mouth. Any pharmacologically acceptable salt is useful in the present invention. However, the preferred pharmacologically acceptable acid addition salts for oral administration are citrate and ascarboxylate. It includes paraginates, including those listed above. These salts are in hydrated form or It may also be in a solvated form.

For renin inhibition, the peptides of the present invention are conventional, non-toxic and pharmaceutically acceptable. In dosage unit formulations containing carriers, adjuvants and vehicles, It can be administered topically, parenterally, by inhalation spray, or rectally. Specification The term parenteral used herein refers to subcutaneous injection, intravenous administration, intramuscular administration, intrasternal injection, or intrasternal injection. or injection techniques. Warm-blooded animals such as mice, rats, horses, dogs, cats, etc. In addition to the treatment of humans, the compounds of the invention are also effective in treating humans. Pharmaceutical compositions of the Tides can be prepared, for example, as sterile injectable aqueous or oil-soluble suspensions. It can be in the form of a sterile injectable preparation. The suspending agent may be mixed with a suitable dispersant or can be formulated according to known techniques using wetting agents and suspending agents. Sterile for injection The agent can be prepared in a non-toxic parenterally acceptable form, such as, for example, as a solution in 1,3-butanediol. It may also be a sterile injectable solution or suspension in a suitable excipient or solvent.

Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solutions.

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Wear. For this purpose, any Any bland fixed oil may also be employed.

Additionally, fatty acids such as oleic acid can be used in the formulation of injectable drugs. .

Furthermore, the peptides of the present invention for inhibiting renin can be administered in the form of herbal medicines for rectal administration. You can also give. These compositions contain drugs that are solid at room temperature but can be absorbed into the rectum. A suitable non-irritating excipient that is liquid at temperature and therefore melts in the rectum to release the drug. It can be prepared by mixing with excipients. Such substances include cocoa butter and Ethylene glycols.

The peptides of the invention are described, for example, in published European patent application no. diuretics, alpha and/or beta adrenergic blockers, central nervous system Agonist, adrenergic neuron blocker, vasodilator, angiotensin When administered in combination with other agents used in antihypertensive treatment such as I-converting enzyme inhibitors, etc. You can also

For example, compounds of the invention: Diuretics: acetazolamide; amiloride; bendroflumethiazide; benzthiazide Bumetanide; Chlorothiazide; Chlorthalidone; Ticlothiazide: Etacry acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacry /n (racemic mixture, or single (+) or (-) enantiomer) individually or as an operating ratio of 9:1 for each enantiomer); methyclothiazide; muzolimine; polythiazide; quinesazone, etaculina salt sodium; nitropurgide sodium: spironolactone: chicli Natene; trimatelene; trichlormethiazide; α-adrenergic blocker : Dibenamine; Phentolamine; Phenoxybenzamine: Brazosin; Lazolin; β-adrenergic blocker: Atenolol: Metoprolol; Na Drol: Flopranolol: Timolol: ((±) -2-[3-(tert -butylamino)-2-hydroxypropoxy]-2-furanilide) Carolol); (2-acetyl-7-(2-hydroxy-3-isopropylamine) /propoxy)benzofuran HCQ) (befunolol); ((±)-1-(iso propylamino)-3-(p-(2-cyclopropylmethoxdiethyl)-pheno xy)-2-propranol HCRX betaxolol); (1-[(3,4-dimethoxyphenethyl)amine]3-(a-tolyloxy) -2-propatol HCl2) (bevantrol);(((±)-1-(4-( (2-inpropo-cow jetoxy)methyl)phenoxy)-3-isopropylamide Nor-2-propa/-ru) fumarate) (vinprolol); (4-(2-hydroxy-3-[4-(phenoxymethyl)-piperidinocope) ropoxy)-indole); (carbazolyl-4,-oxy-5,2-(2-methoxydiphenol)-ethyl amino-2-propatool); (1-((1,1-dimethylethyl)amine)-3-((2-methyl'H-yne) dol-4-yl)oxy)-2-propatol benzoate) (bovintrol) ): (1-(2-exobicyclo[2,2,1]-hebut-2-ylphenoxy)- 3-[(t-methylethyl)-7mi/co2-buC2ha/-/l/HCl2)( Bornaprolol); (o-[2-hydroxy-3-[(2-indol-3-yl-1,l-dimethylene) ruethyl)-amino]propoxy]benzonitrile HC6) (pusyntrol) ; (α-[(tert-butylamino)methyl-7-ethyl-2-ben7'7 methanol) (bufuralol); (3-[3-acetyl-4-[3(tert-butylamino)-2-hydroxy bropyrcophene/lz]-1,1-diethylurea HCl2) ); ((±)-2-[2-[3-[(1,1-dimethylethyl)aminoco-2-hyde Roxypropoxy]phenoxy]-N-methylacetamide HCff) (Setamo roll): (2-Benzimidazolyl-phenyl (2-isopropylamitubrobanol) ).

((±)-3'-acetyl-4"-(2-hydroxy-3-isopropylamino Propoquine)-acetanilide HCl2) (Diacetrol).

(Methyl-4-[2-hydroxy-3-[(1-methylethyl)aminopropoxy) sil]]-benzenepropanoate HCf2) (esmolol); (erythro DL-1-(7-methylindan-4-yloxi7)=3-isopropylamino butan-2-ol): (1-(tert-butylamino)-3-[0-(2- (propynyloxy)femex-2-propatur (pargolol); (1- (tert-butylamino)-3-[o-(6-hydrazino-3-pyridazinyl ) phenoxy]-2-propatol diHC (propatol); ((-)-2-hydroxy-5-4(R)-1-hydroxy-2-[(R)-( 1-methyl-3-phenylpropyl)amino]ethyl]henzamide); (4-Hydroxy-9-[2-hydroxy-3-(isopropylami/)-pro poxy]-7-methyl-5H-furo[3,2-g][,1]-]benzopyran- 5-one (ibrochlorol): (()-5-(tert-butylamino)-2 -Hydroxypropoxy]-3,4-dihydro-1-(2H)-naphthalenone H Cf2) (repobunolol); (4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-beta (4-[3-(tert-butylamino)-2- hydroxypropoxy]-N-methylincarbostyryl HCQ): ((±)- N-2-[4-, (2-hydroxy-3-isopropylaminopropoxy) fluoride [phenyl]ethyl-N-isopropylurea) (Puff F0-R); (3-E[(2-trifluoroacetamido)ethyl]amino]-1-phuninoki Cypropan-2-ol): (N-(3-(o-chlorophenoxy)-2-hydroxypropyl)-N'-( 4'-chloro-2,3-dihydro-3-oxo-5-pyridazinyl) ethylene di amine); ((±)-N-[3-acetyl-4-[2-hydroxy-3'-[(1-methyl ethyl)amino]propoxyphenyl]butanamide) (acebutolol); ((±)-4°-[3-(tert-butylamino)-2-hydroxybropoki Cicospiro [cyclohegyusan-1,2°-indan]-1°-on) (spirene droll); (7-[3-[[12-hydroxy-3-[(2-methylindol-4-yl ) Oxylpropylcoaminobutylcothiophylline) (thioprolol); ((±)-1-tert-butylamino-3-(thiochroman-8-yloxy )-2-propertool) (deltatrol): ((±)-1-tert-butyl Amino-3-(2,3-xylyloxy)-2-propatol HCl2) (xylyloxy) Benolol); (8-[3”(tert-butylamino)-2-hydroxypropylene); [ropoxy]-5-methylcoumarin) (bucumolol); (2(3(tQrt-bucumolol); thylamino)-2-hydroxy-propoxy)benzonitrile HCa) (Bukumo ((±)-2'-[3-(tert-butylamino)-2-hydro Xypropoxy-5°-fluorobutyrophenone) (butophyllorol); (1 -(carbazol-4-yloxy)-3-(isopropylamino)-2-pro (5(3-tert-butylamide/-2-hydroxy) c) Propoxy-3゜4-dihydrocarbotyryl HC+2) (carteolol) ;(1-(tert-butylamino)-3-(2,,5-dichlorophenoxy) -2-propatool) (chloranolol); (1-(indene-4 (or 7) -yloxy)-3-(isopropylamino)-2-propatol HCQ) (1-isopropylamino-3-[(2-methylindole- (4-yl)oxyyo2-propatool) (mebindolol); (1-(4-yl) Setoxy-2,3,5-trimethylphenoxy)-3-isopropylaminopro pan-2-ol) (methipranolol); (1-(isopropylamino)- 3-(o-methoxyphenoxy)-3-[(1-methylethyl)aminoco-2- propatool) (mobrolol): ((1-tert-butylamino)-3-[ (5,6,7,8-tetrahydro-cis-6,7-cyhydroxy-1-naphthyl ) Oxyyo 2-propatool) (nadolol); ((S”)-1-(2-cyclopentylphenoxy)-3-[(1,1-dimethyl ethyl)aminoco-2-propatur sulfate (2:1) (penbutol) ); (4°-[1-hydroxy-2-(amine)ethylcomethanesulfonanilide) (Sotalol); (2-methyl-3-[4-(2-hydroxy-3-tert-butylaminopropylene) poxy)phenyl]-7-medoxyisoquinolin-1-(2H)-one); (1-(4-(2-(4-fluorophenyloxy)ethoxy)phenoxy)- 3-isopropylamino-2-propatol HCl2); ((-)-p-[3- [(3,4-dimethoxyphenethyl)aminoco-2-hydroxypropoxy]- β-methyl-cinnamonitrile) (baclyl 0-ru); ((±)-2-(3'-tert-butylamino-2'-hydroxypropyl thio)-4-(5°-carbamoyl-2°-thenyl)thiazole HCQ) (A rotinolol); ((±)-1-[p-[2-(cyclopropylmethoxy)ethoxy]phenoxy) [C]-3-(isopropylamino)-2-propanol) (thiololol); ((±)-1-[(3-chloro-2-methylindol-4-yl)oxy]- 3-[(2-phenoxyethyl)aminoco-2-propanol) ); ((±)-6-C[2” E[3-(p-butoxyphenoxy)-2-hydro xypropyl]amino]ethyl]amino-1,3-dimethyluracil) Revolol); (4-(cyclohecylamino)-1-(1-naphthrenyl-oxyamino)-2-buta Nord): (1-phenyl-3-[2-[3-(2-cyanophenoxy)-2-hydroxy Propyl]aminoethyl]hydantoin HCf2); (3,4-dihydro-8- (2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2 H-1-benzopyran) to Pratrol); Angiotensin I converting enzyme inhibitor: 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline Putogril); (1-(4-ethoxycarbonyl-2,4(R,R)-dimethylbutanoyl)yl ndrine-2(S)-carboxylic acid; (2E2-C(L-(ethoxycarbonyl) -3-phenyl-propyl]amino]-1-oxopropyl]-1,2,3,4 -tetrahydro-3-in quinolinecarboxylic acid); ((S)-1-[2-[(1-(ethoxycarbonyl)-3-phenylbrobyl) ]Aminoco-1-oxopropyl]octahydro-IH-indole-2-cal Bonic acid HCQ).

(N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl) Thiol-2-methyl-1-oxo-propyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl')-3-(3-mercapto propionyl)-4-thiazolidinecarboxylic acid); (1-(N-[1(S)-e toxdicarbonyl-3-phenylpropyl]-(S)-alanyl)-cis, syn -octahydroindole-2(S)-carboxylic acid HCQ): ’, ((-)-(S)-1-'E(S)-3-mercapto-2-methyl-1-o xobrovircoindoline-2-carboxylic acid): ([1(S), 4S]-1 -[3-(benzoylthio)-2-methyl-1-oxopropyl]-4-phenylene Lucio-L-proline; (3-(CI-ethoxycarbonyl-3-phenyl-( IS)-propylcoamino)-2,3,4,5-tetrahydro-2-oxo-1 -(3S)-Benzazepine-1-acetic acid HCQ: (N-(-2-benzyl-3- mercaptopropanoyl)-8-ethyl-L-cysteine) and S-methyla analog; (N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L -Alanyl-shi-proline maleate) (enalapril); N[1-(S )-carboxy-3-phenylpropyl]-L-alanyl-1-proline; N2-4t-(s)-carboxy-3-phenylpropyl]-L-lysyl-shiichi Proline (lisinopril); Other antihypertensive agents diaminophylline; cryptenamine acetate and tannate; Decervidin; Meremethoxyline procaine; Pargyline: Trimethaphancam sylates, etc., as well as mixtures and combinations thereof; or its salts or other derivative forms.

Typically, individual daily doses for these combinations are below the minimum recommended clinical dose. From approximately 175 doses, the maximum recommended level for the sum when they are administered alone Can be done with a range of bells. Co-administration involves combining the active ingredients and containing appropriate doses of each. This is most easily accomplished by formulating a suitable unit dosage form. Of course, Other methods of co-administration are also possible.

Thus, the novel peptides of the present invention can be used to treat renin-related hypertension and hyperaldosteronism. It has an excellent degree of activity in treating.

In addition, renin inhibitors are disclosed in the international application PCT/US 86102291 (1987). P’CT International Publication Number W○87102581) dated May 7th As such, it may also control the increase in intraocular pressure associated with the use of steroidal anti-inflammatory drugs. Disclosed.

In addition, the peptides of the present invention have novel human retrovirus protease inhibitory properties. Also useful as peptide analogs. Therefore, the peptides of the present invention are retroviral. virus protease, thus inhibiting viral replication. They are , the human immunodeficiency virus that causes acquired immunodeficiency syndrome (AIDS) and related diseases. treatment of human patients infected with human retroviruses such as HIV (HIV). It is useful for

The retroviral capsid and nonstructural proteins are composed of the viral genes gag and pol as a polyprotein, which is further processed by viral protease (PR ) is found in the viral capsid and plays a role in viral function and replication. It is processed to the required mature protein. When PR is absent or non-functional , the virus cannot replicate. Retrovirus PR like HIV-I PR , similar to that exhibited by the more complex aspartic acid protease renin. It has been found that the aspartic acid protease has similar active site characteristics. Ru.

The term human retrovirus (HRV) refers to the human immunodeficiency virus, as is clear to those skilled in the art. Whole virus antibodies, human immunodeficiency virus antibodies, or strains thereof, and human T cells. cell leukemia virus 1 and 2 (TTLV-1 and HTLV-2) or their strains that belong to the same or related virus families and that are associated with various human retroviruses. Like viruses, they produce similar physiological effects in humans.

Patients to be treated must: 1) have measurable viral antibodies or antigens in their serum; one or more strains of human retroviruses as determined by the presence of infected, 2) i) disseminated histoplasmosis, ii) impsoriasis (1so psoriasis), iii,) pneumosis stic) bronchial and pulmonary candidiasis, including pneumonia; iv) non-Hodgkin's (10d gikin) lymphoma, V) or Kaposi's sarcoma. are under 60 years of age with any of the symptomatic AIDS-defining infections; or have peripheral blood patients with an absolute CD 41J lymphocyte count of less than 2007 m'.

The treatment consists of maintaining the inhibitory level of the peptide used according to the invention throughout, Continue until the appearance of a second symptomatic AIDS-defining infection necessitates another treatment.

More particularly, examples of such human retroviruses include human acquired immunodeficiency disease symptoms. Human immunodeficiency virus (HIV), which has been recognized as the cause of HIV/AIDS, and HT LV-I [also known as I or LAV] Duesberg), Proceedings on National Academy On Sciences (Proc, Natl.

Acad, Sci.) U.S.A., 86:755 (1989)]. HI V is a retroactive protein that cleaves condensed polypeptides into functional proteins of mature virus particles. contains the protease HIV-I protease encoded by the virus. [E, P, Li1lehoj, et al. Naru on biaogy (J, Virology), 62:3053 (1 988); C, Debuck et al., Proc. Deings on National Academy on Sciences (Proc. Nak 1. Acad, sci.), 84:8903 (1987)], this The enzyme HIV-I protease is classified as an aspartyl protease. and have homology to other aspartyl proteases such as renin. has been proven [L, H, Pearl et al. ), Nature, 328:351 (1987); Dora (1, Katoh et al), Nature 329 : 654 (1987)]. Inhibition of HIV-I protease inhibits HIV replication. It is useful in the treatment of human AIDS [E. D. Clark] E, D, C1erq), Journal on Medicinal Chemistry ( J. Med. Chem.) 39:1561 (1986). I (IV-I Inhibitors of proteases are useful in the treatment of AIDS.

