3-substituted-1,4-diazepan-2-one antagonists of melanocortin 5-receptor

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I)

where Y represents a group of formula -(CR9R10)n-; X represents -C(=O)-; Z represents a group of formula -(CR13R14)q-; R1 is selected from a group, consisting of (a) C2-C12alkenyl, substituted with 4-chlorophenyl; or (b) C6-C10aryl, optionally substituted with one or two halogen atoms; R2 and R3 represent H; R4 is selected from a group, consisting of H, C1-C12alkyl, optionally substituted with hydroxyl, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted with an amino group or pyperidine, C-bound C1-C18heteroaryl, selected from pyridine and imidazole, C(=O)R15, C(=O)NR16R17 and ONR16C(=NR17)NR18R19; each R5a and R5b represents H, each R6, R7 and R8 is independently selected from a group, consisting of H, C1-C12alkyl and C6-C18aryl, each R9 and R10 represents H; each R13 and R14 represents H; R15 represents H, each R16, R17, R18, R19 and R20 is independently selected from a group, consisting of H, C1-C12alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or any two of R16, R17, taken together with atoms, to which they are bound, form a cyclic group, containing 5 carbon atoms, or n equals to 1; q represents an integer number, selected from a group, consisting of 1, 2, 3, 4 and 5; r equals to 1; or its pharmaceutically acceptable salt.

EFFECT: invention relates to a pharmaceutical composition for treatment of MC5R-associated conditions, which contains a formula (I) compound and a pharmaceutically acceptable carrier, a diluent or a filling agent.

23 cl, 6 tbl, 53 ex

 

The SCOPE of the INVENTION

This invention relates to antagonists of melanocortin-5 receptor. In particular, this invention relates to the family of 1,4-diazepan-2-ones and derivatives thereof, which are antagonists of the melanocortin-5 receptor. This invention also relates to pharmaceutical compositions containing these compounds.

BACKGROUND of the INVENTION

Melanocortin-5 receptor (MC5R) is coupled with G-protein receptor (GPCR), belonging to the family of melanocortin receptors. There are five melanocortin receptors have been identified and cloned to date: MC1R, MC2R, MC3R, MC4R and MC5R. Melanocortin receptors are involved in various physiological functions, providing a number of opportunities for therapeutic intervention in physiological processes by changing (i.e. a statistically significant increase or decrease) or modulation (e.g., increasing regulation or downward regulation) signal activity melanocortin receptor.

Published reviews of melanocortin receptors and their potential as targets for therapy (Wikberg 2001; Bohm 2006). The members of the family of melanocortin receptors are regulated peptide agonists such as ACTH (adrenocorticotropic hormone), and melanocyte-stimulating mountains of the areas (α, β-, γ-MSH)derived from proopiomelanocortin (O.G. ROMs), and peptide antagonists, such as Agouti-signaling protein (ASP) and Agouti-related protein (AGRP). MC1R is widely expressed and is associated with pigmentation in melanocytes and inflammatory responses in many cells involved in the immune system. MC2R is different from other melanocortin receptors because it connects only ACTH, but not MSH ligands. He is highly expressed in the adrenal gland and regulates the synthesis of corticosteroids. MC3R is found in the brain but also in other places in the body and, as it turns out, plays a role in the regulation of energy homeostasis and possible sexual dysfunction. MC4R actually occurs only in the brain, sometimes reported his presence in other places. It is closely related to power control, and is also associated with sexual desire. MC5R is widely expressed in peripheral tissues, especially in the exocrine glands, with a number of receptor is also expressed in the brain. Taking into account the coverage of the activity associated with melanocortin receptors, is necessary when aiming at the target of one of these receptors do it selectively avoid the side effects associated with antagonism or agonism other receptors in this family.

MC5R has cloned and expressed from a variety of species, including Liu is it in 1993 (although called MC2 in this document) (Chhajlani 1993), rat in 1994 (Griffon 1994), mice in 1994 (Gantz 1994; Labbe 1994) and in 1995 (Fathi 1995), representative of the dog (Houseknecht 2003), rhesus (Huang 2000), sheep (Barrett 1994), striped pertino (Ringholm 2002), silver carp (Cerda-Reverter 2003), prickly shark (Klovins 2004), rainbow trout (Haitina 2004) and chicken (Ling 2004), using the MC5R gene, also identified in pigs (Kim 2000). Published patents covering MC5R sequence in humans (Wikberg 2002), mice (Yamada 1997), rhesus (Fong 2003) and dogs (Houseknecht 2003).

A number of studies link MC5R regulating oil secretions, as summarised in 2006 (Zhang 2006). Mice that lack MC5R, have a reduced sebum production, as evidenced by a marked inability to discharge the water from their fur and reduced the amount of sebum extracted from their wool. Largely these mice the rest were generally healthy, with no visible abnormalities (appearance, behavior, growth, muscle mass, fat mass, reproduction, levels of basal and stress-induced corticosterone, glucose and insulin) (Chen 1997). Further research has identified the reduction of pheromones, causing changes in aggressive behavior between mice (Caldwell 2002; Morgan, 2004; Morgan 2004b; Morgan 2006). A mouse whose O.G. ROMs-derived peptide of the native ligands MC5R "knocked out", show a similar phenotype (Yaswen 1999). Rats injected with α-MSH, had licensee on 30-37% of normal sebum production, while removing the intermediate lobe of the hypophysis (source MSH) caused a reduction in oil secretion by 35%, which was restored after administration of α-MSH (Thody 1973). A synergistic effect between α-MSH and testosterone was observed in rats, while testosterone increases sebaceous gland and cell volumes (probably through increased proliferation), α-MSH increases groovetune skin, and the combination increases the excretion of fat (Thody a; Thody 1975 b).

By detecting MC5R transcripts in microarcsecond sebaceous glands (Thiboutot 2000), detection of MC5R in human facial sebaceous glands staining using immune labels (Hatta 2001), detection MC5R mRNA and MC5R in human sebaceous glands, cultured human sebocyti and rat prepucialna cells (Thiboutot 2000) and detection of MC5R in the form punctate particles in the sebaceous glands staining of polyclonal antibodies, it was shown that at the cellular level of the human sebocyti Express MC5R, which can be seen in differentiated, but not undifferentiated sebocyti (Zhang 2006). MC5R mRNA is also found in the sebaceous glands of the skin of wild-type mice, but not in the skin section "MSR-knocked out mice (Chen 1997). Treatment of human sebocyti by cholera toxin (TMS), an extract of the pituitary gland of the ox (TIME), a-MSH or NDP-MSH increases the formation of lipids the x drops synthesis of squalene and the expression of MC5R (Zhang 2003; Zhang 2006). While and MC1R and MC5R found in fat cells, the processing of the primary sebocyte cell culture human NDP-MSH or TIME aroused considerable increase in expression of MC5R compared to serum-free conditions, correlating with the differentiation of sebocyti. An immortalized line of fat cells (SZ-95, TSS-1 and SEB-1) also demonstrate the expression of MC5R (Jeong 2007; Smith 2007a; Phan 2007). These studies suggest that MC5R antagonists can be used to reduce the oil secretion in mammals and, therefore, in the treatment of conditions associated with excessive excretion of fat.

It was found that the family 1,2,4-thiadiazoline derivatives with antagonistic activity of MC5R (138-320 nm) reduce saloobrazovanie as in cultures of human cells sebocyti, and when applied topically to human skin transplanted onto immunodeficient mice (Eisinger 2003a-d; 2006a,b).

Excessive excretion of fat, or seborrhea, is a common ailment. Sebaceous glands are found in most parts of the body with dense concentrations of large glands on the face, scalp scalp and upper torso (Simpson and Cunliffe p43.1). Excretion of fat depends in part on androgenic hormones, possibly partially mediated by 5A-reductase, which converts testosterone to 5a-DHT (hydrotestosterone). Sebum consists of species-specific mixtures of lipids. In humans it consists of approximately 58% of glycerides, 26% of complex wax esters, 12% squalene and 4% cholesterol/esters of cholesterol (Simpson and Cunliffe p43.5). The presence of squalene is almost exclusive feature of human sebum. The function of sebum is not clearly defined, but it is believed that it has fungistatic properties and plays a role in the loss of moisture from the epidermis and its waterproof abilities (Simpson and Cunliffe p43.6; Danby 2005; Porter 2001; Shuster 1976; Kligman 1963).

Excessive excretion of fat associated with the development of common acne. Common acne is a common disease, affecting approximately 80% of the world population at some stage of their life. A person more likely to develop acne than any other disease, although the severity varies considerably (Simpson and Cunliffe p43.16). Acne peaks in prevalence and severity in adolescents aged 14-19 years with approximately 35-40% of the affected, but a significant number of patients (7-24%), it continues beyond the age of 25 (Simpson and Cunliffe p43.15). Patients suffering from acne, one study found that 80% still had symptoms at 30-40 years of age (Simpson and Cunliffe p43.16). Although acne is not a life-threatening disease, it can greatly impact is painted on the quality of life of patients (Follador 2006), while one study of patients with severe acne shows a similar effect as the more serious chronic medical conditions such as asthma, epilepsy, diabetes, back pain or arthritis (Mallon 1999).

It is believed that four main factors involved in the pathogenesis of acne: (i) increased production of sebum (seborrhea), (ii) hyperuricaemia/blockage of the duct that are related to hair and sebaceous glands (acne), (iii) infection duct .acnes, and (iv) the duct inflammation related to hair and sebaceous gland (Simpson and Cunliffe p43.15; Williams 2006). A number of studies have shown a clear link between increased production of sebum and the presence and severity of acne (Simpson and Cunliffe R; Youn 2005; Pierard 1987; Harris 1983; Cotterill 1981; Thody 1975; Pochi 1964). A study in 2007 he established the relationship between sebum excretion and the development of acne in children preteen age (Mourelatos 2007). Sebum is the main nutrient .acnes, thus reducing sebum will reduce subsequent bacterial infection and inflammatory response.

Androgenic sex hormones, seems to play a role in the development of acne with a strong relationship with the production of sebum (Makrantonaki 2007). Pills two oral contraceptives approved by the FDA (Commission on control over drugs and nutrients) for the treatment obycnoje the data eels (Harper 2005), and these compounds apparently act by reducing the androgen-mediated saloobrazovanie. Diet (Cordain 2005; Smith 2007b), stress (Zouboulis, 2004) and genetic factors (Goulden 1999; Bataille 2006) also may play a role in acne, again potentially through increased production of sebum.

Current methods of treatment of common acne primarily focused on the treatment of infections and inflammatory stages of the disease with the help of a large number of different compositions methodistic antibiotics (for example, benzoyl peroxide, tetracycline, erythromycin, clindamycin) and retinoids (e.g., retinoic acid, isotretinoin, adapalene, tazarotene)used or separately, or in combination; some also have anti-inflammatory action (Simpson and Cunliffe p43.36-43.38). Many of these treatments have limited effectiveness, especially in severe cases of acne. A growing problem is the development of antibiotic-resistant strains .acnes (Simpson and Cunliffe p43.37, 43.46; Williams 2006). As Metodista retinoids and benzoyl peroxide cause skin irritation, and retinoids can cause photosensitivity (Williams 2006). Oral treatments include isotretinoin, antibiotics, hormones and steroids. It has been shown that the females antiandrogens reduce sebum production (approximately is entrusted by 40-80%, although no placebo control group) and reduce acne (Simpson and Cunliffe R; Burke 1984; Goodfellow 1984). Laser and based on UV therapy are common, and are expected to act by heating of sebaceous glands with subsequent reduction saloobrazovanie; with reduction as saloobrazovanie and measured acne lesions (Jih 2006; Bhardwaj 2005). Of the many therapies that are suitable for acne, only oral isotretinoin and hormonal therapy act by regulating the sebaceous glands to reduce oil secretions (Clarke 2007).

The most effective treatment of acne, oral isotretinoin (13-CIS-retinoic acid, Roaccutane, Accutane, was introduced in 1983 and still remains the most clinically effective treatment against acne. This is the only known treatment with strong suppressive activity on the production of fat, reduce sebum excretion up to 90% after 8-12 weeks of therapy (60-70% after 2 weeks) (Simpson and Cunliffe p43.47; Jones 1983; Goldstein 1982; King 1982). Metodista retinoids, in contrast, no effect on sebum production. Oral isotretinoin is also anti-inflammatory, reduces the appearance of acne and reduces infection .acnes. The mechanism of action is still unclear, and, apparently, an important role is played by the metabolites of isotretinoin.

Isotretinoin induces apoptosis and prekrseni the cell cycle in human immortalizing SEB-1 sebocytes cell culture (Nelson 2006). Unfortunately, oral isotretinoin has serious side effects; largely it is teratogens, and it needs a registration program for use in the United States. The FDA has issued a warning against online purchase of isotretinoin. During treatment also recommend blood testing for lipids, hold on an empty stomach, and the liver (Williams 2006). Isotretinoin was associated (though not essential) with adverse psychological effects, including suicide and depression (Marqueling 2005).

Other forms of acne, such as nodular acne or fulminant acne, may also be reacting to a substance that reduces sebum. Seborrhea, or excessive production of sebum is often associated with severe acne condition. Seborrheic dermatitis (SD) is a skin disease associated with rich skin fat areas of the scalp, face and torso with a scaly, flaky, itchy redness of the skin, affecting 3-5% of the population; dandruff is a mild form of dermatitis that affects 15-20% of the population. Seborrhea and diabetes occur more frequently in patients with Parkinson's disease or affective disorders (paralysis of the facial nerve, supraorbital damage, polio, syringomyelia, quadriplegia, unilateral damage in Gusarova ganglia and those with HIV/AIDS) (Plewig 1999). Studies have shown the, that seborrheic dermatitis is also associated with chronic alcoholic pancreatitis, hepatitis C virus, and various cancers. It also commonly occurs in patients with genetic disorders such as down syndrome, a disease Hailey-Hailey and cardio-Faccio-cutaneous syndrome (Gupta 2004). To treat these symptoms MC5R antagonists can be used.

Although few in number, but described in different tumors affecting the sebaceous glands or fat cells (for example, Ide, 1999; Mariappan 2004; Kruse 2003). Syndrome Muir-Torre includes adenoma sebaceous glands associated with the internal adenocarcinoma (usually the colon, breast, ovarian or prostate). Preventing the differentiation of fat cells may provide an effective treatment for relief of tumor growth. For this purpose, we used oral isotretinoin (Graefe 2000). The sebaceous gland hyperplasia is a benign hyperplasia of the sebaceous glands, forming a small yellowish papules on the surface of the skin, usually the face. The disease is associated with excessive proliferation of undifferentiated sebocyti, but not with excessive samoobrazovaniem.

Ectopic sebaceous glands (granules, Fordyce) are similar to yellow papules detected in the mouth or on the body of the penis. And those, and others respond to oral isotretinoin. Effective treatment may predstavljati a connection, which reduced the proliferation of sebocyti.

a-MSH demonstrates immunosuppressive effects in humans, reducing the number of inflammatory responses, and MC5R are involved in these immunomodulatory activity. It was found that MC5R mRNA is expressed at high levels in human CD4+ T-helper (TA) cells and at moderate levels in other human peripheral blood leukocytes (Andersen 2005). In mice MC5R found in lymphoid organs (Labbe, 1994) and MC5R found on the surface of murine Pro-B-limfozitah cells, where he, as it turned out, mediates α-MSH activation of JAK2 signaling pathway, enhancing cell proliferation (Buggy 1998). The induction of CD25+ CD4+ regulatory T-cells with a-MSH also, as it turned out, through MC5R (lor 2001).

Due to the above reasons it would be desirable to provide MC5R antagonists that could be applied in a number of therapeutic areas. Therapeutic regulation of biological signal transduction comprises modulation MSR-mediated cellular events, including, inter alia, inhibition or potentiation of the interaction among MSR-binding and activating or deactivating molecules or other substances that regulate the activity of MC5R. Increased capacity for such regulation MC5R can facilitate the development of methods Modulare the project sebaceous excretions or other biological processes and treating conditions associated with such ways as acne, as described above.

The applicants have now identified a family of 1,4-diazepan-2-ones which exhibit antagonistic activity of MC5R, which may be useful in the treatment of MSR-bound States.

BRIEF description of the INVENTION

This invention provides compounds of formula (I):

where

Y represents a group of formula -(CR9R10)n-;

X is selected from the group comprising-C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)s- , and-S(=O)2-;

Z represents a group of formula -(CR13R14)q-;

R1selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C1-C12quinil, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl;

R2and R3each independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted With 2-C12quinil, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl;

R4selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12quinil,3-C12cycloalkyl, optionally substituted C6-C18aryl, optionally substituted With-associated With the1-C18heteroaryl, C(=O)R15C(=O)NR16R17, -C(=NR16)NR17R18, SR20SC(=O)R20, SO2R20, OR20, ONR16R17OCR17R18R20, OC(=O)R20, OC(=O)OR20, OC(=O)NR16R17and ONR16C(=NR17)NR18R19;

each R5aand R5bindependently selected from the group including H, halogen, C1-C12alkyl, C1-C12hydroxyalkyl and C1-C12haloalkyl, or

one or more of R5aand R5btaken together with one or more of R6, R7and R8and the atoms to which they are attached, form a part selected from the group including optional substituted the 3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl;

R6, R7and R8each independently selected from the group including H, halogen, hydroxy, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12quinil, optionally substituted C1-C12heteroalkyl, optionally substituted C1-C10heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, optionally substituted amino, optionally substituted carboxy, C1-C12alkyloxy and optionally substituted thio, or

(a) taken together with the carbon atom to which they are attached, two or more of R6, R7and R8form part selected from the group including optional substituted With2-C12alkenyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18the Rila and optionally substituted C 1-C18heteroaryl, or

(b) one or more of R6, R7and R8taken together with one or more of R5aand R5band the atoms to which they are attached, form a part selected from the group including optional substituted With3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl;

each R9and R10independently selected from the group comprising N and optionally substituted C1-C12alkyl;

each R11and R12independently selected from the group comprising N and optionally substituted C1-C12alkyl;

each R13and R14independently selected from the group including H, halogen, HE1-C12alkyl, C3-C12cycloalkyl,6-C18aryl, C1-C12haloalkyl,1-C12hydroxyalkyl,1-C12alkyloxy and C1-C12haloalkoxy, or

taken together with the carbon to which they are attached, R13and R14form3-C12cycloalkyl group, or

one of R13or R14taken together with one of R15or R20and the atoms to which they are attached, form a cyclic group;

R15independently select the n group, including H, optionally substituted C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl,

each R16, R17, R18, R19and R20independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl, or

any two of R16, R17, R18, R19and R20taken together with the atoms to which they are attached, form an optional substituted cyclic group, or

R15or R20taken together with one of R13or R14and the atoms to which they are attached, form a cyclic group;

n is an integer selected from the group comprising 1, 2, 3, and 4;

q is an integer selected from the group comprising 0, 1, 2, 3, 4 and 5;

r is an integer selected from the group comprising 1, 2, 3, and 4;

s is an integer selected from the group comprising 1, 2, 3, and 4;

or its pharmaceutically acceptable salt or prodrug.

D. the TES invention also relates to pharmaceutical compositions, including the connection of the present invention with a pharmaceutically acceptable carrier, diluent or excipient.

A DETAILED DESCRIPTION of the INVENTION

In this description uses a number of expressions that are well known to the person skilled in the art. However, for the sake of clarity will be determined by the number of expressions.

As used here, the term "unsubstituted" means that there is no Deputy or the only Deputy is hydrogen.

