UA61056C2 - Componuds with properties of growth hormone release, as pharmaceutical composition, a method for stimulating the growth hormone release from the pituitary and a method for increasing animal growth rate - Google Patents

Abstract

Compounds of the formula A-B-C-D(E)p are used to stimulate the release of growth hormone from the pituitary.

Description

Description of the invention

This invention relates to novel peptide derivatives, compositions containing them, and their medical use for the treatment of disorders resulting from growth hormone deficiency.

Growth hormone is a hormone that stimulates the growth of all body tissues that are capable of growth. In addition, it is known that growth hormone has a certain effect on metabolic processes, in particular, it promotes the stimulation of protein synthesis and the mobilization of free fatty acids, and that it causes a change in the direction of energy metabolism from carbohydrate metabolism to fatty acid metabolism. Growth hormone deficiency can lead to 70 some severe disorders, such as dwarfism.

Growth hormone is released from the pituitary gland. The release occurs under the clear direct or indirect control of certain hormones and neurotransmitters. The release of growth hormone can be stimulated by the so-called GH releasing hormone (GHR) and inhibited by somatostatin.

In both cases, these hormones are released from the hypothalamus, but their action is mediated first through specific 12 receptors located in the pituitary gland. Some other compounds that stimulate the release of growth hormone are also known and described. For example, such compounds as arginine, I-3,4-dihydroxyphenyl (I-Uora), glucagon, vasopressin,

RASAR (pituitary adenylyl cyclase-activating peptide), agonists of muscarinic receptors, as well as the synthetic hexapeptide, OSNKR (growth hormone-releasing peptide), promote the release of endogenous growth hormone, either by directly affecting the pituitary gland, or by influencing the release of SNECR and/or somatostatin from the hypothalamus.

In cases of disorders or under such circumstances, when it is necessary to increase the level of growth hormone, the protein nature of these hormones forces the use of parenteral administration into the body. In addition, some natural direct-acting secretory enhancers, such as ONKN and RASAR, are high molecular weight peptides, which also favors parenteral administration.

The use of shorter peptides in order to increase the level of growth hormone in the mammalian body was previously proposed in EP 18 072, EP 83 864, MO 89/07110, MO 89/10933, MO 88/9780, MO 83/02272, MO (U 91/18016, UUO 92/01711 and UUO 93/04081.

The structure of the releasing peptides of growth hormone or derivatives of these peptides is an important factor in the effectiveness of their effect on the release of growth hormones, as well as their bioavailability. Therefore, the subject of this invention are new peptides with the properties of the releasing factor of growth hormones, which are more advanced compared to the currently known peptides of this type. yu

A compound having the general formula 1 "c)

A-V-S-0I( E)r 1 "- dereb or 1; (se)

A is hydrogen or CH) 00 (Спо)в-СО-, where d is 0 or an integer selected from the group: 1, 2, 3, 4, 5; r is 0 or 1; " z is O or an integer selected from the group: 1, 2, 3, 4, 5; 70 V! is hydrogen, imidazolyl, guanidine group, piperazine group, morpholino group, piperidino group 8c or m(223-23), where each of the radicals 22 and BZ is independently hydrogen or lower alkyl, which, alternatively, : c" are replaced by one or more hydroxyl, pyridinyl, or furanyl groups; and also X, when r is 1, represents -MH-, -СНо, -СНЕСН-, -С(Б'5ув1-, in Ко dod is " - (ав) where each of the radicals 5 and КЕ" is independently hydrogen or lower alkyl; B is (GEN), where both sl 50 Her and i are independently 0 or 1;

H and H are amino acid residues (radicals) selected from the group that includes natural 4) II-amino acids or their corresponding O-isomers, or artificial amino acids, such as 1,4-diaminobutyric acid, amino-isobutyric acid, 1,3-diaminopropionic acid, 4-aminophenylalanine, 3-pyridylalanine, 1,2,3,4-tetrahydroisoquinolinic acid, 1,2,3,4-tetrahydronorharman-3-carboxylic acid, M-methylanthranilic acid, anthranilic acid, M -benzylglycine, 3-aminomethyl benzoic acid, 3-amino-3-methyl-butanoic acid, o sarcosine, nipecotic acid or iso-nipecotic acid; when both и and и are equal to 1, the amide bond between Г and Н, as an option, is replaced by the radical -У-МК 18. where Уо is -СО- or -СН»е-, and ВВ is hydrogen , lower alkyl or lower aralkyl;

C is an O-amino acid having the formula -МНА-СН(СНо)у-Б7)-СО-, where m is 0, 1 or 2; and 7 is selected from the group consisting of o, C 65 each of which is variably substituted by halogen, lower alkyl, lower alkyloxy,

lower alkylamino, amino or hydroxy;

Or, when p is 1, is a SO-amino acid having the formula -ME 20-CH(СНо)-2)-СО- or, when p is 0, O is -"ME20-CH((CH") -К2)-СН2-85 or -МЕ29-СН(СНо)т-В2)-СО-85, where

Ke0,1 or 2;

It is 01 or 2; that 01 or 2; 229 is selected from the group consisting of lower alkyl or lower aralkyl;

IN? selected from the group consisting of and each of which is optionally substituted with halogen, lower alkyl, lower alkyloxy, amino or hydroxy; also 25 represents piperazino, morpholino, piperidino, -"OH or M(B. 7-28), where each of the radicals B' and C is independently hydrogen or lower alkyl;

E, when p is 1, represents -МН-СН-(В. 19)-(СНо)у-ВУ, where m is О or an integer selected from the group of numbers: 1,2,3,4, 5 ,6, 7, 8;

VE is hydrogen, imidazolyl, guanidino, piperazino, morpholino, piperidino, -AlsoE717)- B,

Fi mo, , s also o depiee0, 1 or 2, and В В is hydrogen or lower alkyl, di! 11 (sna K ven y g vi2 or Ya Te Is) . | "c) where o is an integer selected from the group: 1, 2, З, each of the radicals 2! and B? is independently hydrogen or lower alkyl, or -- "o.B in the background and each of which is variably substituted by halogen, lower alkyl, lower alkyloxy, amino, alkylamino, hydroxy, or the Amadori rearrangement product from the amino group and hexapyranose or hexapyranosyl-hexapyranose" | - with VU, when p is 1, selected from the group that includes -H, -СООН, -СНо-БУ, -СО- ВЗ or -СНО-ОН, where ВЗ is piperazino, morpholino, piperidino, "OH or -M(B17)3-B", and wherein each of the radicals B? and B/5" is independently hydrogen or lower alkyl; all amide bonds within formula 1, except for the bond between C and O, may independently be substituted by the radical -U-ME8-, where U is -CO- or -CH 2- and BZ is hydrogen, lower alkyl or lower (2) aralkyl, or a pharmaceutically acceptable salt thereof; - also, with the exception of the compounds (3-Aminomethylbenzoyl)-0-2MaI-M-Me-O-RPe-Y ug-MH» o H-AiYIB-Nis-0-2MaI-M-Me-O-RPe-I uv-MH» sl 50 H-AIIB-Niz-M-Me-0-2MaI-M-Me-O-РНе-Гув-МН 2» 3-(H-AIIB-Niz-0-2MaI-M-Me-0-Рпе- MH)-1-morphol inopropane

I) 2-(H-Air-Niz-0-2Ma1I-M-Me-0-Rpe-MH)-2-(1-methyl-2-pyrrolidinyl)ethane (ZK)-Piperidinecarbonyl)-M-Me-0 -2MaI-M-Me-O-RNe-I uv-MH 2 3-(3-Aminomethylbenzoyl)-0-2MaI-M-Me-0-Rpe-MH)-1-morpholinopropane 22 2-(H-Air- Nis-M-Me-0-2Ma1I-M-Me-0-Rpe-MH)-1-(1-methyl-2-pyrrolidinyl)ethane

Gee! 2-(ZK)-Piperidinecarbonyl)-M-Me-0O-2MaI1-m-Me-0-Rpe-MH)-1-(1-methyl-2-pyrrolidinyl)ethane 2-(3-Aminomethylbenzoyl)- M- Me-0-2MaI-M-Me-0-RNpe-MH)-1-(1-mipak-2-pyrrolidinyl)ethane de 3-(H-AIIB-Nis-M-Me-0-2MaI1-M-Me -O-Ppe-MH)-1-morpholinopropane 3-((3K)-Piperidinecarbonyl)-M-Me-0-2Ma1-mM-Me-O-Ppe-MH)-1-morpholinopropane 60 C((3-Aminomethylbenzoyl )-М-Ме-0-2Ма1-М-Ме-0-Рпе-МН)-1-morpholinopropane 2-(3-Aminomethylbenzoyl)-0-2Ма1-М-Ме-О-Р pe-МН)-1- (1-methyl-2-pyrrolidinyl)ethane 2-"(3Y)piperidinecarbonyl)-O-2Ma1-M-Me-O-Ppe-MH)-1-(1-methyl-2-pyrrolidinyl)ethane.

Peptide derivatives that correspond to formula 1 are characterized by increased resistance to proteolytic cleavage by enzymes, which is due to the presence in the peptide series (sequence) of adjacent 65 p-amino acids, variably, in combination with the replacement of the amide bond (-СОМН-) bond - U-MA 718-, mentioned above, for example, aminomethylene (-CHNOMH-), and/or in combination with transformations at the M- or C-end of the peptide chain. The increased bioavailability of the peptide derivatives proposed in this invention, in comparison with the availability of peptides that were proposed in previous editions of the special literature, is obviously a consequence of their resistance to proteolytic cleavage in combination with the small size of the molecules.

In the above formulas and later in the text of this document, special terms correspond to the following definitions.

The components of molecules defined by the term "lower alkyls" in the previous lines of this text should be considered to be such alkyl components containing mainly 1-6 carbon atoms, having a certain length and a straight (linear), branched or cyclic chain configuration. Examples of straight-chain (linear) alkyls are methyl, ethyl, propyl, butyl, and hexyl. Examples of branched chain alkyls are isopropyl, sec-butyl, tert-butyl, isopentyl, and isohexyl. Examples of cyclic alkyls are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The components of the molecules, which in the previous lines of this text are defined by the term "lower alkoxy", should be considered /5 such alkoxy components containing mainly 1-6 carbon atoms, having a certain length and a straight, branched or cyclic chain configuration. Examples of straight-chain alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched-chain alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

The components of the molecules defined by the term "lower alkylamino" in the previous lines of this text should be considered to be such alkylamino components containing mainly 1-6 carbon atoms, having a certain length and a straight, branched or cyclic chain configuration. Examples of straight-chain alkylamino are methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino. Examples of branched alkylamino are isopropylamino, t-butylamino, tert-butylamino, isopentylamino, and isohexylamino. Examples of cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino.

In the context of the present invention, the term "aryl" should be understood as the combined name of aromatic rings, such as i) carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl , thiazole, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl, or isothiazolyl, which is variably substituted by one or more radicals of He zo C 1 -C 6 -alkyl, Su 6 -C 6 -apoxy, halogen, amino or aril Aryl is preferably represented by phenyl, thienyl, imidazolyl, pyridyl, indolyl, quinoline, or naphthyl, which is variably substituted by halogen, amino, hydroxy, C. c-alkyl, or C. c-apoxy. at

Components of molecules defined by the term "aralkyl" in the previous lines of this text should be considered to contain lower alkyl and aryl in their turn - as components - defined in the previous lines of the text. --

The term "halogen" should be understood as the group to which SI, E, Bg and | belong. "at

A standard three-letter code is used for natural amino acids, for example, Aia - for alanine.