A common inhibitor of peptide field A1 or aspartyl protease is HIV -1 protease inhibitor [Nis-Siermeiler et al. , Seelmeier et al), Proceedings Sun National ・Academy Sun Sciences (Proc, Bat 1゜Acad, Sc i,) USA, 85: 6612 (1988)], reduced to a position where it can be cut. from other substrates containing reduced-bond isosteres or statins Also disclosed are inhibitors of [M.

L. Moore et al), Biochemical and Biophysical Research Communications (BiocheIl, Biophys, Res, Co@mun, ).

159:420 (1984); Nis Bilich et al. al), Journal Sun Biological Chemistry (J, Biol, Qhets, ) 263:17905 (1988); Santos D.E. (5andoz.

D, E,) 38 1 2-576-A.

Thus, the peptides of the invention can be administered at doses equivalent to those described above for renin inhibition; Using dosage forms and methods, it is possible to treat retroviruses such as human acquired immunodeficiency syndrome. It is useful in treating diseases caused by Precise volume, dosage form and Methods of administration will be apparent to those skilled in the art, such as physicians or pharmacologists.

Compounds of the invention are shown in the chart and described in detail in the Preparations and Examples. In these charts, the variables are the same as defined above.

Chart A Chart A shows renin-inhibiting peptides with γ-glutamic acid as the polar N-terminal group. The preparation of Tide is described.

BOC-P ro-Phe removed from BOC using diethyl cyanophosphonate -N-MeHi 5-LVA-I 1 e-AMP, i.e. Pr of formula A-1 o-Phe-N-MeHis-LVA-I1e-AMP is commercially available By coupling with N(α)-BOC-α-benzyl-L-glutamic acid, the formula Obtain peptide A-2. BOC-Pr　o-Phe　-N-MeHi　5- Preparation of LVA-1re-AMP is described in 1988 1, which is hereby incorporated by reference. No. 147,073, dated March 20, 1986, and filed on March 5, 1986. It is described in published European Patent Application No. 0173481. Benzyl S Removal of tel is done with ammonium oxalate and palladium catalyst in dimethylformamide. transfer is achieved under hydrogenolysis conditions with formula A- 3 peptides are obtained. Removal of BOC group in formula A-3 with trifluoroacetic acid to obtain the final compound of formula A-5. Simply drop the reaction mixture into ether The product is isolated by lowering. Centrifuge the precipitated product to settle it, and Wash with ter-hexane and dry under vacuum.

Oxidation of the peptide of formula A-3 with m-chlorobenzoic acid produces N-oxy of formula A-4. get de. The final peptide of formula A-6 is obtained by treatment with trifluoroacetic acid as described above. get.

Other peptides of the invention having γ-glutamic acid as the polar N-terminal group are It is prepared in the same manner as described above.

Chart B The renin-inhibiting peptide of the present invention having β-Val as a polar N-terminal group Peptides similar to those described in Chart A were prepared using standard techniques known in the art. and assembled. BOC-β-vari from ethyl 3,3-dimethacrylate The synthesis of the components is described in Chart F below. Ch as transition state insert The peptide of the invention containing a-Va1 is exactly the same as its LVA counterpart. It is prepared in a similar manner. For the synthesis of Cha-Va I alcohol, see here PCT patent application PCT/US89 dated January 27, 1989, cited as 100247.

Chart B shows renin inhibitory peptides with β-Val as the polar N-terminal group. The preparation is described.

The peptide of 2B-1 in which R1° is He-AMP is listed here for reference. No. 147,073, filed January 20, 1988, and published. Prepared as described in European Patent Application No. 147073. R2゜ is The peptide of the formula B-1, which is Mba, is incorporated herein by reference. No. 07/147,073, filed March 20, 1986. 5 Searched by methods similar to those described in previously published published European patent applications. make Using standard techniques known in the art, appropriate peptides are conjugated to BOC-β- Coupling to valine gives compound IIB-2, followed by deprotection to give formula B -3 compound is obtained. The compound of formula B-3 is converted to trifluoroacetic acid (TFA) treatment to remove the BOC group, yielding the final peptide of 2B-4.

Formula B-2 with 2 equivalents of m-chlorobenzoic acid (MCP BA) in dichloromethane The N-oxide of 2B-5 is obtained by treating the compound.

Standard protocol (1-hydroxybenzotriazole-hydration in methanol The tosyl protecting group in NiB-5 was removed using a compound of NiB-6 to obtain compound NiB-6. It will be done. Final deprotection of the final peptide of formula B-7 follows the standard procedure for BOC group removal. (trifluoroacetic acid, dichloromethane). Stir the reaction mixture Directly dropwise into well-stirred 1:1 ether-hexane until the product turns into a flocculent solid. and precipitate. It was isolated by centrifugation, washed twice with ether-hexane, and Drying under vacuum gives the final product as the trifluoroacetate salt.

The Cha-Va I alcohol congener of the peptide 2B-7 was synthesized in a similar manner. achieved. However, in this synthesis, the detosylation of histidine was This is preceded by MCPBA oxidation of gin. Final deprotection and isolation of the product was carried out using LVA Perform as described above for analog.

Other peptides of the invention having β-Val as the polar N-terminal group are as described above. Prepared in a similar manner.

Chart C Chart the synthesis of phosphate residues in a suitably protected form for conjugation to peptides. This is outlined in Section C. Benzyl glyoxylate at C-2 is commercially available with formula C -1 for diisopropylcarbodiimide (DIC) esterification of glyoxylic acid Therefore, it is prepared. J W Perish and R B Joe Nuns U, W.

Perich and R,B, Johns), Synthesis is), 988, 142-144. t-Butyl N.

The initially mixed phosphite was obtained by treatment with N-diethylphosphoramidite. It will be done. Although this species is not isolated, it is oxidized in the reaction system with MCPBA to produce 20-3. A phosphoric acid ester is obtained. By hydrogenolysis removal of benzyl ester, peptidyl An acid of formula C-4 is obtained which is suitable for coupling to a desubstrate.

Chart D The synthesis of the four-carbon analogue of the phosphate residue prepared in Chart C is described in Chart D. . The starting material for this synthesis is commercially available vinyl acetic acid of formula 11. Stingray H, C, Brown, Organic Synthesis by A Boranes (Organic 5tnthesisvia Boranes) , 1975. 51-52, convert the acid to its benzyl ester of formula 12. and then borohydride the olefin of the benzyl ester of formula D-2. A compound of formula D-3 is obtained. The binding of phosphate species is as described above in Chart C. In particular, a phosphoric ester of formula D-4 is obtained, which is processed via hydrogenolysis. to convert to the acid of formula D-5.

Chart E Standard methods for incorporating phosphate residues prepared in Charts C and D into peptides Use the law. Diethyl cyanophosphonate (DEPC) or diisopropylka Using rubodiimide (DIC) as a coupling reagent, formulas C-4 and D-5 acids are coupled with various amines.

Char 1-E is a renin inhibitory peptide with a phosphate residue as the polar N-terminal group. Explain the assembly. Pep of formula E-1 (A-1) using DEPC or DIC Coupling the tide with acid 20-4 prepared as described in Chart C. The product of formula E-2 is obtained. m-chlorobenzoic acid (M CPBA) oxidation proceeds smoothly to obtain the N-oxide of formula E-3.

Deprotection of the peptide of 2E-2 to the final peptide of 2E-4 and peptide of formula E-3. Deprotection of Tido-2E-5 to the final peptide was first performed using 1:1 tetrahydrofuran. - carried out in water (which is 4M hydrochloric acid). 4M hydrochloric acid alone can be used: peptide dissolve as they react. After about 1 hour at room temperature (potassium hydroxide tower ) The reaction mixture is pumped dry, redissolved in water, and lyophilized to the desired to obtain the peptide.

Other peptides of the invention having a phosphate residue as the polar N-terminal group are similar to those described above. Prepared by method.

Chart F Chart F is BOC-β-valine residue from ethyl 3,3-dimethylacrylate Describe the synthesis of Ethyl 2,2-dimethylacrylate of formula F-1 is converted into ammonia When heated in a saturated ethanol solution of F, the Michael addition of ammonia gives the formula F -2 amino ester is formed. This reaction is slow (approximately 10 Despite the half-life (half-life in hours), no amithrisis of the ester is observed. B.O. Addition of the C group yields the compound 2F-3, and hydrolysis of the ester yields the compound 2F-4. of acid is obtained.

Chart G Similar to Chart B, Chart G has β-Vat as the polar N-terminal group. The preparation of renin inhibitory peptides is described. Formula G- where R5° is lie-AMP The peptide of No. 1 is incorporated herein by reference in its application dated October 11, 1988. Prepared as described in PCT patent application PCT/US88103436. It will be done. The peptide of formula G-1 in which R3° is Mba was published on October 11, 1988. by a method similar to that described in application PCT/US 88103436. It is prepared by Using standard techniques known in the art, the appropriate peptides are BOC -coupling with β-valine to obtain compound 2G-2, followed by deprotection. Compound 20-3 is obtained. Compound 2G-3 was converted into trifluoroacetic acid (TF The BOC group is removed by treatment with A) to obtain the final peptide 20-4.

Generally, liquid phase peptide synthesis methods similar to those described below or known in the art are used. Thus, renin-inhibitory polypeptides can be prepared. About the liquid phase method Suitable protecting groups, reagents, and solvents are described in Peptides: Analysis, Synthesis, and Biology ( The Peptides: Analysis.

5ynthesis, and Biology) J, volumes 1-5, E. Gross and T. Mayenhof-r-(E, Gross and T, Me ienhofer), Academic Press , New York, 1979-1983; “Peptide Synthesis in Practice (The P. Ractice of Peptide 5 Synthesis) J, M.A. ・Bodansky (M, Bodansky), Springeruverlag ( Springer 4erlag), New York, 1984. r-peptide synthesis The principles of Peptide is)j　,-T-M.A. Bodansky (M, Bodansky), Shu Springer-Verlag, New York , 1984. (e.g., if necessary, methyl chloride) Dicyclohexylcarbodiimide (DCC) in dichloromethane or dimethylformamide ) and 1-hydroxybenzotriazole (HOBT) or diethylphospho Conventional substances such as lyl cyanide (DEPC) and triethylamine (E’t3N) Using the coupling method of The carboxyl site of the carbonyl (BOC)-substituted amino acid derivative is appropriately protected. can be condensed with an amino acid or an amino functional group of a peptide.

Following completion of the coupling reaction, 2% anisole in methylene chloride (V/V) With or without selective treatment of the N''-BOC site with 50% trifluoroacetic acid. can be removed. Neutralization of the trifluoroacetate obtained in methylene chloride What to achieve with 10% diisopropylethylamine or sodium bicarbonate It's huge.

Starting materials, reactants, reaction conditions and Variations in the foregoing description of the necessary protecting groups are known to the chemist of ordinary skill. or readily available in the literature.

The compounds of the invention may be in free form or remain (previously unprotected). of peptides, carboxyl, amine, hydroxy, or other reactive groups. It can be either protected in one or more places. the protecting group can be any known in the polypeptide art. nitrogen and oxygen Examples of protecting groups are given by T. L. Greene, “Organic Protecting Groups in Organ ic 5ynthesis) J, Wiley, Ni Knee York, ( 1981); ie), “Protecting Groups in Organic Chemistry” in Organic Chemistry)j, Blenheim 0 Press (Ple nua+ Press) (1973); and Jay Furhov and Shi ・Benzlin (J, Fuhrhop and G, Benzlin), O Organic 5synthesis, Fairlark - Described in Verlag Chemie (1983). nitrogen Among the protecting groups, t-butoxycarbonyl (BOC), benzylcarbonyl, Includes acetyl, allyl, phthalyl, benzyl, benzoyl, trityl, etc. Ru.

The following compounds of the invention are preferred.

β-Va l-Phe-N-Meat i s-LVA-MBA or L-His Tidinamide, N-(3-amino-3-methyl-1-oxobutyl)-L-phene Nylalanyl-N-[2-hydroxy-5-methyl-4-[[(2-methylbutylene) ) aminococarbonyl 1-1-(2-methylpropyl)hexyl]-Nα-methane chill-1 [IS-[IRl, 2R*, 4R* (R*) co]-, bis(triflu oroacetate) (salt); β-Va I-Phe-N-MeHi s-CVA-MBA or L-Histidy N-amide, N-(3-amino-3-methyl-1-oxobutyl)-L-phenyl Alanyl-N-[1-(cycloheteisilmethyl)-2-hydroxy-5-methyl -4-[[(2-methylbutyl)aminococarbonyl]hexylro Nα-methy Ru-1CIS-[IRl, 2R*, 4R* (R*)] Co, Bis(trifluoro) loacetate) (salt); y-Glu-Phe-N-MeHi s-CVA-MBA or L-histidine Amide, L-γ-glutamyl-monophenylalanyl-N-[1-(cyclohexyl) silmethyl)-2-hydroxy-5-methyl-4-[[(2-methylbutyl)a minococarbonyl]hexyluro Nα-methyl-1[IS-[IRl, 2R*, 4R* (R*) co]-, bis(trifluoroacetate)) ([); 7-G 　I　u-Phe　-N-MeHi　s-I　1　e-CVA-AMPN○Also is L-histidineamide, L-γ-glutamyl-monophenylalanyl-N-[ 1-(Cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2- Methyl-1-[[(2-pyridinylmethyl)aminococarbonyl]butyl]ami ]carbonyl"hexyl]-Nα-methyl-1N-oxide, [lS-[IR l.

2R*, 4R* (IRl, 2R*)]-, tris(trifluoroacetate ) (salt) d A -G I u-P r o - (OCH3) Tyrr -Hi 5-CV G or L-histidine amide, L-γ-glutamyl-L-prolyl-〇-methy -L-tyrosyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy C-5-methylhexylco, [IRl, 2S*.

3R*) Co, bis(trifluoroacetate) (salt); 7-G I u-P r　o-Ph　e-N-MeHi　5-CVA or L-histidineamide, L -γ-glutamyl-prolyl-phenylalanyl-N-l11-(sic) lohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-Nα-methyl Chil-1[lS-(IRl, 2S*, 3R*)bis(trifluoroacetate) (salt);7-Glu-Pro-Phe-N-MeHis-CVA-MBA-ma or L-histidine amide, L-γ-glutamyl-monoprolyl-monophenyl Alanyl-N-cyclohexylmethyl)-2-hydroxy-5-methyl-4-C [(2-methylbutyl)amino]carbonyl]hexyl]-Nα-methyl-1[ lS-41R*, 2R*.

4R* (R*)]]-, bis(trifluoroacetate) (salt) -G 1 u-P r o-Phe-N-MeHi s-LVA-MBA or L -Histidinamide, L-γ-glutamyl, monoprolyl, and phenylalani RuN-[2-hydroxy-5-methyl-4-[[2-methylbutyl)aminoco] Carbonyl l-1-(2-methylpropyl)hexyl-Nα-methyl-5[IS - [IR*, 2R*.

4R* (R*)]]-, bis(trifluoroacetate) (salt) nia-Gl u-Pro-Phe-N-MeHis-LVA-I 1e-NH(CH,), C H(COOH)(NH-lysine or L-lysine, N6-[N-(5-[[N-[N -(L-D-γ-glutamyl-monoprolyl)-L-phenylalanyl]-N- methyl-histidyl]amine]-4-hydroxy-7-methyl-2-(1- methylethyl)-1-oxooctyl]-L-ynleucyl]-5[2S-(2 R*, 4R*, 5R*)]-, tris(trifluoroacetate) (salt) A-G I u-P r o-Phe -N-MeHi 5-CVA -NH (CH,), CH(COOH)(NH,) or L-histidineamide, L-γ -glutamyl-L~prolyl-1-phenylalanyl-N-[4-[[(5-a mino-5-carboxypentyl)aminococarbonyl]-1-(cyclohexy methyl)-2-hydroxy-5-methylhexyl]-Nα-methyl-1[IS -[IR*.

