Ligands of melanocortin receptors and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

 

The SCOPE of the INVENTION

This invention relates to ligands of melanocortin (MC) receptors, which are conformationally restricted ring element, which provides an increased activity. These ligands preferably demonstrate selectivity for receptors MC-3 and/or MC-4 relative to other melanocortin receptors (in particular receptors MS-1) and suitable for use in the pharmaceutical compositions and treatment methods.

BACKGROUND of the INVENTION

Melanocortin peptides (melanocortin) is a natural peptide hormones in animals and humans that bind and stimulate the MC-receptors. Examples of melanocortins are α-MSH (melanocyte-stimulating hormone), γ-MSH, ACTH (adrenocorticotropic hormone) and their peptide fragments. MSH is known mainly for its ability to regulate peripheral pigmentation, whereas ACTH, as you know, induces steroidogenesis. Melanocortin peptides also mediate a number of other physiological effects. It is reported that they affect motivation, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, the blood flow in the brain, the growth and regeneration of nerves, placental development, with ntes and release of aldosterone, the release of thyroxine, spermatogenesis, the weight of the ovaries, the secretion of prolactin and FSH, uterine bleeding in women, the secretion of the sebaceous glands and pheromones, sexual activity, erection, glucose levels in the blood, intrauterine fetal growth, behavior, caused by food, and other events related to childbirth.

Receptors MC-4 and MC-3 are localized in the hypothalamus region of the brain, which is reputed to be included in the modulation of feeding behavior. It is shown that compounds that demonstrate selectivity relative to receptors MC-3/MC-4, the change in food consumption after intracerebroventricular and peripheral injection in rodents. Specifically, it is shown that agonists reduce food intake, whereas antagonists increase the intake of food. The role of receptors MC-4 and MC-3 in the regulation of body weight in mammals. Suppose that the receptor MC-3 affects the efficiency of the supply and distribution of energy reserves in fat, whereas the receptor MC-4 regulates food intake and possibly power consumption. Thus, these receptor subtypes, apparently, reduce the body weight of the individual and complementary ways. Therefore, compounds that stimulate both receptor MC-3 and MC-4, can be more effective weight loss than compounds that are selective against or receptor MC-3 or MC-4.

it is Widely recognized, what violations of body weight, such as obesity, anorexia and cachexia, are essential tasks for health care, and there is a need for compounds and pharmaceutical compositions that can treat such disorders.

Applicants have discovered a class of compounds, which unexpectedly have high affinity in relation to subtypes of receptors MC-4 and/or MC-3 and which are usually selective in respect of such MC-receptors compared with other subtypes of melanocortin receptors, in particular subtype MS-1.

SUMMARY of INVENTION

The present invention concerns a class of compounds that are ligands for receptors MC-3 and/or MC-4 and contain a ring of 5-8 atoms, which conformationally restricts the orientation of the three side pieces.

Compounds of the present invention include all of their enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts, and these compounds have the formula:

where a represents a conformationally restricted ring system selected from the group including:

a) non-aromatic carbocyclic ring;

(b) an aromatic carbocyclic ring;

c) non-aromatic heterocyclic ring;

d) an aromatic heterocyclic ring;

where these Kohl which contain from 5 to 8 atoms;

W is the lateral fragment having the formula:

where R is selected from the group including:

a) non-aromatic carbocyclic ring;

(b) an aromatic carbocyclic ring;

c) non-aromatic heterocyclic ring;

d) an aromatic heterocyclic ring;

these rings contain from 3 to 12 atoms;

J is selected from the group including:

i) -[C(R")d]k-, where each R" independently represents hydrogen, C1-C12linear or branched alkyl, -SUB, two fragments R", taken together with the oxygen atom may form a carbonyl fragment, two pieces of R for any J or fragments fragment R" and the fragment R' from the fragment of T, taken together, may form a carbocyclic or heterocyclic condensed ring, bicyclic ring or spiroannulated ring comprising from 3 to 7 atoms; the index d has a value of 1 or 2; the index k is set to 1 or 2;

ii) N-;

iii) -NR'-, where R' denotes hydrogen, C1-C6linear or branched alkyl or SUB;

iv) -O-;

v) -S-;

vi) -P(O)- or-P(O)2-;

vii) and mixtures thereof;

L represents a suitable binding fragment;

In includes a fragment selected from the group including:

a) hydrogen;

b) substituted or unsubstituted aromatic carbocyclic to LCA;

c) substituted or unsubstituted aromatic heterocyclic ring;

d) mixtures thereof;

Y represents the lateral fragment, comprising at least one heteroatom;

Z represents a lateral fragment comprising aromatic or nonaromatic ring.

The present invention also concerns pharmaceutical compositions containing the described ligands of receptors MC-3 and/or MC-4, moreover, these ligands have high affinity and selectivity for subtypes of receptors MC-3 and/or MC-4 compared with subtype receptors MS-1.

Data and other objectives, features and advantages will be clear to experts in this field from the following detailed description and appended claims. All percentages, ratios and proportions are mass, unless otherwise noted. All temperatures are given in degrees Celsius (° (C)unless otherwise specified. All documents referenced in the application materials, are part of and incorporated by reference.

DETAILED description of the INVENTION

The present invention relates to ligands of receptors. Melanocarcinoma (MS) class of peptides mediates a wide range of physiological effects. Synthetic peptides and mimetics of peptides that modulate the interaction of natural MS-ligands have different degrees with which lectively and binding. The aim of the present invention are ligands that are selective against receptor MC-4 or selective with respect to both receptors MC-4 and MC-3 with minimum impact on receptors MC-1, MC-2 and MC-5.

Unexpectedly found that the conformational restriction of rotation around the key peptide bond provides ligands of receptors with high selectivity and binding. Key in the present invention is the discovery that the conformationally restricted structure in some embodiments may include structural isostere, inter alia, 5-membered rings and 6-membered rings, as well as chemical bonding, which simply limit the rotation of a normal peptide bond.

Not wishing to be bound by theory, probably suspended (attached) fragments obtained by fixing the rotation of the peptide or mimetic peptide, begin to differ from each other in their physiological and biological functions. Suspended fragments or parts of the Central ring structures described herein as "lateral fragments W" or "fragments", "lateral fragments Y" or "fragments, with the main part, the part with the Quaternary nitrogen or mixtures thereof and lateral fragments Z". Fragments identified as not only to facilitate the differentiation of their intended functionality, as well as mnemonically the way help the specialist in understanding the scope of the invention described herein options. Therefore, the described conventional image fragments (lateral fragments W) can play one or more roles in identifying the necessary physiological and biological reactions. Scope of the present invention is not limited to this need for differentiation of the side pieces for the sake of a clear definition of the boundaries and relationships of each group, section or part.

As regards the term "amino acid", the person skilled in the art will Ponto that this term refers to a naturally occurring constituent elements of the peptides, enzymes and the like, and variants of unnatural origin. The following is not limiting the invention to the usual list of amino acids along with short labels and single-letter codes: alanine (Ala, A), arginine (Arg, R), asparagine (Asp, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, Q), glutamine (Gln, E), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), Proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), valine (Val, V). Other amino acids not found in nature, include: para-benzylpenicillin (Bpa), β-(1-naphthyl)alanine (1-Nal), β-(2-naphthyl)alanine (2-Nal), β-cyclohexylamine (Cha), 3,4-dichlorophenylamino (3,4-Dp), 4-forfinally (4-Fpa), 4-nitrovanillin (4-Npa), 2-titillans (Tha), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), 3-benzothiadiazin (3-Bal), 4-cyanoaniline (4-Ypa), 4-itfinally (4-Ipa), 4-bromovanillin (4-Rpa), 4,4'-biphenylene (Bip), ornithine (Orn), sarcosine (Sar), pentacarbonyliron (Pfp) and βthatβ-diphenylalanine (Dip). For the purposes of the present invention, the amino acids are in L-form (levogyrate), unless otherwise noted. For normal amino acid in D-form denoted by a small letter in a single-letter abbreviation, for example, D-alanine indicate "a", D-threonine indicate "t".

For the purposes of the present invention in the description of individual cases or examples of one or more fragments can be identified or highlighted with an asterisk, for example, R*, J*. This serves only to distinguish one piece from another, and underscores that the example focuses on changes or repetitions in a particular piece. For example, each fragment J, either J or J*, may include the same elements, but for a concrete example, the interest has focused on the value of fragments J.

Substituted fragments-SUB

SUB-fragments are fragments that can replace hydrogen atoms. The term "substituted" used throughout the description and for the purposes of the present invention the term "substituted" is defined as "the replacement of atamasthana, two atoms of hydrogen or three hydrogen atoms from the carbon atom with the formation of the molecule or replacement of hydrogen atoms from adjacent carbon atoms with the formation of the molecule". For example, the Deputy, which requires replacement of a single hydrogen atom, include halogen, hydroxyl and the like. The replacement of two hydrogen atoms include carbonyl, oximino and the like. Replacement of three hydrogen atoms include cyano and the like. The term "substituted" is used throughout this description to indicate that the portion of the molecule, among other things, an aromatic ring, the alkyl chain may have one or more hydrogen atoms replaced by a substituent. For example, 4-hydroxyphenyl is "substituted aromatic carbocyclic ring, and 3-guanidinopropionic is replaced With3alkyl fragment. The designation "-SUB'used to show that Deputy for hydrogen is a fragment, which is able to form hydrogen bonds, among other things, a hydroxyl, a carbonyl.

The following are non-limiting examples of the invention parts of molecules, which can replace one or more hydrogen atoms on the carbon with the formation of SUB-fragments:

i) -NHCOR30;

ii) -COR30;

iii) -COOR30;

iv) -COCH=CH2;

v) -C(=NH)NH2;

vi) -NHC(=NH)NH2;

vii) -N(R30)2;

viii) -NHC6H5/sub> ;

ix) =CHC6H5;

x) -CON(R30)2;

xi) -CONHNH2;

xii) -NHCN;

xiii) -OCN;

xiv) -CN;

xv) F, Cl, Br, I and mixtures thereof;

xvi) =O;

xvii) -OR30;

xviii) -NHCHO;

xix) -OH;

xx) -NHN(R30)2;

xxi) =NR30;

xxii) =NOR30;

xxiii) -NHOR30;

xxiv) -CNO;

xxv) -NCS;

xxvi) =C(R30)2;

xxvii) -SO3M;

xxviii) -OSO3M;

xxix) -SCN;

xxx) -P(O)(OH)R30;

xxxi) -P(O)(R30R30;

xxxii) -P(O)(OH)2;

xxxiii) -SO2NH2;

xxxiv) -SO2R30;

xxxv) -NO2;

xxxvi) -CF3, -CCl3, -CBr3;

xxxvii), and mixtures thereof;

where R30denotes hydrogen, C1-C20linear or branched alkyl, C6-C20aryl, C7-C20alkylaryl and mixtures thereof; M represents hydrogen or a salt-forming cation. Suitable soleobrazutaya cations include sodium, lithium, potassium, calcium, magnesium, ammonium and the like. Not limiting the invention examples alkalinizing fragment include benzyl, 2-phenylethyl, 3-phenylpropyl and 2-phenylpropyl. As described below, fragments, defined as "substituted fragments that can form hydrogen bonds", are SUB'-fragments, examples of which include hydroxyl and carbonyl.

For illustrative purposes the following are conformationally restricted ring having attached thereto W, Y and Z, as well as SUB-substituted fragments. In this example, the SUB is acetate (group (ii)in which R30denotes methyl):

For the purposes of the present invention, the substitution of a hydrogen atom can occur in the main hydrocarbon chain or side chain.

Conformationally restricted ligands of the present invention includes all enantiomeric and diastereomeric forms and their pharmaceutically acceptable salts, which are described here below, and these ligands have the formula:

where a represents a conformationally restricted ring system selected from the group including:

a) non-aromatic carbocyclic ring;

(b) an aromatic carbocyclic ring;

c) non-aromatic heterocyclic ring;

d) an aromatic heterocyclic ring;

where these rings contain from 5 to 8 atoms. The expert can choose any of these four types of ring systems. For the purposes of the present invention, the term "carbocyclic ring" is defined as "any ring that includes only carbon atoms". Carbon atoms, in turn, may be associated with hydrogen atoms, for example, as in the case of cyclohexadiene rings, or two or more links can be taken together with the heteroatom such as the R, the oxygen atom, with the formation of carbonyl groups. Two adjacent hydrogen atoms may be absent, thus forming a double bond between two adjacent carbon atoms, for example, as in cyclohexenyl ring. Rings can be substituted by any number of other atoms in addition to 3 slices W, Y, and Z, are described here below. For the purposes of the present invention, the term "heterocyclic ring" is defined as "a ring that includes at least one atom other than carbon, in particular nitrogen. Not limiting the invention, examples of heterocyclic rings include piperidine, cefoperazon, cestodiasis, Proline, piperazine, pyrrolin and pyrrolidone.

Not limiting the invention, examples of non-aromatic carbocyclic and heterocyclic rings include:

a)

;

b)

;

c)

;

d)

;

e)

;

f)

;

g)

;

h)

;

i)

;

j)

;

k)

;

where fragments of W, Y and Z are described below.

T is selected from the group including:

i) -C(R')d-, where each R' independently represents hydrogen, C1-C6linear or branched alkyl, -SUB or their mixture, d is the index having a value of 1 or 2;

ii) N-;

iii) -NR'-, where R' represents hydrogen, C1-C6linear or branched alkyl, -SUB or fragment W, Y, or Z; in some embodiments, R' is hydrogen and not limiting the invention, examples of which include conformationally restricted analogues with rings having the formula:

iv) -O-

v) -S-

vi) -P(O)-, for example, in combination with conformationally restricted analogues, rings which have the formula:

.

J is selected from the group including:

i) -[C(R")d]k-, where each R" independently represents hydrogen, C1-C12linear or branched alkyl, -SUB, two fragments R", taken together with the oxygen atom may form a carbonyl group, two fragments of R for any J or fragments fragment R" and the fragment R' from the fragment of T, taken together, may form a carbocyclic or heterocyclic condensed ring, bicyclic ring or spiroannulated ring comprising from 3 to 7 atoms; the index d has a value of 1 or 2; the index k is set to 1 or 2; in one embodiment, the at least one fragment J includes the Rupp CF 2-; in another embodiment, J is of the formula-CH2-, -C(O)- and their mixture; options condensed rings J include conformationally restricted ring having the formula:

however, R may form a heterocyclic ring, for example, cyclic simple ether having the formula:

ii) N-;

iii) -NR'-, where R' denotes hydrogen, C1-C6linear or branched alkyl or fragment SUB;

iv) -O-;

v) -S-;

vi) -P(O)- or-P(O)2-for example, in combination with other fragments J or T may form a part having the formula-OP(O)-, -OP(O)R30-, -OP(O)O -, or-OP(O)R30O-;

vii) and mixtures thereof.

Lateral fragments W

Fragments W of the present invention represent the first lateral fragment attached to a conformationally restricted ring. In General, the fragment W has the formula:

where J is such as defined here above. Fragments W of the present invention has several aspects, which, incidentally, concerning the choice of the fragment, fragments, which include the main chain fragment W, and select the area of R.

Fragments R

R is selected from the group including:

a) substituted or unsubstituted non-aromatic carbocyclic ring;

b) substituted or unsubstituted, aromati the definition carbocyclic ring;

c) substituted or unsubstituted non-aromatic heterocyclic ring;

d) substituted or unsubstituted aromatic heterocyclic ring;

where these rings contain from 3 to 12 atoms. Not limiting the invention, examples of aromatic and non-aromatic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, bicyclo[0.1.1]butanal, bicyclo[0.1.2]pentanyl, bicyclo[0.1.3]hexanal (trianel), bicyclo[0.2.2]hexanal, bicyclo[0.1.4]heptanol (karani), bicyclo[2.2.1]heptenyl (norbornyl), bicyclo[0.2.4]octanol (caryophyllene), spiropentane, dicyclopentadienyl, decaline, phenyl, benzyl, naphthyl, indenyl 2N-indenyl, azulene, phenanthrene, anthracene, fluorenyl, acenaphthylene, 1,2,3,4-tetrahydronaphthalene and the like. Not limiting the invention, examples of aromatic and non-aromatic heterocyclic rings include: pyrrolyl 2N-pyrrolyl, 3H-pyrrolyl, pyrazolyl 2N-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-Piran-2-IMT, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil, Deut.-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepine, oxepin, 4H-1,2-diazepine, indenyl 2N-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, is isoxazolyl, 2N-1-benzopyranyl, chinoline, ethenolysis, hintline, 2H-1,4-benzoxazine, pyrrolidinyl, pyrrolyl, honokalani, pyrrolyl, furanyl, thiophenyl, benzimidazolyl and the like. Each of these rings may be substituted as appropriate one or more fragments-SUB.

In one embodiment of the present invention, the fragments of R are phenyl and substituted phenyl, inter alia, 3-forfinal, 4-forfinal, 3,5-differenl, 4-chlorophenyl and 4-hydroxyphenyl.

In another embodiment of the present invention, the fragments of R include a ring which is selected from the group comprising substituted and unsubstituted phenyl, α-naphthyl, β-naphthyl, 1-chinoline, 2-chinoline, 3-chinoline, 4-chinoline, 5-chinoline, 6-chinoline, 7-chinoline, 8-chinoline, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

Another option includes fragments of R, which represent phenyl, α-naphthyl or β-naphthyl.

Fragments of L

L represents a linking group which connects the two or more fragments of conformationally restricted ligands of receptors. The following description of the fragments L applicable to linking groups of the present invention. Linking groups of the present invention may include any atoms or groups of atoms, which appropriately connects two or more fragment of the century One example of a suitable class of fragments of L belongs to the class of binding fragments of the peptide bond, carbonyl and modified carbonyl fragment. In one or more embodiments of the present invention, the fragments of L may be missing.

Not limiting the invention, examples of fragments of L from a given class of peptide bonds, carbonyl and modified carbonyl fragments selected from the group including:

i) -[C(R11)2]p-where R is from 0 to 12;

ii) -[C(R11)2]p(CH=CH)q-where R is from 0 to 12; q is from 1 to 6;

iii) -(R12)tC(X)(R12)t-;

iv) -C(X)NR11-;

v) -C(X)R12C(X);

vi) -C(X)NR11C(X);

vii) -C(X)NR11R12NR11C(X);

viii) -NR11C(X);

ix) -NR11C(X)NR11-;

x) -NR11C(X)R12NR11-;

xi) -NR11R12C(X)NR11-;

xii) -NR11C(X)R12C(X)O-;

xiii) -OC(X)R12C(X)NR11-;

xiv) -NR11C(X)NR11R12-;

xv) -R12NR11C(X)NR11-;

xvi) -R12NR11C(X)NR11R12-;

xvii) -NR11-;

xviii) -R12NR11-;

xix) -NR11R12-;

xx) -NR11N=N-;

xxi) -NR11NR11-;

xxii) -OR12-;

xxiii) -R12O-;

xxiv) -(R12)tOC(O)(R12)t-;

xxv) -(R12)tC(O)O(R12)t-;

xxvi) -(R12) tOC(O)O(R12)t-;

xxvii) -S-;

xxviii) -(R12)tS(R12)t-;

xxix) -(R12)tS(X)(R12)t-;

xxx) -(R12)tS(X)2(R12)t-;

xxxi) -(R12)tNR11S(X)(R12)t-;

xxxii) -(R12)tS(X)NR11(R12)t-;

xxxiii) -(R12)tNR11S(X)2(R12)t-;

xxxiv) -(R12)tS(X)2NR11(R12)t-;

where R11represents hydrogen, linear or branched C1-C10alkyl, hydroxyl, -SUB, or a mixture thereof; R12is1-C16linear or branched, substituted or unsubstituted alkylene, substituted or unsubstituted phenylene, or mixtures thereof; or R11and R12taken together, may form a ring; X represents oxygen, sulfur, =NR11and mixtures thereof; t is 0 or 1.

The following list refers to one of the variants of fragments L:

i) -C(O)NH-;

ii) -C(O)NHC(O)-;

iii) -NHC(O)-;

iv) -NH-;

v) -(CH2)bNH-, where b is from 1 to 3;

vi) -NH(CH2)b-where b is from 1 to 3.

The following list refers to another variant fragments L:

i) -(CH2)p-where p is from 0 to 12;

ii) -C(O)-;

iii) -(CH2)bNH-, where b is from 1 to 3.

Other variants of the present invention may use only-NH - group, as will the surrounding fragment, while some variants use both fragment-C(O)NH - and-NHC(O)-. Still other options are chosen equally from the following fragments L:

i) -C(O)NH)-;

ii) -NHC(O);

iii) -NH-.

Other options may include a combination of carbonyl and modified carbonyl fragments L, for example having the following formula:

i) -C(O)-;

ii) -C(=NH)-;

iii) -C(O)NH-;

iv) -C(=NH)NH-;

v) -NHC(O)-;

vi) -NHC(=NH)-;

vii) -NHC(=NH)NH-;

or only modified carbonyl fragments having the following formula:

i) -C(=NH)-;

ii) -C(=NH)NH-;

iii) -NHC(=NH)-;

iv) -NHC(=NH)NH-.

Examples of fragments of L, where R11and R12, two fragments of R11or two pieces of R12taken together form a ring include conformationally restricted fragments L:

however, the ring formed by R11and R12may also include one or more heteroatoms, for example, in linking the fragments of the formula:

Fragments In

Fragments In the present invention include several specific aspects, and each aspect has a lot of options depending on requirements, the specialist sets for ligands of the receptor.

The fragments do not require a chiral center, but many variants described herein include a chiral center. Some is not limiting the invention examples, with and without chiral center are listed below.

Specialist in the field of ligand-receptor MC-4, MC-3 and MC-4 and MC-3, it will be clear that when any two of R2, R3and R4are the same, does not contain a chiral center, while none of the R2, R3and R4does not contain a chiral center, or two of R2, R3and R4taken together do not form a ring with a chiral center. The fragments represented by the following formula:

where R2, R3and R4described below.

The first aspect relates to fragments, where R2, R3and R4independently selected from the group:

A) rings, including

a) substituted or unsubstituted aromatic carbocyclic rings;

b) substituted or unsubstituted aromatic heterocyclic ring; and

c) mixtures thereof;

B) hydrogen;

(C) SUB-fragments and

D) mixtures thereof.

Not limiting the invention, examples of the substituted or unsubstituted rings corresponding to (A)above, include benzyl, 4-hydroxybenzyl, 3-Chlorobenzyl, 4-Chlorobenzyl, 3,5-dichlorobenzyl, 4-tormentil, (imidazol-2-yl)methyl, (imidazol-4-yl)methyl, 2-phenylethyl, 2-(4-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl and the like.

In one specific embodiment of this first aspect of the fragments, the fragment is In include chiral fragment, having the formula:

where R2and R3each independently represents hydrogen, -C(X)N(R13)2, -N(R13)2, -N+(R13)3D--C(X)N+(R13)3D-, -N(R13)With(X)R14and mixtures thereof, provided that R2and R3are not the same; R13represents hydrogen, C1-C10alkyl or mixtures thereof; R14is1-C16linear or branched, substituted or unsubstituted alkyl, C7-C16linear or branched, substituted or unsubstituted alkylaryl; X represents oxygen, sulfur, =NR13and mixtures thereof; D is a salt-forming anion; R4is7-C16substituted or unsubstituted, alkylaryl, among others, benzyl and substituted benzyl. Specific examples of R2and R3include-CH2C(O)CH3, -NHC(O)CH3, -NHC(O)CH2CH3and-NHC(O)CH2CH2CH3.

One aspect of W consists of the fragments, having the formula:

where J is a formula-CH2-, -C(O)-, and mixtures thereof;

fragments of the L selected from the group including

i) -C(O)NH-;

ii) -C(O)NHC(O)-;

iii) -NHC(O)-;

iv) -NH-;

v) -(CH2)bNH-, where b is from 1 to 3; and

vi) -NH(CH2)b-where b is from 1 to 3;

R is the replacement of the seal or unsubstituted aryl;

In represents hydrogen or a fragment of the formula:

where R2, R3or R4independently selected from the group:

a) rings, including

i) substituted or unsubstituted aromatic carbocyclic rings;

ii) substituted or unsubstituted aromatic heterocyclic ring; and

iii) mixtures thereof

b) hydrogen;

c) a fragment selected from the group comprising-CH2C(O)CH3, -NHC(O)CH3, -NHC(O)CH2CH3and-NHC(O)CH2CH2CH3;

d) at least two of R2, R3or R4taken together form a ring; and

e) mixtures thereof.