The expression "optional substituted", as used throughout the description, means that the group may or may not additionally be substituted or fused (so as to form a condensed polycyclic system) with one or more non-hydrogen replacing group. In certain embodiments of the implementation of the replacement group represent one or more groups independently selected from the group comprising halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, quinil, haloalkyl, haloalkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heteroseksualci, geteroseksualen, aryl, heteroaryl, cycloalkenyl, geterotsiklicheskikh, heteroallyl, arylalkyl, cycloalkenyl, geterotsiklicheskikh, arylalkyl, heteroaromatic, cycloalkylcarbonyl, geterotsiklicheskikh, arylheteroacetic, heteroaryl roadkill, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyalkyl, alkyloxyalkyl, alkyloxyaryl, alkyloxyalkyl, allyloxycarbonyl, alkylaminocarbonyl, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, heterocyclizations, heterocyclizations, aryloxy, phenoxy, benzyloxy, heteroaromatic, arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfonylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinil, alkylsulfonyl, arylsulfonyl, aminosulphonylphenyl, -C(=O)HE, -C(=O)Ra, -C(=O)ORaC(=O)NRaRbC(NOH)RaC(=NRa)NRbRc, NRaRb, NRaC(=O)Rb, NRaC(=O)ORb, NRaC(=O)NRbRc, NRaC(=NRb)NRcRd, NRaSO2Rb, -SRa, SO2NRaRb, -ORa, OC(=O)NRaRbOS(=O)Raand acyl,

where Ra, Rb, Rcand Rdeach independently selected from the group including H, C1-C12alkyl, C1-C12haloalkyl,1-C10alkenyl, C2-C12quinil, C1-C10heteroalkyl,3-C12cycloalkyl,3-C12cycloalkenyl, C1-C12heteroseksualci, C1-C12geteroseksualen,6-C18aryl, C1-C 18heteroaryl and acyl, or any two or more of Ra, Rb, Rcand Rdtaken together with the atoms to which they are attached, form a heterocyclic ring system with 3 to 12 ring atoms.

In one embodiment, each of the optional Deputy independently selected from the group comprising: halogen, =O, =S, -CN, -NO2, -CF3, -F3, alkyl, alkenyl, quinil, haloalkyl, haloalkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heteroseksualci, geteroseksualen, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxyalkyl, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, heterocyclizations, heterocyclizations, aryloxy, heteroaromatic, arylalkyl, heteroallyl, arylalkyl, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, aminoalkyl, -COOH, -SH and acyl.

Examples of particularly suitable optional substituents include F, Cl, Br, I, CH3CH2CH3HE co3, CF3, F3, NO2, NH2and CN.

In the definitions of a number of deputies below found that "the group may be a terminal group or a bridging group. It is assumed that this means that the use of expression of the et to include the situation, where the group is a connecting link between two other parts of the molecule, and where it is a terminal part. The use of an alkyl as an example, some publications use the term "alkylene for bridge group, and therefore, in these other publications there is a distinction between the expressions "alkyl" (terminal group) and alkylen" (bridge group). In this application not made such a distinction, and most groups can be either a bridge group or terminal group.

Multiple expressions begin with the index register showing the number of carbon atoms present in the part. For example, the index register "C1-C6" before the expression "alkyl" indicates that the alkyl portion has 1-6 carbon atoms. In addition, the index register "C1-C18" before the expression "heteroaryl" shows that the heteroaromatic ring may have 1-18 carbon atoms in the composition of the total number of atoms in the ring system.

"Acyl" means R-C(=O)- group in which the R group can be an alkyl, cycloalkyl, geterotsyklicescoe, aryl or heteroaryl group, as defined here. Examples of acyl include acetyl and benzoyl. The group may be a terminal group or Nosticova the group. If the group is a terminal group, it is connected with the remainder of the molecule via a carbonyl carbon.

"Acylamino" means R-C(=O)-NH - group in which the R group can be an alkyl, cycloalkyl, geterotsyklicescoe, aryl or heteroaryl group, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via the nitrogen atom.

"Alkenyl" as a group or part of a group means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched, preferably 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms in the normal chain. A group can contain multiple double bonds in the normal chain, and orientation around each is independently E or Z. Approximate alkeneamine groups include, but are not limited to, ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonanal. The group may be a terminal group or a bridging group.

"Alkenylacyl" refers to alkenyl-O - group in which alkenyl represents, as defined here. The preferred alkenylacyl gr is PPI represents a C 1-C6alkenylamine group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably C1-C14alkyl, more preferably1-C10alkyl, most preferably C1-C6if not stated otherwise. Examples of suitable straight and branched C1-C6alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, hexyl and the like. The group may be a terminal group or a bridging group.

"Alkylamino" includes, monoalkylamines, and dialkylamino, if not specified. "Monoalkylamines" means alkyl-NH - group in which alkyl is as defined here. "Dialkylamino" means (alkyl)2N - group in which each alkyl may be the same or different and each represents, as defined here for alkyl. The alkyl group preferably represents C1-C6alkyl group. The group may be a terminal group or a bridging group. If the group is a terminal group, it concerns the Ana with the remainder of the molecule via the nitrogen atom.

"Alkylaminocarbonyl" refers to a group of the formula (Alkyl)x(H)yN(=O)-, in which x is 1 or 2 and the sum of x+y=2. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via a carbonyl carbon.

"Alkyloxy" refers to alkyl-O - group in which alkyl is as defined here. Preferably alkyloxy represents a C1-C6alkyloxy. Examples include, but are not limited to, methoxy, ethoxy. The group may be a terminal group or a bridging group.

"Alkyloxyalkyl" refers to alkyloxy-alkyl - group in which alkyloxy and alkyl parts are, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Alkyloxyaryl" refers to alkyloxy-aryl group in which alkyloxy and the aryl part is a, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an aryl group.

"Allyloxycarbonyl" refers to alkyl-O-C(=O)- is the Rupp, in which alkyl is as defined here. The alkyl group are preferably C1-C6alkyl group. Examples include, but are not limited to, methoxycarbonyl and etoxycarbonyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via a carbonyl carbon.

"Alkyloxyalkyl" refers to alkyloxy-cycloalkyl - group, in which alkyloxy and cycloalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through cycloalkyl group.

"Alkyloxyalkyl" refers to alkyloxy-heteroaryl - group, in which alkyloxy and heteroaryl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a heteroaryl group.

"Alkyloxyalkyl" refers to alkyloxy-heteroseksualci - group, in which alkyloxy and heterocytolysine part are as defined here. The group can represent erminology group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through geterotsyklicescoe group.

"Alkylsulfonyl" means alkyl-S(=O)- group in which alkyl is as defined here. The alkyl group preferably represents C1-C6alkyl group. Approximate alkylsulfonyl groups include, but are not limited to, methylsulfinyl and ethylsulfinyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Alkylsulfonyl" refers to alkyl-S(=O)2- group in which alkyl is as defined above. The alkyl group preferably represents C1-C6alkyl group. Examples include, but are not limited to, methylsulphonyl and ethylsulfonyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Quinil" as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched, preferably having 2-14 carbon atoms, more preferably 2-12 atmosukarto, more preferably 2-6 carbon atoms in the normal chain. Exemplary patterns include, but are not limited to, ethinyl and PROPYNYL. The group may be a terminal group or a bridging group.

"Alkyloxy" refers to quinil-O - group in which quinil represents, as defined here. The preferred alkyloxy group represents a C1-C6alkyloxy group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Aminoalkyl" means NH2-alkyl - group in which the alkyl group is as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Aminosulfonyl" means the NH2-S(=O)2- group. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Aryl" as a group or part of a group means (i) optional substituted monocyclic or fused polycyclic, aromatic carbon cycle (ring structure, and eUSA ring atoms, in this case, all represent carbon), preferably having 5 to 12 atoms in the ring. Examples of aryl groups include phenyl, naphthyl and the like; (ii) the optional substituted partially saturated bicyclic aromatic carbocyclic portion, in which phenyl and C5-7cycloalkyl or C5-7cycloalkenyl group merged together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. The group may be a terminal group or a bridging group. Basically aryl group represents a C6-C18aryl group.

"Arylalkyl" means aryl-alkenyl - group in which the aryl and alkenyl are as defined here. Approximate arylalkyl group include phenylalkyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through alkenylphenol group.

"Arylalkyl" means an aryl-alkyl - group in which the aryl and the alkyl part is a, as defined here. Preferred arylalkyl groups contain C1-5alkyl part. Approximate arylalkyl groups include benzyl, phenethyl, 1-naphthalenethiol and 2-naphthalenethiol. The group may be a terminal group or bridge g is the SCP. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Arylalkyl" refers to aryl-alkyl-O - group in which alkyl and aryl are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Arylamino" includes, monoarylamino, and diarylamino, if not specified. Monoarylamino means a group of the formula N-, where aryl is as defined here. Diarylamino means a group of the formula (aryl)2N-, where each aryl may be the same or different and each represents, as defined here for aryl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via the nitrogen atom.

"Arylheteroacetic" means aryl-heteroalkyl - group, in which aryl and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through heteroalkyl group.

"Aryloxy" refers to aryl-O - group, in which toroi aryl represents as defined here. Preferably aryloxy represents a C6-C18aryloxy, more preferably6-C10aryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Arylsulfonyl" means an aryl-S(=O)2- the group in which the aryl group is as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Connection" is a connection between atoms in a compound or molecule. Communication can be a single bond, double bond or triple bond.

"Cyclic group" refers to saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic or polycyclic ring system. Examples of cyclic groups include cycloalkyl, cycloalkenyl and aryl.

"Cycloalkenyl" means a non-aromatic monocyclic or cyclical ring system containing at least one carbon-carbon double bond and preferably having 5 to 10 carbon atoms in the ring. Exemplary monocyclic cycloalkenyl to what ICA include cyclopentenyl, cyclohexenyl or cycloheptenyl. Cycloalkenyl group may be substituted by one or more groups of deputies. The group may be a terminal group or a bridging group.

"Cycloalkyl" refers to a saturated monocyclic or fused or spirobicyclic carbon cycle, preferably containing 3-9 carbon in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic system, such as cyclopropyl and cyclohexyl, bicyclic system such as decalin, and polycyclic systems, such as adamantane. The group may be a terminal group or a bridging group.

"Cycloalkenyl" means cycloalkyl-alkyl - group in which cycloalkyl and alkyl parts are, as defined here. Approximate monocyclohexyl group include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Cycloalkylcarbonyl" means cycloalkyl-alkenyl - group, in which cycloalkyl and Alchemilla part are as defined here. the group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through alkenylphenol group.

"Cycloalkylcarbonyl" means cycloalkyl-heteroalkyl - group, in which cycloalkyl and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through heteroalkyl group.

"Cycloalkane" refers to cycloalkyl-O - group in which cycloalkyl represents, as defined here. Preferably cycloalkane represents a C1-C6cycloalkane. Examples include, but are not limited to, cyclopropane, CYCLOBUTANE. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Cycloalkenyl" refers to cycloalkenyl-O - group in which cycloalkenyl represents, as defined here. Preferably cycloalkenyl represents a C1-C6cycloalkenyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule cereseto oxygen.

"Haloalkyl" refers to an alkyl group, as defined here, in which one or more hydrogen atoms replaced with a halogen atom selected from the group comprising fluorine, chlorine, bromine and iodine. Haloalkaline group typically has the formula CnH(2n+1-m)Xmwhere each X is independently selected from the group comprising F, Cl, Br and I. In groups of this type n usually equals 1-10, more preferably 1-6, most preferably 1-3. m usually is 1-6, preferably 1-3. Examples of haloalkyl include vermeil, deformity and trifluoromethyl.

"Haloalkyl" refers to alkenylphenol group, as defined here, in which one or more of the hydrogen atoms replaced by halogen atom, independently selected from the group comprising F, Cl, Br and I.

"Haloalkyl" refers to alkenylphenol group, as defined here, in which one or more hydrogen atoms replaced with a halogen atom, independently selected from the group comprising F, Cl, Br and I.

"Halogen is chlorine, fluorine, bromine or iodine.

"Heteroalkyl" refers to an alkyl group with straight or branched chain, preferably having 2-14 carbon, more preferably 2-10 carbon chain, one or more of which is substituted by a heteroatom selected from S, O, P and N. the Approximate heteroalkyl include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl su is hide and the like. The group may be a terminal group or a bridging group.

"Heteroaryl or separately, or as part of another group refers to groups containing an aromatic ring (preferably 5 - or 6-membered aromatic ring containing one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms constituting the carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulfur. Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, oil[2,3-b]thiophene, furan, isoindolines, santolan, enoxacin, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, tetrazole, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthiridine, cinoxacin, cinnoline, carbazole, phenanthridine, acridine, fenesin, thiazole, isothiazol, phenothiazines, oxazol, isooctanol, furazan, phenoxazine, 2-, 3 - or 4- pyridyl, 2-, 3-, 4-, 5 - or 8 - chinolin, 1-, 3-, 4 - or 5 - ethenolysis, 1-, 2 - or 3 - indolyl, and 2 - or 3-thienyl. The group may be a terminal group or a bridging group.

"Heteroaromatic" means heteroaryl-alkyl group in which the heteroaryl and alkyl parts are, as defined here. Preferred heteroallyl groups contain a lower alkyl cha is th. Approximate heteroallyl group include pyridylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Heteroaromatic" means heteroaryl-alkenyl - group in which the heteroaryl and Alchemilla part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through alkenylphenol group.

"Heterotrimetallic" means heteroaryl-heteroalkyl - group in which the heteroaryl and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through heteroalkyl group.

"Heteroaromatic" refers to heteroaryl-O - group in which heteroaryl represents, as defined here. Preferably heteroaromatic represents a C1-C12heteroaromatic. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule cher the C atom of oxygen.

"Heterocyclic" refers to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group comprising nitrogen, sulfur and oxygen as ring atoms. Examples of heterocyclic parts include heteroseksualci, geteroseksualen and heteroaryl.

"Geteroseksualen" refers to heteroseksualci, as defined here, but it contains at least one double bond. The group may be a terminal group or a bridging group.

"Heteroseksualci" refers to a saturated monocyclic, bicyclic or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably 1-3 heteroatoms, at least one ring. Each ring represents preferably 3-10-membered, more preferably 4-7-membered. Examples of suitable geterotsiklicheskikh substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrofuranyl, piperidyl, piperazin, tetrahydropyranyl, morpholino, 1,3-diazepan, 1,4-diazepan, 1,4-oxazepan and 1,4-Ossetian. The group may be a terminal group or a bridging group.

"Geterotsiklicheskikh" refers to heteroseksualci-lkyl group, in which heterocytolysine and alkyl parts are, as defined here. Approximate geterotsiklicheskikh groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrofuranyl)methyl. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through an alkyl group.

"Geterotsiklicheskikh" refers to heteroseksualci-alkenyl - group, in which heterocytolysine and Alchemilla part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through alkenylphenol group.

"Geterotsiklicheskikh" means heteroseksualci-heteroalkyl - group, in which heterocytolysine and heteroalkyl part are as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through heteroalkyl group.

"Heterocyclizations" refers to heteroseksualci-O - group in which heteroseksualci represents, as defined here. Preferably heterocyclizations represents the t With a 1-C6heterocyclizations. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Heterocyclizations" refers to geteroseksualen-O - group in which geteroseksualen represents, as defined here. Preferably heterocyclizations represents a C1-C6heterocyclizations. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via an oxygen atom.

"Hydroxyalkyl" refers to an alkyl group, as defined here, in which one or more of the hydrogen atoms replaced IT with the group. Hydroxyalkyl group typically has the formula CnH(2n+1-m)(OH)m. In groups of this type n typically equals 1-10, more preferably 1-6, most preferably 1-3. X usually is 1-6, preferably 1-3.

"Lower alkyl" as a group means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched with 1-6 carbon atoms in the chain, more preferably 1-4 carbons, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl sludge is tertiary-butyl). The group may be a terminal group or a bridging group.

"Sulfinil" means R-S(=O)- group in which the R group can be a HE, alkyl, cycloalkyl, geterotsyklicescoe; aryl or heteroaryl group, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Sulfonylamino" means R-S(=O)-NH - group in which the R group can be a HE, alkyl, cycloalkyl, geterotsyklicescoe; aryl or heteroaryl group, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule via the nitrogen atom.

"Sulfonyl" means R-S(=O)2-the group in which the R group can be a HE, alkyl, cycloalkyl, geterotsyklicescoe; aryl or heteroaryl group, as defined here. The group may be a terminal group or a bridging group. If the group is a terminal group, it is connected with the remainder of the molecule through a sulfur atom.

"Sulfonylamino" means R-S(=O)2-NH - group. The group may be a terminal group is or bridge group. If the group is a terminal group, it is connected with the remainder of the molecule via the nitrogen atom.

It is clear that is included in the family of compounds of formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers and geometric isomers in "E" or "Z" configuration isomer or a mixture of E and Z isomers. It is also clear that some isomeric forms, like the diastereomers, enantiomers and geometric isomers can be divided physical and/or chemical methods and by experts in the field of technology.

Some of the compounds disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof, as expected, fall under the scope described and claimed essence of this invention.

This invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (I)where one or more atoms have the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of this invention include isotopes of hydrogen, such as2H and3H, carbon, such as11 C,13C and14With chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, of nitrogen, such as13N and15N, oxygen, such as15Oh,17O and18Oh, phosphorus, such as32P, and sulfur, such as35S.

Certain isotopically-labeled compounds of formula (I), for example, incorporating a radioactive isotope, applicable in studies of tissue distribution of a drug and/or substrate. Radioactive isotopes tritium, i.e3H, and carbon-14, i.e14With, especially applicable for this purpose due to their simple on and easy ways of detection.

Replacement of heavier isotopes such as deuterium, i.e2H, can provide certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred under certain conditions.

Replacement positron emitting isotopes, such as11C,18F,15O and13N, may be applicable in studies of Positron Emission Tomography (PET) to verify the employment of the receptor substrate.

Isotopically labeled compounds of formula (I) can generally be prepared by standard methods known to the expert in this field is t, or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labeled reagents instead of the previously used unlabeled reagent.

In addition, the Formula (I), as implied, is intended to cover, where applicable, solvated and nonsolvated form compounds. Thus, each formula includes compounds having the specified structure, including hydrated and UN-hydrated form.

The expression "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity videoustanovok compounds include pharmaceutically acceptable salts of accession of the acid and the salt of the attaching base. Suitable pharmaceutically acceptable salts of accession of the acid compounds of formula (I) can be prepared from inorganic acid or organic acid. Examples of such inorganic acids are hydrochloric, sulfuric and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, Malinova is, alkylsulfonate, arylsulfonate. For more information pharmaceutically acceptable salts can be found in Remington''s Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of substances that are solids, the person skilled in the art it is clear that patentable compounds, substances, and salts may exist in different crystal or polymorphic forms, all of which, as implied, are within the scope of the present invention and specified formulas.

"Prodrug" means a compound which is converted into the compound of formula (I) in a biological system, usually metabolic means (e.g. by hydrolysis, recovery or oxidation). For example, the ester Prodrug of compounds of formula (I)containing a hydroxyl group, can be transformed by hydrolysis in vivo to the original molecule. Suitable esters of compounds of formula (I)containing a hydroxyl group, are for example acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and salt Hinn acid. As another example, ester Ave the medicine of the compounds of formula (I), contains carboxypropyl, can be converted by hydrolysis in vivo to the original molecule. (Examples of ester prodrugs are those described F.J.Leinweber, Drug Metab. Res., 18:379, 1987.) Similarly, acyl Prodrug compounds of formula (I)containing an amino group can be converted by hydrolysis in vivo to the original molecule. (Most examples of prodrugs for these and other functional groups, including amines described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V.Stella, R.Borchardt, M.Hageman, R.Oliyai, H.Maag and J Tilley; Springer, 2007.)

As with any group of structurally related compounds which possess a particular useful property, certain embodiments of the variables of the compounds of formula (I) are particularly useful for their end application.

In the compounds of this invention Y is a group of the formula -(CR9R10)n-. In one embodiment of the present invention n is 1 and Y is-CR9R10-. In another embodiment, the present invention n is 2 and Y is-CR9R10CR9R10-.

In one embodiment, compounds of the present invention each R9and R10independently selected from N and CH3. In one particular embodiment, R9and R10both are N. Accordingly, in one the embodiment of this invention Y is-CH 2-. In another embodiment of this invention Y is-CH2CH2-. In another embodiment of this invention Y is-C(CH3)2-.

In one embodiment, compounds of this invention R2represents N or C1-C6alkyl. In a particular embodiment, R2represents N.

In one embodiment, compounds of this invention R3represents N or C1-C6alkyl. In a particular embodiment, R3represents N.

In one embodiment, compounds of the present invention X is chosen from the group comprising-C(=O)- and -(CR11R12)s-. In one particular embodiment, X represents-C(=O)-. In one embodiment of the present invention, where X represents a -(CR11R12)s-, s is 1. In another embodiment of the present invention, where X represents a -(CR11R12)sis, s is 2. In one form of each of these embodiments, R11and R12each independently selected from the group comprising N and C1-C6alkyl. In a particular embodiment, as R11and R12represent H, and s is equal to 1 so that X represents-CH 2-.

In one embodiment, compounds of this invention Y is CH3, R2represents H, R3represents H, X represents-C(=O)-. This provides the compounds of formula (II).

where R1, R4, R5a, R5b, R6, R7, R8, Z and r are as defined for formula (I).