2R*, 4R* (R*)]]-, Tris (trifluoroacetate) (salt) ; (HO)zP(0)OCR,C(0)-Pr　o-P　h　e　-, N-M e Hi 5-LVA-I 1 e-AMP or L-histidine amide, N- [N-[1-'(phosphonooxy)acetyl 3-L-phenylalanyl-N- [2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[J[2- Methyl-1-[[(2-pyridinylmethyl)aminococarbonyl]butylcoami ]carbonyl]hexyl]-Nα-methyl-1 dihydrochloride, [IS-[IR*, 2R*, 4R* (2R*.

2R*)l　　　-： (HO) zP (0) O (CHt) 3C (0) P r o P h e N-MeHi 5-LVA-Il e-AMP or L-histidine amide , N-[[1-[1-oxo-4-(phosphonooxy)butyl]-3-hyrolidi carbonyl]-L-phenylalanyl-N-[2-hydroxy-5-methyl -1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-2- pyridinylmethyl)amino]carbonyl]butyl]amino/]carbonyl]hexy ]-Nα-methyl-1 dihydrochloride, EIS-[IR*(S*), 2R*, 4R* (IR*)　　　　-0 The following compounds of the present invention are more preferred.

β-Va 1-Phe-N-MeHi 5-LVA-11e-AMP or L-histidineamide, N-(3-amino-3-methyl-1-oxobutyl)- L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methyl propyl), -4-[[[:2-methyl-t-[[(2-pyridinylmethyl)a [mino]carbonyl]butylkoamino]carbonyl]hexyl]-Nα-methyl- 1 [IS-[IR*, 2R*, 4R* (IR*, 2R1)] Co, Tris(T) (Lifluoromethyl acetate) (salt): β-Va 1-Phe-N-MeHi 5-CVA-I 1 e-AMP also is L-histidineamide, N-(3-amino-3-methyl-1-oxobutyl) -L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy C-5-methyl-4-[C[2-methyl-1-[[(2-pyridinylmethyl)a Mino]carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl- 1 [IS-[IR*, 2R*, 4R* (IR*, 2R*) IE-, Tris(T) (refluoroacetate) (salt) di A-G l u-P r o-Phe -N-MeHi 5-LVA-I l e-AMP or L-histidine amide, L-γ-glutamyl-L-prolyl 1-phenylalanyl-11-[2-hydroxy-b-methyl-1-(2 -methyl-propyl)-4-mouth[[2-methyl-1-[[(2-pyridinylmethythyl Amino]carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methane Chill-1[IS-[IR*.

2R*, 4R* (IR*, 2R*)]]-, Tris(trifluoroacetate g) (salt) d A-Glu-Pro-Phe-N-MeHis-CVA-I le-AMP is L-histidine amide, L-γ-glutamyl-L-prolyl-monophenyl Raniru N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl- 4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]carbonyl]hexyl]-Nα-methyl-1ils-JIR *.

2R*, 4R* (IR*, 2R*) I]-, tris(trifluoroacetate )(salt); β-Va　I-Phe　-NC(CH3)　Hi　5-CVA-I　]　e　- NH(CH,) 4CH(COOH)(NH2) or L-lysine, NC-[N -[5-[[N-[N-(3-amino-3-methyl-1-oxobutyl)-L- phenylalanyl]-N-methyl-L-histidyl]amino]-6-cycloxy -4-hydroxy-2-(1-methylethyl)-1-oxohexyl]-L- inleucyl]-1[2S-(2R*, 4R lines, 5R1)]-, tris(trif fluoroacetate) (salt); 7-G ] u-P r o-Phe -N-MeHi 5-CVA -I I e-NH(CH,), (COOHXNH,) or L-lysine, NC-[N- [6-cyclohexyl-5-[[N (1-L-γ-glutamyl-monoprolyl )-L-phenylalanyl]-N-methyl-L-histidyl]amino l-4-hy Droxy-2-(1-methylethyl)-1-oxohexyl'3-L-isoroy Sill included: 2S - (2R*.

4R*, 5R*)]-, tris(trifluoroacetate) (salt): (HO)2 P(0)OCH,C(0)-Pro-Phe-N-MeHi 5LVA-1 1e-AMP-NO or L-histidine amide, ■-4(phosphonooxy)a cetyl]-L-prolyl-monophenylalanyl-N-12-hydroxy-5- Methyl-1-(2-methylpropyl)-4-[r[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexy ]-NC-methyl-1N-oxide, dihydrochloride, [IS-[IR*.

2R*, 4R* (IR*, 2R*)] -: (HO) 2P (○) O(C H-) 3C(0)-Pro-Phe-N-MeHi 5-LVA-Il e -AMP-No or L-histidineamide, N-1[1-[1-oxo- 4-(phosphonooxy)butyl-3-pyrrolidinyl-L-phene Nylalanyl N7C2-hydroxy-5-methyl-1-(2-methylpropyl) -4-[2-methyl-1-[L(2-2-pyridinylmethyl)amino]carbo nyl]butyl]amino]carbonyl]hexyl 1-NC-methyl-1N-oxy -hydrochloride, [IS-[IR*(S*).

2R*, 4R* (IR*, 2R*)]-0 The following compounds of the present invention are most preferred: Yes.

β-Va I-Phe-N-MeHis-LVA-AMP-No or L-Hi Stidinamide, N-(3-amino-3-methyl-1=oxobutyl)-L-phthalate Phenylalanyl-N-[2-hydroxyl 5-methyl-1-(2-methylpropylene) )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]car [bonyl]butyl]amino]carbonyl]hexyl]-NC-methyl-1N-oxy Sid, [IS-[IR*, 2R*, 4R* (IR*, 2R*)]]-, Tris (Trifluoroacetate) (salt); β-Va I-Phe-N-MeHi 5-CVA-11e -AMP-No or L-histidineamide, N-(3- Ami/-3-methyl-1-butyl)-L-phenylalanyl-N-[1- (cyclohexylmethyl)-2-hydroxy-5-methyl-41[[2-methyl -1-[[(2-pyridinylmethyl)amine]carbonylcobutyl]amino]carbohydrate [IS-[IRl,2 R*, 4R1(IRl, 2R*)]]-, tris(trifluoroacetate-1-) (Salt); 7-Glu-Pro-Phe-N-MeHis-LVA-11e- AMP-NO or L-histidine amide, L-γ-glutamyl-L--7' Lyru-1phenylalanyl-N-[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl) Amino]carbonylbutylamino]carbonyl]hexyl]-Nα-methyl- 1N-oxide, [IS [IR), 2R*, 4R* (IRl, 2R*)]] -, Tris(trifluoroacetate) (salt); 7-Glu-Pro-N-Me His-CVA-Ile-AMP-No or L-histidineamide, L- γ-glutamyl-1-prolyl-1-phenylalanyl-N-[1-(cyclohexyl) xylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[ [(2-pyridinylmethyl)amino]carbonyl]butyl]aminococarbonyl ]hexyl]-Nα-methyl-1N-oxide, [, IS-[IRl, 2R*, 4R* (IRl, 2R*)]-, tris(trifluoroacetate) (salt) ; (HO)*P(0)OCH,C(0)-Pro-Phe-N-MeHi 5- CVG or L-histidineamide, 1-, [(phosphonooxy)acetyl] -L-prolyl-phenylalanyl-N-[1-(cyclohexylmethyl) -2,3-dihydroxy-5-methylhexyl]-Nα-methyl-1-hydrochloride, [13-[IRl, 2R*, 3R*)]-0 Description of preferred specific examples The invention is illustrated by the following Preparations and Examples.

Throughout the following Preparations and Examples and this application: 'H-NMR is This is nuclear magnetic resonance.

AMP is 2-(aminomethyl)pyridinyl.

AMP-No is (2-pyridinylmethyl)amino, pyridine N-oxide .

Ampip is 4-(aminomethyl)piperidine.

β-Asp is β-asparagine.

BOC is t-butoxycarbonyl.

Bz is benzyl.

C is Celsius.

Cbz is benzyloxycarbonyl.

CDCf23 is deuteriochloroform.

Celite is a filter aid.

CVA is Chaψ[CH(OH)CH, koVal.

CVC is 2S-amino-1-cycloxyl-3R,4S-dihydroxy-6-methane. Chillhebutane.

DCC is synchrohekilypodiimide.

DEPC is diethylphosphoryl cyanide.

EtOAc is ethyl acetate.

FTrp is Ntn-formyl-Trp.

g is Durham.

γ-Glu is γ-glutamic acid.

His is histidine.

N-MeHis is Nα-methylhistidine.

HOBTltl-Hydrobovine dibenzotriazole.

HPLC is high efficiency liquid chromatography.

Iba is isobutylamine.

11e is isoleucine.

IR is infrared absorption spectrum.

LVA has C4 (hydroxyl-carrying carbon atom) in the S configuration. Leuψ(CH(OH)CHt)Val.

M is mole.

MBA is 2-methylbutylamino (racemic or optically active).

Me is methyl.

min is minutes.

mQ is milliliter.

MPLC is medium pressure liquid chromatography.

MS is mass spectrum.

ph is phenyl.

Phe is phenylalanine.

Pro is proline.

RIP has the formula H-Pro-Phe-Hi5, which is known as a renin inhibitory peptide. -Phe-Phe-Va-1"Tyr-Lys-OH・2 (CH, C(0)O H,) means a compound having XH, ○.

Sta is a statin.

TBS is tert-butyldimethylsilyl.

TEA is triethylamine.

TFA is trifluoroacetic acid.

THF is tetrahydrofuran.

TLC is thin layer chromatography.

TO8 is p-toluenesulfonyl.

TsOH is p-1-reninsulfonic acid.

Tyr is tyrosine.

(OCH3)'ryr is O-methyltyrosine.

β-Val is β-valine.

Wedge lines indicate bonds that extend up the page relative to the plane on which the compound lies.

Dotted lines indicate bonds extending down the page relative to the plane on which the compound lies.

In the examples below, HPLC is high pressure liquid chromatography and k" is This is the distribution ratio obtained. The solvent system used is shown in parentheses after the distribution ratio, A is 50 % methanol, 50% aqueous phosphate pH 3 buffer, B is 55% methanol, 45% Aqueous phosphate pH 3 buffer; C is 60% methanol, 40% aqueous phosphate pH 3 buffer and D is 65% methanol, 35% aqueous phosphate pH 3 buffer. wave speed was 1.5 mQ/min. The detector was set at 225 or 254 nm.

In the following examples, the renin inhibitory activity (IC5°) of the peptides of the present invention is No. 07, filed January 20, 1988, hereby incorporated by reference. No. 107/147.073 and European Patent Publication No. 107/147.073, published on March S. 1986. The in vitro test described in Application No. 017'3481, pages 103-105 It is measured using a strike.

in vitro IC. is measured in nanomoles. Moreover, the compound of the present invention The product showed renin inhibitory activity during in vivo testing.

Preparation Example I BOC=γ-Glu(α-○Bn)-Pro-Phe-(N-Me) Hi 5-LVA-01e-AMP (Formula A-2) See chart A 125 mg of peptide of formula A-1 and BOC-7-g Iu-a-○Bn6 A stirred solution of 1 mg of diisopropylethylamine in 1 ml of dichloromethane Add 1 μρ followed by 28 μQ of diethyl cyanophosphonate. mixture overnight Stir and then on silica gel using 4-10% methanol in dichloromethane. Chromatography gives 167 mg of the title product as a white solid.

The physical properties are as follows.

Heavy HNMR and FAB HRMS (m+H): 1149.668 Preparation Example 2 B OC-7-Glu-Pro-Phe-(N-Me) Hi 5-LVA-11 e -AMP (Formula A-3) See chart A 163 mg of the title product of Preparation Example 1, 137 mg of ammonium formate, and 5% P d/C 90 mg of dry dimethylformamide 1,4-medium compound was added under alkone to 1 Stir for 8 hours, then filter through Celite and concentrate under high vacuum. Remove the residue Chromatography on silica gel using 5-20% methanol in chloromethane 137.5 mg of the title product are obtained.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1097. '578 Preparation Example 3 BOC-7-Glu-Pro-Phe-(N-Me) Hi 5-LVA-I Ie -AMPN-oxide (Formula A-4) Chart A Reference Preparation Example 2 notation 53 mg of product and 11.5 mg of m-chlorobenzoic acid in a small amount of dichloromethane. The solution was stirred at room temperature for 5 hours, then 10-25% methanol in dichloromethane. Direct chromatography on silica gel using The labeled product is a white solid Obtained as 33°3mg.

Example 1 7-Glu-Pro-Phe-(N-Me)His-LVA He AMP Tris trifluoroacetate (Formula A-5) See chart A 31.5 mg of the title product of Preparation Example 2 in 1:1 trifluoroacetic acid-dichloromethane The solution was allowed to stand for 1 hour in a few drops of It drips steadily. The mixture is stirred for 15 minutes and then spun down in a centrifuge tube. . By slurrying and recentrifuging, the solid was dissolved in 1 ether-hexane and 2 Washing twice and drying under high vacuum gives 36 mg of the title product as a white solid.

The physical properties are as follows.

FAB HRMS (m+M)+959.5707IC,, (nM): 0 ．． 35 Example 2 7-Glu-Pro-Phe-(N-Me)His-LVA-11e -AMP N-oxide trifluoroacetate (2A-6) See chart A 1 of 32.8 mg of the title product of Preparation Example 3: 11-IJ fluoroacetic acid-dichloride The solution in a few drops of lolomethane was allowed to stand for 1 hour, then 1:2 ether-hexane 10 Slowly drop into mρ. The mixture was stirred for 15 minutes and then spun in a centrifuge tube. Rotate and let settle. Slurry and re-centrifuge to remove solids at a ratio of 1:2. Washed twice with Rouge Beef San and dried under high vacuum to obtain 40 mg of the title product as a white solid. get as.

The physical properties are as follows.

FAB HRMS (m+M): 975.5655IC, (nM): 1. 0 Preparation Example 4 BOC-(N-Me)His(Ts)-CVG August 19, 1988 Dates were prepared as set forth in U.S. Patent Application No. 234,413. (S)-amino-1-cyclohexyl-3(R),4(S)-dihydroxy -6-methylhebutane 360mg and BOC-(N-Me)His(Ts ) 800 mg diisopropylethylamine in a stirred solution in 5 mQ of dichloromethane. Add 420 μQ followed by 290 μQ of diethyl anophosphonate. reaction mixture Stir the mixture overnight, then use 3o-40% ethyl acetate in dichloromethane. Chromatography on silica gel gives 518 mg of the title product.

Preparation Example 5 Table of BOC-Phe-(N-Me)His(Ts)-CVG Preparation Example 4 The product is de-BOCed with trifluoroacetic acid under standard conditions.

0.8 mmol of this amine and 320 mg of BOC-Phe in di/yoo methane. Add 270μe of diisopropylethylamine to the stirred solution in 3mQ, followed by diethyl silica. Add 190 μQ of anophosphorisolate.

The reaction mixture was stirred overnight and then diluted with 3o-50% ethyl acetate in dichloromethane. Chromatography on silica gel gives the title product.

CVG The title product of Preparation Example 5 is de-BOCed with trifluoroacetic acid under standard conditions.

3 ml of dichloromethane containing 7325 mg of this Ami and 130 mg of BOC-Pro 150 μL of diisopropylethylamine followed by diethyl cyano into the stirred solution. Add 100 μL of phosphonate. The reaction mixture was stirred overnight, then dichloro Chromatography on silica gel using 30-50% ethyl acetate in methane 345 mg of the title product are obtained.

Preparation Example 7 BOC-7-Glu<a-OBn)-Pro-Phe-(NMe ) His(Ts)-cvc The title product of Preparation Example 6 was treated with trifluorocarbon under standard conditions. De-BOC with acetic acid.