In the most optimal embodiment of the compound according to formula 1, A is hydrogen, 3-M-Me-AMB, -3-AMB or AIBb. If y is equal to 1, G in the compound according to formula 1 can optimally be Aa, Cu, sarcosine, 3-aminomethylbenzoyl, К-nipecotinyl, nipecotic acid or isonipecotic acid, more optimally - 3-aminomethylbenzoyl, К-nipecotinyl, nipecotic acid or isonipecotic acid. If Ци // пт) с is equal to 1, H can optimally represent Niv, РПпе, Тис, Ре (4-МН 5), 3-Руай, SU, Ага, Заг, Рго, Туг, Ага,

Abop, 3-aminomethylbenzoic acid or Y-Ppe, but optimally H can be Niv, Pne or Aa, ;" most optimally H can be Niz or Aa. C in the compound according to formula 1 optimally represents O-2-naphthylalanine (0-2Mai), O-1-naphthylalanine (0-1Mai), O-Pne or O-Tgr, more optimally - O-2Mai! or 45. O-Rrei is most optimal - M-Me-O-2Mai, O-2Mai, O-Rpe, or M-Me-O-RNe. O in the compound according to formula 1

He") is optimally -ME2p-CH(СНо)Кк-К2)-СО-, where K is optimally equal to 1 and K29 is a lower alkyl; more optimally, K is ХО-Рпе or 0-2Май. The most optimal ХО is М-Me-О-РНе-ol, - М-Ме-ОО-РНе, М-Ме-ОО-2МайИ-ol,. M-Me-O-Rpe-MH», M-Me-O-Rpe-MH-Me, or M-Me-0-(4-1)P pe-MH-Me. aw! If in the compound according to formula 1 p is equal to 1, E optimally represents IGuvg-MH 5", Zeg-MH",

MH-(2-(1-piperazino)ethyl), MH-(3-(1-morpholino) propyl), MH-(2-aminoethyl), MH-(4-aminomethylbenzyl), and MH-(benzyl) , Hug-OH, MH-(1-hydroxy-b-amino-25-hexyl), MH-(2-(1-methyl-2-pyrrolidinyl)ethyl, or

FO 3-M,M-dimethyl-aminopropyl; most optimally, E represents MH-(2-(1-methyl-2-pyrrolidinyl)ethyl, 3-M,M-dimethyl-aminopropyl, I ug-MH", or Zeg-MH"o or B" in the compound according to formula 1 is optimally 2-naphthyl.

IN? optimally represents phenyl, m optimally is in the range of 2-6, and Kk 9 optimally represents МН 2, 29 2-morpholinoethyl, 3-morpholinopropyl or (1-methylpyrrolidinyl)ethyl. KO optimally represents -СООН,

F! -CH.-OH, -H-, -"СОМН" or -СОМ(СНЗ)". Examples of specific compounds presented in this invention are (2k)-2-(3-Aminomethylbenzoyl)-M-Me-O-2Ma1I-M-Me)-3-(2-naphthyl)propanol: 60 b5 mo in LYA db on o | c 70 (3-Aminomethylbenzoyl)- M-Me-0-2Ma1-M-Me-0O-Rpe-MH»: sn, o ro on KA DA

Mkhi MN.

M 2 (c) M y och 3-(3-Aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-O-Ppe-MH)-M,M-dimethylaminopropane: x c

KA EU

ON M ranks (in) M with high school

These

H-AIIB-Niz-M-Me-0-2MaI-M-Me-O-RNe-MA 5:

Mo tro i-oi nos sn, nu sny un o not o sn, o s her

Phi - (Ce) (3-Aminomethylbenzoyl)- M-Me-0-2Ma1-M-Me-0O-Rpe-MH: sn, o vo o « t

And mon o what xx - id su g» FI p

H-AIIB-AIa-0-2MaI-M-Me-O-РНе-Г ув-МН 2 r 45 H-Аиб-Нив-О-2Май-М-Me-О-Рпе-МН 2 2-(3- Aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-0-Rpe-MH)-1-morpholinoethane: d ro o n e f h s M A MH

M tk st o u S

F si (3-Aminomethylbenzoyl)- M-Me-0-2MaI-M-Me-O-Rpe-MN-Me: o sn, g kenya Mk , t en v! сн, о и во во 3-(3-Methylaminomethylbenzoyl)-M-Me-0-2MaI-M-Me-0-Рпе-МН)-М,М-dimethylaminopropane: b5 zh di 2 ne nu im, o | sleep, oh Jew (3-Aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-O-Rpe-MN»: sn. o ro nd zi

UA and kri o sn,.O and I

N-AIIB-Niz-M-Me-0-2MaI-M-Me-O-Rpe-MNMe: , M «a

M

AH and Y and MN

MN "sn nd "rev, sch not Go) sn, 0. o o F yu

3-methylaminomethyl-Mte-0-2MaI-Mte-0O-Rpe-MH-CH 3 "c) fi - : FI ise) 0 ev OO no. A.M sn,

МН current: сн, 0 40 . - c "» Piperidine-4-carboxylic acid "M-(1K)-1-(4-(1K)-2-(4-iodophenyl)1-(methylcarbamoyl)ethyl)-M-methylcarbamoyl)-2-( 2-naphthyl)ethyl)-N-methylamide

F iy - i o o EE Sto

AM! sl 70 ma: Mn Z nm nyu o m. z

AND

Structures of unnatural (artificial) amino acid residues: and:

E same m vo ro g. 79

Abbreviation, which is used to indicate the substitution of a peptide bond: b5 o yame-

AND

OT from

Compounds according to formula 1 can be prepared by traditional methods consisting in soluble or solid-phase synthesis of peptides. For example, solid-phase synthesis can mainly be carried out according to the scheme described (retention time) and Motsipo, Zoi Rraze Reriide Zupipevziv, 2pa. VodapezKu ei aiI., Reriide Zupipeziv, 2p., Ed., Mem Mabok, OA, 1976.

As a substitute for the amide bond according to the method described in U. Zazaki and O.N. Sou, Reiriedez Z(1), 1987, pp. 119-121., aminomethylene can be used. Peptide derivatives containing a mono- or di-hexapyranose derivatized amino group can be prepared by the Amadori rearrangement, mainly by the method described by K. Ajiregi (retention time) ei a!., She Zsiepsez 53, 1993, pp. 517-525 . Examples of mono- or di-hexapyranoses are glucose, galactose, maltose, lactose or cellobiose. Derivatives used in the synthesis as starting materials can either be obtained industrially, if necessary providing them with appropriate protecting groups, or such starting materials used for the preparation of component "A" in general formula 1 can be prepared by well-known methods and if necessary to provide protection in itself. Abbreviations used to designate protective groups: te- Oov- Vosh Eshchos- , that. г (c) жо г о щУ ох щ чу 29 . m Vo. neo sia (o) (c) odu i i re» nro . with

Pharmaceutically acceptable salts of acid additives in compounds according to formula 1 include those that are prepared by reacting a peptide with an inorganic or organic acid, for example, with IS o) hydrogen chloride, hydrochloric), hydrogen bromide, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, o-oxalic, toluenesulfonic, trifluoroacetic, sulfamic and fumaric acids. -

In another aspect, this invention relates to a pharmaceutical composition containing - as an active ingredient - a compound according to general formula 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.

Pharmaceutical compositions containing a compound according to the present invention can be prepared using standard techniques described, for example, in Ketipdiopje Rpagtaseciis! Zsiepsevs, 1985. These compositions may appear on sale also in standard forms, for example, in the form of capsules, tablets, from aerosols, suspensions, plasters or means of local application. The pharmaceutical carrier or diluent used in accordance with the present invention may be a standard solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose (sucrose), cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl cellulose ethers. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, b15 fatty acid amines, polyoxyethylene, and water.

Similarly, the carriers or diluents may include any of the sustained-release substances known in the art, such as, for example, glyceryl monostearate, glyceryl distearate, in free (unbound) form or in admixture with paraffin.

If a solid carrier is used for oral administration, the drug may be formulated as 1 50 tablets, placed in hard gelatin capsules in powder or granular form, or formulated in

F-shaped lozenges and rhombuses. The weight amount of the solid carrier can vary widely, but usually it is from 25 mg to g.

A typical tablet, manufactured by a standard method, may have the following components in its composition:

Core:

GF) Active compound (both the unbound compound and its salt) 100mg

Colloidal silicon dioxide (Aegozvia) 1.Bmg o Cellulose, microcryst. (Amisei) 7Omg

Modified cellulose resin (As-0i-50Y) 7.Bmg 60 Magnesium stearate

Shell:

Hydroxypropylmethylcellulose (HPMC), about 9.Omg 65 "Muzhmaseiy 9-40 T, about 0.9mg

"Acylated monoglyceride is used as a plasticizer for the covering film of the shell.

If a liquid carrier is used, the drug may be formulated as a syrup, emulsion, soft gelatin capsules, or a sterile injectable liquid such as an aqueous or anhydrous liquid suspension or solution.

For administration through the nasal cavity or respiratory tract, the drug must contain a compound according to formula 1, dissolved or suspended in a liquid carrier, in particular, in an aqueous carrier, which makes it possible to use this drug in the form of an aerosol. The carrier may contain such additives as solubilizing agents, for example propylene glycol, such surface-active additives as polyethylene glycols of bile acid salts, polypropylene glycols or polyoxyethylene ethers of higher alcohols, such enhancers (enhancers) of absorption 7/0 as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For administration through the skin, the drug can be made in a form suitable for its use with the help of patches or electrophoresis.

Usually, the compounds according to the present invention are packaged in dosage units containing 0.0001-100 mg of the active component, together with a pharmaceutically acceptable amount of carrier per dosage unit.

The dosage of the compounds according to the present invention is optimally 1-500 mg/day, for example, about 100 mg in one dose, if they are administered to patients, for example, humans, as medicine.

It is shown that the compounds according to the general formula 1 are able to promote the release of endogenous growth hormone ip mimo. Thus, these compounds can be used to treat the body in such circumstances, when there is a need to increase the levels of growth hormone in the plasma, namely, when there is a deficiency of growth hormone 2o in the human body, in the case of treating elderly patients, as well as in in case of treatment of livestock.

Therefore, in a specific aspect, this invention relates to a pharmaceutical composition designed to stimulate the release of growth hormone from the pituitary gland. This composition contains as an active component a compound according to formula 1 or a pharmaceutically acceptable salt of this compound together with a pharmaceutically acceptable carrier or diluent.

In another aspect, this invention relates to a method of stimulating the release of growth hormone from the pituitary gland; this i) method consists in administering to the object in need of such administration an effective amount of a compound according to the general formula 1 or a pharmaceutically acceptable salt of this compound.

In yet another aspect, this invention relates to the use of a compound of general formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for stimulating the release of growth hormone from the pituitary gland. at

Compounds according to formula 1 have important pharmacological properties. An example of such properties is the stimulation of the release of growth hormone from the pituitary gland, which produces the effect inherent in growth hormone itself.

The effects of growth hormone include the following: stimulation of the release of growth hormone in the body --

Gathering of ELDERLY PEOPLE; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; "about stimulating the activity of the immune system; acceleration of wound healing, acceleration of rehabilitation of damaged bones; treatment of growth retardation; treatment of kidney disease or failure resulting from growth retardation; treatment of physiological stunting, in particular in children with growth hormone deficiency, as well as stunting caused by chronic diseases; treatment of obesity and growth retardation caused by obesity; treatment of growth retardation associated with Prader-Willi syndrome and Turner syndrome; speeding up the healing of burns and reducing the percentage of hospitalized patients suffering from burns; treatment intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Itsenko-Cushing syndrome; excitement and?" pulsatile release of growth hormone; replacement of growth hormone in the body of stressed patients; treatment of osteochondrodysplasias, Noonan syndrome, schizophrenia, depression, Alzheimer's disease, delayed

Wound healing and physiological deprivation; treatment of pulmonary tract dysfunction and addiction

He" of forced ventilation of the lungs; weakening of the body's protein-catabolic reaction to extensive surgical intervention; reduction of general exhaustion of the body (cachexia) and loss of proteins caused by chronic diseases such as cancer and AIDS; treatment of hyperinsulinemia, in particular nesidioblastosis (hyperplasia of pancreatic islets); accompanying (auxiliary) treatment with the aim of stimulation of ovulation; stimulation of the development of the 5th thymus function of the thymus gland and prevention of age-related weakening of the thymus function; treatment of patients with a suppressed immune system; increasing the strength of the muscles of mobility, preventing the preservation of the strength of the skin

F cover, regulation of metabolic homeostasis, renal homeostasis in the case of age-related lethargy; stimulation of osteoblast development, bone repair and cartilage development; stimulation of the function of the immune system in the body of domestic animals, as well as treatment of age-related disorders in the body of domestic animals; promoting the growth of livestock and stimulating the growth of sheep and goat wool.