In one embodiment, compounds of the present invention and in particular the compounds of formula (I) and formula (II) r is chosen from the group comprising 1, 2, 3 and 4. In one particular embodiment, r is 1. In another particular embodiment, r is 2. In another particular embodiment, r is 3. In another more specific embodiment, r is 4.

In one embodiment, compounds of the present invention and in particular the compounds of formula (I) and formula (II) R5aand R5bindependently selected from N and C1-C6the alkyl. In one embodiment, R5aand R5beach independently selected from N and CH3. In one particular embodiment, R5aand R5bboth are N. In yet another embodiment, at least one of R5aand R5btaken together, at least one of R6, R7and R 8and the atoms to which they are attached, form an optional substituted cycloalkyl group. In one particular embodiment, at least one of R5aand R5btaken together, at least one of R6, R7and R8and the atoms to which they are attached, forms a tsiklogeksilnogo group.

In one embodiment, compounds of this invention Y is CH2, R2represents H, R3represents H, R5aand R5brepresent H, and X represents-C(=O)-, and r is 1. This provides the compounds of formula (III).

,

where R1, R4, R6, R7, R8and Z are as defined for formula (I).

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R13and R14represent H, so Z is a group of the formula - (CH2)q-where q is as defined above.

In one embodiment, compounds of the present invention q is chosen from the group comprising 1, 2, 3 and 4. In one particular embodiment, q is 1. In another particular embodiment, q is 2. In another particular embodiment, q is 3. Another definition is hinnon embodiment, q is 4. This provides compounds where Z represents-CH2-, -(CH2)2-, - (CH2)3- and -(CH2)4respectively.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R14selected from the group including H, C1-C12alkyl, C3-C12cycloalkyl, optionally substituted C6-C18aryl, optionally substituted With-associated With the1-C18heteroaryl, C(=O)NR16R17, OR16and ONR16C(=NR17)NR18R19.

In one embodiment, R4represents a1-With12alkyl. In another embodiment, R4represents C(=O)NR16R17.

In one form of this specific implementation, where R4represents C(=O)NR16R17, R16and R17taken together with the nitrogen atom to which they are attached, form an optional substituted C2-C12geterotsyklicescoe group. In certain embodiments of the implementation of R16and R17taken together with the nitrogen atom to which they are attached, form an optional substituted geterotsyklicescoe group selected from the group comprising piperidine-1-yl, piperidine-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, azetidin-1-yl, cyclohexane, Mohali the-4-yl, piperazine-1-yl, 4-methyl-piperazine-1-yl and azepin-1-yl.

In another particular embodiment, R4is an optional substituted With-associated With the1-C18heteroaryl. In another particular embodiment, R4represents a C3-C12cycloalkyl.

In one embodiment, compounds of this invention R16selected from the group comprising H, CH3CH2CH3CH2CH2CH2CH(CH3)2CH2CH2CH2CH3CH(CH3)CH2CH3CH2CH(CH3)2C(CH3)3cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or their halogenated derivatives.

In one embodiment, compounds of this invention R17selected from the group comprising H, CH3CH2CH3CH2CH2CH3CH(CH3)2CH2CH2CH2CH3CH(CH3)CH2CH3CH2CH(CH3)2, (CH3)3cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl and phenyl, or their halogenated derivatives.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R7represents N.

In one Varian is the first implementation of the present invention and, in particular, compounds of formula (I), (II) and (III) R6and R8each independently selected from the group comprising H, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one specific embodiment of the present invention and, in particular, compounds of formula (I), (II) and (III) R6and R8each independently selected from the group including optional substituted With1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one specific embodiment of the present invention and, in particular, compounds of formula (I), (II) and (III) R6and R8each independently selected from the group including optional substituted With2-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R6selected from the group comprising H, methyl, trifluoromethyl, ethyl, 2,2,2-triptorelin, isopropyl, isoprobe the sludge, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, optionally substituted phenyl and optionally substituted C1-C5heteroaryl.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R6is an optional substituted phenyl, or optionally substituted C1-C18heteroaryl.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R8selected from the group comprising H, methyl, trifluoromethyl, ethyl, 2,2,2-triptorelin, isopropyl, Isopropenyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, optionally substituted phenyl and optionally substituted C1-C5heteroaryl.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R8represents methyl, ethyl, phenyl, or optionally substituted C1-C5heteroaryl.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R6, R7and R8taken together with the carbon atom, to the which they are attached, form part selected from the group including optional substituted With2-C12alkenyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R6, R7and R8taken together with the carbon atom to which they are attached, form an optional substituted With1-C18aryl group.

In one particular embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R6, R7and R8taken together with the carbon atom to which they are attached, form a disubstituted phenyl group. In one embodiment, disubstituted phenyl group represents a 2,4-disubstituted Hairdryer-1-ilen group or a 3,5-disubstituted Hairdryer-1-ilen group. In disubstituted phenyl group, as defined above, can be present a wide range of substituents. Examples of particularly suitable substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-triptorelin, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethyl the filing, butyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, Penta-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol-1-yl and 3,5-dimethyl-pyrazole-1-yl. In one particular embodiment, disubstituted phenyl group is diclofen-1-ilen group.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R1selected from the group including optional substituted With2-C12alkenyl, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R1is an optional substituted With6-C18aryl. With6-C18the aryl may be a monocyclic, bicyclic or polycyclic part. In certain embodiments of the implementation of C6-C18aryl represents monocyclic part. In certain embodiments of the implementation of C6-C18aryl represents a bicyclic part.

In one particular embodiment, R1is an optional substituted With6-C18aryl, selected from the group VK is causa optional substituted phenyl, the biphenyl and optionally substituted naphthyl.

Parts can be unsubstituted or can be substituted by one or more optional substituents. A large number of optional substituents can be used, as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-triptorelin, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, Penta-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, cyano, phenoxy, hydroxy, methoxy, ethoxy, pyrrol-1-yl and 3,5-dimethyl-pyrazole-1-yl.

The substituents can be located in any substitutable position around aryl rings that are available for replacement, as will be clear to the person skilled in the art. Examples of suitable optional substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl-phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-debtor-phenyl, 2-chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro-phenyl, 3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-f the Nile, 4-hydroxy-phenyl, 4-ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-isopropyl-phenyl, 4-cyano-phenyl, 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl, 4-tert-butyl-phenyl, 2,4-dimethoxy-phenyl and 3,4-methylenedioxy-phenyl.

In the case when R1is an optional substituted biphenyl, the point of attachment of R1the remainder of the molecule can be 2, 3 or 4 position relative to the attachment point of the second phenyl ring. As such, the biphenyl can be an optional substituted bifen-2-yl, or optionally substituted bifen-3-yl, or optionally substituted bifen-4-yl. Basically optional substituted biphenyl is an optional substituted bifen-4-yl. Optional substituted biphenyl can be substituted in any suitable position.

In the case when R1is an optional substituted naphthyl, the point of attachment of R1the remainder of the molecule can be in 1 or 2 position. As such, the naphthyl may be an optional substituted naphthas-1-yl, or optionally substituted naphthas-2-yl. Basically optional substituted naphthyl is an optional substituted naphthas-2-yl. Optional substituted naphthyl may be substituted in any suitable position. Examples of suitable optional substituted naphthas-2-the crystals include, but not limited to, 6-fluoro-naphthas-2-yl, 6-bromo-naphthas-2-yl, 6-chloro-naphthas-2-yl, 1-methoxy-naphthas-2-yl, 3-methoxy-naphthas-2-yl, 6-methoxy-naphthas-2-yl, 1-hydroxy-naphthas-2-yl and 6-amino-naphthas-2-yl.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R1is an optional substituted With1-C18heteroaryl. With1-C18heteroaryl may be a monocyclic, bicyclic or polycyclic part. In certain embodiments of the exercise With1-C18heteroaryl represents a monocyclic part. In certain embodiments of the exercise With1-C18heteroaryl represents a bicyclic part. Examples of suitable heteroaryl parts include, but are not limited to, indole-2-yl, indol-3-yl, quinoline-2-yl, quinoline-3-yl, isoquinoline-3-yl, cinoxacin-2-yl, benzo[b]furan-2-yl, benzo[b]thiophene-2-yl, benzo[b]thiophene-5-yl, thiazol-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[a]thiazol-6-yl, pyrazole-1-yl, pyrazole-4-yl and thiophene-2-yl. They can also be optional substituted, as discussed above.

In one embodiment, compounds of the present invention and, in particular, compounds of formula (I), (II) and (III) R1is an optional substituted With2-C12alkenyl. Optional substituted the first of alkenyl may contain one or more double bonds with each of the double bonds, each of the double bonds is independently E or Z configuration. In one embodiment of the present invention of alkenyl contains one double bond, which is in the E configuration.

In one particular form of this variant implementation of R1is an optional substituted With2-C12alkenyl formula:

R13selected from the group including H, halogen and optionally substituted C1-C12alkyl;

R1band R1ceach independently selected from the group including H, halogen, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12quinil, optionally substituted C1-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C2-C12heteroseksualci, optionally substituted C6-C18aryl and optionally substituted C1-C18heteroaryl.

In one form of this variant implementation of R1arepresents N. In one form of this variant implementation of R1brepresents N. This provides compounds where R1formula:

In one embodiment, compounds of the top the invention R 1cis an optional substituted With6-C18aryl. With6-C18the aryl may be a monocyclic, bicyclic or polycyclic part. In certain embodiments of the exercise With6-C18aryl represents monocyclic part. In certain embodiments of the exercise With6-C18aryl represents a bicyclic part.

In one particular embodiment, R1cis an optional substituted With6-C18aryl selected from the group including optional substituted phenyl and optionally substituted naphthyl. Parts can be unsubstituted or can be substituted by one or more optional substituents. You can apply a wide range of optional substituents as defined above. Examples of particularly suitable optional substituents include, but are not limited to, F, Br, Cl, methyl, trifluoromethyl, ethyl, 2,2,2-triptorelin, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, pentyl, 2-methylpentyl, Penta-4-enyl, hexyl, heptyl, octyl, phenyl, NH2, cyano, phenoxy, hydroxy, methoxy, ethoxy, methylenedioxy, pyrrol-1-yl and 3,5-dimethyl-pyrazole-1-yl.

The substituents can be located in any substitutable position around aryl ring, d is accessible for replacement, as will be clear to the person skilled in the art. Examples of suitable optional substituted phenyl compounds include, but are not limited to, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromo-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-hydroxy-phenyl, 4-phenyl-phenyl, 4-methyl-phenyl, 2,4-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-debtor-phenyl, 2-chloro-6-fluoro-phenyl, 3-fluoro-4-chloro-phenyl, 3-methyl-4-chloro-phenyl, 3-chloro-4-fluoro-phenyl, 3-chloro-4-methyl-phenyl, 2-hydroxy-phenyl, 3-hydroxy-phenyl, 4-hydroxy-phenyl, 4 ethoxy-phenyl, 3-phenoxy-phenyl, 4-phenoxy-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-isopropyl-phenyl, 4-cyano-phenyl 3,4-dimethyl-phenyl, 2,4-dimethyl-phenyl, 4-tert-butyl-phenyl, 2,4-dimethoxy-phenyl and 3,4-methylenedioxy-phenyl.

Certain compounds of this invention include the following:

img src="https://img.russianpatents.com/1176/11762433-s.jpg" height="35" width="39" />

or their pharmaceutically acceptable salt or prodrug.

To help the reader with the names of the compounds of the present invention, as discussed above, follows:

(17) 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-6-yl)methyl)-2-naftalindisul-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(45) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-2-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(46) N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-guanidino)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(47) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-3-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(48) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-4-ylmethyl)-1,4-diazepan-6-yl)methyl)-2-naptime

(49) N-(((3S,5S)-3-butyl-1-(2,2-define is ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(50) (E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(51) (E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(52) N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(53) N-(((3S,5S)-3-(cyclohexylmethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(54) N-(((3S,5S)-3-(2-amino-ethyl)-1-(3,5-dichlorobenzyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(55) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(56) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide

(57) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)-2-naptime

(58) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)acrylamide

(59) N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(60) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(61) N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(62) (E)-N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide

(63) (E)-N-(((3S,5S)-3-((1H-imidazol-4-yl)methyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide

(64) (E)-3(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(pyridine-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(65) (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide

(66) 6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(67) 3,4-dichloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

(68) (5S,9S)-5-(2-aminobenzyl)-2-((E)-3-(4-chlorophenyl)acryloyl)-7-(2,2-diphenylether)hexahydro-1H-imidazo[1,5-d][1,4]diazepin-6(5H)-he

(69) N-(((3S,5S)-3-(2-aminobenzyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naptime

(70) N-(((3S,5S)-3-butyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(71) N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)benzyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(72) N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(73) N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1 -((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(74) 6-chloro-N-(((3S,5S)-3-(2-cyclohexylethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(75) 6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(76) 6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(77) 6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(78) N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naptime

(79) 6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naptime

(80) 3,4-dichloro-N-(((3S,5S)-3-(2-hydroxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide

or their pharmaceutically acceptable salts.

Industrial utility

As indicated previously, the compounds of this invention are antagonists MC5R and, therefore, can be used to modulate the activity of MC5R, or its fragment or analogue or functional equivalent by the fact that they are subjected MC5R, or a fragment or analogue or functional equivalent of the effects of the compounds of this invention.

Accordingly, the compounds of this invention can be used to treat any condition in which modulation of the activity of MC5R, or its fragment or analogue or functional equivalent will lead to a beneficial effect on this condition. As such, the compounds of this invention can be used in methods of treatment, prevention or control of the state, either directly or indirectly related to the activity of MC5R, or its fragment or analogue or functional equivalent of a mammal, where the modulating MC5R amount of the compounds of this invention administered to a mammal. One condition associated with the activity of MC5R, represents the excess sloodle the s and state, associated with him. In one embodiment, method condition selected from the group including acne, seborrhea and seborrheic dermatitis. In one embodiment, acne is chosen from the group comprising common acne, acne, nodular acne and lightning eels. In one particular embodiment, the condition is a common acne.

For example, decreasing regulation MC5R leads to a reduction in oil secretion and thus can be used in the treatment or prevention of a number of States in which the observed excess excretion of fat, namely acne, seborrhea and seborrheic dermatitis.

The compounds of this invention can be also suitable for the treatment, prevention or control of a number of conditions that relate to biological processes, controlled MC5R, such as diseases associated with inflammation. The compounds may also be suitable for treating or preventing cancer, such as syndrome Muir-Torre or other cancerous tumors of the sebaceous glands.

Through its effect on the excretion of fat compounds of this invention may also find application in the treatment where it is desirable reduced excretion of fat, namely in cosmetic treatments. The compounds can thus be used in ways to reduce the oil secretion of melicope the surrounding, the method includes a stage on which to impose an effective amount of the compounds of formula (I).

Introduction compounds of formula (I) to a patient, such as people, can be done by topical application, by any of the conventional methods for enteral administration, such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal methods of application. The injection may be in the form of injection loading dose of a substance, or by continuous or intermittent infusion. Active connection usually is included in the pharmaceutically acceptable carrier or diluent and in sufficient quantity for delivery to the patient a therapeutically effective dose.

When applying the compounds of this invention can enter them in any shape or form, which makes the compound bioavailable. The person skilled in the art of preparing formulations can readily select the proper form and type of injection depending on the individual characteristics of the selected compound, of a condition that should be treated, the stage of the condition that should be treated, and other relevant circumstances. The authors refer to Remingtons Pharmaceutical Sciences, 19thedition, Mack Publishing Co. (1995) for more information.

The compounds of this izaberete the Oia can be entered separately or in the form of pharmaceutical compositions together with pharmaceutically acceptable carrier, diluent or excipient. The compounds of this invention, although effective in and of themselves, are usually developed and introduced in the form of their pharmaceutically acceptable salts, because these forms are usually more stable, easier to crystallize and have a high solubility.

However, compounds usually applied in the form of pharmaceutical compositions, which are prepared depending on the desired form of administration. As such, in an additional embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The composition is prepared in the manner well known in the prior art.

The compounds of formula (I) can be applied or enter together with one or more additional drug(s). The compounds of this invention can be used in conjunction with one or more other pharmaceutically active compounds, such as other treatments for acne. In one embodiment, the other pharmaceutically active agent is chosen from the group comprising antibiotics, retinoids, anti-androgens and steroids. Examples of other pharmaceutically active compounds, which can be combined with the compound of the formula (I) and type in simultaneous or sequential matching athelney combinations thereof, may include, as non-limiting example, other substances against acne, such as oral retinoids (such as isotretinoin), local retinoids (such as isotretinoin, adapalene, tazarotene), oral or topical antibiotics (such as clindamycin, erythromycin, minocycline, tetracycline, benzoyl peroxide) or hormonal therapy (e.g., drospirenone, norgestimate - ethinylestradiol, tsiproteronatsetat). As indicated, these components can be entered in a single composition or in separate compositions. With the introduction of separate formulations of the compounds of this invention can be entered sequentially or simultaneously with other drug(s) agent(s).

The compound of the present invention are typically combined with the carrier to obtain a dosage form suitable for the particular patient being treated, and the particular method of administration. For example, a composition intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the compound of the present invention, mixed with an appropriate and suitable amount of carrier which may vary from about 5 to about 99.95 percent of the total composition. Typical dosage forms will generally contain from about 1 mg to about 500 mg of the compound of danagoulian, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg of the compounds of this invention can also be for local delivery in the formulations, such as solutions, ointments, lotions, gels, creams, micro-emulsions or transdermal patches. For example, these local structures can contain from 0.005 to 5% (weight/weight or weight/volume) of compounds of this invention.

The pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for conversion immediately before use in sterile injectable solutions or dispersion. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or mediums include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters, such as etiloleat. Proper fluidity can be maintained, for example, through the application of covering materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surface-active substances.

These compositions can also contain sub is diversified funds such as preservatives, wetting agents, emulsifying agents and dispersing agents. Preventing exposure of microorganisms can be ensured by the inclusion of various antibacterial and antifungal substances such as parabens, chlorobutanol, fenolcarbonove acid and the like. May also be desired inclusion isotonic substances, such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical form can be called by the inclusion of substances which delay absorption such as aluminum monostearate and gelatin.

When necessary and for more effective distribution, the compounds can be included in slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

Injectable formulations can be sterilized, for example by filtration through inhibiting bacteria filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersing in sterile water or other sterile injectable medium immediately before use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms the active compound is mixed at least with one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum Arabic, C) humectants such as glycerol, d) disintegrating agents such as calcium carbonate, potato or manioc starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarders, such as paraffin, f) absorption accelerators such as Quaternary ammonium compounds, g) wetting agents, such as, for example, cetyl alcohol and glycerylmonostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricating agents such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also contain buffer substances.

Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular polyethylene is the glycols and the like.

Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shells, such as intersolubility coating tablets and other coatings well known in the field of pharmaceutical preparation. They may optionally contain mud components and may also include a composition that they release only the active ingredient(s), or preferably, in certain parts of the intestine, optional, extended way. Examples of coating compositions which can be used include polymeric substances and waxes.

When necessary and for more effective distribution, the compounds can be included in slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.

The active compounds can also be microencapsulating form, optionally with one or more of the above-mentioned fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing substance emulgator, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed oil, ground nut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspendresume substances, sweetening, flavouring and otdushivayut substances.

Suspension in addition to the active compounds can contain suspendresume substances, as, for example, ethoxylated isostearyl alcohols, polyoxyethylenated and sorbitane esters, microcrystalline cellulose, aluminum Metagalaxy, bentonite, agar-agar and tragakant and mixtures thereof.

Compositions for rectal or vaginal injection are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating fillers or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature, but liquid at body temperature and, with edutella, melt in the rectum or vaginal cavity and release the active compound.

For topical application, the active substance may be in the form of ointment, cream, suspension, lotion, powder, solution, paste, gel, spray solution, aerosol or oil. Alternatively, the composition can be delivered via liposomes, nanosomes, ribosome or inside-diffuser environment. On the other hand, the composition can include a transdermal patch or a bandage, such as a dressing impregnated with active ingredient and optionally one or more carriers or diluents. For administration in the form of a transdermal delivery system, the introduction of the dosage will, of course, more continuous and not interrupted during the regimen. Methods for manufacturing compositions for local application known in the art.