50mg of this amine and BOC-G lu (α-OB, n) 25°5m diisopropylethylamine 13 g to a stirred solution in dichloromethane 0.5 mf2 Add 1 μL followed by 12 μL of diethylcyanophosbonate. Add the reaction mixture Stir overnight and then clean on silica gel using 3% methanol in dichloromethane. Chromatography gives 75.6 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1112.574 Preparation Example 8 B OC-7-Glu (α-0Bn)-Pro-Phe-(N-Me) Hi 5 -CVG 74.8 mg of the title product of Preparation Example 7 and 1-hydroxybenzotriazole 3 A solution of 4 mg in a small amount of methanol is left overnight and then concentrated under reduced pressure. Jiku Residual silica in 2-4% methanol (saturated with ammonia) in lolomethane Gel chromatography gives 55.0 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+M): 958.5629 Preparation Example 9 B OC-7-Qlu-Pro-Phe-(N-Me)Hi 5-CVG 53.7 mg of the title product of Preparation Example 8, 53 mg of ammonium formate, and 5% P A mixture of 40 mg of d/C in 0.5 ml of dry dimethylformamide was added under Alcon. Stir overnight at 100 mL, then filter through Celite and concentrate under high vacuum. Dichloro Silica gel using 5-20% methanol (saturated with ammonia) in methane The residue was chromatographed above to give 43.8 mg of the title product as a white solid. get it.

The physical properties are as follows.

'HNMR and FAB HRMS (m+M): 906.4732CVG Piss trifluoroacetate 1:1 of 42.8 mg of the labeled product of Preparation Example 9! J Fluoroacetic acid-cyclo A solution of lomethane in 0.3 ml was allowed to stand for 1 hour, then rapidly stirred in a 1:2 solution. Add to 100ml of Beef Sun. Rotate the precipitated solids to settle them. , washed thoroughly with 1:2 ether-hexane and dried under vacuum to give the title product as white. Obtained as a colored solid.

The physical properties are as follows.

FAB HRMS (m+M): 768.4677HPLC (90/10 meta /-ru/ N a Ht P O4-hydrate 5.22 g and Pludic a Burdick & Jackson 85% refill in water 4Q Aqueous phosphate buffer containing 0.76 mQ of phosphoric acid, 225 nm) k': 11. 3 I Cso (nM): 0.41 Preparation Example 10 BOC-Hi 5(Ts)-CVG Application filed on August 19, 1988 2(S)-A, prepared as described in U.S. Patent Application No. 234,413, Mino-1-cyclohexyl-3(R),4(S)-dihydroxy-6-methy 230mg of hebutane, and 500mf2 of BOC-His (Ts) o.

To a stirred solution in 5 ml of methane was added 270 µQ of diisopropylethylamine followed by diisopropylethylamine. Add 190 μQ of ethylthia/phosphonate. The reaction mixture was stirred overnight and then Chromatography on silica gel using 30-40% ethyl acetate in dichloromethane at 322 mg of the title product are obtained.

Preparation Example 11 BOC-(OMe)Tyr-His(Ts)-CVG Preparation Example 10 The title product is de-BOCed with trifluoroacetic acid under standard conditions.

0.5 mmol of this amine and 228 mg of BOC(OMe)Tyr To a stirred solution in 3 mQ of lomethane was added 170 μQ of diisopropylethylamine followed by diisopropylethylamine. Add 120 μe of ethyl cyanophosphonate. The reaction mixture was stirred overnight and then Chromatograph on silica gel using 3-5% methanol in dichloromethane at Raffy gives the title product.

CVG DeBOC the title product of Preparation 11 with trifluoroacetic acid under standard conditions. .

7354mg of this amide and 14omg of dichloromethane 200 μC of diisopropylethylamine followed by diethyl Add 110 μe of cyanophosphonate. The reaction mixture was stirred overnight and then diluted with Chromatography on silica gel using 30-50% ethyl acetate in chloromethane Firing gives 374 mg of the title product.

Preparation Example 13 BOC-7-Glu (α-0Bn)-Pro-(OMe)Ty r-His (Ts) - The labeled product of CVG Preparation Example 12 was prepared under standard conditions. , de-BOC with trifluoroacetic acid.

Dichloromethane of 50 mg of this amine and 25 mg of BOC-Glu (α-OBn) 0.5 m of lomethane (diisopropylethylamine O, E + mQ, Subsequently, 12 μQ of diethyl cyanophosphonate is added. reaction a = stir things overnight and then chromatography on silica gel using 3% methanol in dichloromethane. Graphing gives 67.5 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+M): 1128.567 Preparation Example 14 BOC-7-Glu　(a-OBn)-Pro-(OMe)　Yr　-H i 66.8 mg of the title product of 5-CVG Preparation Example 13 and 1-hydroxyben A solution of 32 mg of zotriazole in a small amount of methanol was left overnight and then under reduced pressure Concentrate with 2-4% methanol (saturated with ammonia) in dichloromethane Silica gel chromatography of the residue using silica gel yielded 52.1 mg of the title product. get.

The physical properties are as follows.

'HNMR and FAB HRMS (m+M): 974.5599 Preparation Example 15 BOC-7-Glu7Pro-(OMe)Tyr-His-CVG 51.0 mg of the title product of Preparation Example 14 and ammonium formate F) Omg, and 40 mg of 5% palladium on carbon and 0.5 m of dry dimethylformamide (in 2 The warm mixture was stirred under argon overnight, then filtered through Celite and concentrated under vacuum. Shrink. Residue on silica gel using 5-10% methanol in dichloromethane Chromatography of the residue gives 42.4 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+M): 884.5117 17- G　u-P　r　　　-(OMe)　Ty　r　-Hi　-CVG　Pi Trifluoroacetate 41.8 mg of the title product of Preparation 15 in 1:1 trifluoroacetic acid-dichloromethane The solution in 0.3 ml of water was allowed to stand for 1 hour, and then stirred rapidly. Slowly drip into 10m12. The precipitated solid is spun down and ether - Thoroughly wash with beef sanitation and dry under high vacuum to obtain 46 mg of the listed product as a white solid. and get it.

The physical properties are as follows.

FAB HRMS (m+H) Near 84.4582I C,. (nM): 0 ．． 19 Preparation Example 16 BOC-β-Val-Phe-(M-Me)His(Ts ) -LVA -I 1 e -AMP N-oxide (2B-5) See chart B 101 mg of the peptide of 2B-2 and 38 mg of m-chlorobenzoic acid in dichloromethane The solution/suspension in 1 ml of methane was stirred overnight and then saturated aqueous sulfite l-IJ Quench with a few drops of umum. Carefully pump off the solution and dissolve the residue in dichloromethane. Chromatography on silica gel using 4-10% methanol in 53.2 g of the title product are obtained as a yellow solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m-4-H): 1102.　e　O.

Preparation Example 17 BOC-β-Va I-Phe-(N-Me)His-LV A-11e-AMP N-oxide (Formula B-6) See chart B 52.1 mg of the title product of Preparation Example 16 and 1-hydroxybenzotriazole A solution of 26 mg in a small amount of methanol is left overnight and then concentrated under reduced pressure. Ji 4 to 6 to 7% methanol (saturated with ammonia) in chloromethane Chromatography of the residue on silica gel gave the title product 20.7m get g.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 948.5913 HPLC (9 5.22 g of 0/10 methanol/NaH,PO,-hydrate and Pludic Aqueous phosphorus containing 0.76ml of 85% phosphoric acid in 4Q of And Jackson Water Acid buffer, 254 nm) k': 8.0 Example 5 β-Va 1-Phe-(N-MeHis)His-LV A-11e-AMP N-oxide tristrifluoroacetate (2B-7) See chart B 20.2 mg of the title product of Preparation 17 in 1:1 trifluoroacetic acid-dichloromethane The solution in 0.3 mQ of water was allowed to stand for 1 hour and then poured into rapidly stirred 1:1 ether-helical solution. Drop into 10 mQ of xane. The mixture was stirred for 15 minutes, then transferred to a centrifuge tube and spun. Rotate and let settle. by slurrying in ether-hexane and recentrifugation. The solid was washed three times under high vacuum and then dried under high vacuum to give 22 mg of the title product as a white solid. Get it as a body.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 848.54011C,. (n M): 2.3 H’PLC (9’O/10 methanol/NaH2PO, -hydrate 5.22g and and 0.76 m of 85% phosphoric acid in Prudick and Jackson Water 412. Containing aqueous phosphate buffer, 254 nm) k': > Preparation Example 18 H-CVA-M ba hydrochloride 19-9 BOC-CVA (O TBS)-oHl. 5 g, and 0.45 mQ of 2(S)-methylbutylamine. Diisopropylethylamine was added to a stirred solution in 12 mL of dichloromethane (2 mL). 8mQ followed by diethylcyanophosphone ho. Add 5ml. reaction mixture Stir the mixture overnight and then rinse with silica gel using 10-20% ethyl acetate in hexane. Chromatography on a column gives the coupled product.

This material in 20 mσ ether was saturated with gaseous hydrogen chloride - then the volatiles were removed. Remove under a stream of nitrogen and dry the residue in vacuo to obtain 1.2 g of the title product.

Preparation Example 19 BOC-(N-Me)His(Ts)-CVA-Mba Preparation Example 18 75.4 mg of labeled product and BOC-(N-Me)His(Ts) 102 mg of diisopropylamine ethyl methane 1.5 m & 80 m of diisopropylamine ethyl to medium stirred solution Add 1 μL followed by 37 μL of diethyl cyanophosphonate. Add the reaction mixture Stirred overnight and then purified on silica gel using 70-80% ethyl acetate in hexane. Flash chromatography gives 106 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H) Near 46.4527 Preparation Example 20 BOC-Phe-(N-Me)His(Ts)-CVAMba The title product of Preparation 19 was dissolved in trifluoride in dichloromethane according to standard procedures. De-BOC with acetic acid.

1 ml of dichloromethane containing 730 mg of this amino and 50 mg of BOC-Ph 32μQ1 of diisopropylethylamine followed by diethyl cyano Add 28 μQ of phosphonate. The reaction mixture 6 If was stirred overnight and then dichloromethane was added. Flash chromatography on silica gel using 70% ethyl acetate in lomethane 87 mg of the title product are obtained.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 893.5207 Preparation Example 21 BOC-β-Va 1-Phe-(N-Me)His(Ts)-CVA-Mb a The title product of Preparation 20 was dissolved in trifluoride in dichloromethane according to standard procedures. De-BOC with acetic acid.

0.10 mmol of this amine and 25.4 mg of BOC-73-Val Add 20 μL of diisopropylethylamine to a stirred solution in 0.8 m of chloromethane (1 Subsequently, 18 μL of diethyl cyanophosphonate is added. Stir the reaction mixture overnight and then flashing on silica gel using 80% ethyl acetate in dichloromethane. Shumatography gives 93.1 mg of the title product.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 992.5881 Preparation Example 22 BOC-β-Va 1-Phe-(N-Me)His-CVA-Mba 91.8 mg of the title product of Preparation Example 21 and 1-hydroxybenzotriazole A solution of 50 mg in a small amount of methanol is left overnight and then concentrated under reduced pressure. Ji Silica gel using 5% methanol (saturated with ammonia) in chloromethane Silica gel chromatography of the above residue gave 68 mg of the title product as a white solid. Get it as a body.

The physical properties are as follows.

'HNMR and FAB HRMS (m1M): 838.7592Mba tri fluoroacetate L of 64.7 mg of the labeled product of Preparation Example 22: 1)'J Fluoroacetic acid-di A solution in 0.4 ml of chloromethane was allowed to stand for 1 hour and then stirred rapidly 1: 4. Slowly drip into the beef san. Simply remove solids by centrifugation. Separated, first reslurried in 1:4 ether-hexane, then spun to settle. Clean by letting. After drying the product under vacuum, the named product 65m get g.

The product is soluble in water and collapses upon addition of aqueous sodium bicarbonate, pH 7. Redissolve upon addition of phosphate buffer.

The physical properties are as follows.

FAB HRMS (m+H) Near 38.5247 ICio (nM): 0 ．． 41 Preparation Example 23 BOC-Phe-(N-Me)His(Ts)-CVA-11 e-AMP PCT Patent Application PCT/US8910 O24 filed January 27, 1989 H-(N-Me)His(T5)-CVA prepared as described in 7. -1] 0.98 mmol of e-AMP and 392 mg of BOC-Phe 260 µL of diisopropylethylamine in a stirred solution in 4.9 mL of lolomethane. Subsequently, 230 μL of diethyl cyanophosphonate is added. Stir the reaction mixture overnight. Stir and then clean on silica gel using 3-6% methanol in dichloromethane. Chromatography gives 587 mg of the title product. Further elute the column 301 mg of the recovered amine is obtained. The proposed structure of the indicated compound is 'HN Supported by MR.

Preparation Example 24 BOC-β-Va 1-Phe-(N-Me)His(T s) -CVA-11e-AMP Preparation Example 23 labeled product according to standard procedure It is therefore de-BOCed with trifluoroacetic acid in dichloromethane.

90.4 mg of this amine and BOC-β-Va,! 26mg dichloromethane 0.75 m (20 μL of diisopropylethylamine followed by diethyl Add 18 μL of lucianophosphonate. The mixture was stirred overnight and then dichloromethane Chromatography on silica gel using 3-5% methanol in lomethane 17 mg of the title product L are obtained.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1126.638 Preparation Example 25 BOC-β-Va I-Phe-(N-Me)Hi 5-CVA-11e -AMP 0.10 mmol of the named product of Preparation Example 24 and 1-hydroxybenzotria A solution of 53 mg of Sol in a small amount of methanol was left overnight and then concentrated under reduced pressure. Ru. With 2-5% methanol (saturated with ammonia) in dichloromethane Silica gel chromatography of the residue on silica gel yielded the title product 74. ．． Get 7 mg.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 972.6314 Preparation Example 25 23.0 mg of the indicated product 1:1 IJ fluoroacetic acid-cyclomethane The solution was allowed to stand for 1 hour in a few drops of 1,2 ether-hexane, then rapidly stirred. Slowly drop into orrN2.

The precipitated solid was spun down, washed twice with 1:2 ether-hexane, and Drying under vacuum gives 26 mg of the title product as a white solid. The solid is water and Soluble in pH 7 phosphate buffer.

The physical properties are as follows.

FAB HRMS (m+H): 872.5787IC,, (nM): 0 ．． 29 Preparation Example 26 BOC-β-Va I-Phe-(N-Me)His-CV A-11e-AMP N-oxide 49.5 mg of the title product of Preparation Example 25 and A solution of 11.8 mg of m-chlorobenzoic acid in a small amount of dichloromethane was prepared at room temperature for 3 hours. Stir and then add 4-7% meth (saturated with ammonia) in dichloromethane. Direct chromatography on silica gel using 37. Obtain 3 mg as a white solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 986.6218HPLC (9 0/10 methanol/Na HtP O4-hydrate 5.22g and pull Contains 0.76 mQ of 85% phosphoric acid in Dick & Jackson Water 4e aqueous phosphate buffer, 254 nm) k': 9.6゛ Example 8 β-Va I-Phe-(N-Me) Hi 5-CVA-11 e-AMP N-oxide tristrifluoroacetate A small amount of 35.9 mg of the title product of Preparation Example 26 1:1) IJ fluoro vinegar The acid solution in dichloromethane was allowed to stand for 1 hour, then rapidly stirred and dissolved in 2 ether. - Slowly drip into 10 ml of hexane. Sedimentation of precipitated solids by rotation washed twice with 1:2 ether-to-beef sanitation and dried under high vacuum to give the title product. Obtain 39 mg as a white solid. The solid is soluble in water and phosphate buffer at pH 7. It is.

The physical properties are as follows.

FAB HRMS (m+H): 888.5736I Cs. (nM): 0 ．． 43 Preparation Example 27 Benzyl glyoxylate (Formula C-2) See chart C 761 mg of glyfuric acid in C-1 was converted to 3 mQ of acetonitrile with the help of heating. dissolve. The solution was diluted with 10 ml of dichloromethane (!) and 4-dimethylamino 122 mg of nopyridine, 3.1 ml of benzyl alcohol, and diisopropylene 1.72 ml of carbodiimide are added. Stir the mixture over the weekend, The solvent is then removed under a stream of nitrogen. Slurry the residue in ether and filter Then wash the filtrate with a small amount of dilute hydrochloric acid and brine, and dry (magnesium sulfate). . Remove the solvent under reduced pressure and transfer the fluoride onto silica gel using 60% ether-oxane. Apply residue to Rano/Uchromatography to remove slight Hensyl alcohol. 1.57 g of pure product are obtained as a colorless oil.