One particularly preferred version of this aspect includes fragments of R3that represent hydrogen, and fragments of R2which have the formula-NR13C(X)R14where R14is1-C4linear alkyl. In one particular series of options R2is-NHC(O)CH3and R3represents hydrogen, whereas R4represents one or more fragments selected from the group comprising benzyl, 4-hydroxybenzyl, 4-Chlorobenzyl, 4-methoxybenzyl, 3-nitrobenzyl and mixtures thereof, while the other variant combines these two fragments with fragments of R4selected from the group comprising benzyl, 2-imidazolidinyl, 4-imidazolidinyl, 4-ft is benzyl, 4-hydroxybenzyl and 4-acetoxybenzoic. These options, this aspect is also presented here in the table below analogues.

Variants of this aspect can easily apply L-amino acids and their derivatives as a source of fragments Century

One variant of this aspect of the fragments W refers to the combination of the fragment, derivative of L-amino acids, with a fragment of R, derived from D-amino acids. For example, a fragment of W containing diaminotoluenes N-acetyltyrosine-D-phenylalanine (N-acetyl-Yf), has the formula:

where J is-C(O)-, J* represents-CH2-, R is phenyl, L is-NHC(O)-.

Another variant of this aspect of the present invention relates to fragments that can be obtained in the usual way from D-amino acids as a source of chiral carbon atom, for example, the fragment having the formula:

where R3is hydrogen, R2represents one or more fragments selected from the group comprising benzyl, 4-hydroxybenzyl, 4-Chlorobenzyl, 4-methoxybenzyl, 3-nitrobenzyl and mixtures thereof; R4represents fragments selected from-C(O)N(H)2, -N(H)2, -N+(H)3D--C(O)N+(R14)3D-, -N(H)C(O)R14and mixtures thereof; R14is7-C16samisen the th or unsubstituted, alkylaryl, not limiting the invention, examples of which are benzyl, 4-hydroxybenzyl, 2-phenylethyl, 3-phenylethyl, 2-(4-hydroxyphenyl)ethyl and the like; D represents a salt-forming anion.

One variant of the fragments W refers to compounds comprising a primary amine, for example, fragment W of the formula:

where SUB-fragment represents one or more substitutions of hydrogen atoms, as defined above. Other non-limiting examples of this option include:

Another aspect of the present invention relates to fragments, together with sulfonamidnuyu binding fragment, providing ligands of receptors, with the fragment W of the formula:

where R2, R3and R4defined above. One variant of this aspect relates to ligands of receptors, in which at least two of R2, R3or R4taken together form a ring, or R4includes aryl or heteroaryl group, and these fragments selected from the group comprising phenyl, benzyl, 2-phenethyl, naphthyl, naphthalene-2-ylmethyl, naphthalene-2-retil and 6-hydroxynaphthalene-2-ylmethyl; not limiting the invention, the sample includes a skeleton having the formula:

where R, R9and R15are the any of the described group.

Another aspect of the present invention relates to fragments where at least one, preferably two of R2, R3and R4include a fragment of forming a hydrogen bond selected from the group:

A)1-C12linear or branched alkyl fragments, substituted by one or more SUB'-fragments, forming hydrogen bonds;

(B) (C2-C12linear or branched alkenyl fragments, substituted by one or more SUB'-fragments, forming hydrogen bonds;

C) hydrogen;

D) SUB'-fragments and

E) mixtures thereof,

where SUB'-fragments are "substitution of the hydrogen atom, which include fragments forming hydrogen bonds".

Not limiting the invention, examples of SUB'-fragments selected from the group including:

i) -NHCOR30;

ii) -OH;

iii) -COOH;

iv) -C(=NH)NH2;

v) -NH2;

vi) -NHC6H5;

vii) -CONH2;

viii) -CONHNH2;

ix) -NHCN;

x) =O;

xi) -NHCHO;

xii) -NHNH2;

xiii) =NH;

xiv) =NOH;

xv) -NHOH;

xvi) -CNO;

xvii) -SO3M;

xviii) -OSO3M;

xix) -P(O)(OH)R30;

xx) -P(O)(R30R30;

xxi) -P(O)(OH)2;

xxii) -SO2NH2;

xxiii) -NO2;

xxiv), and mixtures thereof.

Not limiting the invention, examples of fragments of W, which include a fragment having at least two fragments, abrazos the x hydrogen bonds, have the formula:

Another aspect of the fragments In regards R2, R3and R4one of which contains a fragment of forming a hydrogen bond attached to the ring, or two or three of R2, R3and R4taken together form a ring, an example of which has the formula:

Other examples of this aspect of the fragments W have the formula:

Fragments Y have the formula:

-L-R15

where R15represents a group containing a heteroatom.

The first aspect of the fragments Y relates to esters of Akilov or alkenyl short-chain (lower hydrocarbon radicals, having the formula:

-(CH2)b-R15

where the index b is equal to from 1 to 4; R15represents a linear ester or amide, non-limiting examples of which include-C(O)OCH3; -C(O)OCH2CH3; -C(O)OCH2CH2CH3; -C(O)OCH2CH2CH2CH3; -C(O)OCH(CH3)2; -C(O)OCH2CH(CH3)2; -C(O)OCH2 CH=CHCH3; -C(O)OCH2CH2CH(CH3)2; -C(O)OCH2C(CH3)3; -OC(O)CH3; -OC(O)CH2CH3; -OC(O)CH2CH2CH3; -OC(O)CH(CH3)2; -OC(O)CH2CH2CH2CH3; -OC(O)CH2CH(CH3)2; -OC(O)CH2CH=CHCH3; -OC(O)CH2C(CH3)3; -OC(O)CH2CH2CH(CH3)2; and the like; and substituted or unsubstituted amides of short-chain, non-limiting examples of which include-C(O)NHCH3; -C(O)NHCH2CH3; -C(O)NHCH(CH3)2; -C(O)NHCH2CH2CH3; -C(O)NHCH2CH2CH2CH3; -C(O)NHCH2CH(CH3)2; -C(O)NH2; -C(O)NHCH2CH=CHCH3; -C(O)NHCH2CH2CH(CH3)2; -C(O)NHCH2C(CH3)3; -C(O)NHCH2CH2SCH3; -C(O)NHCH2CH2OH; -NHC(O)CH3; -NHC(O)CH2CH3; -NHC(O)CH2CH2CH3; -NHC(O)CH3; -NHC(O)CH2CH3; -NHC(O)CH(CH3)2; -NHC(O)CH2CH2CH3; -NHC(O)CH2CH2CH2CH3; -NHC(O)CH2CH(CH3)2; -NHC(O)2; -NHC(O)CH2CH=CHCH3; -NHC(O)CH2CH2CH(CH3)2; -NHC(O)CH2C(CH3)3; -NHC(O)CH2CH2SCH3; -NHC(O)CH2CH2OH; -NHC(O)CH3; -NHC(O)CH2CH3; -NHC(O)CH2CH2CH3; and the like.

The second aspect of the fragments Y concern parts of molecules, to the which include guanidine and mimetics guanidine, having the formula:

-(CH2)z-R15

where R15is a fragment selected from the group including:

(a)- (X)N(R16)2,

b) -C(X)NR16N(R16)2,

c) -NR16With(X)N(R16)2and

d) -NHN(R16)2,

where X is =O, =S, NR16and mixtures thereof, R16represents hydrogen, methyl, cyano, hydroxy, nitro, and mixtures thereof; the index z is from 0 to 5.

Not limiting the invention, examples of fragments R15that constitute the second aspect of the fragments Y include:

The third aspect of the present invention in respect of the fragments Y includes 5-membered heterocyclic ring, where R5selected from the group including:

i) triazolyl having the formula:

;

ii) tetrazolyl having the formula:

;

iii) thiazolyl, 2-methylthiazole, 4-methylthiazole, 5-methylthiazole having the formula:

iv) 1,3,4-thiadiazolyl, 2-methyl-1,3,4-thiadiazolyl having the formula:

v) 1,2,5-thiadiazolyl, 3-methyl-1,2,5-thiadiazoles having the formula:

vi) oxazolyl, 2-methoxazole, 4-methoxazole, 5-METI oxazolyl, having the formula:

vii) imidazolyl, 2-methylimidazole, 5-methylimidazole having the formula:

viii) 5-methyl-1,2,4-oxadiazolyl, 2-methyl-1,3,4-oxadiazolyl, 5-amino-1,2,4-oxadiazolyl having the formula:

ix) 1,2-dihydro[1,2,4]triazole-3-one-1-yl, 2-methyl-1,2-dihydro[1,2,4]triazole-3-one-5-yl having the formula:

x) oxazolidin-2-he-3-yl, 4,4-dimethyloxazolidine-2-he-3-yl, imidazolidin-2-on-1-yl, 1-methylimidazolidine-2-on-1-yl having the formula:

xi) 2-methyl-1,3,4-oxadiazolyl, 2-amino-1,3,4-oxadiazolyl, 2-(N,N-dimethylamino)-1,3,4-oxadiazolyl having the formula:

These fragments R15taken together with fragments of L selected from the group including:

i) [CR11)2]p-where R is from 0 to 12, and

ii) -R12NR11-;

give heterocyclic fragments Y, non-limiting examples of which include fragments having the formula:

.

A fourth aspect of the fragments Y applies to parts, where R15includes six-membered heterocyclic ring, non-limiting examples of which include:

i) pyridinoline fragments having the formula:

;

ii) pyrimidinyl the data fragments, having the formula:

;

iii) piperidinylidene fragments having the formula:

.

Another aspect of the present invention refers to fragments R15that represent-NH2HE.

However, in its broadest sense, R15taken together with the linking group having a -(CH2)p-where R is from 0 to 12, may be any fragment selected from the group comprising amino, guanidino, guanyl, amidino, pyrrolyl 2N-pyrrolyl, 3H-pyrrolyl, pyrazolyl 2N-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazolyl, 1,2,3-isoxazolyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-Piran-2-IMT, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinil, Deut.-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepine, oxepin, 4H-1,2-diazepine, indenyl 2N-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl 2N-1-benzopyranyl, chinoline, ethenolysis, hintline, 2H-1,4-benzoxazine, pyrrolidinyl, pyrrolidinyl, pyrrolyl, honokalani, pyrrolyl, benzimidazolyl and mixtures thereof.

Fragments Z

Fragments of Z have the formula:

where R8and R9each independently represents

i) hydrogen;

ii) substituted or unsubstituted phenyl;

iii)7/sub> -C16substituted or unsubstituted, alkylaryl;

iv) naphthyl;

v) chinoline;

vi) imidazolyl;

vii) indolyl;

viii) pyridinyl;

ix)3-C10substituted or unsubstituted non-aromatic carbocyclic ring;

x)2-C10substituted or unsubstituted non-aromatic heterocyclic ring;

xi), and mixtures thereof;

R10represents hydrogen, -C(X)N(R16)2, -N(R16)2, -N+(R16)3D-, -C(X)N+(R16)3D-, -NR16C(X)R17and mixtures thereof; R16represents hydrogen, C1-C10alkyl or mixtures thereof; R17is1-C10linear or branched, substituted or unsubstituted alkyl, C7-C16linear or branched, substituted or unsubstituted alkylaryl; X denotes oxygen, sulfur, =NR16and mixtures thereof; D is a salt-forming anion.

In one embodiment of the present invention R8is hydrogen, R9is indolyl or naphthyl, and R10is-NHC(O)CH3.

However, fragments of Z may include a chiral center, represented by the formula:

where R8, R9and R10have the values specified above.

Another variant of the present invention includes fragments of Z, which are attached is to conformationally restricted ring component by means of a fragment T, containing-O-, -NH-, -S - and the like, and have the formula:

where R8, R9and R10each independently represents

i) hydrogen;

ii) substituted or unsubstituted phenyl;

iii)7-C16substituted or unsubstituted, alkylaryl;

iv) naphthyl;

v) chinoline;

vi) imidazolyl;

vii) indolyl;

viii) pyridinyl;

ix), and mixtures thereof.

In one embodiment of this accession contains the fragment T, R8and R9each represents hydrogen, and R10chosen from:

i) substituted or unsubstituted phenyl;

ii)7-C16substituted or unsubstituted of alkylsilane;

iii) naphthyl, or α, or βbound;

iv) hineline;

v) imidazolyl;

vi) indolyl;

vii) pyridine;

viii) and mixtures thereof.

The ligands of receptors and options

One aspect of the present invention concerns the combination of different aspects of the side pieces W with a variety of conformationally restricted ring and various lateral fragments Y and Z. Some aspects of fragments of W include dipeptide main chain, a dipeptide or mimetics of dipeptides. These variations of W can be combined with conformationally restricted ring any size, such as 5-, 6 - and 7-atom rings, which provides skeletons for receptor ligands of the formula:

where R represents a fragment comprising at least one aromatic ring. This variant of the present invention illustrates a wide range of independent substitutions, which can produce specialist positions F and G relative to the size of the ring a and the side pieces Y and z In the above examples, fragments of G may represent a side chain of amino acids, whereas the fragments of F can represent hydrogen, a suitable blocking group.

In the first embodiment of this aspect of R is aryl, W represents a dipeptide mimetic containing fragments G and F, which are defined below.

Fragments F include:

a) hydrogen;

b) fragments of the SUB, non-limiting examples of which include:

i) -NXC(X)R30,

ii) -C(X)R30,

iii) -C(X)N(R30)2,

iv) -R30,

where R30is1-C22linear or branched, substituted or unsubstituted alkyl; C3-C22linear or branched, substituted or unsubstituted cycloalkyl; C2-C22linear or branched, substituted or unsubstituted of alkenyl; C3-C22linear or branched, substituted or unsubstituted cycloalkenyl; C1-C22linear or branched, substituted or unsubstituted heteroalkyl; C1-C22 linear or branched, substituted or unsubstituted cyclogeranyl; C2-C22linear or branched, substituted or unsubstituted heteroalkyl; C2-C22linear or branched, substituted or unsubstituted cyclogeranyl and mixtures thereof.

Fragments of G include:

a)6-C12substituted or unsubstituted aryl, for example phenyl, 4-hydroxyphenyl, 4-were, naphthyl;

(b) (C6-C12substituted or unsubstituted heteroaryl, for example indolyl;

c7-C17substituted or unsubstituted alkylaryl, for example benzyl, 4-hydroxybenzyl;

d)3-C17substituted or unsubstituted acceleratorkey, and

e) mixtures thereof.

However, one aspect of the option with the dipeptide mimetic refers to ones major chains, such as skeletons for receptor ligands having the formula:

The present invention also includes some aspects that relate to the presence of the 4-carbon of conformationally restricted segment connecting the dipeptide fragment W or dipeptide mimetic W and fragment Z.

One variant of the present invention relating to analogues with chetyrekhtomnym segment of the shining fragments of W and Z, has the formula:

where T represents-CH-, -N -, and mixtures thereof; R, J, L, Y, B and Z are such as defined above, the index n is from 1 to 4.

For this option, 4-atomic carbon segment fragments-J*R, taken together, form the fragments selected from the group comprising From1-C12linear or branched alkyl, C6-C12substituted or unsubstituted aryl, C6-C12substituted or unsubstituted heteroaryl,7-C17substituted or unsubstituted alkylaryl,3-C17substituted or unsubstituted acceleratorkey and mixtures thereof.

Another example of this aspect has the formula:

where R, J, L, J*, T, Y, B and Z are such as defined above, the index n is from 1 to 4.

One aspect of receptor ligands the present invention relates to conformationally constrained peptides containing 4 amino acids or mimetics of peptides having Y-f-R-W as the Central amino acid elements [tyrosine-D-phenylethylenediamine (Tyr-D-Phe-Arg-Trp-NH2)], with the core structure of General formula:

where a fragment of T in position 4 represents-NH; fragment J in positions 3 and 6 each represents-C(O)-, provided that conformationally restricted ring has the formula:

Another option tyrosine-D-fenilalanina residue containing fragment W relates to compounds, an example of which is the receptor ligand having the formula:

Another option conformational restrictions tetrapeptide relates to peptide 4 residues with N-f-R-W as the Central amino acid elements, histidinol-D-phenylethylenediamine (His-D-Phe-Arg-Trp-NH2), a conformationally restricted and then optionally modified with the formation of one or more of the basic structures of the General formula:

where W represents the residue His-D-Phe. Due to the presence of amino acids histidine as part of W this option contains a fragment having a heterocyclic fragment R4that includes the aspect of fragments, which relates to conformationally restricted fragments In forming hydrogen bonds. Variations in these circular structures, where the fragments Y and Z are modified, as well as fragments of J include variant of the present invention, which is reflected in the following examples.

The following are non-limiting examples of the invention variants of this conformationally restricted patterns:

Another variant of the present invention relates to 5-membered ring ligands of receptors MC-4 and MC-4 and/or MC-3, for example, ligands with conformationally restricted structure formula:

with their modifications, which provide the following non-limiting examples of ligands of receptors:

Below is not limiting the invention description of some of the variants of the present invention. Following is the code to the following tables conformationally restricted ligands of receptors MC-4, MC-3 and MC-4 and MC-3.

The following formulas represent non-limiting examples of conformationally restricted ring indicating the position of the fragments W, Y, and Z.

One variant of the present invention includes 3-guanidinopropionic fragment Y, attached to the rings A-W, however, another aspect of the present invention replaces the 3-guanidinopropionic below fragments of Y. Y is selected from the group consisting of:

i) -(CH2)3NHC(=NH)NH2;

ii) -(CH2)4NHC(=NH)NH2;

iii) -(CH2)5NHC(=NH)NH2;

iv)-(CH 2)3C(=NH)NH2;

v) -(CH2)4C(=NH)NH2;

vi) -(CH2)5C(=NH)NH2;

vii) -(CH2)3NH2;

viii) -(CH2)4NH2;

ix) -(CH2)5NH2;

x) -(CH2)6NH2;

The first category of analogues of ligands of the receptors according to the present invention relates to conformationally restricted ring containing pyrolidine skeleton of the formula:

where each carbon marked with an asterisk can have any configuration. Table I contains not limiting the invention, examples of analogs that comprise the first aspect of this category, and these analogs have the formula:

where R, R2, R3, R4and R9defined in table I, however, 3-aminopropylene intermediates that described in example 1, are also suitable analogues of ligands, receptors and represent the repetition of this aspect of the present invention.

td align="center"> phenyl
TABLE I
No.RR2R3R4R9
1phenyl-NHC(O)CH3Nbenzil phenyl
2benzil-NHC(O)CH3Nbenzilphenyl
33-forfinal-NHC(O)CH3Nbenzilphenyl
44-forfinal-NHC(O)CH3Nbenzilphenyl
53,5-differenl-NHC(O)CH3Nbenzilphenyl
64-chlorophenyl-NHC(O)CH3Nbenzilphenyl
74-hydroxyphenyl-NHC(O)CH3Nbenzilphenyl
8phenyl-NHC(O)CH3N4-imidazolidinylphenyl
9benzil-NHC(O)CH3N4-imidazolidinylphenyl
103-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
114-forfinal-NHC(O)CH3N4-imidazolidinyl
123,5-differenl-NHC(O)CH3N4-imidazolidinylphenyl
134-chlorophenyl-NHC(O)CH3N4-imidazolidinylphenyl
144-hydroxyphenyl-NHC(O)CH3N4-imidazolidinylphenyl
15phenyl-NHC(O)CH3N4-chlorbenzylphenyl
16benzil-NHC(O)CH3N4-chlorbenzylphenyl
173-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
184-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
193,5-differenl-NHC(O)CH3N4-chlorbenzylphenyl
204-chlorophenyl-NHC(O)CH3N4-chlorbenzylphenyl
214-hydroxyphenyl-NHC(O)CH3 N4-chlorbenzylphenyl
22phenyl-NHC(O)CH3N4-hydroxybenzylphenyl
23benzil-NHC(O)CH3N4-hydroxybenzylphenyl
243-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
254-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
263,5-differenl-NHC(O)CH3N4-hydroxybenzylphenyl
274-chlorophenyl-NHC(O)CH3N4-hydroxybenzylphenyl
284-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzylphenyl
29phenyl-NHC(O)CH3Nbenzil2-naphthyl
30benzil-NHC(O)CH3Nbenzil2-naphthyl
31 3-forfinal-NHC(O)CH3Nbenzil2-naphthyl
324-forfinal-NHC(O)CH3Nbenzil2-naphthyl
333,5-differenl-NHC(O)CH3Nbenzil2-naphthyl
344-chlorophenyl-NHC(O)CH3Nbenzil2-naphthyl
354-hydroxyphenyl-NHC(O)CH3Nbenzil2-naphthyl
36phenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
37benzil-NHC(O)CH3N4-imidazolidinyl2-naphthyl
383-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
394-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
403,5-differenl-NHC(O)CH3N4-imidazolidinyl 2-naphthyl
414-chlorophenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
424-hydroxyphenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
43phenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
44benzil-NHC(O)CH3N4-chlorbenzyl2-naphthyl
453-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
464-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
473,5-differenl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
484-chlorophenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
494-hydroxyphenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
50phenyl -NHC(O)CH3N4-hydroxybenzyl2-naphthyl
51benzil-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
523-forfinal-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
534-forfinal-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
543,5-differenl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
554-chlorophenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
564-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
574-forfinalNNbenzil2-naphthyl
58phenylHNbenzil2-naphthyl
594-forfinalHN4-hydroxybenzyl2-naphthyl
60 phenyl-NHC(O)CH3N2-naphthylmethyl2-naphthyl

The following is a diagram of a synthetic way of getting analogues 1-60, but you can get other options pyrrolidone skeleton, using modifications of this General scheme.

Reagents and conditions: (a) (Vos)2Oh, the tea, 0°to count; (b) TMEDA, sec-BuLi, -78°-40°C; CH2=CHCH2Br from -78°to count

For connections 60-88 R9= phenyl; for connections 89-120 R9= 2-naphthyl.

Reagents and conditions: (C) NaH, PhCH2Br (analogues 60-88), NaphCH2Br (analogues 61-120), 0°to count

Reagents and conditions: (d) BH3-THF, N2About2/NaOH, count; (e) CH3SO2Cl, tea, 0°to count

Reagents and conditions: (f) NaN3that 70°With; (g) TFA-H2O-CH2Cl2, count;

Reagents and conditions: (h) Boc-D-Phe (analogues 1, 8, 15, 22, 29, 36, 43, 50, 58 and 60); Boc-homo-D-Phe (analogues 2, 9, 16, 23, 30, 37, 44 and 51); Boc-D-Phe(3-F) (analogues 3, 10, 17, 24, 31, 38, 45 and 52); Boc-D-Phe(4-F) (analogues 4, 11, 18, 25, 32, 39, 46, 53, 57 and 59); Boc-D-Phe(3,5-F) (analogues 5, 12, 19, 26, 33, 40, 47 and 54); Boc-D-Phe(4-Cl) (analogues 6, 13, 20, 27, 34, 41, 48 and 55); Boc-D-Phe(4-OH) (analogues 7, 14, 21, 28, 35, 42, 49 and 56); 1-hydroxybenzotriazole, N-ethylmorpholine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, comnt

Reagents and conditions: (i) TFA-H2O-CH2Cl2, comnt

Reagents and conditions: (j) AcNHCH(CH2Phe)CO2H (analogues 1-7, 29-35, 57 and 58); N-Ac-histidine (analogues 8-14 and 36-42); AcNHCH[CH2Phe(4-Cl)]CO2H (analogues 15-21, 43-49); N-Ac-tyrosine (analogues 22-28, 50-56, 59); AcNHCH(CH2Naph)CO2H (analogue 60); 1-hydroxybenzotriazole, N-methylmorpholine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, comnt

Reagents and conditions: (k) H2Pd/C

Reagents and conditions: (l) BocNHC(SCH3)=NBoc, HgCl2, comnt

Reagents and conditions: (m) TFA:CH2Cl2:anisole, comnt

GETTING PYRROLIDINONE SYNTHETIC intermediates

The following is the method of obtaining the intermediate product with pyrrolidinium skeleton of the formula:

where R9for this example is 2-nattily fragment.

2-S-(3-Azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin

Obtain N-Boc-3-R-hydroxypyrrolidine (1):di-tert-BUTYLCARBAMATE (14.0 g, 63.1 mmol) is added to a stirred solution of 3-R-hydroxypyrrolidine (5.0 g, 57,4 mol) and triethylamine (16 ml, 114,8 mmol) in dichloro the Ana (58 ml) at 0° C. the resulting solution was allowed to warm to room temperature and stirred for 4 hours. This solution was diluted with dichloromethane (50 ml), washed twice 1N HCl and twice aqueous solution of NaHCO3. Then the organic layer is dried over Na2SO4, filtered and concentrated in vacuo, obtaining the desired product (9,9 g, 92%) as a white solid, which is pure enough for use without additional purification.

Obtain N-Boc-2-S-allyl-4-R-hydroxypyrrolidine (2):A solution of N-Boc-3-R-hydroxypyrrolidine1(3.0 g, 16.0 mmol) and TMEDA (6.4 ml, 40,1 mmol) dissolved in THF (50 ml) and cooled to -78°C. To this reaction mixture is added with stirring a solution of 1.3M sec-utility (50 ml) in cyclohexane. The resulting mixture, orange, allowed to warm to -40°and mix of 2.75 hours. This mixture was again cooled to -78°and add allylbromide (3.1 ml, was 35.3 mmol). This mixture is slowly warmed to room temperature with stirring for 4.5 hours. The reaction mixture was quenched with aqueous solution of NH4Cl and extracted with ethyl acetate (150 ml). Then the organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The oily residue is purified on silica gel (CH2Cl2/acetone, 3:1)to give the desired product (2.0 g, 56%) as a colourless oil.

Obtain N-Boc-2-S-allyl-4-R-(naphthalene-2-ylethoxy)pyrrolidine (3):Sodium hydride (408 mg, 11.5 mmol) is added by portions to a stirred solution of N-Boc-2-S-allyl-4-R-hydroxypyrrolidine2(2.0 g, 8,8 mmol) in DMF at 0°and the reaction mixture is stirred for 20 minutes. Then add 2-(methyl bromide)naphthalene (2.9 g, 13,2 mmol) in DMF (5 ml) and the resulting solution is stirred 5 hours at room temperature. The reaction mixture was quenched with aqueous solution of NH4Cl and extracted twice with ethyl acetate. The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo, receiving a yellow oil. This oily residue is purified on silica gel (hexane/EtOAc, 6:1)to give the desired product (2.7 g, 84%) as a colourless oil.

Obtain N-Boc-2-S-(3-hydroxypropyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidine (4):1.0m Solution of a complex of borane-tetrahydrofuran (THF) in THF (11 ml, 11 mmol) is added slowly to a solution of N-Boc-2-S-allyl-4-R-(naphthalene-2-ylethoxy)pyrrolidine3(2.7 g, 7,3 mmol) in THF (15 ml) and the reaction mixture is stirred for 0.5 hour, then carefully add H2On (4,1 ml), and then add 3.0 M NaOH (7.3 ml) and 33% H2O2(5.0 ml). This mixture is stirred for 2 hours and then extracted with EtOAc (50 ml). The organic layer is dried over Na2SO4, filtered and concentrated in vacuo to a yellow oil. MA is lenity the residue is purified on silica gel (hexane/EtOAc, 1:1)to give the desired product (712 mg) as oil.

Obtain N-Boc-2-S-(3-methanesulfonylaminoethyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidine (5):Methanesulfonanilide (0,215 ml, 2.8 mmol) is added to a stirred solution of N-Boc-2-S-(3-hydroxypropyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidine4(712 mg) and triethylamine (of 0.39 ml, 2.8 mmol) in dichloromethane (6 ml) at 0°and the reaction mixture was stirred at room temperature for 0.75 hour. This reaction mixture is quenched with saturated aqueous NaHCO3and extracted twice with dichloromethane (25 ml). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo, obtaining the desired product (856 mg, 100%) as oil which is sufficiently pure for use without additional purification.

Obtain N-Boc-2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidine (6):Sodium azide (361 mg, of 5.50 mmol) are added to a solution of N-Boc-2-S-(3-methanesulfonylaminoethyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidine5(856 mg, of 1.85 mmol) in DMSO (7 ml) and the reaction mixture is stirred at 70°C for 3 hours. This reaction mixture is quenched with H2O and extracted with EtOAc (30 ml). The extract is dried over Na2SO4, filtered and concentrated in vacuo to an oil, orange in color. The oily residue is purified on silica gel (hexane/EtOAc, 3:1), obtaining t is ebuenyi product (584 mg, 78%) as a colourless oil.

Getting 2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidine (7):Prepared solution of TFA:H2O:CH2Cl2(1:0,1:1; 20 ml) is added to a round bottom flask containing N-Boc-2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin6(2.85 g, 6.95 mmol) and the reaction mixture is stirred for 1 hour. This mixture was concentrated in vacuo, obtaining the desired product (3.0 g, 100%) as a TFA salt. Crude oil is used as an intermediate product in the synthesis of compounds of the present invention without further purification.

Pyrolidine synthetic intermediate product having the formula:

you can get replacement 2-(methyl bromide)naphthalene-benzylbromide in the conditions described above to obtain compound3.

EXAMPLE 1

2-S-Acetylamino-N-{2-[2-S-(3-aminopropyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (11)

Getting 2-S-N-(tert-butoxycarbonyl)amino-1-[2-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-3-phenylpropane-1-it (8):To a solution of 2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidine(1.0 g, 2.36 mmol), N-(tert-butoxycarbonyl)-D-phenylalanine (625 mg, 2.36 mmol), 1-hydroxybenzotriazole (641 mg, 4,72 mmol) and N-methylmorpholin is (0.8 ml, 7,07 mmol) in DMF (9.4 ml) add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (506 mg, and 2.83 mmol) and the mixture was stirred at room temperature for 1.25 hours. The reaction is quenched with saturated aqueous NH4Cl and extracted with EtOAc (75 ml). The organic layer was washed with H2O (100 ml), saturated salt solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo to an oil, painted in brown color. The crude oily residue purified on silica gel (hexane/EtOAc, 3:2)to give the desired product (986 mg, 75%) as a white solid.

Getting 2-S-amino-1-[2-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-3-phenylpropane-1-it (9):A solution of TFA:CH2Cl2:H2O (1:1:0,1; 10 ml) is added to a round bottom flask containing 2-S-N-(tert-butoxycarbonyl)amino-1-[2-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-3-phenylpropane-1-he8(986 mg, 1.77 mmol) and the reaction mixture was stirred at room temperature for 1.0 hour. This solution concentrate, getting salt triperoxonane acid of the desired compound (1.0 g, 99%) as a colourless oil which is sufficiently pure for the next interaction without additional purification.

Getting 2-S-acetylamino-N-{2-[2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydro is Setenil)propionamide (10): To a solution of 2-S-amino-1-[2-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-3-phenylpropane-1-it9(1.5 g, 2,63 mmol), N-acetyl-L-tyrosine (586 mg, 2,63 mmol), 1-hydroxybenzotriazole (709 mg, the 5.25 mmol) and N-methylmorpholine (0.9 ml, 7,88 mmol) in DMF (8,8 ml) was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (564 mg, 3,15 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction is quenched with saturated aqueous NH4Cl and twice extracted with EtOAc (75 ml). The combined organic layers washed with N2O (80 ml), saturated salt solution (80 ml), dried over Na2SO4, filtered and concentrated in vacuo to an oil. Crude oil is purified on silica gel (acetone/CH2Cl2, 3:2)to give the desired compound (1,03 g, 60%) as a white solid.

Getting 2-S-acetylamino-N-{2-[2-S-(3-aminopropyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (11):A solution of 2-S-acetylamino-N-{2-[2-S-(3-azithromy)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide10(1,03 g, 1.56 mmol) and pyridine (0,07 ml, 0.78 mmol) in methanol (5.0 ml) rinsed with argon and then add 10 (wt.%) palladium on carbon (500 mg). This reaction mixture is stirred in hydrogen atmosphere for 5 hours. Next, the reaction mixture is filtered is through a layer of celite to remove the catalyst and concentrating the filtrate in vacuo, receiving a connection of the present invention (871 mg, 88%) as a white solid.

This technique can be used to obtain 3-aminopropylene analogues that represent repetition pyrrolidinyl skeletons. The substances thus obtained are sufficiently pure to be used directly in obtaining guanidinopropionic analogues of the present invention.

EXAMPLE 2

2-S-Acetylamino-N-{2-[2-S-(3-guanidinopropionic)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (13)

Getting 2-S-acetylamino-N-{1-R-benzyl-2-[2-S-(3-N,N'-bis(tert-butoxycarbonyl)guanidinopropionic)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (12):The mercury chloride(II) (113 mg, 0.24 mmol) are added to a solution of 2-S-acetylamino-N-{2-[2-S-(3-aminopropyl)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-1-R-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide11(125 mg, 0.20 mmol), 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (57 mg, 0.2 mmol) and triethylamine (0.1 ml, 0.59 mmol) in dry DMF (2 ml) and the reaction mixture stirred at 0°C for 1 hour. Then the reaction mixture was diluted with EtOAc (75 ml), filtered through a layer of celite and concentrate the filtrate in vacuum to give crude product as oil. The crude product is purified on silica gel (CH2Clsub> 2/methanol, 14:1)to give the desired product (170 mg, 98%) as a white solid.

Getting 2-S-acetylamino-N-{1-R-benzyl-2-[2-S-(3-guanidinopropionic)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (13):A solution of TFA:CH2Cl2:anisole (40:55:5; 3.0 ml) is added to a round bottom flask containing 2-S-acetylamino-N-{1-R-benzyl-2-[2-S-(3-N,N'-bis(tert-butoxycarbonyl)guanidinopropionic)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide12(170 mg, 0,19 mmol)and the reaction mixture is stirred for at 3.25 hours. Then the reaction mixture was diluted with dichloromethane and concentrated in vacuo. The crude product is purified by the method of preparative HPLC with reversed phase, receiving compound No. 50 of table I (57 mg, 44%) as a white powder.

Another category of analogues of ligands of the receptors according to the present invention relates to conformationally restricted ring, including piperidinyl skeleton of the formula:

where each carbon marked with an asterisk can have any configuration. Table II contains not limiting the present invention, examples of analogs that includes the first aspect of this category, and these analogs have the formula:

where R, R2, R3, R4and R9ODA is defined in table II.

N
TABLE II
No.RR2R3R4R9
61phenyl-NHC(O)CH3Nbenzilphenyl
624-chlorophenyl-NHC(O)CH3Nbenzilphenyl
634-forfinal-NHC(O)CH3Nbenzilphenyl
643,4-differenl-NHC(O)CH3Nbenzilphenyl
65phenyl-NHC(O)CH3N2-imidazolidinylphenyl
664-chlorophenyl-NHC(O)CH3N2-imidazolidinylphenyl
674-forfinal-NHC(O)CH3N2-imidazolidinylphenyl
683,4-differenl-NHC(O)CH3N2-imidazolidinylphenyl
69-NHC(O)CH3N4-imidazolidinylphenyl
704-chlorophenyl-NHC(O)CH3N4-imidazolidinylphenyl
714-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
723,4-differenl-NHC(O)CH3N4-imidazolidinylphenyl
73phenyl-NHC(O)CH3N4-terbisilphenyl
744-chlorophenyl-NHC(O)CH3N4-terbisilphenyl
754-forfinal-NHC(O)CH3N4-terbisilphenyl
763,4-differenl-NHC(O)CH3N4-terbisilphenyl
77phenyl-NHC(O)CH3N4-hydroxybenzylphenyl
784-chlorophenyl-NHC(O)CH3N4-hydroxybenzyl phenyl
794-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
803,4-differenl-NHC(O)CH3N4-hydroxybenzylphenyl
81phenyl-NHC(O)CH3N4-chlorbenzylphenyl
824-chlorophenyl-NHC(O)CH3N4-chlorbenzylphenyl
834-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
843,4-differenl-NHC(O)CH3N4-chlorbenzylphenyl
85phenyl-NHC(O)CH3N4-acetoxybenzoicphenyl
864-chlorophenyl-NHC(O)CH3N4-acetoxybenzoicphenyl
874-forfinal-NHC(O)CH3N4-acetoxybenzoicphenyl
883,4-differenl-NHC(O)H 3N4-acetoxybenzoicphenyl
89phenyl-NHC(O)CH3Nbenzil2-naphthyl
904-chlorophenyl-NHC(O)CH3Nbenzil2-naphthyl
914-forfinal-NHC(O)CH3Nbenzil2-naphthyl
923,4-differenl-NHC(O)CH3Nbenzil2-naphthyl
93phenyl-NHC(O)CH3N2-imidazolidinyl2-naphthyl
944-chlorophenyl-NHC(O)CH3N2-imidazolidinyl2-naphthyl
954-forfinal-NHC(O)CH3N2-imidazolidinyl2-naphthyl
963,4-differenl-NHC(O)CH3N2-imidazolidinyl2-naphthyl
97phenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
984-chlorophenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
994-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
1003,4-differenl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
101phenyl-NHC(O)CH3N4-terbisil2-naphthyl
1024-chlorophenyl-NHC(O)CH3N4-terbisil2-naphthyl
1034-forfinal-NHC(O)CH3N4-terbisil2-naphthyl
1043,4-differenl-NHC(O)CH3N4-terbisil2-naphthyl
105phenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
1064-chlorophenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
1074-forfinal-NHC(O)CH34-hydroxybenzyl2-naphthyl
1083,4-differenl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
109phenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
1104-chlorophenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
1114-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
1123,4-differenl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
113phenyl-NHC(O)CH3N4-acetoxybenzoic2-naphthyl
1144-chlorophenyl-NHC(O)CH3N4-acetoxybenzoic2-naphthyl
1154-forfinal-NHC(O)CH3N4-acetoxybenzoic2-naphthyl
1163,4-differenl-NHC(O)CH3N4-acetoxybenzoic2-naphthyl
117phenylNNbenzil2-naphthyl
1184-chlorophenylHNbenzil2-naphthyl
1194-forfinalHNbenzil2-naphthyl
1203,4-differenlHNbenzil2-naphthyl

The following is a diagram of a synthetic way of getting analogues 61-120, but you can get other options connections piperidinium skeleton, using modifications of this General scheme.

Reagents and conditions: (a) CbzCl, 0°C; CH2=CHCH2MgCl from -78°0°With; (b) Zn/HOAc.

For compounds 1-28 R9= phenyl; for connections 29-60 R9= 2-naphthyl.

Reagents and conditions: (C) K-selectride, 10°With; (d) NaH, PhCH2Br (compound 1-28), NaphCH2Br (analogues 89-120), 0°to count

Reagents and conditions: (e) (BH3-THF, N2About2/NaOH, 0°to count

Reagents and conditions: (f) (BocNH)2C=NH, diisopropylsalicylic Ph3P, 0°to count

Reagents and conditions: (g) (H2Pd/C, pyridine, comnt

Reagents and conditions: (h) Fmoc-D-phenylalanine (analogues 61, 65, 69, 73, 77, 71, 85, 89, 93, 97, 101, 105, 109, 113 and 57); Fmoc-D-(4-chloro)phenylalanine (analogues 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114 and 118); Fmoc-D-(4-fluoro)phenylalanine (analogues 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115 and 119); Fmoc-D-(3,4-debtor)phenylalanine (analogues 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116 and 120); (isopropyl)2NEt, PyBroP, -20aboutC.

Reagents and conditions: (i) piperidine, comnt

Reagents and conditions: (j) EDCI, HOBt, N-acetyl-L-phenylalanine (analogues 61-64, 89-92 and 117-120); N-acetyl(2-imidazolyl)-L-histidine (analogues 65-68 and 93-96); N-acetyl-L-histidine (analogues 69-72 and 97-100); N-acetyl-L-(4-fluoro)phenylalanine (analogues 73-76 and 101-104); N-acetyl-L-tyrosine (analogues 77-80 and 105-108); N-acetyl-L-(4-chloro)phenylalanine (compound 81-84 and 109-112), N-acetyl-L-(4-acetyl)tyrosine (analogues 85-88 and 113-116).

Reagents and conditions: (k) TFA, comnt

GETTING PIPERIDINOVYH SYNTHETIC intermediates

The following is the method of obtaining the intermediate product with pyrrolidinium skeleton of the formula:

where R9for this example is 2-nattily fragment.

N,N'-Di-tert-butoxycarbonyl-N-{3-S-[4-R-(naphthalene-2-olmeto the si)piperidine-2-yl]propyl}guanidine (20)

Obtaining N-Cbz-6-allyl-2,3-dihydro-1H-pyridine-4-it (14):To a solution of 4-methoxypyridine (50 ml, 0,492 mol) in toluene (1 l) add benzylchloride (70,3 ml, 0,492 mol) at 0°C. the resulting mixture was stirred at 0°C for 30 minutes and then cooled to -75°and add allylanisole (295,5 ml, 0,591 mol). The solution is maintained at -75°C for 4 hours and allowed to warm to 0°then add 20% solution of HCl to quench the reaction. The organic layer is separated and purified on silica gel, obtaining the desired product.

Obtaining N-Cbz-2-S-arylpiperazine-4-it (15):To a solution of N-Cbz-6-allyl-2,3-dihydro-1H-pyridine-4-it14(34,2 g, 0,126 mol) in HOAc (238 ml) at room temperature add zinc dust. The solution is refluxed for 30 minutes, cooled to room temperature and remove the solids by filtration through celite. The product produce by processing to neutral product.

Obtaining N-Cbz-2-S-allyl-4-R-hydroxypiperidine (16):To a solution of N-Cbz-2-S-arylpiperazine-4-it15(34,2 g, 0.125 mol) in THF (700 ml) at 10°With add-selectride (135 ml, 0,150 mol). After 5 minutes the reaction is quenched with water (60 ml). Processing to neutral product gives the desired substance, which was purified on silica gel.

Obtaining N-Cbz-2-S-allyl-4-R-(naphthalene-2-ylethoxy)piperidine (17):To a solution of N-Cbz-2-S-allyl-4-R-Hydra is Capitalina 16(22,11 g, 0.08 mol) in DMF (300 ml) at 0°With added 60% NaH (4,2 g, 0,103 mol). After stirring for 30 minutes, add 2-(methyl bromide)naphthalene (21,3 g 0,096 mol) and stirred the reaction mixture for 24 hours at room temperature, after which the reaction mixture is cooled to 0°C and quenched by adding water. Processing to neutral reaction after purification on silica gel gives the desired product.

Obtaining N-Cbz-2-S-(3-hydroxy)propyl-4-R-(naphthalene-2-ylethoxy)piperidine (18):to a solution of N-Cbz-2-S-allyl-4-R-(naphthalene-2-ylethoxy)piperidine17(1,59 g, a 3.83 mmol) in THF (39 ml) at 0°With added borane/THF (4,2 ml, 4,221 mmol) and allow the reaction mixture to warm to room temperature for 30 minutes. The reaction is quenched with water, then 3M NaOH (2.4 ml) and 30% hydrogen peroxide (2.4 ml). Processing to neutral reaction after purification on silica gel gives the desired product.

Obtaining N,N'-di-tert-butoxycarbonyl-N-{3-S-[4-R-(naphthalene-2-ylethoxy)-N-Cbz-piperidine-2-yl]propyl}guanidine (19):To a solution of N-Cbz-2-S-(3-hydroxy)propyl-4-R-(naphthalene-2-ylethoxy)piperidine (4,96 g, 11,89 mmol), triphenylphosphine (3,74 g, 14,26 mmol) and 1,3-bis(tert-butoxycarbonyl)guanidine (3.7 g, 14,27 mmol) in THF add diisopropylethylamine (2,81 ml, 14,27 mmol) at a temperature of less than 3°C. the Solution is allowed to warm to room temperature, quenched by adding water, process until neutral is th product, then purified on silica gel, obtaining the desired product.

Obtaining N,N'-di-tert-butoxycarbonyl-N-{3-S-[4-R-(naphthalene-2-ylethoxy)piperidine-2-yl]propyl}guanidine (20):A suspension of N,N'-di-tert-butoxycarbonyl-N-{3-S-[4-R-(naphthalene-2-ylethoxy)-N-Cbz-piperidine-2-yl]propyl}guanidine19(9,05 g, 13,43 mmol), pyridine (1.06 g, 13,42 mmol) and 10% Pd/C (4.5 g) in methanol (120 ml) hydronaut at room temperature. Solids are removed by filtration and the obtained residue after concentration of purified on silica gel, obtaining the desired product.

Piperidinyl synthetic intermediate product of the formula:

can be obtained by replacing 2-(methyl bromide)naphthalene-benzylbromide in the conditions described above to obtain compound 17.

EXAMPLE 3

2-Acetylamino-N-{1-(4-terbisil)-2-[2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)piperidine-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (24)

Getting N-fluoren-9-Eletropaulo ether [2-[2-[3-(N',N"-di-tert-butoxycarbonylamino)propyl]-4-naphtalen-2-ylethoxy)piperidine-1-yl]-1-(4-terbisil)-2-oxoethyl]carbamino acid (21):To a solution of N,N'-di-tert-butoxycarbonyl-N-{3-S-[4-R-(naphthalene-2-ylethoxy)piperidine-2-yl]propyl}guanidine20(0,41 g, 0,759 mmol), N-Fmoc-(4-fluoro)phenylalanine (0,339 g, 0,836 mmol) and diisopropylethylamine (ml 0529, 3,036 mmol) in dichloromethane added PyBroP (0,707 g, 1,517 mmol) at -20°C. the Solution was kept at -20°within 24 hours, then remove the solvent in vacuo and the resulting residue purified on silica gel, obtaining the desired product.

Obtaining N,N'-di-tert-butoxycarbonyl-N-{3-[1-[2-amino-3-(4-forfinal)propionyl]-4-(naphtalen-2-ylethoxy)piperidine-2-yl]propyl}guanidine (22):The solution N-fluoren-9-Eletropaulo ether [2-[2-[3-(N',N"-di-tert-butoxycarbonylamino)propyl]-4-naphtalen-2-ylethoxy)piperidine-1-yl]-1-(4-terbisil)-2-oxoethyl]carbamino acid21(0,122 g, 0,132 mmol) and piperidine (0.25 ml) in dichloromethane was stirred at room temperature for 30 minutes. Concentration in vacuo gives the crude product, which was purified on silica gel.

Getting 2-acetylamino-N-[2-[2-[3-(N',N"-di-tert-butoxycarbonylamino)propyl]-4-(naphtalen-2-ylethoxy)piperidine-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (23):To a solution of N,N'-di-tert-butoxycarbonyl-N-{3-[1-[2-amino-3-(4-forfinal)propionyl]-4-(naphtalen-2-ylethoxy)piperidine-2-yl]propyl}guanidine22(77 mg, 0,109 mmol), N-acetyltyrosine (29.3 mg, 0,131 mmol) and 1-hydroxybenzotriazole (31 mg, rate £ 0.162 mmol) in DMF (2 ml) at 0°add the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The solution was stirred at 0°C for 2 hours, then distribute between the ether and aqueous bicarbonate, the organic phase is dried, concentrated in vacuo and purified on silica gel, obtaining the desired product.

Getting 2-acetylamino-{1-(4-terbisil-2-[2-(3-guanidino)propyl]-4-(naphtalen-2-ylethoxy)piperidine-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (24):To a solution of 2-acetylamino-N-[2-[2-[3-(N',N"-di-tert-butoxycarbonylamino)propyl]-4-(naphtalen-2-ylethoxy)piperidine-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide23(55 mg, 0.06 mmol) in dichloromethane (2 ml) is added triperoxonane acid (0.3 ml) and the solution was stirred at room temperature for 7 hours. The concentration and purification on silica gel to give the desired product, similar 107 from table II.

Another category of analogues of ligands of the receptors according to the present invention relates to conformationally restricted ring comprising 5-getapiversion skeleton of the formula:

where each carbon marked with an asterisk can have any configuration. Table II contains not limiting the invention, examples of analogs that includes the first aspect of this category, and these analogs have the formula:

where R, R2, R3, R4and R9defined in table III.

benziltd align="center"> 149
TABLE III
No.RR2R3R4R9
121phenyl-NHCOCH3Nbenzilbenzil
1224-chlorophenyl-NHCOCH3Nbenzilbenzil
1234-forfinal-NHCOCH3Nbenzilbenzil
1243,4-differenl-NHCOCH3Nbenzilbenzil
125phenyl-NHCOCH3N2-imidazolidinylbenzil
1264-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
1274-forfinal-NHCOCH3N2-imidazolidinylbenzil
1283,4-differenl-NHCOCH3N2-imidazolidinylbenzil
129phenyl-NHCOCH3N4-imidazolidinyl
1304-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
1314-forfinal-NHCOCH3N4-imidazolidinylbenzil
1323,4-differenl-NHCOCH3N4-imidazolidinylbenzil
133phenyl-NHCOCH3N4-terbisilbenzil
1344-chlorophenyl-NHCOCH3N4-terbisilbenzil
1354-forfinal-NHCOCH3N4-terbisilbenzil
1363,4-differenl-NHCOCH3N4-terbisilbenzil
137phenyl-NHCOCH3N4-hydroxybenzylbenzil
1384-chlorophenyl-NHCOCH3N4-hydroxybenzylbenzil
1394-forfinal-NHCOCH3 N4-hydroxybenzylbenzil
1403,4-differenl-NHCOCH3N4-hydroxybenzylbenzil
141phenyl-NHCOCH3N4-chlorbenzylbenzil
1424-chlorophenyl-NHCOCH3N4-chlorbenzylbenzil
1434-forfinal-NHCOCH3N4-chlorbenzylbenzil
1443,4-differenl-NHCOCH3N4-chlorbenzylbenzil
145phenyl-NHCOCH3N4-acetoxybenzoicbenzil
1464-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
1474-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
1483,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
phenyl-NHCOCH3Nbenzil2-naphthylmethyl
1504-chlorophenyl-NHCOCH3Nbenzil2-naphthylmethyl
1514-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
1523,4-differenl-NHCOCH3Nbenzil2-naphthylmethyl
153phenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
1544-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
1554-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
1563,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
157phenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
1584-chlorophenyl-NCOCH 3N4-imidazolidinyl2-naphthylmethyl
1594-forfinal-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
1603,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
161phenyl-NHCOCH3N4-terbisil2-naphthylmethyl
1624-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
1634-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
1643,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
165phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
1664-chlorophenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
1674-forfinal-NHCOCH34-hydroxybenzyl2-naphthylmethyl
1683,4-differenl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
169phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
1704-chlorophenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
1714-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
1723,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
173phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
1744-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
1754-forfinal-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
1763,4-differenl-NHCOCH3N4-zeaxanthin 2-naphthylmethyl
177phenylNNbenzil2-naphthylmethyl
1784-chlorophenylHNbenzil2-naphthylmethyl
1794-forfinalHNbenzil2-naphthylmethyl
1803,4-differenlHNbenzil2-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 121-180, but you can get other ways of compounds with 5-getapiversion skeleton, using modifications of this General scheme.

Reagents and conditions: (a) acetic anhydride/pyridine, br I.

Reagents and conditions: (b) O,N-dimethylhydroxylamine, HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (C) LAH, THF, -60°C.

Reagents and conditions: (d) NaBH(OAc)3, DMF, 0°to count

Reagents and conditions: (e) ClCH2COCl, Et3N, CH2Cl20°to count

Reagents and conditions: (f)TFA/CH 2Cl2, comnt

Reagents and conditions: (g)) pyridine, CH2Cl2, comnt

Reagents and conditions: (h) N-BOC-amino acid, EDCI, HOBt, DMF).

Reagents and conditions: (i) TFA/CH2Cl2, comnt

Reagents and conditions: (j) N-acetylaminocinnamic, EDCI, HOBt, DMF).

Reagents and conditions: (k) H2, PtO2, MeOH.

GETTING 5-KEEPERING INTERMEDIATE PRODUCT

The following is the method of obtaining 5-keepering intermediate product having the formula:

where R9for this example is 2-naphthylmethyl fragment.

3-S-[4-(2-naphthalene-2-retil)-5-oxopiperidine-2-yl]propionitrile (31)

Getting 2-N-(tert-butoxycarbonyl)amino-4-cyanobutane acid (25):In the flask is charged with N-tert-butoxycarbonylamino (24.6 g, 100 mmol), acetic anhydride (112 g, 110 mmol) and pyridine (180 ml). The mixture is stirred for 18 hours, then concentrated in vacuo. The residue is partitioned between EtOAc and water and the organic layer washed several times with a solution of citric acid, then saturated NaCl. The organic phase is dried and concentrated in vacuo, obtaining the desired product, is which is used without further purification.

Obtain tert-butyl ester [3-cyano-1-(methoxymethylethoxy)propyl]carbamino acid (26):A solution of 2-N-(tert-butoxycarbonyl)amino-4-cyanobutane acid25(22,8 g, 100 mmol), hydrochloride of O,N-dimethoxyphenethylamine (10.6 g, 110 mmol), hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°C, then allowed to warm and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, obtaining a residue, which is triturated with a mixture of diethyl ether/hexane, getting a white solid, which was collected by filtration. The product is sufficiently pure for use without additional purification.

Getting 2-S-N-Boc-amino-4-cyanophthalide (27):To a solution of tert-butyl methyl ether [3-cyano-1-(methoxymethylethoxy)propyl]carbamino acid26(27,1 g, 100 mmol) in 500 ml THF at temperatures from -30°-25°With added LAH (100 ml 1M solution in THF) in about 10 minutes, and then the reaction mixture is cooled to -55°and continue stirring to use the e 3 hours. After cooling to -60°the reaction is quenched by adding citric acid in methanol (1:1 wt.). During the mixing the temperature of the support at about -45°C. the mixture is allowed to warm to room temperature and partitioned between EtOAc and water and the aqueous phase is again extracted with EtOAc. The combined organic phases are washed with saturated NaCl solution, dried and concentrated in vacuum to give crude aldehyde, which is used without further purification.

Obtaining 3-S-N-Boc-amino-4-(2-naphthalene-2-ylethylamine)butylnitrite (28):The crude aldehyde 2-S-N-Boc-amino-4-cyanobutane27dissolved in DMF (200 ml) and add a solution of 2-naphthylamine (17.1 g, 100 mmol) in 125 ml of DMF. This solution is cooled to 0°and add triacetoxyborohydride sodium (42,4 g, 200 mmol). The suspension is stirred at 0°C and allowed to warm for 2 hours to room temperature. Add saturated aqueous sodium bicarbonate solution until there is no further gas evolution. The solution is extracted with diethyl ether, dried and concentrated, to give crude product, which was purified on silica gel.

Obtaining 3-S-N-Boc-amino-4-[(2-chloroacetyl-2-naphthalene-2-retil)amino]butylnitrite (29):To a solution of 3-S-N-Boc-amino-4-(2-naphthalene-2-ylethylamine)butylnitrite28cases (36.8 g, 100 mmol) and triethylamine (27.8 ml, 200 mmol) in dichloromethane (500 ml) at 0°With added dropwise chlorine is acetylchloride (14,7 g, 130 mmol). The resulting solution was incubated in a bath with ice for another hour, the solution was concentrated in vacuo and the crude substance is purified on silica gel.

Obtaining 3-S-amino-4-[(2-chloroacetyl-2-naphthalene-2-retil)amino]butylnitrite (30):A solution of 3-S-N-Boc-amino-4-[(2-chloroacetyl-2-naphthalene-2-retil)amino]butylnitrite29(44.4 g, 100 mmol), triperoxonane acid (50 ml) and dichloromethane (500 ml) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The crude product can be used without additional purification.

Obtaining 3-S-[4-(2-naphthalene-2-retil)-5-oxopiperidine-2-yl]propionitrile (31):Salt triperoxonane acid 3-S-amino-4-[(2-chloroacetyl-2-naphthalene-2-retil)amino]butylnitrite30(45,8 g, 100 mmol) is placed in dichloromethane (1000 ml) and added dropwise pyridine (50 ml). The solution was stirred at room temperature for 24 hours and then concentrated in vacuo. The resulting crude product was then purified on silica gel, obtaining the desired product in the form of triptoreline salt.

EXAMPLE 4

2-Acetylamino-N-{2-[2-(3-aminopropyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-benzyl-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (34)

Obtain tert-butyl ester [2-[2-(2-cyanoethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]carbamino acid (32):The salt solution triperoxonane is islote 3-S-[4-(2-naphthalene-2-retil)-5-oxopiperidine-2-yl]propionitrile 31(42,1 g, 100 mmol), (R)-2-N-(tert-butoxycarbonyl)amino-3-(4-forfinal)propanoic acid (34,0 g, 120 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°and then give the mixture heated and stirred for further 2 hours at room temperature. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, getting a white foamy residue.

Obtain 3-[1-[2-amino-3-(4-forfinal)propionyl]-4-(2-naphthalene-2-retil)-5-oxopiperidine-2-yl]propionitrile (33): Pactor tert-butyl ester [2-[2-(2-cyanoethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]carbamino acid32(57,2 g, 100 mmol), triperoxonane acid (50 ml) and dichloromethane (500 ml) was stirred at room temperature for 2 hours. The crude product is dissolved in dichloromethane and washed the organic layer with saturated sodium bicarbonate solution, dried and concentrated in vacuo. The desired product is obtained with a yield of 94%.

Getting 2-acetylamino-N-[2-[2-(2-cyanoethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-GI is roxiprin)propionamide (34): A solution of 3-[1-[2-amino-3-(4-forfinal)propionyl]-4-(2-naphthalene-2-retil)-5-oxopiperidine-2-yl]propionitrile33(47,2 g, 100 mmol), N-acetyl-L-tyrosine (22,3 g, 120 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°S, and then allowed to warm and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuum to give crude product, which was purified on silica gel.

Getting 2-acetylamino-N-[2-[2-(3-amino-ethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (35):To a suspension of 2-acetylamino-N-[2-[2-(2-cyanoethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide34(57 mg) and PtO2(11 mg, 20 wt.%) in methanol (3 ml) add one drop of concentrated HCl. The solution hydronaut at a pressure of 3.15 kg/cm2(45 psi) for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo, obtaining the final product, which is purified by the method of preparative HPLC using a mixture of clonicel:TFA:water and getting 26 mg. This product complies with the analogue 167 table III.

Another aspect of this category of analogues of ligands of receptors relates to conformationally restricted ring comprising 5-getapiversion skeleton of the formula:

where Y includes guanidino-fragment. Table IV contains not limiting the invention, examples of analogs that includes the first aspect of this category, and these analogs have the formula:

where R, R2, R3, R4and R9defined in table IV.

tr>
TABLE IV
No.RR2R3R4R9
181phenyl-NHCOCH3Nbenzilbenzil
1824-chlorophenyl-NHCOCH3Nbenzilbenzil
1834-forfinal-NHCOCH3Nbenzilbenzil
1843,4-differenl-NHCOCH3Nbenzilbenzil
185 phenyl-NHCOCH3N2-imidazolidinylbenzil
1864-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
1874-forfinal-NHCOCH3N2-imidazolidinylbenzil
1883,4-differenl-NHCOCH3N2-imidazolidinylbenzil
189phenyl-NHCOCH3N4-imidazolidinylbenzil
1904-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
1914-forfinal-NHCOCH3N4-imidazolidinylbenzil
1923,4-differenl-NHCOCH3N4-imidazolidinylbenzil
193phenyl-NHCOCH3N4-terbisilbenzil
1944-chlorophenyl-NHCOCH3N 4-terbisilbenzil
1954-forfinal-NHCOCH3N4-terbisilbenzil
1963,4-differenl-NHCOCH3N4-terbisilbenzil
197phenyl-NHCOCH3N4-hydroxybenzylbenzil
1984-chlorophenyl-NHCOCH3N4-hydroxybenzylbenzil
1994-forfinal-NHCOCH3N4-hydroxybenzylbenzil
2003,4-differenl-NHCOCH3N4-hydroxybenzylbenzil
201phenyl-NHCOCH3N4-chlorbenzylbenzil
2024-chlorophenyl-NHCOCH3N4-chlorbenzylbenzil
2034-forfinal-NHCOCH3N4-chlorbenzylbenzil
2043,4-differenl -NHCOCH3N4-chlorbenzylbenzil
205phenyl-NHCOCH3N4-acetoxybenzoicbenzil
2064-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
2074-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
2083,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
209phenyl-NHCOCH3Nbenzil2-naphthylmethyl
2104-chlorophenyl-NHCOCH3Nbenzil2-naphthylmethyl
2114-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
2123,4-differenl-NHCOCH3Nbenzil2-naphthylmethyl
213phenyl-NHCOCH3N2-imidazolidinyl2-altimeter
2144-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
2154-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
2163,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
217phenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
2184-chlorophenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
2194-forfinal-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
2203,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
221phenyl-NHCOCH3N4-terbisil2-naphthylmethyl
2224-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
2234-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
2243,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
225phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2264-chlorophenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2274-forfinal-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2283,4-differenl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
229phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
2304-chlorophenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
2314-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
232 3,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
233phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2344-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2354-forfinal-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2363,4-differenl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
237phenylNNbenzil2-naphthylmethyl
2384-chlorophenylHNbenzil2-naphthylmethyl
2394-forfinalHNbenzil2-naphthylmethyl
2403,4-differenlHNbenzil2-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 181-240 based on synthetic intermediate is about product, which can be obtained analogously to the compound described in example 3, similar 167 above.

Reagents and conditions: (a) BocNHC(SCH3)=NBoc, HgCl2, comnt

Reagents and conditions: (b) TFA:CH2Cl2, comnt

EXAMPLE 5

2-Acetylamino-N-[2-[2-(3-guanidinopropionic)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(tormentil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (37)

Getting 2-acetylamino-N-[2-[2-[3-(N',N"-di-BOC-guanidino)propyl]-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (36):The mercury chloride(II) (10,3 mg of 0.038 mmol) are added to a solution of 2-acetylamino-N-[2-[2-(3-amino-ethyl)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide35(26 mg, of 0.038 mmol), 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (11 mg, of 0.038 mmol) and triethylamine (21 μl, 0,152 mmol) in dry DMF (2.0 ml) and the reaction mixture stirred at 0°C for 1 hour. Then the reaction mixture was diluted with EtOAc, filtered through a layer of celite and concentrate the filtrate in vacuum to give crude product as oil. Selected crude product is purified on silica gel (CH2Cl2/methanol, 14:1)to give the desired product as a white solid.

Getting 2-acetylamino-N-[2-[2-(3-what guanidinopropionic)-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (37): A solution of 2-acetylamino-N-[2-[2-[3-(N',N"-di-Boc-guanidino)propyl]-4-(2-naphthalene-2-retil)-5-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide36(35 mg, 38 mmol), triperoxonane acid (1 ml) and dichloromethane (2 ml) was stirred at room temperature for 5 hours. This solution was concentrated in vacuo and the crude product is purified on silica gel (acetonitrile:TFA:water)to give 24 mg (yield 84%) of the final product, which corresponds to the analog 227 (table IV).

Another category of analogues of ligands of the receptors according to the present invention relates to conformationally restricted ring comprising 3-getapiversion skeleton of the formula:

where the carbon marked with an asterisk can have any configuration. Table V contains not limiting the invention, examples of analogs that includes the first aspect of this category, and these analogs have the formula:

where R, R2, R3, R4and R9defined in table V.

benzil
TABLE V
No.RR2R3R4R9
241phenyl-NHCOCH3N/td> benzilbenzil
2424-chlorophenyl-NHCOCH3Nbenzilbenzil
2434-forfinal-NHCOCH3Nbenzilbenzil
2443,4-differenl-NHCOCH3Nbenzilbenzil
245phenyl-NHCOCH3N2-imidazolidinylbenzil
2464-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
2474-forfinal-NHCOCH3N2-imidazolidinylbenzil
2483,4-differenl-NHCOCH3N2-imidazolidinylbenzil
249phenyl-NHCOCH3N4-imidazolidinylbenzil
2504-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
2514-forfei the -NHCOCH3N4-imidazolidinylbenzil
2523,4-differenl-NHCOCH3N4-imidazolidinylbenzil
253phenyl-NHCOCH3N4-terbisilbenzil
2544-chlorophenyl-NHCOCH3N4-terbisilbenzil
2554-forfinal-NHCOCH3N4-terbisilbenzil
2563,4-differenl-NHCOCH3N4-terbisilbenzil
257phenyl-NHCOCH3N4-hydroxybenzylbenzil
2584-chlorophenyl-NHCOCH3N4-hydroxybenzylbenzil
2594-forfinal-NHCOCH3N4-hydroxybenzylbenzil
2603,4-differenl-NHCOCH3N4-hydroxybenzyl
261phenyl-NHCOCH3N4-chlorbenzylbenzil
2624-chlorophenyl-NHCOCH3N4-chlorbenzylbenzil
2634-forfinal-NHCOCH3N4-chlorbenzylbenzil
2643,4-differenl-NHCOCH3N4-chlorbenzylbenzil
265phenyl-NHCOCH3N4-acetoxybenzoicbenzil
2664-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
2674-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
2683,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
269phenyl-NHCOCH3Nbenzil2-naphthylmethyl
2704-chlorophenyl-NHCOCH3 Nbenzil2-naphthylmethyl
2714-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
2723,4-differenl-NHCOCH3Nbenzil2-naphthylmethyl
273phenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
2744-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
2754-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
2763,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
277phenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
2784-chlorophenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
2794-forfinal-NHCOCH3N4-imidazol shall lmutil 2-naphthylmethyl
2803,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
281phenyl-NHCOCH3N4-terbisil2-naphthylmethyl
2824-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
2834-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
2843,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
285phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2864-chlorophenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2874-forfinal-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
2883,4-differenl-NHCOCH3N4-hydroxybenzyl2-the NAF shall ylmethyl
289phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
2904-chlorophenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
2914-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
2923,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
293phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2944-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2954-forfinal-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
2963,4-differenl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
297phenylNNbenzil2-naphthylmethyl
2984-chlorophenyl HNbenzil2-naphthylmethyl
2994-forfinalHNbenzil2-naphthylmethyl
3003,4-differenlHNbenzil2-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 241-300, but you can get other options connections pieperazinove skeleton, using modifications of this basic schema.

Reagents and conditions: (a) EDCI, HOBt, DMF).

Reagents and conditions: (b) TFA:CH2Cl2:H2Oh, count; (C) 2-nitrosodiphenylamine, Thea, CH2Cl20°to count

Reagents and conditions: (d) BrCH2CH2Br, K2CO3, DMF, 55°C.

Reagents and conditions: (e) para-thiophenol, K2CO3, acetonitrile, comnt

Reagents and conditions: (f) EDCI, HOBt, DMF).

Reagents and conditions: (g) (H2:PtO2, MeOH.

OBTAINING 3-KEEPERING INTERMEDIATE PRODUCT

The following is the method of obtaining 3-keepering intermediate product of the formula:

where R9for this example is 2-nattily fragment.

Methyl ester 2-[3-(3-benzyloxycarbonylamino)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (42)

Obtain methyl ester of 2-(5-N-Cbz-amino-2-N-Boc-aminophenylamino)-3-naphthalene-2-ylpropionic acid (38):A solution of methyl ester of 1-amino-3-naphthalene-2-ylpropionic acid (22.9 g, 100 mmol), 5-benzyloxycarbonylamino-2-tert-butoxycarbonylamino acid (33.6 g, 100 ml), hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°C, then allowed to warm and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, obtaining a residue, which is purified on silica gel.

Obtain methyl ester of 2-(2-amino-5-N-Cbz-aminophenylamino)-3-naphthalene-2-ylpropionic acid (39):methyl ester of 2-(5-N-Cbz-amino-2-N-Boc-aminophenylamino)-3-naphthalene-2-ylpropionic acid38(6.0 g, or 10.3 mmol) was dissolved in 32 ml of the solution obtained from the 2:1:0, parts of dichloromethane/TFA/water. The reaction mixture is stirred for 3 hours. The solvent is removed in vacuum and the residue is treated with 1,2-dichloromethane, which is also removed in vacuum. Repeat this several times and get 9,84 g crude residue, which is used in the next stage without additional purification.

Obtaining methyl ester 2-[5-N-Cbz-amino-2-(2-nitrobenzenesulfonamide)pentanediamine]-3-naphthalene-2-ylpropionic acid (40):methyl ester 2-(2-amino-5-N-Cbz-aminophenylamino)-3-naphthalene-2-ylpropionic acid39dissolved in dichloromethane (200 ml), triethylamine (0.5 ml) and cool the solution in a bath with ice. Add ortho-nitrosodiphenylamine (4.5 g, to 20.6 mmol) and continue stirring with cooling for 1 hour and then at room temperature for another 6 hours. The reaction mixture was treated with 1M citric acid and extracted with ethyl acetate solution. The organic layer was washed with saturated aqueous sodium carbonate and water. The crude substance is purified on silica gel (1:1 hexane/ethyl acetate)to give the desired product (3.6 g).

Obtaining methyl ester 2-[3-(3-benzyloxycarbonylamino)-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (41):A mixture of methyl ester of 2-[5-benzyloxycarbonylamino-2-(2-nitrobenzenesulfonamide)pentanediamine]-3-naphthalene-2-ylpropionic acids is 40(2.4 g, 3.63 mmol), dibromoethane (3.8 ml, 4,36 mmol), potassium carbonate (5.0 g, 36,3 mmol) in DMF (50 ml) was stirred at 55°C for 18 hours. The reaction mixture is cooled to room temperature, treated with 1M KHSO4and the resulting solution was extracted with ethyl acetate. The crude product is purified on silica gel (graded elution with mixture of EtOAc/hexane 1:2, 1:1, 100% EtOAc, then EtOAc with 5% Meon)to give 2.76 g of the desired product.

Obtaining methyl ester 2-[3-(3-N-benzyloxycarbonylamino)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (42): A mixture of methyl ester of 2-[3-(3-benzyloxycarbonylamino)-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid41(1.9 g, 2.8 mmol), para-thiophenol (1.6 g, 12.4 mmol) and K2CO3(2.3 g, of 16.6 mmol) in acetonitrile (10 ml) was stirred at room temperature for 18 hours. Then the reaction mixture was concentrated in vacuo and the resulting residue is treated with 1M HCl (10 ml). The aqueous phase is extracted with EtOAc and purified on silica gel (graded elution with mixture of EtOAc/hexane 1:1, 100% EtOAc, then EtOAc with 5% Meon)to give 2.58 g of the desired product.

3-Getapiversion intermediate product of the formula:

can be obtained by replacing the methyl ester of 1-amino-3-naphthalene-2-ylpropionic acid phenylalanine in the synthesis of the unity 38described here above.

EXAMPLE 6

2-[4-[2-[2-Acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic (44)

Obtaining methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-N-Cbz-aminopropyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (43):A solution of methyl ester 2-[3-(3-N-Cbz-aminopropyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid42(of 50.4 g, 100 mmol), 2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionic acid (38,8 g, 100 mmol), hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°and then allow the mixture to warm to room temperature and stirred for further 2 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, obtaining a residue, which is purified on silica gel.

Obtaining methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-3-NAF is Alin-2-ylpropionic acid (44): A solution of methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-N-Cbz-aminopropyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid43(a total of 8.74 g, 10 mmol) is suspended in methanol (100 ml) and hydronaut in the presence of 10% Pd/C at a pressure of 2.81 kg/cm2(40 psi) for 16 hours. The solution is filtered to remove the catalyst and the crude product purified by the method of preparative HPLC using a linear gradient of acetonitrile in water with 0.1% TFA, obtaining the desired product corresponding to similar 287 table V.

Another iteration of this category of analogues of ligands of receptors relates to analogues of the formula:

where R, R2, R3, R4and R9defined in table VI.

323
TABLE VI
No.RR2R3R4R9
301phenyl-NHCOCH3Nbenzilbenzil
3024-chlorophenyl-NHCOCH3Nbenzilbenzil
3034-forfinal-NHCOCH3Nbenzil benzil
3043,4-differenl-NHCOCH3Nbenzilbenzil
305phenyl-NHCOCH3N2-imidazolidinylbenzil
3064-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
3074-forfinal-NHCOCH3N2-imidazolidinylbenzil
3083,4-differenl-NHCOCH3N2-imidazolidinylbenzil
309phenyl-NHCOCH3N4-imidazolidinylbenzil
3104-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
3114-forfinal-NHCOCH3N4-imidazolidinylbenzil
3123,4-differenl-NHCOCH3N4-imidazolidinylbenzil
313phenyl -NHCOCH3N4-terbisilbenzil
3144-chlorophenyl-NHCOCH3N4-terbisilbenzil
3154-forfinal-NHCOCH3N4-terbisilbenzil
3163,4-differenl-NHCOCH3N4-terbisilbenzil
317phenyl-NHCOCH3N4-hydroxybenzylbenzil
3184-chlorophenyl-NHCOCH3N4-hydroxybenzylbenzil
3194-forfinal-NHCOCH3N4-hydroxybenzylbenzil
3203,4-differenl-NHCOCH3N4-hydroxybenzylbenzil
321phenyl-NHCOCH3N4-chlorbenzylbenzil
3224-chlorophenyl-NHCOCH3N4-chlorbenzylbenzil
4-forfinal-NHCOCH3N4-chlorbenzylbenzil
3243,4-differenl-NHCOCH3N4-chlorbenzylbenzil
325phenyl-NHCOCH3N4-acetoxybenzoicbenzil
3264-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
3274-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
3283,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
329phenyl-NHCOCH3Nbenzil2-naphthylmethyl
3304-chlorophenyl-NHCOCH3Nbenzil2-naphthylmethyl
3314-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
3323,4-differenl-NHCOCH3N benzil2-naphthylmethyl
333phenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3344-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3354-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3363,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
337phenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
3384-chlorophenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
3394-forfinal-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
3403,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
341phenyl-NHCOCH3N4-Torben the Il 2-naphthylmethyl
3424-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
3434-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
3443,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
345phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
3464-chlorophenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
3474-forfinal-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
3483,4-differenl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
349phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
3504-chlorophenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl/td>
3514-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
3523,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
353phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
3544-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
3554-forfinal-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
3563,4-differenl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
3574-hydroxyphenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3584-hydroxyphenyl-NHCOCH3N4-terbisil2-naphthylmethyl
3594-hydroxyphenyl-NHCOCH3N4-hydroxybenzyl2-aftermath the
3604-hydroxyphenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 301-360, but you can get other ways of compounds with 3-getapiversion skeleton, using modifications of this General scheme.

Reagents and conditions: (h) BocNHC(SCH3)=NBoc, HgCl2, comnt

Reagents and conditions: (i) TFA:CH2Cl2, comnt

EXAMPLE 7

Methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]propionic acid (46)

Obtaining methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-N,N'-bis(tert-butoxycarbonyl)guanidinopropionic)-2-oxopiperidin-1-yl]propionic acid (45):The mercury chloride(II) (5.7 g, 12 mmol) are added to a solution of methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid44(7,4 g, 10 mmol), 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (2.9 g, 10 mmol) and triethylamine (of 4.2 ml, 30 mmol) in dry DMF (100 ml) and the reaction mixture paramashiva the t at 0° C for 1 hour. Then the reaction mixture was diluted with EtOAc, filtered through celite and concentrate the filtrate in vacuum to give crude product. Selected crude product is purified on silica gel (CH2Cl2/methanol, 14:1)to give the desired product.

Obtaining methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]propionic acid (46):A solution of methyl ester 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-N,N'-bis(tert-butoxycarbonyl)guanidinopropionic)-2-oxopiperidin-1-yl]propionic acid45(10.4 g, 10 mmol), triperoxonane acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Another aspect of this category relates to analogues, where R10represents the fragment-CONH2that provides receptor ligands of the formula:

where R, R2, R3, R4and R9defined in table VII, or ligands of the formula:

where R, R2, R3, R4and R9/sup> defined in table VIII.

TABLE VII
No.RR2R3R4R9
361phenyl-NHCOCH3Nbenzilbenzil
3624-chlorophenyl-NHCOCH3Nbenzilbenzil
3634-forfinal-NHCOCH3Nbenzilbenzil
3643,4-differenl-NHCOCH3Nbenzilbenzil
365phenyl-NHCOCH3N2-imidazolidinylbenzil
3664-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
3674-forfinal-NHCOCH3N2-imidazolidinylbenzil
3683,4-differenl-NHCOCH3N2-imidazolidinylbenzil
369phenyl-NHCOCH3N4-imidazolidinylbenzil
3704-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
3714-forfinal-NHCOCH3N4-imidazolidinylbenzil
3723,4-differenl-NHCOCH3N4-imidazolidinylbenzil
373phenyl-NHCOCH3N4-terbisilbenzil
3744-chlorophenyl-NHCOCH3N4-terbisilbenzil
3754-forfinal-NHCOCH3N4-terbisilbenzil
3763,4-differenl-NHCOCH3N4-terbisilbenzil
377phenyl-NHCOCH3N4-hydroxybenzylbenzil
3784-chlorophenyl-NHCOCH3N 4-hydroxybenzylbenzil
3794-forfinal-NHCOCH3N4-hydroxybenzylbenzil
3803,4-differenl-NHCOCH3N4-hydroxybenzylbenzil
381phenyl-NHCOCH3N4-chlorbenzylbenzil
3824-chlorophenyl-NHCOCH3N4-chlorbenzylbenzil
3834-forfinal-NHCOCH3N4-chlorbenzylbenzil
3843,4-differenl-NHCOCH3N4-chlorbenzylbenzil
385phenyl-NHCOCH3N4-acetoxybenzoicbenzil
3864-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
3874-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
388 3,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
389phenyl-NHCOCH3Nbenzil2-naphthylmethyl
3904-chlorophenyl-NHCOCH3Nbenzil2-naphthylmethyl
3914-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
3923,4-differenl-NHCOCH3Nbenzil2-naphthylmethyl
393phenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3944-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3954-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
3963,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
397phenyl-NHCOCH3 N4-imidazolidinyl2-naphthylmethyl
3984-chlorophenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
3994-forfinal-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
4003,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
401phenyl-NHCOCH3N4-terbisil2-naphthylmethyl
4024-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
4034-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
4043,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
405phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4064-chlorophenyl-NHCOCH3NHydroxybenzyl 2-naphthylmethyl
4074-forfinal-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4083,4-differenl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
409phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
4104-chlorophenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
4114-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
4123,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
413phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4144-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4154-forfinal-NHCOCH3N4-acetoxybenzoic2 naftel the Teal
4163,4-differenl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4174-hydroxyphenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
4184-hydroxyphenyl-NHCOCH3N4-terbisil2-naphthylmethyl
4194-hydroxyphenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4204-hydroxyphenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl

TABLE VIII
No.RR2R3R4R9
421phenyl-NHCOCH3Nbenzilbenzil
4224-chlorophenyl-NHCOCH3Nbenzilbenzil
4234-forfinal-NHCOCH3N benzilbenzil
4243,4-differenl-NHCOCH3Nbenzilbenzil
425phenyl-NHCOCH3N2-imidazolidinylbenzil
4264-chlorophenyl-NHCOCH3N2-imidazolidinylbenzil
4274-forfinal-NHCOCH3N2-imidazolidinylbenzil
4283,4-differenl-NHCOCH3N2-imidazolidinylbenzil
429phenyl-NHCOCH3N4-imidazolidinylbenzil
4304-chlorophenyl-NHCOCH3N4-imidazolidinylbenzil
4314-forfinal-NHCOCH3N4-imidazolidinylbenzil
4323,4-differenl-NHCOCH3N4-imidazolidinylbenzil
433 phenyl-NHCOCH3N4-terbisilbenzil
4344-chlorophenyl-NHCOCH3N4-terbisilbenzil
4354-forfinal-NHCOCH3N4-terbisilbenzil
4363,4-differenl-NHCOCH3N4-terbisilbenzil
437phenyl-NHCOCH3N4-hydroxybenzylbenzil
4384-chlorophenyl-NHCOCH3N4-hydroxybenzylbenzil
4394-forfinal-NHCOCH3N4-hydroxybenzylbenzil
4403,4-differenl-NHCOCH3N4-hydroxybenzylbenzil
441phenyl-NHCOCH3N4-chlorbenzylbenzil
4424-chlorophenyl-NHCOCH3N4-chlorbenzyl benzil
4434-forfinal-NHCOCH3N4-chlorbenzylbenzil
4443,4-differenl-NHCOCH3N4-chlorbenzylbenzil
445phenyl-NHCOCH3N4-acetoxybenzoicbenzil
4464-chlorophenyl-NHCOCH3N4-acetoxybenzoicbenzil
4474-forfinal-NHCOCH3N4-acetoxybenzoicbenzil
4483,4-differenl-NHCOCH3N4-acetoxybenzoicbenzil
449phenyl-NHCOCH3Nbenzil2-naphthylmethyl
4504-chlorophenyl-NHCOCH3Nbenzil2-naphthylmethyl
4514-forfinal-NHCOCH3Nbenzil2-naphthylmethyl
4523,4-differenl-NHCOCH3 Nbenzil2-naphthylmethyl
453phenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
4544-chlorophenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
4554-forfinal-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
4563,4-differenl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
457phenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
4584-chlorophenyl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
4594-forfinal-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
4603,4-differenl-NHCOCH3N4-imidazolidinyl2-naphthylmethyl
461phenyl-NHCOCH3 N4-terbisil2-naphthylmethyl
4624-chlorophenyl-NHCOCH3N4-terbisil2-naphthylmethyl
4634-forfinal-NHCOCH3N4-terbisil2-naphthylmethyl
4643,4-differenl-NHCOCH3N4-terbisil2-naphthylmethyl
465phenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4664-chlorophenyl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4674-forfinal-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
4683,4-differenl-NHCOCH3N4-hydroxybenzyl2-naphthylmethyl
469phenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
4704-chlorophenyl-NHCOCH3N4-Harbin the Il 2-naphthylmethyl
4714-forfinal-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
4723,4-differenl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl
473phenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4744-chlorophenyl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4754-forfinal-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4763,4-differenl-NHCOCH3N4-acetoxybenzoic2-naphthylmethyl
4774-hydroxyphenyl-NHCOCH3N2-imidazolidinyl2-naphthylmethyl
4784-hydroxyphenyl-NHCOCH3N4-terbisil2-naphthylmethyl
4794-hydroxyphenyl-NHCOCH3N4 hydroxybenzo the 2-naphthylmethyl
4804-hydroxyphenyl-NHCOCH3N4-chlorbenzyl2-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 361-420. The following diagram R9is 2-naphthylmethyl, but you can get other options connections piperazinonyl skeleton, using modifications of this General scheme. For example, if 1-amino-3-naphthalene-2-ylpropionic acid be replaced by phenylalanine in the synthesis of compound 38, the result will be the analogues, where R9represents benzyl.

Reagents and conditions: (a) LiOH, 0°C.

Reagents and conditions: (b) NH2CH3, PyBOP, comnt

Reagents and conditions: (C) TFA/CH2Cl2, comnt

Reagents and conditions: (d) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (e) H2, 10% Pd/C, MeOH.

EXAMPLE 8

2-[4-[2-[2-Acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic (51)

Getting 2-{3-(N-Cbz-aminopropyl)-4-[2-N-Boc-amino-3-(4-forfinal)propionyl 2-oxopiperidin-1-yl]-3-nafta is in-2-yl}propionic acid (47): A mixture of methyl ester of 2-[5-N-Cbz-amino-2-(2-N-Boc-amino)pentanediamine]-3-naphthalene-2-ylpropionic acid (0,755 g, 1 mmol) in THF (15 ml) is cooled in a bath of ice and treated with LiOH solution (0.12 g, 5 mmol) in water (7.5 ml). This solution is stirred for 1 hour at 0°With, then allow it to warm to room temperature and stirred for further 3 hours. Then the reaction mixture was diluted with water (30 ml), cooled in a bath with ice and acidified with 1M HCl to pH 3-4. The resulting solution was extracted with EtOAc. The organic phase is dried and concentrated in vacuo, obtaining of 0.58 g (75%) of the desired product.

Getting benzyl ether {3-[1-[2-N-Boc-amino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid (48):To a mixture of 2-{3-(N-Cbz-aminopropyl)-4-[2-N-Boc-amino-3-(4-forfinal)propionyl 2-oxopiperidin-1-yl]-3-naphthalene-2-yl}propionic acid47(0.6 g, 0.77 mmol), 2M methylamine (3 ml) in DMF (15 ml) add hexaphosphate benzotriazol-1-electropermeabilization (PyBOP) (0.6 g, 1.15 mmol). This solution is stirred for 18 hours, then diluted with water (80 ml) and extracted with EtOAc solution. The organic phase is dried, concentrated in vacuo and the resulting crude product was then purified on silica gel (EtOAc/hexane, 1:3, then 1:1 and 10% methanol in EtOAc)to give 0.56 g of the desired product.

Getting benzyl ether {3-[1-[2-the Mino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naftalin-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid (49): A solution of benzyl ether {3-[1-[2-N-Boc-amino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid48,triperoxonane acid (50 ml) and dichloromethane (500 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Getting benzyl ether {3-[1-[2-[2-acetylamino-2-(4-hydroxyphenyl)-2-acetylamino]-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphtalen-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid (50):Benzyl ether of {3-[1-[2-amino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naftalin-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid49(66,8 g, 100 mmol), N-acetyl-L-tyrosine (26,8 g, 120 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°With, then give the mixture heated and stirred for further 2 hours at room temperature. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc, extras is Giroud water, dried and concentrated in vacuo, receiving the requested connection.

Getting 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic (51):Benzyl ether of {3-[1-[2-[2-acetylamino-2-(4-hydroxyphenyl)-2-acetylamino]-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphtalen-2-retil)-3-oxopiperidin-2-yl]propyl}carbamino acid50(8,59 g, 10 mmol) is suspended in methanol (100 ml) and hydronaut in the presence of 10% Pd/C at 2,81 kg/cm2(40 psi) for 16 hours. The solution is filtered, removing the catalyst and the crude product was then purified by the method of preparative HPLC using a linear gradient of acetonitrile in water with 0.1% TFA and receiving the desired product, similar ligand receptor 457.

Examples of ligands of the receptor of the present invention, are presented in table VIII, the analogues 421-480 include guanidinopropionic fragment. These analogues can be conveniently obtained by modification of the methods described herein above for the conversion of compounds35in connection37.

Another aspect of the present invention relates to 3-getapiversion receptor ligands of the formula:

where R, R2, R4, R9and R17defined here in the following table IX.

TABLE IX
No.RR2R4R9R17
481phenyl-NHCOCH3benzilphenylmethyl
4824-chlorophenyl-NHCOCH3benzilphenylmethyl
4834-forfinal-NHCOCH3benzilphenylmethyl
4843,4-differenl-NHCOCH3benzilphenylmethyl
485phenyl-NHCOCH32-imidazolidinylphenylmethyl
4864-chlorophenyl-NHCOCH32-imidazolidinylphenylmethyl
4874-forfinal-NHCOCH32-imidazolidinylphenylmethyl
4883,4-differenl-NHCOCH32-imidazolidinylphenylmethyl
489phenyl-NHCOCH3 4-imidazolidinylphenylmethyl
4904-chlorophenyl-NHCOCH34-imidazolidinylphenylmethyl
4914-forfinal-NHCOCH34-imidazolidinylphenylmethyl
4923,4-differenl-NHCOCH34-imidazolidinylphenylmethyl
493phenyl-NHCOCH34-terbisilphenylmethyl
4944-chlorophenyl-NHCOCH34-terbisilphenylmethyl
4954-forfinal-NHCOCH34-terbisilphenylmethyl
4963,4-differenl-NHCOCH34-terbisilphenylmethyl
497phenyl-NHCOCH34-hydroxybenzylphenylmethyl
4984-chlorophenyl-NHCOCH34-hydroxybenzylphenyl methyl
4994-forfinal-NHCOCH34-hydroxybenzylphenylmethyl
5003,4-differenl-NHCOCH34-hydroxybenzylphenylmethyl
501phenyl-NHCOCH34-chlorbenzylphenylmethyl
5024-chlorophenyl-NHCOCH34-chlorbenzylphenylmethyl
5034-forfinal-NHCOCH34-chlorbenzylphenylmethyl
5043,4-differenl-NHCOCH34-chlorbenzylphenylmethyl
505phenyl-NHCOCH34-acetoxybenzoicphenylmethyl
5064-chlorophenyl-NHCOCH34-acetoxybenzoicphenylmethyl
5074-forfinal-NHCOCH34-acetoxybenzoicphenylmethyl
5083,4-ditto is phenyl -NHCOCH34-acetoxybenzoicphenylmethyl
509phenyl-NHCOCH3benzil2-naphthylmethylmethyl
5104-chlorophenyl-NHCOCH3benzil2-naphthylmethylmethyl
5114-forfinal-NHCOCH3benzil2-naphthylmethylmethyl
5123,4-differenl-NHCOCH3benzil2-naphthylmethylmethyl
513phenyl-NHCOCH32-imidazolidinyl2-naphthylmethylmethyl
5144-chlorophenyl-NHCOCH32-imidazolidinyl2-naphthylmethylmethyl
5154-forfinal-NHCOCH32-imidazolidinyl2-naphthylmethylmethyl
5163,4-differenl-NHCOCH32-imidazolidinyl2-naphthylmethylmethyl
517phenylNHCOCH 34-imidazolidinyl2-naphthylmethylmethyl
5184-chlorophenyl-NHCOCH34-imidazolidinyl2-naphthylmethylmethyl
5194-forfinal-NHCOCH34-imidazolidinyl2-naphthylmethylmethyl
5203,4-differenl-NHCOCH34-imidazolidinyl2-naphthylmethylmethyl
521phenyl-NHCOCH34-terbisil2-naphthylmethylmethyl
5224-chlorophenyl-NHCOCH34-terbisil2-naphthylmethylmethyl
5234-forfinal-NHCOCH34-terbisil2-naphthylmethylmethyl
5243,4-differenl-NHCOCH34-terbisil2-naphthylmethylmethyl
525phenyl-NHCOCH34-hydroxybenzyl2-naphthylmethylmethyl
5264-chlorphen the l -NHCOCH34-hydroxybenzyl2-naphthylmethylmethyl
5274-forfinal-NHCOCH34-hydroxybenzyl2-naphthylmethylmethyl
5283,4-differenl-NHCOCH34-hydroxybenzyl2-naphthylmethylmethyl
529phenyl-NHCOCH34-chlorbenzyl2-naphthylmethylmethyl
5304-chlorophenyl-NHCOCH34-chlorbenzyl2-naphthylmethylmethyl
5314-forfinal-NHCOCH34-chlorbenzyl2-naphthylmethylmethyl
5323,4-differenl-NHCOCH34-chlorbenzyl2-naphthylmethylmethyl
533phenyl-NHCOCH34-acetoxybenzoic2-naphthylmethylmethyl
5344-chlorophenyl-NHCOCH34-acetoxybenzoic2-naphthylmethylmethyl
535 4-forfinal-NHCOCH34-acetoxybenzoic2-naphthylmethylmethyl
5363,4-differenl-NHCOCH34-acetoxybenzoic2-naphthylmethylmethyl

The following is a diagram of a synthetic way of getting analogues 481-536, other compounds with 3-getapiversion skeleton, for example, R17equal to the ethyl, propylene, and the like, can be obtained by using a modification of this General scheme.

Reagents and conditions: (a) TBDMSCl, DMF, 0°to count

Reagents and conditions: (b) 2-nitrobenzenesulfonamide, K2CO3, DME, 0°to count

Reagents and conditions: (C) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (d) BrCH2CH2Br, K2CO3, DMF, 55°C.

Reagents and conditions: (e) LiOH, 0°C.

Reagents and conditions: (f) NH2CH3, PyBOP, comnt

Reagents and conditions: (g) para-thiophenol, K2CO3, acetonitrile count

Reagents and conditions: (h) (Boc)2 O, TEA, DHM, comnt

Reagents and conditions: (i) tetrabutylammonium, water, comnt

Reagents and conditions: (j) Ac2O, pyridine, DMAP, DHM, comnt

Reagents and conditions: (k) TFA, DHM, comnt

Reagents and conditions: (l) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (m) TFA, DHM, comnt

Reagents and conditions: (n) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

OBTAINING 3-KEEPERING INTERMEDIATE PRODUCT

The following is the method of obtaining 3-keepering intermediate product having the formula:

2-{3-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-oxopiperidin-1-yl}-N-methyl-3-naphthalene-2-ylpropionic (58)

Obtaining 2-amino-4-(tert-butyldimethylsilyloxy)butyric acid (52): Imidazole (20.4 g, 300 mmol) are added to a solution of homoserine (11.9 g, 100 mmol) in DMF (100 ml) and stirred solution of 15 minutes while cooling to 0°C. Add tert-butyldimethylsilyloxy (13,7 g, 91 mmol) and the mixture is stirred for ten minutes at 0°and 4 hours at room temperature. The reaction mixture was poured into water (3 l) and the resulting solid collected f is trovanjem. The isolated product is dried and used without further purification.

Getting 4-(tert-butyldimethylsilyloxy)-2-(2-nitrobenzenesulfonamide)butyric acid (53): 2-Amino-4-(tert-butyldimethylsilyloxy)butyric acid52(23.3 g, 10 mmol) dissolved in a mixture of 1,2-dimethoxyethane (800 ml), water (800 ml) and K2CO3(20.7 g, 150 mmol) and the resulting solution was cooled to 0°C. After 15 minutes, add 2-nitrobenzenesulfonamide (26,6 g, 120 mmol), remove the cooling bath and stir the mixture for 18 hours. The reaction mixture was acidified with 1N HCl to pH 3-4 and the solution extracted with EtOAc several times. The combined organic layers are dried and concentrated in vacuo and the crude product is purified on silica gel, receiving 19.3 g (46%) of the desired product.

Obtaining methyl ester 2-[4-(tert-butyldimethylsilyloxy)-2-(2-nitrobenzenesulfonamide)Butylimino]-3-naphthalene-2-ylpropionic acid (54):Solution4-(tert-butyldimethylsilyloxy)-2-(2-nitrobenzenesulfonamide)butyric acid53(41,9 g, 100 mmol), methyl ester 2-amino-3-naphthalene-2-ylpropionic acid (22.9 g, 100 mmol), hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture was stirred for 2 hours at 0°With, then Yes the t to be heated and stirred for further 2 hours at room temperature. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuum to give crude product, which was purified on silica gel, getting to 34.7 g (55%).

Obtaining methyl ester 2-[3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (55):The mixture ofmethyl ester 2-[4-(tert-butyldimethylsilyloxy)-2-(2-nitrobenzenesulfonamide)Butylimino]-3-naphthalene-2-ylpropionic acid54(63 g, 100 mmol), 1,2-dibromethane (10.3 ml, 120 mmol), potassium carbonate (138 g, 1 mol) in DMF (500 ml) was stirred at 55°C for 18 hours. The reaction mixture is cooled to room temperature, treated with 1M KHSO4and the resulting solution was extracted with ethyl acetate. The crude product is purified on silica gel (graded elution with mixtures of EtOAc/hexane 1:2, 1:1, 100% EtOAc, then EtOAc to 5% MeOH)to give 50,8 g (77%) of the desired product.

Getting 2-[3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid (56):The mixture ofmethyl ester 2-[3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid55(65,6 g, 100 mmol) in THF (1000 ml) is cooled in a bath with ice is m and treated with LiOH solution (21 g, 500 mmol) in water (750 ml). This solution was stirred at 0°C for 1 hour and then allowed to warm to room temperature and stirred for further 3 hours. Then the reaction mixture was diluted with water (3 l), cooled in a bath with ice and acidified with 1M HCl to pH 3-4. The resulting solution was extracted with EtOAc. The organic phase is dried and concentrated in vacuo, receiving, or 48.2 g (75%) of the desired product.

Getting 2-[3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic (57):the mixture of2-[3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-3-naphthalene-2-ylpropionic acid56(6.4 g, 10 mmol), 2M methylamine (40 ml) in DMF (200 ml) add hexaphosphate benzotriazol-1-electropermeabilization (PyBOP) (7,8 g, 15 mmol). The solution is stirred for 18 hours, then diluted with water (500 ml) and extracted with EtOAc. The organic phase is dried, concentrated in vacuo and the resulting crude product was then purified on silica gel (EtOAc/hexane 1:3, then 1:1 and 10% methanol in EtOAc)to give the desired product.

Getting 2-{3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxopiperidin-1-yl}-N-methyl-3-naphthalene-2-ylpropionic (58):2-[3-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(2-nitrobenzenesulfonyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic57(6.5 g, 10 mmol), t is everysunday acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer was washed with a saturated solution of bicarbonate, dried and concentrated in vacuo, obtaining the desired product.

EXAMPLE 9

2-[1-{2-[2-Acetylamino-3-(hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl}-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester of acetic acid

Obtain tert-butyl ester 2-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid (59):di-tert-BUTYLCARBAMATE (26,2 g, 120 mol) are added to stir the solution2-{3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxopiperidin-1-yl}-N-methyl-3-naphthalene-2-ylpropionic58(45,5 g, 100 mol) and triethylamine (32 ml, 230 mol)dissolved in dichloromethane (150 ml) at 0°C. the resulting solution was allowed to warm to room temperature and stirred for 4 hours. Then diluted with a solution of dichloromethane (100 ml), washed twice 1N HCl and twice aqueous solution of NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo, obtaining the desired product, which is sufficiently pure for use without purification.

Obtain tert-butyl ester 2-(2-hydroxyethyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid (60):A solution of tert-Putilov the th ester 2-[2-(tert-butyldimethylsilyloxy)ethyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid 59(15.9 g,23.5 mmol) and1M of tetrabutylammonium (40 ml) is stirred for 24 hours. The reaction solution is filtered through a layer of silica gel, the filtrate was concentrated in vacuo and the resulting crude product was then purified on silica gel (EtOAc/hexane 1:2, 1:1, then 5% methanol in EtOAc)to give the desired product.

Obtain tert-butyl ester 2-(2-acetoxyethyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid (61):A solution of tert-butyl methyl ether 2-(2-hydroxyethyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid60(4.4 g,10 mmol), acetic anhydride (13 ml), pyridine (1 ml) and N,N-dimethylaminopyridine (0.25 g) in dichloromethane (50 ml) is stirred for 1.5 hours. Then the solution is extracted with water and 1N HCl. The organic phase is dried, concentrated in vacuo and purify the resulting crude product on silica gel (EtOAc/hexane 1:3, then 1:1)to give the desired product.

Getting 2-[4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid (62):tert-Butyl ether 2-(2-acetoxyethyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-1-carboxylic acid61(4.8 g, 10 mmol), triperoxonane acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and organizes the th layer is washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Getting 2-[1-(2-N-Boc-amino-3-(4-forfinal)propionyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid (63):A solution of 2-[4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid62(38,3 g, 100 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°With, then give the mixture heated and stirred for further 2 hours at room temperature. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc, extracted with water, dried and concentrated in vacuo, obtaining a residue, which is purified on silica gel.

Getting 2-{1-[2-amino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl}ethyl ester acetic acid (64):2-[1-(2-N-Boc-amino-3-(4-forfinal)propionyl)-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid63,(6.3 g, 10 mmol),triperoxonane acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product solution is between dichloromethane and the organic layer washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Getting 2-[1-{2-[2-acetylamino-3-(hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl}-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid (65):A solution of 2-{1-[2-amino-3-(4-forfinal)propionyl]-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl}ethyl ester acetic acid64(54.9 g, 100 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (150 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°With, then give the mixture heated and stirred for further 2 hours at room temperature. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc, extracted with water, dried and concentrated in vacuo, obtaining a residue, which is purified on silica gel.

Another iteration of this category and iteration aspect of the present invention, which relates to the fragment Y, where R15includes-NH2or HE covers receptor ligands of the formula:

where R, R2, R3, R4and R9defined here in the following table X.

No.RR2R3R4R9
537phenyl-NHC(O)CH3Nbenzilphenyl
538benzil-NHC(O)CH3Nbenzilphenyl
5393-forfinal-NHC(O)CH3Nbenzilphenyl
5404-forfinal-NHC(O)CH3Nbenzilphenyl
5413,5-differenl-NHC(O)CH3Nbenzilphenyl
5424-chlorophenyl-NHC(O)CH3Nbenzilphenyl
5434-hydroxyphenyl-NHC(O)CH3Nbenzilphenyl
544phenyl-NHC(O)CH3N4-imidazolidinylphenyl
545benzil-NHC(O)CH3N4-imidazolidinylphenyl
5463-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
5474-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
5483,5-differenl-NHC(O)CH3N4-imidazolidinylphenyl
5494-chlorophenyl-NHC(O)CH3N4-imidazolidinylphenyl
5504-hydroxyphenyl-NHC(O)CH3N4-imidazolidinylphenyl
551phenyl-NHC(O)CH3N4-chlorbenzylphenyl
552benzil-NHC(O)CH3N4-chlorbenzylphenyl
5533-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
5544-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
5553,5-differenl-NHC(O)CH3 N4-chlorbenzylphenyl
5564-chlorophenyl-NHC(O)CH3N4-chlorbenzylphenyl
5574-hydroxyphenyl-NHC(O)CH3N4-chlorbenzylphenyl
558phenyl-NHC(O)CH3N4-hydroxybenzylphenyl
559benzil-NHC(O)CH3N4-hydroxybenzylphenyl
5603-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
5614-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
5623,5-differenl-NHC(O)CH3N4-hydroxybenzylphenyl
5634-chlorophenyl-NHC(O)CH3N4-hydroxybenzylphenyl
5644-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzylthe dryer is l
565phenyl-NHC(O)CH3Nbenzil2-naphthyl
566benzil-NHC(O)CH3Nbenzil2-naphthyl
5673-forfinal-NHC(O)CH3Nbenzil2-naphthyl
5684-forfinal-NHC(O)CH3Nbenzil2-naphthyl
5693,5-differenl-NHC(O)CH3Nbenzil2-naphthyl
5704-chlorophenyl-NHC(O)CH3Nbenzil2-naphthyl
5714-hydroxyphenyl-NHC(O)CH3Nbenzil2-naphthyl
572phenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
573benzil-NHC(O)CH3N4-imidazolidinyl2-naphthyl
5743-forfinal-NHC(O)CH3N4-imidazol shall lmutil 2-naphthyl
5754-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
5763,5-differenl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
5774-chlorophenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
5784-hydroxyphenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
579phenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
580benzil-NHC(O)CH3N4-chlorbenzyl2-naphthyl
5813-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
5824-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
5833,5-differenl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
584 4-chlorophenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
5854-hydroxyphenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
586phenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
587benzil-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5883-forfinal-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5894-forfinal-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5903,5-differenl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5914-chlorophenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5924-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
5934-forfinalHN benzil2-naphthyl
594phenylHNbenzil2-naphthyl
5954-forfinalHN4-hydroxybenzyl2-naphthyl
596phenyl-NHC(O)CH3N2-naphthylmethyl2-naphthyl

The following is a diagram of a synthetic way of getting analogues 537-596, but you can get other ways of compounds with 3-getapiversion skeleton, for example, 3-hydroxyproline analogs and the like, using a modification of this General scheme.

Reagents and conditions: (a) NaOCH3/CH3OH

EXAMPLE 10

Getting 2-[4-[2-[2-acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(2-hydroxyethyl)piperazine-1-yl]-N-methyl-3-naphthalene-2-ylpropionic (66):To a solution of 2-[1-{2-[2-acetylamino-3-(hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl}-4-(1-methylcarbamoyl-2-naphthalene-2-retil)piperazine-2-yl]ethyl ester acetic acid65(7.5 g, 10 mmol) in methanol (50 ml) is added freshly prepared NaOCH3(0.55 g, 10.1 mmol) and stir the solution overnight. This solution was concentrated in vacuo, the obtained residue distribution is elaut between dichloromethane and water, the organic layer is dried and concentrated in vacuo, obtaining the desired product.

Another category of analogues of ligands of the receptor of the present invention relates to 2,5-substituted 3-getapiversion, including conformationally restricted ring skeleton of the formula:

where the carbon atoms marked with an asterisk can have any configuration. Table XI includes not limiting the present invention examples of one aspect of the analogues in this category, and these analogs have the formula:

where R, R2, R4and R9defined in table XI.

2-naphthyl
TABLE XI
No.RR2R3R4R9
597phenyl-NHC(O)CH3Nbenzilphenyl
598benzil-NHC(O)CH3Nbenzilphenyl
5993-forfinal-NHC(O)CH3Nbenzilphenyl
6004-forfinal-NHC(O)CH3 Nbenzilphenyl
6013,5-differenl-NHC(O)CH3Nbenzilphenyl
6024-chlorophenyl-NHC(O)CH3Nbenzilphenyl
6034-hydroxyphenyl-NHC(O)CH3Nbenzilphenyl
604phenyl-NHC(O)CH3N4-imidazolidinylphenyl
605benzil-NHC(O)CH3N4-imidazolidinylphenyl
6063-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
6074-forfinal-NHC(O)CH3N4-imidazolidinylphenyl
6083,5-differenl-NHC(O)CH3N4-imidazolidinylphenyl
6094-chlorophenyl-NHC(O)CH3N4-imidazolidinylphenyl
61 4-hydroxyphenyl-NHC(O)CH3N4-imidazolidinylphenyl
611phenyl-NHC(O)CH3N4-chlorbenzylphenyl
612benzil-NHC(O)CH3N4-chlorbenzylphenyl
6133-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
6144-forfinal-NHC(O)CH3N4-chlorbenzylphenyl
6153,5-differenl-NHC(O)CH3N4-chlorbenzylphenyl
6164-chlorophenyl-NHC(O)CH3N4-chlorbenzylphenyl
6174-hydroxyphenyl-NHC(O)CH3N4-chlorbenzylphenyl
618phenyl-NHC(O)CH3N4-hydroxybenzylphenyl
619benzil-NHC(O)CH3N4-hydroxy shall ensil phenyl
6203-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
6214-forfinal-NHC(O)CH3N4-hydroxybenzylphenyl
6223,5-differenl-NHC(O)CH3N4-hydroxybenzylphenyl
6234-chlorophenyl-NHC(O)CH3N4-hydroxybenzylphenyl
6244-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzylphenyl
625phenyl-NHC(O)CH3Nbenzil2-naphthyl
626benzil-NHC(O)CH3Nbenzil2-naphthyl
6273-forfinal-NHC(O)CH3Nbenzil2-naphthyl
6284-forfinal-NHC(O)CH3Nbenzil2-naphthyl
6293,5-differenl-NHC(och 3Nbenzil2-naphthyl
6304-chlorophenyl-NHC(O)CH3Nbenzil2-naphthyl
6314-hydroxyphenyl-NHC(O)CH3Nbenzil2-naphthyl
632phenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
633benzil-NHC(O)CH3N4-imidazolidinyl2-naphthyl
6343-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
6354-forfinal-NHC(O)CH3N4-imidazolidinyl2-naphthyl
6363,5-differenl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
6374-chlorophenyl-NHC(O)CH3N4-imidazolidinyl2-naphthyl
6384-hydroxyphenyl-NHC(O)CH3N4-imidazolidinyl
639phenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
640benzil-NHC(O)CH3N4-chlorbenzyl2-naphthyl
6413-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
6424-forfinal-NHC(O)CH3N4-chlorbenzyl2-naphthyl
6433,5-differenl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
6444-chlorophenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
6454-hydroxyphenyl-NHC(O)CH3N4-chlorbenzyl2-naphthyl
646phenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
647benzil-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
6483-forfinal-NHC(O)CH 3N4-hydroxybenzyl2-naphthyl
6494-forfinal-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
6503,5-differenl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
6514-chlorophenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
6524-hydroxyphenyl-NHC(O)CH3N4-hydroxybenzyl2-naphthyl
6534-forfinalHNbenzil2-naphthyl
654phenylHNbenzil2-naphthyl
6554-forfinalHN4-hydroxybenzyl2-naphthyl
656phenyl-NHC(O)CH3N2-naphthylmethyl2-naphthyl

The following is a diagram of a synthetic way of getting analogues 597-656, but you can get other options and iteration 3-keepering skeleton, PR is changing modifications of this General scheme.

Reagents and conditions: (a) O,N-dimethylhydroxylamine, HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (b) LAH, THF, -60°C.

Reagents and conditions: (C) NaBH(OAc)3, DMF, 0°to count

Reagents and conditions: (d) ClCH2COCl, Et3N, DMF, CH2Cl20°to count

Reagents and conditions: (e) N-BOC-amino acid, EDCI, HOBt, DMF).

Reagents and conditions: (f) TFA/CH2Cl2, comnt

Reagents and conditions: (g) EDCI, HOBt, DMF).

Reagents and conditions: (h) Pd-mobile, cyclohexane, EtOH/AcOH, boiling under reflux.

OBTAINING 2,5-SUBSTITUTED 3-KEEPERING INTERMEDIATE PRODUCT

The following is the method of obtaining the intermediate product with 2,5-substituted 3-getapiversion skeleton of the formula:

for the following examples R9represents 2-naphthyl, and R15is 1-benzyl-1H-imidazol-4-yl.

3-(1-Benzyl-1H-imidazol-4-ylmethyl)-6-naphthalene-2-iletileri-2-he (70)

Obtain tert-butyl ester [1-(methoxymethylethoxy)-2-naftol is n-2-ileti]carbamino acid (67): 2-N-Boc-amino-3-naphthalene-2-ylpropionic acid (2.0 g, 6.3 mmol), hydrochloride of O,N-dimethoxyphenethylamine (0,61 g, 6.6 mmol), hydroxybenzotriazole (1.2 g, 9.4 mmol) and N-methylmorpholine (2 ml, of 18.9 mmol) in DMF (15 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.8 g, 9.4 mmol). The resulting mixture is stirred for 2 hours at 0°With, then allow the mixture to warm up and stirred at room temperature for 18 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, obtaining an oily residue, which was purified on silica gel, obtaining 2.0 g (88%) of a white solid.

Obtain tert-butyl methyl ether (1-formyl-2-naphthalene-2-retil)carbamino acid (68):To a solution of tert-butyl methyl ether [1-(methoxymethylethoxy)-2-naphthalene-2-ileti]carbamino acid67(5.0 g, a 13.4 mmol) in THF (40 ml) at -30°-25°add 10 minutes'lah (16,7 ml of 1M solution in THF), and then the reaction mixture cooled down to -55°and continue stirring for 3 hours. After cooling to -60°the reaction is quenched by adding citric acid in methanol (1:1, mass.). During blanking keep the temperature at about -45°C. Then allow the mixture to warm up to CONTROLTEMPLATES and partitioned between EtOAc and water and the aqueous phase is again extracted with EtOAc. The combined organic phases are washed with saturated NaCl solution, dried and concentrated in vacuum to give crude aldehyde as a white solid, which is used without further purification.

Obtaining methyl ester 3-(1-benzyl-1H-imidazol-4-yl)-2-(2-N-Boc-amino-3-naphthalene-2-ylpropyl)aminopropionic acid (69):The crude aldehyde: tert-butyl methyl ether (1-formyl-2-naphthalene-2-retil)carbamino acid68,dissolved in THF (40 ml) and add a solution of methyl ester hydrochloride 2-amino-3-(1-benzyl-1H-imidazol-4-yl)propionic acid (4.6 g, a 13.9 mmol) in DMF (40 ml). This solution is cooled to 0°and add triacetoxyborohydride sodium (5.9 g, 27.8 mmol). The suspension is stirred at 0°C and allowed to warm for 2 hours to room temperature, and then stirred for 18 hours. Add saturated aqueous sodium bicarbonate solution until gas evolution stops. This solution was extracted with diethyl ether, dried and concentrated, to give crude product, which was purified on silica gel, obtaining 4.6 g of a yellow oil.

Obtaining 3-(1-benzyl-1H-imidazol-4-ylmethyl)-6-naphthalene-2-iletileri-2-she (70):Methyl ester of 3-(1-benzyl-1H-imidazol-4-yl)-2-(2-N-Boc-amino-3-naphthalene-2-ylpropyl)aminopropionic acid69(4.6 g, 8.5 mmol) dissolved in a mixture triperoxonane KIS the PTA/dichloromethane (1:1) (20 ml) and stirred for 1 hour at room temperature. The solution is concentrated in vacuo to an oil, which is transferred several times in diethyl ether and concentrated in vacuo to remove traces triperoxonane acid. The oil obtained is dissolved in ethanol (35 ml) and refluxed for 3 hours. The solvent is removed in vacuum, obtaining the desired product.

EXAMPLE 11

2-Acetylamino-N-{1-(4-terbisil)-2-[2-(1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (74)

Obtain tert-butyl ester [2-[2-(1-benzyl-1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-1-(4-terbisil)-2 - oxoethyl]carbamino acid (71):A solution of 3-(1-benzyl-1H-imidazol-4-ylmethyl)-6-naphthalene-2-iletileri-2-it70(1.63 g, 4 mmol), (R)-2-N-(tert-butoxycarbonyl)amino-3-(4-forfinal)propanoic acid (1.4 g, 4.8 mmol), 1-hydroxybenzotriazole (0.6 g, 4.4 mmol) and N-methylmorpholine (13,2 ml of 12.0 mmol) in DMF (15 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.2 g, 6 mmol). The resulting mixture is stirred for 2 hours at 0°With, then allow the mixture to warm up and stirred at room temperature for another 18 hours. The reaction solution was diluted with water and extracted with EtOAc solution. The organic layers are combined with the shat and concentrated in vacuo, getting an orange sticky solid, which was purified on silica gel (EtOAc/MeOH 9:1)to give 1.2 g of white solid.

Getting 4-[2-amino-3-(4-forfinal)propionyl]-3-(1-benzyl-1H-imidazol-4-ylmethyl)-6-naphthalene-2-iletileri-2-she (72):tert-Butyl ether [2-[2-(1-benzyl-1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]carbamino acid71(30 mg, 0,044 mmol), dissolved in a mixture triperoxonane acid/dichloromethane (0.5 ml). After 1 hour the solution was concentrated in vacuo and the residue purified by the method With18preparative HPLC with reversed phase, receiving 25 mg of a white solid.

Getting 2-acetylamino-N-[2-[2-(1-benzyl-1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide (73):A solution of 4-[2-amino-3-(4-forfinal)propionyl]-3-(1-benzyl-1H-imidazol-4-ylmethyl)-6-naphthalene-2-iletileri-2-it72(0,415 g of 0.615 mmol), N-acetyl-L-tyrosine (0,140 g of 0.615 mmol), 1-hydroxybenzotriazole (0.125 g, 0,922 mmol) and N-methylmorpholine (13,2 ml of 12.0 mmol) in DMF (4 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,235 g of 1.23 mmol). The resulting mixture is stirred for 2 hours at 0°C, then allowed to warm and stirred at room temperature for another 18 hours. The reaction solution was diluted with water and extracted with EtOAc solution. The organic layers are combined, dried, concentrated in vacuo and purified by the method With18preparative HPLC with reversed phase, receiving 0,22 g brownish-white solid.

Getting 2-acetylamino-N-{1-(4-terbisil)-2-[2-(1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide (74):2-Acetylamino-N-[2-[2-(1-benzyl-1H-imidazol-4-ylmethyl)-5-naphthalene-2-ylmethyl-3-oxopiperidin-1-yl]-1-(4-terbisil)-2-oxoethyl]-3-(4-hydroxyphenyl)propionamide73(0,22 g, 0.28 mmol) dissolved in a mixture of ethanol/acetic acid (4:1) (3 ml). Add cyclohexane (3 ml) and Pd-mobile and the solution is refluxed, periodically adding cyclohexane. The reaction mixture was checked by TLC and after 2 days, cooled and filtered through celite to remove the catalyst. The filtrate was concentrated in vacuo, getting the oil cleanse method With18preparative HPLC with reversed phase, obtaining the desired product.

Another aspect of the present invention relates to analogues, where at least two of R2, R3and R4taken together form a ring, for example, receptor ligands of the formula:

where R, R9and R10defined in table XII.

No.
TABLE XII
RR2R9
657phenylNbenzil
6584-forfinalNbenzil
6593,4-differenlNbenzil
6604-chlorophenylNbenzil
6614-methylNbenzil
6624-methoxyNbenzil
663naphthylNbenzil
664phenyl-CO2CH3benzil
6654-forfinal-CO2CH3benzil
6663,4-differenl-CO2CH3benzil
6674-chlorophenyl-CO2CH3benzil
6684-methyl-CO2CH3benzil
6694-methoxy-CO2CH3benzil
670naphthyl-CO2CH3b is nil
671phenyl-CONH2benzil
6724-forfinal-CONH2benzil
6733,4-differenl-CONH2benzil
6744-chlorophenyl-CONH2benzil
6754-methyl-CONH2benzil
6764-methoxy-CONH2benzil
677naphthyl-CONH2benzil
678phenyl-CONHCH3benzil
6794-forfinal-CONHCH3benzil
6803,4-differenl-CONHCH3benzil
6814-chlorophenyl-CONHCH3benzil
6824-methyl-CONHCH3benzil
6834-methoxy-CONHCH3benzil
684naphthyl-CONHCH3benzil
685the dryer is l N2-naphthylmethyl
6864-forfinalN2-naphthylmethyl
6873,4-differenlN2-naphthylmethyl
6884-chlorophenylN2-naphthylmethyl
6894-methylN2-naphthylmethyl
6904-methoxyN2-naphthylmethyl
691naphthylN2-naphthylmethyl
692phenyl-CO2CH32-naphthylmethyl
6934-forfinal-CO2CH32-naphthylmethyl
6943,4-differenl-CO2CH32-naphthylmethyl
6954-chlorophenyl-CO2CH32-naphthylmethyl
6964-methyl-CO2CH32-naphthylmethyl
6974-methoxy-CO2CH32-naphthylmethyl
698naphthyl-CO2CH32-naphthylmethyl
699phenyl-CONH22-naphthylmethyl
7004-forfinal-CONH22-naphthylmethyl
7013,4-differenl-CONH22-naphthylmethyl
7024-chlorophenyl-CONH22-naphthylmethyl
7034-methyl-CONH22-naphthylmethyl
7044-methoxy-CONH22-naphthylmethyl
705naphthyl-CONH22-naphthylmethyl
706phenyl-CONHCH32-naphthylmethyl
7074-forfinal-CONHCH32-naphthylmethyl
7083,4-differenl-CONHCH32-naphthylmethyl
7094-chlorophenyl-CONHCH32-naphthylmethyl
7104-methyl-CONHCH32-naphthylmethyl
7114-methoxy-CONHCH32-naphthylmethyl
712naphthyl-CONHCH 32-naphthylmethyl

The following is a diagram of a synthetic way of getting analogues 657-663 and 685-691, but you can get other options and iteration 3-keepering skeleton, using modifications of this General technique.

Reagents and conditions: (a) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (b) TFA/CH2Cl2, comnt

Reagents and conditions: (C) HOBt, EDCI, N-methylmorpholine, DMF, 0°C.

Reagents and conditions: (d) TFA/CH2Cl2, comnt

Reagents and conditions: (e) H2, 10% Pd/C, MeOH.

OBTAINING 3-KEEPERING INTERMEDIATE PRODUCT

The following is the method of obtaining 3-keepering intermediate product having the formula:

where for this example, R9represents benzyl.

Benzyl ester [3-(3-oxo-4-penetentiary-2-yl)propyl]carbamino acid (77)

Obtain tert-butyl ester (4-N-Cbz-amino-1-phenetically)carbamino acid (75):The solution phenethylamine (12.1 g, 100 mmol), 5-benzyloxycarbonylamino-2-tert-butoxycarbonylamino acid (33.6 g, 100 mmol), hydroxybenzotriazole the (16.2 g, 120 mmol) and N-methylmorpholine (132 ml, 120 mmol) in DMF (15 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24,9 g, 130 mmol). The resulting mixture is stirred for 2 hours at 0°With, then allow the mixture to warm up and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo, obtaining a residue, which is purified on silica gel.

Getting benzyl ester (4-amino-4-phenetically)carbamino acid (76):tert-Butyl ester (4-N-Cbz-amino-1-phenetically)carbamino acid75(47,0 g, 100 mmol) is dissolved in 300 ml of a solution obtained from a 2:1:0.1 parts of dichloromethane, TFA and water. The reaction mixture is stirred for 3 hours. The solvent is removed in vacuum and the residue is treated with 1,2-dichloromethane, which is also removed in vacuum. Repeat this several times and get a crude residue, which is used in the next stage without additional purification.

Getting benzyl ester [3-(3-oxo-4-penetentiary-2-yl)propyl]carbamino acid (77):A mixture of benzyl ether (4-amino-4-phenetically)carbamino acid76(36,9 g, 100 mmol), dibromoethane (12.9 ml, 4,36 mmol), potassium carbonate (69 g, 500 is mol) in DMF (500 ml) was stirred at 55° C for 18 hours. The reaction mixture is cooled to room temperature, treated with 1M KHSO4and the resulting solution was extracted with ethyl acetate. The crude product is purified on silica gel (graded elution with mixture of EtOAc/hexane 1:2, 1:1, 100% EtOAc, then EtOAc with 5% Meon), obtaining the desired product.

EXAMPLE 12

Methyl ester of 2-(3-(3-aminopropyl)-4-{3-(4-forfinal)-2-[(1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino]propionyl}-2-oxopiperidin-1-yl)-3-naphthalene-2-ylpropionic acid (82)

Getting benzyl ester (3-{1-[2-N-Boc-amino-3-(4-forfinal)propionyl]-3-oxo-4-penetentiary-2-yl}propyl)carbamino acid (78):A solution of benzyl ester [3-(3-oxo-4-penetentiary-2-yl)propyl]carbamino acid77(3,95 g, 10 mmol), (R)-2-N-(tert-butoxycarbonyl)amino-3-(4-forfinal)propanoic acid (3,40 g, 12 mmol), 1-hydroxybenzotriazole (of 1.62 g, 12 mmol) and N-methylmorpholine (13,2 ml of 12.0 mmol) in DMF (15 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,49 g, 13 mmol). The resulting mixture is stirred for 2 hours at 0°With, then allow the mixture to warm up and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solution was extracted with EtOAc, dried and concentrated in vacuo, obtaining the desired product.

Getting benzyl ester (3-{1-[2-and the Ino-3-(4-forfinal)propionyl]-3-oxo-4-penetentiary-2-yl}propyl)carbamino acid (79): A solution of benzyl ether (3-{1-[2-N-Boc-amino-3-(4-forfinal)propionyl]-3-oxo-4-penetentiary-2-yl}propyl)carbamino acid78(6.6 g, 10 mmol), triperoxonane acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Obtain tert-butyl ester 3-[2-[2-(3-N-Cbz-aminopropyl)-3-oxo-4-penetentiary-1-yl]-1-(4-terbisil)-2-oxoethylidene]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (80):A solution of benzyl ether(3-{1-[2-amino-3-(4-forfinal)propionyl]-3-oxo-4-penetentiary-2-yl}propyl)carbamino acid79(5.6 g, 10 mmol), N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.8 g, 10 mmol), hydroxybenzotriazole (of 1.62 g, 12 mmol) and N-methylmorpholine (13,2 ml, 12 mmol) in DMF (50 ml) cooled to 0°and slowly add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2,49 g, 13 mmol). The resulting mixture is stirred for 2 hours at 0°With, then allow the mixture to warm up and stirred at room temperature for another 2 hours. The reaction solution was diluted with water and the resulting solution was extracted with EtOAc, dried and concentrated in vacuum to give crude product, which was purified n is silica gel.

Getting benzyl ester [3-(1-{3-(4-forfinal)-2-[(1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino]propionyl}-3-oxo-4-penetentiary-2-yl)propyl]carbamino acid (81): a Solution of tert-butyl ester 3-[2-[2-(3-N-Cbz-aminopropyl)-3-oxo-4-penetentiary-1-yl]-1-(4-terbisil)-2-oxoethylidene]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 80 (8,2 g, 10 mmol), triperoxonane acid (5 ml) and dichloromethane (50 ml) was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product is dissolved in dichloromethane and the organic layer washed with saturated sodium bicarbonate solution, dried and concentrated in vacuo, obtaining the desired product.

Obtain methyl ester of 2-(3-(3-aminopropyl)-4-{3-(4-perfecr)-2-[(1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino]propionyl}-2-oxopiperidin-1-yl)-3-naphthalene-2-ylpropionic acid (82): a Solution of benzyl ester [3-(1-{3-(4-forfinal)-2-[(1,2,3,4-tetrahydroisoquinoline-3-carbonyl)amino]propionyl}-3-oxo-4-penetentiary-2-yl)propyl]carbamino acid 81 (7.2 g, 10 mmol) is suspended in methanol (100 ml) and hydronaut in the presence of 10% Pd/C at 2,81 kg/cm2(40 psi) for 24 hours. The solution is filtered to remove the catalyst and the crude product purified by the method of preparative HPLC using a linear gradient of acetonitrile in water with 0.1% TFA and obtaining the desired product.

In the according to the according to the above methods were obtained the following compounds of the present invention:

(S)-2-(S)-4-((R)-2-amino-3-(4-forfinal)propanol)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)-N-methyl-3-(naphthalene-2-yl)propanamide:

HRFAB(position.) m/e: Calculated for C29H33FN4O4(M+H)+521,2564 Found 521,2575.

2-[4-[2-Amino-3-(4-forfinal)propionyl]-3-(3-aminopropyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CD3OD, δ) (rotamer): 7,98-of 7.82 (m, 3H), 7,75-of 7.70 (m, 1H), of 7.64 was 7.45 (m, 3H), 7,40-7,22 (m, 2H), 7.18 in-7,05 (m, 2H), 5,75-of 5.40 (m, 1H), 5,10-of 4.90 (m, 4H), 4,70 is 4.35 (m, 2H), 3,70 was 3.05 (m, 7H), 2,96-to 2.55 (m, SH), 2,50 is 2.10(m, 2H), 1,40-of 0.62 (m, 4H);

13With NMR, δ: 170,8, 168,2, 165,0, 161,0, 134,7, 133,6, 132,7, 131,6, 131,4, 130,1, 128,1, 127,6, 126,4, 125,9, 115,8, 115,6, 57,3, 56,4, 55,3, 51,4, 51,0, 42,1, 41,4, 41,1, 38,3, 36,5, 34,4, 29,1, 25,3, 23,7;

HRFAB(position.) m/e: Calculated for C30H36FN5O3(M+N)+: 534,2880 Found: 534,2893; Elemental analysis: Calculated for C30H36FN5O3·(2,98 TFU·0,16 N2O) (MB 876,31): 49,28%, N To 4.52%, N 7,99%Found: 49,28%, N To 4.52%, N at 8.36%.

2-[4-[2-Amino-3-(4-forfinal)propionyl]-3-(3-guanidino-propyl)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CDCl3that δ) (rotamer): 7,92-the 7.65 (m, 5H), 7,58-7,35 (m, 4H), 7,32-to 7.15 (m, 3H), 7,12-to 6.95 (m, 3H), 5,70-the ceiling of 5.60 (m, 1H), 4,65-of 5.50 (m, 2H), 3,71-to 3.38 (m, 2H), 3,35-3,00 (m, 6N), 2,98-of 2.30 (m, 5H), of 2.72 (s, 2H), 1,20-a 1.08 (m, 2H), 0,85-of 0.62 (m, 3H);

13With NMR, δ: 175,0, 170,0, 168,0, 166,0, 165,9, 162,7, 162,2,158,8, 136,1, 135,2, 134,3, 133,2, 133,1, 132,5, 131,5, 129,7, 129,1, 128,9, 128,8, 127,9, 127,4, 117,7, 117,4, 117,1, 113,7, 67,3, 58,6, 58,0, 57,7, 57,0, 52,4, 433,43,1, 42,8, 41,7, 39,5, 38,6, 38,1, 36,6, 36,0, 31,4, 30,4, 26,8, 26,0, 25,7, 15,8;

HRFAB(b,) m/e: 576,3098 Calculated for C31H38FN7O3(M+H)+Found 576,3106; Elemental analysis: Calculated for C31H38FN7O3, (2,9TFA) (MB 906,35): 48,77%, N 4,55%, N 10,82%Found: 49,18%, N 4,25%, N 11,12%,

2-[4-[2-[2-Acetylamino-3-(4-hydroxyphenyl)propionamido]-3-(4-forfinal)propionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CDCl3that δ): 8,18-8,02 (m, 1H), 7,80-of 7.70 (m, 6N), 7,24-7,20 (m, N), 7,10-6,98 (m, 4H), 6,95-PC 6.82 (m, 5H), 6,38-4,70 (m, N), 4,22 (s, 1H), 3,65-3,55 (m, 1H), 3.25 to up 3.22 (m, 2H), 3,22-3,00 (m, 3H), 2,98-2,60 m, 8H), of 1.30 (s, N), 1,22-0,85 (m, 6N);

13With NMR, δ: 168,7, 168,5, 167,3, 167,1, 166,9, 166,0, 161,1, 160,4, 158,4, 155,3, 153,1, 153,0, 151,1, 134,5, 134,3, 134,2, 132,2, 131,5, 131,3, 131,0, 130,7, 129,7, 129,4, 128,6, 128,5, 128,4, 128,2, 127,8, 127,7, 126,4, 126,2, 126,1, 126,0, 125,9, 125,7, 125,6, 125,4, 125,3, 125,0, 124,9, 124,8, 124,7, 124,6, 124,4, 123,8, 123,3, 113,0, 112,8, 112,3, 77,2, 74,9, 67,3, 65,5, 64,5, 63,2, 61,8, 57,8, 55,1, 53,2, 47,7, 47,3, 38,6, 37,6, 36,3, 35,8, 35,5, 34,9, 34,4, 32,1, 31,8, 28,1, 27,6, 26,6, 25,7, 23,7, 22,4, 22,0, 18,4, 16,6, 12,8, 11,7, 11,2,

2-[4-[2-Acetylamino-3-(4-forfinal)propionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-yl-propionamide:

1H NMR (CD3OD, δ): of 7.90-to 7.68 (m, 4H), 7,52-7,38 (m, 3H), 7,30-to 7.15 (m, 2H), 7,05-6,92 (m, 2H), 5,62-of 5.48 (m, 1H), 4.80 to 4,50 (m, 1H), 4,20-of 3.85 (m, 1H), 3,70 of-2.32 (m, 13H), with 1.92 (s, 3H), 1,25-of 0.68 (m, 4H);

13With NMR, δ: 173,0, 172,0, 171,9, 171,0, 169,0, 166,0, 164,0, 162,1, 158,8, 136,3, 135,2, 134,2, 134,1, 134,0, 132,8, 132,7, 132,3, 132,2, 129,6, 129,2, 129,1, 128,9, 127,9, 127,4, 117,1, 116,8, 11,5, 112,3, 59,1, 58,5, 58,0, 56,7, 52,3, 52,1, 49,5, 43,4, 42,9, 42,5, 41,8, 38,5, 35,7, 30,2, 27,0, 26,1, 25,9, 22,8, 22,7;

HRFAB(position.) m/e: Calculated for C33H10FN7O4(M+N)+: 618,3204 Found: 618,3213; Elemental analysis: Calculated for C33H40FN7O4, (2,75·TFA, 0,8·CH3CN) (MB 964,13): 49,96%, N 4,72%, N 11,33%Found: 51.89ˆ%, N With 4.64%, N 11,34%,

{1-(4-Terbisil)-2-[2-(3-guanidinopropionic)-4- (1-methylcarbamoyl-2-naphthalene-2-retil)-3-oxopiperidin-1-yl]-2-oxoethyl}amide 2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid:

1H NMR (CD3OD, δ): 8,32-6,85 (m, 15 NM), 5,50-to 4.38 (m, 13H), 4,05-of 2.20 (m, 17H), 1,10-0,5 (m, 4H);

13With NMR, δ: 174,9, 174,0, 173,5, 173,0, 172,8, 171,0, 168,0, 166,0, 163,0, 158,8, 136,3, 135,2, 134,2, 134,0, 132,7, 132,6, 129,6, 129,3, 129,2, 129,1, 128,9, 128,6, 128,5, 127,8, 127,5, 127,3, 116,7, 116,5, 116,4, 67,3, 58,9, 58,3, 56,8, 56,0, 52,0, 51,8, 50,3, 49,7, 49,5, 49,2, 48,9, 43,1, 42,5, 41,7, 38,3, 35,7, 32,9, 30,3, 27,0, 25,9, 22,6, 22,5;

HRFAB (position.) m/e: Calculated for C43H49FN8O5(M+H)+: 777,3888 Found: 777,39000; Elemental analysis: Calculated for C43H49FN8O5, (1,80·TFA, 0,09·N2O) (MB 983,77): 56,89%, N 5,22%, N Is 11.39%Found: 56,99%, N 5,24%, N 11,57%,

2-[4-[2-Amino-3-phenylpropionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CD3OD, δ): 7,92 for 7.12 (m, 11N), 5,69-the ceiling of 5.60 (m, 1H), 4,65-of 4.05 (m, 2H), 3,65-3,00 (m, N), 2,80 to 2.35 (m, 5H), 1,28-1,08 (m, 1H), 0.75 in (ush. s, 2H);

13With NMR, δ: 175,0, 171,0, 169,0, 163,6, 163,2, 162,7, 158,8, 136,0, 135,5, 135,2, 14,3, 131,2, 130,5, 129,7, 129,1, 129,0, 128,7, 127,9, 127,4, 120,3, 116,4, 61,2, 58,5, 57,9, 57,1, 52,4, 50,3, 42,9, 42,8, 41,7, 39,1, 38,4, 36,0, 30,4, 26,8, 26,0; HRFAB (position.) m/e: Calculated for C31H39N7O3(M+H)+: 558,3193 Found: 558,3180; Elemental analysis: Calculated for C31H39N7O3, (2,91·TFA, 0,08·H2O) (MB 890,62): 49,65%, H 4,75%, N Br11.01%Found: 49,65%, N 4,76%, N 10,83%,

2-[4-[2-[2-Amino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CD3OD, δ) (rotamer): 7.68 per-7,42 (m, 6N), 7,38-to 7.15 (m, 5H), 7,08-6,92 (m, 8H), 6,82-6,70 (m, 3H), 6,60-6.48 in (m, 3H), 5,48 is 5.38 (m, 1H), 4.95 points-is 4.85 (m, 2H), 4,35-of 4.25 (m, 1H), 3,82-3,68 (m, 2H), to 3.58-3.42 points (m, 1H), 3,22 of 2.92 (m, 3H), 2,85-2,48 (m, 8H), 2,45 of-2.32 (m, 1H), 2,28-of 2.15 (m, 1H), 0.88 to 0,38 (m, 4H);

13With NMR, δ: 175,0, 176,0, 175,0, 172,0, 170,0, 158,7, 137,7, 136,0, 135,2, 134,3, 132,0, 130,9, 130,1, 129,7, 129,0, 128,9, 128,8, 128,7, 127,8, 127,4, 126,2, 117,2, 58,9, 57,8, 56,9, 56,0, 52,1, 50,3, 43,0, 41,8, 39,3, 38,2, 36,1, 30,3, 26,8, 25,9;

HRFAB(position.) m/e: Calculated for C40H48N8O5(M+H)+: 721,3826 Found: 721,3807; Elemental analysis: Calculated for C40H48N8O5(3,4·TFA, 0,3·CH3CN) (MB 1120,9): 50,79%, N 4,70%, N 10,37%, Found: 51,16%, N 4,62%, N the 10.40%,

2-[4-[2-[2-Acetylamino-3-(4-hydroxyphenyl)propionamido]-3-phenylpropionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR(CD3OD, δ): a 7.85-7,30 (m, 7H), 7,30-7,05 (m, 5H),? 7.04 baby mortality-of 6.90 (m, 2H), 6,72-6,55 (m, 2H), 5,68-5,40(who, 1H), 4,62 is 4.35 (m, 2H), 4,18-of 3.06 (m, 7H), 2,98-2,31 (m, 10H), 1,90 (s, 3H), 1.30 and 0.50 in (m, 4H);

13With NMR, δ: 174,0, 173,5, 173,0, 172,5, 171,0, 168,0, 159,0, 157,8, 138,0, 136,3, 135,2, 134,2, 131,7, 130,9, 130,9, 130,2, 130,0, 129,6, 129,2, 129,0, 128,9, 128,6, 127,8, 127,3, 116,6, 59,0, 58,0, 56,7, 52,0, 50,3, 50,0, 49,7, 49,4, 49,1, 42,9, 42,6, 41,8; 39,5, 39,3, 38,8, 38,5, 35,7, 31,7, 30,2, 27,0, 26,0, 25,8, 22,8;

HRFAB(position.) m/e: Calculated for C42H50N8O6(M+H)+: 763,3932 Found: 763,3918; Elemental analysis: Calculated for C42H50N8O6(2,1·TFA, 0,5·CH3CN) (MB 1022,88): To 55.42%, N 528%, N 11,64%Found: 56,30%, N 521%, N of 11.69%,

2-[4-[2-[2-Acetylamino-3-(1H-imidazol-5-yl)propionamido]-3-phenylpropionyl]-3-(3-guanidinopropionic)-2-oxopiperidin-1-yl]-N-methyl-3-naphthalene-2-ylpropionic:

1H NMR (CD1OD, δ): 8,78 (s, 1H), of 7.90-the 7.65 (m, 5H), was 7.36-7,40 (m, 4H), 7,35-to 7.18 (m, 8H), 5,70-the 5.65 (m, 1H), 4.75 V-4,55 (m, 4H), 4,25-of 3.78 (m, 2H), 3,62 is-3.45 (m, 3H), 3.25 to 3,10 (m, 3H), is 3.08-2,82 (m, 5H), 2,78 (s, 3H), 2,70-to 2.42 (m, 3H), of 1.95 (s, 3H), 1,10-1,00 (m, 1H), 0,85-0,65 (m, 3H);

13With NMR, δ: 174,0, 173,0, 171,0, 169,0, 164,0, 163,0, 158,0, 137,9, 136,2, 135,3, 135,2, 134,3, 131,3, 131,0, 1302, 130,0, 129,6, 129,2, 129,0, 128,9, 128,8, 128,7, 127,8, 127,3, 120,3, 118,8, 116,5, 114,6, 59,1, 58,0, 56,8, 54,0, 53,7, 52,2, 50,3, 50,0, 43,0, 42,8, 41,8, 39,3, 35,9, 31,6, 30,3, 28,6, 26,9, 26,1, 25,9, 22,9,

HRFAB(position.) m/e: Calculated for C39H48N10O5(M+H)+: 737,3887 Found: 737,3888; Elemental analysis: Calculated for C39H48N10O5(4,0·TFA, 1,7·N3O) (MB 1223,59): 46,14%, N 4,56%, N Of 11.45%, Found: 46,84%, N 4,56%, N 11,49%,

2-S-Acetylamino-N-{1-R-benzyl--[2-S-(3-guanidinopropionic)-4-R-(naphthalene-2-ylethoxy)pyrrolidin-1-yl]-2-oxoethyl}-3-(4-hydroxyphenyl)propionamide:

MC(ESI) m/z 679 (M+1);1H NMR (300 MHz, CD3OD) δ: 7,70-of 7.90 (m, 4H), 7,40-of 7.60 (m, 3H), 7,00-7,30 (m, 7H), 6,74 (m, 2H), 4,50-4,80 (m, 4H), 3,85-4,20 (m, 2H), 2,70-3,30 (m, 8H), 1,40-2,10 (m, N).

(S)-N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropane-2-yl)-1,2,3,4-tetrahydroquinolin-3-carboxamide:

MC(ESI) m/z: 633 (M+1);

1H NMR (300 MHz, CD3OD) 7,70-of 7.90 (m, 4 H), 7,10-of 7.60 (m, N), to 4.92 (m, 2H), and 4.68 (m, 2H), and 4.40 (m, 2H), 4,00-4,30 (m, 4H), 2,90-3,50 (m, 6N), 1,80-2,20 (m, 3H), 1,58 (m, 3H).

(R)-2-acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-elmalki)pyrrolidin-1-yl)-1-oxo-3-phenylpropane-2-yl)-3-phenylpropanamide: PG-701985,

MC(ESI) m/z 663 (M+1);

1H NMR (300 MHz, CD3OD) 7,70-of 8.00 (m, 4H), 7,00-of 7.60 (m, 13H), 4,50-4,80 (m, 4H), 3,80-4,20 (m, 3H), 2,70-3,70 (m, 8H), 1.60-to 2,10 (m, 6N), to 1.48 (m, 3H).

(R)-2-acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropane-2-yl)-3-(1H-imidazol-4-yl)propanamide:

MC(ESI) m/z: 653 (M+H);

1H NMR (300 MHz, CD3OD) 7,70-of 8.00 (m, 4H), 7,40-of 7.60 (m, 3H), 7,10-7,35 (m, 7H), 4,50-of 4.90 (m, 4H), 3,90-4,30 (m, 3H), 2,90-of 3.60 (m, 8H), 1,80-2,20 (m, 6N), 1,40-1,60 (m, 3H).

(S)-2-acetamido-N1-((R)-1-(2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropane-2-yl)pentanedione:

MC(ESI)m/z: 644 (M+1);

1H NMR (300 MHz, CD3OD) 7,70-of 7.90 (m, 4H), 7,10-of 7.60 (m, 8H), 4,30-4,80 (m, 4H), 3,90-of 4.25 (m, 3H), 2,90-of 3.80 (m, 6N), a 1.75-2.40 a (m, 10H), 1,40-1,60 (m, 3H).

(S)-N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-ACS is-3-phenylpropane-2-yl)piperidine-2-carboxamide:

MC(ESI) m/z: 585 (M+1);

1H NMR (300 MHz, CD3OD) of 7.75-of 8.00 (m, 4H), 7,10-of 7.60 (m, 8H), 4,50-5,00 (m, 4H), 3,90-4,30 (m, 3H), 2,90-of 3.85 (m, 7H), 1.30 and of 2.20 (m, N).

N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxo-3-phenylpropane-2-yl)-3-phenylpropanamide:

MC(ESI) m/z: 606 (M+1);

1H NMR (300 MHz, CD3OD) of 7.75-of 7.90 (m, 4H), 7,10-of 7.60 (m, 13H), 4,50-of 4.90 (m, 3H), 3,80-4,20 (m, 2H), 2,80-of 3.60 (m, 8H), of 2.56 (m, 2H),), 1,70-2,10 (m, 3H), 1,30-1,60 (m, N).

(R)-2-acetamido-N-((R)-3-(4-forfinal)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxoprop-2-yl)-3-phenylpropanamide:

MC(ESI) m/z681 (M+1);

1H NMR (300 MHz, CD3COCD3) 6,70-8,00 (m, N), 4,60-5,10 (m, 4H), 4,00-and 4.40 (m, 2H), 2,60-of 3.80(m, 8H), 1,40-2,10 (m, N).

(R)-2-acetamido-3-(4-chloranil)-N-((R)-3-(4-forfinal)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)-pyrrolidin-1-yl)-1-oxoprop-2-yl)propanamide:

MC(ESI) m/z: 715 (M+1);

1H NMR (300 MHz, CD3COCD3) 7,00-8,00 (m, 15 NM), 4,60-5,10 (m, 3H), 4,10-and 4.40 (m, 2H), 2,60-of 3.80(m, N), 1,40-of 2.20 (m, N).

N-((R)-3-(4-forfinal)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxoprop-2-yl)-3-(4-hydroxyphenyl)propanamide:

MC(ESI) m/z 640 (M+1);

1H NMR (300 MHz, CD3COCD3) 6,70-8,00 (m, 15 NM), 4,60-5,10 (m, 3H), 4,10-4,50 (m, 2H), 2.40 a-3,70 (m, N), 1,40-2,10 (m, 6N).

(S)-2-acetamido-N-((R)-3-(4-chlorophenyl)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-1-oxoprop-2-yl)-3-phenylpropanamide:

MC(ESI) m/z: 697 (M+1);

1 H NMR (300 MHz, CD3OD) of 7.75-of 7.90 (m, 4H), 7,40-of 7.55 (m, 3H), 7,10-7,30 (m, N), 3,90-of 4.90 (m, 6N), 2,70-of 3.60 (m, 8H), 1,40-of 2.20 (m, N).

(S)-2-acetamido-N-((R)-1-((2S,4R)-2-(3-guanidinopropionic)-4-(naphthalene-2-ylethoxy)pyrrolidin-1-yl)-3-(4-hydroxyphenyl)-1-oxoprop-2-yl)-3-phenylpropanamide:

MC(ESI) m/z 679 (M+1);

1H NMR (300 MHz, CD3OD) 7,70-of 7.90 (m, 4H), 7,40-of 7.55 (m, 3H), 7,15-to 7.35 (m, 5H), 6,95-7,10 (m, 2H), 6,70-to 6.80 (m, 2H), 4,55-of 4.90 (m, 4H), 3,80-4,20 (m, 2H), 2,60-of 3.60 (m, 8H), 2,70-of 3.60 (m, 8H), 1,40-of 2.20 (m, N).

The present invention also concerns methods of treating one or more disease conditions. One aspect of the present invention relates to a method of treating disorders selected from the group including insulin resistance, glucose intolerance, diabetes mellitus type 2, coronary artery disease, high blood pressure, hypertension, dyslipidemia, cancer (such as endometrial, cervical, ovarian, breast, prostate, gall bladder, colon), menstrual irregularity, hirsutism, infertility, gall bladder disease, restrictive lung pathology, seizures, sleep apnea, gout, osteoarthritis and thromboembolic disease, in need thereof of a mammal, and the method includes a step of introducing the indicated patient connection, which is described above.

Another aspect of the present invention relates to methods of treating one or b is more violations selected from the group including breach of body weight, CNS-depressio, behavioral disturbances, impaired memory, impaired cardiovascular function, inflammation, sepsis, septic shock, cardiogenic shock, hypovolemic shock, sexual dysfunction, erectile dysfunction, muscle atrophy, diseases associated with growth and recovery of the nerves and the intrauterine development of the fetus, the needy in this animal, and the method includes a step of introducing a specified patient connection, which is described here above.