For the purpose of use in the above cases, the dose of the drug may vary depending on

F) the use of a specific variant of the compound according to formula 1, depending on the mode and method of administration and the desired therapeutic result. However, to achieve effective release of endogenous growth hormone, the optimal dose that can be administered to patients and animals can be from 0.0001-10Omg/kg of body weight per day. Typically, dosage units for oral or nasal administration contain from about 0.0001mg to about 100mg, most preferably from about 0.001mg to 50mg, of a compound of formula 1 in admixture with a pharmaceutically acceptable carrier or diluent.

Compounds according to formula 1 can be introduced in the form of pharmaceutically acceptable salt additives to acids, or, if necessary, in the form of salts of alkali or alkaline earth metals or lower 65 alkylammonium. There are reasons to believe that the use of such variants of compounds in the form of salts provides approximately the same order of biological activity as in the case of the use of unbound basic compounds.

Alternatively, the pharmaceutical composition according to the present invention may contain a compound according to formula 1 in combination with one or more compounds of different activity, for example, with an antibiotic or other pharmaceutically active material. It can be another agent that enhances secretion, such as ONKR (1 or 6) or SNKN or their analogues, growth hormone or its analogue, or somatomedin, for example, ISE-1 or ISE-2.

The method of introducing the drug into the body consists in any effective transportation of the active compound to the desired organ or part of the body; the ways of such transportation include oral, nasal (through the nasal cavity), pulmonary, transdermal or parenteral; at the same time, the preference of 70 will be given to the oral route.

Apart from the pharmaceutical use of the compounds according to formula 1, they can be useful as a tool to study the regulation of the ability of growth hormones to be released by migo.

Compounds according to formula 1 can also be useful as a tool for evaluating the releasing capacity of the pituitary gland in relation to the secretion of growth hormone ip mimo. For example, in order to determine their effect on growth hormone /5 Serum samples taken before and after the introduction of these compounds into the human body can be tested.

Comparison of growth hormones in each serum sample allows direct determination of the ability of the patient's pituitary gland to release growth hormone.

Compounds according to formula 1 can be introduced into the body of economically important agricultural livestock for the purpose of accelerating livestock growth and increasing the size and weight of these animals and increasing milk yield.

Compounds of formula 1 can be further evaluated by studying their efficacy and potential properties for the release of growth hormone in rat somatotrophic cells.

Self-trophic rat cells can be prepared, generally following the previous descriptions (Spep eyi pri.,

Epdoshypoiyusdu 1991, 129, 3337-3342 and Spey aY, Epdoshypoiodu, 1989, 124, 2791-2798). Rats are deprived of life by beheading. After that, the pituitary glands are instantly removed from their bodies. Next, the pituitary glands are fermented with 0.296 collagenase (n 0.29 hyalurinidase) in Hanks' balanced salt solution. After that, the cells are i) resuspended in the Ocirressoz Moailey Eadier substrate containing 0.379565 MaHsSoO»z, 10905 horse serum, 2.5905 calf serum, 195 non-concentrated amino acids, 195 glutamine and 195 penicillin/streptomycin, and the concentration is brought to 1.5xX10 9 cells/ Jr. One ml of this suspension is placed in each of the cells (Te) of the 24-cell panel and left before the release evaluation experiment for 2-3 days.

On the day of the experiment, the cells are washed twice in the above-mentioned substrate containing 25 milligram molecules of HERE5, pH7.4. The release of growth hormone is initiated by the addition of a substrate containing 25 av! milligram molecules of NEREZ and the test compound. Incubation lasts 15 minutes at 37"C. After incubation, the volume of growth hormone released into the substrate is measured using a standard radioimmunoassay (RIA). --

Compounds according to formula 1 can be evaluated by their effect on the release of growth hormone in the mimo in the body of female rats anesthetized in pentoethylbarbituric acid, as described in previous works (Vegetsi et al.

Epdoshypoisdu 1991, 129, 2592-2598). In a specific case, adult male Sprague-Dawley rats were anesthetized by intraperitoneal injection of pentoethylbarbituric acid at the rate of 5Omg/kg body weight. "

After achieving complete anesthesia, implantation was performed in the carotid artery and jugular vein using a tracheometric cannula and catheters. After a 15-minute recovery at time O, a blood sample was taken. The pituitary secretion enhancer was administered intravenously, the blood samples were kept on ice for 15 minutes, after which they were centrifuged for 2 minutes at 12,000 rpm. The amount of growth hormone was determined by decanting the serum and using the standard KIA "".

Next, the invention is illustrated by examples, which in no way can limit the scope of application of the invention provided by its FORMULA.

Ge") The compound, the preparation of which is described in the following example, was isolated as a salt of trifluoroacetic acid (TEA). -

Example 1 av! Preparation of 2(8)-2-(3-Aminomethylbenzoyl)-M-Me-0-2Ma!-MaI-Me)-3-phenylpropanol. I pray 42) this is our torment about 4 and Fu about fi name) . 165.7 mg of Bos-M-Me-0-2MaI-onH and 165.2 mg of (K)-methylamino-3-phenyl-propan-1-yl (prepared from 60 N-M-Me-O-Rpe-OH according to MeKeppop, M. u.; Meuegv, A, 1. 3. Abod. Spet. 1993, 58, 3568-71) and 68.1 mg of NO When dissolved in a mixture of 2 ml of UOME and 4 ml of OSM at 0"C. 115 mg of ESAS was added and the mixture was stirred for 1H at 0"C and after that for 18 hours. at room temperature.

Then, before adding 50 ml of EUAs, OSM was removed from the mixture with a stream of nitrogen, and the resulting solution was extracted sequentially with 100 ml of 595 aqueous solution of ManSoO»z, 100 ml of NaO, 100 ml of 595 aqueous solution of KNZOH 62 and 100 ml of H»O. The resulting organic phase was dried (Ma».5O) and concentrated in a vacuum on a rotary evaporator to obtain an oily substance. 502.bmg of 3-Boc-aminomethylbenzoic acid was dissolved in 1ml of OSM by adding 2 drops of OME and then converted into a symmetrical anhydride by stirring with 191.bmg of EVAS for 10 minutes.

A solution of the mentioned lyophilized 2(K)-(H-M-Me-O2MaI-M-Me)-3-phenylpropanol and 342 μl of OIEA in ml of OSM was added to this mixture and the reaction was continued for 20 hours at room temperature. The reaction mixture was then concentrated to obtain an oily substance and re-dissolved in 5 bbml EAs. The resulting solution was extracted sequentially with 100 ml of 595 aqueous solution of MansSo»z, 100 ml of NaOH, 100 ml of 595 aqueous solution

KNZO) and 100 ml of H2O. The resulting organic phase was dried with Ma»5O); and concentrated in vacuo on a 7/0 rotary evaporator to an oily substance. After that, the oily substance was dissolved in 4 ml of OSM / TEAu in a ratio of 1:11 and mixed. After 10 minutes, the mixture was concentrated with a stream of nitrogen, and the resulting oily substance was re-dissolved in 200 ml of 7095 CH zSM / 0.03 M CARRIER and 480 ml of H 20 was added to the solution. The crude product was then purified using semi-preparative chromatography NRI C for seven runs on a 25 mm x 250 mm column , packed with 7Tu- 6-18 silica gel material, 75 which was equilibrated in advance with 28956th SNZSM in 0.05M (Mn.)»5O54, the pH of which was adjusted to 2.5 using

AM NBO,.

The column was eluted using a gradient of 2895 - 38956 SNUZSM in 0.05 M (MNI)»ZO»4, at pH 2.5, at a rate of 1 Oml/minute for 47 minutes and 40"C; fractions containing the peptide were collected, diluted with vol with NaO particles and processed using a Zer-Rake cC18 cartridge (UUaiegv rai y:51910), which was equilibrated with 0.190 TEA.The peptide was eluted from a Zer-Rake 7095 SNZSM 0.196 TEA cartridge and separated from the eluate by lyophilization after dilution with water.

The final product was characterized using analytical chromatography KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). Mass spectrometry agrees with the expected structure within the experimental error of the method (according to the results of mass spectrometry - 0.9 atomic s mass units). at

Chromatographic analysis of CR-NRIS was performed using UV detection at 214 nm and

C-18-silica gel column Mudas 218TRB4, 4.bmm x 250mm, 5u (Pe Zeragayope Sgotsr, Nezregia), elution took place at a speed of Tml/min. And the temperature is 427C. Two different elution modes were used:

A1: The column was equilibrated with 5906th of SZSM in a buffer consisting of 0.1M (MH 454)25045, the pH of which was (Ce) adjusted to 2.5 with 4M NaSO"), and eluted with a gradient of SZSM from 595 to 6095 in the same buffer for 50 minutes.

B1: The column was equilibrated with 595 СНЗСМ / 0.195 ТРА / Н»О and eluted with a gradient from 596 СНеСМ / 0.195 «з

ТРА / Н2О to 6095 СНЗСМ / 0.195 ТРА / НоО for 50 minutes. -

The detected retention time using modes A1 and B1 is 29.90 minutes and 31.52, respectively

MINUTES. (Se)

Synthesis of 3-Boc-aminomethylbenzoic acid 25g of 3-cyanobenzoic acid was dissolved in 7Oml of 2595 МН z/Н2О, and 200ml was added under a nitrogen atmosphere

NYO and 5g 1095 Ra/С. The mixture was hydrogenated under atmospheric pressure at room temperature, while gradually bringing the pH to 10.5 by adding 1295 МН 3з/Н2О. After absorption of about 41 N" for 18 h, the reaction was stopped and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to a volume of 20 ml, and the unreacted starting material was removed by extraction with ethyl acetate after acidification with 200 ml of 1.5 M hydrochloric (hydrochloric) acid. The phase of the aqueous solution was concentrated to dryness and re-dissolved in 400 ml of TNE and 343 ml of 1M Mahon. Zb0g solution was added

Vos-anhydride in 700 ml of TNE, and the mixture was stirred during the day (overnight). After that, the reaction mixture was acidified to a pH of 3 M with HCl and extracted with 300 ml of EtOAc. The organic phase was evaporated to foam

Ge) condition. The output was 22g. - Abbreviations:

HA. room temperature (ab) EBAS: M-ethyl-M"-(3-dimethylaminopropyl)-carbodiimide hydrochloride

EtOAc: ethyl acetate 1.

Vos: i-butyloxycarbonyl 4) M-Me-0-2Mai!: M-methyl-O-2-naphthylalanine

OSM: dichloromethane

RIEA: action of propylethylamine

OME: M,IM-dimethylformamide o NoOPry: 1-hydroxy-7-azabenzotriazole

M-Me-O-Rpe-ol: M-methyl-O-phenylapaninol ime) TEA: trifluoroacetic acid

TNE: tetrahydrofuran bo Prillad 2 3-(3-Aminomethylbenzoyl))- M-Me-0-2MaI-M-Me-0-Rpe-MH)-M,M-dimethylaminopropane b5 not LA 23 z

At o sn, 0 z

Vos-M-Me-O-Rpe-OH (279mg) was dissolved in HYOME (4ml) and stirred for 10 minutes with NOVI (168mg) and ESAS (230mg). 3-Dimethylamino-1-propylamine (188 μl) was added, and the mixture was stirred for 18 h at room temperature.

After that, 595% of an aqueous solution of bicarbonate of soda (50 ml) was added, and the resulting mixture was extracted from

EtOAc (50 ml) and the organic phase were dried over Ma»5Ou4 and concentrated in vacuo to obtain an oily substance.

This oily substance was stirred for 10 minutes at room temperature with TEA/OSM 1:1 (bml). t After that, TPA / OSM was evaporated with a stream of nitrogen, and the obtained oily substance was dissolved in a mixture of 7090

SNZSM (10 ml), 1 M NOA (3 ml) and water (37 ml), and the resulting mixture was immediately frozen and lyophilized.

After lyophilization, the product was dissolved in OME (bml) and OSM (12 ml). It was added to this mixture while stirring

Vos-M-Me-0-2MaI-OnH (494 mg), NOAI (204 mg), OIEA (171 μl) and - after cooling to 0"С - EOAS (288 mg). After stirring for 18 h at room temperature, the OSM was evaporated with a stream of nitrogen and EtOAc (100ml) was added. This mixture was extracted twice with 595 aqueous sodium bicarbonate solution (100ml) and water (100ml) and dried over Ma".5O) and concentrated in vacuo to give an oily substance (480mg). This oily substance was stirred for 10 minutes at at room temperature with TPA/OSM 1:1 (bml). The TEA/OSM was then evaporated with a stream of nitrogen and the resulting oil was dissolved in 70956 SNHSM (10ml). 1M-HCII (ml) and water (47ml) were added, and the resulting mixture was immediately frozen and lyophilized to obtain an oily substance (2 NOSI, s

H-m-Me-0-2MaI-M-Me-0-Rpe-MH-(CH2)3-M(CHnaz)2). Half of the volume of the mentioned oily substance (2 NOSI, o

H-M-Me-0-2MaI-M-Me-O-Rpe-MH-(CH 25)3-MSH(CHZ)2) was dissolved in OSM (OUml) and 2 drops of OME and OIEA (342 μl) were added. This solution was added to a solution of Vos-BAMV-OH (503mg) and EOAS (192mg) in OSM (5ml), which was stirred for 15 minutes at room temperature. After stirring for 20 g, the reaction mixture was concentrated to obtain an oily substance using a stream of nitrogen and stirred for 15 minutes with 595 g of aqueous sodium bicarbonate solution (10 Oml). IC o)

After that, EtOAc (50 ml) was added, the organic phase was separated and extracted with 596 aqueous sodium hydrogen carbonate solution (100 ml) and water (100 ml), and then dried over Na»5O) and concentrated in a vacuum to obtain an oily substance (340 ). This oily substance was stirred for 10 minutes at room temperature with TEA/OSM in a ratio of 1:1 (bml). Next, TEA/OSM was evaporated with a stream of nitrogen and the resulting ! ! ' in (Ce) the oil was dissolved in 7096th CH with CM (1Oml) and diluted with water to a final volume of 5bml. The crude product was purified using semi-preparative chromatography NRI C in eight runs and lyophilized using procedures similar to those described in example 1. The obtained final product was studied using analytical chromatography CR-NPR (retention time) and plasma desorption mass spectrometry (molecular weight ). " 20 The obtained molecular mass (MH 7:608.2 atomic mass units) is consistent with the expected structure (theor. sh-v s MH" 608.8 atomic mass units), within the limits of the experimental permissible error of the method. Retention time. KR-NRI C using the elution modes A1 and B1, described in example 1, was 25.23 and 26.58 minutes, respectively.

Example C 3-(3K)-3-Piperidinecarbonyl)-M-Me-0-2Ma1-M-Me-O-Rpe-MH)-1-M,M-dimethylaminopropane

Fro z OKA o y I sn, s o sh Half 2 NSI, H-M-Me-0-2MaI-M-Me-0-Rpe-MN-(CH»)z-M(CH3)», obtained as the oily substance in example 2 was dissolved in OSM (Oml) and 2 drops of OME, and OIEA (342 μl) was added.

This solution was added to a solution of Bos-1B)-nipecotic acid (459mg) and EOAS (192mg) in OSM (5ml), which was previously stirred for 15 minutes at room temperature.

GF) After stirring for 20 g, the reaction mixture was concentrated to obtain an oily substance with a flow

HF nitrogen and stirred for 15 minutes with 5956 aqueous solution of sodium bicarbonate (100 ml).

After that, E(Ac (50 ml) was added, the organic phase was separated and extracted with a 595% aqueous solution of sodium hydrogen carbonate (100 ml) and water (100 ml), then dried over Na»5O) and concentrated in a vacuum until an oily substance was obtained.

This oily substance was stirred for 10 minutes at room temperature with TEA/OSM 1:1 (bml). Next, the TEA/USM was evaporated with a stream of nitrogen, and the resulting oily substance was dissolved in 7095 CH with CM (1 Oml) and diluted with water to a final volume of 5 bml. This crude product was then purified using semi-preparative HPLC chromatography in five runs and lyophilized using procedures similar to those described in Example 1.

The obtained final product was studied using analytical chromatography KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH ": 586.3 atomic mass units) is consistent with the expected structure (theor. MH "585.8 atomic mass units), within the experimental permissible error of the method. Retention time of KR-NRI C using elution modes

A1 and B1, described in example 1, was 25.33 and 26.35 minutes, respectively.

Example 4 2-(3K)-3-Piperidinecarbonyl)-M-Me-O-2MaI-M-Me-O-Rpe-MH)-1-(1-methyl-2-pyrrolidinyl)ethane

MN X M games

Phi Phi t Vos-M-Me-O-Rpe-OH (279mg) was dissolved in OME (1Oml) and stirred for 10 minutes with NOVI (168mg) and EVAS (38v4mg). 2-(Aminoethyl)-1-methyl-pyrrolidine (29 µL) and OIEA (171 µL) were added, and the mixture was stirred for 20

H at room temperature. After that, the mixture was concentrated to obtain an oily substance, which was dissolved in 5 ml of water and lyophilized. The product was re-dissolved in 25 ml of water and then applied to the Zer-Rak cartridge? C18 UU/aiegv (retention time). 2Zh:43345), which was equilibrated with 0.03 M hydrochloric acid.

The product was eluted on a Zer-Raqf with 7095 SNZSM in 0.03 M hydrochloric acid and separated from the eluate by lyophilization after dilution with water. The resulting material was stirred for 10 minutes at room temperature with TPA/OSM 1-1 (bml). After that, the TEA/OSM was evaporated with a stream of nitrogen, and the resulting oily substance was dissolved in 7095 CHZSM (1 Oml) and 1 M hydrochloric acid (2 ml) was added. After dilution with water (5 Oml), the product was separated by lyophilization. The resulting material was dissolved in OME (3 ml) of water and stirred at 18 N at room temperature after adding Vos-M-Me-O-2MaI-OnH (329mg), NOAI (136bmg), o

EORAS (230Omg) and OSIEA (171μl). Then EAs (500ml) was added and this mixture was extracted with 5956th aqueous solution of sodium bicarbonate (50ml), with 590th aqueous solution of potassium hydrogen sulfate (500ml) and with water (50ml). The organic phase was dried with sodium sulfate and concentrated in vacuo to an oily substance. and 3o This oily substance was stirred for 10 minutes at room temperature with TEA/OSM 1:1 (bml). After that IS o)

The TEA/OSM was evaporated with a stream of nitrogen and the resulting oil was dissolved in 7095 CH3SM (1Oml) and 1M hydrochloric acid (3ml) was added. The product was isolated by lyophilization after diluting it with water (50 ml). -- 286 mg of this lyophilized product was dissolved in OSM (15 mL) and OIEA (171 L). This solution was added to a solution of Bos-(K)-nipecotic acid (459 mg) and EVAS (192 mg) in OSM (1 O mL), which was stirred before with this for 25 minutes at room temperature.

After stirring at 20N, the reaction mixture was concentrated until an oily substance was obtained with a stream of nitrogen, after which it was re-dissolved in EtOAc (100 ml) and extracted with a 596 aqueous solution of sodium hydrogen carbonate (5 Oml), with a 590 aqueous solution of potassium hydrosulfate (5Oml) and with water (5Oml). The organic phase c was dried with sodium sulfate and concentrated in vacuo to obtain an oily substance. c This oily substance was stirred for 10 minutes at room temperature with TPA/OSM 1:1 (bml). Then TPA/USM :z" was evaporated with a stream of nitrogen and the resulting oil was dissolved in 7095 SNHZSM (1Oml) and diluted with water to a final volume of 5Oml.

Next, this crude product was purified using semi-preparative NRI C chromatography in three runs and was lyophilized using procedures similar to those described in example 1. The final product obtained was studied using analytical KR-NRI C chromatography (retention time) and plasma desorption mass spectrometry - (molecular weight). The obtained molecular weight (MH ": 612.2 atomic mass units) agrees with the expected structure (theor. MH: 612.39 atomic mass units), within the limits of the experimentally permissible error of the method. o The retention time of KR-NRI C using the At elution mode described in example 1 was 25.80

F minutes.

Example 5. dream

FI

60 (Kk)-2-(M-tert-Butoxycarbonyl-M-methylamino)-3-(2-naphthyl) propionic acid complex methyl ester. body weight, 65 cm,

(K)-2-tert-Butoxycarbonyl-M-methylamino-3-(2-naphthyl)-propionic acid (5.0g, 16b.4mmol) was dissolved in dry OME (50ml). Iodomethane (6 b, 2 ml, 98.4 mmol) and silver(I) oxide (13.3 g, 57 4 mmol) were added, and the mixture was stirred for a day. The reaction mixture was filtered and the filtrate was extracted with methylene chloride (200 ml).

The organic phase was washed with m/th potassium cyanide (2x5Oml; 5905) and water (3x75ml). Next, the organic phase was dried (M9504) and the solvent was removed under vacuum. The residue (precipitate) was subjected to chromatographic treatment (Silica gel, 5x4OsMm) using ethyl acetate and heptane (1:22) as an eluent, obtaining 4.98 g of (Kk) 2-(M-tert-Butoxycarbonyl-M-methylamino)-3- (2-naphthyl) propionic acid complex methyl ester.

TN-MME (SOSIz): 1.30, 1.35 (two in, 9H); 2.71, 2.75 (two in, ZN); 3.19, 3.47 (two tons, 35 2H); 3.74, 3.77 70 two 8, ZN); 4.65, 5.05 (two aa, 1n), 7.29-7.82 (t, tn) (mixture of rotamers) (P)-2-N-tert-Butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid. (K)-2-(M-tert-Butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid complex methyl ether (21.73g; 65.57mmol) was dissolved in 1,4- dioxane (200 ml) and water (20 ml) was added. The reaction mixture was cooled in a water bath and lithium hydroxide (1.73 g; 72.13 mmol) was added. After 15 minutes, water (140 ml) was added, and the reaction mixture was then further stirred for 3 hours at room temperature. Ethyl acetate (400ml) and water (300ml) were added, and the pH was adjusted to 2.5 using 1M sodium hydrogen sulfate (1100ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic phases were washed with water (300 mL), dried (Mo 5 O)), and the solvent was removed in vacuo to yield 20.1 g at (Kk) 2-(M-tert-Butoxycarbonyl-M-methylamino)-3-(2-naphthyl) propionic acid.

H-MMK (0OM5O) 1.18, 1.21 (two in, 9H), 2.62, 2.66 (two in, ZN); 3.11-3.58 (t, 2H); 4.75, 4.90 (two aa, 1n), p 29 7.АВ-7.88 (t, 7Н); 1.85 (from (Bg), 1H)(mixture of rotamers) o (K)2-Formylamino-3-(2-naphthyl)propionic acid. (K)-2-amino-3-(2-naphthyl) propionic acid (18.11 g, 84.14 mmol) was dissolved in formic acid (204 ml) and av! acetic anhydride (7 Oml) was added dropwise. The reaction mixture was heated at 557C and stirred for 3 hours at room temperature. Ice water (/Oml) was added dropwise and stirred at 07C for 20 minutes. The reaction mixture was filtered and washed with ice water (20 ml), yielding 20.26 g (Kk) (se) of 2-formylamino-3-(2-naphthyl) propionic acid. 7"nH-MME (OM): 3.05 (ad, 1H); 3.27 (da, 1H); 4.64 (t, IN); 7.48-7.87 (t, 7H); 7.95 (c, 1H), 8.45 (a, 1H); 12.9 (in (Bg), 1H). "(8)-Methylamino-3-(2-naphthyl)propan-1-ol. - - "

(K)-2-Formylamino-3-(2-naphthyl)propionic acid (4.37 g; 18 mmol) was dissolved in dry tetrahydrofuran

He") (100 ml) and sodium borohydride (1.6 g; 43.2 mmol) was added. Iodine (4.57 g; 18 mmol) was dissolved in dry tetrahydrofuran (40 ml) and added dropwise to the reaction mixture at a temperature not exceeding 40°C.

After this addition, the reaction mixture was heated to reflux temperature (with reverse cooling) for about 12 hours. Potassium hydroxide (5 Oml, 20905) was added. The phase of the aqueous solution was extracted with complex methyl tert-butyl ether (4x5Oml). The combined organic layers were washed with saturated sodium chloride (15 Oml), dried (Mo9505), and the solvent was removed in vacuo. The residue (precipitate) was subjected to

FO chromatographic treatment (Ziiisa: 5x4Osm) using OSM/methanol/ammonia (100:10:1), obtaining 1.81g (Kk) of methylamino-3-(2-naphthyl)propan-1-ol. 7H-MMe (SOCI3): 2.43 (in, ZN); 2.88-3.05 (t, ZN); 3.10 (in (Bg), 2H); 3.42 (yes, tn); 3.69 (ad, 1H): 7.30-7.82 (t, 7H).

M-(1 kA -IM-(1 KO-2-Pdroxy-1 o -(2-naphthyl)methyl)ethyl)-M-methylcarbamoyl1|-2-(2-naphthyl)ethyl)-M-methylcarbamic acid complex tert -butyl ether (name) p. bo ver on (K)-(M-7ret-Butoxycarbonyl-M-methylamino)-3-(2-naphthyl) propionic acid (0.55g, 1.67mmol) and (K) bomethylamino-3-(2-naphthyl) ) propan-1-yl (0.38 g, 2.00 mmol) was dissolved in methylene chloride (15 ml) and dimethylformamide

(7.Bml). The reaction mixture was cooled in an ice bath. 1-Pdroxy-7-azabenzotriazole (0.24 g; 2.09 mmol) and N-(3-dimethylaminopropyl)-Methylcarbodiimide hydrochloride (0.38 g; 2.0 mmol) were added. The reaction mixture was stirred for 12 hours at room temperature. Then the reaction mixture was concentrated in vacuo. Ethyl acetate (200 mL) was added, and the organic solution was washed with water (100 mL), sodium bicarbonate/sodium carbonate (pH 9) (75 mL), sodium hydrogen sulfate (75 mL, 1090), water (100 mL), and dried (Ma5O)). The solvent was removed in vacuo, and the residue (precipitate) was chromatographed (5 mm, 2 x 45 cm) using ethyl acetate, yielding 0.259 g of

М-41к)-1-(4-К1К)-2-pdroxy-1-((2-naphthyl)methyl)ethyl)-M-methylcarbamoschi-2-(2-naphthyl)ethyl)-M-methylcarbamine 7/0 complex tert-butyl ether of acids. 7TnH-MME (0M50): 0.80-1.99 (several in, 9H); 2.45-4.20 (t, 12 H); 4.70-5.12 (t, 2H) (selected peak values, mixture of rotamers) (2k)-M4-(1k)-2-hydroxy-1-((2-naphthyl)methyl)ethyl)-M-methyl-2-methylamino -3-(2-naphthyl) propionamide.

I'm from. still he oo

M-C1 t)-1-(M-(1

KO-2-hydroxy-1-((2-naphthyl)methyl)ethyl)-M-methylcarbamoyl|-2-(2-naphthyl)ethyl)-M-methylcarbamic acid complex tert-butyl ether (0.25g; 0.475mmol) ) was dissolved in OSM (Zml). Trifluoroacetic acid (1 ml) was added, and the reaction mixture was stirred for 20 minutes. The solvent was removed in vacuo. OSM (5 mL) was added and removed under vacuum, and the operation was repeated. The residue (precipitate) was dissolved in methanol (5 ml). Sodium hydrogencarbonate/sodium carbonate (5 ml; pH 2.0) was added with 29 g, and the solution was extracted with ethyl acetate (2x10 ml). The organic (U phase was dried (MaBO,), the solvent was removed, obtaining 0.22 g of (2k)-M4-(1

K)-2-hydroxy-1-(2-naphthyl)methyl)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.

TN-MME (SOS): 170, 2.37, 2.45, 2.93 (four 5, 6H); 2.56-3.05 (t, 2H), 3.52-3.85 (t, 7H); 4.25, 4.97 (two t, 1H), 6.86-7.78 (t, 14H) (selected peak values, mixture of rotamers). i-o 3o (2k)-2-(3-Aminomethylbenzoyl)-M-Me-0-2Ma1I-M-Me)-3-(2-naphthyl)propanol IS o) 2 ne KAH li «-

Y (Ce) f 3-Bos-aminomethylbenzoic acid (502.b6mg) was dissolved in SOCM (bml) and then converted into the symmetrical anhydride by stirring with EOAS (191.bmg) for 15 minutes.

A solution of (25k)-M-(1 KO)-2-hydroxy-1 - c -(2-naphthyl)methyl)ethyl)-M-methyl-2-methylamino-3-(2-naphthyl)propionamide was added to this mixture (200mg) in OSM (B5ml), after which the reaction continued for 20 N at room temperature. "» The reaction mixture was further concentrated to obtain an oily substance and re-dissolved in EtOAc (100 ml). This solution was successively extracted with 596 aqueous solution of ManHsSoO»z (2x50 ml), 596 aqueous solution

KNBZO) (2x50ml) and NiO (2x50O0ml). The resulting organic phase was dried with Ma».5Ou; and concentrated in (o) vacuum on a rotary evaporator to obtain an oily substance. After that, the oily substance was dissolved in OSM/TRA 1:1 (bml) and mixed. After 10 minutes, the mixture was concentrated with a stream of nitrogen, and the resulting oil was re-dissolved in 7095 SNUZSM / 0.195 ТРА (5 ml) and diluted with water to a volume («c) of 100 ml. pg 50 This crude product was further purified by semi-preparative HRI C chromatography in two runs and lyophilized using procedures similar to those described in Example 1. 4) The final product obtained was studied by means of KR-HRI C chromatographic analysis (retention time) and plasma desorption mass spectrometry (molecular mass). The obtained molecular mass (MH ": 559.5 atomic mass units) agrees with the expected structure (theor. MH "560.72 atomic mass units) within the experimental error of the method.

GF) The retention time of KR-NRI C using elution modes A1 and B1, described in EXAMPLE 1, was 33.07 and 34.63 minutes, respectively. o Example 6 H-AIIB-Niz-0-2MaI-M-Me-0-Rpe-MH" 60 b5

I and o o "not DYA well I t you nn and not o sn, o 70 lEh

The peptide was synthesized according to the Ethos scheme on an Arried Viozuzietz 431A peptide synthesizer, calibration 0.22 mmol, using UV protocols proposed by the manufacturer RazimMos, using intermediate bonds

NVT for NMR and UV monitoring of the deprotection of the protective Ethos group. For the synthesis, we used 75 starting resin cat.y: O-1675 manufactured by Vaspegp Reipspetikayep As, Vybrepadaboi, Zm/ygepapa (427 mg), which is GEtos-2,4-dimethyloxy-4-(carboxymethyloxy)-benzhydryl-amine, attached to amino-methyl-polystyrene resin through an amide bond. The capacity (productivity) of substitution was

About 55 mmol/g. We used such protected derivatives of amino acids as Etos-M-Me-O-Rpe-OH, Htos-O0-2MaI-OH,

Etos-Niv(Tg) and Etos-AIR-ON. The chemical bond Ethos-M-Me-O-Rpe-OH is implemented as a double bond. After synthesis, the peptide was hydrolyzed from 750 mg of peptide resin by stirring for 180 minutes at room temperature with a mixture of 1 ml of TPA, 10 mg of phenol, 200 μl of ethanedithiol, 400 μl of thioanisole, and 40 O0 μl of H2O.

The hydrolyzed mixture was filtered, and the filtrate was concentrated to about 2 ml with a stream of nitrogen. The crude peptide was precipitated from this oily substance using 50 ml of diethyl ether and washed twice with 50 ml of diethyl ether. The crude peptide was dried and purified by semi-preparative HRIS chromatography, single-run SM, lyophilized using procedures similar to those described in example 1.

The obtained final product was studied using chromatographic analysis of KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH ": 598.5 atomic mass units) agrees with the expected structure (theor. MH "598.73 atomic mass units) within the experimental error of the method. X,

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 24, 68, and 25.58 minutes, respectively.

Example 7 H-AIIB-Niz-0-2MaI-M-Me-O-RNpe-zeg-MN» o

M uv, -

NO, (Se) ne p: o pr i i « z) - s This compound was synthesized using procedures similar to those described in example 6. The obtained final product was studied using chromatographic analysis of KR-NRI C (retention time) and mass spectrometry » plasma desorption (molecular weight). The obtained molecular weight (MH ": 685.6 atomic mass units) agrees with the expected structure (theor. MH "685.81 atomic mass units) within the experimental error of the method.

Me. The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 24.42 and 25.92 minutes, respectively. o Example 8 (3-Aminomethylbenzoyl)-O-2MaI-M-Me-O-Rpe-MH2

Fo "KA i 3 ra m. 9 | es o and fi I

F! This compound was synthesized using procedures similar to those described in Example 6. The only exception was that the coupling of Etos-0O-2Mai-OH was carried out using NATO as an activating reagent. where N-M-Me-O-Rpe-resin (0.23 mmol) was combined for 150 minutes with 30 mmol of Ethos-O-2MaI-OH, using 1 mmol of NATI in the presence of OIEA (2 mmol). 6o The obtained final product was studied using chromatographic analysis of KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH ": 511.2 atomic mass units) agrees with the expected structure (theor. MH " 509.6 atomic mass units) within the experimental error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 30.73 and 32.47 minutes, respectively.

Example 9 (4-Piperidinecarbonyl)-0-2MaI-M-Me-0-Rpe-MH2

Look at her, oh KG vi

This compound was synthesized using procedures similar to those described in EXAMPLE 8. The obtained final 7/0 product was studied using KR-NRI-S chromatographic analysis (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular weight (MN) ": 486.8 atomic mass units) agrees with the expected structure (theor. MH" 487.6 atomic mass units) within the experimental error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 75, 27.03 and 28.48 minutes, respectively.

Example 10 (ZR)-3-piperidinecarbonyl)-0-2MaI-M-Me-О0-Рпе-МН»

And fi

This compound was synthesized using procedures similar to those described in example 8. The obtained final product was studied by means of chromatographic analysis EP-NRI C (retention time) and mass spectrometry (3 plasma desorption (molecular weight). The obtained molecular weight (MH ": 486.9 atomic mass units) is consistent with the expected structure (theor. MH" 487.6 atomic mass units) within the experimental error of the method. , was 28.03 and 29.50 minutes, respectively. that)

Example 11 (3Z-Aminomethylbenzoyl-M-Me-0-2MaI-M-Me-O-Rpe-MH" about sn, 8 that "- lower ve. about about (Ce)

This compound was synthesized using procedures similar to those described in Example 8, except that "the last residue (precipitate) is introduced using a symmetrical anhydride coupling.

Bos-3-Aminomethylbenzoic acid (251mg) was stirred for 15 minutes with EVAS (9bmg) in OSM. After that, resin (429 mg) was added and stirring was continued for 18 hours. Another difference is that the time spent on hydrolysis with separation of the peptide from the resin was reduced to 60 minutes. The obtained final "" product was studied using chromatographic analysis of KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular weight (MH 7:522.9 atomic mass units) is consistent with the expected structure (theor. MH "523.6 atomic mass units) within the experimental limits

There are errors in the method. - The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 28.83 and 30.13 minutes, respectively. o Example 12 H-AIIB-Niz-M-Me-0-2MaI-M-Me-0-Rpe-MN» with 50 her s y rya o ro 4) pat M. u ne o sp o o

F) ! !

This compound was synthesized using procedures similar to those described in EXAMPLE 8; in this example, where both Etos-M-Me-O-2MaI-OH and Etos-Niz(Tt) coupling was implemented using NAT/, and the time spent on hydrolysis with separation of the peptide from the resin was reduced to 60 minutes. The obtained final product 60 was studied using EP-NRI C chromatographic analysis (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH 7:612.3 atomic mass units) agrees with the expected structure (theor. MH 7:612.8 atomic mass units) within the experimental error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 24.33 and 26.20 minutes, respectively.

Example 13 (3-Aminomethylbenzoyl)-0-2Ma!I-M-Me-0-Rpe-MH»

This compound was synthesized using procedures similar to those described in example 8. The obtained final product 70 was studied using chromatographic analysis of KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular weight (MH 7:587.2 atomic mass units) is consistent with the expected structure (theor. MH "586.74 atomic mass units) within the experimental error of the method. The retention time of KR-NRI C using the A1 and VI elution modes, described in example 1, was 21.13 and 22.60 minutes, respectively.

Example 14 (3-AmBIomethylbenzoate)- M-Me-O-2MaI-M-Me-O-Rpe-MH

In nn

X mn,

This compound was synthesized using procedures similar to those described in example 11. The final product obtained was studied using chromatographic analysis of KR-NRI C (retention time) and mass spectrometry of plasma desorption (molecular weight). The obtained molecular mass (MH 7:601.6 atomic mass units) agrees with the expected structure (theor. MH 7:601.77 atomic mass units) within the limits of the experimental and) error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 20.40 and 21.70 minutes, respectively. Example 15 ((3K)-3-piperidinecarbonyl)-M-Me-O-Rpe-M-Me-O-Rpe-Y ugz-MH"

DZ and sun, 6 - o f t (av) o sun, 9 oo: yo and (Se)

MN

This compound was synthesized using procedures similar to those described in example 11. The final product obtained was studied by means of chromatographic analysis of KR-NRI C (retention time) and mass spectrometry "20 plasma desorption (molecular weight). The obtained molecular mass (MH 7:579.4 atomic mass units) is consistent with the expected structure (theor. MH 7:579.8 atomic mass units) within the experimental range

And method errors. and?" The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 19.88 and 21.20 minutes, respectively.

Example 16 H-AIIB-Niz-M-Me-0-Rpe-M-Me-O-Rpe-Y uz-MN"

This compound was synthesized using procedures similar to those described in example 12. The obtained final product was studied by means of chromatographic analysis KR-NRI C (retention time ) and plasma desorption mass spectrometry (molecular mass). The obtained molecular mass (MH 7:690.6 atomic mass units) agrees with the expected structure (theor. MH 7:690.9 atomic mass units) within experimental (Ф) error method. ka The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 15.71 and 17.82 minutes, respectively. in Example 17 ((ZK)-3-Piperidinecarbonyl)-M-Me- 0-2MaI-M-Me-0-Rpe-MN" b5

"ik odu o sn, oh and Z

This compound was synthesized using procedures similar to those described in Example 11.3

Ethos-M-Me-0O-Rpe-OH, /Ethos-M-Me-O0-2Mai-OH and Bos-(K)-Nipecotic acid, where the combination is Ethos-M-Me-O-2Ma!-one , as well as Vos-(K)-Nipecotic acid were realized using NATI. The obtained final product was studied using chromatographic analysis of KR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH 7:500.7 atomic mass units) agrees with the expected structure (theor. MH 7:501.7 atomic mass units) within the experimental error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 28.18 and 29.55 minutes, respectively.

Example 18 Н-АЙрБ-АЙа-0-2МаИ-мМ-Ме-О-РПе-И uz-МН" not b Ne o I, z Mn x Mn noru M shchi t, nn, se

This compound was synthesized using procedures similar to those described in example 11. The obtained final i) product was studied using chromatographic analysis of CR-NRI C (retention time) and plasma desorption mass spectrometry (molecular weight). The obtained molecular mass (MH 7:660.7 atomic mass units) is consistent with the expected structure (theor. MH 7:660.8 atomic mass units) within the limits of the experimental "(About error of the method.

The retention time of KR-NRI C using the A1 and VI elution modes described in example 1 was 25.63 and 26.75 minutes, respectively. (av)

Example 19 H-3-Aminomethylbenzoyl-M-Me-0-2Ma1-M-Me-0O-Rpe-MH-CHnuz - | (Te) o EE s, 0 "but where much" in s sv, (in) ;"

Vos-ZAMV-OH (115 mg, 0.458 mmol), 1-hydroxy-7-azabenzotriazole (b2 mg, 0.458 mmol) and 15 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (97 mg, 0.504 mmol) were dissolved in OSM (ml ) and OME (Iml) and stirred for 15 minutes. First, M-methyl-2-methylamino-M-(1 K)-1 - -(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (185 mg, 0.458 mmol) dissolved in OSM (5 ml) was added , and then diisopropylethylamine (8 Oml, 0.458 mmol), and the mixture was stirred for 20 hours. The organic phase was washed with sodium hydrogencarbonate (5Oml, 595) H20 (5Oml), saturated with sodium chloride (5Oml), dried with sodium sulfate and evaporated in vacuo.

Ф The residue (precipitate) was dissolved in SOHC (2 ml) and treated with TEA (2 ml) for 10 minutes. Volatile components were removed by Mo flow. The residue (precipitate) was dissolved in 5 Oml of 2095 Mesm and diluted with water to a volume of 500 ml.

Semi-preparative NRIS 1Oml/min., 5 runs, 30-40956 Mesm/o0.1mM (Mn.)»zO,X rnag,5

Detection 27bnm, Zer-Raiz, 7096 Mesm/0.195 TEA, lyophilization

GF) RO-M5 Theor. 536.7 7 Exper. 535.71

NRGIS JSC g; (retention time) 31.20 min.

B1 f (holding time) 36.35 minutes. 60 Example 20 H-AIIB-Niv-M-Me-O-2Ma!-M-Me-O-Rpe-MNMe b5

M mi o ne o Ki o E nd nn u sv, ne Ge) sn, 0

FI

Ethos-1-Niv(Trityl)-OH (1.54g, 2.4vmmol) (VASNEM B-1570) and 1-hydroxyaza-benzotriazole (338mg, 2.4v8mmol) were dissolved in 1 mL of OME, cooled to 0-4" and added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475mg, 2.48mmol) The reaction mixture was stirred for 15 minutes at 0-47C.

M-Methyl-2-methylamino-M-((1K)-1--"Methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (50mg, 1.24mmol), dissolved in methylene chloride (18ml), was cooled to 0"C, then added to the mixture and stirred for 1 hour at 0-47C, and then diisopropylethylamine (0.425ml, 2.48mmol) was added. The temperature of the mixture was slowly raised to room temperature, and the mixture was stirred after reaching this temperature for 72 hours. OSM was evaporated in a flow of Mo, 100 ml of ethyl acetate was added to the mixture, and it was washed with sodium bicarbonate (2x10Oml, 595) and potassium hydrosulfate (10Oml, 590). The phases were separated and the organic phase was dried over sodium sulfate and evaporated in vacuo. The residue (precipitate) was dissolved in OME (8ml) and reacted with piperidine for 15 minutes, diluted with HO (100ml) and quenched with acetic acid (1.5ml).

Acetonitrile was added, and the mixture was diluted with H 50 to a volume of 250 ml. The clear solution was added to 10 g of "Zerrakv" w/maieg, washed with H»2O/O.05 t HCl and eluted with 5HOml 3596 MesSmM/0.03 M HCl. It was given and diluted (3

But to the volume of 200 ml and lyophilized.

Bos-o aminoisobutyric acid (756 mg, 3.72 mmol), 1-hydroxyazabenzotriazole hydrate (506 mg, 3.72 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 3.72 mmol) were dissolved in OME (bml) and after with 20 15 minutes, added H-1-Niz(Trityl)U-MMer2MaI-MMeoRpe-MNeNZ, 2 NS. was dissolved in OSM (12 ml), after which diisopropylethylamine (0.637 ml) was added and stirred for 72 hours. OSM was evaporated in a flow of Mo, 100 ml of ethyl acetate was added to the M) mixture and washed with sodium bicarbonate (2x5Oml, 5905) and potassium hydrogen sulfate (5Oml, 595). The phases were separated and the organic phase was dried over sodium sulfate and evaporated in vacuo.

The residue (precipitate) was dissolved in OSM (bml), cooled to 0-4"C, and treated with TEA (bml) for 10 min. at - 0-47. Volatile components were removed with a flow of M o. The oily residue was dissolved in ZbBml of 7095 acetonitrile, ! | . . ! (Ce) diluted NoO to a volume of 5Oml and added 1Oml of concentrated hydrochloric acid (12-molar) and stirred for 72 hours. The mixture was diluted with water to 200ml and neutralized with solid potassium carbonate, after which the final dilution of NoO to volume 400 ml.

Semi-preparative NRIS « 20 RO-MB5, theory: 550.7, exper. 550.1 -in

NRI S JSC g; (holding time). 31.75 minutes. s B1 f (retention time) 36.15 min. Example 21 3-methylaminomethylbenzoyl-M-Me-0-2Ma!I-M-Me-0-Rpe-MH-CHz fi g ? - OB ne o (94 I4 o n "MN tive ai MN" sl 50 sn, 0 42)

Bos-MMezAMV-OH (658mg, 2.4v8mmol), 1-hydroxyazabenzotriazole hydrate (338mg, 2.48mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475mg, 2.48mmol) were dissolved in bml of OME and stirred for 29 within 15 minutes. (PI M-Methyl-2-methylamino-M-((1P1)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthylpropionamide (50mg, 1.24mmol)) dissolved in methylene chloride (12ml) was added after to which diisopropylethylamine (0.425 mL, 2.48 mmol) was added.The mixture was stirred for 20 hours.

OSM was evaporated in a flow of Mo, and 75 ml of ethyl acetate was added to the mixture, after which it was washed with sodium bicarbonate (2x5Oml, 595) and potassium hydrogen sulfate (5Oml, 595). The phases were separated and the organic phase was dried over sodium sulfate and evaporated in vacuo. The residue (precipitate) was dissolved in 1Oml of methylene chloride, cooled to 0-47 and treated with TEA (1Oml) for 10 minutes. at 0-4"C. Volatile components were removed with a flow of Mo. The oily residue (precipitate) was dissolved in 25 ml of 70956 MesSmM/0.195 TPA and diluted with H 50 to a volume of bOOml. bo Semi-preparative NRIS

Large column, 40 ml/min., 8 runs 28-408; R. 11 (1) 2304, 276 NM.

Zerrak, Lyophilization

РО-М5 Theory: 550.7, exper. 550.1

NRGIS JSC g; (holding time) 31.75 minutes.

B1 f (holding time) 36.15 minutes.

Example 22

Piperidine-4-carboxylic acid M-((1 K-1 -(M-(1 KO-2-(4-iodophenyl)-1 - (methylcarbamoyl)ethyl)-M-methylcarbamoyl)-2-(2-naphthyl) ethyl)-M-methylamide o E Sn o

A.M sleep 5 tr

NM ns o

And I

(2K)-2-(M-(epi-butoxycarbonyl-M-methylamino)-3-(4-iodophenyl)propionic acid in 1 pod ne A OH "ne o i sn, o c

It was prepared according to Sap U. Spet. (1977), 55, 906. o 7TN-MME: (SOSIi) a 1.34 (z, 4.5Н), 1.38 (в, 4.5Н), 2.70 (8, 1.5Н), 2.75 (в, 1.5Н); 2.85-3.10 (t, MH), 3.2-3.4 (t, 1H); 4.4-4.6 (t, 0.5H), 6.9-7.0 (t, 2H), 7.62 (a, U-10H2, 2H2), 9.5- 10 (rev, 1H)

M-((1 2)-2-(4-Iodophenyl)-1 -"methylcarbamoyl)ethyl)-M-methylcarbamic acid (ep-butyl ether soroyu sn 0 35.-.!ix, (2kK)-2-(M-heg-butoxycarbon-M-methylamino)-3-(4-iodophenide)propionic acid (2.00g, 4.9mmol) was dissolved in methylene chloride (20ml) Hydroxybenzotriazole hydrate (0.67g, 4.9mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.99g, 4.9mmol) were added and the mixture was stirred for 15 minutes. Methylamine (0.38g 4095 solution in methanol, 4.9 mmol) was added and the mixture was stirred. Methylene chloride (40 ml) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) w-v s and sodium hydrogen sulfate solution (1095, 500 ml). Organic phase dried (Mao5O54) and the solvent was removed in vacuo. The residue (precipitate) was chromatographed on a silica gel base (2.5x20 cm) using ethyl acetate/heptane (2:71) as eluent, yielding 1.77 g

M-(1K)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-M-methylcarbamic acid (eg-butyl ether.

ТН-ММе: (СОСИ3) (selected peak values for the main rotamer) 4 1.39 (in, 9Н); 2.75 (in, ZN); 2.80 (a, b ZN); 3.29 (ad, 1Hn), 4.88 (i, 1H). (22)-3-(4-Iodophenyl)-M-methyl-2-(methylamino)propionamide -

AND

0

E i-th neon, 4") iv)

M-(1 0 )-2-(4-Iodophenyl)-1-(methylcarbamoyl)ethyl)-M-methylcarbamic acid egp-butyl ether (1.7g; 4.Omol) was dissolved in methylene chloride (1Oml) and trifluoroacetic acid ( 5 ml). The mixture was stirred for 1 hour. Methylene chloride (30ml) and water (30ml) were added. Solid sodium bicarbonate was added to obtain pHV. The organic phase was separated, dried (Ma 3504) and evaporated in a vacuum, obtaining 1.22 d of (2k)-3-(4-iodophenyl)-M-methyl-2-(methylamino)propionamide. ime) H-MMK: (SOSI") a 2.28 (z, ZN), 2.68 (aa, 1H); 2.81 (a, ZN); 3.08-3.19 (t, 2H); 6.95 (a, 2H); 7.63 (a, 2H)

M-Methyl-M-(1P)-1-(M-methyl-M-(1 k-1 -(methyl 60 carbamoyl)-2-(4-iodophenyl)ethyl)carbamoyl)-2-(2-naphthyl) ethyl) carbamic acid (eg-butyl ether b5 she fo eto t mnZ sn, 0 70 : I (2K)-2-(M-(ep-butoxycarbonyl-M-methylamino)-3-(2-naphthyl)propionic acid (1.10 g; 3.30 mmol) was dissolved in methylene chloride (1 mL) and NOAI (0.45 g, 3.1 mmol) and EBAS (0.66 mg, 3.5 mmol) were added. After stirring for 15 minutes, (2K)-3-(4-iodophenyl)- M-methyl-2-(methylamino)propionamide (1.0g, C,/mmol) and diisopropylethylamine (0.45g, C, 4mmol) and the mixture was stirred overnight.Methylene chloride (30ml) was added and the mixture was washed with saturated aq. of sodium bicarbonate (30 ml) and sodium hydrogen sulfate solution (1096, 30 ml). The organic phase was dried (M95O03), and the solvent was removed in vacuo. The residue (precipitate) was subjected to chromatography on a silica gel base (2.5x20 cm) using ethyl acetate/heptane (2: 71) as an eluent, obtaining 1.74 g of M-methyl-M-(1K)-1-(M-methyl-M-(1K)-1 -(methyl carbamoyl)-2 -(4-iodophenyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid (eg-butyl ether. 20 7ТН-ММЕХ(СОСИз) (selected peak values for the main rotamer) 4 1.38(5,9Н); 2.18(4, ЗН); 2.45 (in, ZN); 2.15 (c, ZNOB.O5 (t, 1H); 5.42 (t, 1H). (2853-М-((1.К)-2-(4-Iodophenyl)-1 -(methylcarbamoyl)ethyl)-М -methyl-2-methylamino-3-(2-naphthyl)propionamide fi o, sho o no

Ne ik im sn (Se)

MN MN that Shchi - yu «c) ! "-

M-Methyl-M-(1 kA -(M-methyl-(1 kA -(methyl 35 carbamoyl)-2-(4-iodophenyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid (eg -butyl ether was dissolved in a mixture of methylene chloride and trifluoroacetic acid and stirred for 15 minutes. Methylene chloride (20 ml) and water (30 ml) were added. The mixture was adjusted to pH by adding solid sodium bicarbonate.

The organic phase was separated, dried (Mo5O5) and evaporated in a vacuum, obtaining 1.40 g of (2K)-M-(1 «

KO-2-(4-iodophenyl)-1-methylcarbamoyl)ethyl)-M-methyl-2-methylamino-3-(2-naphthyl)propionamide. - 70 7H-MME: (SOCI»z) (selected peaks values for the main rotamer) a 1.79 (z, ZN), 2.02 (4, ZN); 2.55 (v, c ZN); 3.78 (ad, 1n); 5.44 (ach, 1n 4-(M-(123-1-(M-(12)-2-(4-Iodophenyl)-1 -(methyl carbomoyl)ethyl)-M-methylcarbamoyl)-2-(2-naphthyl )ethyl)-M-methylcarbamoyl)piperidine-1-carboxylic acid and butylethyl ether

And M -p

F SU many with would sn, o 5B not (c)

H

F! N.esn, 1-ep-butoxycarbonylpiperidine-4-carboxylic acid (14mg, 0.6bmmol) was dissolved in methylene chloride (10ml), and NOAI (9mg, 0.bbmmol) and EVAS (140mg, 0:7bmmol) were added. After 15 minutes of stirring, (225)-M-(1 k)-2-(4-iodophenyl)-1-(methylcarbamoyl)ethyl)-M-methyl-2-methylamino-3-(2-naphthyl)propionamide (35Omg , 0.ppmmol) and diisopropylethylamine (85 mg, 0.ppmmol). and the mixture was stirred for a day. Methylene chloride (200ml) was added, and the mixture was washed with a saturated aqueous solution of sodium bicarbonate (20ml) and a solution of sodium hydrogensulfate (1095, 20ml). The organic phase was dried (Ma95O)5), and the solvent was removed in vacuo. The residue (precipitate) was subjected to chromatographic processing on a silica gel base (2.5x20 cm), using ethyl acetate as an eluent, obtaining 412 mg

4-(«M-(1k)-1-(4-(1k)-2-(4-iodophenyl)-1-(methylcarbomoyl)ethyl)-M-methylcarbamoyl)-2-(2-naphthyl)ethyl) -M-methylcarbamoyl)piperidine-1-carboxylic acid (eg-butyl ether. 4-(«M-(1

KO-1-(4-(1kK)-2-(4-iodophenyl)-1-(methylcarbomoyl)ethyl)-M-methylcarbamoyl)-2-(2-naphthyl)ethyl)-M-methylcarbamoyl) piperidine-1 - carboxylic acid and (eg)-butyl ether (412mg, 0.5bmmol) was dissolved in a mixture of methylene chloride (5ml) and trifluoroacetic acid (bml) and stirred for 5 minutes. Methylene chloride (20ml) and a saturated aqueous solution of sodium hydrogencarbonate (20ml) were added. By adding solid of sodium bicarbonate, the mixture was adjusted to pH 8. The phases were separated, and the organic phase was dried (Mo950O4) and evaporated, yielding 255 mg 7/0 of the main compound.

ТН-ММе: (СОСИ3) (selected peak values for the main rotamer) а 2.32 (а, ЗН); 2.58 (in, ZN); 2.68 (8.3H); 5.33 (t, 1H); 5.84 (i, 1H)

NRIS: p (holding time) - 33.35 minutes (AT) ROM: t/2 640.8 (MEAN)"

Abbreviation nvt O-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

MM M-methyl pyrrole don

NATO O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

TA- Trityl nov 7-hydroxybenzotriazole hydrate 3-АтВ 3-Aminomethylbenzoyl

M-Me-3-AMV 3-methylaminomethylbenzoyl p

Claims (20)