The physical properties are as follows.

'HNMRδ: 2.48.4.21.5.24.7.4 Preparation example 28 (benzyl oxycarbonyl) methyl di-tert-butyl phosphate (formula C-3) 500 mg of the title product of Reference Preparation 27 and IH-Tetrazole 422 mg of phosphoramidite reagent in solution/suspension in dry tetrahydrofuraf 3-Q. 0.84 ml is added under argon. It generates heat and soon the tetrazole dissolves. do. After 2 hours, m-cube was added with water cooling near the end of the addition to suppress the exothermic reaction. A solution of 570 mg of lolobenzoic acid in dichloromethane AmQ is added slowly.

The reaction mixture was subjected to aqueous work-up with a sodium bisulfite wash and the material was Flash chromatography on silica gel using % acetone-dichloromethane 978 mg of the title product are obtained as a colorless oil.

The physical properties are as follows.

'HNMRδ: 1.48.4.55.5.23.7.4FAB HRMS (m +H): 359.1652 Preparation Example 29 Carboxymethyl di-tert-phosph rate (formula C-4) see chart C 575 mg of the title product of Preparation Example 28 under hydrogen at 60 ps i ethanol SmQ The medium solution was shaken overnight with 5% palladium on carbon, then filtered through Celite. pass iI under reduced pressure! Concentrate the liquid to obtain 293 mg of the title product as a colorless oil. .

The physical properties are as follows.

'HNMRδ: 1.49.1.51.4, 54.8.6alu Example 30 Vinyl vinegar Benzyl acid (Formula D-2) Refer to chart D Vinyl acetic acid 5m (2, benzyl alcohol 5.7 mQ of dichloromethane, and 0.61 g of 4-dimethylaminopyridine. 50 m (dacarbazine in a stirred solution in 2, 8, 2 Add mQ via addition funnel over approximately 45 minutes. This addition makes the solution mild. It boils quickly. After 18 hours, the mixture was filtered from diisopropylurea and the filtrate was Concentrate under reduced pressure. Ether-hexane was added to the residue and the mixture was filtered again. do. The m solution was washed with dilute acid and dilute base, dried (magnesium sulfate), and dried under reduced pressure. to obtain a yellow source. Distillation under high vacuum through a short column (boiling point 80~ 82°/approx. 0.1 mmHg) to obtain 8.94 g of the title product as a colorless liquid. Ru.

The physical properties are as follows.

'HNMRδ: 3.14.5.14.5.16~6.20.5.88~ (Formula D -3) See chart D Under argon, in a flame drying room with a septum rubber lid (borane - Tetrahydrofuran (only LM) 25rrH2 is added by rinsing. stir The solution was cooled in a water bath and 3.53 g of 2-methyl-2-butene was added to the dry solution. Add solution in trahydrofuran BmQ via cannula over approximately 15 minutes. do. Following the addition, the clear solution was warmed to 0.000 and continued until the quenching was complete. Hold it there. After 90 minutes, 4.41 g of the title product of Preparation Example 30 (blunt material) was added to 20 The mixture is stirred for an additional 30 minutes at o'c. Then water Carefully add 1 mQ followed by 8.3 mQ of 30% hydrogen peroxide and 3N hydroxide. Add 9.3 mQ of sodium mixture. The mixture was extracted three times with ether and Wash the organic phase with dilute base and dry with sodium sulfite (magnesium sulfate) under reduced pressure. Concentrate with On silica gel using 50-100% ether-pentane. Flash chromatography of the residue yielded 2.21 g of the title product as a colorless oil. and get it.

The properties of the object are as follows.

'HNMRδ: 1.61, 1.91, 2.50.369.513, g case law 32 3-(hensyloxycarbonyl)propyl di-tert-butyl phosphate (Formula D-4) 777 mg of the product described in Chart D Preparation Example 31 and IH-tetra A solution/suspension of 560 mg of phosphoramide in dry tetrahydrofuran mQ Add 1.15 ml of Deight reagent. It generates heat and the tetrazole soon dissolves. Understand. After 18 hours, while cooling on ice near the end of the addition to suppress the exothermic reaction, Slowly add a solution of 812 mg m-chlorobenzoic acid in 6 mf dichloromethane. do. The reaction mixture was worked up aqueous with a sodium bisulfite wash and the material was concentrated between 5 and 10 Flash chromatography on silica gel using % acetone-dichloromethane 1.46 g of the title product are obtained as a colorless oil.

The physical properties are as follows.

'HNMRδ: 1.47.1.51.2.0.2.51.4.0.5°12.7 ．． 4 FAB-HRMS (rr++H): 387.1944 Preparation Example 333-carbo Xypropyl di-tert-butyl phosphate (Formula D-5) See chart D light A solution of 155 mg of the named product of Preparation Example 32 in 2 ml of ethanol at 60 ps i Shake overnight with 5% palladium on carbon under hydrogen and then pass through Celite. Filter. Concentrate the filtrate under reduced pressure to obtain 100 mg of the title compound as a colorless oil.

The physical properties are as follows.

'HNMRδ: 1.47.1.53.2.0.2.5.4.0.7.3 Preparation Example 34 (t-Bu○), P (0) OCR, C〇-Pro-Phe-(N- Me) Hi 5-LVA-11e-AMP (Formula E-2) See chart E 83 mg of the peptide of formula E-1 and 54 mg of the acid of C-4 of Preparation Example 29 in dichloromethane. Add 19 μL of diisopropylcarbodiimide to the solution in 0.6 r+l of lomethane. Ru. After 18 hours, the reaction mixture was dissolved in dichloromethane (saturated with ammonia). Direct chromatography on silica gel using 4-6% methanol 55.3 mg of the above product are obtained as a white solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1080.622 Preparation Example 35 (t''-Bu, O), P(0)'OCH, C○-Pro-Phe -(N-Me ) Hi 5-LVA-I l e-AMP'N-oxide (Formula E-3) Product 48.1 of Reference Preparation Example 34 in Chart E. mg and m-chlorobenzoic acid , a 10 mg solution was stirred for 2 hours and then quenched with a few drops of aqueous sodium bisulfite. Chi. The solvent was removed by pumping and the solution was dissolved in dichloromethane (saturated with ammonia). ) Chromatography the residue on silica gel using 4-6% methanol. Product 31. ,7. mg is obtained as a white image.

The physical properties are as follows.

'HNMR and FAB HEMS (m+H): 1096.621 Example 9- (HO), P (0) OCR, Co-Pro-Phe-(N-Me) Hi 5 -LVA-I l e-AMP bishydrochloride (formula E-4) chart E The solution containing 20.2 mg of the product described in Preparation Example 34 in 0.5 m of 4M hydrochloric acid was allowed to stand for 1 hour. and then remove the solvent via a potassium hydroxide trap under high vacuum. residue Dissolve in absolute alcohol, then carefully pump out and repeat the process for 1 Repeat times. The residue was then dissolved in water and the solution lyophilized to give the title product 18. Obtain 5 mg as a flocculent white solid.

The physical properties are as follows.

FAB HRMS (m+H): 956.5042HPLC (90/10 methanol 5.22 g of NaHtPOa-hydrate and Pludic and Jacques Aqueous phosphate buffer containing 85% phosphoric acid 0.76 mρ in Son's water 4Q, 254 nm)K”.

1.7 (N-Me) Hr 5-LVA-IIe-AMPN-oxide bis hydrochloride (Formula E-5) See chart E A solution of 47 mg of the title product of Preparation Example 35 in 1 mf2 of 4M hydrochloric acid was allowed to stand for 1 hour, and then The solvent is then pumped under high vacuum through a potassium hydroxide trap; Repeat the principle once. The residue was dissolved in absolute ethanol, which was then dissolved in water, The solution is lyophilized to give 41 mg of the title product as a flocculent white solid.

The physical properties are as follows.

FAB HRMS (m+H): 984.4945HPLC (90/10 methanol 5.2 g of Sol Z Na Hz p O4-hydrate and Prudick &amp; Aqueous phosphate buffer containing 0.76 mf2 of 85% phosphoric acid in Jackson Water 412 liquid, 254nm) k': 1.7 IC,o (nM): 2.5 Preparation Example 36 (t-BuO), P(0)O(CH,), C0-Pr.

-Phe -His (Ts) -LVA-I l e -AMP No. 07/147,073, filed January 20, 1988; As described in published European patent application no. 017348L, published on March 5, 986 Pro-Phe-His (Ts)-LVA-II prepared as needed e-AMP, 98.4 mg of a tosyl-protecting group analog of the peptide of formula A-1, and and a stirred solution of about 0.3 mmol of the acid of formula D-5 of Preparation Example 33 in dichloromethane LmQ. Add 35 μL of diisopropylethylamine to the solution, followed by diethyl shea/phosphonate. Add 20 μL. The reaction mixture was stirred overnight and then diluted with 4- The title compound was chromatographed on silica gel using 7% methanol. 106 mg are obtained as a tan foam.

The physical properties are as follows.

'HNMR and FAB HRMS (m-'', H): 1262 Preparation Example 37 (t Bud)yP (○) O(CHt) 3co Pr.

-Phe -Hi 5-LVA-I 1 e-AMP Preparation Example 36 Product 3 1.6 mg and a small amount of methanol, 11 mg of 1-hydroxybenzotriazole The solution in the bottle is allowed to stand overnight and then concentrated under reduced pressure. (Ammo in dichloromethane) Chromatography on silica gel using 5-7% methanol (saturated with 32.1 mg of product is obtained, which is an unidentified silicon-derived product. It is a desired compound that contains natural contaminants.

The product was separated from the contaminants by rechromatography to yield 15.8 mg of Get a payback.

The physical properties are as follows.

'HNMR and FAB HRM'S (m+H): 1108.654 Example 11 (HO) 2P (0) ○ (CH2) 3CO-P r o -Phe-Hi s-LVA-I Ie-AMP bishydrochloride 15.5 mg of the title product of M Preparation 37 in tetrahydrofuran. , 25ml/l solution Add 0.25 mC of 8M hydrochloric acid to the solution. After 1 hour, pass through the potassium hydroxide trap. The solvent was removed by pumping under high vacuum, the residue was dissolved in water, lyophilized and expressed as 14.8 mg of product are obtained as a white solid.

The physical properties are as follows.

FAB HRMS (m+H): 996.5354I Cso (nM): 0.45 Preparation Example 38 (t-Bud), P(0)O(CH,), C0-Pr.

-Phe-Hi 5(Ts)-LVA-I Ie-AMPN-oxide 38.1 mg of the title product of Preparation Example 36 and 12 mg of m-chlorobenzoic acid The solution in 0.3 mQ of lolomethane was allowed to stand for 2 hours and quenched with solid sodium sulfite. do. Mixture on silica gel with 3-7% methanol in dichloromethane Chromatography gives 27.8 mg of the title compound as a white solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1278 Preparation Example 39 (t- Bud), P(0)O(CH,), C0-Pr.

-Phe-His-LVA-11e-AMP N-oxide 25.7 mg of the title product of Preparation 38 and 1-hydroxybenzotriazole A solution of 11 mg in a small amount of methanol is left overnight and then concentrated under reduced pressure. Ji Silica using 5-8% methanol (saturated with ammonia) in chloromethane The residue was subjected to silica gel chromatography on Kagel and the title compound was 18.0m get g.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1124.652 Example 12 (HO)2P(0)O(CH2) 3C○-Pro-Phe-His-LVA- 11e-AMP N-oxide bis hydrochloride Solution of 14.9 mg of the title product of Preparation Example 39 in 0.25 rJ of tetrahydrofuran Add 0.26% of 8M hydrochloric acid to the solution. After 1 hour, via a potassium hydroxide trap, The solvent was pumped off and the residue was dissolved in water and lyophilized to give the title product 11.0 m g as a white solid.

The physical properties are as follows.

FAB HRMS (m+H): 1012.534I C=o (nM): 1.9 Preparation example 40 (t-Bud), P (0) OCH, CO-Phe-(N-Me) Hi s (Ts) -LVA-11e -M P No. 07/147,073, filed January 20, 1988; Described in published European patent application no. 017481, published on March 5, 986 H-Phe-(N-Me)His(Ts)-LVA-IL prepared in 124 mg of e-AMP, and about 0.25 mmol of formula C-4 acid of m11129 49 μL of diisopropylethylamine was added to the stirred solution in 1 mQ of dichloromethane. Subsequently, 26 μL of diethyl cyanophosphonate is added. Stir the reaction mixture overnight and then crystallization on silica gel using 3-6% methanol in dichloromethane. 129 mg of the title compound are obtained by chromatography.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 1137.581i (t- Bud), P (0)○CH, CO-Phe-(N-Me) Hi 5-LVA -I l 36.1 mg of the title product of e-AMP Preparation Example 40 and 1-hydro A solution of 13 mg of xybenzotriazole in a small amount of methanol was left overnight and then Concentrate under reduced pressure. 5-7 in dichloromethane (iH with ammonia) Expressed by silica gel chromatography on silica gel using % methanol 13.2 mg of compound are obtained as a white solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 983.5724 Example 13 (HO)=P (0)OCH*COPhe (NMe)His-LVA-11 e-AMP Bis Hydrochloride Preparation Example 41 13 mg of 4M hydrochloric acid 0.5 mf2 The medium solution is allowed to stand for 90 minutes and then evaporated to dryness under nitrogen. Dissolve the residue in water, This solution is lyophilized to give 12.5 mg of the title product as a white solid.

The physical properties are as follows.

FAB HRMS (m+H): 871.83I C3o (nM): 1 :5 Preparation example 42 (t B uo) tP (0) 0CHtC〇-Phe-β-A sp(α-0Bn)-LVA-I 1e-AMP dated October 11, 1988 As stated in the PCT patent application PCT/U S88103436 H-Phe-β-Asp(α-0Bn)-LVA- of formula G-1 prepared in 17 mg of IIe-AMPl, and about 0.3 mg of the 2C-4 acid of Preparation Example 29. in 0.5 ml of rimole dichloromethane and 0.7 mQ of dimethylformamide Add 31 μL of diisopropylethylamine to the stirred solution followed by diethylcyanophospho Add 27 μL of nate. The reaction mixture was stirred overnight and then dissolved in dichloromethane. chromatography on silica gel using 3-8% methanol of 78.0 mg of the compound is obtained.

The physical properties are as follows.

IHNMR and FAB HRMS (m+N): LO37 Preparation Example 43 (t- Bud), P(0)OCH, Co-Phe-β-As p-LVA-Tl e - 77 mg of the product described in AMP Preparation Example 42, 50 mg of ammonium formate, A mixture of 40 mg of 5% palladium and 1 mQ of dimethylformamide on Oyohi carbon. Stir under argon for 2 days, then filter through Celite and concentrate under vacuum. . Chromatog on silica gel using 5-15% methanol in dichloromethane Ruffy the residue to obtain 33.3 mg of the title product as a white solid.

The physical properties are as follows.

'HNMR and FAB HRMS (m+H): 947 Example 14 (HO) , P(0)CH,C0-Phe-β-Asp-LVA-11e-AMP hydrochloride A solution of 33.3 mg of the title product of Example 43 in 0.4 mQ of tetrahydrofuran Add 0.2 m of concentrated hydrochloric acid. After 45 minutes, remove the volatiles with a pump and pour the residue into water. Redissolve in and lyophilize to give 25.8 mg of the title product.

The physical properties are as follows.

FAB HRMS (m+H): 873.3:+56P h e -(N-M e)His(Ts)-CVG dated August 19, 1988 H-Pro-Phe- prepared as described in patent application no. (N-Me)His(Ts)-CVG 50mg and Formula C- of Preparation Example 29 A stirred solution of about 0.2 mmol of the acid No. 4 in 0.2 ml of dichloromethane was dissolved in diisopropylene. Add 13 μL of pyrucarbodiimide. After 24 hours, the mixture was diluted with 3-5% methane. Chromatography on silica gel with alcohol-dichloromethane yielded the indicated compound. 37.1 mg of product are obtained as a white foam.