One specific embodiment of the present invention is directed to a method of regulation disorders of body weight, selected from the group including obesity, anorexia and cachexia.

Melanocarcinoma functional activity and selectivity

Functional activity can be assessed using various methods known in this field. Examples of such methods are measuring the response of second messengers, including camp, the use of the modified cellular systems, giving a color reaction with accumulation of secondary information elements, such as camp, for example, as described in the work of Chen et al. 1995 (Anal. Biochem. 1995, 226, 349-54), Cytosensor Microphysiometer techniques (cytosensor microphysiometry methods) (see Boyfield et al. 1996), or you can apply a study of the physiological effect of calling is the R compounds of the present invention, when using the compounds of this invention by themselves or in combination with natural or synthetic MSH peptides.

Compounds of the present invention preferably (i.e. selective) interact with the MC-4 and/or MC-3 compared to other melanocortin receptors. Selectivity is particularly important when the compound is administered to humans or other animals to reduce side effects associated with their introduction. MS-3/MC-4 selectivity connections define here as the ratio EU50compounds for receptor MC-1 ("EC50-MC-1") to EC50compounds for receptor MC-3 (EU50-MS-3")/MS-4 ("EC50-MC-4"), and values of the EU50measured as described above. The following formula:

MS-3 selectivity=[EU50-MS-1]/[EC50-MC-3]

MS-4 selectivity=[EC50-MC-1]/[EU50-MS-4]

Connection define here as "relatively selective receptor MC-3", if the above ratio for "MC-3 selectivity is at least about 10, preferably at least about 100 and more preferably at least about 500.

Connection define here as "relatively selective receptor MC-4", if the above ratio for "MC-4 selectivity is at least about 10, preferably at least about 100 or more p is edocfile, at least about 500.

The results of the tests of the claimed compounds are presented in Tables XIII and XIV.

Methods of application and composition

The present invention also relates to compositions which contain the above-described ligands of receptors.

For example, the present invention relates to pharmaceutical compositions containing:

a) an effective amount of the compounds or one or more of its pharmaceutically acceptable salts and

(b) pharmaceutically acceptable carriers, excipients and other ingredients to balance.

"Safe and effective amount" of the compounds of the present invention is an amount that is effective for interaction with receptors MC-4 and/or MC-3 in animals, preferably mammals, more preferably humans, without undue adverse side effects (such as toxicity, irritation or allergic response), corresponding to a reasonable value benefit/risk when used according to this invention. It is clear that the specific "safe and effective amount" will vary depending on such factors as the particular condition to be treated, the physical condition of the patient, duration of treatment, the nature of concurrent therapy (if any), the specific dosage form, the use of which has been created excipients, the solubility in these compounds of formula (I) and regimen required for this composition.

The compositions of this invention contain, besides the compounds being considered one or more pharmaceutically acceptable excipients. As used in this description, the expression "pharmaceutically acceptable excipient" means one or more compatible solid or liquid ingredients that are suitable for administration to an animal, preferably a mammal, more preferably human. Used the term "compatible" means that the components of the composition can mix with this connection and with each other so that there was no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use. Pharmaceutically acceptable excipients, of course, must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to an animal, preferably a mammal, more preferably human, subject to treatment.

Some examples of substances which can serve as pharmaceutically acceptable excipients or components thereof are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; a is ulose and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; agar; alginic acid; wetting agents and lubricants such as sodium lauryl sulfate; tinted agents; flavoring agents; for tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline and buffers, such as phosphate, citrate and acetate.

The choice of pharmaceutically acceptable excipients used in conjunction with this compound, determined mainly intended as a way of introduction connections. If the connection should be introduced in the form of injection, the preferred pharmaceutically acceptable excipients are sterile water, saline solution or a mixture whose pH is preferably adjusted to approximately 4-10 using pharmaceutical buffer; you may also want suspendisse agent.

In particular, pharmaceutically acceptable excipients for system use, including the Ute sugar, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, lactose, vegetable oils, synthetic oils, polyols, alginic acid, phosphate, acetate and citrate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred excipients for parenteral administration include propylene glycol, etiloleat, pyrrolidone, ethanol and sesame oil. Pharmaceutically acceptable excipient in compositions for parenteral administration is preferably at least about 90 wt.% from the whole composition.

The compositions of this invention preferably are offered in the form of unit dosage forms. Used herein, the expression "unit dosage form" refers to a composition of this invention containing a number of compounds of formula (I), which is suitable for administration to an animal, preferably a mammal, more preferably human as a single dose in accordance with good medical practice. These compositions preferably contain from about 1 to 750 mg, more preferably from about 3 to 500 mg, more preferably about 5 to 300 mg of the compounds of formula (I).

Based on their ability to agonizing or anlagenservice receptors MC-4 and/or MC-3, present from Britanie also applies to the use of the described ligands, in the methods of treating obesity and other disorders of body weight, including, for example, anorexia and cachexia. These compounds can also be used in methods of treatment of disorders that are the result of violations of body weight, including, but not limited to, insulin resistance, glucose intolerance, diabetes mellitus type 2, coronary artery disease, high blood pressure, hypertension, dyslipidemia, cancer (such as endometrial, cervical, ovarian, breast cancer, prostate cancer, gall bladder, colon), menstrual irregularity, hirsutism, infertility, gall bladder disease, restrictive lung pathology, seizures, sleep apnea, gout, osteoarthritis, and thromboembolic disease. The invention also concerns the treatment of disorders related to behavior, memory (including training), cardio-vascular function, inflammation, sepsis, cardiogenic and hypovolemic shock, sexual dysfunction, erectile dysfunction, muscle atrophy, growth and recovery of nerves, intrauterine development of the fetus and the like.

The terms "treatment" and "treatment" is used here to denote the fact that the introduction of the compounds of the present invention at least facilitates disease by acting through receptors MC-3 or MC-4. Thus, these t rmine include: prevention of the occurrence of a pathological state in a mammal, especially if a mammal is predisposed to acquiring the disease, but still the disease is not diagnosed; the inhibition of the development of the disease condition; and/or relief or reversal of the disease condition.

Therefore, the compounds of this invention can be obtained in the form of pharmaceutical compositions for use in the treatment or prevention of such conditions. Use the standard methods of preparation of pharmaceutical preparations, such as disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., the latest edition, and Peptide and Protein Drug Delivery/ Marcel Dekker, NY, 1991.

The compositions of this invention can be any of a variety of forms, suitable, for example, for oral, rectal, local, nasal, ocular, transdermal, pulmonary or parenteral administration. Depending on the specific way of introduction, you can apply a variety of pharmaceutically acceptable excipients are well known in this field. They include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. You can include conventional pharmaceutically active materials, which essentially does not interfere with the inhibitory activity of the compounds of formula (I). The number of excipient used in combination with the compound of the formula (I)is the I sufficient to provide a practical quantity of material for administration in the form of a unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of the present invention, described in Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2d Edition (1976), included in the application materials by reference.

You can apply a variety of dosage forms for oral management, including solid forms such as tablets, capsules, granules, and bulk powders. Data forms for oral administration include a safe and effective amount, usually at least 5% and preferably from about 25 to 50% of compounds of formula (I). Tablets can imagine pressed tablets, tablets, powdered, tablet with intersolubility coated sugar coated film or repeatedly pressed tablets that contain suitable binders, lubricants, diluents, dezintegriruetsja agents, colorants, flavoring agents, agents promoting the flow, and melting agents. Liquid dosage forms for oral administration include aqueous solutions, emulsions, suspensions, solutions and/or suspensions recovered from nishiuchi granules and effervescent preparations recovered from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspendresume agents, diluents, sweetening Agay is you, the melting agents, dyes and fragrances.

Pharmaceutically acceptable excipients that are suitable for a unit dosage forms are well known in this field. Tablets usually contain well-known pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin, polyvinylpyrrolidone and sucrose; dezintegriruetsja agents, such as starch, alginic acid and crosscarmellose; lubricants such as magnesium stearate, stearic acid and talc. To improve the flow characteristics of the powder mixture can be applied slip agents, such as silicon dioxide. To improve the appearance, you can add tint agents, such as dyes, FD&C Sweetening agents and flavoring agents, such as aspartame, saccharin, menthol, peppermint and fruit flavors that are useful adjuvants for chewable tablets. Capsules typically include one or more solid diluents disclosed above. The feature selection excipient depends on secondary considerations like taste, cost, and storage stability, which are not critical for the purposes of this invention and can be easily carried out by a specialist in this field.

Compositions for pearling the reception also include liquid solutions, emulsions, suspensions and the like. Pharmaceutically acceptable excipients that are suitable for preparations of such compositions is well known in this field. Typical components of excipients for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. Typical suspendresume agents for suspensions include methylcellulose, sodium carboxymethyl cellulose, Avicel® RC-591, tragakant and sodium alginate; typical wetting agents include lecithin and Polysorbate 80; and typical preservatives include methylparaben, propylparaben, and sodium benzoate. Liquid compositions for oral administration may also contain one or more components, such as sweetening agents, and dyes disclosed above.

Such compositions also may be coated with well-known methods, typically a pH-dependent coating or time-dependent, so that the considered connection would be released in the gastrointestinal tract in the vicinity of where the appropriate local application or at different times, extending the required action. Such dosage forms typically include, but are not limited to, one or more of the following materials: acetated cellulose, polyvinylacetate, phthalate of hydroxypropylmethylcellulose, ethylcellulose, covering Eudagit® , waxes and shellac.

Since the compounds of the present invention are peptide nature, the preferred method of administration is parenteral (preferred intravenous injection or nasal introduction in the form of unit dosage forms. Preferred unit dosage forms include suspensions and solutions containing a safe and effective amount of the compounds of formula (I). When parenteral unit dosage form typically contains from about 1 mg to 3 g, more often from about 10 mg to 1 g of compound of formula (I), although the number of input connections depends on the relative affinity of the receptor subtypes MC-4/MC-3, its selectivity with respect to other receptors, including other melanocortin receptors and other

The composition of the invention under examination may optionally include other active drugs.

Other compositions useful for systemic delivery of the considered compounds include dosage forms for sublingual and transbukkalno reception. Such compositions typically contain one or more soluble substances, fillers, such as sucrose, sorbitol and mannitol; a binder such as Arabian gum, microcrystalline cellulose, carboxymethyl cellulose and hypromellose. You can also VK is ucit agents, promoting sliding, lubricants, sweetening agents, colorants, antioxidants and flavoring agents disclosed above.

Methods introduction

As shown, the compositions of this invention can be applied locally or systemically. Systemic application includes any method of introducing the compounds of formula (I) in the tissues of the body, namely, intra-articular, vnutriobolochechnoe, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, nasal, pulmonary and oral administration. The compounds of formula (I) of the present invention preferably systemically, more preferably parenterally, and most preferably by intravenous injection.

The specific dosage of connection to be the introduction, duration of treatment, as well as local or systemic treatment interdependent. Dosage and regimen, depending on factors such as the specific compound of formula (I), indications for treatment, personal property of the patient (such as weight), compliance with the treatment regimen and the presence and severity of side effects.

Usually, an adult man with a mass of about 70 kg is administered from about 1 mg to 6 g, usually from about 100 mg to 3 g of compound of formula (I) on the day when the system acceptance. It is clear that these dose ranges are listed only what about, for example, and that the daily dose can be adjusted depending on the above factors.

As is known and practiced in the field, all the preparations for parenteral administration must be sterile. For mammals, especially for humans (assuming a body weight of approximately 70 kg) is preferred individual dose from about 0.001 to 100 mg

The preferred method of system of injection is intravenous delivery. With this method of delivery preferred individual doses of from about 0.01 to 100 mg, more preferably from about 0.1 to 100 mg

In all previous cases, the compounds of this invention, of course, you can enter one or as mixtures, and compositions can also include additional drugs or excipients, as appropriate to the evidence.

The compound of the present invention can be delivered to your preferred location in the body, using the appropriate system of drug delivery. System drug delivery are well known in this field. For example, methods of drug delivery, useful compounds of the present invention is the binding of this compound with an active molecule that can pass through biological barriers (see, for example, Zlokovic, B.V., Pharmaceutical Research, Vol. 12, pp. 1395-1406 (1995)). A specific example is the interaction of the compounds of this invention with a fragment of insulin for the implementation of the transport through Hematogen efliciency barrier (Fukuta, M. et al., Pharmaceutical Res., Vol. 11, pp.1681-1688 (1994)). An overview of methods of drug delivery, suitable for compounds of the present invention, see Zlokovic, B.V., Pharmaceutical Res., Vol.12, pp.1395-1406 (1995) and Pardridge, W.M., Pharmacol. Toxicol., Vol.71, pp.3-10 (1992).

Table XIII
Binding and agonistic activity of analogues of 2,4-cefoperazone
ConnectionR1R2MC1MSMS
KiEC50(Emax)KiEU50(Emax)KiEU50(Emax)
PG-771950FH75015180 (122)5152 (108)60,6 (131)
PG-772006FAc211,5 (98)710 (64)1,50,28 (94)
PG-771990F3,56,5 (128)0,92 (77)0,50,6 (152)
PG-772512F 31331 (152)90128 (89)68 (99)
PG-970951HH4298 (90)86232 (41)5,510 (84)

Table XIV
Binding and agonistic activity of analogues of 2.5-cefoperazone
ConnectionR1R2MC1MSMS
KiEC50(Emax)KiEC50(Emax)KiEU50(Emax)
PG-741335F9810 (112)17607,5 (103)
PG-772006F33410 (175)249413 (78)
PG-714922F6254 (79) 62203,7 (35)
PG-714924F12990 (86)950,82,8 (100)
PG-742006H325151 (104)537466 (112)10235 (109)
PG-742007F12872 (105)215811 (95)6517 (106)
PG-742737F9,226 (110)845(104)246 (110)
PG-759004OHAc2488 (136)25225 (179)288,5 (106)
PG-743250H25382 (114)853684 (55)7278 (79)
PG-759393H14710 (109)946267 (118) 10810 (134)
PG-762565H15713 (119)1804 (116)343 (98)
PG-767017FAc329147 (119)17715290 (96)75167 (81)
PG-773396F270614380 (141)273614 (55)93220 (68)

1. Connection, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts, with the specified connection has the formula:

where a represents a conformationally restricted ring system selected from the group including:

where the carbon atoms marked with an asterisk can have any stereochemical configuration or a mixture thereof;

where Y has the formula

-(CH2)b-R15,

where the index b is equal to from 1 to 4;

R15is HE, NH2, guanidino;

where Z has the formula

p num="1014">

where R8is hydrogen; R9is naphthylmethyl; R10represents-C(X)N(R16)2where each R16independently represents hydrogen or C1-C10alkyl, and X is oxygen;

or Z represents naphthylmethyl;

where W has the formula:

where R represents phenyl, optionally substituted with halogen or HE group;

where the fragment L is selected from the group including

-NH - or-NHC(O)-;

Represents a hydrogen or a fragment having the formula:

where fragments of R2, R3and R4independently selected from the group comprising hydrogen, -NHC(O)CH3, benzyl, optionally substituted by a hydroxy-group or halogen, imidazolylalkyl;

or fragments of R2, R3and R4together represent naphthalenyl or ethenolysis;

or one of R2, R3and R4represents hydrogen and two of R2, R3or R4taken together, constitute piperidino ring or tetrahydroisoquinoline ring, optionally substituted by a group-C(O)CH3.

2. The compound according to claim 1, where a represents a conformationally restricted ring system selected from g is uppy, including

where the carbon atoms marked with an asterisk can have any stereochemical configuration or a mixture thereof.

3. The compound according to claim 1 or 2, where W has the formula

where R represents phenyl, optionally substituted with halogen; fragment of L represents the group-NHC(O)-.

4. The compound according to claim 3, where R is selected from the group comprising phenyl, 3-forfinal, 4-forfinal, 4-chlorophenyl.

5. The compound according to claim 1 or 2, where the fragment W has the formula:

or the formula

where R2, R3and R4independently selected from the group comprising hydrogen, -NHC(O)CH3, benzyl, optionally substituted by a hydroxy-group or halogen, imidazolylalkyl.

6. The compound according to claim 5, where R2is-NHC(O)CH3and R4is a fragment selected from the group comprising benzyl, 2-imidazolidinyl, 4-imidazolidinyl, 4-tormentil and 4-hydroxybenzyl.

7. The compound according to claim 1 or 2, where the fragment W has the formula

where one of R2, R3and R4represents hydrogen and two of R2, R3or R4taken together, constitute piperidin the TV ring or tetrahydroisoquinoline ring, optionally substituted by a group-C(O)CH3.

8. The compound according to claim 1, where Y has the formula

-(CH2)b-R15,

where R15is guanidino and the index b is equal to from 1 to 3.

9. The compound according to claim 1, where Y has the formula

-(CH2)b-R15,

where R15represents-NH2and the index b is equal to 3.

10. The compound according to claim 1, where Y has the formula

-(CH2)b-R15,

where R15is HE and the index b is equal to 3.

11. The compound according to claim 1, where Y has the formula

12. The compound according to claim 1, where Z has the formula

where R8is hydrogen; R9is 1-naphthylmethyl, 2-naphthylmethyl; R10represents-C(X)N(R16)2where each R16independently represents hydrogen or C1-C10alkyl, and X is oxygen.

13. The connection section 12, where R10represents-CONH2, -CONHCH3.

14. The connection indicated in paragraph 13, where R9is 2-naphthylmethyl,

15. The compound according to claim 1, containing a structure selected from the

or

16. The compound according to claim 1, where L represents a group-NH-.

17. Headlight is aseptically composition, having agonistic activity against MS-3/MC-4 receptors containing

A) an effective amount of the compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts, with the specified connection has the formula

where a represents a conformationally restricted ring system selected from the group including

where the carbon atoms marked with an asterisk can have any stereochemical configuration or a mixture thereof;

where Y has the formula

-(CH2)b-R15,

where the index b is equal to from 1 to 4;

R15is HE, NH2, guanidino;

where Z has the formula

where R8is hydrogen; R9is naphthylmethyl; R10represents-C(X)N(R16)2where each R16independently represents hydrogen or C1-C10alkyl, and X is oxygen;

or Z represents naphthylmethyl;

where W has the formula:

where R represents phenyl, optionally substituted by halogen is m or IT group;

where the fragment L is selected from the group including

-NH - or-NHC(O)-;

Represents a hydrogen or a fragment having the formula

where fragments of R2, R3and R4independently selected from the group comprising hydrogen, -NHC(O)CH3, benzyl, optionally substituted by a hydroxy-group or halogen, imidazolylalkyl;

or fragments of R2, R3and R4together represent naphthalenyl or ethenolysis;

or one of R2, R3and R4represents hydrogen and two of R2, R3or R4taken together, constitute piperidino ring or tetrahydroisoquinoline ring, optionally substituted by a group-C(O)CH3,

C) carriers, excipients and auxiliary ingredients.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds that inhibit binding ligands with α4β1-integrin (VLA-4) selectively. Compounds have the formula (I):

wherein W means unsubstituted phenyl or phenyl substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom, (C1-C4)-alkoxy-group and halogen alkyl; W1 means unsubstituted phenylene or phenylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, pyridylene, pyridylene substituted with 1-3 substitutes taken among (C1-C6)-alkyl, halogen atom and (C1-C4)-alkoxy-group, 2-oxopyrrolylene or thiazolylene; A means oxygen atom (O); R means -(CH2)n- wherein n = 1 or 2; X means -C(O)-; M is taken among the following groups: a)

wherein means divalent 5- or 6-membered heterocyclic radical wherein nitrogen atom is located in the joining point to X wherein Q represents -CH2-, -O- or -S-; R1, R2 and R3 are taken independently among the group involving: hydrogen atom (-H), hydroxyl group (-OH), quinolinyloxy-group, -NH2, mono- or dialkylamino-group, (C1-C6)-alkylsulfonylamino-, arylsulfonylamino-, naphthyloxy-, phenyloxy-group substituted optionally with di-(C1-C6)-alkylamine, (C1-C6)-alkyl, benzyloxymethyl, halogen atom, phenyl, (C1-C4)-alkoxy-group; or two adjacent R1, R2 and R3 taken in common can form alkylene- or alkylenenedioxy-group substituted optionally with 1-3 alkyl groups; R4 means hydrogen atom (H), lower alkyl; Y is taken among a bond, (C2-C8)-alkenylene group, (C2-C8)-alkynylene group, -C(O)-, -C(O)NH- and -(CH2)kY2 wherein k is taken among 1, 2 and 3; Y2 means a direct bond or divalent radical taken among -O-, -S-, -S(O)-, -S(O)2- and -NY3- wherein Y3 is taken among hydrogen atom (H), lower alkyl; Z means (C3-C8)-cycloalkylene, optionally substituted phenylene, pyridylene, piperidylene, piperazinylene; A1 means a direct bond, -(CH2)t-alkynyl wherein t is taken among 1, 2 and 3; R5 means -OH, lower alkoxy-group, , ; b) means wherein R11 is taken among , -NR12- wherein R12 is taken among hydrogen atom (-H), optionally substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl; Z3 is taken among a direct bond, (C1-C12)-alkyl wherein one or some carbon atoms can be replaced with -O- or -NR13- wherein R13 means hydrogen atom (-H), lower alkyl, wherein x = 0 or 1; y = 1, 2 or 3; R14 means hydrogen atom (-H), ; and when R11 means NR12 then Z3 is taken among: wherein 14Ra means hydrogen (H), halogen atom; , and ; Q2 means wherein R17 and R18 mean hydrogen atom (H), lower alkyl; or phenylene that can be substituted; L1 means -COOH or -COOR19 wherein R19 means lower alkyl. Compounds of the formula (I) inhibit activity of VLA-4-mediated adhesion of cells that allows their using in pharmaceutical compositions.

EFFECT: valuable medicinal properties of compounds and compositions.

21 cl, 11 tbl, 283 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (1): and its salts wherein X means unsubstituted monocyclic (5-6-membered) ring system comprising nitrogen atom (N); or X means condensed bicyclic (9-12-membered) ring system comprising N-atom that can be substituted with substitute -SO2-phenyl; Z represents hydrogen atom (H) or means a condensed bicyclic (9-12-membered) unsubstituted or substituted ring system comprising at least one heteroatom, N-atom; Ar represents unsubstituted phenyl ring; each among L1, L2 and L3 represents independently a bond, -CO, -SO2 or -CH2 wherein at least one among L2 and L3 must involve -CO or -SO2; L2 and L3 can represent can represent independently -CONH or -CONHCH2 also; n = 0, 1 or 2; each R1 and R2 represents independently hydrogen atom (H) or a direct (C1-C6)-alkyl chain; Y comprises at least one substituted or unsubstituted phenyl ring or 5-6-membered heteroaromatic ring comprising at least one N-atom as a heteroatom; wherein optional substituted are chosen among the group consisting of halogen atom, alkyl, -COOH, -OH or -NH2; or Y represents 6,7-dihydropyrrolo[3,4-b]pyridine-5-one; wherein ring nitrogen atom can be oxidized optionally. Also, invention relates to a pharmaceutical composition used in treatment states regulated by chemokine CXCR4 or CCR5 receptors based on these compounds. Invention provides preparing new compounds and medicinal agents based on thereof for aims in treatment of HIV- and FIV-infected patients.

EFFECT: valuable medicinal properties of compounds and composition.

15 cl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-phenylpyridine of the general formula: (I) wherein R means halogen or halogen atom; R1 means -(C≡C)mR1' or -(CR'=CR'')mR1'; X means -C(O)N(R8)-, -N(R8)C(O)- or -N(R8)-(CH2)p- wherein m = 0-4 and p = 1-2; values of radicals R1', R2, R3', R3, R4, R4', R8, R' and R'' are given above, and to their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. New compounds are neurokinine-1 antagonists and can be used as medicinal agents in treatment of diseases mediated by neurokinine-1 receptors.

EFFECT: valuable medicinal properties of derivatives.

13 cl, 119 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention relates to a new method for preparing derivative of pyridine of the formula [d]: wherein values of R1, R3 and R4 are given below. Method involves interaction of a new derivative of pyridone of the formula [a]: wherein R3 represent halogen atom, cyano-group or nitro-group; R4 represents hydrogen atom or halogen atom with derivative of α-diazoester of the formula [f]: -N2CHCOR1 [f] wherein R1 represents (C1-C6)-alkoxy-group, and this interaction is carried out in the presence of acid. Proposed method is suitable and profit method for preparing derivatives of pyridine of the formula [d] possessing with specific system of substitutes and eliciting the herbicide activity.

EFFECT: improved preparing method.

8 cl, 2 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

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