The formula of the invention of 1. A compound according to the general formula (1) А-В-С-0(-ЕЕ)р 11) "о зо where р is equal to 0 or 1, A is hydrogen or в (СНе)д- 0 (СНо)в -СО-, where o 4 is equal to 0 or a whole number selected from the group: 1,2,3,4,5, d is equal to 0 or 1, z is equal to O or a whole number "from the number selected from the group: 1,2, 3,4,5, B is hydrogen, imidazolyl, guanidino, piperazino, morpholino, piperidino or Ш(К 23-83, where each is a radical КБ? and КЗ independently represents hydrogen or lower alkyl, optionally substituted by one or (Ce) by several hydroxyl, pyridinyl or furanyl groups, and X, if r is 1, is -MH-, -CH", -"СНУСН-, -С(В5Х1-, " LI shi c - ' ' or ; » where each of the radicals B'Z and VK!" is independently hydrogen or lower alkyl, B is (C) -(H)y, where each of z and i is independently equal to 0 or 1, Сb and H are amino acids residues (radicals) selected from the group that includes natural - ІІ-amino acids or their corresponding O-isomers, or unnatural (artificial) amino acids, such as о 1,4-diaminobut Foric acid, aminoisobutyric acid, 1,3-diaminopropionic acid, 4-aminophenylalanine, 3-pyridylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydronorharman-3-carboxylic acid acid, M-methylanthranilic acid, anthranilic acid, M-benzylglycine, 3-aminomethylbenzoic acid, 3-amino-3-methylbutanoic acid, sarcosine, nipecotic acid or isonipecotic acid, and wherein when both u and y are equal to 1, the amide bond between c and H can be variably replaced by U-MA 18., where U is -CO- or -CH»e-, and "8 is hydrogen, lower alkyl or lower aralkyl, C is an O-amino acid with by the formula -МН-СН(СНо)У-Б7)-СО-, where o m is equal to 0, 1 or 2, and B" is selected from the group to which belong de 1 i F, Phi e f DE 9, ' M . ra N' e or c each of which is optionally replaced by halogen, lower alkyl, lower alkyloxy, lower alkylamino, because amino or hydroxy, O, if p is equal to 1, is a SO-amino acid with the formula -МК 20 СН(СНо)Б)-СО- or, if p is equal to 0, О is -МЕ22-СН((СНо)-2)- СНо- ВЗ or -МЕ 20-СН((СНо)т-2)-СВ5, where K is 0, 1 or 2, Y is 0, 1 or 2, t is 0, 1 or 2, th is selected from the group to which are lower alkyl or lower aralkyl; IN? selected from the group to which they belong Le. ef puf each of which is optionally substituted with halogen, lower alkyl, lower alkyloxy, amino or hydroxy, and 29 is piperazino, morpholino, piperidino, -OH or -M(B 7-KU), where each of the radicals K/ and KZ independently represents hydrogen or lower alkyl, E, if p is equal to 1, represents -МН-СН(В 79)-(СН»),- VU, where m is equal to 0 or a whole number selected from the group: 1,2,3 ,4,5,6,7,8, BZ is hydrogen, imidazolyl, guanidino, piperazino, morpholino, piperidino, -М(В 173-812, (СН) сч - ) о І ю where п is equal to 0, 1 or 2, and KU represents hydrogen or lower alkyl, (ав) в в!! x chi - - M (Snav - (sna x or o k o "so d'i2 k where o is equal to a whole number selected from the group: 1 , 2, 3, each of the radicals B! and B? independently represents "70 hydrogen or lower alkyl, or 8 c , z" '. ' or 1 M chn Z Z (e)) - each of which is optionally substituted with halogen, lower alkyl, lower alkyloxy, amino, alkylamino, hydroxy, or the product of the Amadori rearrangement from the amino group and hexapyranose or hexapyranosylhexapyranose (ав) and with BZ, if p is equal to 1, selected from the group consisting of H, -"СООН, -СНо-Б 13-СО-Б "С or -СНо-ОН, where БЗ is piperazino, morpholino, piperidino, "ОН or -М( In 7173-75, where each of B" and 2!?. 0 is independently hydrogen or lower alkyl, all amide bonds in formula 1, except for the bond between C and 0, may independently be substituted by -Y- M B 18-, where U represents -CO- or -СНо-, and BZ represents hydrogen, lower alkyl or lower aralkyl, or a pharmaceutically acceptable salt thereof, with the exception of compounds HF) (33-aminomethylbenzoyl)-0-2MaI- M-Me-O-RPe-I uv-MN », 7 H-AIIB-Niz-0-2MaI-M-Me-O-РНе-Г uv-MN », N-AIIB-Niz-M-Me-0 -2MaI-M-Me-O-РНе-Гув-МН », in 3-(Н-АЙБ-Низ-0-2МаИ-М-Ме-0-Рпе-МН)-1-morpholinopropane, 2-(Н- Air-Niz-0-2MaI-M-Me-0-P pe-MH)-(1-methyl-2-pyrrolides nil)ethane, (ZK)-piperidinecarbonyl)-M-Me-0-2MaI-M-Me-O-РНе-I ug-MH», 3-(3-aminomethylbenzoyl)-0-2MaI-M-Me-0О -Rpe-MH)1-morpholinopropane, 2-(H-Air-Niz-M-Me-0-2MaI-mM-Me-0-Rpe-MH)-(1-methyl-2-pyrrolidinyl)ethane, 2- ((ZK)-piperidinecarbonyl)-M-Me-0-2MaI-M-Me-O-RPpe-MH)-(1-methyl-2-pyrrolidinyl)ethane, because 2-(3-aminomethylbenzoyl)-M-Me -0-2MaI-Me-O-Rpe-MH)-(1-methyl-2-pyrrolidinyl)ethane, 3-(H-AIB-Niz-M-Me-0-2MaI-M-Me-O-Rpe-MH)-1-morpholinopropane, 3-(ZK)-piperidinecarbonyl)-M-Me-0-2MaI-m -Me-0-Rpe-MH)-1-morpholinopropane, 3-(3-aminomethylbenzoyl)-M-Me-0-2MaI-m-Me-0-Rpe-MH)-1-morpholinopropane, 2-(3- aminomethylbenzoyl)-0-2MaI-M-Me-0-Rpe-MH)-(1-methyl-2-pyrrolidinyl)ethane, 2-((ZK)-piperidinecarbonyl)-0-2MaI-M-Me-0-Rpe -MH)-(1-methyl-2-pyrrolidinyl)ethane. 2. The compound according to claim 1, which differs in that A is hydrogen, 3-AMB, M-Me-3-AMB or AB. C. The compound of claim 1, wherein y is 1 and y is 0, and C is selected from the group consisting of 33-aminomethylbenzoyl, nipecotic acid and isonipecotic acid. 70 4. The compound according to claim 1, which is distinguished by the fact that и is equal to 1, y is equal to 1, C is AIB, and H is selected from the group to which Niv, РНе and Aа belong. 5. The compound according to claim 1, which differs in that C is selected from the group to which O-2-Ma! and O-Rpe. 6. The compound according to claim 1, which differs in that if p is equal to 1, ОХО is О-РНе or О-2Май. 7. The compound according to claim 1, which differs in that if p is equal to 0, OO is Ю-Рпе-МН" or 0-2Май!- МН". 8. The compound according to claim 1, which differs in that E, if p is equal to 1, is - МН-СН(В 79)-(СНо)-ВУ, where m is equal to 0 or a whole number selected from the group: 1, 2,3,4, BZ is hydrogen, morpholino, piperidino, M(B 17)-212 ф M сч в/з (о) where n is equal to 0, 1 or 2, and B? represents hydrogen or lower alkyl, each of the radicals B 1! and B/2 is independently hydrogen or lower alkyl, BO, if p is 1, is selected from the group consisting of -H, -СООН, -СНо-КУ, -СО-ВС or -СНо-ОН, where BZ is piperazino, morpholino, piperidino, -OH or -M(B 7733-29), where each of the radicals B" and B" independently represents hydrogen or lower alkyl. 9. The compound according to claim 1, which differs in that at least one of the amide bonds between A and B, between B and C, between o O and (Er and between G and H is replaced by -CO-M(CH 3)- -- 10. A compound selected from the group consisting of (k)-2-(3-aminomethylbenzoyl)-M-Me-O-2Ma!I-m-Me)-3-phenylpropanol or its TEA salt; i-o 3-(3-aminomethylbenzoyl))M-Me-O-2Ma!I-M-Me-O-Ppe-MH)-1-1M,M-dimethylaminopropane or its TEA salt; 3-(3K)-3-piperidinecarbonyl)-M-Me-O-2MaI-M-Me-O-Rpe-MH)-1-M,M-dimethylaminopropane or its TEA salt; 2-((3K)-3-piperidinecarbonyl)-M-Me-O-2Ma1I-M-Me-O-RPpe-MH)-(1-methyl-2-pyrrolidinyl)ethane or its TEA salt; "du H-AIB-Niz-0-2MaI-M-Me-O-RNpe-zeg-MN" or its TEA-salt; -o (3Z-aminomethylbenzoyl)-0-2MaI-M-Me-O-РНе-Гув-МН» or its TEA-salt; c (4-piperidinecarbonyl)-0-2MaI-M-Me-O-Rpe-MH » or its TEA salt; :z" (3K)-3-piperidinecarbonyl)-O-2MaI-M-Me-O-Rpe-MH" or its TEA salt; (3Z-aminomethylbenzoyl)-O-Rpe-M-Me-O-Rpe-MH" or its TEA salt; (3Z-aminomethylbenzoyl)-M-Me-0-Rpe-M-Me-O-Rpe-I ugz-MN » or its TEA salt; b" 15 (3K)-3-piperidinecarbonyl)-M-Me-O0-RPpe-M-Me-O-RNe-I uv-MH" or its TEA-salt; H-AIIB-Niz-M-Me-0O-Rpe-M-Me-O-РНе-Гув-МН » or its TEA salt; - (3K)-3-piperidinecarbonyl)-M-Me-0-2MaI-M-Me-O-Rpe-MH" or its TEA salt; o (2k)-2-(3-aminomethylbenzoyl)-M-Me-O-2MaI-M-Me)-3-(2-naphthyl)propanol or its TEA salt; (3Z-aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-O-Rpe-MH» or its TEA salt; 1 20 3-(3-aminomethylbenzoyl)-M-Me-O-Rpe-MH)-1-M,M-dimethylaminopropane; F H-AIIB-Niz-M-Me-0-2MaI-M-Me-O-РНе-МН 5, or its TEA salt; (3Z-aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-O-RPe-H uv- MH"; Н-АЙБ-АИа-0-2МаИ-М-Ме-О-РНе-Г ув-МН», or its TEA-salt; H-AiYIB-Niz-0-2MaI-M-Me-O-РНе-МН", or its TEA salt; 2-(3-aminomethylbenzoyl)-M-Me-O-2MaI-M-Me-O-Rpe-MH)I-1-morpholinoethane; HF) (3-aminomethylbenzoyl)-M-Me-0-2MaI-M-Me-O-Rpe-MH-Me; 7 3-(3-methylaminomethylbenzoyl)-M-Me-0-2MaI-M-Me-0-Rpe-MH)-1-M,M-dimethylaminopropane, (3Z-aminomethylbenzoyl)-M-Me-0-2MaI- M-Me-O-Rpe-M-Me», N-AIIB-Niz-M-Me-0-2MaI-M-Me-O-RNne-MN »5; bo 3-aminomethylbenzoyl-M-Me-O-2MaI-M-Me-O-Rpe-MH-CH" or its TEA salt; Z-methylaminomethylbenzoyl-M-Me-0-2MaI-M-Me-O0-Ppe-MH-CH z or its TEA salt; N-AIB-Niz-M-Me-0-2MaI-M-Me-O-Rpe-MNMe or its Neisil; and piperidine-4-carboxylic acid -M- (12k)-1-(4-(1Kk)-2-(4-iodophenyl)-1-(methylcarbamoyl) ethyl)-M-methylcarbamoyl)-2-(2-naphthyl )ethyl)-M-methylamide, or its pharmaceutically acceptable salt. for 11. A pharmaceutical composition that contains as an active component a compound according to any of items 1 to 10 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 12. The composition according to claim 11, which is characterized by the fact that, in the form of dosage units, it contains from about to about 200 mg of the main compound according to any of items 1 to 10 or a pharmaceutically acceptable salt of this compound. 13. A pharmaceutical composition for stimulating the release of growth hormone from the pituitary gland, containing as an active ingredient a compound according to any one of items 1 to 10 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 70 14. Pharmaceutical composition according to claims 11, 12 or 13, which differs in that it is intended for oral, transdermal, nasal, pulmonary or parenteral administration. 15. The method of stimulating the release of growth hormone from the pituitary gland, which, if necessary, involves the introduction of an effective volume of the compound according to any of items 1 to 10, or its pharmaceutically acceptable salt, or the composition according to any of items 11, 12 or 14. 16. The method according to claim 15, characterized in that the effective volume of the compound according to any one of items 1 to 10, or a pharmaceutically acceptable salt thereof, or an ester thereof, can be from about 0.0001 to about 100 mg/kg body weight per day, most optimally from about 0.001 to about 50 mg/kg body weight per day. 17. A method of increasing the speed and intensity of growth of animals, increasing milk yield or the productivity of obtaining wool from domestic animals, or overcoming ailments, which, if necessary, involves the introduction into the body of an effective volume of the compound according to any of items 1 to 10 or a pharmaceutically acceptable salt thereof, or a composition according to any of clauses 11, 12 or 14. 18. A compound according to any of paragraphs from 1 to 10 or its pharmaceutically acceptable salt, which differs in that it is used as a medicine. 19. A compound according to any of paragraphs from 1 to 10 or its pharmaceutically acceptable salt, which differs in that it is used for the manufacture of a medicine to stimulate the release of growth hormone from the pituitary gland. 20. The compound according to any of the points from 1 to 10 or its pharmaceutically acceptable salt, which differs in that i) it is used for the manufacture of a medicine intended for introduction into the body of animals for the purpose of increasing the speed and intensity of their growth, increasing milk production and the productivity of obtaining wool from domestic animals or overcoming ailments. "oh I | | | Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 11, 11/15/2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. "- (Se) - and? (o) - («c) 1 4) ime) 60 b5