The physical properties are as follows.

'HNMR and FAB HRMS (m-i-H): 1043 525 Preparation Example 4 5 (t-Bud) 2P (○) OCH, Co-Pro-Phe -(N-M e) 37 mg of the title product of Hi 5-CVG Preparation Example 44 and 1-hydroxyhydrogen A solution of 20 mg of cintriazole in a small amount of methanol was allowed to stand overnight and then reduced under reduced pressure. Concentrate below. 4-6% methano (saturated with ammonia) in dichloromethane Chromatography of the residue on silica gel using ．． Obtain 4 mg as a white solid.

The physical properties are as follows.

IHNMR and FAB MS (m+H): 889 Example 15 (HO), P(0)OCH, Co-Pro-Phe-(N-Me)Hi 5-CVA hydrochloric acid salt A solution of 19.2 mg of the title product of Preparation Example 45 in a small amount of 4M hydrochloric acid was allowed to stand for 75 minutes. , and then pump off the solvent. Dissolve the residue in 1 tsp of anhydrous Metcool and add this Carefully pump out; repeat this process once. Dissolve the residue in water , the solution is lyophilized to give 16.9 mg of the title product as a flocculent white solid.

The physical properties are as follows.

FAB HRMS (m+H): 777°3956I C6o (nM): 3.4 3111 Example 45 Ethyl 3-ami/-3,3-dimethylpropanoate (Formula F-2) See chart F 641 mg of ethyl dimethylacrylate was added to 10 m of a saturated ethanol solution of ammonia. Dissolve in f2. Thick-walled glass containers that can be sealed with Teflon Ace thread plugs Contain in The solution was cooled to -15° in an ice-salt bath and poured into a leftcher bottle. Re-saturate with ammonia. The test tube is sealed and heated behind safety equipment. Heat to 80℃. After 22 hours, the test tube was cooled and purged with nitrogen to remove the ammonia. Remove most of the near. Removal of residual solvent under reduced pressure yielded the title product 645m g is obtained, which is contaminated with a small amount of starting material.

The physical properties are as follows.

'HNMRl, 23; 1.30; 1.65; 2.39; 4.15al146 3 -butyloxycarbonylamino-3,3-dimethylpropanoate ethyl (2F- 3) 645 mg of the labeled product of Chart F Preparation Example 45 in 10 mQ of dichloromethane Add 970 mg of BOC anhydride to the solution. After 3 days, concentrate the solution and remove the cruelty. Chromatography on silica gel using 10% ethyl acetate in tin 880 mg of the title product are obtained as a colorless oil.

The physical properties are as follows.

'HNMR' 1.26; 1.38: 1.44: 2.67; 4.13; 4. 9 Preparation Example 47 3-Butyloxycarbonylamino-3,3-dimethylpropanoic acid ( 2F-4) Chart F Reference Preparation Example 46 491 mg (2,00 milligrams) 2.2 mg of 1M potassium hydroxide was added to a solution of Add. Stir the mixture vigorously overnight, then remove the tetrahydrofuran under nitrogen. do. The remaining aqueous phase is washed once with dichloromethane and then acidified. White The precipitate was extracted with three portions of dichloromethane and the combined organic phases were dried over magnesium sulfate. Dry and concentrate under reduced pressure to yield 358 mg of the title product as a colorless oil.

The physical properties are as follows.

'HNMRl, 41; 1.46; 2.75 Preparation example 48 3-butyloxycarbo Nylamino-3,3-dimethylprop/yl-Phe-Asp (a-OBn) -LVA-Mba　(Formula G-2; R3, is Mba) See chart G 12.2 mg of the labeled product of Preparation Example 47 and H-Phe-A”Sp of 20-2 (OBn)-LVA-Mba (in the formula, R30 is Mba) 28゜1mg dichloride 10 μL of diisobutylene ethylamine and a stirred solution in Lofuran O, AmQ. Add 19 μQ of diethylphosphoryl.

After 18 hours, the mixture was purified using 2-3% methanol in dichloromethane. Chromatography on a column gave 40.9 mg of the title product as a yellow solid. Ru.

The physical properties are as follows.

'HNMRo, 7-0.9. 1.0 to 1.6. 2.38. 2.5-3.7 ．． 4.7. 5.0. 7.1~7.3FAB MS (m+H)-853 Preparation Example 493-Butyloxycarbonylamine/-3,3-dimethylpropanoyl -Phe-Asp (a-OBn)-LVA-I Ie-AMP (Formula G2: Rso is Ile-AMP) See chart G 28 mg of the title product of Preparation Example 47 and H-Phe-Asp(OBn)-LVA -11e-AMP 78.8 mg dikuoo methane 0.7 mQ and dimethyl fluoride Diisopropylethylamine 21 μσ and and 18 μC of diethylphosphoryl. After 18 hours, the mixture was dissolved in dichloromethane. Chromatography on silica gel using 4-6% methanol in Notation product 82,! Obtain 5 mg as a white solid.

The physical properties are as follows.

IHNMRO, 7-0.9. '1.10. 1.15. 1.2~1.8°2. 39. 2.5-2.8. 4.3-4.5. 5.1. 7.0-7.5.　 8゜FAB MS (M+H)=987 987 preparation 3-butyloxycarbonylamino-3,3-dimethylpropanoy Lu-Ph e-(N-Me)His(Ts)-LVA-Mba (formula B-2: Rto is M b a) See chart B 31.5 mg of the title product of Preparation Example 47 and H of formula B-1 where R6° is Mba -Ph　e　-(N-Me)His(Ts)-LVA-Mb　ao, 12 Millimoles of chlorofuran 1. To the stirred suspension in Oma/isopropylethyl alcohol Add 25 μQ of amine and 23 μQ of diethylphosphoryl. After 18 hours, mix Expressed by flash chromatography on silica gel with ethyl acetate 114 mg of product are obtained as a yellowish porridge.

The physical properties are as follows.

'HNMRo, 5-1.6. 1.83. 2.0. 2.20.　2.57゜ 2.9~3.0.68~7.6 FAB HRMS (m+H)=952.5593 Preparation Example 513-Butyloxy Carbonylamino-3,3-dimethylprop/yl-Phe-(N-Me)Hi 5(Ts)-LVA-r　e-AMP (Formula B-2:R, . is Ile-AM P) See chart B 2B-1 in which 24 mg of the title product of Preparation Example 47 and R3° is Ile-AMp H-Phe-(N-Me)His(Ts)-LVA-IIe-AMP A stirred solution of 91.2 μmol/diisopropyl ether in 0.9 ml of chloromethane was added overnight. Add 19 μQ of thylamine and 17 μQ of diethylphosphoryl. 18 hours later , the mixture was chromatographed on silica gel using 3-5% methanol in dichloromethane. Matography gives 84 mg of the title product as a white solid.

The physical properties are as follows.

'HN M R0, 6-1.8. 1.8-3.6. 2.38. 2.76 ゜4.4～4.6. 7.0-7.9. 8.49FAB’HRMS (m+ H)=1086.616 Preparation Example 523-Butyloxycarbonylamino-3,3 -dimethylpropanoyl-Phe-Asp-LVA-Mba (formula G-3, R3, is Mba) See Chart G, H at 60 psi, below, labeled product of Preparation Example 48 A small solution of 43 μmol in methanol with about 30 mg of 5% Pd/C for 18 hours. Shake and then filter through Celite. Concentrate the filtrate under reduced pressure and extract the residue. Chromatography on silica gel using 4-14% methanol in lolomethane 28.9 mg of the title product are obtained as a white solid.

The physical properties are as follows.

FAB HRMS (m+H)=800.4571HPLC (70/30 methane 5,22 g of N a H2P O4-hydrate and Prudic and - Aqueous phosphate buffer containing 0.76 m& of 85% phosphoric acid in Jackson Water 4Q ;225nm) k'-Tylpropanoyl-Phe-Asp-LVA-AMP (Formula G-3: R3, is Ile-AMP) See chart G 82 mg of the title product of Preparation Example 49, 53 mg of ammonium formate, and 5% Pd. /C30mg dimethylformamide 0. Stir overnight under compound lucon in SmCmC. Stir. At this point, the mixture is solid and enough methanol is added to The fluidity is restored and the mixture is stirred for a further 4 days. Pass the mixture through celite Filter and concentrate the filtrate under reduced pressure. Silica at 5-15% in dichloromethane Chromatography of the residue above gave 69.4 mg of the title product as a white solid. get it.

The physical properties are as follows.

'HNMRo, 6-0.9. 1.02. 1.08. 1.31. 1.6～ 1, 9. , 2.2-2.8. 4.2-4.6. 7.0-7.2. 7.5゜ 8.34 FAB HRMS (m+H)-896,5484HPLC (70/30 methanol /Na H2p O4-hydrate 5.22g and Prudic and ・Aqueous phosphoric acid solution containing 0.76 m12 of 85% phosphoric acid in Jackson Water 472 liquid solution, 254 nm) k″ = 6.6 Preparation Example 543-Butyloxycarbonylamino-3,3-7methylprobanoyl -Phe-(N-Me)His-LVA-Mba, (Formula B-3: R2o is Mba) See chart B 1'12 mg of the title product of Preparation 50 and 1-hydroxybenzotriazole A solution of 50 mg in 1 mQ methanol is allowed to stand for 18 hours and then concentrated under reduced pressure. . The residue was dissolved in 25-5% methanol (saturated with ammonia) in dichloromethane. 69.8 mg of the title product were chromatographed on silica gel using Obtained as a white solid.

The physical properties are as follows.

IHNMR0.7-0.9. 1.1 to 1.8. 2.0. 2.4. 2.7 7, 3.0-3.6. 7. ．． 1~7.6FAB MS (m+H)=798 ．． 5487HPLC (90/10 meta/-L/Na H2P O4-hydrate 5.22 g and Pludic & Shaxon water 4 (85% phosphoric acid in 2 0.76 m (aqueous phosphate buffer station containing!; 22,5 nm) k' = 6.7 Preparation Example 553-Butyloxycarbonylamino-3,3-dimethylpropameyl -Phe-(N-Me)His-LVA-I] e-AMP (formula B3: R20 is Ile-AMP) See chart B 83.9 mg of the title product of Preparation 51 and 1-hydroxybenzotriazole A solution of 35 mg in 1 ml of methanol was allowed to stand for 18 hours and then concentrated under reduced pressure. Ru. With 3-5% methanol (saturated with ammonia) in dichloromethane The residue was chromatographed on silica gel to give 65.9 mg of the title product. Obtained as a white solid.

The physical properties are as follows.

'HNMR0.4~0.6. 0.7-1.8. 2.0-2.4. 2.9゜ 3.3, 4.4~4.7, 7.1~7.7, 8.48FAB HRMS (m-! -H) = 932.5984 HPLC (90/10 methanol/Na Ht P　O4-hydrate 5.22g and Prudick and Jackson water 412 aqueous phosphate buffer containing 0.76 mQ of 85% phosphoric acid); 254 nm)k ’ = 7.3 Example 16 3-amino-3,3-dimethylpropanoyl-Phe-B-Asp -LVA-Mba trifluoroacetate (Formula G-4: Rso is Mba ) Chart G Reference Preparation Example 52 1: ITFA-di Ku o.

Approximately 0.5 m of methane (7 m) was added. The solution was allowed to stand for 2 hours, then stirred rapidly. Add to 10 m of 1:1 hexane. Transfer the product to a fritted disc ( Microporous), washed thoroughly with 1:1 ether-hexane, and dried under high vacuum. Drying to constant weight gives 13 mg of the title product as a white solid.

The physical properties are as follows.

FAB RMS (m+H) = 662.4494 Actual m Example 17 3-amino-3, 3-Dimethylpropanoyl-Phe-B-Phe-Asp-LVA-11e-A MP trifluoroacetate (Formula G4: R30 is rle-AMP) See chart G light To 57.2 mg of the labeled product of Preparation Example 53 was added 1:1 to 1/fluoroacetic acid-dichloride. Approximately 0.5 m+2 of lolomethane is added. The solution was allowed to stand for 1 hour, then stirred rapidly. Add to 15 mL of stirred 1:1 ether-hexane. Fritt the product filtered through a microporous disk, washed thoroughly with 1:1 ether-hexane, Drying to constant weight under high vacuum gives 69 mg of the title product as a white solid. child has a solubility in 0.9% aqueous sodium chloride of greater than 5 mg/mQ .

The physical properties are as follows.

FAB MS (m+H)=796 HP L (, (70/30 methanol/Na Hx P O4-hydrate 5. 2 g and 0.76 85% phosphoric acid in Prudick and Jackson Water 4Q Phosphate buffer containing mf2); 254 nm) k'=6.2 Example 18 3 -Amino-3,3-dimethylpropanoyl-Phe(NMe)His LVA Mba-trifluoroacetate (Formula B 4: Rto is Mba) Cha See part B Adjustment +, 5 + l F, 1: 1)'J to 58.6 mg of the indicated product of 4 Approximately 0.5 mQ of fluoroacetic acid-dichloromethane is added. Leave the solution for 1 hour , then add 15 m of beef starch (2 mL) to rapidly stirred 1:1 ether. The product was filtered through a free disk (microporous) and added to 1:1 ether. Thoroughly wash with beef sanitation and dry under high vacuum to a constant weight to obtain 53 mg of the indicated product. Obtained as a colored solid. 5 mg of this material for 0.9% aqueous sodium chloride 　/　The solubility exceeds mρ.

The physical properties are as follows.

FAB HRMS (m2H) = 898.4949 Example 193-amino-3, 3-dimethylpropanoyl-Phe-(N-Me) Hi 5-LVA-I 1 e-AMP trifluorocoacetate (2B-4/R3゜ is Ile-AMP) See chart B To 52.5 mg of the title product of Preparation Example 56 was added 1:1 trifluoroacetic acid-dichloromethane. Approximately 0.5 ml of water is added. The solution was allowed to stand for 1 hour, then stirred rapidly. Add to 15 ml of 1:1 ether-hexane. frit the product (microporous), thoroughly washed with 1:1 ether and beef san, and Drying under vacuum to constant weight gives 59 mg of the title product as a white solid. this thing The substance is easily dissolved in water and pH 7 buffer.

The physical properties are as follows.

FAB HRMS (m+H)=832.5480 Examples 20-37 Commercially available or readily prepared by methods known in the art Similar processes and techniques as described above using starting materials and reactants Accordingly, the following compounds of the invention are prepared with the indicated physical properties.

(20) 7-Gl　u-P　ro-Phe　-N-MeHi　5-LVA- [le-NH(CH,), CH(COOH)(NH,) or lysine, N 6-[N-(5[[N-[N-(1-D-γ-glutamyl-1-prolyl) )-L-phenylalanyl-N-methyl-L-histidyl]amino]-4- Hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]- L-inleucyl]-1[2S-(2R*, 4R*, 5R*)]-, Tris(T) fluoroacetate) (salt) IC5Q: 3.9X 10-11M FAB-0-1l: (m+H) (21) 7-Glu- at 997.6095 Pro-N-MeHi 5-CVA-1! e-NH(CH2) 4CH(COO H) (NH2) or L-lysine, N6-[N-C6-cyclohekinru5- JCN III-L-γ-glutamyl-L-floryl)-L-phenylara Nirlo N-methyl-L-histidyl]amine]-4-hydroxy-1-(1- methylethyl)-1-oxohexyl]-L-inreutur], r2s-(2R *, 4R*, 5R*)]-, tris(trifluoroacetate) (salt) IC6゜: 2.5X 10-@M FA, B-HRMS: (m+H)'(22)7-Gl at 1037.642 u-Pro-Phe-N-MeHi 5-CVA-NH(CH,), CH(CO OH) (NH,) or L-histidine amide, L-γ-glutamyl monopropylene Ryl-1phenylalanyl-N-[4-[[5-amino-5-carboxypene] aminococarbonyl]-1-(cyclohexylmethyl)-2-hydroxy C-5-)Tilhex'/L EN U-methyl-1HXs-Hta*.