Compositions used for local applications usually contain a pharmaceutically acceptable carrier, which can be any environment that is toxicologically and pharmaceutically acceptable. Conventional pharmaceutically acceptable carriers that can be used in the compositions of this invention include water, ethanol, acetone, isopropyl alcohol, stearyl alcohol, freons, polyvinylpyrrolidone, propylene glycol, polyethylene glycol, fragrances, gel-producing Mat is the rials, mineral oil, stearic acid, spermaceti, sorbitan, Monolit, Polysorbate, "twins", sorbitol, methylcellulose, percolator, mineral oil (liquid paraffin), which can represent any product is petroleum-based; modified or unmodified vegetable oils such as peanut oil, wheatgerm oil, linseed oil, jojoba oil, oil of apricot pits, walnut oil, palm oil, pistachio oil, sesame oil, rapeseed oil, juniper oil, oil from corn germ, peach seed oil, poppy seed oil, pine oil, castor oil, oil from soybeans, safflower oil, coconut oil, hazelnut oil, grape seed oil, avocado oil, soybean oil, sweet almond oil, oil of calophylla, castor oil, olive oil, sunflower oil, or animal oils such as whale blubber, seal fat, menhatoy fat, liver fat halibut, cod liver oil, cod, tuna, turtle fat, fat horses ' hooves, goat legs, mink, otter, marmot and the like; synthetic oils such as silicone oil, such as dimethylpolysiloxane; alkyl and alkeneamine esters of fatty acids, such as isopropyl esters of myristic, palmitic and stearic acids and fatty esters which are solid at room temperature; waxes, such as lanolin wax, candelilla wax, spermaceti, cocoa butter, Shea butter, silicone waxes, hydrogenated oils which are solid at room temperature, the sugar-glycerides, oleates, myristate, linoleates, stearates, paraffin, beeswax, Carnauba wax, ozokerite, candelilla wax, microcrystalline wax; fatty alcohols, such as lauric, cetyl, ministerului, stearyl, palmately and alerby alcohols; polyoxyethylene fatty alcohols, and wax esters, lanolin and its derivatives, perhydrosqualene and saturated esters, Etisalat, isopropyl alkalinity, such as isopropylmyristate, mutiliated and deterministic, existiert, triglyceride esters, triglycerides octinomos and decanoas acid, cetirizine, stearylamine (porcelanowe oil), fatty acids, polyhydric alcohols, polyester derivatives, fatty acid monoglycerides, polyethylene glycol, propylene glycol, alkylalkoxysilane, ammoniumnitrate, Soaps of fatty acids and hydrogenated polyisobutene and mixtures of waxes and oils.

Compositions for topical application can be in various forms. However, the composition can often take the form of an aqueous or oil solution or dispersion, or emulsion, and the and gel, or cream. The emulsion may be an emulsion of the type oil-in-water or emulsion of the type water-in-oil.

The oil phase of the emulsions of the type water-in-oil or oil-in-water may contain, for example: (a) hydrocarbon oils such as paraffin or mineral oil; (b) waxes, such as beeswax or paraffin wax; natural oils such as sunflower oil, oil of apricot pits, oil from the oil tree or jojoba oil; d) silicone oils such as Dimethicone, cyclomethicone or acidisation; (e) fatty acid esters, such as isopropyl, isopropylmyristate, dioctylmaleate, glyceridae and zetostearilovy; (f) fatty alcohols such as cetyl alcohol or stearyl alcohol and their mixture (for example, clearily alcohol); (g) polypropylenglycol or polietilenglikolya ethers such as PPG-14 butyl ether; or h) mixtures thereof.

Used emulsifiers can be any emulsifier known in the art for use in the emulsions of the type water-in-oil or oil-in-water. Known cosmetically acceptable emulsifiers include; a) sesquioleate, such as servicesecurity available commercially, for example, under the trade name Arlacel 83 (ICI), or polyglyceryl-2-sesquioleate; (b) ethoxylated esters of derivatives of natural oils such as p is latexjerry ester of hydrogenated castor oil, available commercially, for example, under the trade name Arlacel 989 (ICI); (C) silicone emulsifiers such as siliconpower available commercially, for example, under the trade name ABIL WS08 (h.Goldschmidt AG); (d) anionic emulsifiers, such as Soaps of fatty acids such as stearate and potassium sulfates of fatty acids, such as cetostearyl sodium, commercially available under the trade name Dehydag (Henkel); (e) ethoxylated fatty alcohols, for example the emulsifiers available commercially under the trade name Brij (ICI); (f) esters sorbitan, for example the emulsifiers available commercially under the trade name Span (ICI); (g) ethoxylated esters sorbitan, for example the emulsifiers available commercially under the trade name Tween (ICI); (h) ethoxylated fatty acid esters, such as ethoxylated stearates, for example the emulsifiers available commercially under the trade name Myrj (ICI); (i) ethoxylated mono-, di - and triglycerides, for example the emulsifiers available commercially under the trade name Labrafil (Alfa Chem.); j) non-ionic self emulsifiable waxes, for example beeswax, available commercially under the trade name Polawax (Croda); k) ethoxylated fatty acids, for example the emulsifiers available commercially under the trade name Tefose (Alfa Chem.); l) methylglucose esters, such as polyglyceryl-3 methylglucose stearate, available commercially under the name Tegocare 450 (Degussa Goldschmidt); or m) mixtures thereof.

Gels for local application can be aqueous or nonaqueous. Water gels are preferred. The gel will contain a thickener or gelatinous substance to impart sufficient viscosity to gel. A number of thickeners can be used in accordance with the nature of the liquid carrier and the desired viscosity, and they are listed below. Particularly suitable thickener is a copolymer acryloyldimethyltaurate acid (or its salts), preferably a copolymer of the monomer with another vinyl monomer. For example, the thickener is a copolymer salt acryloyldimethyltaurate acid with other vinyl monomer. Salt can be a salt of alkali metals of group 1, but more preferably is an ammonium salt. Examples of suitable copolymer thickeners are: (i) ammonium acryloyldimethyltaurate 1 vinyl pyrrolidone copolymer, i.e. a copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone (1-vinyl-2-pyrrolidone).

The composition may further include other active ingredients of skin care products, which are well known in the prior art, which can be effective to support the normal functioning of the skin. One group of preferred compositions include hydro is sovanny milk protein to regulate sebum production.

The composition may further include other components that are well known to the person skilled in the technical field, such as emollients, moisturizers, stabilizing emulsion, salt, preservatives, chelating substances or complexing compounds (connecting link), abrasives, antioxidants, stabilizers, pH regulators, surfactants, thickeners, diluents, flavors and dyes.

Compositions for topical application may preferably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such amplifiers dermal penetration include dimethyl sulfoxide and related analogues.

The SYNTHESIS of COMPOUNDS of THIS INVENTION

The General approach for the synthesis of the claimed products flows through the key intermediate product And produced as described in schemes 1 or 2.

Figure 1 amino acid-derived V-N(R2)-Y-CO2H (V=R1X or a protective group of the amine R1) is transformed into amide Weinrebe by activation of the carboxyl group and amidation of N-methylmethanamine. The addition of vinyl Grignard reagent produces aminoalkylindole, which is subjected to a paired connection with R6R7R8C-(CR5aR5b)sub> rNH2aminoven component (shown as WNH2for the sake of simplicity). The resulting secondary amine acelerou under standard conditions of peptide compounds with protected amino acid, P2-NHCH(U)-CO2H, where U represents either end of the side chain ZR4protected final side chain ZR4-R3or predecessor, which requires chemical modification for the formation of the terminal side chain ZR4. Removing the protective group P2with subsequent intramolecular by reductive amination of the ketone using standard conditions for the restoration, such as H2/Pd catalyst, NaBH4, NaBH3CN or NaBH(OAc)3with the formation of the key intermediate product A. If Y=CH2or CH2CH2then a is formed as the predominant diastereoisomer. If V=R1X and U=ZR4, And is the final product.

Scheme 1: Synthesis of intermediate product And by intramolecular reductive amination

Figure 2 an alternative path to the desired intermediate product And begins with the same education amide Weinrebe, addition of vinyl Grignard reagent and amine conjugated addition. At this stage, secondary amine protected by a protective group of the amine R4. The ketone is then reset the valid miniroot protected aminalonum ether, H2N(U)-CO2R5producing a mixture of diastereomers, which is conducted through the subsequent stages of the reaction. The ring system are then produced by removing the protective groups R4and R5followed by the formation of amide bond using standard reagents peptide compounds. Alternatively, the protective group R4remove and reach cyclization via thermal or base-induced cyclization with R5secure complex with ether. Cyclization produces a mixture of two diastereoisomers, a and b, of which the preferred diastereomers can be separated by chromatography.

Scheme 2: Synthesis of intermediate product And by intramolecular reductive amination

The key intermediate product And may represent the final product, if U=ZR4and V=R1X, but in other cases into the final product, as shown in schemes 3, 4 and 5.

In figure 3, where V=R1X, the final product is obtained by modifying the side chain U, for example by removal of the protective group R3or the removal of the protective group R3then further chemical modification.

Scheme 3: V=R1X

In figure 4, where V=P1the final product is obtained by removal of the safety group, R 1with the subsequent introduction of a substituent R1X. If U=ZR4this produces the final product. Alternatively, the side chain of U then modify to obtain the final ZR4group, as in figure 3.

Figure 4: V=P1

In scheme 5, where V=P1the final product is obtained, first, by modifying the side chain of U to obtain the final ZR4group as in scheme 3. This is followed by removing the protective group P1with the subsequent introduction of a substituent R1X.

Figure 5: V=P1

It is also possible to modify the Deputy W, if necessary, during the sequence of these reactions.

EXAMPLES

The following examples are intended to illustrate the disclosed embodiments and should not be construed as limiting. Additional connections other than those described below, can be obtained using the following schemes reactions, as noted above, or suitable variations thereof or modifications. All source materials described in the Examples below, commercially available or easily synthesized by specialists in this field.

Equipment

Analysis of HPLC (high performance liquid chromatography) was performed on the cleaning system Agilent 1100 series with a Phenomenex Synergi 4µ Max-RP 80A, 50×2.00 mm analytical HPLC stake is the NCA, detecting peaks by UV. In the standard analysis used a flow rate of 1 ml/min 0,05% triperoxonane acid (TFA) in water (solvent A) and 0.05% TFA in 90:10 acetonitrile:water (solvent B), using a gradient from 5% B (start) up to 95% b for 9 minutes. Mass spectra were obtained on an Applied Biosystems MDS Sciex API 2000 LC/MS/MS triple quadrupole mass spectrometer and analyzed yourspouse mass spectrometry (ISMS). Preparative HPLC was performed on Waters Delta Prep 3000 HPLC system with detected peaks by UV (Waters model 486 custom absorption detector), using a Phenomenex Luna C5 10µ 100A, 250×21,20 mm (20 mg scale), Phenomenex Luna 15µ C8(2) 100A, 250×30,00 mm (50 mg scale) or Phenomenex Luna 15µ C8(2) 100A, 250×50,00 mm (100 mg scale) HPLC column. For a system of solvent used different gradients of 0.05% TFA in water (solvent A) and 0.05% TFA in 90:10 acetonitrile:water (solvent B).

The following examples 1-6 offer General methods of synthesis, which can be followed for carrying out the transformations described in schemes 1-5. For the formation of different end-products using these techniques, you need to change the variable group on the source material, or to change the variable group on one of the reagents depending on the nature of the reaction. The person skilled in the art it will be clear from reading the General methods, how to change or source material is, or the reagents used in the method for producing different end products. In addition, depending on the starting materials and reagents, you may need and/or desire to make minor modifications described in the General methods in order to provide the most easy synthesis of the required end product.

Example 1 - General methods - formation of amide Weinrebe

THIEF (benzotriazol-1-yl-oxy-Tris-(dimethylamino)-phosphodiester phosphate) reagent (100 mmol) and diisopropylethylamine (DIPEA) (100 mmol) is added to a stirred solution of amino acids (1) (100 mmol) in dichloromethane (DCM) (100 ml). The solution is then stirred at room temperature for 10 min before adding the pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (100 mmol) and DIPEA (100 mmol) followed by stirring at room temperature overnight. DCM then removed by rotary evaporation and the residue is absorbed in ethyl acetate (EtOAc) (200 ml). The organic phase is then washed with 1 N. HCl (3×100 ml), N2O (3×100 ml), saturated aqueous Panso3(3×100 ml) and with brine (1×10 ml). The organic phase is then dried (MgSO4) and EtOAc is removed to obtain the amide Weinrebe (2) in the form of white solids or oils.

Example 2 is a General method for the ka - attach vinyl Grignard to amide Weinreb for the formation of α,β - unsaturated ketones of the formula (3)

To Amida Weinrebe (2) (15 mmol) in DCM (10 ml) at 0°C. add vinylmania (45 mmol) in THF (45 ml). The reaction is stirred for 2 hours and checked by means of HPLC. The reaction is then cooled rapidly by adding thereto a mixture of ice and 1 M HCl (200 ml). The aqueous mixture is extracted with DCM (3×100 ml) and the organic layers are combined and washed with 1 M HCl (2×200 ml) and N2O (3×100 ml). The organic phase is dried (MgSO4to a solution of α,β-unsaturated ketone (3). α,β-Unsaturated ketone (3) can be distinguished by a rotary evaporation or it can be used in solution without additional purification. If the goal is to use α,β-unsaturated ketone (3) in the solution, reduce the volume to 100 ml using rotary evaporation and stored for future use.

Example 3 General method - conjugate connection amine to α,β-unsaturated ketones of the formula (3) to obtain compounds of the formula (4)

To Amin W-NH2(7.4 mmol) in DCM (10 ml) add a solution of α,β-unsaturated ketone (3) (5.7 mmol) in DCM (50 ml). The solution was stirred at room temperature for 15 minutes or until until the analysis shows that all of the (3) spent. A solution of compound 4) directly used without purification for the subsequent reaction.

Example 4 General method - acylation of aminoketone (4)

Amino acid P2-NHCH(U)-CO2H (15 mmol) and DIC (15 mmol) are added to a DCM solution containing 10 mmol of adduct 4 paired connection. The reaction was stirred at room temperature overnight. DCM removed with rotary evaporation and the residue is then subjected to column chromatography on silica gel using white spirit:tO to get 5.

Alternatively, DIC can be replaced by HATU (2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) (15 mmol) and DIPEA (15 mmol). The reaction was stirred at room temperature overnight. DCM removed with rotary evaporation and the residue is absorbed in tO (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×100 ml), a saturated solution of ammonium chloride (2×100 ml) and with brine (2×100 ml). The organic phase is dried and the solvent is removed under reduced pressure. The residue is subjected to column chromatography on silica gel using petroleum ether : tO to get 5.

Example 5 - General method - removing the protective group P2and cyclization

The methodology selected for removal of the protective group R2will vary depending on the specific nature of the protective gr is PPI. As will be appreciated by the person skilled in the art, it is possible to use a larger number of potential protective groups, and the person skilled in the art will easily be able to determine a suitable method for removing any protective groups of the techniques known from the prior art. However, in order to help the reader, are common methods of removal of the most well-known protective groups.

R2= Fmoc: compound 5 (2 mmol) in DCM (3 ml) add diethylamine (20 mmol). The reaction was stirred at room temperature for 1 hour. DCM and diethylamin then removed using rotary evaporation. Add DCM (5 ml) and then triacetoxyborohydride sodium (3 mmol) and the reaction stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (NgSO4and remove DCM to obtain cyklinowanie product A. It can be cleaned using flash chromatography on silica gel or use without purification.

R2=Vos: compound 5 (2 mmol) in DCM (3 ml) is added TFA (3 ml) and the reaction stirred at room temperature for 2 hours. DCM and TFA then removed using rotary evaporation. Then add DCM (5 ml) and triacetoxyborohydride sodium (3 mmol) and the reaction stirred overnight at room temperature. The organic phase is washed on Ishenim solution of sodium bicarbonate (25 ml), dried (MgSO4and remove DCM to obtain cyklinowanie product A. It can be cleaned using flash chromatography on silica gel or use without purification.

R2=Cbz: a Mixture of crude 5 (1 mmol) and 5% Pd/C (200 mg) in 2-propanol (15 ml) is shaken at room temperature under hydrogen (30 psi (pounds per square inch)) within 24 hours. The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to obtain the crude product. To obtain And can be applied purified using flash chromatography on silica gel (100% EtOAc).

Example 6 - General method - removing the protective group P1and obtaining derivatives with R1X

The methodology selected for removal of the protective group R1will vary depending on the specific nature of the protective group. As will be appreciated by the person skilled in the art, it is possible to apply a large number of possible protective groups, and the person skilled in the art will easily be able to determine a suitable method for removing any protective groups of the techniques known from the prior art. However, in order to help the reader, are common methods of removal of the most well-known protective groups.

Removing the protective groups, R1=Cbz:

To cyklinowanie product (1 mmol) in which the ethanol (5 ml) is added a catalytic Pd/C. The reaction is stirred in an atmosphere of hydrogen overnight. The reaction mixture was filtered through Celite and the methanol is removed with rotary evaporation to obtain the free amine. The amine can be used in subsequent reactions without purification.

Removing the protective groups, R1=Vos:

To cyklinowanie product (1 mmol) in DCM (1 ml) is added TFA (1 ml) and the reaction stirred at room temperature for 2 hours. The solvent is removed via rotary evaporation to obtain the amine TFA salt, which can be used in subsequent reactions without purification.

Removing the protective groups, R1=ll:

To cyklinowanie product (1 mmol) in DCM (6 ml) is added 1,3-dimethylbarbituric acid (0.2 mmol) and palladium tetranitroaniline (10 mg). The reaction of the vacuum and stirred at room temperature for 1 hour. DCM removed under reduced pressure to obtain the crude free amine, which can be used in subsequent reactions without purification.

Obtaining derivatives with P1X, when X=S(=O):

To the free amine (1 mmol) in DCM (5 ml) is added DIPEA (1 mmol), THIEF reagent (1.5 mmol) and the acid component R1CO2H (1.5 mmol). The reaction was stirred at room temperature for 2 hours. Rotary evaporation and preparative HPLC gives purified adduct.

Example 7 - Synthesis with the unity 7 6-chloro-2-naphthoic acid

A suspension of 6-bromo-2-naphthoic acid (3.0 g, 11,47 mmol), CuCl (11,7 g, 114,64 mmol) and Cul (2,19 g, 11,50 mmol) in degassed DMF (dimethylformamide) (45 ml) was heated to boiling under argon in the dark for 4 hours. After cooling to room temperature the solution decantation in N2O (200 ml) and the resulting mixture was extracted with tO (2×500 ml). The combined organic layers are then washed N2O (4×500 ml), then with brine (1×500 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to dryness. The residue was ground into powder with CH3CN and the resulting solid then was led from tO to obtain the pure product 7 (2.2 g, 93%) in the form of an off-white solid. HPLC (high performance liquid chromatography) tp6,47 minutes

Example 8 - Synthesis of compound 8 (S)-2-phenylbutane

To a suspension of sodium borohydride (2,36 g of 62.4 mmol) in THF (tetrahydrofuran) (50 ml) was slowly added to the solution (8)-2-phenylalkanoic acid (4,27 g, 26.0 mmol) in THF (40 ml) at 0°C. the Mixture was stirred until then, until stopped the formation of gas. A solution of iodine (6.60 g, 26.0 mmol) in THF (40 ml) was then slowly added at 0°C. After addition, the resulting mixture was allowed to warm to room temperature and was stirred for 1 hour. auktsionnyi solution is then slowly poured into 1 N. a solution of HCl (280 ml) and the resulting mixture was diluted tO (250 ml). The aqueous layer was extracted with tO (150 ml × 3) and the combined organic layers are then washed with saturated Panso3(aq.), 0.5 M PA2S2O3(aq.) and salt solution. This organic solution was dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product. Purification with flash chromatography on silica gel (petroleum ether : tO 4:1) was obtained the desired product 8 in the form of a colorless oil in quantitative yield. HPLC tR5,24 minutes

Example 9 - Synthesis of compound 9 (S)-1-mesilate-2-phenylbutane

To a mixture of alcohol 8 (3,9 g, 26.0 mmol) and triethylamine (5.5 ml, to 39.5 mmol) in DCM (90 ml) was slowly added a solution of methanesulfonamide (4,47 g of 39.0 mmol) in DCM (30 ml) at 0°C. After addition, the resulting mixture was allowed to warm to room temperature and was stirred for 2 hours. Then added 1 N. HCl (70 ml) to the above mixture and the aqueous layer was extracted with DCM (1×70 ml). The combined organic layers were washed with brine (150 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product 9 in the form of a colorless oil. This crude product is then used in the next step without additional cleaning is. HPLC tR6.48 in minutes

Example 10 Synthesis of compound 10 (S)-1-azido-2-phenylbutane

Suspension nelfinavir 9 (5,93 g, 26.0 mmol) and sodium azide (5.7 g, 78,0 mmol) in DMF (60 ml) was heated at 85°C for 3 hours. After cooling to room temperature the mixture was diluted with H2O (200 ml) and was extracted with EtOAc (250 ml). The organic layer is then washed H2O (4×150 ml), then with brine (150 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product. Purification with flash chromatography on silica gel (100% petroleum ether as eluent) received net product azide 10 (a 4.03 g, 88%) in the form of a colorless oil. HPLC tRto 7.67 minutes

Example 11 Synthesis of compound (11) (S)-2-phenylethylamine

A mixture of azide 10 (4.0 g, of 22.8 mmol) and Lindlar catalyst (1.5 g) in tO (50 ml) was shaken at room temperature under H2(40 psi) overnight. The mixture then was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to obtain the crude product amine 11 (3.4 g, 100%) in the form of a light yellow oil. This crude product was used for conjugated addition reactions without additional purification. MS (ESI) 150 (M+1); HPLC tR1,84 minutes

Example 12 - Synthesis of compounds 12 benzyl-(methoxy(ethyl)amino)-2-oxoethylidene

To bz(habasit)-glycine (10 g, of 47.8 mmol, Aldrich) in DCM (100 ml) was added a THIEF reagent (21,5 g, to 48.6 mmol) and DIPEA (6.5 ml, 46,0 mmol). After stirring at room temperature for 10 min was added N,O-dimethylhydroxylamine hydrochloride (4.9 g, a 50.2 mmol) and DIPEA (6.5 ml, 46,0 mmol). The reaction was stirred at room temperature overnight. DCM was removed via rotary evaporation and the residue was absorbed in tO (100 ml). The organic phase was washed with water (3×100 ml), saturated sodium bicarbonate solution (3×100 ml), water (3×100 ml), 1 M hydrochloric acid (3×100 ml), with brine (3×100 ml). The organic phase was dried (magnesium sulfate) and tO removed to obtain the amide Weinrebe 12 in the form of a white solid (7.78 g, 64%).

Example 13 Synthesis of compound 13 benzyl 2-exabot-3-talkabout

To Amida Weinrebe 12 (to 3.89 g, 15,42 mmol) in DCM (10 ml) at 0°C was added vinylmania (45 mmol) in THF (45 ml). The reaction was stirred for 2 hours and examined using HPLC. The reaction was added to a mixture of ice and 1 M hydrochloric acid (200 ml). The aqueous mixture was extracted with DCM (3×100 ml) and washed 1 M hydrochloric acid (2×200 ml) and water (3×100 ml). The organic phase was dried (magnesium sulfate) and the volume was reduced to 100 ml using rotary evaporation. α,β-Unsaturated ketone 13 was stored and used in solution without purification.

<> Example 14 Synthesis of compound 14 (S)-9-fluorenylmethyl 7-[(S)-2-phenylbutyl]-2-methyl-15-phenyl-6,10,13-trioxa-14-oxa-7,12-diazotation-5-ylcarbamate

To (S)-phenylethylamine (0.14 g, 0.9 mmol) in DCM (3 ml) was added α,β-unsaturated ketone 13 (0.9 mmol) in DCM (7.5 ml). After stirring at room temperature for 15 min was added Fmoc-L-Homoleucine (0.4 g, of 1.09 mmol) and DIC (of 0.18 ml of 1.16 mmol). The reaction was stirred at room temperature overnight. DCM was removed via rotary evaporation and the residue was purified column chromatography (silica gel, 1:1 to 0:1 petroleum ether : tO) to obtain 14 (0.54 g, 84%).

Example 15 Synthesis of compound 15 benzyl ((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methylcarbamate

To compound 14 (0.54 g, 0.75 mmol) in DCM (3 ml) was added diethylamine (1.5 ml, 14.5 mmol). The reaction was stirred at room temperature for 1 hour. DCM and diethylamin removed using rotary evaporation. Added DCM (5 ml) and triacetoxyborohydride sodium (0.2 g, were 0.94 mmol) and the reaction was stirred overnight at room temperature. The organic phase is washed with saturated sodium bicarbonate solution (25 ml), dried (magnesium sulfate) and DCM was removed to obtain cyklinowanie product, which was purified using column chromatography (silica gel, petroleum ether : tO is (C) to obtain 0.32 g (89%) 15.

Example 16 Synthesis of compound 16 (3S,5S)-5-(aminomethyl)-3-isopentyl-1-((S)-2-phenylbutyl)-1,4-diazepan-2-it

To cyklinowanie product 15 (0.32 g, 0.67 mmol) in methanol (5 ml) was added the catalyst, Pd/C. the Reaction was stirred in hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite and the methanol was removed via rotary evaporation to obtain the amine 16 (0,23 g, 100%)which was used in the next step without purification,

Example 17 Synthesis of compound 17 6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide

To the amine 16 (0,12 mg, 0.34 mmol) in DCM (1 ml) was added DIPEA (0.1 ml, or 0.57 mmol), THIEF reagent (0.16 g, 0.36 mmol) and 6-chloro-2-naphthoic acid (0.07 g, 0.34 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under high vacuum and the residue was purified using preparative HPLC to obtain 32,0 mg (18%) 17 in the form of the TFA salt. The TFA salt (30 mg) in DCM (15 ml), washed with saturated sodium bicarbonate solution (15 ml). DCM was removed and added 1 M HCl (2 ml) and acetonitrile (2 ml). Removal of solvent using lyophilization received 24 mg 17 in the form of an HCl salt. MS (ESI) 534,4 (M+1); HPLC tRof 7.64 minutes

NMR:1H NMR (CDCl3, 400 MHz): 8,08 to 7.75 (m, 5H), 7,41 (dd, J=8,8, 2,OHz, 1H), 7,32-7,13 (m, 5H), 4,05-to 3.99 (m, 2H), 3,64-of 3.54 (m, 2H), 3,29 (m, 1H), 3,23-of 3.12 (m, 3H), 2,88-2,82 (m, 1H), 2,04-of 1.94 (m, H), 1,69 is 1.58 (m, 3H), 1,51 -1,47 (m, 1H), 0,90-of 0.83 (m, 3H), 0,81-0,76 (m, 9H).

NMR:13With NMR (CDCl3, 100 MHz): 167,6, 142,4, 135,5, 133,7, 130,8 (2C), to 130.6, 128,7 (2C), 128,3, USD 128.0 (2C), 127,8, 127,6, 127,4, 126,9, 126,4, 125,1, 56,6, 46,7, 46,5, 35,3, 32,2, 29,6, 28,9, 28,0, 26,6, 22,9, 22,6, 22,3, 14,3, 12,1 UV: λmax=235 nm, ε=34100; λ2=287 nm, ε=5750.

Example 18 Synthesis of compound 18 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthalide

To a mixture of 2-naphthoic acid (5.8 g, or 33.7 mmol), 2-amino-N-methoxy-N-methylacetamide (Gly amide Weinreb; prepared from Boc-Gly amide Weinrebe 27, as an alternative to the method of Example 22) (3.8 g, 32.1 mmol) and DIPEA (12.0 ml, for 68.9 mmol) in DCM (70 ml) was added a THIEF (14.9 g, or 33.7 mmol) in one portion at room temperature. The resulting mixture was stirred for 1 hour, then added a saturated aqueous solution of NaHCO3.

The organic layer was washed with brine (5×60 ml) and 1 N. HCl (2×30 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product 18, which was used in subsequent reactions without further purification.

Example 19 Synthesis of compound 19 N-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-naphthalide

To a solution of 18 (3.5 g, is 12.85 mmol) in dry THF (10 ml) was slowly added a solution of vinylmania in THF (1 M, 31 ml) at 0°C. After addition the mixture was stirred at room temperature is round within 1 hour then poured into ice-cold solution of 1 N. HCl (50 ml). The aqueous layer was extracted with DCM (3×80 ml) and the combined organic layers were dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude α,β-unsaturated ketone 19. MS (ESI) 240 (M+1); HPLC tR5,46 minutes.

Example 20 Synthesis of compound 20 N-(4-(3,5-dichloraniline)-2-oxobutyl)-2-naphthalide

To a solution of 3,5-dichloraniline (12 mg, 0,068 mmol) in DCM (0.2 ml) was added a solution of α,β-unsaturated ketone 19 (13 mg, 0,054 mmol) in DCM (0.5 ml) at room temperature. The resulting mixture was stirred until then, until all of the α,β-unsaturated ketone has not trashdolls (within one hour), and then used for reactions acylation/cyclization without purification. MS (ESI) 415 (M+1); HPLC tR6.00 minutes.

Example 21 Synthesis of compound 21 allyl 2-(methoxy(methyl)amino)-2-oxoethylidene

To ll(allyloxycarbonyl)-glycine (1.45 g, 9.1 mmol) in DCM (20 ml) was added a THIEF reagent (3.3 grams, 7,46 mmol) and DIPEA (1.5 ml, about 10.7 mmol). After stirring at room temperature for 10 min was added N,O-dimethylhydroxylamine hydrochloride (0.8 g, 8.2 mmol) and DIPEA (1.5 ml, about 10.7 mmol). The reaction was stirred at room temperature overnight. DCM was removed via rotary evaporation and the residue is absorbed in EtOAc (100 ml). The organic the second phase was washed with water (3×100 ml), a saturated solution of sodium bicarbonate (3×50 ml), water (3×50 ml), 1 M hydrochloric acid (3×50 ml), with brine (3×50 ml). The organic phase was dried (magnesium sulfate) and the EtOAc was removed to obtain the amide Weinrebe 21 in the form of white solids (0,43 g, 23%).

Alternatively, tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylidene 27 (Boc-Gly amide Weinrebe, 1.4 g, 6.4 mmol) in DCM (5 ml) and TFA (3 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, followed by addition of DCM (20 ml) and then DIPEA before the main. The solution was cooled to 0°C. and allyl chloroformate was added to 1.4 ml of 13.2 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was neutralized 1 M hydrochloric acid and was extracted with EtOAc. EtOAc was removed via rotary evaporation and the residue was subjected to column chromatography on silica gel using petroleum ether : tO (1:1 to 0:1), affording amide Weinrebe 21 (0,86 g, 66%).

Example 22 Synthesis of compound 22 allyl 2-exabot-3-talkabout

To Amida Weinrebe 21 (of 0.43 g, 2.1 mmol) in DCM (5 ml) at 0°C. was added vinyl minibrain (10 mmol) in THF (10 ml). The reaction was stirred for 2 hours and examined using HPLC. The reaction was added to a mixture of ice and 1 M hydrochloric acid (100 ml). The aqueous mixture was extracted with DCM (3×50 ml) and washed 1 M hydrochloric acid (2×100 ml) and water (3×50 ml). The organic phase was dried (magnesium sulfate) and the volume reduced to 50 ml using rotary evaporation. α,β-Unsaturated ketone 22 was stored and used in solution without further purification.

Example 23 Synthesis of compound 23 (S)-2-(allyloxycarbonyl)-3-(naphthalene-2-yl) propanoic acid

To a stirred mixture of L-3-(2-naphthyl)alanine hydrochloride (5.0 g, to 19.8 mmol), PA2CO3(7,3 g and 69.3 mmol) and 1,4-dioxane (30 ml) in N2O (50 ml) was added allylchloroformate (2,1 ml of 19.8 mmol) at 0°C. the Resulting mixture was stirred for 16 hours, then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and at 0°C was acidified to pH 2. The aqueous phase was extracted with ethyl acetate (3×20 ml), the combined organic phase was washed N2O (50 ml) and with brine (20 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to obtain Aloc-2Nal-OH 23 in the form of a colorless oil (5.8 g, 97%)which was used in the next step without additional purification. HPLC tR6,60 minutes

Example 24 Synthesis of compound 24 (S)-allyl 1-(methoxy(methyl)amino)-3-(naphthalene-2-yl)-1-oxoprop-2-ylcarbamate

To a stirred mixture of acid 23 (of 5.84 g of 19.5 mmol), DIPEA (3,7 ml of 2.09 mmol) and the THIEF (8,63 g of 19.5 mmol) in DCM (10 ml) was added pre-smiling the hydrated solution of N,O-dimethylhydroxylamine hydrochloride (1.9 g, a 19.5 mmol) and DIPEA (7.3 ml, to 41.6 mmol) in DCM (10 ml) at room temperature. Stirring is continued for 16 hours, the reaction mixture was washed 1 N. HCl (3×60 ml), H2O (3×60 ml), saturated aqueous NaHCO3(3×60 ml) and with brine (60 ml), dried over MgSO4. Purification chromatography on silica gel using 20% tO in petroleum ether as eluent got amide Weinrebe 24 (4.83 g, 71%) in the form of a colorless oil. MS (ESI) 343 (M+1); HPLC tR7,07 minutes

Example 25 Synthesis of compound 25 (S)-allyl 1-(naphthalene-2-yl)-3-oxopent-4-EN-2-ylcarbamate

At 0°C was added a solution of vinylmania in THF (1 to 1.5 ml, 1 M) in a single portion to the amide Weinrebe 24 (1,58 g, to 4.62 mmol) under nitrogen with stirring. The resulting mixture was allowed to mix for 2 hours, and poured into a mixture of 1 N. HCl/ice (50 ml). The aqueous mixture was extracted with DCM (3×20 ml), obedinenny the DCM extract was washed 1 N. HCl (50 ml), saturated aqueous NaHCO3(50 ml) and with brine (20 ml), dried over gSO4. The solvent was removed under reduced pressure, providing an α,β-unsaturated ketone 25 (1,14 g, 80%)which was used in the next step without additional purification. MS(ESI) 310 (M+1); HPLC tR7,51 minutes

Example 26 Synthesis of compound 26 (S)-allyl 5-(2,2-diphenylethylamine)-1-(naphthalene-2-yl)-3-oxopent-2-ylcarbamate

To a stirred solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) in DCM (55 ml) was added vinylmation 25 (0.71 g, 2.3 mmol) in one portion. Stirring was continued for 2 hours with the reaction mixture used for the reactions acylation/cyclization without purification. MS(ESI) 507 (M+1); HPLC tR7,22 minutes

Example 27 Synthesis of compound 27 tert-butyl 2-(methoxy(methyl)amino)-2-oxoethylidene (Boc-Gly amide Weinreb)

To a stirred mixture of Boc-Gly-OH (20 g, 114,1 mmol), DIPEA (to 19.8 ml, 114,1 mmol) and the THIEF (50.5 g, 114,1 mmol) in DCM (20 ml) was added a pre-mixed solution of N,O-dimethylhydroxylamine (11.2 g, 114,1 mmol) and DIPEA (to 19.8 ml, 114,1 mmol) in DCM (20 ml) at room temperature. The resulting mixture was stirred for 16 hours, then washed 1 N HCl (3×120 ml), H2O (3×120 ml), saturated aqueous (Panso3(3×120 ml) and with brine (40 ml), dried over MgSO4that was filtered and concentrated under reduced pressure to obtain 27 in the form of a white solid (20 g, 80%)which was used in the next step without additional purification. MS(ESI) 219 (M+1); HPLC tR4,12 minutes.

Example 28 Synthesis of compound 28 tert-butyl 2-exabot-3-talkabout

At 0°C solution of vinylmania in THF (184 ml, 1 M) was added in one portion to the amide Weinrebe 27 (20 g, of 91.6 mmol) under azo is om with stirring. The resulting mixture was allowed to mix for 2 hours and poured into a mixture of 1H. HCl/ice (400 ml). The aqueous mixture was extracted with DCM (5×100 ml), the combined DCM extract was washed 1 N. HCl (2×100 ml), saturated aqueous Panso3(100 ml) and with brine (100 ml), then dried over MgSO4. The solvent was removed under reduced pressure, the obtained ketone 28 (12.9 g, 76%) in the form of a pale yellow oil, which was used in the next step without additional purification. MS(ESI) 186 (M+1); HPLC tR4,19 minutes.

Example 29 Synthesis of compound 29 tert-butyl 4-(2,2-diphenylethylamine)-2-oxobutyrate

To peremeshivaem solution of 2,2-diphenylethylamine (0.33 g, of 1.66 mmol) in DCM (10 ml) was added α,β-unsaturated ketone 28 (0.31 g, of 1.66 mmol) at room temperature. Stirring was continued for 2 hours, the crude reaction mixture 29 was used for reactions acylation/cyclization without purification. MS(ESI) 383 (M+1); HPLC tR5,98 minutes.

Example 30 Synthesis of compound 30 (S)-tert-butyl 3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-dosagecan-6-carboxylate

To a suspension of the salt of Cbz-L-Asp-OtBu-DCHA (10.1 g, 20.0 mmol), N,O-dimethylhydroxylamine-HCl (5.9 g, of 60.5 mmol) and DIPEA (12.0 ml, for 68.9 mmol) in DCM (150 ml) was added a THIEF (10.6 g, 24,0 mmol) in one portion at room temperature. The resulting suspension was stirred for 3 hours then added N 2O (100 ml). The organic layer was washed 1 N. HCl (2×100 ml), saturated aqueous NaHCO3(2×100 ml) and with brine (3×100 ml) and then dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product. Purification using flash chromatography on silica gel (pet. ether/ tO 1:2) gave 30 (6.4 g, 87%) in the form of a colorless oil. MS (ESI) 367 (M+1); HPLC tR6.87 in minutes.

Example 31 Synthesis of compound 31 (S)-3-methyl-4,8-dioxo-10-phenyl-2,9-dioxa-3,7-dosagecan-6-carboxylic acid

Compound 30 (300 mg, 0.82 mmol) was dissolved in TFA/DCM (1:1) solution (2 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue re-dissolved in DCM (10 ml). This solution was washed for 1H. HCl (1×10 ml) and the organic layer was dried over MgSO4that was filtered and concentrated under reduced pressure to obtain the crude product 31 (235 mg, 92%)which was used in subsequent reactions without further purification. MS (ESI) 311 (M+1); HPLC tR4,96 minutes.

Example 32 Synthesis of compound 32 (S)-benzyl 8-(2,2-diphenylether)-3,16,16-trimethyl-4,7,11,14-tetraoxo-2,15-dioxo-3,8,13-triazapentadiene-6-ylcarbamate

Compound 32 was obtained from compound 29 and 31, following the method of Example 14. MS (ESI) 65 (M+1); HPLC tR8,31 minutes.

Example 33 Synthesis of compound 33 tert-butyl ((3S,5S)-1-(2,2-diphenylether)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methylcarbamate

The crude mixture 32 (350 mg) and 5% Pd/C (200 mg) in 2-propanol (15 ml) which was at room temperature under hydrogen (30 psi) for 24 hours. The mixture then was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification using flash chromatography on silica gel (100% tO) gave 33 (175 mg, 65% over 3 steps) in the form of a white solid. MS (ESI) 525 (M+1); HPLC tR6,24 minutes.

Example 34 Synthesis of compound 34 2-((2S,7S)-7-(aminomethyl)-4-(2,2-diphenylether)-3-oxo-1,4-diazepan-2-yl)-N-methoxy-N-methylacetamide

Compound 33 (175 mg, of 0.333 mmol) was dissolved in TFA/DCM (1:1) solution (1 ml) and the resulting mixture was stirred at room temperature for 2 hours. The solvents were removed under reduced pressure and the residue re-dissolved in tO (20 ml). A saturated aqueous solution of NaHCO3(10 ml) and saline (10 ml) was added to the above solution and the aqueous layer was extracted with tO (9×20 ml). The combined organic layers were dried over NgSO4that was filtered and concentrated under reduced pressure to obtain neocide the aqueous product 34 (120 mg, 85%) in the form of a yellow solid, which was used in subsequent reactions without further purification. MS (ESI) 425 (M+1); HPLC fR5,20 minutes.

Example 35 Synthesis of compound 35 N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthalide

To a solution of 34 (50 mg, 0.118 the mmol) and 6-fluoro-2-naphthoic acid (27 mg, 0,142 mmol) in DCM (4 ml) was added DIC (22 μl, 0,142 mmol) at room temperature. The resulting mixture was stirred for 2 hours, then the solvent was removed under reduced pressure to obtain the crude product. Purification using flash chromatography on silica gel (elwira petroleum ether : tO (1:1), then tO) gave 35 (29 mg, 41%) in the form of a white solid. MS (ESI) 597 (M+1); HPLC tR6.75 minutes.

Example 36 Synthesis of compound 36 N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxoethyl)-1,4-diazepan-5-yl)methyl)-6-fluoro-2-naphthalide

To a solution of 35 (29 mg, 0,049 mmol) in dry THF (1 ml) was added LiAlH(OtBu)3(38 mg, 0,145 mmol) in one portion at room temperature and the resulting suspension was stirred overnight. This slurry is then slowly poured into a cold (0°C) 0.4 M aqueous solution of KHSO4(2 ml, 0.8 mmol) and the resulting mixture was diluted tO (3 ml). The aqueous layer was extracted with tO (3×3 ml) and the combined organic layer is washed 1 N. HCl (3×6 ml), saturated aqueous NaHCO3(1×6 ml) and with brine (1×6 ml). The organic solution is then dried over MgSO4that was filtered and concentrated under reduced pressure to obtain 36 (24 mg, 91%). MS (ESI) 538 (M+1); HPLC tR6,41 minutes.

Example 37 Synthesis of BOC-Glu(piperidine)-37 (S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(piperidine-1-yl)pentanol acid

HATU (2.5 g) and DIPEA (1.5 ml) was added to Boc-L-Glu(OH)-OBn (2.0 g) in DCM (50 ml)was stirred for 10 minutes, then added piperidine (0.7 ml) and the reaction was stirred overnight at room temperature. The reaction was washed with sodium bicarbonate solution (2x), saturated NH4Cl (2x), brine solution (2x), dried over MgSO4that was filtered and boiled away to obtain 2.9 g of the BOC-L-Glu (piperidine)-AFP. Benzyl ester (0.6 g) was dissolved in tO (15 ml) with catalytic Pd/C and was hydrogenosomal for 1 hour, was filtered through Celite and boiled away tO using rotary evaporation to obtain 0.51 g of 37.

Example 38 Synthesis of compound 38 1-phenyl-9-(2,2-diphenylether)-3,6,10-trioxo-2,11-dioxa-4,9-diasteranes-13-ene

2.2-Diphenylethylamine (412 mg, of 2.09 mmol) was added to a solution of Cbz-vinylmation 13 (1.9 mmol) in DCM (40 ml). After 5 min added Alloc-Cl (0,41 ml of 3.80 mmol) and DIPEA (0,99 ml, 5,70 mmol) and the reaction was stirred for 1 cha is and. The solution was washed us. NaHC3and boiled away the dryness to obtain a brown oil. Purification using column chromatography (gel SiO2, pet. ether/tO) has obtained 815 mg 38.

Example 39 Synthesis of compound 39 (S)-allyl 2-amino-3-(pyridin-2-yl)propanoate

To a solution of BOC-L-3-(2-pyridyl)-l-HE (810 mg, totaling 3.04 mmol) in DCM (12 ml) was added allyl alcohol (0,31 ml, 4,56 mmol)and then HATU (1736 mg of 4.57 mmol) and DIPEA (0,79 ml of 4.57 mmol). After stirring for 2 hours the solution was concentrated and half mixture was purified column chromatography (gel SiO2, pet. ether/tO) to obtain 670 mg of the BOC-L-3-(2-pyridyl)-l-Ollil. A portion of this product (290 mg, 0.95 mmol) was dissolved in DCM (3 ml) and TFA (3 ml) and was stirred for 5 min. the Solution was concentrated, then added DCM, washed feast upon. NaHCO3and boiled away the dryness to obtain 39 in the form of a colorless oil (280 mg)which was used without purification in the next step.

Example 40 Synthesis of compound 40 (2S)-allyl 2-(9-(2,2-diphenylether)-3,10-dioxo-1-phenyl-2,11-dioxa-4,9-diasteranes-13-ene-6-ylamino)-3-(pyridin-2-yl)propanoate

Protected aminoketone 38 (474 mg, 0.95 mmol), L-3-(2-pyridyl)-l-Ollil 39 (0.95 mmol) and N(SLA)3(403 mg, 1,90 mmol) in DCM (6,7 ml) was stirred for 17 hours. Added saturated NaHCO3, was extracted with DCM (3x) and the organic is their extracts were combined and washed with saturated Panso 3and H2O, dried over MgSO4and boiled away the dryness to obtain 40 (810 mg) in the form of a pale yellow oil (as a mixture of diastereoisomers), which was used in subsequent reactions without purification.

Example 41 Synthesis of compound 41 (2S)-2-(1-(benzyloxycarbonylamino)-4-(2,2-diphenylethylamine)butane-2-ylamino)-3-(pyridin-2-yl)propanoic acid

ll/allyl-protected derivative 40 (656 mg, 0.95 mmol) was dissolved in DCM (10 ml) and the solution was degirolami under vacuum. Added 1,3-dimethylbarbituric acid (296 mg, 1,90 mmol) and catalytic PD(h3)4(220 mg, 0,19 mmol) and the reaction was stirred for 1 hour to obtain a solution of 41 to remove the protective groups, which was used in the next step without purification.

Example 42 Synthesis of compounds 42 and 43: benzyl((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-2-ylmethyl)-1,4-diazepan-5-yl)methylcarbamate and benzyl((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-2-ylmethyl)-1,4-diazepan-5-yl)methylcarbamate

To the crude 41 to remove the protective groups (0.95 mmol) in DCM (10 ml) was added HATU (541 mg, 1,43 mmol), then DIPEA (0,50 ml, to 2.85 mmol). After 30 min the solution was washed (feast upon. NaHCO3, saline solution), dried (MgSO4and boiled away. Two diastereoisomeric product divided column chromatography (gel SiO2 , pet. ether/tO) to obtain 260 mg of the previously lirovannomu (3S,5S) isomer 42 and 175 mg later lirovannomu (3S,5R) isomer 43.

Example 43 Synthesis of compound 44 (3S,5S)-5-(aminomethyl)-1-(2,2-diphenylether)-3-(pyridine-2-ylmethyl)-1,4-diazepan-2-it

Cbz-group preferred diastereoisomer 42 was removed by hydrogenation (H2, 1 ATM.) suspension 42 (35 mg) and Pd/C (50 mg) in tO/methanol overnight. The solution was filtered through Celite and boiled away to get 44 in the form of a colorless oil (25 mg).

Example 44 Synthesis of compound 45 (E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-2-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide

To the crude free amine 44 (25 mg, 0.06 mmol) in DCM was added 4-harkrisnowo acid (13 mg, 0.07 mmol), DIPEA (25 μl, 0.14 mmol) and the THIEF (31 mg, 0.07 mmol). After stirring overnight the solution was washed (feast upon. NaHCO3, brine), dried (MgSO4and boiled away under high vacuum, the residue was purified using preparative HPLC to obtain 30 mg 45. MS (ESI) 579,3 (M+1); HPLC tR6,60 minutes

Example 45 Synthesis of compounds 46-80.

Compounds 17 and 45-80 with substituents as identified in Table 1, were obtained, as in the previous examples, according to the paths specified in schemes 1-5, as bodytag is but in table 2, with the experimental properties are summarized in table 3.

CH2
Table 1
The identity of connections
Connection.R1XR2R3YZR4W
176-chloro-2-naphtolNNCH2CH2CH2/Pr(S)-2-phenylbutyl
454-chlorocinnamoylNNCH2CH2(2-pyridinyl)2.2-diphenylether
462-naphtolNNCH2(CH2)2ON(=NH)NH22.2-diphenylether
472-naphtol NNCH2CH2(3-pyridinyl)2.2-diphenylether
482-naphtolNNCH2CH2(4-pyridinyl)2.2-diphenylether
492-naphtolNNCH2(CH2)3CH32.2-diphenylether
504-chlorocinnamoylNNCH2(CH2)3CH32.2-diphenylether
514-chlorocinnamoylNNCH2(CH2)2CONH22.2-diphenylether
522-naphtol NNCH2(CH2)2CONH22.2-diphenylether
532-naphtolNNCH2CH2cyclohexyl2.2-diphenylether
544-chlorocinnamoylNNCH2CH2cyclohexyl2.2-diphenylether
552-naphtolNNCH2(CH2)2WITH(1-piperidinyl)2.2-diphenylether
564-chlorocinnamoylNNCH2(CH2)2WITH(1-piperidinyl)2.2-diphenylether
572-naphtol NNCH2(CH2)2Ph2.2-diphenylether
584-chlorocinnamoylNNCH2(CH2)2Ph2.2-diphenylether
592-naphtolNNCH2(CH2)2cyclohexyl2.2-diphenylether
604-chlorocinnamoylNNCH2(CH2)2cyclohexyl2.2-diphenylether
612-naphtolNNCH2CH2Ph2.2-diphenylether
624-chlorocinnamoylN NCH2CH2Ph2.2-diphenylether
634-chlorocinnamoylNNCH2CH2(imidazol-3-yl)2.2-diphenylether
644-chlorocinnamoylNNCH2CH2N(2-pyridyl)2.2-diphenylether
654-chlorocinnamoylNNCH2CH2WITH(1-piperidinyl)2.2-diphenylether
666-chloro-2-naphtolNNCH2CH2CO(1-piperidinyl)(S)-2-phenylbutyl
673,4-dichlorobenzoylNNCH2WITH(1-piperidinyl)(S)-2-phenylbutyl
684-chlorocinnamoylNNCH2CH2(2-NH2-Ph)2.2-diphenylether
692-naphtolNNCH2CH2(2-NH2-Ph)2.2-diphenylether
706-chloro-2-naphtolNNCH2(CH2)3CH3(S)-2-phenylbutyl
712-naphtolNNCH2CH2(2-(piperidine-1-yl)phenyl-2.2-diphenylether
722-naphtolNNCH2 (CH2)2CON(Me)nBu(S)-2-phenylbutyl
732-naphtolNNCH2(CH2)2CONHcHex(S)-2-phenylbutyl
746-chloro-2-naphtolNNCH2(CH2)2Snekh(S)-2-phenylbutyl
756-chloro-2-naphtolNNCH2PNEC(S)-2-phenylbutyl
766-chloro-2-naphtolNNCH2(CH2)4HE(S)-2-phenylbutyl
776-chloro-2-naphtolNNCH2(With the 2)2OMe(S)-2-phenylbutyl
786-chloro-2-naphtolNNCH2(CH2)2OBn(S)-2-phenylbutyl
796-chloro-2-naphtolNNCH2iBu(S)-2-phenylbutyl
803,4-dichlorobenzoylNNCH2(CH2)2HE(S)-2-phenylbutyl

Table 2
The synthesis of compounds
Connection.The path AndScheme 1: VN(R2)-Y-CO2HP2NH-CH(U)-CO2HPrevrasheniya in the productModification U
17Cbz-Gly-OHFmoc-L-HoLeu-OHScheme 4no
45Scheme 2Cbz-Gly-OHN-(β-(2-pyridyl)-1-A1A-OallylScheme 4no
46Scheme 1Alloc-Gly-OHBoc-L-Canavanine(Fmoc)-OHScheme 4removing the protective group P3
47Scheme 12-naphthoic-Gly-OHFmo-L-3-la-OHScheme 3no
48Scheme 12-naphthoic-Gly-OHFmoc-L-4-la-OHScheme 3no
49Scheme 1Cbz-Gly-OHBoc-L-Nle-OHScheme 4no
50Scheme 1 Cbz-Gly-OHBoc-L-Nle-OHScheme 4no
51Scheme 1Cbz-Gly-OHBoc-L-Gln-OHScheme 4no
52Scheme 1Cbz-Gly-OHBoc-L-Gln-OHScheme 4no
53Scheme 1Cbz-Gly-OHBoc-L-Cha-OHScheme 4no
54Scheme 1Cbz-Gly-OHBoc-L-Cha-OHScheme 4no
55Scheme 1Cbz-Gly-OHBoc-L-Glu(1-piperidinyl)-HEScheme 4no
56Scheme 1Cbz-Gly-OHBoc-L-Glu(1-piperidinyl)-HEScheme 4 no
57Scheme 1Cbz-Gly-OHBoc-L-Hfe-OHScheme 4no
58Scheme 1Cbz-Gly-OHBoc-L-Hfe-OHScheme 4no
59Scheme 1Cbz-Gly-OHBoc-L-hCha-OHScheme 4no
60Scheme 1Cbz-Gly-OHBoc-L-hCha-OHScheme 4no
61Scheme 1Cbz-Gly-OHBoc-L-Phe-OHScheme 4no
62Scheme 1Cbz-Gly-OHBoc-L-Phe-OHScheme 4no
63Scheme 1Cbz-Gly-OH Fmoc-L-His(Boc)-OHScheme 4removing the protective group P3
64Scheme 1Cbz-Gly-OHFmoc-L-Asp(OtBu)-OHScheme 4removing the protective group P3the amidation
65Scheme 1Cbz-Gly-OHFmoc-L-Asp(OtBu)-OHScheme 4removing the protective group P3the amidation
66Scheme 1Cbz-Gly-OHBOC-L-Gln(piperidyl)-OHScheme 4no
67Scheme 1Cbz-Gly-OHBOC-L-Gln(piperidyl)-OHScheme 4no
68Scheme 1Fmoc-Gly-OHBoc-L-(2-NO2)-Phe-OHScheme 5nitroglycerine
69CX is mA 1 Fmoc-Gly-OHBoc-L-(2-NO2)-Phe-OHScheme 4nitroglycerine
70Scheme 1Cbz-Gly-OHBoc-L-Nle-OHScheme 4no
71Scheme 1Fmoc-Gly-OHBoc-L-(2-NO2)-Phe-OHScheme 5nitroglycerine, then dialkylamino alkylamino
72Scheme 12-naphthoic-GlyBoc-L-Gln(Me, nBu)-OHScheme 4no
73Scheme 12-naphthoic-GlyBoc-L-Gln(chex)-OHScheme 4no
74Scheme 1Cbz-GlyFmoc-L-HoCha-OHScheme 4no
75Schema Cbz-GlyFmoc-L-2-aminooctanoic acidScheme 4no
76Scheme 1Cbz-GlyBoc-L-5-HO-Nle-OHScheme 4no
77Scheme 1Cbz-GlyFmoc-L-HoSer(Me)-OHScheme 4no
78Scheme 1Alloc-GlyBoc-L-HoSer(Bzl)-OHScheme 4no
79Scheme 1Cbz-GlyBoc-L-Leu-OHScheme 4no
80Scheme 1Boc-GlyCbz-L-Asp[N(Me)OMe]Scheme 4The transformation of R3in the aldehyde, then recovery

Example 46 - test radioligand binding human MC5R

Evaluation of binding to the unity of the human MC5R (hMC5R) by moving 125I-labeled NDP-MSH receptor ligand peptide was carried out mainly as described in the specifications produced by Perkin Elmer to accompany them frozen hMC5R membranes (Perkin Elmer catalog number RBXMC5M400UA).

[125I] NDP-MSH: labeled radioactive label self-production and purified by HPLC:

Na125I (0.5 MCI, to 17.4 CI/mg) was added to 50 μl of sodium phosphate (50 mm, pH 7.4) in an Eppendorf tube, pre-coated with IODOGEN. After incubation for 10 minutes in phosphate buffer containing iodine added to NDP-MSH (10 μl of 1 mg/ml) in a separate Eppendorf tube. It was incubated for another 10 minutes. Iodized NDP-MSH was purified by HPLC on Bond SB 300 column, using solvent A: 0.05% of TFA and solvent B: 90% acetonitrile of 0.045% TFA with a linear gradient, 0-67% within 60 minutes.125I NDP-MSH was suirable in 52 minutes after unlabeled starting material (48 minutes), calculated and stored in the freezer. It was used not later than 48 hours as radioactive decay and decomposition of the ligand, which led to significantly reduced the specific binding observed after 72 hours.

Reagents:

Incubation buffer: 25 mm HEPES(N-2-hydroxyethylpiperazine-N-2-econsultancy acid)-KOH (pH 7.0), 1.5 mm CaCl2, 1 mm MgSO4, 0.1 M NaCl, 1 mm 1,10-phenanthroline and 1 tablet proteasome inhibitor Complete the who/100 ml (Roche, catalog number 1873580).

Frozen membrane PMS Perkin Elmer; catalog number RBXMC5M400UA, 0.4 ml/vial; 400 microspine/vial, 0,78 mg/ml protein concentration.

Tubes of frozen membranes were rapidly thawed immediately before use, diluted in binding buffer and shook. Kept resuspendable membrane on ice until then, until they were added to the wells.

Protocol binding for 400 microspine on the tube:

Tests performed in 96-well polypropylene plates. Membrane (0.78 µg 40 μl of 1:40 dilution in incubation buffer) was added to a [125I] NDP-MSH (0,84 nm; 2200 CI/mmol) and test compounds in a total volume of 140 μl. They were incubated for 1 hour at 37°C. Nonspecific binding was determined using a 3 mm NDP-MSH. The tablet was filtered using a Tomtec harvester cells with GF/A filters (Wallac) (pre-soaked in 0.6% of polyethylenimine) and washed three times with 1.0 ml ice-cold wash buffer (above the incubation buffer without 1,10-phenanthroline and tablets proteasome inhibitor Complete™). The filters were dried in a 37°C oven, put in a bag for samples and added 5 ml Betaplatescint (Wallac). The resulting filters were counted in magazines in Microbeta Trilux (Wallac) for 1 minute. Nonspecific binding only at 5%. Data analysis was performed using GraphPad Prism 4, sadas wavaw competitive binding with single-site model and the constant coefficient of the hill. Used the following equation: Y=Bottom value + (the Upper value - Lower value)/1/10(X-logEC50), where X= log(concentration), and Y = the binding to match with the data.

Example 47 - Activity of selected compounds: binding hMCSR

Typical compounds of this invention were tested for binding in the test hMC5R as in Example 46, as shown in Table 3. Compounds were tested as their triptorelin, or cleaners containing hydrochloride salt or free base.

Table 3
Connection properties
x = <10 μm; XX = <1 μm, xxx = <100 nm
Connection.MS (M+1)fR(minutes)MC5R radioligand IC50
17534,37,66XXX
45579,36,60X
46579,3of 5.83XX
47 569by 5.87XX
48569of 5.83X
495347,27XX
50544,57,42XX
51559,46,59XX
52549,46.42 perXX
53574,5of 7.69XX
54584,57,83XX
55617,7? 7.04 baby mortalityXX
56627,57,11XXX
575827,44XX
58592,4at 7.55XX
59588,48,00XX
60598,48,15XX
61568,17,28XX
62578,37,45XX
63568,15,91X
64622,3of 6.49XX
65613,47,03XX
66603,2of 7.23XXX
67587,27,01X
68593,36,56X
69583,36,38XX
70520,27,40XX
71651,36,85X
72571,17,11XX
73583,36,98XX
74574,28,16X
75548,37,86XXX
76536,2to 6.57XXX
77522,46,72XXX
78598,27,49X
79520,1X
80492,26,16X

Example 48 - Test radioligand binding MC5R using MC receptors from other species

Radioligand binding and testing camp was also performed using membranes and cells expressing MC5R cloned from other species (mouse MC5R membrane from Euroscreen, dog, macaque-rhesus, cynomolgus monkey and Guinea pigs, cloned and expressed from cDNA libraries, as described in Examples 50 and 52. The plasma membrane of the cells tested in radioligand test as in Example 46).

Example 49 - Activity of selected compounds: MC5R other types

Typical compounds of this invention were tested for binding to MC5R from other species, as described in Example 48, the results are shown in Table 4.

Table 4
The binding of selected compounds with MC5R of different types
Connection.human MC5R (membrane) IC50(NM)mouse MC5R (membrane) IC50(nm)MC5R macaque-rhesus (membrane) IC50
1730 nm2300 nm3760 nm

These results demonstrate the selectivity of the compounds of this invention for human MC5R compared to MC5R in other species. Although there is activity in other species, it is significantly reduced compared to human MC5R, which would not be expected, considering the high receptor homology between species.

Example 50 - Test radioligand binding MC1R, MC3R and MC4R person

Tests radioligand binding was performed using commercial or prepared in-house design hMC1R, hMC3R and DMC4R membranes and [125I] NDP-MSH according hMC5R the method in Example 46.

The plasma membrane of its own design prepared from transfected mammalian cells (prepared as in Example 52, using plasmid DNA containing the human MC1R, MC3R or MC4R gene in the plasmid vector with the replication origin of mammal)

Attached to the substrate, the cells were washed with warm buffer saline Khanka (HBSS). 1 ml of cold HBSS was added to each vessel and the cells were describle rubber scraper. Of erased cells were added in 50 ml tube on ice. The tablets were then rinsed twice with 5 ml cold HBSS, and it is also added in p is obliku. The cells were centrifuged at 1000×g for 5 minutes in a bench top centrifuge and the supernatant decantation. The remaining cellular precipitate resuspendable in 0.25 M sucrose. The cell suspension was again centrifuged as before and the precipitate resuspendable in 5 ml of 0.25 M sucrose containing protease inhibitors. Cells are homogenized using a 10-second pulsations Ika a dispersant, followed 30 seconds on ice. Homogenization and incubation on ice was repeated three times. The mixture was then centrifuged at 1260×g for 5 minutes. The supernatant decantation in another centrifuge tube, to which was added a buffer containing 50 mm Tris (Tris(hydroxymethyl)aminomethane), pH 7.4, 12.5 mm MgCl2, 5 mm EGTA (etilenvinilatsetata acid) and protease inhibitors to bring the volume to 30 ml was centrifuged at 30000×g for 90 minutes at 4°C. the Resulting precipitate resuspendable in 1 ml of the above buffer, which also contained 10% glycerol. Took aliquots of membranes in cryoprobes, which were quickly frozen in a bath of dry ice/ethanol before storage at -80°C until until required for use.

Example 51 - selectivity of selected compounds: binding hMCR

Typical compounds of this invention were tested for binding in the test hMC1R, hMCSR, hMC4R and hMC5R, as described in Primero and 50, the results are listed in Table 5.

Table 5
The selectivity of binding hMCR selected compounds
Connection.human MC5R IC50(nm)human MC1R IC50(nm)human MC3R IC50(nm)human MC4R IC50(nm)
1730 nm>nm3050 nm>10000 nm
6650 nm>nm4960 nm>10000 nm

These results demonstrate the selectivity of the compounds of this invention for human MC5R in comparison with other members of the human melanocortin receptor family.

Example 52 - inhibition or stimulation of camp signal in cells expressing MC5R person

Transient transfection of cell lines mammals:

The cell line of mammalian cells human embryonic kidney (SOME 293)contained in the modified poposal Dulbecco environment Needle (DMEM) with 5% embryonic bovine serum, L-glutamine, high glucose and antibiotics/antifungals. The day before transfection cells were Persiani using trypsin/EDTA and seeded into a 75 cm2the vessels so that they were approximately 90% confluent the next day. The next day, the cell medium was replaced with fresh DMEM containing antibiotic/antifungal agent. Approximately 100 µl transfection lipid Turbofectin 8.0 (Origene Technologies, MD, USA) was diluted in 1.0 ml serum not containing antibiotic/antifungal agent OptiMEM in a sterile 15 ml tube and incubated for 5 minutes at room temperature. After incubation, approximately 10-20 μg of plasmid DNA expressing the gene of interest (for example: pCMV6-XL4:Homo sapiens melanocortin 5 receptor (Origene Technologies, MD, USA), diluted in transfection mixture and incubated for a further 30 minutes at room temperature. The solution of DNA/lipid then added drop by drop to the medium covering the cells with a gentle rocking of the vessel. 24 hours after transfection cells were Persiani and sown directly into two 75 cm2vessel and left to recover. 48 hours after transfection cells were collected for use in the test solution for cell dissociation.

Test stimulation of cyclic adenosine monophosphate [camp]:

Cells of SOME 293, temporarily expressing melanocortin MC receptor, were suspended in a stimulating buffer (buffer saline Khanka (HBSS), with 0.1% bovine serum albumin, protease inhibitors and 0.5 mm 3-isobutyl-1-methylxanthines) at 4×106cells/ml 5 ál of cells plus compounds/peptides, as described below, was added to the wells of 384-well the tablet as soon as possible after resuspendable.

For detection of antagonistic activity of the diluted test compounds at varying concentrations in a stimulating buffer in a fourfold concentrate and added to 2.5 μl in the wells containing cells. 2,5 ál four times the desired concentration of NDP-MSH or alpha-MSH was added to all wells containing compounds. The negative control wells contained twice concentrated NDP-MSH or alpha-MSH separately without a connection.

For detection of antagonistic activity of the diluted test compounds at varying concentrations in a stimulating buffer in double concentrate and added 5 μl to the wells containing cells. The positive control wells contained only NDP-MSH or alpha-MSH (without connections) in double concentrate.

Wells monitoring the basal level (camp) contained only stimulating buffer (without agonist or connections). The tablet included well-known concentration camp (standard is you) in the stimulus buffer, but the cells in these wells was not added. The tablet is then incubated for 30 minutes at 37°C with mild agitation. After incubation added 10 ál lyse buffer (10% tween-20, 1 M HEPES, 0.1% of BSA (bovine serum albumin), protease inhibitors, ddH2O (double-distilled water)) to all wells subject to measurement. Discovery camp then performed using a set of Alphascreen cAMP (Perkin Elmer, USA), as briefly described below. Breeding 10 ál pellet acceptor/ml lyse buffer prepared in low light conditions. 5 µl of the diluted granules acceptor was added to each well being measured, the tablet then incubated for 30 minutes at room temperature in the dark with careful agitation. In low light conditions donor pellets were diluted in 10 ál/ml lyse buffer, to which was added to 0.75 ál of biotinylated camp/ml lyse buffer. This mixture was allowed to incubated for 30 minutes at room temperature (in the dark) before continuing the test. After incubation, 5 µl/ml of a mixture of biotinylated camp/donor granules were added per well in low light conditions and the plate incubated in the dark at room temperature for an additional hour. Tablets read on a tablet reader Envision (Perkin Elmer) after 1 hour and ~16 hours incubate is. The concentration of camp in the cells was determined using the 'standard curve', derived from the results of known concentrations of camp, as described below.

Each analytical tablet contained a standard curve of known concentrations of camp in 10-fold dilutions. It is an essential part of the analysis, as there is a high mejplanetnye variability. Tablets read on megamarketinccom tablet reader Envision equipped Alphascreen technology, and raw data were imported into the software GraphPad Prism 4 (GraphPad, USA) for analysis. Curve adjusted to known concentrations using non-linear regression, in particular using a sigmoidal equation "dose - response" (Y = Lower value + (the Lower the value + (the Upper value-Lower value)/1+10logEC50-X), where the equation shows the response as a function of logarithm of concentration. X represents the logarithm of the concentration of peptide/compound, and Y is the response. Also in this equation are considered lower plateau, the top plateau of the curve and EC50(effective concentration, 50%)

Example 53 - Activity of selected compounds: hMC5R

Typical compounds of this invention were tested for agonism or antagonism hMC5R as described in Example 52, the results are listed in Table 6.

Table 6
Agonism and antagonism hMC5 selected connections
Connection.human MC5R EU50(camp, agonism) (nm)human MC5R IC50(camp, the antagonism of 10-6M alpha-MSH) (nm)
17>100006000
66>10000600

Links

Andersen, G.N.; Hagglund, M.; Nagaeva, O.; Frangsmyr, L.; Petrovska, R.; Mincheva-Nilsson,

L.; Wikberg, J.E.S. Scand. J. Immunol. 2005, 61, 279-284 "Quantitative measurement of

the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin

peptide gene expression in substes of human peripheral blood leukocytes" Barrett, P.; MacDonald, A.; Helliwell, R.; Davidson, G.; Morgan, P.J. Molec. Endocrin. 1994, 12,

203-213 "Cloning and expression of a new member of the melanocyte-stimulating

hormone receptor family" Bataille, V.; Snieder, H.; MacGregor, A.J.; Sasieni, P.; Spector, T.D. J. Invest. Dermatol. 2002,

119, 1317-1322 " The Influence of Genetics and Environmental Factors in the

Pathogenesis of Acne: A Twin Study of Acne in Women Bhardwaj, S.S.; Rohrer, IE; Arndt, K.A. Semin. Cutan. Med. Surg. 2005, 24, 107-112 "Lasers

and light therapy for acne vulgaris" Bohm, M.; Luger, T.A.; Tobin, D.J.; Garcia-Borron, J.C. J. Invest. Dermatol. 2006, 126, 1966-

1975 "Melanocortin Receptor Ligands: New Horizons for Skin Biology and Clinical

Dermatology" Buggy, J.J. Biochem J. 1998, 331, 211 to 216 "Binding of α-melanocyte-stimulating hormone to its

G-protein-coupled receptor on B-lymphocytes activates the Jak/STAT pathway" Burke, V.M.; Cunlife, W.J.; Br. J. Dermatol. 1984, 112 124-126 " Oral spironolactone therapy

for female patients with acne, hirsutism or androgenic alopecia" Caldwell, H.K.; Lepri, J.J. Chem. Senses 2002, 27, 91-94 "Disruption of the fifth melanocortin

receptor alters the urinary excretion of aggression-modifying pheromones in male house

mice" Cerda-Reverter, J.M.; Ling, M.K.; Schioth, H.B.; Peter, R. E. J. Neurochem. 2003, 1354-1367

"Molecular cloning, characterization and brain mapping of the melanocortin 5 receptor in

goldfish" Chen, W.; Kelly, M.A.; Opitz-Araya, X.; Thomas, R. E.; Low, M.J.; Cone, R.D. Cell, 1997, 91,

789-798 "Exocrine gland dysfunction in MC5-R-deficient micee: evidence for coordinated

regulation of exocrine gland function by melanocortin peptides" Chhajlani, V.; Muceniece, R.; Wikberg, J.E.S. BBRC 1993, 195, 866-873 "Molecular Cloning of

a Novel Human Melanocortin Receptor" Clarke, S.B.; Nelson, M.; George, R.E.; Thiboutot, D.M. Dermatol. Clin. 2007, 25, 137-146

"Pharmacologic Modulation of Sebaceous Gland Activity: Mechanisms and Clinical

Applications.

Cordain, L. Sem. Cut. Med Surg. 2005, 24, 84-91 "Implications for the Role of Diet in Acne Cotterill, J.A.; Cunliffe, W.J.; Williamson, B. Brit. J. Dermatol. 1971, 85, 93-94 "Severity of Acne

and Sebum Excretion Rate"

Danby, F.W. J. Am. Acad. Dermatol. 2005, 52, 1071-1072 "Why we have sebaceous glands" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L.; Zhao, B. WO 03/040117 15 May 2003a "Novel 1,2,4-thiadiazole

derivatives as melanocortin receptor modulators" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L,; Zhao, B. WO 03040118A1 15 May 2003b "Novel 1,2,4-thiadiazolium

derivatives as melanocortin receptor modulators" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L.; Zhao, B. 2003 US/0162819A1 Aug 28 2003 "Novel 1,2,4-thiadiazolium

derivatives as melanocortin receptor modulators" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L.; Zhao, B. 2003 US/0176425A1 Sep 18 2003d "Novel 1,2,4-thiadiazole

derivatives a melanocortin receptor modulators" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L.; Zhao, B. 2006 US/0030604A1 Feb 9 2006 "Novel 1,2,4-thiadiazolium

derivatives as melanocortin receptor modulators" Eisinger, M.; Fitzpatrick, L.J.; Lee, D.H.; Pan, K.; Plata-Salaman, C.; Reitz, A.B.; Smith-

Swintosky, V.L.; Zhao, B. 2006 US/0128772A1 Jun 15 2006b "Novel 1,2,4-thiadiazole

derivatives as melanocortin receptor modulators" Fathi, Z.; Iben, L.G.; Parker, E.M. Neurochemical Res. 1995, 20, 107-113 "Cloning, Expression,

and Tissue Distribution of a Fifth Melanocortin Receptor Subtype" Follador, I.; Campelo, L. Expert Rev. Dermatol. 2006, 1 181-184 "Impact of acne on quality of

life Fong, T.M.; Van der Ploeg, LH.T.; Huang, R.-R.C. US 6645738B1 Nov 11 2003 "DNA

molecules encoding the melanocortin 5 receptor protein from rhesus monkey" Gantz, I.; Shimoto, Y.; Konda, Y.; Miwa, H.; Dickinson, C.J.; Yamada, T. BBRC 1994, 200,

1214-1220 "Molecular cloning, expression and characterization of a fifth melanocortin

receptor" Goldstein, J.A.; Socha-Szott, A.; Thomsen, R.J.; Pochi, P.E.; Shalita, A.R.; Strauss, J.S. Am. J.

Dermatol. 1982, 6, 760-765 "Comparative effect of isotretinoin and etretinate on acne and

sebaceous gland secretion" Goodfellow, A.; Alaghband-Zadeh, J.; Carter, G.; Cream, J.J.; Holland, S.; Scully, J.; Wise, P.

Brit. J. Dermatol. 1984, 111, 209-214 "Oral spironolactone improves acne vulgaris and

reduces sebum excretion" Goulden, V.; Mcgeown, C.H.; Cunliffe, W.J. Brit. J. Dermatol. 1999, 141, 297-300 "Familial Risk

of Adult Acne: A comparison between first-degree realatives of affected and unaffected

individuals"

Graefe, T.; Wollina, U.; Schuiz, H.-J.; Burgdorf, W. Dermatology 2000, 200, 331-333 "Muir-Torre

Syndrome - Treatment with Isotretinoin and Interferon Alpha-2a Can Prevent Tumour

Development Griffon, N.; Mignon, V.; Facchinetti, P.; Diaz, J.; Schwartz, J.-C.; Sokoloff, P. BBRC 1994, 200,

1007-1014 "Molecular cloning and characterization of the rat fifth melanocortin receptor" Gupta, A.K.; Bluhm, R. Journal of the European Academy of Dermatology and Venereology

2004 18:1 13"Seborrheic dermatitis" Haitina, T.; Klovins, J.; Andersson, J.; Fredriksson, R.; Lagerstrom, M.C.; Larhamar, D.;

Larson, E.T.; Schioth, H.B. Biochem. J. 2004, 380, 475-486 "Cloning, tissue distribution,

pharmacology and three-dimensional modelling of melanocortin receotors 4 and 5 in

rainbow trout suggest a close evolutionary relationships of these subtypes" Harper, J.C. Semin. Cutan. Med. Surg. 2005, 24, 103-106 "Hormonal Therapy for Acne using

oral contraceptive pills Harris, H.H.; Downing, D.T.; Stewart, M.E.; Strauss, J.S. J. Am. Acad. Dermatol. 1983, 8, 200-

203 "Sustainable rates of sebum secretion in acne patients and mayched normal controls Hatta, N.; Dixon, C.; Ray, A.J.; Phillips, S.R.; Cunliffe, W.J.; Dale, M.; Todd, C.; Meggit, S.;

Birch-Machin, M.A.; Rees, J.L. J. Invest. Dermatol. 2001, 116, 564-570 "Expression,

candidate gene, and population studies of the melanocortin 5 receptor" Houseknecht, K.L; Robertson, A.S.; Xiao, X. 2003 US/0110518A1 Jun 12 2003 "Melanocortin-5

receptor sequences and uses thereof" Huang, R.-R.C.; Singh, G.; Van der Ploeg, L.H.T.; Fong, T.M. J. Receptor & Signal

Transduction Res. 2000, 20, 47-59 "Species-dependent pharmacological properties of the

melanocortin-5 receptor" Ide, F.; Shimoyama, I.; Hone, N.; Kaneko, T.; Matsumoto, M. Oral Surg. Oral Med. Oral Pathol.

Oral Radiol. Endod. 1999, 87, 721-724 "Benign lymphoepithelial lesion of the parotid gland

with sebaceous differentiation" Jeong, S.K.; Hwang, S.W.; Choi, S.Y.; An, J.M.; Seo, J.T.; Zouboulis, C.C.; Lee, S.H. J.

Investigative Dermatol. 2007, 127, pS72 "Intracellular calcium mobilization is mediated by

the melanocortin receptors in SZ95 sebocytes" (Abstract 431, Society for Investigative

Dermatology, May 2007, Los Angeles CA) Jih, M.H-; Friedman, P.M.; Goldberg, L.H.; Robles, M.; Glaich, A.S.; Kimyai-Asadi, A.J. Am.

Acad. Dermatol. 2006, 55, 80-87 "The 1450-nm diode laser for facial inflammatory acne

vulgaris: Dose-response and 12-month follow-up study". Jones, D.H.; King, K.; Miller, A.J.; Cunliffe, W.J. Brit. J. Dermatol. 1983, 108, 333-343 "A dose-response study of 13-cis-retinoic acid in acne vulgaris" Kirn, K.S-; Marklund, S.; Rothschild, M.F. Animal Genetics 2000, 31, 230-231. "The porcine

melanocortin-5-receptor (MC5R) gene: polymorphisms, linkage and physical mapping"

King, K.; Jones, D.H.; Daltrey, D.C.;Cunliffe, W.J. Brit. J. Dermatol. 1982, 107, 583-590 "A

double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and

microbial population"

Kligman, A.M. Brit. J. Dermatol. 1963, 75, 307-319 "The uses of sebum" Klovins, J.; Haitina, T.; Ringholm, A.; Lowgren, M.; Fridmanis, D.; Slaidina, M.; Stier, S.;

Schioth, H.B. Eur. J. Biochem. 2004, 271, 4320-4331 "Cloning of two melanocortin (MC)

receptors in Sunny dogfish" Kruse, R.; Rdtten.A.; Schweiger, N.; Jakob, E.; Mathiak, M.; Propping, P.; Mangold, E.;

Bisceglia, M; Ruzicka, T.J. Invest. Dermatol. 2003, 120, 858-864 "Frequency of

Microsatellite Instability in Unselected Sebaceous Gland Neoplasias and Hyperplasias" Labbe, 0.; Desarnaud, F.; Eggerickx, D.; Vassart, G.; Parmentier, M. Biochem. 1994, 33, 4543-

4549 "Molecular Cloning of a mouse melanocortin 5 receptor gene widely expressed in

peripheral tisssues" Ling, M.K.; Hotta, E.; Kilianova, Z.; Haitina, T.; Ringholm, A.; Johansson, L; Gallo-Payet, N.;

Takeuchi, S.; Schioth, H.B. Brit. J. Pharmacol. 2004, 143, 626-637 "The melanocortin

receptor subtypes in chicken have high preference to ACTH-derived peptides" Makrantonaki, E.; Zouboulis, C.C. Brit. J. Dermatol. 2007, 156, 428-432 "Testosterone

metabolism to 5a-dihydrotestosterone and synthesis of sebaceous lipids is regulated by

the peroxisome prol iterator-activated receptor ligand linoleic acid in human sebocytes" Mariappan, M.R.; Fadare, O.; Jain, D. Arch. Pathol. Lab. Med. 2004, 128, 245-246 "Sebaceous

Differentiation in Salivary Glands" Mallon, E.; Newton, J.N.; Klassen, A.; Stewart-Brown, S.L; Ryan, T.J.; Finlay, A.Y. Brit. J.

Dermatol. 1999, 140, 672-676 "The quality of life in acne: a comparison with general

medical conditions using generic questionanaires" Marqueling A.L; Zane, L.T. Semin. Cutan. Med. Surg. 2005, 24, 92-102 "Depression and

Suicidal Behavior in Acne Patients Treated with Isotretinoin: A Systematic Review" Morgan, C.; Thomas, R. E.; Ma, W.; Novotny, M.V.; Cone, R.D. Chem. Senses 2004a, 29, 111-

115 "Melanocortin-5 receptor deficiency = MKD reduces a pheromonal signal for aggression in

male mice Morgan, C.; Thomas, R.E.; Cone, R.D. Horm. Behav.2004b, 45, 58-83 "Melanocortin-5

receptor deficiency = MKD promotes defensiv behaviour in male mice" Morgan, C.; Cone, R.D. Behaviour Genetics 2006, 36, 291-300 "Melanocortin-5 receptor

deficiency = MKD in mice blocks a novel pathway influencing pheromone-induced aggression" Mourelatos, K.; Eady, E.A.; Cunliffe, W.J.; dark, S.M.; Cove, J.H. Brit. J. Dermatol. 2007, 156,

22-31 "Temporal changes in sebum excretion and propionibacterial colonization in

preadolescent children with and without acne"

Nelson, A.M.; Gilliland, K.L; Cong, Z.; Thiboutot, D.M. J. Investigative Dermatol. 2006, 126, 2178-2189 "13-c/s-Retinoic Acid Dosage Apoptosis and Cell Cycle Arrest in Human SEB-

1 Sebocytes" Phan, J.; Kanchanapoomi, M.; Liu, P.; Jalian, H.; Gilliland, K.; Nelson, A.; Thiboutot, D.; Kirn, J.

J. Investigative Dermatol. 2007, 127, pS126 "P. acnes dosage inflammation via TLR2 and

upregulates antimicrobial activity in sebocytes" (Abstract 754, Society for Investigative

Dermatology, May 2007, Los Angeles, CA)

Pierard, G.E.; Pierard-Franchimont, T.L. Dermatologica 1987, 175, 5-9 "Seborrhoea in Acne-Prone and Acne-Free Patients" Plewig G, Jansen T. Seborrheic dermatitis. In: Freedberg IM, EisenAZ, Wolff K, Austen KF,

Goldsmith LA, Katz Sl, Fitzpatrick TB,(Eds). Dermatology in General Medicine, 5th ed.

New York: McGraw Hill, 1999: 1482-1489 Pochi, P.E.; Strauss, J.S. J. Invest. Dematol. 1964, 43, 383-388 "Sebum production, casual

sebum levels, titratable acidity of sebum and urinary fractioonal 17 under red light conditions excretion in

males with acne Porter, A.M.W. J. Royal Soc. Med. 2001, 94, 236-237 "Why do we have apocrine and

sebaceous glands" Ringholm, A.; Fredriksson, R.; Poliakova, N.; Yan, Y.-L; Postlethwait, J.H.; Larhammar, D.;

Schioth, H.B. J. Neurochem. 2002, 82, 6-18 "One melanocortin 4 and two melanocortin 5

receptors from zebrafish show remarkable conservation in structure and pharmacology" Smith, K.R.; Nelson, A.; Cong, Z.; Thiboutot, D. J. Investigative Dermatol. 2007a, 127, pS68

"Iron status affects human sebocyte survival (408 Abstract, Society for Investigative

Dermatology, May 2007, Los Angeles, CA) Smith, R.N.; Mann, N.J.; Braue, A.; Makelainen, H.; Varigos, G.A. J. Am. Acad. Dermatol.

2007b, 57, 247-256 "The effect of a high-protein, low glycemic-load diet versus a

conventional, high glycemic-load diet on biochemical paameters associated with acne

vulgaris: A randomized investigator-masked, controlled trial" Shuster, S. Lancet 1976, 7973, 1328-1329 "Biological purpose of acne" Taylor, A.; Namba, K. Immunologyy Cell/about/. 2001, 79, 358-367 "In vitro induction of

CD25+CD4+ regulatory T cells by the neuropeptide alpha-melanocyte-stimulating

hormone (α-MSH)" Thiboutot, D.; Sivarajah, A.; Gilliland, K.; Cong, Z.; Clawson, G. J. Invest. Dermatol. 2000, 115,

614-619 "The melanocortin 5 receptor is expressed in human sebaceous glands and rat

preputial cells"

Thody, A.J.; Shuster, S. Nature 1973, 245, 207-209 "Possible role of MSH in the mammal" Thody, A.J.; Cooper, M.F.; Bowden, P.E.; Shuster, S. J. Endocrinol. 1975a, 67, 18P-19P "The sebaceous gland response to α-melanocyte-stimulating hormone and testosterone"

Thody, A.J.; Shuster, S.J. Endocrinol. 1975 b, 64, 503-510 Control of sebaceous gland function

in the rat by α-melanocyte-stimulating hormone" Thody, A.J.; Goolamali, S.K.; Burton, J.L.; Plummer, N.A.; Shuster, S. Brit. J. Dermatol. 1975 with,

92, 43-47 " Plasma a-MSH levels in acne vulgaris" Wikberg, J.E.S. Exp. Opin. Ther. Patents 2001, 11, 61-76 "Melanocortin receptors: new

opportunities in drug discovery";

Wikberg, J.; Chhajlani, V. US 6448032B1 Sep 10 2002 "Human melanocyte stimulating hormone

receptor polypeptide and DNA Williams, C.; Layton, A.M. Exp. Rev. Dermatol. 2006, 1, 429-438 "Treatment of Acne: an

update"

Yamada, T.; Gantz, I. US 5622860, Apr. 22 1997, "Genes Encoding Melanocortin Receptors" Yaswen, L; Diehl, N.; Brennan, M.B.; Hochgeschwender, U. Nature Med. 1999, 5, 1066-1070

"Obesity on the mouse model of proo-opiomelanocortin deficiency = MKD responds to peripheral

melanocortin" Youn, S.-W.; Park, E.-S.; Lee, D.-H.; Huh, C.-H.; Park, K.-C. Brit. J. Dermatol. 2005, 153, 919-

924 "Does facial sebum secretion really affect the development of acne?" Zhang, L.; Anthonavage, M.; Huang, Q.; Li, W.-H.; Eisinger, M. Ann. N.Y. Acad. Sci. 2003, 994,

154-161 " Proopiomelanocortin peptides and sebogenesis" Zhang, L.; Li, W.-H.; Anthonavage, M.; Eisinger, M. Peptides 2006, 27, 413-420 "Melanocortin-5

receptor: a marker of human sebocyte differentiation" Zouboulis, C.C-; Bohm, M. Exp. Dermatol. 2004, 13, 31-35 "Neurocrine regulation ofsebocytes - a patogenetic link between stress and acne"

Details of certain embodiments described in this invention should not be construed as limitations. Various equivalents and modifications can be made without deviating from the essence and scope of this invention and it is understood that such equivalent embodiments of a part of this invention.

1. The compound of formula (I):

where
Y represents a group of formula -(CR9R10)n-;
X represents-C(=O)-;
Z represents a group of formula -(CR13R14)q-;
R1selected from the group consisting of
(a) C2-C12alkenyl, substituted 4-chlorophenyl; or
(b) C6-C10aryl, optionally substituted by one or two halogen atoms;
R2and R3represent H;
R4selected from the group consisting of H, C1-C12the alkyl, optionally substituted by hydroxy, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted amino group or a piperidine, C-bound C1-C18heteroaryl selected from pyridine and imidazole, C(=O)R15C(=O)NR16R17and ONR16C(=NR17)NR18R19;
each R5aand R5brepresents H,
each R6, R7and R8independently selected from the group, with the standing of H, C1-C12the alkyl and C6-C18aryl,
each R9and R10represents H;
each R13and R14represents H;
R15represents H,
each R16, R17, R18, R19and R20independently selected from the group consisting of H, C1-C12of alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or
any two of R16, R17taken together with the atoms to which they are attached, form a cyclic group containing 5 carbon atoms, or
n = 1;
q is an integer selected from the group consisting of 1, 2, 3, 4 and 5;
r is 1;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R1represents a C6-C10aryl, optionally substituted by one or two halogen atoms.

3. The compound according to claim 2, where R1represents phenyl, optionally substituted by one or two halogen atoms.

4. The compound according to claim 2, where R1represents naphthyl, optionally substituted by one or two halogen atoms.

5. The compound according to claim 1, where R1represents a C2-C12alkenyl, substituted 4-chlorophenyl.

6. The compound according to any one of claims 1 to 5, where q is selected from the group consisting of 1, 2, 3 and 4.

7. The compound according to any one of claims 1 to 5, where q is 1.

8. The connection is the yubom one of claims 1 to 5, where q equals 2.

9. The compound according to any one of claims 1 to 5, where q equals 3.

10. The compound according to any one of claims 1 to 5, where q is 4.

11. The compound according to any one of claims 1 to 5, where R4selected from the group consisting of H, C3-C12cycloalkyl, C1-C12of alkyl, C6aryl, optionally substituted amino group or a piperidine, C-linked heteroaryl selected from pyridine and imidazole, C(=O)NR16R17and ONR16C(=NR17)NR18R19.

12. Connection to item 11, where R4represents C(=O)NR16R17.

13. The connection section 12, where R16and R17taken together with the nitrogen atom to which they are attached, form a cyclic group containing 5 carbon atoms.

14. The connection section 12, where each of R16and R17independently selected from the group consisting of H, CH3CH2CH3CH2CH2CH3CH(CH3)2CH2CH2CH2CH3CH(CH3)CH2CH3CH2CH(CH3)2C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

15. The compound according to any one of claims 1 to 5, 12-14, where R7represents H.

16. The compound according to any one of claims 1 to 5, 12-14, where each of R6and R8independently selected from the group consisting of C1-C12the alkyl or C6aryl.

17. The compound according to any one of claims 1 to 5, 12-14, RG is R 6selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, penttila, 2-methylpentyl and phenyl.

18. The connection 17, where R6represents phenyl.

19. The compound according to any one of claims 1 to 5, 12-14, 18, where R8selected from the group consisting of H, methyl, ethyl, isopropyl, propyl, 2-ethylpropyl, 3,3-dimethylpropyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethylbutyl, 2-ethylbutyl, penttila, 2-methylpentyl, hexyl, heptyl, Attila and phenyl.

20. The connection according to claim 19, where R8represents methyl, ethyl or phenyl.

21. The compound according to claim 1, selected from the group consisting of:
N-(((3S,5S)-1-(2,2-diphenylether)-3-(2-(guanidinate)ethyl)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-3-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-4-ylmethyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-N-(((3S,5S)-3-butyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
(E)-N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
N-(((3S,5S)-3-(3-amino-3-oxopropyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-(cyclohe Silmaril)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-N-(((3S,5S)-3-(cyclohexylmethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1,4-diazepan-5-yl)methyl)acrylamide;
N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-phenethyl-1,4-diazepan-5-yl)methyl)acrylamide;
N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-3-(2-cyclohexylethyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)acrylamide;
(N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
(E)-N-(((3S,5S)-3-benzyl-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
(E)-N-(((3S,5S)-3-((1H-imidazol-4-yl)methyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(pyridine-2-ylmethyl)-1,4-diazepan-5-yl)methyl)acrylamide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(pyridine-2-ylamino)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide;
(E)-3-(4-chlorophenyl)-N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-oxo-2-(piperidine-1-yl)ethyl)-1,4-diazepan-5-yl)methyl)acrylamide;
6-chloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)p is sawdust)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
3,4-dichloro-N-(((3S,5S)-2-oxo-3-(3-oxo-3-(piperidine-1-yl)propyl)-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide;
(E)-N-(((3S,5S)-3-(2-aminobenzyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-3-(4-chlorophenyl)acrylamide;
N-(((3S,5S)-3-(2-aminobenzyl)-1-(2,2-diphenylether)-2-oxo-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-butyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthalide;
6-chloro-N-(((3S,5S)-3-isopentyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-1-(2,2-diphenylether)-2-oxo-3-(2-(piperidine-1-yl)benzyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-(3-(butyl(methyl)amino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-(3-(cyclohexylamino)-3-oxopropyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
6-chloro-N-(((3S,5S)-3-(2-cyclohexylethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
6-chloro-N-(((3S,5S)-3-hexyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
6-chloro-N-(((3S,5S)-3-(4-hydroxybutyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
6-chloro-N-(((3S,5S)-3-(2-methoxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide;
N-(((3S,5S)-3-(2-(benzyloxy)ethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-6-chloro-2-naphthalide; and
6-chloro-N-(((3S,5S)-3-isobutyl-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)-2-naphthalide.

22. The compound according to claim 1, where the specified connection is out is a 3,4-dichloro-N-(((3S,5S)-3-(2-hydroxyethyl)-2-oxo-1-((S)-2-phenylbutyl)-1,4-diazepan-5-yl)methyl)benzamide.

23. Pharmaceutical composition for treating 5R-bound States containing compound according to any one of claims 1 to 22 and a pharmaceutically acceptable carrier, diluent or excipient.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: described are novel crystalline forms of (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one: Form I, Form II, Form III, Form IV and Form VI, each characterised by X-ray powder diffraction (XRPD) data and infrared spectrum data, and a method of producing crystalline Form VI. The preferred form is Form VI, which has antifungal and antimicrobial activity, has the least impurity content, the highest uniform quality of the product, the highest uniform physical characteristics, including colour, rate of dissolution, easiness of handling and longest stability compared to the amorphous form.

EFFECT: improved properties of the compound.

19 cl, 22 ex, 25 tbl, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formulas

and or pharmaceutically acceptable salts thereof, wherein the values R1-R13, Ra, Rb, Rc, Rd, Rf, Rq, n are presented in the patent claim possessing the properties of protein p53 activator.

EFFECT: compounds may be used in treating cancer and diseases caused by a fungal, bacterial or parasitic infection, eg malaria.

16 cl, 38 dwg, 12 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazolone derivatives used as drugs being kinase inhibitors, described by formula (I), wherein; R1 represents a C1-C3 alkyl radical or a hydrogen atom, and/or an aryl radical, Ar1 is specified in or , R represents the group R2-S-, R2 is thereby specified in the radicals like T1-(CH2)n, wherein n=0, 1, 2 or 3, and T1 represents a metal, vinyl, alkyl, alkynyl, nitrile, C3- or C4-cycloalkyl radical, hal, Z-O, Z-CO, wherein Z represents C1-C3 alkyl or hal, hal represents F, Cl, Br or I, or the group CCl3, or the group R3-NH-, R3 is thereby specified in the radicals like T2-(CH2)n, wherein n=0, 1 or 2, and T2 represents a metal, vinyl radical, Z-O, Z-CONH-, -CH-(OZ)2, ZCO, wherein Z represents H or C1-C4 linear or branched alkyl, NH2, C3-cycloalkyl, aryl, substituted aryl, or R3 represents H, or the group R4-CONH-, R4 is thereby specified in C3-C5 branched alkyl, or Ar2- or Ar2-3-, Ar2 is specified in a phenyl radical, substituted phenyl or benzodioxolyl; and have IC50 less than 5 mcM.

EFFECT: invention also refers to pharmaceutical compositions based on the compounds of formula I for treating neurodegenerative disorders and to using these compounds as DYRKIA inhibitors.

11 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I) presented below wherein the radicals and symbols have the values presented in the patent claim, and/or to its racemate, enantiomer, diastereomers or its pharmaceutically acceptable salts and/or esters. The invention also refers to a method for preparing it, using it in preparing a drug preparation and to drug preparations containing the compound of formula (I).

EFFECT: compound of formula has analgesic action and may be used as an active compound for pain management.

20 cl, 3 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: disclosed is an agent which is one of the derivatives of N-substituted 1,4-diazabicyclo[2.2.2.]octane, which exhibits antiviral activity on DNA viruses. The disclosed agent can be used in veterinary and healthcare.

EFFECT: higher antiviral activity towards DNA viruses.

6 dwg, 3 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R1 is: C1-6alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; halo-C2-6alkenyl; C3-7cycloalkyl; C3-7cycloalkyl-C1-6alkyl; C1-6alkyl-C3-6cycloalkyl-C1-6alkyl; C1-6alkoxy; C1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C1-6alkyl; phenyl-C1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C1-3alkyl; R2 is: hydrogen or C1-6alkyl; and each Ra and Rb is independently: hydrogen; C1-6alkyl; C1-6alkoxy; halo; hydroxy or oxo; or Ra and Rb together form C1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R1 is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH2)q-S(O)rRf; -(CH2)q-C(=O)-NRgRh; -(CH2)q-N(Rf)-C(=O)-Ri or -(CH2)q-C(=O)-Ri; where q is 0, r is 0 or 2, each Rf, Rg and Rh is independently hydrogen or alkyl, and each Ri is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C4-C7-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -ORa, -NRbH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where Ra is hydrogen or C1-6alkyl, Rb is C1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

EFFECT: obtaining novel compounds which can be used in medicine to treat depression, anxiety or both.

14 cl, 1 tbl, 28 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted N-phenylpyrrolidinyl methylpyrrolidine amides of formula , where R, R1, R2 and R3 are identical or different and independently denote H, (C1-C4)alkyl, CF3; R4 denotes phenyl, cyclohexyl, pyridinyl, furanyl, isoxazolyl, quinolinyl, naphthyridinyl, indolyl, benzoimidazolyl, benzofuranyl, chromanyl, 4-oxo-4H-chromenyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxolyl and 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]][1,4]diazepinyl; where said R4 is optionally substituted one to more times with a substitute selected from halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, CF3, hydroxymethyl, 2-hydroxyethylamino, methoxyethylamide, benzyloxymethyl, piperidinyl, N-acetylpiperidinyl, pyrrolyl, imidazolyl, 5-oxo-4,5-dihydropyrazolyl; or pharmaceutically acceptable salt thereof or enantiomer or diastereomer thereof.

EFFECT: compounds have modulating activity on histamine H3 receptor, which enables use thereof to prepare a pharmaceutical composition.

10 cl, 3 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula which includes treating a diamine of formula in an aprotic solvent with an oxadiazole of formula , which, in the presence of a water-binding agent in a mixture with a tertiary amine, at temperature of 10-100°C and pressure of 1-6 bar, is converted to a compound of formula which, without separation, is then converted by hydrogenation and addition of para-toluene sulphonic acid and ammonia to an amidine of formula 1.

EFFECT: method enables to conduct synthesis without separating the intermediate product and replacing the solvent, avoids use of hot filtration and increases output of the product.

3 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I

,

wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to form A of N-(4-(7-azabicyclo[2.2.1]heptan-7-yl-)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide, where said form A is characterised by peak at approximately 7.9 degree, peak at approximately 11.9 degree, peak at approximately 14.4 degree and peak at approximately 15.8 degree in powder X-ray. Invention also relates to pharmaceutical composition and set based on said form A, application of form A, method of CFTR modulation.

EFFECT: obtained is novel form of quinoline derivative, which is modulator of CFTR activity.

12 cl, 3 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to piperidine compounds of formula and their pharmaceutically acceptable salts, based on them pharmaceutical composition, treatment method with therein application and therein application for treatment of gastrointestinal diseases. In formula (I) m represents integer number 1 or 2; n represents integer number from 0 to 2, A is selected from phenyl group and benzimidazole group, where phenyl group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, aminogroup and halogen, and benzimidazole group is substituted with one or more groups, independently selected from C1-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxygroup, C3-C7 cyclic alkyl group, aminogroup, halogen and oxogroup; X represents hydroxyl or OCONR1R2, where R1 and R2 are independently selected from hydrogen and C1-C6 linear or branched alkyl group, or R1 and R2 form 5-7-membered heterocyclic ring or 3,5-dimethylpiperidine ring, together with nitrogen atom, to which they are attached, and B is selected from phenyl group, phenoxygroup, thienyl group and naphthyl group, where phenyl group, phenoxygroup, thienyl group or naphthyl group is substituted with one or more groups, independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 linear or branched alkyl group and C1-C6 linear or branched alkoxygroup.

EFFECT: obtaining novel compounds.

25 cl, 3 tbl, 163 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound, which contains pyridine ring, represented by formula (1) , where R0 represents C1-6alkoxygroup, C1-6alkoxy-C1-6alkoxygroup, C1-6alkoxy-C1-6alkyl group, 1,3-dioxan-2-yl-C1-6alkyl group or group CR01C(=NOR02) (where each of R01 and R02 independently represents C1-6alkyl group), R1 represents C1-2 alkoxycarbonyl group, acetyl group or benzoyl group, which can be substituted with nitrogroup, X represents halogen atom, and n represents quantity of X substituents and equals integer number from 0 to 3, and when n equals 2 or more, X substituents can be similar or different from each other, which can be synthesised in industrially profitable way and used as intermediate compound for obtaining tetrazolyloxime derivatives which demonstrate fungicidal activity.

EFFECT: industrially profitable methods of obtaining tetrazolyloxime derivatives are described.

10 cl, 3 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline form of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-e-[2-(pyridin-2-yl)ethenyl]indazole, which can prove to be efficient in treatment of abnormal growth of cells. Said crystalline form is in fact pure polymorph of XLI form and has powder X-ray image including peak at diffraction angle (2θ) 6.0±0.1 and additionally including, at least, one peak at diffraction angle (2θ), selected from 11.5±0.1, 21.0±0.1 and 26.9±0.1. Said crystalline form can also include peaks at diffraction angle (2θ) 11.9±0.1, 15.6±0.1, 16.2±0.1, 16.5±0.1, 22.8±0.1 and 23.1±0.1. Peaks on powder X-ray image are measured with application of CuKα radiation (=1,54056 Å). In addition said crystalline form has NMR spectrum in solid body, including 13C chemical shifts at 150.1±0.2 and 27.5±0.2 ppm.

EFFECT: crystalline form possesses improved light resistance and has more correct shape of crystals Invention also relates to pharmaceutical composition, which includes said crystalline form.

6 cl, 16 dwg, 15 tbl, 7 ex

Up!