2R*, 4R* (R*) > 1-, Tris (trifluoroacetate) (salt) lC5o・1.9X10-'M FAB-HRMS: 924.5560 (m+M)” (23) 7-G l　u-P　r　o-Ph　e　-N-MeHi　s-CVA-MBA or L -Histidinamide, L-γ-glutamyl-, one-prolyl-, and one-phenylalani RuN-cyclo^xylmethyl)-2-hydroxy-5-methyl-4-f: [ (2-methylbutyl)aminococarbonyl]hexylcoNα-methyl-1[I S-[IR*.

2R*, 4R* (R*)] l-, bis(trifluoroacetate) (salt) I.C. : 2.8X 10-”M FAB HRMS: 865.5506 (m+H)” (24) 7-G] u-Pro-Phe-N-MeHis-CVA-1ie-AMP or L -Histidinamide, L-γ-glutamyl-L-prolyl-monophenylalani Roux N-mouth 1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4 -[[[2-methyl-1-E[(2-pyridinylmethyl)amino]carbonyl] butyl]amino/]carbonyl]hexyl]-Nα-methyl-1[IS-[IR* , 2R*, 4R* (IR*, 2R*)) l-, Tris(trifluoroacetate g) (salt) IC5゜:　2.9　X　10-10MFAB-0-1O:　at 999 (m+ H)” (low resolution mass spectra only) (25) 7-Glu-Pro-Phe-N-MeHi 5-CVA-T Ie -AMP-No or [GOUSIN does not list the name of this compound] I.C. : 3.2 X 10-”M FAB-HRMS: At 1015 (m-I-H) (only) (26) 7-Gl　u-P　ro-Phe　-N-MeHi　s-LVA- MBA or L-histidine amide, L-γ-glutamyl-prolyl- Phenylalanyl-N-[2-hydroxy-5-methyl-4-[[2-methylbutylene] thyl)-aminococarbonyl]-1-(2-methylpropyl)hexyl-Nα- Methyl-5[IS-[lR1IC'.

2R*, 4R* (R*)]]-, bis(trifluoroacetate) (salt) I.C. :5.5XL○-10M FAB-HRMS: (m+H)”(27)7-Glu at 825.5245 -Phe-β-Asp-LVA-MBA or L-asparagine, N2-(N- L-γ-glutamyl-monophenylalanyl)-N-[2-hydroxy-5-methyl thyl-4-[[(2-methylbutyl)aminococarbonyl]-1-(2-methyl propyl)hexyl], [IS-[IR*, 2R*, 4R* (R1)]]- , mono(trifluoroacetate') (salt) IC,. : 6. OX I O- 'M FAB-HRMS 2692.4249 (m+H)” (2B) 7-G l u-Phe -N-MeHi 5-LVA-I I e-AMP or L-MeHi Stidine amide, L-γ-glutamyl-1-phenylalanyl-N-[2-hyphenyl] Droxy5-methyl-1-(2-methylpropyl)-,4-[[[2-methyl Co[[2-pyridinylmethyl)amino]carbonyl]butylcoamino]carbo Nyl]hexyl]-Nα-methyl-1[IS-[IR*, 2R*, 4R* (t R*, 2R*) co]-, tris(trifluoroacetate) (salt) ICso: 1. OX 10-@M FAB-HRMS: (m+H)”(29)y-G 1 at 862.5193 u-Phe-N-MeHi s-LVA-MBA or L-histidine amide , L-γ-glutamyl-monophenylalanyl-N-[2-hydroxy-5-methane Chyl-4-[[(2-methylbutyl)ami/dicarbonyl sil E-Nα-methyl-, is-:tR*,2R*,4R*(R*)2, bi (trifluoroacetate) (salt) IC50: 3. OX 10-”M A’B-HRMS: 728.4733 (30) 7-G I u-Phe -N-MeH i s-CVA-MBA or L-histidineamide, L-γ -Glutamyl-1-phenylalanyl-N- [t- (cyclohexylmethylene) )-2-hydroxy-5-methyl-4-[C(2-methylbutyl)aminococa [rubonyl]hexyl]-Nα-methyl-, [IS- [IR*, 2R*.

4R*(R*)]co, bis(trifluoroacetate) (salt) IC,. : 2 ．． 3X 1 0-”M FAB-HRMS: (m+H) (3 1) 7 -G at 765.5020 l u-Phe -N-MeH i s-LVA-I l e -AMP-NO or L-histidineamide, L-γ-glutamyl-L-phenylalanyl-N -12-hydroxy-5-methyl-1-(2-methylpropyl)-4-C[C 2-Methyl-1-[J2-pyridinylmethyl)amino]carbonyl]-2-methy [rubutyl]amine]carbonyl]hexyl]-Nα-methyl-, N-oxide, [is- [IR*, 2R*, 4R* (IR*, 2R*)] Co, Tris(T) fluoroacetate) (salt) I.C. : 2.2x 1 0-’M FAB-HRMS: (m+H)” at 878 (low resolution mass spectrum only ) (32)7-G I u-Phe-N-MeH i s-CVA-1 1 e -AMP-NO or L-histidine amide, L-γ-glutamyl-L roof Phenylalanyl-N-[:1-(cyclohedoxylmethyl)-2-hydroxy -5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)ami ]carbonylcobutyl]amino]carbonyl]hexyl]-Nα-methyl-, N-oxide, [IS-[1R*, 2R*, 4R* (IR*, 2R*)G-, Tris (trifluoroacetate) (salt) TC5o: 9.1 x l O-”MFAB-HRMS: 918.546 At 5 (m-i-H)” (33) β-Va 1-Phe-NC(CH3)H i 5-LVA-11e-NH(CH2), CH(COOH)(NH,) or is L-lysine, N6-CN-[5-ECN-[N-(3-amino-3 -Methyl-1-oxobutyl)-L-phenylalanylyoN-methyl-L-hypolymer stidyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl) -1-oxobutyl]-L-isoleucyl]-5[2S-(2R*, 4R*, 5 R*) Tris (trifluoroacetate) (salt) I.C. : 3.2X 10-8M FAB-HRMS: (M+H)” (34) β-Va at 870.5806 1-Phe-NC(CH3)His-CVA-11e-NH(CH,), (CO OH) (NH2) or L-lysine, N6 gN[5:[N (3-methyl-1-oxobutyl)-L-phenylalanyl-N-methyl- L-Histidyl]amino]-6-cyclohequine-4-hydroxy-2-(1- methylethyl)-1-oxohexyl]-L-ynleucyl]-1E2S, (2 R*, 4R*, 5R*)]-, tris(trifluoroacetate) (salt) I.C. : 2.5X 10-11M FAB-0-1l: (m+H)” (35) β-Va at 910.6408 1-Phe-NC(CH3)His-CVA-NH(CH,),(CO OH)(CH,) or L-histidineamide, N-(3-amino-3-methyl -1-oxobutyl)-L-phenylalanyl-N-[4-[[(5-amino- 5-carboxypentyl)aminococarbonyl]-1-(cyclohexylmethyl )-2-hydroxy-5-methylhexyl]-Nα-methyl-1[IS-:lR *, 2R*, 4R* (R*) Cony, Tris (trifluoroacetate) (salt) ) FAB-HRMS: (m+H)” (36) β-Va at 797.5260 1-Phe-NC(CH3)His-LVA-11e-Amp ip or L -Histidinamide, N-(3-amino-3-methyl-1-oxobutyl)-L -phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) ropyru)-4EEE2-methyl-1-[[(4-piperidylmethyl)aminococa carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-1[IS - [IR*, 2R*, 4R* (IR*, 2R*)] Co, Tris (Trifluor loazetate) (salt) IC,. :3. lX10-”M FAB-HRMS: (m+H)” (37) β-Val at 838.5900 -Phe-NC(CH3)His-LVA-NH-CH CH7), NH2) C(0)-Ampip or L-histidineamide, N-(3-ami/-3 -Methyl-1-oxobutyl)-L-phenylalanyl-N-[2-hydroxy -5-Methyl-1-(4-aminobutyl)-4-[[[2-methyl-1-[[( 4-piperidylmethyl)amino]carbonyl]butyljamino]carbonyl]he xyl]-Nα-methyl-1[IS-[IR*, 2R*.

4R* (IR*, 2R*) co]-, tetrakis (trifluoroacetate) ( salt) I.C. :3.4X10-7M FAB-HEMS: (m+H)' formula chart at 853.6047 ^6-a7-C8Dg ELO'11 '12 '13 Engineering X1-(CH2), ・C-L1 Formula chart (continued) Chart A Pro-Phe・N-MeHLs-LVA・Engineering La-AapBoa-rG1u ( OBn)-Pro-Phe-N-MaHls-LVA-11*-Aa+pBoc -7G1u-1'ro-i'h@-N-MaHls-LVA-11a-AIII p%1u-f’ro-Ph@-N-MaHls-LVA-Els-Aap-+0 ^・6 Chart B Phe-N-MaHls(τs)・LVA-R20BOC-β-Val-! 'h e-N-MaHLs (1g)-LVA-R202TFA・β-Val-Fh*- N-M@HLg-LVA41*-AM? -40B・7 Chart C ↓ (BueO)2P(0)QC)12GO2B! 1↓ (BueO)2F(0)OCH2CO2H chart E Chart D (Bu”O)2!’(0)O(CH2)3CO2Bzl(Bu”0)2F(0) O(Ck12)3CO2H chart F Chart G F’ha-β-＾jp(OBn)-LVA-R30G・I international search report 1m□1111. Il+I□AIlyu, rhb-Ilx-, PCT/IJS 9 0101764 International Search Report

Claims (9)

[Claims] 1. Non-cleavable corresponding to positions 10 and 11 of renin substrate (angiotensinogen) Has a transition state insert and has formula L1 at the N-terminus: ▲ Numerical formula, chemical formula, table, etc. I'm here▼ [In the formula, X is a) H2N-, b) H2NC(CH3)2-, c) HO2C-, d) (H2N)(HO2C)CH-, or e) (HO)2P(O)O-: wherein n is inclusive and represents 1 to 5. Do. 2. Non-cleavable corresponding to positions 10 and 11 of renin substrate (angiotensinogen) In peptides with transition state inserts, at the N-terminus the formula L1: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X1 is a) H2N-, b) H2NC(CH3)3-, c) HO2C-, d) (H2N)(HO2C)CH-, or e) (HO)2(O)O-; Herein, n is inclusive and represents 1 to 5. Improvements characterized by: 3. Formula I: A6-B7-C8-D9-E10-F11-G12-H13 I [wherein A6 is Formula L1: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ a monovalent group of; Here, either B7 does not exist or there is a formula L2: ▲ mathematical formula, chemical formula, table, etc. ▼L2 divalent group; Here, C is the formula L3 or L4: ▲There are mathematical formulas, chemical formulas, tables, etc.▼L3▲There are mathematical formulas, chemical formulas, tables, etc.▼L4 divalent group; Here, D9 is the formula L4 or L5: ▲There are mathematical formulas, chemical formulas, tables, etc.▼L4▲There are mathematical formulas, chemical formulas, tables, etc.▼L5 divalent group; Here, E10-F11 is the formula L6 to L10: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼L6▲There are mathematical formulas, chemical formulas, tables, etc.▼L7▲There are mathematical formulas, chemical formulas, tables, etc. ▼L8▲There are mathematical formulas, chemical formulas, tables, etc.▼L9▲There are mathematical formulas, chemical formulas, tables, etc. ▼ Any divalent group from L10, or formula L11: ▲ Numerical formula, chemical formula, table etc. ▼ Monovalent group of L11; Here, G12 does not exist or formula L13: ▲ Numerical formula, chemical formula, table, etc. ▼Divalent group of L4; Here, H13 is a) -O-R5, or b)-N(R1)(R5); Here, X1 is a) H2N-, b) H2NC(CH3)2-, c) HO2C-, d) (H2N) (HO2C) CH-, or e) ▲ Numerical formulas, chemical formulas, tables, etc. ▼Here, Q1 is a) -CH2-, b) -CH(OH)-, c) -O-, or d) -S-; Here, M1 is a) -C(O)-, or b) -CH2-; Here, V1 is a) -O-, or b) -N(R1)-; Here, Y1 is a) -OH, or b) -NH2; Here, P1 is a)-N3, b) -CN, c) C1-C6 alkyl, d) C1-C6 cycloalkyl, e) aryl, or f) Het; Here, m is 1 or 2; Here, n is inclusive from 1 to 5; Here, p is inclusive from 0 to 5; Here, the aryl is a) C1-C5 alkyl, b) hydroxy; c) hydroxy (C1-C5 alkyl), d) C1-C5 alkoxy, e) amino, f) amino (C1-C5 alkyl), g) halogen; h) -CHO, i) -CO2H, j) -CO2-(C1-C5 alkyl), k) -CONH2, l) -CONH (C1-C5 alkyl), m) nitro, n) mercapto, o) Mercapto (C1-C5 alkyl), P)-SO3H, q)-SO2NH2, r)-CN phenyl or naphthyl substituted by 0 to 3 of; t is a 5- or 6-membered group containing 1 to 3 heteroatoms (nitrogen, oxygen, sulfur) a saturated or unsaturated ring, and any of the heterocycles is a benzene ring or other heterocycle. Includes any bicyclic ring fused to a bare ring, if chemically possible, the nitrogen and The sulfur atom may be in oxidized form; and a) C1-C5 alkyl, b) hydroxy; c) hydroxy (C1-C5 alkyl), d) C1-C5 alkoxy, e) amino, f) amino (C1-C5 alkyl), g) halogen; h) -CHO, i) -CO2H, j) -CO2-(C1-C5 alkyl), k) -CONH2, l) -CONH (C1-C5 alkyl), m) nitro, n) mercapto, o) Mercapto (C1-C5 alkyl), P)-SO3H, q)-SO2NH2, r)-CN R1 is substituted with 0 to 3 of the following; a) hydrogen, or b) C1-C5 alkyl; Here, R2 is a) Hydrogen, b) C1-C6 alkyl, c)-(CH2)p-aryl, d)-(CH2)p-Het, e)-(CH2)p-CO2H, f)-(CH2)p-NH2, g)-(CH2)p-CH(NH2)(CO2H), h) C3-C7 cycloal kill, or i) 1- or 2-adamartyl; Here, R3 is a) Hydrogen, b) C1-C5 alkyl, c) aryl, d) C3-C7 cycloalkyl, e) Het, f) C1-C3 alkoxy, or g) C1-C3 alkylthio; Here, R4 is a) Hydrogen, b) C1-C8 alkyl, c) C3-C7 cycloalkyl, or d) -CH(R1)(R6); Here, R5 is a) Hydrogen, b) C1-C10 alkyl, c) (CH2)p-alkyl, d) (CH2)p-Het, e)-(CH2)p-cycloalkyl, f)-(CH2)p-CH(NH2)( CO2H), g) CRt(CH2)p(NH2)C(O)-Het, or h) -(CH2)n-R7: Here, R6 is a) Hydrogen, b) hydroxy; c) C1-C5 alkyl, d) C3-C7 cycloalkyl, e) aryl, f) Het, g) C1-C3 alkoxy, or h) C1-C3 alkylthio; Here, R7 is a) hydroxy; b) amino, c) -CO2H, d) -SO3H, e) -SO2NH2, f) guazinyl, or g) means a polyhydroxy-substituted alkyl group] or its carboxy, amino or other reactive group protected forms; or pharmaceutically acceptable acids or bases thereof; addition salt, where at each occurrence all of the defined variables are independent variables and 1) When E10-F11 is L11, G12 and H13 are both absent, and 2) When X1 is H2N-, H2NC(CH3)2- or HO2C-, E 10. The peptide of claim 1, wherein 10-F11 is not L11. 4. A6 is a formula L1 in which X1 is (H2N)(HO2C)CH- and n is 2 is a monovalent group of; where B7 is absent and is Pro or a derivative thereof; where C8 is Ph e, (OCH3)Tyr or a derivative thereof; Here, D9 is N-MeHis, His, β-Asp or a derivative thereof; E10-F11 is LVA, CVA, CVG or a derivative thereof; G12 is H13 is AMP, AMP-NO, MB A or NH(CH2)4CH(NH2)(COOH) Claim 3 Peptides described. 5. γ-Glu-Pro-Phe-N-MeHis-LVA-Ile-AMP or L-histidineamide, L-γ-glutamyl-L-prolyl-L-phenyl Alanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl ]butyl]amino]carbonyl]hexyl]-Nα-methyl-, [1S-[1R *,2R*,4R*(1R*,2R*)]-, Tris(trifluoroacetate) g) (salt); γ-GlU-Pro-Phe-N-MeHis-LVA-Ile-AMP-NO or L-histidineamide, L-γ-glutamyl-L-prolyl-L-phenylene Lualanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl) -4-[[(2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl [butyl]amino]carbonyl]hexyl]-Nα-methyl-,N-oxide , [1S-[1R*,2R*,4R*(1R*,2R*)]]-, Tris(Tris γ-Glu-Pro-Phe-N-MeHis- CVG or L-histidineamide, L-γ-glutamyl-L-prolyl-L- Phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy C-5-methylhexyl]-Nα-methyl-, [1S-(1R*,2S*,3R *) Bis(trifluoroacetate) (salt); γ-Glu-Pro-(OCH3 ) Tyr-His-CVG or L-histidineamide, L-γ-glutamyl- L-prolyl-O-methyl-L-tyrosyl-N-[1-(cyclohexylmethyl )-2,3-dihydroxy-5-methylhexyl]-, [1R*,2S*,3R *)]-, bis(trifluoroacetate) (salt); γ-Glu-Pro-Ph e-N-MeHis-LVA-Ile-NH(CH2)4(COOH)(NH2 ) or L-lysine, N6-[N-(5-[[N-[N-(1-D-γ-gluta Mil-L-prolyl)-L-phenylalanyl]-N-methyl-L-histidyl [amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-o xooctyl]-L-isoleucyl]-, [2S-(2R*, 4R*, 5R*) ]-, Tris(trifluoroacetate) (salt); γ-Glu-Pro-Phe -N-MeHis-CVA-Ile-NH(CH2)4CH(COOH)(NH 2) or L-lysine, N6-[N-[6-cyclohexyl-5-[[N[(1 -L-γ-glutamyl-L-prolyl)-L-phenylalanyl]-N-methyl -L-histidyl]amino]-4-hydroxy-2-(1-methylethyl)-1 -oxohexyl]-L-isoleucyl], [2S-(2R*,4R*,5R* )]-, tris(trifluoroacetate) (salt); γ-Glu-Pro-Phe-N-MeHis-CVA-NH(CH2)4CH (COOH) (NH2) or L-histidineamide, L-γ-glutamyl-L -Prolyl-L-ferralalanyl-N-[4-[[(5-amino-5-carbo xypentyl)amino]carbonyl]-1-(cyclohexylmethyl)-2-hypolymer Droxy-5-methylhexyl]-Nα-methyl-, [1S-[1R*,2R* ,4R*(R*)]]-, tris(trifluoroacetate) (salt); γ-Glu-Pro-Phe-N-MeHis-CVA-MBA or L-His Tidinamide, L-γ-glutamyl-L-prolyl-L-phenylalanyl-N -cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[(2-methyl (rubutyl)amino]carbonyl]hexyl]-Nα-methyl-, [1S-[1R *,2R*,4R*(R*)]]-, bis(trifluoroacetate) (salt); γ-Glu-Pro-Phe-N-MeHis-CVA-Ile-AMP or L-histidineamide, L-γ-glutamyl-L-prolyl-L-phenyla Nyl-N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4 -[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl] butyl]amino]carbonyl]hexyl]-Nα-methyl-, [1S-[1R* ,2R*,4R*(1R*,2R*)]]-, tris(trifluoroacetate )(salt); γ-Glu-Pro-Phe-N-MeHis-CVA-Ile-AMP-NO or L-histidineamide, L-γ-glutamyl-L-prolyl-L-phenylene Lualanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-5-methy Ru-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo Nyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, N-oxy de, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, tris(tris) γ-Glu-Pro-Phe-N-MeHis -LVA-MBA or -histidineamide, L-γ-glutamyl-L-pro Lyle-L-phenylalanyl-N-[2-hydroxy-5-methyl-4-[[2 -methylbutyl)amino]carbonyl]-1-(2-methylpropyl)hexyl -Nα-methyl-, [1S-[1R*,2R*,4R*(R*)]]-, bis( trifluoroacetate) (salt); γ-Glu-Phe-β-Asp-LVA- MBA or L-asparagine, N2-(N-L-γ-glutamyl-L-phenylene lualanyl)-N-[2-hydroxy-5-methyl-4-[[(2-methylbutyl [amino]carbonyl]-1-(2-methylpropyl)hexyl], [1S- [1R*,2R*,4R*(R*)]]-, mono(trifluoroacetate) ( salt); γ-Glu-Phe-N-MeHls-LVA-Ile-AMP or -histidineamide, L-γ-glutamyl-L-phenylalanyl-N-[2- Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl -]-[[2-pyridinylmethyl)amino]carbonyl]butyl1amino]car [bonyl]hexyl]-Nα-methyl-, [1S-[1R*,2R*,4R*(1 R*,2R*)]-, tris(trifluoroacetate) (salt); γ-Glu -Phe-N-MeHis-LVA-MBA or L-histidineamide, L- γ-glutamyl-L-phenylalanyl-N-[2-hydroxy-5-methyl- 4-[[(2-methylbutyl)amino]carbonyl]-1-(2-methylpropyl hexyl]-Nα-methyl-, [1S-[1R*,2R*,4R*(R*) ]-, bis(trifluoroacetate) (salt); γ-Glu-Phe-N-Me His-CVA-MBA or Histidineamide, L-γ-glutamyl-L -phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy- 5-Methyl-4-[[(2-methylbutyl)amino]carbonyl]hexyl]- Nα-methyl-, [1S-[1R*,2R*,4R*(R*)]]-, bis(t) γ-Glu-Phe-N-MeHis-LVA -Ile-AMP-NO or L-histidineamide, L-γ-glutamyl-L -phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) ropyru)-4-[[[2-methyl-1-[[2-pyridinylmethyl)amino]ka [rubonyl]-2-methylbutyl]amino]carbonyl]hexyl]-Nα-methy Ru-, N-oxide, [1S-[1R*,2R*,4R*(1R*,2R*)] ]-, tris(trifluoroacetate) (salt); or γ-Glu-Phe-N-MeHis-CVA-Ile-AMP-NO or L -histidineamide, L-γ-glutamyl-L-phenylalanyl-N-[1- (cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl Ru-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino] carbonyl]hexyl]-Nα-methyl-, N-oxide, [1S-[1R*, 2R*,4R*(1R*,2R*)]]-, tris(trifluoroacetate) (salt) The peptide according to claim 4, which is selected from the group consisting of: 6. A6 is a monovalent of formula L1 where X1 is H2NC(CH3)2- and n is 1 is the basis; B7 does not exist here; where C8 is Phe or a derivative thereof; where D9 is N-MeHis , β-Asp or a derivative thereof; Here, E10-F11 is LVA, CVA or a derivative thereof; here, G 12 is absent and is He or a derivative thereof; where H13 is AMP, A MP-NO, MBA, NH(CH2)4CH(NH2)(COOH), Ampi p or NH-CH((CH2)4NH2)C(O)-Ampip The peptide according to scope item 3. 7. β-Val-Phe-N-MeHis-LVA-Ile-AMP-NO is L-histidineamide, N-(3-amino-3-methyl-1-oxobutyl) -L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methyl (2-methyl-1-[[(2-pyridinylmethyl)ami ]carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, N-oxide, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, Tris (trifluoroacetate) (salt); β-Val-Phe-N-MeHi s-CVA-MBA or L-histidineamide, N-(3-amino-3-methyl (1-oxobutyl)-L-phenylalanyl-N-[1-(cyclohexyl) methyl)-2-hydroxy-5-methyl-4-[[(2-methylbutyl)amino ]carbonyl]hexyl]-Nα-methyl-, [1S-[1R*,2R*,4R *(R*)]]-, bis(trifluoroacetate) (salt); β-Val-Phe-N-MeHis-CVA-Ile-AMP or Shi-His Tidinamide, N-(3-amino-3-methyl-1-oxobutyl)-L-phene Nylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-5-methane thyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]car [bonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, [1S- [1R*, 2R*, 4R* (1R*, 2R*)]]-, tris(trifluoroir) acetate) (salt); β-Val-Phe-N-MeHis-CVA-Ile-AMP-NO or L -Histidinamide, N-(3-amino-3-methyl-1-oxobutyl)-L -phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy- 5-Methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino [carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, N -oxide, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, Lis(trifluoroacetate) (salt); β-Val-Phe-β-Asp-L VA-MBA or L-asparagine, N2-[N-(3-amino-3-methyl -1-oxobutyl)-L-phenylalanyl]-N-[2-hydroxy-5- Methyl-4-[[(2-methylbutyl)amino 1carbonyl]-1-(2-methyl lupropyl)hexyl]-, [1S[1R*,2R*,4R*(R*)]]-, Mono(trifluoroacetate) (salt); β-Val-Phe-β-Asp-L VA-Ile-AMP or L-asparagine, N2-[N-(3-amino-3 -Methyl-1-oxobutyl)-L-phenylalanyl]-N-[2-hydroxy C-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[ (2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl] hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, Bis(trifluoroacetate) (salt); β-Val-Phe-N-MeHis-LVA-MBA or L-histidine Mido, N-(3-amino-3-methyl-1-oxobutyl)-L-phenylara Nyl-N-[2-hydroxy-5-methyl-4-[[(2-methylbutyl)ami ]carbonyl]-1-(2-methylpropyl)hexyl]-Nα-methyl-, [1S-[1R*,2R*,4R*(R*)]]-, bis(trifluoroacetate) salt); β-Val-Phe-N-MeHis-LVA-Ile-AMP or L-His Tidinamide, N-(3-amino-3-methyl-1-oxobutyl)-L-phene Nylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl )-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo nyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, [1S-[ 1R*, 2R*, 4R* (1R*, 2R*)]]-, Tris(trifluoroacetate) Tate) (salt); β-Val-Phe-NC(CH3)His-LVA-Ile-NH(CH2) 4CH(COOH)(NH2) or L-lysine, N6-[N-[5-[[N- [N-(3-amino-3-methyl-1-oxobutyl)-L-phenylalanyl ]-N-methyl-L-histidyl]amino]-4-hydroxy-7-methyl-2 -(1-methylethyl)-1-oxobutyl]-L-isoleucyl]-, [2S -(2R*,4R*,5R*)], tris(trifluoroacetate) (salt); β-Val-Phe-NC(CH3)His-CVA-Ile-NH(CH2) 4CH(COOH)(NH2) or L-lysine, N6-[N-[5-[[N- [N-(3-amino-3-methyl-1-oxobutyl)-L-phenylalanyl ]-N-methyl-L-histidyl]amino]-6-cyclohexyl-4-hydro xy-2-(1-methylethyl)-1-oxohexyl]-L-isoleucyl] -, [2S-(2R*,4R*,5R*)]-, Tris(trifluoroacetate g) (salt); β-Val-Phe-NC(CH3)His-CVA-NH(CH2)4CH( COOH) (CH2) or L-histidineamide, N-(3-amino-3-methane) thyl-1-oxobutyl)-L-phenylalanyl-N-[4-[[5-amino -5-carboxypentyl)amino]carbonyl]-1-(cyclohexylmethylene) )-2-hydroxy-5-methylhexyl]-Nα-methyl-, [1S-[1 R*, 2R*, 4R*(R*)]]-, tris(trifluoroacetate) (salt ); β-Val-Phe-NC(CH3)-LVA-Ile-AMPip or L- Histidineamide, N-(3-amino-3-methyl-1-oxobutyl)-L- Phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropylene) pill)-4-[[[2-methyl-1-[[(4-piperidylmethyl)amino]ka [rubonyl]butyl]amino]carbonyl]hexyl]-Nα-methyl-, [1S -[1R*,2R*,4R*(1R*,2R*)]]-, tris(trifluoro acetate) (salt); or β-Val-Phe-NC(CH3)His-NH-CH((CH2)4NH2 )C(O)-AMPip or L-histidineamide, N-(3-amino-3- Methyl-1-oxobutyl)-L-phenylalanyl-N-[2-hydroxy- 5-Methyl-1-(4-aminobutyl)-4-[[[2-methyl-1-[[(4 -piperidylmethyl)amino]carbonyl]butyl]amino]carbonyl]hex sil]-Nα-methyl-, [1S-[1R*,2R*,4R*(1R*,2R* )]]-, Tetrakis (trifluoroacetate) (salt) 7. The peptide according to claim 6, which is selected from the group consisting of: 8. A8 is a formula L in which X1 is (HO)2P(O)O- and n is 1 or 3 is a monovalent group of 1; where B7 is absent and is Pro or a derivative thereof; where C8 is Ph e or a derivative thereof; where D9 is β-Asp, N-MeHis or It is a derivative thereof; Here, E10-F11 is LVA, CVG or a derivative thereof; here, G 12 is absent and is He or a derivative thereof; where H13 is absent; The peptide according to claim 3, which is AMP, AMP-NO or MBA. 9. (HO)2P(O)OCH2C(O)-Phe-β-Asp-LVA-Il e-AMP or L-asparagine, N-[2-hydroxy-5-methyl-1- (2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N2- [N-[(phosphonooxy)acetyl]-L-phenylalanyl]-, monohydrochloride , [1S-[1R*,2R*,4R*(1R*,2R*)]]-;(HO)2P (O)OCH2C(O)-Phe-N-MeHis-LVA-Ile-AMP or L-histidine amide, N-[(phosphonooxy)acetyl]-L-phenylene Lualanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl) -4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl [butyl]amino]carbonyl]hexyl]-Nα-methyl-, dihydrochloride, [ 1S-[1R*,2R*,4R*(1R*,2R*)]]; (HO)2P(O) OCH2C(O)-Pro-Phe-N-MeHis-LVA-Ile-AMP or -histidineamide, N-[N-[1-[(phosphonooxy)acetyl ]-L-prolyl]-L-phenylalanyl]-N-[2-hydroxy-5-methane Thyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-methylpropyl) lysinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl ]-Nα-methyl-, dihydrochloride, [1S-[1R*,2R*,4R*(2R*, 2R*)]]-; (HO)2P(O)OCH2C(O)-Pro-Phe-N- MeHis-LVA-Ile-AMP-NO or L-histidineamide, 1- [(phosphonooxy)acetyl]-L-prolyl-L-phenylalanyl-N- [2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- Methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]ami ]carbonyl]hexyl]-Nα-methyl, N-oxide, dihydrochloride, [1S -[1R,2R*,4R*(1R*,2R*)]]-;(HO)2P(O)O( CH2)3C(O)-Pro-Phe-N-MeHis-LVA-Ile-AM P or L-histidine amide, N-[[1-[1-oxo-4-(phosphono- xy)butyl]-3-pyrrolidinyl]carbonyl]-L-phenylalanyl-N -[2-Hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2 -Methyl-1-[[(2-2-pyridinylmethyl)amino]carbonyl]butyl ]Amino]carbonyl]hexyl]-Nα-methyl-, dihydrochloride, [1S-[1 R*(S*), 2R*, 4R*(1R*)]]-:; (HO)2P(O)O(CH2)3C(O)-Pro-Phe-N-MeHis -LVA-Ile-AMP-NO or L-histidineamide, N-[[1-[ 1-oxo-4-(phosphonooxy)butyl]-3-pyrrolidinyl]carbonyl ]-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methyl tylpropyl)-4-[[[2-methyl-1-[[(2-2-pyridinylmethyl )amino]carbonyl]butyl]amino]carbonyl]hexyl]-Nα-methy Ru-, N-oxide, monohydrochloride, [1S-[1R*(S*),2R*,4R*( 1R*, 2R*)]]-; or (HO)2P(O)OCH2C(O)-Pro-Phe-N-MeHis-CV G or L-histidine amide, 1-[(phosphonooxy)acetyl]-L-propylene lolyl-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3 -dihydroxy-5-methylhexyl]-Nα-methyl-, monohydrochloride, [1S- (1R*, 2S*, 3R*)]- 9. The peptide according to claim 8, which is selected from the group consisting of: