3-carbamoyl-2-pyridone derivatives

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

 

The invention relates to derivatives of 3-carbarnoyl-2-pyridone having agonistic activity against the cannabinoid receptors, to pharmaceutical compositions and medical application.

Cannabinoid (CB) was opened in 1960 as the main active substance in marijuana, which when administered operates primarily through the Central nervous system, causing delusions, euphoria, disorientation in time and space, etc.

In 1990 it was found that in the Central nervous system, for example, in the brain, there is a cannabinoid receptor type 1 (CB1), seven transmembrane sites which are associated with G-protein, and, in addition, that agonists of this receptor involved in the implementation of higher order brain function by inhibiting the release of neurotransmitters through the regulation system of signal transmission in the cell, for example, by regulating the activity of adenylate cyclase, Ca2+channel types N and P/Q, the activation of voltage gated K+channel and activation of the kinase MAR via this receptor, in addition, it was found that the receptor exists also in peripheral tissues and has minor activity in systems that are not related to the nervous system, for example, it has anti-inflammatory activity and softens albernoa hypotension and muscle spasm. Also found in immune tissues such as the spleen, there is a cannabinoid receptor type 2 (CB2), and that agonists of this receptor inhibit the activation of immune cells or inflammatory cells, showing immunosuppressive activity, anti-inflammatory activity and analgesic activity (non-patent publication 1). After the discovery of these facts began an intensive study of the potential application of agonists of cannabinoid receptors in medicine.

The use of cannabinoid receptors in the quality of medicines already described, for example, for treatment of allergic diseases use quinolone derivatives (patent publications 1, 2, 3, 4 and 5), derivatives of 3,4-dihydroisoquinoline (patent publication 6), pyridone derivatives (patent publication 7) and other quinolone derivatives (patent publication 8). Moreover, in patent publications 10 and 11 described antipruritic activity of these compounds.

Itching is a kind of biological reactions, and the famous itching peripheral and Central itching. For example, an itch, including inflammatory reactions, such as swelling, atopic dermatitis, rash, senile xerosis and contact dermatitis, is a peripheral itch that may occur when you activate nerve endings (receptors itching) sensory nerve is elocon, located on the border of the epidermis and dermis, under the action of the chemical, physical, electrical and other incentives. On the other hand, refractory itching, for example, systemic dermatitis patient with renal failure that occurs after dialysis is considered Central itching caused by binding of an opioid peptide with the receptor.

Drugs currently used to treat itching, include, for example, diphenhydramine, and crotamiton. The first effective as antihistamines swelling and rashes, mediated by histamine, but not effective for other types of itching. The latter also has anti-inflammatory activity in the addition of steroid drugs and is used in ointments for the treatment of itching from eczema and so on, but its mechanism of action is not precisely known.

By the way, atopic dermatitis is a skin disease, usually accompanied by very severe itching and inflammation of skin with atopic location, and a decrease in the barrier function with alternating bumps and hollows. Currently, there are only two types of drugs that reduce inflammation with proven efficacy, namely, steroids for internal and external use and calcineurin-inhibiting drugs,which are called the means with immunosuppressive activity or immunoregulatory means and used for outdoor applications, such as tacrolimus and iridal. However, these medicines have serious disadvantages, such as resistance to steroids in some patients, a variety of systemic and local side effects and return of symptoms after discontinuation of steroids. Moreover, although the immunoregulatory agent for external use, mechanism of action which is very different from the mechanism of action of steroids used for outdoor applications, is a highly effective, especially in the case of exanthema in the face and neck, it has a characteristic stimulating effect on the skin, it is prohibited to apply, especially on the surface of bullosa observed in atopic dermatitis and the like, and its application requires detailed documentation and attention. These drugs against atopic dermatitis provide symptomatic treatment, which consists in a moderate reduction of symptoms, but do not lead to regression of the disease and eliminate its causes (non-patent publication 2).

On the other hand, itching refers to the sensation that causes a desire to scratch, rip off, blowing, etc. that is accompanied by itching and refers to the signs of atopic dermatitis, which is more than just complicate the patient's life. That is, if the itch, by which is meant not only scabies and from which the CSO is most damaging to the patient, to reduce or mitigate, this will lead to the improvement of QOL (quality of life), but also may be an indirect effect, namely, that the state of the exanthema is improved by decreasing the desire to itch. In light of the above, it is desirable to develop a safe antipruritic agent, which will reduce the amount of drugs : symptomatic treatment of or completely eliminate it, which is efficient and can be transported with a long introduction.

As a variant of such a medicinal product is indicated remedy for external application, which acts only on the area of application and allows you to avoid systemic effects, which occur when an internal application. That is, in contrast to funds for oral administration, which are absorbed from the digestive tract, appeared percutaneous liniment for external application, which provides absorption of drugs directly into the affected area by release zero order, makes it possible to avoid the effect of the first pass through the liver and dose-dependent systemic side effects, and, in addition, it allows you to adjust the concentration of the drug in the affected area for a long time is about the time, the advantage of this drug is also the possibility of its safe use with common skin diseases, particularly in elderly people, sick people and babies. Actually, although steroid drugs have high anti-inflammatory activity and its attendant antipruritic activity, they are not for oral use except remission severe symptoms. On the other hand, it is well known that the skin has a powerful barrier function for many drugs, so drugs that are effective when administered orally, does not have the desired effectiveness in skin introduction.

The authors of the present invention conducted a thorough investigation, in which it was found that when applying the derived 3-carbarnoyl-2-pyridone, shown below, on the area of skin affected by the disease, specified derivative acts directly on the peripheral cannabinoid receptor, showing excellent antipruritic activity.

Although pyridone derivatives, like the aforementioned compounds of the present invention, are commercially available and are supplied Interbioscreen Corp., Interchim Corp., Asinex Corp. and Ambinter Corp Sarl. as reagents, the pharmacological activity of these compounds n is described.

(Patent publication 1)

International publication No. 99/02499 Avenue

(Patent publication 2)

International publication No. 00/40562 Avenue

(Patent publication 3)

International publication No. 2004/103974 Avenue

(Patent publication 4)

International publication No. 04/103974 Avenue

(Patent publication 5)

International publication No. 04/104000 Avenue

(Patent publication 6)

International publication No. 02/10135 Avenue

(Patent publication 7)

International publication No. 02/053543 Avenue

(Patent publication 8)

International publication No. 03/061699 Avenue

(Patent publication 9)

International publication No. 02/065997 Avenue

(Patent publication 10)

International publication No. 03/035109 Avenue

(Patent publication 11)

International publication No. 03/070277 Avenue

(Non-patent publication 1)

Nature, 1993, vol. 365, p.61-65

(Non-patent publication 2)

The leadership of the Japanese Association of dermatologists for the treatment of atopic dermatitis, 2004, revised edition, “Japanese skin society magazine”, 2004, p. 114-135

Available compounds with agonistic activity against the cannabinoid receptor, in particular, compounds with excellent absorption dermal or oral administration. In particular, offered f is rmaceuticals composition, drugs against atopic dermatitis and pruritus tools, especially antipruritic tools for oral administration and external application, which contain these compounds as the active ingredient.

The authors of the present invention have found, as described below 3-carbarnoyl-2-Spiridonova derivatives, which are active agonists of cannabinoid receptor, have low inhibitory activity against the enzyme (CYP), minor side effects, associated with the Central nervous system, excellent photostability and/or remarkable absorption dermal or oral administration. Moreover, it was found that a pharmaceutical composition which contains the compound as an active ingredient, can be effectively used as a drug against atopic dermatitis, and as an antipruritic means, especially, antipruritic tools for oral administration and external application.

Thus, the present invention relates to:

1) to the compound of formula (I):

where R1means C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents A, C2-Calcaneal or C2-Calciner;

R2OSN which denotes C1-Salkil or C1-Celecoxi C1-Salkil;

R3means C1-Salkil or C1-Celecoxi; or

R2and R3taken together with the adjacent carbon atoms, may form an optionally substituted non-aromatic 5-to 10-membered carbon ring which may be substituted with one group selected from-O-, -S-, -SO - and-SO2-;

R4means hydrogen or hydroxy;

G stands for a group represented by the formula:

where R5means hydrogen or C1-Salkil;

X1means a single bond, C1-Salminen, optionally substituted with one to three substituents selected from the group of substituents B, C2-Calcanean, optionally substituted with one to three substituents selected from the group of substituents B, or C2-Calcinit, optionally substituted with one to three substituents selected from the group of substituents B;

X2means C1-Salminen, which may be substituted by one or two groups-O -, or-NR6-where R6means hydrogen, C1-Salkil or benzyl, and may be optionally substituted with one to three substituents selected from the group of substituents B, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents C, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents C, areldil, optional the part substituted by one or two substituents, selected from the group of substituents C, heteroaryl, optionally substituted by one or two substituents selected from the group of substituents C, or non-aromatic heterocyclyl, optionally substituted by one or two substituents selected from the group of substituents C;

X3means a single bond, C1-Salminen, which can be replaced by a heteroatom and may be optionally substituted with one to three substituents selected from the group of substituents B, C2-Calcanean, optionally substituted with one to three substituents selected from the group of substituents B, C2-Calcinit, optionally substituted with one to three substituents selected from the group of substituents B, or carbonyl;

the group represented by the formula:

means a group selected from groups represented by the formulas:

where Rameans C1-Salkil and n is 0, 1 or 2;

the group represented by the formula:

means a group selected from groups represented by the formulas:

where Rbmeans hydrogen or C1-Salkil; p is 0, 1 or 2; q is an integer from 1 to 4;

Y represents-O-, -S-, -N(R6)-, where R6means hydrogen or C1-Salkil, optionally substituted with one to three substituents selected is passed from a group of substituents D, or a group selected from groups represented by the formulas:

where R7means C1-Salkil; m is 1 or 2;

Z denotes hydrogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, C3-Cal, optionally substituted by one or two substituents selected from the group of substituents C, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C1-Sarkilarini, C6-SLR, optionally substituted with one to three substituents selected from the group of substituents F, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents E, a group represented by the formula: -C(NH2)-NR8-CO-NR8R9where R8each independently mean hydrogen or C1-Salkil, or a group represented by the formula: -C(=W)-R10where R10means C1-Salkil, hydroxys-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituent and, selected from the group of substituents E, hydrazine, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents E; W denotes an oxygen atom or a sulfur atom;

the group of substituents A: halogen, C3-Cicloalchil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and the group represented by formula: -C(=O)-R11where R11means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Say, it is certainly substituted with one to three substituents, selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;

the group of substituents B: halogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents A, C3-Cicloalchil, C2-Salkini, C2-Salminen, which may be substituted by a group-O-, hydroxy, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and the group represented by formula: -C(=O)-R12where R12means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from g is uppy substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;

the group of substituents C: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, oxo, cyano, azide, nitro and phenyl;

the group of substituents D: halogen, C1-Salkil, Halogens-Salkil, C3-Cicloalchil, hydroxy, C1-Sarcoxie, hydroxys-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, carboxy, cyano, azide, nitro, three(C1-Salkil)ammonium, di(C1-Salkil)benzylamine, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, the group represented by formula: -C(=O)-R13where R13means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three mixing what italiani, selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and a group represented by the formula: -O-C(=O)-R14where R14means C1-Salkil, C3-Cicloalchil, C1-Sarcoxie, C3-Styleability, C6-Six, optionally substituted with one to three substituents selected from the group of substituents F, heteroaromatic, optionally substituted with one to three substituents selected from the group of substituents F, amino group, optionally substituted by one or two substituents selected from the group of substituents E, piperidino, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;

the group of substituents E: C1-Salkil, (C1-Salkil)carbonyl, (C1-Celecoxi)carbonyl, (C6-Ser)carbonyl, heteroarylboronic, (amino, optionally substituted by one or two groups of C1-Salkil or C6-Ser)carbonyl, C1-Sarkilarini, C6-Sly and heteroarylboronic;

the group of substituents F: halogen, C1-Salkil, Halogens-Salkil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, methylenedioxy, benzyloxy, carbarnoyl, optionally substituted by one or two groups of C1-Salkil, cyano, azide, nitro, oxo and phenyl;

provided that if-X1-X2-X3-C(=O)-Y-Z stands for a group represented by the formula (II):

R2and R3taken together with the adjacent carbon atoms, form a 6-membered non-aromatic carbon ring;

its pharmaceutically acceptable salt or MES;

2) the compound according to item 1), where R1means C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents A, or C4-Salkini, its pharmaceutically acceptable salt or MES;

3) the compound according to item 1), where R1means n-butyl, isopentyl, 3-methyl-2-butenyl, 4,4,4-tripcomputer, 2-methoxyethyl, cyclohexylmethyl or phenyl, optionally substituted with one to three substituents selected from the group of substituents (F)methyl, its pharmaceutically acceptable salt or MES;

4) the compound according to any one of items 1)-3), where R2means C1-Salkil or C1-Calculate C1-Salkil, and R3means C1-Salkil or C1-Calculate, its pharmaceutically acceptable salt or MES;

5) the compound according to any one of items 1)-3), where R 2means ethyl, n-propyl, isopropyl or methoxymethyl, and R3means methyl, ethyl or metiloksi, its pharmaceutically acceptable salt or MES;

6) the compound according to any one of items 1)-3), where R2and R3taken together with the adjacent carbon atoms, form a non-aromatic 7-10-membered carbon ring, optionally substituted C1-Calcilo, its pharmaceutically acceptable salt or MES;

7) the compound according to any one of items 1)-3), where R2and R3taken together with the adjacent carbon atoms, form a non-aromatic 8-membered carbon ring, its pharmaceutically acceptable salt or MES;

8) the compound according to any one of items 1)to 7), where R4means hydrogen, its pharmaceutically acceptable salt or MES;

9) the compound according to any one of items 1)-8), where R5means hydrogen, its pharmaceutically acceptable salt or MES;

10) the compound according to any one of items 1)to 9), where X1and X3denote a single bond, and X2means linear C1-Salminen, optionally substituted by one or two substituents selected from the group of substituents B, its pharmaceutically acceptable salt or MES;

11) the compound according to any one of items 1)to 9), where X1and X3each independently means a single bond or C1-Salminen, and X2means C3-Sziklahalom the PII, optionally substituted by one or two substituents selected from the group of substituents C, its pharmaceutically acceptable salt or MES;

12) the compound according to any one of items 1)to 9), where X1means a single bond, X3means C1-Sakilan or C2-Calcanean, and X2means heteroaryl, optionally substituted by one or two substituents selected from the group of substituents C, its pharmaceutically acceptable salt or MES;

13) the compound according to any one of items 1)-12), where Y represents-O-, Z denotes hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, its pharmaceutically acceptable salt or MES;

14) the compound according to any one of items 1)-12), where Y represents-N(R6)-, where R6is as defined in paragraph (1), its pharmaceutically acceptable salt or MES;

15) the compound according to any one of items 1)-12), where Y stands for a group represented by the formula:

where m is as defined in paragraph (1), its pharmaceutically acceptable salt or MES;

16) to the compound of formula (II)

where R1Ameans C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents G, C3-Salkini, or C3-Calciner;

R2A means C1-Salkil or C1-Celecoxi C1-Salkil;

R3Ameans C1-Salkil or C1-Celecoxi; or

R2Aand R3Ataken together with the adjacent carbon atoms, may form an optionally substituted non-aromatic 5-to 10-membered carbon ring;

R4Ameans hydrogen or hydroxy;

R15Ameans hydrogen or C1-Salkil;

X1Ameans a single bond or C1-Sakilan;

X2Ameans linear C1-Salminen, optionally substituted by one or two substituents selected from the group of substituents H, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents I, or heteroaryl, optionally substituted by one or two substituents selected from the group of substituents I;

X3Ameans a single bond, C1-Salminen, or C2-Calcanean;

the group of substituents G: halogen, C3-Cicloalchil, C1-Sarcoxie, Halogens-Sarcoxie, cyano, azide, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents J, and heteroaryl, optionally substituted with one to three substituents selected from the group of substituents J;

the group of substituents H: halogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents G, C3-Cicloalchil, C2-Salkini, C2-Salminen, which is may be replaced by a group-O-, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents J, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents J, and non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents J;

group Deputy I: halogen, C1-Salkil and phenyl;

group Vice J: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, cyano, nitro and phenyl;

its pharmaceutically acceptable salt or MES;

17) the compound according to item 16), where the group represented by the formula:

means a group selected from groups represented by the formulas:

where Me denotes methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl,

the group represented by the formula:

means a group selected from groups represented by the formulas:

where Me denotes methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; R15Ais as defined in paragraph 16);

its pharmaceutically acceptable salt or MES;

18) the connection pun is the 17), where R15Ameans hydrogen, its pharmaceutically acceptable salt or MES;

19) a pharmaceutical composition containing the compound according to any one of items 1)-18) as an active ingredient;

20) the pharmaceutical composition according to paragraph 19), which is a tool for the treatment of atopic dermatitis;

21) the pharmaceutical composition according to paragraph 19, which represents an antipruritic agent;

22) use of the compound or its pharmaceutically acceptable salt or MES according to any one of items 1)-18) for the medicinal product for the prevention and/or treatment of atopic dermatitis;

23) the method of prevention and/or treatment of atopic dermatitis in a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the compound or its pharmaceutically acceptable salt or MES according to any one of items 1)-18), and facilitating, thus, its symptoms;

24) use of the compound or its pharmaceutically acceptable salt or MES according to any one of items 1)-18) for the medicinal product for the prevention and/or treatment of itching;

25) the method of relief of itching in a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the compound or farmacevtichesky acceptable salt or MES according to any one of items 1)-18), and

26) the compound of the formula:

where R16Bmeans hydroxy, C1-Calculate or chlorine;

and its pharmaceutically acceptable salt or MES.

In addition, the following aspects are included in the present invention.

The aspect of the present invention applies to:

{1} the compound of formula (BB):

where RBameans C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents A, C2-Calcaneal or C2-Calciner;

RBbmeans C1-Salkil;

RBcmeans C1-Salkil or C1-Celecoxi; or

RBband RBctaken together with the adjacent carbon atoms, may form an optionally substituted non-aromatic 5-to 10-membered carbon ring which may be substituted with one group selected from-O-, -S-, -SO - and-SO2-;

RBdmeans hydrogen or hydroxy;

GBmeans a group represented by the formula:

where RBemeans hydrogen or C1-Salkil;

XBameans a single bond or C1-Salminen, optionally substituted with one to three substituents selected from the group of substituents B;

XBbmeans C1-Salminen, which may be substituted by one or two groups-O -, or-NRBf-where RBfmeans hydrogen, C1-Salkil or benzyl, and optionally substituted with one to three substituents, selected from the group of substituents BBb, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents CBc, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents CBc, areldil, optionally substituted by one or two substituents selected from the group of substituents C, heteroaryl, optionally substituted by one or two substituents selected from the group of substituents CBcor non-aromatic heterocyclyl, optionally substituted by one or two substituents selected from the group of substituents CBc;

XBcmeans a single bond, C1-Salminen, which can be replaced by a heteroatom, and optionally substituted with one to three substituents selected from the group of substituents BBb, C2-Calcanean, optionally substituted with one to three substituents selected from the group of substituents BBbor carbonyl;

ring GBameans a group selected from groups represented by the formulas:

where RBjmeans C1-Salkil; n is 0, 1 or 2;

ring GBbmeans a group selected from groups represented by the formulas:

where RBkmeans hydrogen or C1-Salkil; s is 0, 1 is 2; t is an integer from 1 to 4;

YBameans-O-, -S-, -N(RBz)-, where RBzmeans hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents DBdor

group selected from groups represented by the formulas:

where RBgmeans C1-Salkil; m is 1 or 2;

ZBameans hydrogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents DBd, C3-Cal, optionally substituted by one or two substituents selected from the group of substituents CBc, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, C1-Sarkilarini, C6-SLR, optionally substituted with one to three substituents selected from the group of substituents FBf, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBf, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents EBe, a group represented by the formula: -C(NH2)-NR Bha-CO-NRBhbRBiwhere RBha, RBhband RBieach independently mean hydrogen or C1-Salkil, or a group represented by the formula: -C(=WBa)-RBlwhere RBlmeans C1-Salkil, optionally substituted by one or two substituents selected from the group of substituents DBd, hydroxys-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents EBehydrazine, optionally substituted by one or two substituents selected from the group of substituents EBe, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBfor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents EBe; WBameans an oxygen atom or a sulfur atom;

the group of substituents (ABe: halogen, C3-Cicloalchil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, cyano, azide, nitro, C1-Sarkilarini, C6-SLR, optionally substituted with one to three replace the s, selected from the group of substituents FBf, heteroarylboronic, optionally substituted with one to three substituents selected from the group of substituents FBf, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBf, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBfand the group represented by formula: -C(=O)-RBmwhere RBmmeans hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBfor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBf;

a group of deputies of the BBb: halogen, C3-Cicloalchil, C2-Salkini, C2-Salminen, hydroxy, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, oxo, amino group, optionally substituted one or dumaguette, selected from the group of substituents EBe, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfor heteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBf, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBfand the group represented by formula: -C(=O)-RBnwhere RBnmeans hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBfor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBf;

the group of substituents CBc: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, oxo, cyano, azide, nitro and phenyl;

the group of substituents DBd: halogen, C1-Salkil, Halogens-Salkil, C3-Cicloalchil, hydroxy, C1-Sarcoxie, hydroxys-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, the CSR amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, carboxy, cyano, azide, nitro, three(C1-Salkil)ammonium, di(C1-Salkil)benzylamine, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBf, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBfthe group represented by the formula: -(=O)-R13where R13means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and the group represented by formula: -C(=O)-RBpwhere RBpmeans C1-Salkil, C3-Cicloalchil, C1-Sarcoxie, C3-Styleability, C6-Six, optionally substituted with one to three substituents, vibrancies group of substituents F Bfheteroaromatic, optionally substituted with one to three substituents selected from the group of substituents FBf, amino group, optionally substituted by one or two substituents selected from the group of substituents EBe, piperidino, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents FBfheteroaryl, optionally substituted with one to three substituents selected from the group of substituents FBfor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents FBf;

the group of substituents EBeC1-Salkil, (C1-Salkil)carbonyl, (C1-Celecoxi)carbonyl, (C6-Ser)carbonyl, heteroarylboronic, (amino, optionally substituted by one or two groups of C1-Salkil or C6-Ser)carbonyl, C1-Sarkilarini, C6-Sly and heteroarylboronic;

the group of substituents FBf: halogen, C1-Salkil, Halogens-Salkil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, methylenedioxy, benzyloxy, carbarnoyl, optionally substituted by one or two groups of C1-Salkil, cyano, azide, nitro, oxo and phenyl;

provided that if-XBa-XBb-XBc-C(=)-YBa-ZBemeans a group represented by the formula (BB),

RBband RBc, VZ is taken together with the adjacent carbon atoms, do not form a 6-membered non-aromatic carbon ring;

its pharmaceutically acceptable salt or MES;

{2} the connection point {1}, where RBameans C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents (ABa, its pharmaceutically acceptable salt or MES;

{3} the connection point {1} or {2}, where RBameans n-butyl, cyclohexylmethyl, or phenyl, optionally substituted with one to three substituents selected from the group of substituents FBf)methyl, its pharmaceutically acceptable salt or MES;

{4} the compound according to any one of items {1}-{3}, where RBband RBceach independently denotes a C1-Salkil, its pharmaceutically acceptable salt or MES;

{5} the compound according to any one of items {1}-{3}, where RBband RBctaken together with the adjacent carbon atoms, form a non-aromatic 7-10-membered carbon ring, optionally substituted C1-Calcilo, its pharmaceutically acceptable salt or MES;

{6} the compound according to any one of items {1}-{5}, where RBdmeans hydrogen, its pharmaceutically acceptable salt or MES;

{7} the compound according to any one of items {1}-{6}, where RBemeans hydrogen, its pharmaceutically acceptable salt or MES;

{8} the compound according to any one of items {1}-{7}, where XBaand XBcabout the mean single bond, and XBbmeans linear C1-Salminen, optionally substituted by one Deputy, is selected from C1-Salkil, optionally substituted by one Deputy, selected from the group of substituents BBband the group of substituents BBb, its pharmaceutically acceptable salt or MES;

{9} the compound according to any one of items {1}-{7}, where XBbmeans heteroaryl, optionally substituted by one or two substituents selected from the group of substituents CBc, its pharmaceutically acceptable salt or MES;

{10} the compound according to any one of items {1}-{9}, where YBameans-O-, and ZBameans hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, its pharmaceutically acceptable salt or MES;

{11} the compound according to any one of items {1}-{9}, where YBameans-N(RBz)-, where RBzis the same as defined in the item {1}, its pharmaceutically acceptable salt or MES;

{12} the compound according to any one of items {1}-{9}, where YBameans a group represented by the formula:

where u is as defined in the item {1};

its pharmaceutically acceptable salt or MES;

{13} the pharmaceutical composition containing the compound according to any one of items {1}-{12} as the active ingred the enta,

{14} the pharmaceutical composition according to paragraph {13}, which can be used as an antipruritic funds

{15} the pharmaceutical composition according to paragraph {13}, which can be used as anti-asthma drugs,

{16} the pharmaceutical composition according to the item {1}, which can be used as a therapeutic agent for the treatment of chronic obstructive pulmonary disease.

In addition, the following aspects are included in the present invention.

The aspect of the present invention applies to:

[1] to the compound of formula (A):

where Rameans C1-Salkil, optionally substituted by one to three substituents selected from the group of substituents (Aa, C2-Calcaneal or C2-Calciner;

Rbmeans C1-Salkil;

Rcmeans C1-Salkil or C1-Celecoxi; or

Rband Rctaken together with the adjacent carbon atoms, may form a 5-to 10-membered cycloalkane containing one double bond, which can be substituted in the ring by one group selected from-O-, -S-, -SO - and-SO2-;

Rdmeans hydrogen or hydroxy;

G stands for a group represented by the formula:

where Remeans hydrogen or C1-Salkil;

Xameans a single bond or C1-Sakilan;

XbOsnach the em C1-Salminen, which may be substituted by one or two groups-O -, or-N(Rf)-, where Rfmeans hydrogen and C1-Salkil, or aralkyl, optionally substituted with one to three substituents selected from the group of substituents Bb, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents Cc, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents Cc, areldil, optionally substituted by one or two substituents selected from the group of substituents Cc, heteroaryl, optionally substituted by one or two substituents selected from the group of substituents Ccor non-aromatic heterocyclyl, optionally substituted by one or two substituents selected from the group of substituents Cc;

XCmeans a single bond, C1-Salminen, C2-Calcanean, C2-Calcinit or carbonyl;

ring Gameans a group selected from groups represented by the formulas:

where Rjmeans hydrogen or C1-Salkil;

ring Gbmeans a group represented by the formula:

where Rkmeans C1-Salkil; s is 0, 1 or 2; t is an integer from 1 to 4;

Yameans-O-, -S-, -N(Rz)-, where Rz means hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents Ddor a group selected from groups represented by the formulas:

where Rgmeans C1-Salkil; u is 1 or 2;

Zameans hydrogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents Dd, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, C1-Sarkilarini, C6-SLR, optionally substituted with one to three substituents selected from the group of substituents Ff, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ff, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ee, a group represented by the formula: -C(NH2)-NRha-CO-NRhbRiwhere Rha, Rhband Rieach independently mean hydrogen or C1-Salkil, or a group represented by the formula: -C(=Wa)-Rlwhere Rlmeans C1-Salkil, optionally substituted by one or two to cover the firs, selected from the group of substituents Dd, hydroxys-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents Eehydrazine, optionally substituted by one or two substituents selected from the group of substituents Ee, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ffor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ee; Wameans an oxygen atom or a sulfur atom;

the group of substituents (Aa: halogen, C3-Cicloalchil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, cyano, azide, nitro, C1-Sarkilarini, C6-SLR, optionally substituted with one to three substituents selected from the group of substituents Ff, heteroarylboronic optionally substituted with one to three substituents selected from the group of substituents Ff, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F heteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ff, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ffand a group represented by the formula: -C(=O)-Rmwhere Rmmeans hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ffor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ff;

a group of deputies of the Bb: halogen, C3-Cicloalchil, C2-Salkini, C2-Salminen, hydroxy, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffor heteroaryl, optionally substituted by one to three substituents selected from the group of the s Vice F f, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ffand a group represented by the formula: -C(=O)-Rnwhere Rnmeans hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ffor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;

the group of substituents Cc: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, cyano, azide, nitro and phenyl;

the group of substituents Dd: halogen, C1-Salkil, Halogens-Salkil, C3-Cicloalchil, hydroxy, C1-Sarcoxie, hydroxys-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, carboxy, cyano, azide, nitro, three(C1-Salkil)ammonium, di(C1-Salkil)benzylamine, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ff, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ffthe group represented by the formula: -C(=O)-Rpwhere Rpmeans hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ffor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ffand the group represented by the formula: -O-C(=O)-Rqwhere Rqmeans C1-Salkil, C3-Cicloalchil, C1-Sarcoxie, C3-Styleability, C6-Six, optionally substituted with one to three substituents selected from the group of substituents Ffheteroaromatic, optionally substituted with one to three substituents selected from the group of substituents Ff, amino group, optionally substituted by one or two substituents selected from the group of substituents Ee, piperidino, C6-Ser optionally substituted with one to three substituents, selected from the group of substituents Ffheteroaryl, optionally substituted with one to three substituents selected from the group of substituents Ffor non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents Ff;

the group of substituents EeC1-Salkil, (C1-Salkil)carbonyl, (C1-Celecoxi)carbonyl, (C6-Ser)carbonyl, heteroarylboronic, aminocarbonyl, optionally substituted by one or two groups of C1-Salkil or C6-Say, C1-Sarkilarini, C6-Sly and heteroarylboronic;

the group of substituents Ff: halogen, C1-Salkil, Halogens-Salkil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, methylenedioxy, benzyloxy, carbarnoyl, optionally substituted by one or two groups of C1-Salkil, cyano, azide, nitro, oxo and phenyl;

however, if-Xa-Xb-Xc-C(=O)-Ya-Zameans a group represented by the formula (B):

Rband Rctaken together with the adjacent carbon atoms, form a 6-membered non-aromatic carbon ring; its pharmaceutically acceptable salt or MES;

[2] the compound according to item [1], where Rameans C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents (Aahis farmaceuticas is acceptable salt or MES;

[3] the compound according to item [1] or [2], where Rameans n-butyl, cyclohexylmethyl or phenylmethyl, optionally substituted with one to three substituents selected from the group of substituents Ff, its pharmaceutically acceptable salt or MES;

[4] the compound according to paragraphs [1]-[3], where Rband Rceach independently denotes a C1-Salkil, its pharmaceutically acceptable salt or MES;

[5] the compound according to any one of paragraphs [1]-[3], where Rband Rctaken together with the adjacent carbon atoms, form a 7-10-membered cycloalkene, its pharmaceutically acceptable salt or MES;

[6] the compound according to any one of paragraphs [1]-[5], where R4means hydrogen, its pharmaceutically acceptable salt or MES;

[7] the compound according to any one of paragraphs [1]-[6], where Remeans hydrogen, its pharmaceutically acceptable salt or MES;

[8] the compound according to any one of paragraphs [1]-[7], where Xaand Xcdenote a single bond, and Xbmeans C1-Salminen, optionally substituted by one Deputy, is selected from C1-Salkil, optionally substituted by a group selected from the group of substituents Bband one Deputy selected from the substituent Bb, its pharmaceutically acceptable salt or MES;

[9] the compound according to any one of paragraphs [1]-[7], where Xbmeans heteroaryl, optional the tion substituted by one or two substituents, selected from the group of substituents C, its pharmaceutically acceptable salt or MES;

[10] the compound according to any one of items [1]to[9], where Yameans-O-, and Zameans hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, its pharmaceutically acceptable salt or MES;

[11] the compound according to any one of items [1]to[9], where Yameans-N(Rz)-, where Rzis as defined in paragraph [1], its pharmaceutically acceptable salt or MES;

[12] the compound according to any one of items [1]to[9], where Yameans a group represented by the formula:

where u is as defined in paragraph [1];

its pharmaceutically acceptable salt or MES;

[13] the pharmaceutical composition containing the compound according to any one of items [1]to[12] as an active ingredient,

[14] the antipruritic agent containing as an active ingredient the compound according to any one of paragraphs[1]-[12].

The values of all the terms explained below. In the present description, each term is used in the General meaning, and when used alone or in combination with other terms have the same value.

The term “halogen” includes fluorine atom, chlorine atom, bromine atom and iodine atom.

The term “heteroatom” on the denotes the nitrogen atom, an oxygen atom and a sulfur atom.

The term "alkyl" includes C1-C10 linear or branched alkyl. As an example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. If the number of carbon atoms refers to "alkyl", which contains the number of carbon atoms in the specified interval.

The term “halogenated” includes C1-C10 linear or branched alkyl, in which one or more atoms of halogen placed in the possible positions. As an example, chloromethyl, dichloromethyl, deformity, trifluoromethyl, chloroethyl (for example, 2-chloroethyl and the like), dichlorethyl (for example, 1,2-dichloroethyl, 2,2-dichloroethyl etc.), chlorpropyl (for example, 2-chloropropyl, 3-chloropropyl and the like), etc. If the number of carbon atoms refers to “halogenated”, which contains the number of carbon atoms in the specified interval.

The term “hydroxyalkyl” includes C1-C10 linear or branched alkyl, in which one or more hydroxyl groups are placed in the possible positions. As an example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxyphenyl, 6-hydroxyhexyl, 7-hydroxyethyl, 8-hydroxyacyl etc. If MC is shown the number of carbon atoms, means “hydroxyalkyl”, which contains the number of carbon atoms in the specified interval.

Alkyl from the definition of “alkylthio” is as defined the above ”alkyl”. Example “alkylthio” can be, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutyric, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, etc. If the number of carbon atoms refers to “alkylthio”, which contains the number of carbon atoms in the specified interval.

Alkyl from the definition of “alkylaryl” is as defined the above “alkyl”. Example “alkylcarboxylic” can be, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, octanoyl, lauroyl etc. If the number of carbon atoms refers to “alkylaryl”, which contains the number of carbon atoms in the specified interval.

Alkyl from the definition of “alkylsulfonyl” is as defined the above “alkyl”. Example alkylsulfonyl can serve methanesulfonyl, econsultancy etc. If the number of carbon atoms refers to “alkylsulfonyl”, which contains the number of carbon atoms in the specified interval.

The term “cycloalkyl” includes C3-Cal. As an example Pref is STI cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. If the number of carbon atoms refers to “cycloalkyl”, which contains the number of carbon atoms in the specified interval.

The term “alkenyl” includes C2-C10 linear or branched alkyl containing one or more double bonds. As an example, vinyl, 1-propenyl, allyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1,3-butadienyl, 3-methyl-2-butenyl etc. If the number of carbon atoms refers to “alkenyl”, which contains the number of carbon atoms in the specified interval.

The term “quinil” includes C2-C10 linear or branched alkyl containing one or more triple bonds. As an example, ethinyl, propargyl etc. If the number of carbon atoms refers to “quinil”, which contains the number of carbon atoms in the specified interval.

Alkyl from the definition of “alkoxy” is the same as the above-defined “alkyl”. Example alkoxy can serve as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like, If the number of carbon atoms refers to “alkoxy”, which contains the number of carbon atoms, j is seesa in the specified interval.

The term “halogenoalkane” includes the above-described alkoxy, in which one or more atoms of halogen placed in the possible positions. As an example, dichloromethoxy, deformedarse, triptoreline, triptoreline (2,2,2-triptoreline and the like), etc. If the number of carbon atoms refers to “halogenoalkane”, which contains the number of carbon atoms in the specified interval.

Cycloalkyl from the definition of “cycloalkane” is the same as defined above “cycloalkyl”. Example “cycloalkane” can serve cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, cyclooctylamine etc. If the number of carbon atoms refers to “cycloalkyl”, which contains the number of carbon atoms in the specified interval.

Alkoxy from the definition of “alkoxycarbonyl” is as defined the above “alkoxy”. Example “alkoxycarbonyl” can serve methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, n-hexyloxymethyl, n-heptyloxybiphenyl, n-octyloxybiphenyl etc. If the number of carbon atoms refers to “alkoxycarbonyl”, which contains the number of carbon atoms in the specified interval.

Those who min “alkylene” includes C1-C10 linear or branched alkylen. As an example, methylene, ethylene,

1-mutilation, 1-ethylethylene, 1,1-dimethylethylene,

1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene,

1-ethyl-2-mutilation, trimethylene, 1-metallisation,

2-metallisation, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene,

2.2-dimethyltrimethylene, 1-ethyltryptamine, 2-ethyltryptamine,

1,1-determination, 1,2-determination,

2.2-determination, 2,2-di-n-propertisation,

2-ethyl-2-metallisation, tetramethylene, 1-methyltyramine,

2-methyltyramine, 1,1-dimethyltrimethylene,

1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, pentamethylene,

hexamethylen, heptameron, octamethylene, nonmotile,

decamethrin etc. If the number of carbon atoms refers to “alkylen”, which contains the number of carbon atoms in the specified interval.

The term “linear alkylene” includes linear, i.e., unbranched, alkylen. As an example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile, decamethrin etc. If the number of carbon atoms refers to “linear alkylene”, which contains the number of carbon atoms in the specified interval.

The term “albaniles” includes C2-C10 linear or branched alkylene, with the holding of one or more double bonds. As an example, vinile, 1-propanole, allele, Isopropenyl, 1-butylen, 2-butylen, 3-butylen, 2-penttinen, 1,3-butadienyl, 3-methyl-2-butylen etc. If the number of carbon atoms refers to “albaniles”, which contains the number of carbon atoms in the specified interval.

The term “akinyan” includes C2-C10 linear or branched alkylene containing one or more triple bonds. As an example, ethynylene, 1-propylen etc. If the number of carbon atoms refers to “akinyan”, which contains the number of carbon atoms in the specified interval.

The term “cycloalkenyl” includes C3-C10 monocyclic or bicyclic alcander. As an example cyclopropane, CYCLOBUTANE, cyclopentanediol, cyclohexanediol, cycloheptenyl, cyclooctyl, bicyclo[2,2,2]octanediyl, bicyclo[2,2,1]heptanediol, adamantidis etc. One carbon atom may participate in the formation of two relations. As an example, cyclohexane-1,1-diyl etc. If the number of carbon atoms refers to “cycloalkenyl”, which contains the number of carbon atoms in the specified interval.

The term “cycloalkenyl” includes C3-C10 cycloalkenyl. As an example, cyclopropa diyl, cyclobutanediyl, cyclopentanediol, cyclohexanediol, cycloheptenyl, cyclooctanol etc. If possible, one carbon atom can participate in the formation of two relations. As example 2-cyclohexene-1,1-diyl etc. If the number of carbon atoms refers to “cycloalkenyl”, which contains the number of carbon atoms in the specified interval.

The term “aryl” includes C6-aryl. As an example, phenyl, naphthyl, antril, tenantry etc. If the number of carbon atoms refers to “aryl”, which contains the number of carbon atoms in the specified interval.

The term “aralkyl” includes groups in which the above “alkyl” substituted by the above “aryl”. As an example, benzyl, phenylethyl (e.g., 1-phenylethyl, 2-phenylethyl, phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl etc.), naphthylmethyl (for example, 1-naphthylmethyl, 2-naphthylmethyl etc).

The term “areldil” includes C6-Sir. As an example, phenylene, naftilan, entrylen, phenanthrolin etc. If the number of carbon atoms refers to “areldil”, which contains the number of carbon atoms in the specified interval.

Aryl from the definition of “aryloxy” is as defined the above “aryl”. “Ari is hydroxy can serve phenoxy, naphthoxy (for example, 1-naphthoxy, 2-naphthoxy etc.), antioxy (for example, 1-antioxi, 2-antioxi etc.), ventriloque (for example, 1-phenantroline, 2-phenantroline and the like), etc. If the number of carbon atoms refers to “aryloxy”, which contains the number of carbon atoms in the specified interval.

Aryl from the definition of “arylcarbamoyl” is as defined the above “aryl”. Example “arylcarbamoyl” can serve as benzoyl, Naftoli etc. If the number of carbon atoms refers to “arylcarbamoyl”, which contains the number of carbon atoms in the specified interval.

Aryl from the definition of “arylsulfonyl” is as defined the above ”aryl”. Example arylsulfonyl” can serve phenylsulfonyl, aftercooler etc. If the number of carbon atoms refers to “arylsulfonyl”, which contains the number of carbon atoms in the specified interval.

The term “heteroaryl” includes C1-C9 heteroaryl, which contains one to four nitrogen atoms, oxygen and/or sulfur, for example, furyl (e.g. 2-furyl, 3-furyl), thienyl (for example, 2-thienyl, 3-thienyl), pyrrolyl (for example, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (for example, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazole is l (for example, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl), tetrazolyl (for example, 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolin (for example, 3-isothiazole, 4-isothiazole, 5-isothiazolin), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (for example, 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furutani (for example, 3-furutani), pyrazinyl (for example, 2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), benzofuran (e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl, 5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothiazyl (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl, 5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (for example, 1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), dibenzofuran, benzoxazolyl, Minoxidil (for example, 2-Minoxidil, 5-Minoxidil, 6-Minoxidil), cannoli (for example, 3-cinnamyl, 4-cinnolin, 5-cinnolin, 6-cinnolin, 7-cinnolin, 8-cinnolin), chinadoll (for example, 2-chinadoll, 4-chinadoll, 5-chinadoll, 6-chinadoll, 7-chinadoll, 8-chinadoll), chinolin (for example, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-hin the Lil, 8-chinolin), phthalazine (for example, 1-phthalazine, 5-phthalazine, 6-phthalazine), ethanolic (for example, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic, 8-ethanolic), peril, pteridinyl (for example, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridines, acridines (for example, 1-acridine, 2-acridines, 3-acridines, 4-acridine, 9-acridine), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazines (for example, 1-phenazine, 2-phenazine), phenothiazines (for example, 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl), etc.

The term “heteroaryl” includes C1-C9 heteroaryl containing from one to four nitrogen atoms, oxygen and/or sulfur, for example, purandar, theoffender, pyrrolidinyl, imidazolidinyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolin, pyridinyl, pyridazinyl, pyrimidinyl, forsander, pyrazinyl, oxadiazolyl, benzofuranyl, benzothiophene, benzimidazole, dibenzofurane, benzoxazolyl, minoksidil, cinnoline, chinazolinei, chinaindia, phthalazinium, izohinolinove, parential, pteridinyl, carbazolyl, phenanthridinium, credential, indolinyl, isoindolyl, finsinger, phenothiazinyl etc.

repectfully heteroallyl X 2includes thiazole-1,4-diyl, thiazole-1,5-diyl, thiazole-3,5-diyl, pyridine-2,5-diyl, pyrimidine-2,5-diyl etc.

Heteroaryl from the definition of “heteroarylboronic” is the same as defined above “heteroaryl”. Example “heteroarylboronic” can serve as pyridylcarbonyl etc.

Heteroaryl from the definition of “heteroarylboronic” is the same as defined above “heteroaryl”. Example heteroarylboronic” can serve fullcolor,

thienylmethyl, pyrrolidinyl, imidazolylalkyl,

personalality, triazolylmethyl, tetraallylsilane,

oxazolidinyl, isoxazolidinone, triazolylmethyl,

thiadiazolidine, isothiazolinones, pyridylsulfonyl,

pyridinylmethyl, pyrimidinemethanol, pursenality,

personalality, oxadiazolidine, benzofuranyl,

benzothiazolone, benzimidazolecarbamic,

dibenzobarrelenes, benzoxazolinone,

hinoksalinovym, canaliculitis, chinaseaisland,

chinaillon, phthalazinedione, ethynodiolthinyl,

polysulfonyl, peridiniales, carbosulfan,

financeminister, criminality, indolylmethane,

isoindolines, penisenlargement, finitedimensional and

so what.

The term “nonaromatic heterocyclic group” include C1-C9 non-aromatic ring containing from one to four nitrogen atoms, oxygen and/or sulfur, for example, oxirane, 1-pyrrolidyl, 2-pyrrolyl, 3-pyrrolyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrazolidone, 3-pyrazolidone, 4-pyrazolidine, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazine derivatives, 2-piperazinil, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl etc.

The term “non-aromatic heterocyclyl” includes C1-C9 non-aromatic collodial containing from one to four nitrogen atoms, oxygen and/or sulfur, for example, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolidinyl, pyrazolidine, pyrazolidine, piperidine, piperazinyl, morpholinyl, tetrahydropyranyl etc.

Example 5-10-membered of cycloalkane containing one double bond, which may contain in the ring group selected from-O-, -S-, -SO - and-SO2-”may be, for example, cyclopentene, dihydropyran, dihydrothiophene, dihydrothiophene-1-oxide, dihydrothiophene-1,1-dioxide, cyclohexene, cycloheptene, cyclooctene, cyclonona, cyclodecene etc. is predpochtitelen 7-10-membered cycloalkene, for example, such as cyclohepten, cyclooctene, cyclonona and cyclodecene.

The terms “optionally substituted alkyl”, “optionally substituted aryl“, “optionally substituted heteroaryl“, “optionally substituted non-aromatic heterocyclic group”, “optionally substituted alkylene”, “optionally substituted, aryloxy”, “optionally substituted, heteroaromatic”, “optionally substituted arylsulfonyl”, “optionally substituted heteroarylboronic”, “optionally substituted cycloalkenyl”, “optionally substituted cycloalkenyl”, “optionally substituted areldil”, “optionally substituted heteroaryl”, “optionally substituted non-aromatic heterocyclyl”, “optionally substituted amino group”, “optionally substituted hydrazine” are to unsubstituted or having substituents.

If substituents are present in arbitrary positions, which may be substituted, may contain one or more (permitted number) identical or different substituents.

The substituents include, for example, hydroxy, carboxy, halogen (fluorine atom, chlorine atom, bromine atom, iodine atom), halogenated (for example, CF3CH2CF3CH2CCl3and the like), halogenoalkane, alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, and so is.), alkenyl (e.g., vinyl), formyl, acyl (e.g. acetyl, propionyl, butyryl, pivaloyl, benzoyl, pyridylcarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl etc.), quinil (for example, ethinyl), cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), alkylene (for example, trimethylene, pentamethylene, hexamethylene etc.), albaniles (for example, 2-propene-1,3-diyl, 3-penten-1,5-diyl, 3-hexene-1,6-diyl and the like), alkoxy (for example, methoxy, ethoxy, propoxy, butoxy etc.), alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl and the like), nitro, nitroso, oxo, optionally substituted amino (for example, amino, alkylamino (for example, methylamino, ethylamino, dimethylamino and the like), formylamino, acylamino (for example, acetylamino, benzoylamine etc.)), azide, aryl (e.g. phenyl and the like), aryloxy (for example, phenoxy), cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto, alkylthio (for example, methylthio, ethylthio etc.), alkylsulfonyl (for example, methanesulfonyl, econsultancy), arylsulfonyl (for example, benzazolyl and the like), optionally substituted: carbarnoyl, sulfamoyl, formyloxy, halogenfree, oxazol, mercapto, diaformin, dicarboxy, dithiocarbonic, thiocarbamoyl, sulfine, sulfo, sulfamido, hydrazino, ureido, amidino, guanidino, formyloxy, thioxo, alkoxyalkane, alkylthiols etc./p>

If you specify the number or type of substituents, then the substitution is performed in the specified range.

The preferred compound of formula (I) is a compound that contains each of the following partial structures (a)-(r) independently, or contains the fragmentary structure in any possible combination. a) R1means C1-Salkil, optionally substituted with one to three substituents selected from the above group of substituents A, or C4-Salkini, b) R1means C1-Salkil, optionally substituted with one to three substituents selected from the above group of substituents A, c) R1means n-butyl, isopentyl, 3-methyl-2-butenyl, 4,4,4-tripcomputer, 2-methoxyethyl, cyclohexylmethyl or phenyl, optionally substituted with one to three substituents selected from the above group of substituents (F)methyl, (d) R2means C1-Salkil or C1-Calculate C1-Salkil, e) R2means C1-Salkil, f) R3means C1-Salkil or C1-Calculate, g) R3means C1-Salkil, h) R2and R3taken together with the adjacent carbon atoms, form a 7-10-membered cycloalkene, i) R2and R3taken together with the adjacent carbon atoms, form 8-membered cycloalkene, j) R4means hydrogen or a hydroxy-group, k) R4means hydrogen, l) R5means hydrogen, m) X1and X3 denote a single bond, and X2means C1-Salminen, optionally substituted by one or two substituents selected from the above group of substituents B, n) X1and X3each independently means a single bond or C1-Salminen, and X2means C3-Cicloalchil, optionally substituted by one or two substituents selected from the above group of substituents C, o) X1means a single bond, X3means C1-Sakilan or C2-Calcanean, X2means heteroaryl, optionally substituted by one or two substituents selected from the above group of substituents C, p) Y represents-O-, and Z denotes hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the above group of substituents D, q), Y represents-N(R6)-, where R6is the same as defined above, r) Y preferably stands for a group represented by the formula:

where m is as defined above, but is not limited to them.

Below are the specific preferred combinations.

(R1, R2, R3, R4, R5, X1, X2, X3), (Y, Z)) preferably correspond to (a, d, f, j, l, m, p), (a, d, f, j, l, n, p), (a, d, f, j, l, o, p), (a, d, f, k, l, m, p), (a, d, f, k, l, n, p), (a, d, f, K, l, o, p), (a, d, g, j, l, m, p), (a, d, g, j, l, n, p), (a, d, g, j, l, o, p), (a, d, g, k, l, m, p), (a, d, g, k, l, n, p), (a, d, g, k, l, o, p), (a, e, f, j, l, m, p), (a, e, f, j, l, n, p), (a e, f, j, l, o, p), (a, e, f, k, l, m, p), (a, e, f, k, l, n, p), (a, e, f, k, l, o, p), (a, e, g, j, l, m, p), (a, e, g, j, l, n, p), (a, e, g, j, l, o, p), (a, e, g, k, l, m, p), (a, e, g, k, l, n, p), (a, e, g, k, l, o, p), (b, d, f, j, l, m, p), (b, d, f, j, l, n, p), (b, d, f, j, l, o, p), (b, d, f, k, l, m, p), (b, d, f, k, l, n, p), (b, d, f, k, l, o, p), (b, d, g, j, l, m, p), (b, d, g, j, l, n, p), (b, d, g, j, l, o, p), (b, d, g, k, l, m, p), (b, d, g, k ], n, p), (b, d, g, k, l, o, p), (b, e, f, j, l, m, p), (b, e, f, j, l, n, p), (b, e, f, j, l, o, p), (b, e, f, k, l, m, p), (b, e, f, k, l, n, p), (b, e, f, k, l, o, p), (b, e, g, j, l, m, p), (b, e, g, j, l, n, p), (b, e, g, j, l, o, p), (b, e, g, k, l, m, p), (b, e, g, k, l, n, p), (b, e, g, k, l, o, p), (c, d, f, j, l, m, p), (c, d, f, j, l, n, p), (c, d, f, j, l, o, p), (c, d, f, k, l, m, p), (c, d, f, k, l, n, p), (c, d, f, k, l, o, p), (c, d, g, j, l, m, p), (c, d, g, j, l, n, p), (c, d, g, j, l, o, p), (c, d, g, k, l, m, p), (c, d, g, k, l, n, p), (c, d, g, k, l, o, p), (c, e, f, j, l, m, p), (c, e, f, j, l, n, p), (c, e, f, j, l, o, p), (c, e, f, k, l, m, p), (c, e, f, k, l, n, p), (c, e, f, k, l, o, R), (C, e, g, j, l, m, p), (c, e, g, j, l, n, p), (c, e, g, j, l, o, p), (c, e, g, k, l, m, p), (c, e, g, k, l, n, p), or (c, e, g, k, l, o, p),

(R1, R2, R3, R4, R5, X1, X2, X3), Y) preferably correspond to (a, d, f, j, l, m, q), (a, d, f, j, l, m, r), (a, d, f, j, l, n, q), (a, d, f, j, l, n, r), (a, d, f, j, l, o, q), (a, d, f, j, l, o, g), (a, d, f, k, l, m, q), (a, d, f, k, l, m, r), (a, d, f, k, l, n, q), (a, d, f, k, l, n, r), (a, d, f, k, l, o, q), (a, d, f, k, l, o, r), (a, d, g, j, l, m, q), (a, d, g, j, l, m, r), (a, d, g, j, l, n, q), (a, d, g, j, l, n, r), (a, d, g, j, l, o, q), (a, d, g, j, l, o, r), (a, d, g, k, l, m, q), (a, d, g, k, l, m, r), (a, d, g, k, l, n, q), (a, d, g, k, l, n, r), (a, d, g, k, l, o, q), (a, d, g, k, l, o, r), (a, e, f, j, l, m, q), (a, e, f, j, l, m, r), (a, e, f, j, l, n, q), (a, e, f, j, l, n, r), (a, e, f, j, l, o, q), (a, e, f, j, l, o, r), (a, e, f, k, l, m, q), (a, e, f, k, l, m, r), (a, e, f, k, l, n, q), (a, e, f, k, l, n, r), (a, e, f, k, l, o, q), (a, e, f, k, l, o, r), (a, e, g, j, l, m, q), (a, e, g, j, l, m, r), (a, e, g, j, l, n, q), (a, e, g, j, l, n, r), (a, e, g, j, l, o, q), (a, e, g, j, l, o, r), (a, e, g, k, l, m, q), (a, e, g, k, l, m, r), (a, e, g, k, l, n, q), (a, e, g, k, l, n, r), (a, e, g, k, l, o, q), (a, e, g, k, ), o, r), (b, d, f, j, l, m, q), (b, d, f, j, l, m, r), (b, d, f, j, l, n, q), (b, d, f, j, l, n, r), (b, d, f, j, l, o, q), (b, d, f, j, l, o, r), (b, d, f, k, l, m, q), (b, d, f, k, l, m, r), (b, d, f, k, l, n, q), (b, d, f, k, l, n, r), (b, d, f, k, l, o, q), (b, d, f, k, l, o, r), (b, d, g, j, l, m, q), (b, d, g, j, l, m, r), (b, d, g, j, l, n, q), (b, d, g, j, l, n, r), (b, d, g, j, l, o, q), (b, d, g, j, l, o, r), (b, d, g, k, l, m, q), (b, d, g, k, l, m, r), (b, d, g, k, l, n, q), (b, d, g, k, l, n, r), (b, d, g, k, l, o, q), (b, d, g, k, l, o, r), (b, e, f, j, l, m, q), (b, e, f, j, l, m, r), (b, e, f, j, l, n, q), (b, e, f, j, l, n, r), (b, e, f, j, l, o, q), (b, e, f, j, l, o, r), (b, e, f, k, l, m, q), (b, e, f, k, l, m, r), (b, e, f, k, l, n, q), (b, e, f, k, l, n, r), (b, e, f, k, l, o, q), (b, e, f, k, l, o, r), (b, e, g, j, l, m, q), (b, e, g, j, l, m, r), (b, e, g, j, l, n, q), (b, e, g, j, l, n, r), (b, e, g, j, l, o, q), (b, e, g, j, l, o, r), (b, e, g, k, l, m, q), (b, e, g, k, l, m, r), (b, e, g, k, l, n, q), (b, e, g, k, l, n, r), (b, e, g, k, l, o, q), (b, e, g, k, l, o, r), (c, d, f, j, l, m, q), (c, d, f, j, l, m, r), (c, d, f, j, l, n, q), (c, d, f, j, l, n, r), (c, d, f, j, l, o, q), (c, d, f, j, l, o, g), (C, d, f, k, l, m, q), (c, d, f, k, l, m, r), (c, d, f, k, l, n, q), (c, d, f, k, l, n, r), (c, d, f, k, l, o, q), (c, d, f, k, l, o, r), (c, d, g, j, l, m, q), (c, d, g, j, l, m, r), (c, d, g, j, l, n, q), (c, d, g, j, l, n, r), (c, d, g, j, l, o, q), (c, d, g, j, l, o, r), (c, d, g, k, l, m, q), (c, d, g, k, l, m, r), (c, d, g, k, l, n, q), (c, d, g, k, l, n, r), (c, d, g, k, l, o, q), (c, d, g, k, l, o, r), (c, e, f, j, l, m, g), (c, e, f, j, l, m, r), (c, e, f, j, l, n, q), (c, e, f, j, l, n, r), (c, e, f, j, l, o, q), (c, e, f, j, l, o, r), (c, e, f, k, l, m, q), (c, e, f, k, l, m, r), (c, e, f, k, l, n, q), (c, e, f, k, l, n, r), (c, e, f, k, l, o, q), (c, e, f, k, l, o, r), (c, e, g, j, l, m, q), (c, e, g, j, l, m, r), (c, e, g, j, l, n, q), (c, e, g, j, l, n, r), (c, e, g, j, l, o, q), (c, e, g, j, l, o, r), (c, e, g, k, l, m, q), (c, e, g, k, l, m, r), (c, e, g, k, l, n, q), (c, e, g, k, l, n, r), (c, e, g, k, l, o, q), or (c, e, g, k, l, o, r),

(R1, (R2-R3), R4, R5, X1, X2, X), (Y, Z)) preferably correspond to (a, h, j, l, m, p), (a, h, j, l, n, p), (a, h, j, l, o, p), (a, h, k, l, m, p), (a, h, k, l, n, p), (a, h, k, ], o, p), (a, i, j, l, m, p), (a, i, j, l, n, p), (a, i, j, l, o, p), (a, i, k, l, m, p), (a, i, k, I, n, p), (a, i, k, l, o, p), (b, h, j, l, m, p), (b, h, j, l, n, p), (b, h, j, l, o, p), (b, h, k, l, m, p), (b, h, k, l, n, p), (b, h, k, l, o, p), (b, i, j, l, in, p), (b, i, j, l, n, p), (b, i, j, l, o, p), (b, i, k, l, m, p), (b, i, k, l, n, p), (b, i, k, l, o, p), (c, h, j, l, m, p), (c, h, j, l, n, p), (C, h, j, l, o, R), (s, h, K, l, m, p), (C, h, K, l, n, p), (c, h, k, l, o, p), (c, i, j, l, m, p), (c, i, j, l, n, p), (c, i, j, l, o, p), (c, i, k, l, m, p), (c, i, k, l, n, p), or (c, i, k, l, o, p), or,

(R1, (R2-R3), R4, R5, X1, X2, X3), Y) preferably correspond to (a, h, j, l, m, q), (a, h, j, l, m, r), (a, h, j, l, n, q), (a, h, j, l, n, r), (a, h, j, l, o, q), (a, h, j, l, o, r), (a, h, k, l, m, q), (a, h, k, l, m, r), (a, h, k, l, n, q), (a, h, k, l, n, r), (a, h, k, l, o, q), (a, h, k, l, o, r), (a, i, j, l, m, q), (a, i, j, l, m, r), (a, i, j, l, n, q), (a, i, j, l, n, r), (a, i, j, l, o, q), (a, i, j, l, o, r), (a, i, k, l, m, q), (a, i, k, l, m, r), (a, i, k, l, n, q), (a, i, k, l, n, r), (a, i, k, l, o, q), (a, i, k, l, o, r), (b, h, j, l, m, q), (b, h, j, l, m, r), (b, h, j, l, n, q), (b, h, j, l, n, r), (b, h, j, l, o, q), (b, h, j, l, o, g), (b, h, k, l, m, q), (b, h, k, l, m, r), (b, h, k, l, n, q), (b, h, k, l, n, r)(b, h, k, l, o, q), (b, h, k, l, o, r), (b, i, j, l, m, q), (b, i, j, l, m, r), (b, i, j, l, n, q), (b, i, j, l, n, r), (b, i, j, l, o, q), (b, i, j, l, o, r), (b, i, k, l, m, q), (b, i, k, l, m, r), (b, i, k, l, n, q), (b, i, k, l, n, r), (b, i, k, l, o, q), (b, i, k, l, o, r), (c, h, j, l, m, q), (c, h, j, l, m, r), (c, h, j, l, n, q), (c, h, j, l, n, r), (c, h, j, l, o, q), (c, h, j, l, o, r), (c, h, k, l, m, q), (c, h, k, l, m, r), (c, h, k, l, n, q), (c, h, k, l, n, r), (c, h, k, l, o, q), (c, h, k, l, o, r), (c, i, j, l, m, q), (c, i, j, l, m, r), (c, i, j, l, n, q), (c, i, j, l, n, r), (c, i, j, l, o, q), (c, i, j, l, o, g), (s, i, k, l, m, q), (c, i, k, l, m, r), (c, i, k, l, n, q), (c, i, k, l, n, r), (c, i, k, l, o, q), or (c, i, k, l, o, r).

In addition, below the por is maintained preferred compounds of formula (II), contains the possible combinations of fragmentary patterns A and fragmented patterns B.

Specifically, the preferred compound contains the following combinations (fragment A, fragment B):

The following is the preferred connection.

(1) 3-methyl-2-{[2-oxo-1-(2-oxoethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylbutyrate,

(2) 5-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]Valerian acid,

(3) (E)-3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4-hexenoic acid,

(4) methyl-2-{[5,6-dimethyl-1-(2-morpholine-4-retil)-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}-3-methylbutyrate,

(5) 1-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarbonyl acid,

(6) methyl{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetoxy}-(2,2-dimethyl[1,3]dioxolane-4-the l)acetate,

(7) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydroxypyridine-3-carbonyl)amino]-4-methylsulfinylbutyl,

(8) methyl-4-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(9) 1-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid,

(10) 2-{[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexylcarbamate acid,

(11) 2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3,3-dimethylsilane acid,

(12) {[1-(2-methoxyethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(13) 2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-matlakala acid,

(14) 4-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}-1,1-dimethylpiperidin-1-s,

(15) 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4,4,4-cryptomelane acid,

(16) ({2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}methylamino)acetic acid,

(17) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclopent-1-ankurb the new acid,

(18) 1-{[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}cyclohexylcarbamate acid,

(19) {[1-(4-cyanomethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(20) 1,1-dimethyl-2-oxo-2-[N'-carbamoylating]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(21) [(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]phenylacetic acid,

(22) of methyl{[1-(2-Chlorobenzyl)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(23) {1-methyl-1-[(pyridine-3-carbothioic)carbarnoyl]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(24) 2-phenyl[1,3]dioxane-5-silt ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(25) biphenyl-4-yl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(26) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-phenylpropionate acid,

(27) 2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid,

(28) {[1-(2-cyanoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(29) 1-[(1-butyl-5-the Teal-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarbonyl acid,

(30) dimethyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]succinate,

(31) 4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid,

(32) methyl-1-{[1-(1-ethylpyrrolidin-2,2-ylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(33) 2-[(1-benzo[1,3]dioxol-5-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-matlakala acid,

(34) (1-{[2-(3,4-acid)ethyl]methylcarbamoyl}-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(35) {1-[2-(3,4-acid)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(36) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3,3-dimethylsilane acid,

(37) methyl{[1-(4-methoxybenzyl)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(38) ethyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydroxypyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(39) 1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclopropanecarbonyl acid,

(40) ethyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclopentanecarboxylate,

(41) 2-[(-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid,

(42) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-matlakala acid,

(43) diethyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]glutarate,

(44) methyl[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]phenyl acetate,

(45) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-matlakala acid,

(46) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate,

(47) [1-methyl-1-(morpholine-4-ylcarbonyl)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(48) {[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenylacetic acid,

(49) 2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-matlakala acid,

(50) {2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiazol-4-yl}acetic acid,

(51) methyl[(1-butyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(52) of methyl{[1-(3-Chlorobenzyl)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(53) {[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(54) methyl(benzyl{2-[(1-qi is logically-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]ethyl}amino)acetate,

(55) methyl 3-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-phenylpropionate,

(56) {1-[2-(4-methoxyphenyl)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(57) [1-(2-benzo[1,3]dioxol-5-iletileri)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(58) [(1-butyl-2-oxo-1,2,5,6,7,8,9,10,11,12-decapitaciones[b]pyridine-3-carbonyl)amino]phenylacetic acid,

(59) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-(4-methoxyphenyl)acetate

(60) methyl-2-{[1-(3-methoxycarbonylaminophenyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-2-methylpropionate,

(61) (1-methyl-1-dibenzoyltartaric)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(62) {1,1-dimethyl-2-oxo-2-[(pyridine-2-carbonyl)amino]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(63) methyl-2-{[1-(1-ethylpyrrolidin-2-2-ylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(64) {2-[4-(2-hydroxyethyl)piperazine-1-yl]-1,1-dimethyl-2-oxoethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(65) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-Gex is hydrochinon-3-carbonyl)amino]-(4-hydroxyphenyl)acetate,

(66) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-hydroxyphenyl)acetic acid,

(67) methyl{[1-(2-methoxyethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(68) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-damageresistant[b]pyridine-3-carbonyl)amino]acetic acid 2-pyridin-2-jatiluwih ether,

(69) 1-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexylcarbamate acid,

(70) [1-methyl-1-(methylcarbamoylmethyl)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(71) methyl-2-[(1-heptyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(72) methyl{[5,6-dimethyl-2-oxo-1-(4-trifloromethyl)-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(73) methyl-2-{[1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-2-methylpropionate,

(74) ethyl-2-{[1-(3-methoxycarbonylaminophenyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(75) methyl{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]ethylamino}acetate

(76) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4-methylthiazole-5-carboxylic acid,

(77) 4-[(1-qi is logically-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2,2-dimethylsilane acid,

(78) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(79) {[1-(4-terbisil)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenylacetic acid,

(80) benzyl(2-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}ethyl)dimethylamine,

(81) (2 benzolsulfonate-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(82) {1,1-dimethyl-2-oxo-2-[N'-(pyridine-3-carbonyl)hydrazine]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(83) 3,3-dimethyl-2-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyric acid,

(84) methyl[(1-butyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]phenyl acetate,

(85) methyl{[1-(3-methanesulfonyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(86) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid 2-morpholine-4-jatiluwih ether,

(87) {[1-(3-cyanopropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(88) dibutil(2-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl the XI}ethyl)methylammonium,

(89) [2-(4-isobutylpyrazine-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(90) 4,4,4-Cryptor-3-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyric acid,

(91) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4,4-dimethyl-Valerian acid,

(92) (2-methanesulfonyl-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(93) methyl-2-[(1-butyl-2-oxo-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(94) methyl{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionamide}acetate

(95) [1-methyl-1-(2-morpholine-4-iletileri)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(96) [1-(2-hydroxy-1,1-bis-hydroxyethylaminomethyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(97) 1,1-dimethyl-2-oxo-2-[N'-isopropylcarbamate]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(98) {[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}thiophene-2-ilocana acid,

(99) methyl[(1-fu is an-2-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(100) benzofuran-2-yl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(101) 2-carbazole-9-jatiluwih ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(102) [1,1-dimethyl-2-oxo-2-(3-propellerpowered-1-yl)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(103) {1-[(minoriteter)carbarnoyl]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(104) {1-[bis-(2-hydroxyethyl)carbarnoyl]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(105) methyl 3-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate,

(106) methyl{[1-(2-cyanoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(107) 2-(2-oxopyrrolidin-1-yl)ethyl ester [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(108) 2-acetylaminobenzoic ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(109) tert-butyl methyl ether (1-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}piperidin the-4-yl)carbamino acid,

(110) [2-(3-butylcarbamoyl-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(111) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]naphthalene-1-ilocana acid,

(112) (4-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}butyl)trimethylammonium,

(113) [1-(2-carbamoylation)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(114) [2-(4-methanesulfonamido-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(115) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate

(116) methyl[(1-isobutyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(117) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(2-methoxyphenyl)acetic acid,

(118) ethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclopent-1-enecarboxylate,

(119) methyl-4-{[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]methyl}cyclohexanecarboxylate,

(120) {1-methyl-1-[1-(propane-2-sulfonyl)piperidin-ylcarbonyl]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(121) 1,1-dimethyl-2-oxo-2-[(pyridine-3-carbonyl)amino]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(122) methyl{[2-oxo-1-(4-trifloromethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(123) methyl-2-{[1-(1-ethylpyrrolidin-2-2-ylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(124) phenylcarbamoyloxy ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(125) (2 benzoylamino-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(126) methyl[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexylacetate,

(127) methyl-2-[(5,6-dimethyl-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(128) (2 isopropylpiperazine-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(129) methyl{[1-(4-methylbenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(130) [2-(3-carbamoylbiphenyl-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(131) (2-methanesulfonamide the in-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(132) [2-(4-acetylpiperidine-1-yl-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(133) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-4-methylvalerate,

(134) (1-carbarnoyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(135) 1,1-dimethyl-2-oxo-2-[N'-(thiophene-2-carbonyl)-hydrazine]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(136) methyl{[1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(137) methyl-4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]benzoate,

(138) methyl 6-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]hexanoate,

(139) (2-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}ethyl)trimethylammonium,

(140) {1-[2-(4-hydroxyphenyl)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(141) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-2-methylpropionate,

(142) 1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanone the OIC acid,

(143) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]naphthalene-1-ylacetic,

(144) {1-[2-(3,4-dihydroxyphenyl)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(145) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]propionate,

(146) {1,1-dimethyl-2-oxo-2-[(pyridine-4-carbonyl)amino]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(147) {1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexyl}acetic acid,

(148) ethyl-1-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}piperazine-4-carboxylate,

(149) [(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-3-ilocana acid,

(150) [1-(carbamoylmethyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(151) {1,1-dimethyl-2-oxo-2-[4-(propane-2-sulfonyl)piperazine-1-yl]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(152) (1-methyl-1-thioacetimidate)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(153) (2-{2-[(1-cycle is exility-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}ethyl)-triethylammonium,

(154) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid,

(155) 2-{[2-oxo-1-(tetrahydrofuran-2-yl-methyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexylcarbamate acid,

(156) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-3-ilocana acid,

(157) [1-(4-carbamoylbiphenyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(158) methyl[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]phenyl acetate,

(159) 2-tert-butoxycarbonylamino ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(160) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-hydroxyphenyl)acetate,

(161) benzo[b]thiophene-2-yl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(162) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-(4-hydroxyphenyl)-propionate,

(163) methyl 3-[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-phenylpropionate,

(164) 2-methylsulfonylamino ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]vinegar is Oh acid,

(165) 2-pyrrolidin-1-jatiluwih ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(166) tert-butyl ether 4-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}piperazine-1-carboxylic acid,

(167) [2-(4-hydrazinecarbothioamide-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(168) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-(1H-indol-2-yl)propionate,

(169) [1-(cyanomethylene)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(170) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(171) {[1-(4-Chlorobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(172) (3-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}propyl)trimethylammonium,

(173) [(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenylacetic acid,

(174) butyl(2-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}ethyl)dimethylamine,

(175) [2-(4-meanswhen aminopiperidin-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(176)

(177) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-4-methylsulfinylbutyl,

(178) [1,1-dimethyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(179) (1-methyl-1-phenylcarbamoyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(180) {2-[4-(3-isopropyl-ureido)piperidine-1-yl]-1,1-dimethyl-2-oxoethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(181) {1,1-dimethyl-2-oxo-2-[4-(piperidine-1-carbonyl)piperidine-1-yl]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(182) 2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate acid,

(183) dimethyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]succinate,

(184) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-forfinal)acetic acid,

(185) {[(2-hydroxyethyl)methylcarbamoyl]phenylmethyl}amide 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(186) [1-(4-methanesulfonylaminoethyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(187) methyl-2-[(1-b the Teal-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylbutyrate,

(188) methyl{[1-(3-cyanopropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(189) methyl-2-methyl-2-{[2-oxo-1-(2-piperidine-1-retil)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}propionate,

(190) ethyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]cyclohexanecarboxylate,

(191) methyl-2-methyl-2-{[2-oxo-1-(2-oxo[1,3]dioxolane-4-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}propionate,

(192) [(1-benzyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenylacetic acid,

(193) (1,1-dimethyl-2-{4-[methyl(propan-2-sulfonyl)amino]piperidine-1-yl}-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(194) 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-5-methylhexanoic acid,

(195) methyl-2-{[1-(1-ethylpyrrolidin-2-2-ylmethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-4,4-dimethylvaleric,

(196) [1-(2-hydroxy-1-hydroxyethylaminomethyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(197) [2-(N'-benzoylhydrazone)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(198) {[1-(3-methylbutyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyrid the n-3-carbonyl]amino}phenylacetic acid,

(199) methyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanesulfonic acid,

(200) [2-(4-carbamoylbiphenyl-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(201) {1-[2-(4-hydroxy-3-methoxyphenyl)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(202) [1-(2,3-dihydroxypropane)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(203) methyl{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]ethoxy}acetate

(204) (1-hydrazinophenyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(205) {1,1-dimethyl-2-oxo-2-[4-(propane-2-sulfonylamino)piperidine-1-yl]ethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(206) (1-benzylcarbamoyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(207) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-2-methylpropionate,

(208) {1,1-dimethyl-2-[4-(2-methylpropan-2-sulfonylamino)piperidine-1-yl]-2-oxoethyl}amide 1-cyclohexylmethyl-2-the CSR-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(209) methyl 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-phenylpropionate,

(210) ethyl-2-{[1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(211) 1-diethylcarbamazine ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(212) [1-(5-carbamoylation-2-ylcarbonyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(213) [1-(2-acetylaminophenol)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(214) [2-(4-isopropylpiperazine-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(215) [1-(2-hydrooximethylcarbamil)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(216) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(2-methoxyphenyl)acetate

(217) methyl-1-(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)pyrrolidin-2-carboxylate,

(218) methyl-1-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(219) methyl({2-[(1-cyclog Kilmer-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionyl}methylamino)acetate,

(220) ethyl ether {2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiazol-4-yl}acetic acid,

(221) 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]ethylpropane,

(222) {[1-(3-methylbutyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}thiophene-2-ilocana acid,

(223) [(1-butyl-2-oxo-1,2,5,6,7,8,9,10,11,12-decapitaciones[b]pyridine-3-carbonyl)amino]phenylacetic acid,

(224) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate

(225) methyl-4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(226) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(227) methyl[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(228) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]furan-2-ilocana acid,

(229) ethyl ether {2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiazol-4-yl}octoxynol acid,

(230) ethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4-methylthiazole-5-carboxylic acid,

(231) dimethyl-2-[(1-butyl-2-oxo-1,2,5,6,7,89,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]succinate,

(232) of methyl{[1-(4-cyanomethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(233) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-phenyl acetate,

(234) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-4-methylsulfinylbutyl,

(235) methyl 3-methyl-2-{[2-oxo-1-(2-piperidine-1-retil)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(236) ethyl-2-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(237) ethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]cyclohexanecarboxylate,

(238) 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]ethylbenzoic,

(239) methyl-2-methyl-2-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}propionate,

(240) 5-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]methylvalerate,

(241) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(242) 2-hydroxy-1-hydroxymethylation ester 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3,3-dimethylmaleic acid,

(243) diethylcarbamazine ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(244) [1-(6-hydroxyhexanoic)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(245) methyl[(1-cyclohexylmethyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(246) methyl-2-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate,

(247) {1-[bis-(2-hydroxyethyl)carbarnoyl]-2,2-dimethylpropyl}amide 1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid,

(248) methyl-2-[(1-allyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(249) ethyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(250) methyl 3-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]propionate,

(251) 2,2,2-triptoreline ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(252) {(2-[(2-hydroxyethyl)methylcarbamoyl]cyclohexyl)amide 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(253) 2-dibutylaminoethanol ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(254) {1-[2-(3,4-bis-benzyloxyphenyl)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-about the co-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(255) methyl[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]phenyl acetate,

(256) methyl-2-[(1,6-dibutil-2-oxo-5-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(257) methyl{[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(258) 2-hydroxy-1-hydroxymethylation ester 2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylmalonic acid,

(259) {[1-(3-cyanopropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(260) [1-(5-hydroxymethyluracil)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(261) (S)-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-2-ilocana acid,

(262) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]methylbenzoate,

(263) 4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]butyrate,

(264) [1-(2-hydroxy-1-hydroxyethylaminomethyl)-2,2-dimethylpropyl]amide 1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid,

(265) {[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}furan-2-ilocana acid,

(266) [2-(4-hydroxypiperidine-1-yl)-1,1-dimethyl-2-oxoid the l]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(267) 2-diethylaminoethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(268) [1,1-dimethyl-2-(4-methylcarbamoylmethyl-1-yl)-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(269) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-(4-hydroxyphenyl)propionate,

(270) methyl-2-[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylbutyrate,

(271) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenylacetic acid,

(272) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylbutyrate,

(273) methyl-2-[(1-[1,3]dioxane-2-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(274) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10,11,12-decapitaciones[b]pyridine-3-carbonyl)amino]phenyl acetate,

(275) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-hydroxyphenyl)acetate,

(276) methyl-2-{[1-(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-2-methylpropionate,

(277) methyl-1-[(1,6-dibutil-2-oxo-5-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(278) {[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-oktay rollout[b]pyridine-3-carbonyl]amino}phenylacetic acid,

(279) [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-2-ilocana acid,

(280) [1-(3-hydroxypropylamino)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(281) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-methoxyphenyl)acetate

(282) {2-[4-(2-hydrooximethylcarbamil)piperidine-1-yl]-1,1-dimethyl-2-oxoethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(283) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylvalerate,

(284) methyl-2-[(1-cyclohexylmethyl-5-methoxy-6-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(285) methyl-2-[(1-[1,3]dioxolane-2-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(286) methyl ester 2-[(1-butyl-2-oxo-2,5,6,7-tetrahydro-1H-[1]pyridine-3-carbonyl)amino]-3-methylmalonic acid,

(287) methyl{[1-(4-terbisil)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(288) methyl-1-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]cyclohexanecarboxylate,

(289) 2-dimethylaminoethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(290) butikerna roximately ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(291) 4-dimethylamino-butyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(292) methyl-2-[(1-benzo[1,3]dioxol-5-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(293) [1-(1-methanesulfonamido-4-ylcarbonyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(294) [1-(1-benzosulfimide-4-ylcarbonyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(295) {1-[(2,3-dihydroxypropyl)methylcarbamoyl]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(296) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylbutyrate,

(297) 1-cyclohexyloxycarbonyloxy ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(298) 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionamidine ether piperidine-1-carboxylic acid,

(299) [1-(2-hydrooximethylcarbamil)-2,2-dimethylpropyl]amide 1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid,

(300) methyl-2-[(1-cyclohexylmethyl--oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-thiazol-4-ylpropionic,

(301) [1-(3-hydroxy-2,2-dimethylpropanoyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(302) methyl{[1-(4-Chlorobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(303) methyl 3-methyl-2-{[2-oxo-1-(2-piperidine-1-retil)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(304) (4-chloro-phenyl)-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(305) methyl{[1-(4-Chlorobenzyl)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(306) methyl-2-{[1-(3-methanesulfonyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(307) methyl-2-[(1,6-dibutil-2-oxo-5-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2-methylpropionate,

(308) ethyl-2-{[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(309) {[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}thiophene-2-ilocana acid,

(310) [1-(4-hydroxy-butylcarbamoyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(311) {1-[(2-hydroxyethyl)methylcarbamoyl]-2-methylpropyl}amide 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(312) {(-[(2-hydroxyethylmethylcellulose]-2,2-dimethylpropyl)amide 1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(313) methyl-2-[(1-butyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-4-methylvalerate,

(314) methyl-2-{[5,6-dimethyl-1-(3-methylbutyl)-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}-3-methylbutyrate,

(315) methyl-2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-2-methylpropionate,

(316) ([(2-hydroxyethyl)methylcarbamoyl]-2-methylpropyl)amide 1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid,

(317) 1-butylcarbamoyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(318) {1-[(2,3-dihydroxypropyl)methylcarbamoyl]-2,2-dimethylpropyl}amide 1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid,

(319) {1-[2-(2-hydroxyethoxy)ethylcarbamate]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(320) (2-acetylamino-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(321) {2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiazol-4-yl}Okrokana acid,

(322) (4-carbamoylmethyl-2-yl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(323) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-about therotically[b]pyridine-3-carbonyl)amino]succinate,

(324) methyl-2-[(1-cyclohexylmethyl-4-hydroxy-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(325) methyl-1-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(326) methyl-1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclopentanecarboxylate,

(327) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4,4-dimethylvaleric,

(328) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3,3-dimethylbutyryl,

(329) methyl-2-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(330) methyl-2-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(331) methyl-2-[(1-butyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(332) methyl-1-[(1-butyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(333) methyl-1-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(334) methyl-1-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(335) methyl-1-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(36) methyl-1-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarboxylate,

(337) methyl 3-methyl-2-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(338) methyl-1-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(339) methyl 3,3-dimethyl-2-{[2-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(340) methyl-2-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(341) methyl-1-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(342) ethyl-2-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(343) methyl{[1-(3-methylbutyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(344) methyl-2-{[1-(2-methoxyethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(345) methyl-2-[(1-butyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(346) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylbutyrate,

(347) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-4-methylvalerate,

(348) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,67,8-hexahydroquinoline-3-carbonyl)amino]-4-methylvalerate,

(349) ethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(350) isopropyl 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(351) methyl-2-[(1-allyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(352) 2,2-dimethyl[1,3]dioxolane-4-ymetray ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(353) 2-hydroxy-1-hydroxymethylation ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(354) 2,3-dihydroxypropyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate acid,

(355) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-phenylpropionate,

(356) methyl-2-[(4-cyclohexylmethyl-3-oxo--3,4,5,6,7,8-hexahydro-naphthalene-2-carbonyl)amino]-3-phenylpropionate,

(357) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylvalerate,

(358) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-3-methylvalerate,

(359) methoxymethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(360) (1-DIMET carbamoyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(361) methyl-2-[(1-cyclohexylmethyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(362) methyl-1-[(1-butyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(363) methyl-1-[(1-cyclohexylmethyl-2-oxo-2,5,6,7,8,9-hexahydroquinoline-1H-cyclohepta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(364) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10,11,12-decapitaciones[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(365) methyl[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]phenyl acetate,

(366) methyl[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]phenyl acetate,

(367) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]-2-methylpropionate,

(368) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]phenyl acetate,

(369) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(370) methyl-1-{[1-(4-terbisil)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}cyclohexanecarboxylate,

(371) methyl-2-{[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}-3-methylbutyrate,

(372) methyl-2-{[5-ethyl-1-(4-terbisil)-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl]amino}-3-methylbutyrate,

(373) phenyl-2-[(1-cyclohexylmethyl the l-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(374) methyl-1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonyl)amino]cyclohexanecarboxylate,

(375) methyl-1-[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(376) ethyl-2-[(1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(377) {1-[(2-hydroxyethyl)methylcarbamoyl]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(378) ethyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(379) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3,3-dimethylbutyryl,

(380) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2-methylpropionate,

(381) methyl-2-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2-methylpropionate,

(382) (2-oxitetraciclina-3-yl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(383) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3,3-dimethylbutyryl,

(384) methyl-2-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3,3-dimethylbutyryl,

(385) methyl{[5-ethyl-1-(4-terbisil)-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl]and the Ino}phenylacetate,

(386) methyl{[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}phenyl acetate,

(387) S-methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylthiopropionate,

(388) 5-methyl-2-oxo[1,3]dioxol-4-ymetray ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(389) 2-oxo[1,3]dioxolane-4-silt ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(390) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-4-methylvalerate,

(391) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate,

(392) methyl-2-{[1-(3-useprofile)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-2-methylpropionate,

(393) [1-(methoxymethylethoxy)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(394) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-phenylpropionate,

(395) methyl-2-{[1-(2-cyanoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(396) 2-hydroxy-1-hydroxymethylation ester 2-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3,3-dimethylsilanol to the slots,

(397) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-3-ylacetic,

(398) methyl-2-{[1-(3-cyanopropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(399) methyl[(1-benzyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(400) (R)-cyclohexyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(401) [1-(1-isopropylcarbodiimide-4-ylcarbonyl)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(402) 2-hydroxy-1-hydroxymethylation ester 2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3,3-dimethylmaleic acid,

(403) 2-hydroxy-1-hydroxymethylation ester 2-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylmalonic acid,

(404) 1-isopropoxycarbonyloxymethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(405) 3-dimethylaminopropylamine ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(406) methyl (R)-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]propionate,

(407) 2-(2-dioxopiperidin-1-yl)ethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(408) methyl (R)-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(409) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate,

(410) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3-methylvalerate,

(411) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-methylbutyrate,

(412) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-phenylpropionate,

(413) methyl-1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclopropanecarboxylate,

(414) 2-perately ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid,

(415) 1-(ethoxycarbonyl)ethyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(416) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-3-ylacetic,

(417) methyl-2-{[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(418) methyl{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}phenyl acetate,

(419) methyl-2-{[1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]feast the Dean-3-carbonyl]amino}-2-methylpropionate,

(420) isobutyltrimethoxysilane ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid,

(421) methyl-2-{[1-(4-cyanomethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(422) methyl-2-{[1-(4-methoxybenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(423) methyl (S)-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(424) methyl-2-[(1-cyclohexylmethyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-4-methylvalerate,

(425) methyl-2-{[1-(4-terbisil)-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}-3-methylbutyrate,

(426) methyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-phenylpropionate,

(427) methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-3-methylvalerate,

(428) methyl-1-{[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl]amino}cyclohexanecarboxylate,

(429) methyl-1-{[5-ethyl-1-(4-terbisil)-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl]amino}cyclohexanecarboxylate,

(430) diethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]malonate,

(431) methyl[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-2-acetat,

(432) [(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-2-ilocana acid,

(433) methyl-2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(434) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiophene-2-ylacetic,

(435) methyl-2-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3,3-dimethylbutyryl,

(436) methyl{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}furan-2-ylacetic,

(437) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-(4-forfinal)acetate,

(438) methyl 3-methyl-2-{[2-oxo-1-(4-trifloromethyl)-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(439) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenyl acetate,

(440) methyl 3-methyl-2-{[1-(4-methylbenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}butyrate,

(441) methyl-1-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexanecarboxylate,

(442) methyl-2-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-2-methylpropionate,

(443) methyl-1-[(1-furan-2-ylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cycle is hexanecarboxylic,

(444) [1,1-dimethyl-2-oxo-2-(4-propellerpowered-1-yl)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(445) methyl (S)-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]propionate,

(446) (S)-cyclohexyl-1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate,

(447) methyl-1-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(448) ethyl-2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate,

(449) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(450) methyl-2-[(1-butyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(451) methyl-2-[(1-cyclohexylmethyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-4-methylvalerate,

(452) methyl-2-[(1-cyclohexylmethyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]-3,3-dimethylbutyryl,

(453) methyl{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}thiophene-2-ylacetic,

(454) methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]furan-2-ylacetic,

(455) methyl{[6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydro what iridin-3-carbonyl]amino}thiophene-2-ylacetic,

(456) methyl-2-[(1-benzyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-methylbutyrate,

(457) methyl{[1-(3-methylbutyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}thiophene-2-ylacetic,

(458) methyl-2-{[1-(4-Chlorobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-3-methylbutyrate,

(459) (4-carbamoylmethyl-2-yl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(460) (4-aminosalicylate-2-yl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(461) [2-(4-benzosulfimide-1-yl)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(462) 1-{[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]methyl}cyclohexylcarbamate acid,

(463) (S)-3-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}-5-methylhexanoic acid,

(464) (1-{[1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}cyclohexyl)acetic acid,

(465) {2-[3-(2-hydrooximethylcarbamil)piperidine-1-yl]-1,1-dimethyl-2-oxoethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(466) {5-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]Piri is in-3-carbonyl)amino]thiophene-3-yl}acetic acid,

(467) (1-{[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]methyl}cyclohexyl)acetic acid,

(468) 4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-4-methylvaleramide acid,

(469) [1,1-dimethyl-2-oxo-2-(2-pyridin-4-ylacetic-1-amino)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(470) [2-(2,2-dimethoxypropionate)-1,1-dimethyl-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(471) [1,1-dimethyl-2-(2-morpholine-4-ylacetamide)-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(472) {2-[(1-benzyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]thiazol-4-yl}acetic acid,

(473) [1,1-dimethyl-2-oxo-2-(3-intercorporeality-1-yl)ethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid,

(474) {1,1-dimethyl-2-[4-(morpholine-4-carbonyl)piperidine-1-yl]-2-oxoethyl}amide 1-cyclohexylmethyl-2-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid.

As a rule, the compounds of the present invention have a high activity against both receptors CB1 and CB2, or to each of them. The activity value determined mainly by the efficiency of the Yu-binding (Ki value) of the receptor, moreover, the lower the Ki value, the higher the activity (activity in vitro). Although the binding activity of compounds of the present invention with respect to both or either of receptors normally found in a wide range, from 0.1 nm to 5000 nm, and the degree of selectivity with respect to both receptors (Ki values for receptors CB1 and CB2) also changes when applying the compound to the skin (activity in vivo, the effect of suppression of itching will occur if the compound has a Ki of 50 nm or below. Therefore, the preferred compound is a compound with a Ki value of 50 nm or below. Real antipruritic activity of the compounds of the present invention is determined by dissolving the test compound in a solvent and applying it on the skin together with the connection 40/80, which causes itching, while the effect of the compounds is determined by the density required to suppress itching to 50% or more compared with the control group. The connection is considered the most preferred, if it significantly limits itching, 50% or more, when the density of the active ingredient 3% or less.

In addition, suppression of itching also can be achieved by oral administration.

The typical compounds of the present invention are low inhibitory activity against the enzyme (CYP), a small p the adverse effects, associated with the Central nervous system, excellent photostability, etc.

Compounds of the present invention can be obtained by using the following methods.

In the description below, the following abbreviations are used:

Me: methyl

Et: ethyl

n-Pr: n-propyl

i-Pr: isopropyl

n-Bu: n-butyl

Ac: acetyl

DBU: 1,8-diazabicyclo[5,4,0]undecene

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

HOBt: 1-hydroxybenzotriazole

Ms: methanesulfonyl

Diglyme: dimethyl ether of diethylene glycol

Trislim: dimethyl ether of triethylene glycol

TFUCK: triperoxonane acid

TLC: thin layer chromatography

THF: tetrahydrofuran

Ts: paratoluenesulfonyl

WSCD: hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Compounds of the present invention can be synthesized using the compounds (V) with a carboxyl group in the third position as a key intermediate compounds. Data key intermediate compounds are synthesized using any of the methods shown in schemes 1-3, and R1, R2, R3and R4enter in the process of carrying out the method. Although R1-R4directly included in the partial structures of the compounds of the present invention, when possible, a functional group capable of chemical transformation, BBO is it in advance and then they are converted into the functional group of compounds of the present invention. This example is described below.

Scheme 1

where R1, R2, R3and R4are as defined above.

Scheme 1: This method is suitable for the synthesis of compounds where R2means alkyl, and R3means alkyl or alkoxy. The ketone (I) and formate (R4=H) is dissolved in a solvent such as ether or the like, and mix together with a methanol solution of sodium methoxide at a temperature of from the freezing temperature of water to room temperature for 12-24 hours, then β-diketone can be obtained in the form of sodium salt (II). If the compound (II) is suspended in DMF without additional purification and refluxed in the presence of a small excess of acetic acid, and catalytic amounts of piperidine and derived cyanoacetamide (III) within a few hours up to 24 hours to receive the derived 3-cyanopyridine (IV). If R1previously entered a suitable functional group in the next stage it can be transformed into a functional group of another species. In the case of formation of isomers, both isomers or only the desired isomer allocate chromatography on silica gel or by recrystallization of the phase containing the compound (IV). If the connection IV, containing a nitrile group, is subjected to boiling under reflux is a period of from several hours to 24 hours, in alcohol containing water, sodium hydroxide or potassium hydroxide in an amount of from 1 to several mass equivalents, and get targeted 3-carboxylic acid (V). It is believed that the reaction is complete, if the original substance is not detected with TLC or HPLC. The key intermediate compound V with a sufficient degree of purity, as a rule, can be obtained by recrystallization.

Scheme 2

where R1and R4are as defined above; R2and R3taken together with the adjacent carbon atoms, form a 5-to 10-membered cycloalkyl, which may contain in the ring one group selected from-O-, -S-, -SO - and-SO2-.

Scheme 2: This method is particularly suitable for the synthesis of compounds where R2and R3connected with the formation of cyclic groups. That is, if the cyclic ketone (VI) is heated together with the primary amine (VII) in the high-boiling solvent, such as toluene, diglyme or griglen within 3-24 hours at the temperature of reflux distilled solvent until complete dehydration using dehydrator Dean-stark receive UNIMIN (VIII). If the compound (VII) has a low boiling point in order to transform it into the corresponding compound (VIII), the compound (VI) and compound (VII) was stirred at room temperature with a catalytic quantity is ω acid catalyst, such as concentrated hydrochloric acid or concentrated sulphuric acid. Moreover, even if the methylene group in the compound (VI) is replaced by oxygen atom or a sulfur atom, the reaction develops in a similar way. In addition, if R1previously entered a suitable functional group, it can be converted into another functional group in any phase. Ethoxymethylenemalonic add to the compound (VIII), refluxed for 1 to 10 hours and get 3-methyl ester (IX), where R4means hydrogen. If instead of malonic ester used trimethylmethanaminium receive 3-methyl ester (X), where R4means a hydroxyl group. In this case, it is preferable to use a solvent with a high boiling point, such as trislim. Although it is preferable to purify the compound (IX) and the compound (X) by chromatography on silica gel or by recrystallization, as a rule, they are not clear, and the target key intermediate compound (V) can be obtained by immediately adding the required water-containing alcoholic solvent such as methanol or ethanol, or a solvent such as THF or the like, if the connection is insoluble in alcohol, and mixing with a small excess or more mass equivalents of the lithium hydroxide, sodium hydroxide, potassium hydroxide or the like during the period of time from 0.5 to several hours. The compound (V), synthesized using this method, can be obtained as the key intermediate compound with a sufficient degree of purity after recrystallization.

Scheme 3

where R1, R2and R3are as defined above; R is C1-Salkil.

Scheme 3: If the ketone (I or VI) and dimethylformamidine heated at 100°C to the temperature of reflux distilled solvent within 12-24 hours, get ketamin (XI). As dimethylformamidine usually use dimethylformamidine, which is commercially available. If the crude compound (XI) is stirred with cinoxacin ether in a solvent such as methanol, at room temperature, ether (XII) precipitates as insoluble solids. The compound (XII) is dissolved in DMF, THF, DMSO or similar solvents and mixed with a slight excess of sodium hydride at a temperature from room temperature up to 60°C for from 0.5 to several hours. Then add the alkylating agent (R1-X), stirred at a temperature of from room temperature up to 50°C for one to several hours and receive the compound (XIII) and compound (XIV), substituted by perlamutrovuyu or on the second position, as a rule, in the ratio of 1:1. At the same time a suitable functional group can be requested to enter in R1. X alkylating agent preferably means chlorine, bromine, iodine, toluensulfonate, methanesulfonate etc. Compound (XIV) can be easily removed by chromatography on silica gel or by recrystallization. Then the compound (XIII) hydrolyzing the above-mentioned way and get the key intermediate compound (V).

The compound (V), which can be synthesized using the above method, is a key intermediate compound that can be used as the starting material for the synthesis of all compounds of the present invention, and methods of way more are described in detail in reference examples. However, the method of obtaining the compound (V) is not limited to these three methods.

Next, as an example, in which pre-enter a suitable functional group and turn it into a desired functional group in a suitable phase, the described method of introducing an amino group into the end part of R1.

where R1, R2, R3and R4are as defined above; A' is C1-Sallenave group, optionally substituted by one or two substituents selected from the above group of substituents A.

Complex 3-ether (XVII) is produced from compound (I) or compound (VI) and compound (XV) according to the method of scheme 1 or 2. A hydroxyl group can be converted into various functional groups. For example, by reacting compound (XVII) in a solvent such as THF or methylene chloride, chlorinated toluensulfonate and chlorinated methanesulfonate in the presence of a tertiary base such as pyridine or triethylamine, at temperatures between the freezing temperature of water to room temperature, respectively receive toilet or mesilate. These substituents can easily react nucleophilic substitution as a leaving group that can be transformed into other functional groups. For example, by reacting with sodium azide in a solvent such as DMF or DMSO, at temperatures from 100°C to the temperature of reflux distilled solvent, these substituents can be converted into azides (XVIII). Azide can easily be restored in the presence of a catalyst or triphenylphosphine and the like, to obtain amino compounds (XIX). The compound (XIX) can then be not only easily converted into compounds containing other functional groups, such as secondary amine, tertiary amine, amide, sulfonamide and carbamate, which are widely used as partial structures in pharmaceuticals, but also used for p the receipt of new intermediate compounds by introduction of appropriate protective groups. While it is not necessary to explain to the experts in this field how specific transformations of these functional groups, specific methods are, for example, Harryson, I., Harrysn, S., Compendium of Organic Synthesis Vol I-II, Wiley-Interscience, NY (1971,1977), Hegedus, L.S., Wade, L., Compendium of Organic Synthesis Vol III, John Wiley & Sons, NY (1977), Sandler, S.R., Karo, W., Organic Functional Group Preparations, 2nd Ed., Academic Press, NY (1983), Experimental chemistry course, 4th Ed., Organic Synthesis I-V, Maruzen (1992) and other publications. Carboxylic acid (V), where R1 modified, can be obtained by hydrolysis of various compounds (XX)obtained in this manner. As for the other functional groups, the above methods are only based.

The following are ways of turning the key intermediates (V) 3-carbamoyl derivative (XXII-XXV), which are characteristic features of the compounds of the present invention. There is no need to explain to the experts in the field of methods of conversion of carboxylic acids into amides. Although it is enough to follow the methods described in the following documents, such as, for example, Harryson, I., Harryson, S., Compendium of Organic Synthesis Vol I-II, Wiley-Interscience, NY (1971,1977), Hegedus, L.S., Wade, L., Compendium of Organic Synthesis Vol III, John Wiley & Sons, NY (1977), Sandler, S.R., Karo, W., Organic Functional Group Preparations, 2nd Ed., Academic Press, NY (1983), Experimental chemistry course, 4th Ed., Organic Synthesis I-V, Maruzen (1992) and others, the following specific methods commonly used for the teaching of amides of acids.

where R1, R2, R3, R4, R5X1X2X3, Y, Z, G, G1and G2are as defined above.

Carboxylic acid (V) is subjected to interaction with oxalylamino in a solvent such as dichloromethane or THF, in the presence of catalytic amount of DMF at room temperature to obtain the acid chloride. In addition to interaction with oxalylamino, carboxylic acid (V) can also be converted into the acid chloride by boiling under reflux in the presence of thionyl chloride in a non-polar solvent such as benzene or methylene chloride, or in the absence of solvent. By reacting the crude acid chloride with the amine (XXI) in a solvent such as methylene chloride or THF, in the presence of such a base as triethylamine or pyridine, at a temperature of from cooling on ice to room temperature for from one to six hours, get amide (XXII). If the amino group of compound (XXI) forms a salt, for example, inorganic acid, in the reaction mixture should also add the tertiary amine in a quantity sufficient to neutralize the acid. The compound (XXII) can also be obtained directly from compound (XXI) and the compound (V) in the presence of an activating means, such as, for example, WSCD-HOBt. what if the reaction proceeds slowly, you can apply microwave irradiation, after which a reaction that does not leak under normal conditions, is completed in several tens of minutes. The selection is difficult secreted product can be facilitated by use of reagent fixed on the polymer carrier.

Compound (XXI) can be divided into compound (XXIII), compound (XXIV) and compound (XV) depending on the type of G. furthermore, if necessary, the fragment-Y-Z can be converted into various functional groups using the appropriate methods. For example, if-Y-Z means alkoxy in the compound (XXIII) or the compound (XXIV), then after turning alkoxygroup in gelegenheid when using carboxylic acid XXVI, resulting from hydrolysis, halogenmethyl can be subjected to interaction with alcohols, mercaptans or amines with the formation of compounds (XXIII), where Y represents an oxygen atom, a sulfur atom or nitrogen atom, respectively. In this case, you can use the previously described method of amidation.

where R1, R2, R3, R4, R5X1X2X3, Y and Z are as defined above.

If in the alpha-position of the carbonyl exists an asymmetric center and is in the process of hydrolysis is racemization, then as Deputy Z input a security GRU is PU, such as, for example, benzydamine group or tert-bucilina group, which is easily subjected to acid hydrolysis at room temperature under conditions of low pH. Compounds of the present invention have a variety of patterns, and the compound (XXIII) can not only be a compound of the present invention, but can also be used as intermediate compounds for more complex derivatives, and are described in more detail in the examples.

The examples of the preparation of various compounds of the present invention using a carboxylic acid (XXVI) include, for example, amides (XXVIII) by reacting with compounds (XXVII), which contain an amino group. In this case, for example, if a protected amino group is present in the end portion of the molecule, after removal of the protective group can enter another Deputy and the amino group can be easily converted to other functional groups such as amides, sulfonamides and carbamates, which are widely used as partial structures in pharmaceuticals.

In the present invention can be used not only the connection of the present invention, having agonistic activity against cannabinoid receptor, but its salt, permitted for use in the medical industry, and is and MES.

If the connection of the present invention has optical isomers, stereoisomers and geometric isomers, all isomers are included in the scope of the present invention.

Salt, permitted for use in the medical industry include basic salts, for example alkali metal salts, such as salts of sodium and potassium; salts of alkaline earth metals such as calcium salts and magnesium; ammonium salts; salts of aliphatic amines, such as salt, trimethylamine salt of triethylamine, salt dicyclohexylamine, ethanolamine salt, diethanolamine salt, triethanolamine salt and the salt of procaine; salts aralkylamines, such as N,N-dibenziletilendiaminom; salts of heterocyclic aromatic amines, such as salt of pyridine, picoline salt, quinoline salt and salt of isoquinoline; Quaternary salts ammonium, such as salt Tetramethylammonium, salt Tetramethylammonium, salt designed, salt benzyltriethylammonium, salt benzyltrimethylammonium, salt methyltrioctylammonium and tetrabutylammonium salt; salts of basic amino acids such as arginine salt and lysine salt; acid salts include, for example, salts of inorganic acids, such as hydrochloride, sulfates, nitrates, phosphates, carbonates, bicarbonates and perchlorate; organic acid salts such as acetates, propionate, lactates, maleate, fumarate, tartratami, malaty, citrates and Scola is ATA; the sulfonates, such as methanesulfonate, isethionate, benzosulfimide and p-toluensulfonate; salts of amino acids such as aspartate and glutamate.

The solvate include a solvate of the compounds of the present invention or a solvate salts permitted for use in the medical industry, such as monosulfate, desolate, monohydrate, dihydrate etc.

Antipruritic agent in accordance with the present invention can be used as a therapeutic agent for the treatment of itching of allergic or non-allergic in nature, for example, atopic dermatitis, urticaria, contact dermatitis, normal psoriasis, senile xerosis, dialysis kidney or liver failure. In addition, suppression of itching conduct for the prevention of disease and secondary damage resulting from scratching, beating, and other actions related itch.

Compounds of the present invention possess excellent stability, photostability and distribution and may be used for the prevention or treatment of other diseases, in which participates the receptor for cannabinoids, if they have low toxicity associated with inhibition of enzymes (CYP) and the influence on the Central nervous system. For example, in the description of Nature, vol. 365, p.61 to 65, (1993) indicated that agony the t cannabinoid receptor has anti-inflammatory activity and analgesic activity in the description of Journal of Cannabis Therapeutics, vol. 2, No. 1, p. 59 to 71 (2002) indicate that the cannabinoid receptor has bronchodilator activity, and in the description of international publication No. 03/035109, the prospectus stated that the cannabinoid receptor possesses antipruritic activity.

That is, the compounds of the present invention can be used as an antipruritic tools, anti-inflammatory agents, anti-allergic medicines, analgesic tools, medicines for pain (therapeutic agent against painful sensitivity, a therapeutic agent against neuropathic pain, a therapeutic agent against psychogenic pain, a therapeutic agent against acute pain, a therapeutic agent against chronic pain and the like), a therapeutic agent against human immunodeficiency, immunosuppressive funds immunoregulatory tools, therapeutic agents against autoimmune disease, a therapeutic agent against chronic articular rheumatism, a therapeutic agent against osteoarthritis, a therapeutic agent against multiple sclerosis, anti-asthma drugs (as inhibitor inflammatory infiltration cells in the respiratory tract, inhibitor increased irritability of the respiratory p is TEI, a bronchodilator, an inhibitor of the secretion of mucus and the like), a therapeutic agent against chronic obstructive pulmonary disease, a therapeutic agent against emphysema, a therapeutic agent against lung fibrosis, tools, suppressing cough, a therapeutic agent against allergic rhinitis, a therapeutic agent against dermatitis (therapeutic agent against atopic dermatitis, therapeutic agent against urticaria, a therapeutic agent against contact dermatitis, a therapeutic agent against ordinary psoriasis), a therapeutic agent against inflammatory bowel disease, a therapeutic agent against atherosclerosis, a therapeutic agent against glaucoma therapeutic agent against anorexia, etc.

In the treatment of diseases associated with the present invention, the compounds of the present invention can be used together or in combination with other therapeutic agents. In the treatment of itching of allergic or non-allergic in nature, for example, atopic dermatitis, urticaria, contact dermatitis, normal psoriasis, senile xerosis, dialysis renal or hepatic insufficiency, the compounds of the present invention can be used as an antipruritic means which, either alone or in combination with an agonist of the receptor of corticosteroids, immunosuppressive agent, by means of inhibiting PDE IV inhibitor of the formation of IgE antibodies, an antagonist of histamine H1 receptor, an antagonist of histamine H4 receptor, the receptor antagonist of chemokine, an antagonist of VLA-4, non-steroidal anti-inflammatory agent or an agonist of PPAR-gamma.

In addition, when the disease of the Airways compounds of the present invention can also be used along or in combination with an agonist of the receptor of corticosteroids, immunosuppressive agent, by means of inhibiting PDE IV inhibitor of the formation of IgE antibodies, an antagonist of histamine H1 receptor, an antagonist of histamine H4 receptor, the receptor antagonist of chemokine, an antagonist of VLA-4, non-steroidal anti-inflammatory agent, an agonist of PPAR-gamma, a leukotriene receptor antagonist, an inhibitor of leukotriene synthesis, an antagonist of the prostaglandin receptor, an antagonist of the thromboxane A2 receptor, beta2 receptor antagonist, an anticholinergic agent, inhibitor selection of fat cells and means for depressing the cough.

When used in medicine compound of the present invention obtained as a medicine for oral or parenteral administration. The pharmaceutical composition containing the compound of the present invention may be recip is in a form for oral or parenteral administration. That is, the composition can also be obtained in the form of a medicine for oral administration such as tablet, capsule, granule, powder medicine and syrup, and medicines for parenteral administration, including solutions for injection, such as intravenous injection, intramuscular injection and subcutaneous injection, or in the form of medicines for skin injection, such as a suspension formulation for inhalation, eye drops, nasal drops, suppositories, gel, salve, or ointment with the distribution of droplet sizes.

To get these medicines can make use of appropriate media, environment, solvents, bases, etc. known to specialists in this field. For example, in the case of tablets active ingredient and auxiliary ingredient is mixed, pressed and molded. As an auxiliary ingredient use environment, permitted for use in the composition of medicines, such as binders (for example, corn starch and the like), fillers (e.g. lactose, microcrystalline cellulose and the like), dezintegriruetsja means (for example, starch glycolate, sodium and the like) or lubricants (such as magnesium stearate and the like). The tablet may have a suitable coating. For the LM is of such drugs, such as syrup, liquid medicine and suspension, using, for example, suspendresume tools (such as methylcellulose and the like), emulsifying means (such as lecithin and the like) and preservatives. Dosage forms for injection may be in the form of a solution, suspension or oil or emulsion of water and may contain an emulsion stabilizer, dispersing agent, etc. In the case of medicinal forms for inhalation, these drugs are used in the form of liquid compositions suitable for use in the inhaler, and in the case of eye drops, these drugs are used in the form of liquid compositions or in the form of a suspension. To obtain gel active ingredient, a solvent and generouse tool mix and result in a gel-like state. For obtaining ointment with a distribution of droplet sizes used active ingredient, solvent, ointment base, etc.

Although the dose of a compound of the present invention varies depending on the method of administration, symptoms, age, weight and sex of the patient, the type used in conjunction medicines (if such use takes place) and so on, and finally established by the attending physician, in the case of oral administration a daily dose of from 0.01 to 100 mg per 1 kg of body weight, predpochtite the flax from 0.01 to 10 mg and more preferably from 0.1 to 10 mg, in the case of parenteral administration, the daily dose is from about 0.001 to 100 mg per 1 kg of body weight, preferably from 0.001 to 1 mg, and more preferably from 0.01 to 1 mg of the Indicated daily dose divided to introduce one to four times.

For a more specific description of the present invention listed below are reference examples and examples. However, the methods of synthesis of compounds of the present invention is not limited to the methods described in this specification.

Examples

As a 3-pyridinecarboxylic acids can be used commercially available acid or acid synthesized using the following methods.

Example 1. Synthesis of 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01)

Under nitrogen atmosphere a solution of cyclooctanone (15 g, 118 mmol) and cyclohexylethylamine (16,1 g, 142 mmol) in toluene (300 ml) is refluxed under conditions of azeotropic dehydration for 6 hours. Then add diethylethylenediamine (24 ml, 142 mmol) and the mixture is again refluxed for 2 hours. Then the solvent is removed from the reaction mixture by distillation under reduced pressure, the residue is dissolved in a mixed solvent of THF (200 ml) and methanol (200 ml)and add 2M aqueous sodium hydroxide solution and the mixture is peremeshivayte for 2 hours at room temperature. The solvent is removed from the reaction mixture by distillation under reduced pressure, to the residue water is added and the aqueous layer washed with diethyl ether once. Then after acidification 2M hydrochloric acid, the aqueous layer was extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and get a pale yellow solid (AA01, 21,5 g, 57%, TPL: 162-163°C).

NMR: (DMSO-d6) 1,00-of 1.88 (m, 19H), a 2.71 (t, 2H, J=5,7), of 3.00 (t, 2H, J=5,7), of 4.05 (d, 2H, J=6,3), to 8.20 (s, 1H).

Example 2. Synthesis of 1-(4-terbisil)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridineboronic acid (AA02)

The solution cyclooctanone (of 7.55 g, to 59.8 mmol) and performanceline (8,20 g, 71,8 mmol) in toluene (100 ml) is heated in a nitrogen atmosphere under reflux under conditions of azeotropic dehydration for 6 hours. Then add diethylethylenediamine (12.1 ml, to 59.8 mmol) and the mixture is again refluxed for 2 hours. The solvent is removed from the reaction mixture by distillation under reduced pressure, to the residue add THF (100 ml), methanol (100 ml) and 2M aqueous sodium hydroxide solution in that order, then the mixture is stirred for 2 hours at room temperature. The solvent is removed from the reaction mixture by distillation at bonigen the m pressure, to the residue water is added and washed with diethyl ether once. Then to the aqueous layer add 2M hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and get a pale yellow solid (AA02, 9,8 g, 50%, TPL: 170-172°C).

NMR: (CDCl3) 1,36-of 1.88 (m, 8H), to 2.67 (t, 2H, J=6,0), is 2.88 (t, 2H, J=6,0), 5,46 (s, 2H), 7,00-7,16 (m, 4H), of 8.37 (s, 1H), 14,47 (Sirs, 1H).

Example 3. Synthesis of 1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carboxylic acid (AA03)

A solution of 4-heptanone (5.0 mm, 35,75 mmol), n-butylamine (4,25 ml, the 4.29 mmol) and three drops of concentrated hydrochloric acid is stirred under nitrogen atmosphere in the course of 18.5 hours at room temperature. Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate, then the solvent is removed by distillation under reduced pressure. The obtained oily substance was dissolved in 2-methoxyethanol ether (40 ml), heated and mixed with dimethylethoxysilane (5,66 g, 32.5 mmol) at 120°C for 3 hours. The solvent is removed by distillation under reduced pressure, then the residue purified column chromatography on silica gel (100 g) (ethyl acetate-hexane at a ratio of 1:1, for the eat 2:1) and get a dark reddish-brown oily substance. The resulting material without purification was dissolved in THF (20 ml) and add 1M aqueous solution of lithium hydroxide (15,18 ml) and water (4,82 ml), the mixture is then stirred for 2 hours at room temperature. The mixture is then diluted with water and washed with diethyl ether. After acidification of 2M hydrochloric acid, the aqueous layer was extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and get a pale yellow solid (AA03, 1.68 g, 18%).

NMR: (CDCl3) a 1.01 (t, 3H, J=7,5), of 1.12 (t, 3H, J=7,5), to 1.22 (t, 3H, J=7,5), 1,40-1,90 (m, 6H), 2,53 (square, 2H, J=7,5), 2,70 (m, 2H), 4,13 (t, 2H, J=7,5), with 8.33 (s, 1H), 14,79 (Sirs, 1H)

Example 4. Synthesis of methyl-1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA04)

1) Synthesis of methyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate

The solution cyclooctanone ($15.87 with ml, 120 mmol) and DMF of dimethylacetal heated in nitrogen atmosphere and stirred at 100°C for 12 hours. Then the solvent is removed by distillation under reduced pressure and obtain a pale yellow oily substance (16,54 g). The resulting substance was dissolved in methanol (50 ml), add methylcinnamic (8,87 ml, 100,37 mmol) and stirred at room temperature. The precipitated solid is separated by filtration, prom is live diethyl ether and obtain the target compound as a colourless solid (13.8 g, 49%, TPL: 220-224°C).

NMR: (CDCl3) 1,58-of 1.88 (m, 8H), at 2.59 (t, 2H, J=6,0), 2,82 (t, 2H, J=6,0), 3,90 (s, 3H), of 8.04 (s, 1H), KZT 12.39 (width, 1H).

2) Synthesis of methyl-1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA04)

Methyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (300 mg, of 1.27 mmol) was dissolved in DMF (5 ml) under nitrogen atmosphere, add sodium hydride (61 mg, 1.53 mmol) and stirred at room temperature for 30 minutes. Then add 4-cyanobenzylidene (to 274.9 mg of 1.40 mmol) and the mixture is stirred at room temperature for another 1 hour. Then to the reaction mixture are added water and 5% citric acid solution and the resulting mixture extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (10 g) (ethyl acetate-hexane in the ratio 1:1) and receive a colourless solid, methyl-1-(4-cyanobenzyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA04, 100 mg, 22%, TPL: 72-75°C) and colourless solid, methyl-2-(4-cianfrocca)-5,6,7,8,9,10-hexahydrocyclooct[b]pyridine-3-carboxylate (123 mg, 28%, TPL: 122-123°C).

AA04

NMR: (CDCl3) 1,38-of 1.93 (m, 8H), 2,61 (t, 2H, J=6,0), a 2.75 (t, 2H, J=6,0), 3,90 (s, 3H), 5,44 (width, 2H), 7.23 percent (d, 2H, J=8,4), 7,60 (d, 2H, J=8,4), 8,01 (s, 1H).

methyl-2-(4-cianfrocca)-5,6,7,8,9,10-hexahydrite is the[b]pyridine-3-carboxylate

NMR: (CDCl3) of 1.28 to 1.34 (m, 4H), 1,60-1,80 (m, 4H), of 2.72 (t, 2H, J=6,3), 2,85 (t, 2H, J=6,3), 3,91 (s, 3H), to 5.56 (s, 2H), 7,65 (s, 4H), 7,92 (s, 1H).

Example 5. Synthesis of methyl-1-(3-cyanopropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA05)

2-Oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-methylcarbazole (8 g, 34 mmol)obtained in example 4 was dissolved in DMF (160 ml) under nitrogen atmosphere, add sodium hydride (1.63 g, a 40.8 mmol) and the mixture was stirred at 50°C for 1 hour. The mixture is then cooled to room temperature, add 4-bromobutyronitrile (3,71 ml, or 37.4 mmol) and the mixture was stirred at 50°C for 2 hours. Then add water and 5% citric acid solution, then the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous sodium sulfate, the solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (160 g) (ethyl acetate-hexane in the ratio 3:7) and obtain a colorless oily substance (AA05, 3,71 g, 36%, TPL: 82-84°C) and the corresponding O-alkyl (39%).

AA05

NMR: (CDCl3) 1,38-of 1.93 (m, 8H), 2,04-of 2.16 (m, 2H), by 2.55 (t, 2H, J=5,7), 2,60 (t, 2H, J=6,0), 2,90 (t, 2H, J=6,0), 3,90 (s, 3H), is 4.21 (t, 2H, J=6,0)), 8,01 (s, 1H).

Example 6. Synthesis of ethyl-1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylate (AA06)

Toluene solution (50 ml) of 3-pentanone (5.0 g, to 58.1 mmol) and benzylamine (6,23 g, to 58.1 mmol) is refluxed in conditions of azeotropic dehydration for 3 hours. Then add diethylethylenediamine (12,56 g, to 58.1 mmol) and the mixture refluxed for another 5 hours. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (300 g) (ethyl acetate-hexane at a ratio of 1:5, then 1:3 and 2:1) and obtain a pale yellow oily substance (AA06, 1.92 g, 11.0 per cent).

NMR: (CDCl3) of 1.12 (t, 3H, J=7,7), to 1.38 (t, 3H, J=7,2), of 2.15 (s, 3H), 2,64 (square, 2H, J=7,5), 4,36 (square, 2H, J=7,2), 5,43 (width, 2H), 7,11 (d, 2H, J=6,9), 7,20-to 7.32 (m, 3H), of 8.04 (s, 1H).

Example 7. Synthesis of 1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (AA07)

2M sodium hydroxide solution (7.9 ml, 15.8 mmol) is added to the solution obtained in example 6 ethyl-1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylate (AA06, 1.92 g, 6.3 mmol) in methanol/THF (7.9 ml/7.9 ml) at room temperature and stirred at the same temperature for 2 hours. The reaction mixture was diluted with water (10 ml) and washed with ether (20 ml). To the aqueous layer add 2M hydrochloric acid (8 ml, 16 mmol) and the mixture was twice extracted with ethyl acetate (20 ml). The organic layer is washed twice with water (20 ml) and dried with anhydrous sodium sulfate. The solvent UD is given by distillation under reduced pressure, and receives a yellow oily 1-benzyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (AA07, 1,43 g). The product is left to crystallize overnight. The resulting crystals are recrystallized from ethyl acetate and get a white elongated crystals (AA07, and 1.00 g, 58.5 per cent).

TPL: 113-114°C.

NMR: (CDCl3) of 1.18 (t, 3H, J=7,7), 2,24 (s, 3H), 2,73 (square, 2H, J=7,5), 5,49 (Sirs, 2H), to 7.09 (m, 2H), 7,29-7,38 (m, 3H), scored 8.38 (s, 1H), 14,53 (Sirs, 1H).

Example 8. Synthesis of ethyl-1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08)

Toluene solution (40 ml) tetrahydrothiopyran-4-it (of 5.05 g of 43.5 mmol) and aminometilbensana (5,41 g, 47,8 mm) is refluxed under conditions of azeotropic dehydration for 4 hours, then add diethylethylenediamine (9,40 g of 43.5 mmol), the mixture is then refluxed for a further 17 hours. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (160 g) (ethyl acetate-toluene in the ratio of 1:5, then 2:3) and get a red oily ethyl-1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08, 8,17 g, 31.5 per cent).

NMR: (CDCl3) 1,00-1,25 (m, 5H), to 1.38 (t, 3H, J=7,2), 1,60 is 1.96 (m, 6H), 2,90-3,03 (m, 4H), 3,62 (s, 2H), 3,93 (width, 2H), 4,36 (square, 2H, J=7,2), 7,89 (s, 1H).

Example 9. Synthesis of 1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (AA09)

4M Races is the thief of sodium hydroxide (15.2 ml, 60,8 mm) are added to a methanol solution (30 ml) ethyl-1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylate (AA08, 8,16 g, a 24.3 mmol)obtained in example 8 at room temperature and the mixture is refluxed for 30 minutes. The reaction mixture was diluted with water (100 ml) and washed with ether (100 ml). To the aqueous layer add 5M hydrochloric acid solution (13 ml, 65 mmol), precipitated crystals are separated by filtration, washed with water to give brown crystals of 1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (of 6.78 g). The obtained crystals are recrystallized from a mixture of ethanol-water, getting a light brown crystalline powder (AA09, 6,30 g, 84.3 percent).

TPL: 144-145°C

NMR: (DMSO-d6) 0,99-1,25 (m, 5H), 1,46-to 1.87 (m, 6H), of 2.97 (t, 2H, J=6,0)and 3.15 (t, 2H, J=6,0), of 3.78 (s, 2H), 4,07 (width, 2H), 8,24 (s, 1H), 14,84 (s, 1H).

Example 11. Synthesis of 1,5-dibutil-6-methyl-2-oxo-1,2-dihydropyridines-3-carbonitrile (AA11)

A mixture of 28% methanolic solution of sodium methoxide (39 ml, 202 mmol) and ether (260 ml) and cooled in an atmosphere of nitrogen up to 3°C in a bath with ice and added dropwise a mixture of 2-heptanone (22.84 to g, 200 mmol) and ethylformate (16,15 g, 218 mmol) for about 20 minutes. The resulting mixture was stirred at the same temperature for 30 minutes, then warmed to room temp the atmospheric temperature and continue to stir for a further 20 hours. The precipitated product is removed by filtration and washed with a sufficient amount of air (approximately 620 g). The mother liquor and wash are combined and concentrated, obtaining 29,34 g of the crude product. The crude product is washed several times with hexane and ether, and get powdered sodium salt of 3-[1-hydroxyethylidene]heptane-2-it (11,33 g, 34.5 per cent) color yellow ochre.

The obtained Sol (2,13 g, 13 mmol) suspended in DMF (10 ml)at room temperature add n-butylcyanoacrylate (1.40 g, 10 mmol), acetic acid (0.75 ml, of 13.1 mmol) and piperidine (0,20 ml, 2.02 mmol) in that order, then the mixture is refluxed at 135°C for 7 hours. Then the reaction mixture is left to stand at room temperature for 13 hours, then poured into ice water and the resulting mixture was twice extracted with ethyl acetate. The organic layer is washed once with dilute hydrochloric acid and twice with water, then dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and get 2,03 g of a red oily crude product. The crude product is purified by chromatography on silica gel and get the target of 1.5-dibutil-6-methyl-2-oxo-1,2-dihydropyridines-3-carbonitrile (AA11, 420 mg, 17.3%) and 1-butyl-2-oxo-6-pentyl-1,2-dihydropyridines-3-carbonitrile (230 mg, 9.4 per cent).

AA11

NMR:(CDCl3) of 0.95 (t, 3H, J=6,9), and 0.98 (t, 3H, J=6,9), of 1.5-1.7 (m, 8H), 2,42 (s, 3H), ca 2,4 (m, 2H), 4,08 (2H, m), EUR 7.57 (1H, s).

1-butyl-2-oxo-6-pentyl-1,2-dihydropyridines-3-carbonitril

NMR: (CDCl3) to 0.94 (t, 3H, J=6,8), and 0.98 (t, 3H, J=7,2), 1.3 to 1.7 (m, 10H)to 2.66 (m, 2H), Android 4.04 (m, 2H), 6,11 (ABd, 1H, J=7,5), To 7.67 (ABd, 1H, J=7,5).

Example 12. Synthesis of 1,5-dibutil-6-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (AA12)

1,5-Dibutil-6-methyl-2-oxo-1,2-dihydropyridines-3-carbonitrile (AA11, 420 mg, 1,705 mmol)obtained in example 11, was dissolved in 80% aqueous ethanol and the solution is refluxed in the presence of potassium hydroxide (770 mg, 13.7 mmol) for 22 hours. The solvent is removed by distillation under reduced pressure, to the residue water is added and the mixture was once washed with ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid (3 ml) and the precipitated solid is separated by filtration and washed with water. Then the solid is dried in air and get a solid 1.5 to dibutil-6-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid colors of yellow ochre (AA12, 352 mg, 78%, TPL:106-108°C).

NMR: (CDCl3) of 0.95 (t, 3H, J=7,2), a 1.01 (t, 3H, J=7,3), is 1.3-1.8 (m, 8H), 2.49 USD (s, 3H), of 2.51 (t, 2H, J=7,5), 4,17 (m, 2H), 8,29 (s, 1H).

Example 13. Synthesis of 1-butyl-6-methyl-2-oxo-5-pentyl-1,2-dihydropyridines-3-carboxylic acid (AA13)

Connection AA13 synthesized from 2-octanone, analogicopoesie example 12.

TPL: 106-109°C

NMR: (CDCl3) of 0.93 (t, 3H, J=6,9), a 1.01 (t, 3H, J=7,2), is 1.3-1.8 (m, 10H), 2,49 (s, 3H), of 2.50 (m, 2H), 4,17 (2, 2H), 8,29 (s, 1H), 14,77 (Sirs, 1H).

Example 14. Synthesis of 1-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (AA14)

Connection AA14 synthesized from 2-butanone, similar to the method of example 12.

TPL: 148-151°C

NMR: of 2.21 (s, 3H), of 2.38 (s, 3H), of 5.50 (s, 2H), a 7.1 to 7.15 (m, 2H), 7,2-7,4 (m, 3H), of 8.37 (s, 1H), of 14.57 (Sirs, 1H).

Example 15. Synthesis of 1-butyl-6-ethyl-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (AA15)

Connection AA15 synthesized from 2-pentanone, similar to the method of example 12.

TPL: 121°C

NMR: (CDCl3) and 1.00 (t, 3H, J=7,2), of 1.27 (t, 3H, J=7,6), and 2.79 (m, 2H), 1,71 (m, 2H), of 2.23 (s, 3H), 2,79 (square, 2H, J=7,6), 8,29 (s, 1H), 14,77 (Sirs, 1H).

Example 16. Synthesis of ethyl-1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA16)

Toluene solution (30 ml) of cyclooctanone (to 4.23 g, 33,52 mmol) and aminometilbensana (4,36 ml, 33,52 mmol) is refluxed in conditions of azeotropic dehydration for 15 hours. The reaction mixture is allowed to cool to room temperature, then concentrated under reduced pressure. The residue is distilled under reduced pressure and get 5,90 g of a colorless oily substance (80%, TPL: 120-122°C).

The resulting substance (1,15 g, 519 mmol) is stirred triglyme (7 ml) in the presence of triethylmethylammonium acid (from 0.88 ml, 4,15 mmol) at 135°C for 36 hours. To the reaction mixture was added diluted hydrochloric acid and the mixture is extracted with toluene. The organic layer is washed with water and saturated salt solution, dried, concentrated, then the residue purified column chromatography on silica gel (hexane-ethyl acetate (15-25%)) and get the product as a colourless solid (AA16, 667 mg, 45%).

NMR: (CDCl3) 0,89-to 1.98 (m, 22H), 2,60-2,96 (m, 4H), 4,20 is 4.35 (m, 2H), 4,45 (square, 2H, J=7,2), 13,71 (s, 1H).

Example 17. Synthesis of methyl-1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA17)

To a mixture of cyclooctanone (3,84 g, 30,43 mmol) and butylamine (3,01 ml, 30,43 mmol) is added two drops of concentrated hydrochloric acid and the mixture is stirred at room temperature for 15 hours. Add the diluted aqueous solution of sodium carbonate and ethyl acetate to separate the reaction mixture and the organic layer washed with water and saturated salt solution. The organic layer is dried, the solvent is removed by distillation and get 4,72 g of a colorless oily substance (86%). The resulting Imin (4,67 g, 25,76 mmol) is subjected to interaction by the above method with trimethylmethanaminium acid (3.42 g, 18 mm) in triglyme (40 ml) and receive a viscous yellow oily substance (AA17, 2,62 g, 47%).

NMR: (CDCl 3) to 0.96 (t, 2H, J=7,2), 1,36-of 1.81 (m, 12H), to 2.67 (m, 2H), 2,86 (t, 2H, J=6,0), 3,94-was 4.02 (m, 2H), 13,55 (s, 1H).

Example 18. Synthesis of ethyl-1-(3-hydroxypropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA18)

Cyclooctane (10,00 g, 79,18 mmol) dissolved in toluene (140 ml) and refluxed in the presence of 2-amino-1-propanol (6,10 ml, 79,75 mmol) in conditions of azeotropic dehydration in the course of 14.5 hours. Then add diethylethylenediamine (16.0 ml, 79,18 mmol) and the solution refluxed for a further 5.5 hours. Then the solution is concentrated under reduced pressure until the amount of solvent will not be reduced approximately by half, and the residue is purified column chromatography on silica gel (192 g) (ethyl acetate-hexane (1:1), ethyl acetate, a mixture of ethyl acetate-methanol (4:1) in that order, getting a brown oily substance (AA18, 13,63 g, 56%).

NMR: (CDCl3) 1,35-of 1.55 (m, 4H), to 1.38 (t, 3H, J=7,2), 1,63 of-1.83 (m, 4H), 1,86-of 1.97 (m, 2H), 2,58-2,62 (m, 2H), 2,88-of 2.93 (m, 2H), 3,52-3,55 (m, 2H), 4,32 (Sirs, 2H), 4,37 (square, 2H, J=7,2), 7,95 (s, 1H).

Example 19. Synthesis of ethyl-1-(3-methanesulfonyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA19)

Ethyl-1-(3-hydroxypropyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA18, 13,63 g, 44,34 mmol)obtained in example 15, was dissolved in anhydrous THF (105 ml), ZAT is under stirring and cooling on ice, add triethylamine (9.28 are ml, 66,53 mmol) and methanesulfonamide (4,12 ml, 53,23 mmol), the mixture is then stirred for 45 minutes. The reaction mixture is acidified, pouring into dilute aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and water, then dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (176 g) (ethyl acetate, then ethyl acetate : methanol (9:1) in that order and receive light orange oily substance (AA19, the 7.85 g, 46%).

NMR: (CDCl3) 1,35 is 1.58 (m, 7H), 1,62-of 1.84 (m, 4H), 2,14-of 2.26 (m, 2H), 2,58-2,62 (m, 2H), 2,86-2,90 (m, 2H), 3,06 (s, 3H), 4,20-the 4.29 (m, 2H), 4,32-of 4.44 (m, 4H), of 7.96 (s, 1H).

Example 20. Synthesis of ethyl-1-(3-useprofile)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA20)

Ethyl-1-(3-methanesulfonyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA19, the 7.85 g, 20,36 mmol)obtained in example 19 was dissolved in anhydrous DMF (60 ml), then cooled on ice to the solution was added sodium azide (2,13 g, 32.76ˆ mmol) and the mixture is stirred for another 40 minutes. The mixture is then warmed to room temperature and stirred for further 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water and sushi is t anhydrous magnesium sulfate. Then the solvent is removed by distillation and receives a yellow oily substance (AA20, 6,74 g, 99.5%pure).

NMR: (CDCl3) 1,35-of 1.55 (m, 4H), of 1.39 (t, 3H, J=7,2), 1,62 of-1.83 (m, 4H), 1.93 and-2,04 (m, 2H), 2.57 m-2,61 (m, 2H), 2,87-only 2.91 (m, 2H), 3.46 in (t, 2H, J=6,3), 4,13-is 4.21 (m, 2H), 4,37 (square, 2H, J=7,2), of 7.96 (s, 1H);

IR (chloroform): 2100, 1728, 1693, 1650, 1591, 1543, 1482, 1453, 1439, 1414, 1380, 1363, 1351, 1319.

Example 21. Synthesis of ethyl-1-(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA21)

Ethyl-1-(3-useprofile)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA20, 3.25 g, 9,78 mmol)obtained in example 20 was dissolved in anhydrous THF (33 ml), add water (16 ml), followed by triphenylphosphine (is 3.08 g, 11,73 mmol) and the mixture refluxed for 1 hour and 30 minutes. The reaction mixture is acidified with diluted aqueous hydrochloric acid solution and then washed with ethyl ether. The aqueous layer was removed by distillation and obtain a pale yellow solid. The solid is suspended in anhydrous THF (50 ml), then with stirring and cooling the solution on ice, add triethylamine (4,10 ml, 29,40 mmol) and methanesulfonamide (1,67 ml, 21,58 mmol), the mixture is then stirred for 50 minutes. The mixture is then warmed to room temperature and stirred for further 2 hours. The reaction mixture is acidified, pouring in a dilute aqueous solution chloritoid is one acid, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (42 g) (ethyl acetate, then ethyl acetate : methanol (17:3) in that order) and get a pale yellow residue (1.90 g). The obtained residue is recrystallized from a mixture of ethyl acetate-hexane and get colorless prismatic crystals (AA21, 1,69 g, 45%).

TPL: 138-139°C

NMR: (CDCl3) 1,35-and 1.54 (m, 4H), to 1.38 (s, 3H), 1,62-to 1.82 (m, 4H), 1,92 2,03 (m, 2H), 2.57 m-2,61 (m, 2H), 2,84-only 2.91 (m, 2H), 2,96 (s, 3H), is 3.08-and 3.16 (m, 2H), 4,21-4,30 (m, 2H), 4,35 (square, 2H, J=7,2), of 5.84 (Sirs, 1H), to 7.93 (s, 1H);

IR (chloroform): 3235, 1727, 1695, 1646, 1589, 1543, 1481, 1453, 1440, 1411, 1363, 1328.

Elemental analysis (C18H28N2O5S)

Calculated (%): C, 56,23; H, 7,34; N, 7,29; S, 8.34 Per.

Found (Percent): C, 56,11; H, 7,28; N, 7,28; S 8,07.

Example 22. Synthesis of 1-(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA22)

Ethyl-1-(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA21, 1.66 g, 4,33 mmol)obtained in example 21 were dissolved in methanol (17 ml), added 4M aqueous sodium hydroxide solution (4,32 ml, 17,40 mmol) and the mixture is heated at 50°C for 5 hours. The reaction mixture is then poured the water. The aqueous layer was washed with ethyl ether, then acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed with water, dried with anhydrous magnesium sulfate and obtain colorless needle crystals (AA22, 1.52 g, 98%).

TPL: 197-198°C

NMR: (DMSO-d6) 1,28-1,49 (m, 4H), 1,55-to 1.67 (m, 2H), 1,69-of 1.92 (m, 4H), 2,68 was 2.76(m, 2H), 2,92 (s, 3H), 2,97-3,14 (m, 4H), 4,14-4,24 (m, 2H), 7,16 (t, 1H, J=6,0), 8,21 (s, 1H), the 14.90 (s, 1H);

IR (nujol): 3203, 2675, 1701, 1622, 1551, 1463, 1442, 1415, 1374, 1316.

Elemental analysis (C16H24N2O5S)

Calculated (%): C, 53,91; H, 6,79; N, 7,86; S 9,00.

Found(Percent): C, 53,87; H, To 6.67; N, 7,89; S 8,90.

Example 23. Synthesis of ethyl-1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA23)

Ethyl-1-(3-useprofile)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA20, 1.73 g, to 5.21 mmol)obtained in example 20 was dissolved in THF (17 ml), add water (8.5 ml), followed by triphenylphosphine (1.64 g, and 6.25 mmol) and the mixture is refluxed for 90 minutes. The reaction mixture was poured into water and washed with ethyl ether. The aqueous layer was concentrated under reduced pressure and receives a yellow oily amine (1,58 g). The obtained amine was dissolved in anhydrous THF (15 ml), then with stirring and cooling the solution on ice, add pyridine (0,83 ml, 10,26 mmol) and methylcarbonate, before the mixture is stirred for 50 minutes. The mixture is then stirred at room temperature for two hours and 20 minutes. Then the reaction mixture is acidified, pouring into dilute aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium bicarbonate solution, then dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (66 g) (ethyl acetate, then ethyl acetate : methanol (4:1) in that order) and get a pale yellow solid (AA23, 643 mg). The obtained solid is recrystallized from a mixture of ethyl acetate-hexane and get pale yellow needle crystals (AA23, 568 mg, 30%).

TPL: 103-104°C

NMR: (CDCl3) 1,36-and 1.54 (m, 4H), to 1.38 (t, 3H, J=7,2), 1,62-to 1.82 (m, 4H), 1,83-of 1.94 (m, 2H), 2,56-2,60 (m, 2H), 2,84-is 2.88 (m, 2H), 3,16-of 3.27 (m, 2H), 3,66 (s, 3H), 4,12-to 4.23 (m, 2H), 4,36 (square, 2H, J=7,2), 5,64 (Sirs, 1H), to 7.93 (s, 1H).

Example 24. Synthesis of 1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA24)

Ethyl-1-(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA23, 560 mg, 1.54 mmol)obtained in example 23, was dissolved in methanol (6 ml), added 4M aqueous sodium hydroxide solution (1,15 ml, 4,63 mmol) and the mixture stirred at room temperature for one hour and 50 minutes. actionnow mixture was poured into water and washed with ethyl ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed with water and dried with anhydrous magnesium sulfate, the solvent is removed by distillation and obtain a colorless oily substance (AA24, 544 mg). The obtained oily substance is recrystallized from a mixture of ethyl acetate-hexane and obtain colorless needle crystals (AA24, 502 mg, 97%).

TPL: 148-149°C

NMR: (CDCl3) 1,35-of 1.56 (m, 4H), 1.60-to to 1.86 (m, 4H), 1,88 is 2.01 (m, 2H), 2,65-2,69 (m, 2H), 2,93-of 2.97 (m, 2H), 3,24 (square, 2H, J=6,3), of 3.69 (s, 3H), 4,20-4,30 (m, 2H), 5,44 (Sirs, 1H), 8.30 to (s, 1H), 14,54 (s, 1H);

IR (chloroform): 3451, 2693, 1721, 1626, 1567, 1544, 1513, 1464, 1412, 1381, 1364, 1333, 1316.

Elemental analysis (C17H24N2O5)

Calculated (%): C, 60,70; H, 7,19; N, 8,33.

Found(Percent): C, 60,52; H, 7,11; N, 8,32.

The following 3-pyridinecarboxamide acid (AA25-AA41) synthesized using a method similar to the above. Structural formulas and the results of NMR analysis are shown in tables 1-3.

Table 1
no connect.Structure1H-NMR (DMSO-d6/S)
AA 1,00-1,30 (t, 5H), to 1.22 (t, 3H, J=7,5), 1,55-1,90 (t, 6N), 2,24 (s, 3H), 2,82 (square, 2H, J=7,2), 3,90-4,20(t, 2H), 8,29 (s, 1H)
AAto 1.00 (t, 3H, J=7,5), 1,35-of 1.55(m, 6H), 1.60-to 1,86 (t, 6N), 2,63-a 2.71 (t, 2H), 2,90-to 2.99 (t, 2H), 3,99-is 4.21 (t, 2H), of 8.27 (s, 1H), 14,78 (Sirs, 1H)
AAof 1.10 (t, 3H, J=7,5), 1,20 of 1.28 (m, 4H), 1,52-1,64 (t, 2H), of 2.51-2,59 (square, 2H, J=7,5), 2,84-2,90 (t, 2H), 3,30 (s, 3H), and 3.72 (t, 2H, J=5,1), 4,36 (t, 2H, J=5,1), at 8.36 (s, 1H)
AA1,32-and 1.54 (m, 4H), of 1.66 (m, 4H), to 2.67 (t, 2H, J=6,0), 3,11 (t, 2H, J=6,0), 3,30 (s, 3H), and 3.72 (t, 2H, J=5,4), and 4.40 (t, 2H, J=5,4), 8,30 (s, 1H), 14,64 (width, 1H)
AA1,35-1,90 (m, 8H), 1,90-2,10 (m, 2H), 2,15-to 2.40 (m, 2H), 2,60-of 2.75 (m, 2H), 2,85-3,00 (m, 2H), 4,15-4,30 (m, 2H), 8,30 (s, 1H)
AAof 1.02 (d, 6H, J=6,6), 1,40-of 1.85 (m, 12H), to 2.67 (m, 2H), 2,93 (m, 2H), 4.16 the (m, 2H), of 8.27 (s, 1H)
AAof 0.98 (d, 6H, J=6,6), of 1.39 (t, 3H, J=6,3), 1,43 and 1.80 (m, 11H), 2,58 (m, 2H), 2,85 (m, 2H), 4.09 to (m, 2H), 4,37 (d, 2H, J=6,6), to 7.93 (s, 1H)

Table 2
no connect.Structure1H-NMR (DMSO-d6/S)
AAof 1.02 (d, 6H, J=6,6), of 1.28 (t, 3H, J=7,5), 1,56-of 1.66 (m, 2H), 1,78 (m, 1H), of 2.23 (s, 3H), 2,79 (square, 2H, J=7,5), 4,10-is 4.21 (m, 2H), 8,28 (s, 1H)
AA0,99 (d, 6H, J=6,6), to 1.22 (t, 3H, J=7,5), to 1.38 (t, 3H, J=7,5), 1,54-to 1.79 (m, 3H), and 2.14 (s, 3H), 2,70 (square, 2H, J=7,5), 4.09 to (m, 2H), 4,36 (square, 2H, J=7,5), 4,36 (d, 2H, J=7,5), 7,95 (s, 1H)
AACDCl31,2l (t, 3H, J=7,7 in), 2.25 (s, 3H), 2,73 (square, 2H, J=7,4), 5,42 (Sirs, 2H), 6,86 (m, 1H), of 6.96 (DDD, 1H, J=10,8, 7.4 and 2,3), to 7.15 (dt, 1H, J=9.9 and 8,3), 8,39 (s, 1H), 14,31 (Sirs, 1H)
AA1,37-of 1.55 (m, 4H), of 1.65 and 1.80 (m, 4H), 2,64-of 2.72 (m, 2H), 2,82-2,9l (m, 2H), 5,42 (s, 2H), 6,85 (m, 1H), 6,95 (m, 1H), 7,15 (m, 1H), scored 8.38 (s, 1H), 14,34 (Sirs, 1H)
AAof 1.39 (t, 3H, J=7,2), 1,35-and 1.54 (m, 4H), 1,63 is 1.75 (m, 4H), 2,55-to 2.65 (m, 2H), 2,73-2,82 (m, 2H), 4,37 (square, 2H, J=7,2), to 5.35 (s, 2H, 6,86 (m, 1H), 6,95 (m, 1H), to 7.09 (m, 1H), 8,03 (s, 1H)
AACDCl31,2l (t, 3H, J=7,7 in), 2.25 (s, 3H), 2,72 (square, 2H, J=7,6), 5,46 (Sirs, 2H), for 6.81-of 6.96 (m, 3H), 8,39 (s, 1H), 14,35 (Sirs, 1H)
AA1,36-of 1.55 (m, 4H), 1,66-1,8l (m, 4H), 2,64-of 2.72 (m, 2H), 2,82-2,89 (m, 2H), 5,46 (s, 2H), 6,79-of 6.96 (m, 3H), scored 8.38 (s, 1H), 14,38 (Sirs, 1H)

Table 3
no connect.Structure1H-NMR (DMSO-d6/S)
AAof 1.39 (t, 3H, J=7,2), 1,35-of 1.53 (m, 4H), 1,63 is 1.75 (m, 4H), of 2.56 2.63 in (m, 2H), 2,71 is 2.80 (m, 2H), to 4.38 (square, 2H, J=7,2), of 5.40 (s, 2H), 6,72-6,87 (m, 2H), 6,95 (m, 1H), 8,02 (s, 1H)
AADMSO-d6of 1.05 (t, 3H, J=7,5), 2,24 (s, 3H), 2,75 (square, 2H, J=7,5), of 5.48 (s, 2H), 7,15-7,25 (m, 4H), 8,32 (s, 1H), 14,68 (s, 1H)
AACDCl3of 1.20 (t, 3H, J=7,7), 2,24 (s, 3H), 2,72 (square, 2H, J=7,7),5,44 (Sirs, 2H), 7,05 (d, 2H, J=8,7), 7,33 (d, 2H, J=8,4), scored 8.38 (s, 1H), 14,39 (Sirs, 1H)

As aminecontaining derivatives can be used commercially available compounds, or compounds synthesized using the following methods.

Example 25. Synthesis of the hydrochloride of the methyl ester of N-α-(2-benzo[b]thienyl)glycine (BB01)

In accordance with the method described in Tetrahedron, Vol.53, No. 48, pp. 16463-16470, 1997, hydrochloride N-α-(2-benzo[b]thienyl)glycine (2,694 g, 9.17 mmol) suspended in methanol (27 ml), then with stirring and cooling on ice for 5 minutes is added dropwise thionyl chloride (2,02 ml, 27,69 mmol). The mixture is then stirred at room temperature for 63 hours. The solvent is removed by distillation under reduced pressure, the residue is washed with acetone and obtain colorless crystals (BB01, 2,546 g, 89%).

TPL: 196-198°C

NMR: (DMSO-d6) of 3.78 (s, 3H), 5,79 (s, 1H), 7,38-7,46 (m, 2H), 7,68 (s, 1H), 7,92 (m, 1H), 8,01 (m, 1H), 9,36 (Sirs, 3H).

Example 26. Synthesis of the hydrochloride of the methyl ester of N-α-(4-biphenyl)glycine (BB02)

In accordance with the method described in Tetrahedron, Vol 53, No. 48, pp. 16463-16470, 1997, hydrochloride N-α-(4-biphenyl)glycine (2,148 g, 9,17 mmol) suspended in methanol (24 ml), followed by cooling on ice for 5 minutes is added dropwise thionyl chloride (1,67 ml, 22,90 mmol). The mixture is then stirred at room the Oh temperature for 20 hours and get colorless crystals (BB02, 1,760 g, 69%).

TPL: 224-225°C

NMR: (DMSO-d6) 3,74 (s, 3H), to 5.35 (s, 1H), 7,40 (m, 1H), 7,46-to 7.61 (m, 2H), 7,58-to 7.61 (m, 2H), 7.68 per-7,71 (m, 2H), 7,75 for 7.78 (m, 2H), remaining 9.08 (Sirs, 3H).

Example 27. Synthesis of ethyl-4-amino-3-triftormetilfullerenov (BB03)

1) Synthesis of ethyl-4-nitro-3-triftormetilfullerenov

Ethylbromoacetate (1.2 g, 10.9 mmol) is added to a suspension of 4-nitro-3-triptoreline (2.0 g, to 9.66 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone, the mixture is then stirred at room temperature for 6 hours. Then the reaction mixture was poured into ice water, acidified with 2n. hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, then with water and dried with anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and get 4-nitro-3-triftormetilfullerenov (3,24 g (theoretical quantity: 2.83 g), 100%) as a yellow solid, which is used in the next stage without purification.

NMR: (CDCl3) to 1.32 (t, 3H, J=7,2), 4,30 (square, 2H, J=7,2), and 4.75 (s, 2H), 7,10 (DD, 1H, J=2,7, 9,0), 7,33 (d, 1H, J=2,4), 8,01 (d, 1H, 9,0).

2) Synthesis of ethyl-4-amino-3-triftormetilfullerenov

To a solution of 4-nitro-3-triftoratsetilatsetonom (3,24 g (theoretical quantity: 2.83 g, to 9.66 mmol), obtained in stage 1), ethyl acetate (30 ml) is added 10% palladium on coal (0.3 g) and odor the D. The catalyst is separated by filtration, the solvent is removed under reduced pressure and get the crude 4-amino-3-triftormetilfullerenov (BB03, is 3.08 g (theoretical quantity: 2,54 g) 100%) as an oily substance.

NMR: (CDCl3) of 1.30 (t, 3H, J=7,2), 4,27 (square, 2H, J=7,2), 4,56 (s, 2H), 6,76 (d, 1H, J=8,7), of 6.96 (DD, 1H, J=3,0, 9,0), 7,01 (d, 1H, J=2,7).

Experimental example 28.

Synthesis of monohydrochloride methyl-4-aminotetrahydrofuran-4-carboxylate (BB04)

Thionyl chloride (as 4.02 ml, with 55.1 mmol) is added to anhydrous methanol solution (100 ml) monohydrochloride 4-amino-4-carboxyrhodamine (5,00 g, 27.5 mmol) in a bath with ice, the mixture is then refluxed for 2.5 hours. The solvent is removed by distillation under reduced pressure, the crude product is washed with ethyl acetate and dried under reduced pressure, obtaining a colorless solid (BB04, of 5.06 g).

NMR: (DMSO) 1,84-of 1.93 (m, 2H), 2,02-of 2.09 (m, 2H), 3,57 at 3.69 (m, 2H), 3,79 (s, 3H), 3,80-3,88 (m, 2H), 8,89 (Sirs, 3H).

Experimental example 29.

Synthesis of monohydrochloride 3-(4-aminotetrahydrofuran-4-yl)ethylpropylamine (BB05)

1) Synthesis of ethyl 4-tert-butoxycarbonylmethylene-4-carboxylate

The triethylamine (5,41 ml, 38,8 mm) and di-tert-butyldicarbonate (7,13 ml, was 31.0 mmol) is added dropwise in that order to both voennogo solution monohydrochloride methyl-4-aminotetrahydrofuran-4-carboxylate (of 5.06 g, from 25.8 mmol) in 1,4-dioxane (50 ml) in a bath with ice. The reaction mixture was stirred at room temperature for 6 hours, then the reaction mixture in a bath with ice add di-tert-butyldicarbonate (2,97 ml, 12.9 mmol) and the mixture continued to stir at room temperature overnight. Then the reaction mixture was poured into 2n. an aqueous solution of hydrochloric acid (12 ml) and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline solution in this order, then dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (ethyl acetate-hexane in a ratio of from 3:7 to 1:0) and obtain a colorless oily substance (of 5.24 g).

NMR: (CDCl3) of 1.44 (s, 9H), 1,86-1,90 (m, 2H), 2,14-of 2.24 (m, 2H), 3,64-and 3.72 (m, 2H, in), 3.75 (s, 3H), 3,78-a-3.84 (m, 2H), 4,78 (Sirs, 1H).

2) Synthesistert-butyl(4-formyltetrahydrofolate-4-yl)carbamate

Toluene solution of hydride diisobutylaluminum (72,3 ml, 73,0 mmol) is added dropwise to an anhydrous solution of methyl-4-tert-butoxycarbonylmethylene-4-carboxylate (4,74 g, and 18.3 mmol), obtained in stage 1), in toluene (50 ml) at -78°C for 1 hour. The reaction mixture was stirred at the same temperature for 20 minutes, then within 10 minutes we use the t dropwise a saturated aqueous solution of ammonium chloride (20 ml) and the mixture stirred at room temperature for 15 minutes. Then add methanol (3 ml) and the mixture continued to stir at room temperature for 20 minutes. Precipitated insoluble substance is removed by filtration through celite and the filtrate is extracted with ethyl acetate. The organic layer is washed with water and saturated saline solution in this order, then dried with anhydrous magnesium sulfate. The crude product is purified column chromatography on silica gel (ethyl acetate-hexane in a ratio of from 3:7 to 1:0) and obtain the target product as a colorless oily substance (2.00 g) and N-tert-butyl(4-hydroxyethylacrylate-4-yl)carbamate (1,32 g).

NMR: (CDCl3) a 1.45 (s, 9H), 1.70 to about 1.75 (m, 2H), 1,99-of 2.08 (m, 2H), 3,64-and 3.72 (m, 2H), 3,78-a 3.87 (m, 2H), 4,88 (Sirs, 1H), 9,48 (s, 1H).

3) Synthesis of 3-(4-tert-butoxycarbonylmethylene-4-yl)acrylate

To a solution of N-tert-butyl(4-formyltetrahydrofolate-4-yl)carbamate (2.0 g, 8,7 mmol), obtained in stage 2), in anhydrous THF (50 ml) at room temperature add (carbomethoxyamino)triphenylphosphorane (3,19 g, 9.2 mmol). The reaction mixture is refluxed under nitrogen atmosphere for 6.5 hours and add (carbomethoxyamino)triphenylphosphorane (3,19 g, 9.2 mmol), then the reaction mixture continued to heat under reflux for 17 hours. The solvent is removed by distillation under reduced pressure, the residue is purified the column chromatography on silica gel (ethyl acetate-hexane in a ratio of from 3:7 to 1:0), receiving a colorless oily substance (2,71 g).

NMR: (CDCl3) of 1.29 (t, 3H, J=7.2 Hz), the 1.44 (s, 9H), 1,82 is 1.91 (m, 2H), 1,97 is 2.01 (m, 2H), 3,65-a 3.83 (m, 4H), 4,20 (square, 2H, J=7,2 Hz), of 4.57 (s, 1H), of 5.89 (d, 1H, J=15,9 Hz)6,94 (d, 1H, J=15,9 Hz).

4) Synthesis of 3-(4-tert-butoxycarbonylmethylene-4-yl)ethylpropane

To a solution of 3-(4-tert-butoxycarbonylmethylene-4-yl)acrylate obtained in stage 3), in a mixture of ethyl acetate (30 ml) and methanol (12 ml) at room temperature add the catalyst is 5% palladium on coal. The reaction mixture was stirred in a stream of hydrogen gas at room temperature for 75 minutes. The palladium catalyst was removed by filtration through celite and the filtrate concentrated and dried, obtaining a colorless oily substance (2,69 g).

NMR: (CDCl3) of 1.26 (t, 3H, J=7.2 Hz), the 1.44 (s, 9H), 1,61-to 1.67 (m, 2H), 1,91-of 1.95 (m, 2H), 2.05 is-2,11 (m, 2H), 2,28 is 2.33 (m, 2H), 3,57-with 3.79 (m, 4H), 4,13 (square, 2H, J=7,2 Hz), 4,29 (Sirs, 1H).

5) Synthesis of monohydrochloride 3-(4-aminotetrahydrofuran-4-yl)ethylpropylamine (BB05)

4h. a solution of hydrochloric acid in ethyl acetate (12.9 ml, 51.6 mmol) are added to a solution of 3-(4-tert-butoxycarbonylmethylene-4-yl)ethylpropylamine (2,59 g, 8.6 mmol), obtained in stage 4), ethyl acetate (40 ml) in a bath with ice. The reaction mixture was stirred at room temperature for 4 hours, add 4n. a solution of hydrochloric acid in ethyl acetate (4.3 ml,and 17.2 mmol) and stirring is continued at room temperature for 1 hour. The obtained solid is filtered, obtaining a colorless solid (BB05, 1.28 g).

NMR: (DMSO) of 1.20 (t, 3H, J=7.2 Hz), 1,67 was 1.69 (m, 4H), 1,96-2,02 (m, 2H), 2,44-2,47 (m, 2H), 3,49 is 3.57 (m, 2H), 3,69 is 3.76 (m, 2H), 4,08 (square, 2H, J=7,2 Hz), 8,16 (Sirs, 3H).

Experimental example 30.

Synthesis of monohydrochloride methyl-1-amino-4,4-dimethylcyclopropanecarboxylate (BB06)

1) Synthesis of 1,1-dimethyl-4-methylenecycloartanol

Bromide methyltriphenylphosphonium (2,97 g, 8.3 mmol) are added to a solution of sodium hydride (0.35 g, 8,7 mmol) in anhydrous DMSO (8 ml) in a bath with ice. The reaction mixture was stirred at room temperature for 10 minutes and slowly add a solution of 4,4-dimethylcyclohexanone (1.0 g, 7.9 mmol) in anhydrous DMSO (1.5 ml) in a bath with ice. The reaction mixture was stirred at room temperature for 18 hours and poured into ice water. The organic layer is extracted with diethyl ether, then washed with water, dried with anhydrous magnesium sulfate and removed by filtration. The filtrate is concentrated to reduce the volume approximately twice. The obtained insoluble substance is removed by filtration, then the filtrate is evaporated under reduced pressure and obtain a colorless oily substance (0,91 g).

NMR: (CDCl3) to 0.94 (s, 6H), of 1.35 (t, 4H, J=6.6 Hz), 2,15 (t, 4H, J=6.9 Hz), 4,58 (s, 2H).

2) Synthesis of 7,7-dimethyl-1-azaspiro[3.5]nonan-2-it

Chloral phenylisocyanate acid (of 0.67 ml, 7.7 mmol) is added dropwise to a solution of 1,1-dimethyl-4-methylenecycloartanol (0,91 g, 7.4 mmol), obtained in stage 1), in anhydrous diethyl ether (11 ml) in a bath with ice. The reaction mixture was stirred at room temperature for 1 hour, then add chlorosulfonylisocyanate acid (of 0.67 ml, 7.7 mmol) in a bath with ice and stirring is continued at room temperature for 1 hour. To the reaction mixture in a bath with ice add chlorosulfonylisocyanate acid (0,32 ml, 3.7 mmol), stirred at room temperature for another 2 hours, then alternately add the aqueous solution (4.5 ml) pentahydrate sodium thiosulfate (4,56 g, 18.4 mmol) and 10% potassium hydroxide solution in a bath with ice, the pH was adjusted to approximately 10, and then the reaction mixture is stirred for 2 hours. Insoluble matter is removed by filtration and the filtrate is extracted with chloroform. Then the organic layer is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure and obtain a colorless solid (0.75 g).

NMR: (DMSO) to 0.89 (s, 6H), 1.18 to to 1.38 (m, 4H), 1,55-to 1.61 (m, 4H), 2,50-2,52 (m, 2H), 8,19 (Sirs, 1H).

3) Synthesis of monohydrochloride methyl-1-amino-4,4-dimethylcyclopropanecarboxylate

Concentrated hydrochloric acid (0,55 ml) is added to methanol (14 ml) solution of 7,7-dimethyl-1-and is Aspiro[3.5]nonan-2-she (0.75 g, 4.5 mmol), obtained in stage 2), at room temperature. The reaction mixture is refluxed for 9 hours, the solvent is removed by distillation under reduced pressure and obtain a colorless solid (BB06, of 1.05 g).

NMR: (DMSO) to 0.89 (s, 3H), of 0.91 (s, 3H), 1,24-of 1.40 (m, 6H), 1,65-of 1.73 (m, 2H), 2,75 (s, 2H), 3,66 (s, 3H), 8,07 (Sirs, 3H).

Example 31. Synthesis of methyl 1-amino-4,4-diverticulosisdoxycycline (BB07) and methyl-1-amino-4-fluoro-3-cyclohexanecarboxylate (BB08)

1) Synthesis of methyl 1-tert-butoxycarbonylamino-4,4-diverticulosisdoxycycline

Methyl-1-tert-butoxycarbonylamino-4-oxocyclohexanecarboxylate (1.24 g, 4,39 mmol) dissolved in dichloromethane (13 ml), then slowly added DAST (TRIFLUORIDE (dimethylamino)sulfur) (7,0 ml, 52,65 mmol) and the mixture is stirred at room temperature for 2 days. The reaction mixture is slowly added dropwise to ice water (80 ml) under stirring, then the mixture was stirred at 0°C for 1 hour. Add dichloromethane (110 ml), the organic layer washed with water and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layer is dried with sodium sulfate and then evaporated under reduced pressure. The organic layer is purified column chromatography on silica gel, obtaining a mixture containing the target substance (556 mg).

1H-NMR: (DMSO-d6): 1,36 (s, 9H), 1,8-2,1 (m, 8H)and 3.59 (s, 3H), 7,4 (Sirs, 1H);19F NMR: (DMSO-d6): -99,9 (d, 1F, J=229), -91,4 (d, 1F, J=236).

2) Synthesis of methyl 1-amino-4,4-diverticulosisdoxycycline (BB07) and methyl-1-amino-4-fluoro-3-cyclohexanecarboxylate (BB08)

Methyl-1-tert-butoxycarbonylamino-4,4-diverticulopexia obtained in stage 1), dissolved in methanol (2.5 ml), add 10% solution of hydrochloric acid in methanol (3,38 g, 9,27 mmol) and the mixture is stirred for 3 days. The solvent is removed from the reaction mixture by distillation. To induce crystallization, the reaction mixture is added an appropriate amount of diethyl ether, and then the crystals (421 mg) was isolated. The resulting crystals are dissolved in chloroform, then the solution is alkalinized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform (30 ml×2). The organic layer is separated by distillation under reduced pressure and purified column chromatography on silica gel, receiving methyl-1-amino-4,4-diverticulopexia (BB07, 191 mg) and methyl 1-amino-4-fluoro-3-cyclohexanecarboxylate (BB08, 55 mg).

methyl-1-amino-4,4-diverticulopexia (BB07):

1H NMR: (CDCl3): 1,69-to 2.29 (m, 10H), 3,74 (s, 3H).

methyl-1-amino-4-fluoro-3-cyclohexanecarboxylate (BB08):

1H NMR: (CDCl3): to 1.8-2.7 (m, 6H), 1,97 (Sirs, 2H, in), 3.75 (s, 3H), 5,1-5,2 (m, 1H).

Experimental example 32.

Synthesis of methyl-1-AMI is about-4-forceclassiccontrolpanel (BB09)

Methyl-1-amino-4-fluoro-3-cyclohexanecarboxylate (52 mg) dissolved in a mixture of methanol (2 ml) and ethyl acetate (2 ml), then add 10% palladium on coal (35 mg) and within 14 hours serves hydrogen gas. The insoluble substance is filtered off, the solvent is removed by distillation under reduced pressure and get the mixture containing the target substance (BB09 38 mg).

1H NMR: (CDCl3): of 1.4-2.3 (m, 10H), and 3.72 (s, 3H), 4,6-4,9(m, 1H).

Experimental example 33.

Synthesis of monohydrochloride methyl-1-amino-4,4-diverticulosisdoxycycline (BB10)

1) Synthesis of methyl-1-benzyloxycarbonylamino-4,4-diverticulosisdoxycycline

Methyl-1-benzyloxycarbonylamino-4-oxocyclohexanecarboxylate (1,03 g, 3,37 mmol) dissolved in dichloromethane (10 ml)to the resulting solution at room temperature is slowly added DAST (TRIFLUORIDE (dimethylamino)sulfur) (4,45 ml, 33,67 mmol) and the mixture is stirred at room temperature for 25 hours. Then the reaction mixture under stirring slowly added dropwise to ice water (40 ml) and the mixture was stirred at 0°C for 15 minutes. Then add dichloromethane (30 ml), the organic layer washed with water (25 ml×2) and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layer is dried with sodium sulfate and then removed by distillation of the ri reduced pressure. The organic layer is purified column chromatography on silica gel, obtaining a mixture containing the target compound (718 mg).

1H NMR: (CDCl3): to 1.8-2.7 (m, 8H), 3,70 (Sirs, 3H), equal to 4.97-5,16 (m, 3H), 7,29-7,39 (m, 5H).

2) Synthesis of the hydrochloride of methyl 1-amino-4,4-diverticulosisdoxycycline

Methyl-1-benzyloxycarbonylamino-4,4-diverticulopexia obtained in stage 1), dissolved in a mixture of ethyl acetate (50 ml) and methanol (25 ml), then add 4n. a solution of hydrochloric acid in ethyl acetate (1,03 ml). Then add 10% palladium on coal (120 mg) and serves gaseous hydrogen (from 4.5 to 5 atmospheres), then the mixture is stirred at room temperature for 2 days. Insoluble matter is removed by filtration, the filtrate is removed by distillation under reduced pressure and get the crystals containing the target compound (BB10, 467 mg).

1H NMR: (DMSO-d6): 1.8 to 2.3 (m, 8H), 3,79 (s, 3H), 8,92 (Sirs, 3H),19F NMR (DMSO-d6): -97,3 (d, 1F, J=235), -95,3 (d, 1F, J=235).

Example 34. Synthesis of ethyl-2-amino-4-fluoro-4-methylvalerate (BB11)

Ethyl-2-(benzylamino)-4-fluoro-4-methylvalerate (approximately 6.0 g) is dissolved in ethanol (60 ml), add 10% palladium on coal (2.0 g) and serves hydrogen gas at room temperature, the mixture is then stirred for 14 hours. The insoluble substance is filtered off, then the races is varicel removed by distillation under reduced pressure, to the residue while cooling on ice, add methyl tert-butyl ether (40 ml) and sulfuric acid (1,53 g)dissolved in water (40 ml), the mixture is then stirred for 10 minutes. The organic layer removed and the aqueous layer was washed with methyl tert-butyl ether (30 ml×2). To the water layer while cooling on ice, add potassium carbonate (to 4.14 g, 30.0 mmol), pH adjusted to 10, and then the aqueous layer was extracted with a mixture of isopropylacetate and dichloromethane in the ratio of 4:1 (40 ml×4). The organic layer is dried with magnesium sulfate, the solvent is removed by distillation under reduced pressure and get oily mixture containing the target substance (BB11, 1.08 g).

1H-NMR: (CDCl3) of 1.27 (t, 3H, J=6,9), of 1.40 (d, 3H, J=3,0), of 1.47 (d, 3H, J=3,0), 1,86 (Sirs, 2H), 1.8-to 2.2 (m, 2H), 3,69 (DD, 1H, J=5,1, 7,8), 4,19 (square, 2H, J=7,2).

Example 35. Synthesis of the hydrochloride of ethyl-4-amino-6-fluoro-6-methylvalerate (BB12)

1) Synthesis of ethyl-2-benzyloxycarbonylamino-4-fluoro-4-methylvalerate.

2-amino-4-fluoro-4-methylethylacetate (approximately 0,60 g) dissolved in tetrahydrofuran (8 ml) and added dropwise pyridine (0.6 ml, was 7.45 mmol). Then while cooling on ice, add Z-chloride (0,53 ml, and 3.72 mm) and the mixture is stirred at room temperature for 4.5 hours. To the mixture while cooling on ice, add water (8 ml), pH adjusted to 2 by adding 2n. an aqueous solution of hydrochloric acid. The mixture is extracted with et is lacerata (50 ml×2), the organic layer was washed with water (15 ml), saturated aqueous sodium hydrogen carbonate (15 ml) and water (15 ml) in that order. The organic layer is dried with sodium sulfate, and then separated by distillation under reduced pressure and purified column chromatography on silica gel. Then the solvent of the eluate is removed by distillation under reduced pressure and get the target oily compound (730 mg).

1H-NMR: (CDCl3) of 1.27 (t, 3H, J=7,2), of 1.42 (d, 6H, J=21,6), 1,95-2,22 (m, 2H), 4,20 (square, 2H, J=6,6), 4,47 (dt, 1H, J=4,8, 12,6), 5,12 (s, 2H), 5,42 (d, 1H, J=5,7), 7.3 to 7.4 (m, 5H).

2) Synthesis of (E)-4-benzyloxycarbonylamino-6-fluoro-6-methyl-2-ethylmalonate

Ethyl-2-benzyloxycarbonylamino-4-fluoro-4-methylvalerate (1,16 g, 3.73 mmol), obtained in stage 1), dissolved in toluene (15,8 ml) and to the resulting solution at -78°C is added dropwise 1,01M solution hydride diisobutylaluminum in toluene (7,38 ml). At the same temperature, the solution is stirred for 1 hour and added dropwise a saturated aqueous solution of ammonium chloride (3 ml) and methanol (1 ml). The temperature of the reaction mixture was raised to room temperature and water is added, then the reaction mixture was extracted with ethyl acetate (100 ml×2). The organic layer was washed with water (30 ml) and saturated salt solution (50 ml). The organic layer is dried with sodium sulfate and evaporated under reduced pressure, obtaining an oily mixture of 1.15 g). Mac is aristoi mixture is added tetrahydrofuran (13,8 ml) and carbatetraphenylporphin (1.04 g, 2,98 mmol), the mixture is then refluxed for two hours. The solvent is removed by distillation under reduced pressure, the residue is a mixture of purified column chromatography on silica gel, and then the solvent of the eluate is removed by distillation under reduced pressure and get the target oily compound (599 mg).

1H-NMR: (CDCl3) of 1.29 (t, 3H, J=6,9), of 1.41 (d, 6H, J=21,3), 1,8-2,0 (m, 2H), 4,19 (square, 2H, J=7,2), 4,57 (width, 1H), 5,11 (s, 2H), 5,95 (d, 1H, J=15,6), 6.87 in (DD, 1H, J=5,1, 15,6), 7,3-7,4 (m, 5H).

3) synthesis of the hydrochloride of ethyl-4-amino-6-fluoro-6-methylvalerate (BB12)

(E)-4-benzyloxycarbonylamino-6-fluoro-6-methyl-2-Etisalat (590 mg, about 1.75 mmol), obtained in stage 2), dissolved in ethyl acetate (7,1 ml) and added dropwise 4n. a solution of hydrochloric acid in ethyl acetate (0,87 ml of 3.50 ml) and ethanol (3.5 ml). Then add 10% palladium on coal (100 mg) and serves hydrogen gas for 3 hours. The insoluble substance is filtered off, the solvent is removed by distillation under reduced pressure and get targeted crystals (BB12, 454 mg).

1H-NMR: (DMSO-d6): to 1.19 (t, 3H, J=6,9), to 1.37 (d, 6H, J=21,6), 1,8-2,0 (m, 4H), of 2.5-3.3 (m, 3H), 4,07 (square, 2H, J=7,2), 7,97 (Sirs, 3H).

Example 36. Synthesis of hydrochloride (1 aminocyclohexanone)acetic acid (BB13)

1) Synthesis of (1-nitrocyclohexane)methanol

Ethanol solution (5 ml) nitrocyclohexane (5,00 g of 38.7 mmol) and the hydroxide is sodium (12.5 g, 0.3 mmol) is heated to 55°C, add 35% formalin solution (3.0 ml, 35 mmol), then the mixture is heated and stirred at the same temperature for 1.5 hours. The reaction mixture is diluted with water, added 2M hydrochloric acid (0.5 ml, 1 mmol) and extracted with ethyl acetate (15 ml) twice. The organic layer was washed with 5% aqueous sodium bicarbonate solution (10 ml) and water (20 ml), then dried with anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (Highflash 3L, is Yamazen Corporation, a mixture of hexane and ethyl acetate in the ratio 3:1) and obtain colorless oily (1-nitrocyclohexane)methanol (of 6.96 g).

NMR: (d6-DMSO) 1,20-1,72 (m, 8H), 2,17 was 2.25 (m, 2H), 3,65 (d, 2H, J=4,5), 5,33 (t, 2H, J=5,1).

2) Synthesis of ethyl(1-nitrocyclohexanone)acetate

In a nitrogen atmosphere to a solution of (1-nitrocyclohexane)methanol (of 6.96 g, 35 mmol), obtained in stage 1), in DMF (70 ml) is added while cooling on ice NaH (2,32 g, 58 mmol), the mixture is then stirred for 20 minutes, until the temperature rises to normal. Then add dropwise Bromeliaceae (9,96 g, 58,0 mmol) and the mixture is stirred at room temperature overnight. The reaction mixture was diluted with water (200 ml), added 2M hydrochloric acid (20 ml, 40 mmol) and extracted with ethyl acetate (50 ml) twice. the content of inorganic fillers layer was washed with 5% aqueous sodium bicarbonate solution (20 ml) and water (50 ml), then dried with anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (Highflash 4L is Yamazen Corporation, a mixture of hexane and ethyl acetate in the ratio 5:1) and obtain a pale yellow oily ethyl(1-nitrocyclohexanone)acetate (vs. 5.47 g, 57%).

NMR: (d6-DMSO) to 1.19 (t, 3H, J=7,2), 1,30-of 1.65 (m, 6H), of 1.80(m, 2H), 2,20 (DD, 2H, J=14.4 and 5,7), 3,83 (s, 2H), 4,11 (square, 2H, J=7,2), 4,11 (s, 2H).

3) Synthesis of 4-oxa-1-azaspiro[5.5]undecane-2-it

In a nitrogen atmosphere to a methanol solution (90 ml) (1 nitrocyclohexanone)acetic acid ethyl ester (4.5 g, 18.2 mmol), obtained in stage 2)add ammonium formate (5.75 g, to 91.1 mmol) and 10% Pd on coal (4.5 mg), then the mixture is heated and stirred at 50°C during the night. The mixture is then filtered through celite, the filtrate concentrated under reduced pressure, the residue is purified column chromatography on silica gel (Highflash 3L, is Yamazen Corporation, a mixture of hexane and ethyl acetate in the ratio of 5:1, 1:1 and 1:2) and obtain orange crystals of 4-oxa-1-azaspiro[5.5]undecane-2-it (1,67 g, 54%).

NMR: (d6-DMSO) 1,20-1,50 (m, 6H), 1,58 (d, 4H, J=9,9), of 3.57 (s, 2H), 3,92 (s, 2H), 8,04 (s, 1H).

4) Synthesis of hydrochloride (1 aminocyclohexanone)acetic acid

To 4-oxa-1-azaspiro[5.5]undecane-2-ONU (1,67 g, 9.9 mmol), obtained in stage 3)add 6N. hydrochloric acid (30 ml, 180 mmol) and the mixture nagrevayut stirred at 100°C for 1.5 hours. The solvent is removed by distillation under reduced pressure, to the residue is added toluene (100 ml) and twice carry out azeotropic dehydration under reduced pressure, obtaining a pale-yellow crystals. The crystals add another portion of toluene (50 ml) and carry out azeotropic dehydration, then the crystals are washed with ether and obtain white crystals of the hydrochloride (1 aminocyclohexanone)acetic acid (BB13, 1,91 g, 87%).

NMR: (d6-DMSO) of 1.20 and 1.80 (m, 10H), 3,61 (s, 2H), 4,12 (s, 2H), of 7.96 (s, 3H), 12,77 (Sirs, 1H).

Example 37. Synthesis of 2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-triptoreline}acetic acid (XI-088)

1) Synthesis of diethyl-2-(4-nitro-3-triptoreline)malonate

Sodium hydride (60% in oil) (0.33 g, 8.25 mmol) are added to a solution of diethylmalonate (1.23 ml, 8,14 mmol) in dimethylformamide (20 ml) while cooling on ice and the mixture was directly stirred for 4 hours. To the reaction mixture while cooling on ice, add 5-bromo-2-nitrobenzotrifluoride (2.0 g, 7.41 mmol), then the temperature was raised to room temperature, then the mixture is heated and stirred at 70°C for 3 hours. The reaction solution was poured into ice water and acidified with 2n. hydrochloric acid, then the solution is extracted with ethyl acetate. The organic layer was washed with 5% aqueous races is the thief of sodium bicarbonate and water, then dried over anhydrous sodium sulfate and evaporated the solvent under reduced pressure. The residue is subjected to column chromatography on silica gel (45 g) and elute with a mixture of ethyl acetate and n-hexane in the ratio of 1:5. The eluate concentrated under reduced pressure and receives a yellow oily diethyl-2-(4-nitro-3-triptoreline)malonate (1.1 g, 42%).

NMR: (CDCl3) of 1.29 (t, 6H, J=7,2), 4,25 (square, 2H, J=6,9), 4,27 (square, 2H, J=7,2), and 4.75 (s, 1H), 7,80-a 7.92 (m, 3H).

2) Synthesis of diethyl-2-(4-amino-3-triptoreline)malonate

To a solution of diethyl-2-(4-nitro-3-triptoreline)malonate (1.1 g, a 3.15 mmol), obtained in stage 1), ethyl acetate (20 ml) is added 10% palladium on coal (0.1 g) and the solution is subjected to hydrogenation. The catalyst was removed by filtration, the solvent was concentrated under reduced pressure and receives a yellow oily diethyl-2-(4-amino-3-triptoreline)malonate (1,38 g (content of 0.39%), 68%), which is used in the next stage without purification.

NMR: (CDCl3) of 1.20 and 1.35 (m, 6H), 4,10-4,30 (m, 4H), 6,77 (d, 1H, J=8,4), 7,34-7,46 (m, 2H).

3) Synthesis of diethyl-2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-triptoreline}malonate

A solution of the acid chloride obtained by dissolving 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (0.25 g, 0.79, which mmol), obtained in stage 3), tetrahydrofur the e (3 ml), add oxalicacid (0,076 ml, 0.87 mmol) and drops (using a capillary pipette) of dimethylformamide and stirring at room temperature for 30 minutes. To a solution of 2-(4-amino-3-triptoreline)diethylmalonate (1,38 g (content of 0.39%), was 1.69 mmol) in tetrahydrofuran (3 ml) was added triethylamine (0.33 ml, is 2.37 mmol) and then a solution of the acid chloride obtained by the above method, then stirred at room temperature for six hours. Then the reaction mixture was poured into ice water, acidified with 2n. hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, then with water and dried over anhydrous sodium sulfate, then the solvent concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel (30 g) (mixture of ethyl acetate and n-hexane in the ratio 1:5). The eluate concentrated under reduced pressure and receives a yellow oily diethyl-2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-triptoreline}malonate (0,29 g, 59%).

TPL: 160-162°C

NMR: (CDCl3) of 1.27 (t, 6H, J=7,2), 1,05-1,90 (m, 19H), 2,62-of 2.72 (m, 2H), 2,88-of 2.97 (m, 2H), 3,90-4,20 (m, 2H), 4,15-4,30 (m, 4H), to 4.62 (s, 1H), 7,60 (DD, 1H, J=1,8, 8,4), to 7.68 (d, 1H, J=1,8), 8,35 (s, 1H), to 8.41 (d, 1H, J=8,4), of 12.53 (s, 1H).

4) Synthesis of 2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro icaocca[b]pyridine-3-carbonyl)amino]-3-triptoreline}acetic acid (XI-088)

Diethyl-2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-triptoreline}malonate (0,29 g, 0.47 mmol), obtained in stage 3), dissolved in a mixture of tetrahydrofuran and methanol (1:1) (3.8 ml)at room temperature add 1H. an aqueous solution of sodium hydroxide (1.9 ml, 1,90 mmol) and the mixture is stirred for 25 hours. The mixture is then stirred at 80°C for 9 hours. Then the reaction mixture was poured into ice water, acidified with 2n. hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate and the solvents are concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel (12 g) (mixture of chloroform, methanol and water in a ratio of 32:9:1). The eluate concentrated under reduced pressure, recrystallized from a mixture of acetone-water (1:10) and get the white needle crystals of 2-{4-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-3-triptoreline}acetic acid (XI-088, 0.09 g, 37%).

NMR: (DMSO-d6) 1,05-of 1.84 (m, 19H), 2,63-2,77 (m, 2H), 2,90 was 3.05 (m, 2H), 3,69 (s, 2H), 3,90-4,20 (m, 2H), 7,56 (d, 1H, J=9,0), 7,63 (m, 1H), to 8.20 (d, 1H, J=8,7), of 8.27 (s, 1H).

Example 38. Synthesis of methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate (I-081)

1-C is klagebilder-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01, 0.20 g, to 0.63 mmol)obtained in example 1 was dissolved in anhydrous dichloromethane (2.0 ml) and cooled on ice add oxalicacid (82 μl, 0.95 mmol) and a drop of DMF. The temperature was raised to room temperature and the solution stirred for 1 hour, then the solvent is removed by distillation under reduced pressure. The residue is dissolved in THF (2.0 ml) and added the hydrochloride of the methyl ester of glycine (0,119 g, 0,948 mmol) and triethylamine (to 0.263 ml, 1,89 mmol). The mixture is stirred at room temperature for 1 hour, add water and extracted with ethyl acetate while cooling on ice. The organic layer was washed with saturated salt solution and then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel and get light red crystals I-081 (195 mg, 80%).

Example 39. Synthesis of [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid (I-355)

Methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetate (I-081, 0.12 g, 0,309 mmol)obtained in example 38, dissolved in a solvent mixture containing methanol (1.0 ml) and THF (1.0 ml), then added a 2M aqueous solution of sodium hydroxide (0,46 ml). The solution is stirred for 1 hour, then neutralize the 2M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution, then dried over anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure and obtain colorless crystals of I-355 (120 mg, 100%).

IR (KBr): 2926, 2852, 1739, 1657, 1536.

Example 40. Synthesis of methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]butyrate (III-005)

In nitrogen atmosphere 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01, 0.15 g, 0.47 mm)obtained in example 1 was dissolved in dichloromethane (1.5 ml)while cooling on ice, add oxalicacid (62 μl, 0.71 mmol) and a drop of DMF, the mixture is then stirred at room temperature. After 1 hour the solvent is removed by distillation under reduced pressure, to the residue is added dichloromethane (5 ml), then the hydrochloride of methyl-3-aminobutyrate (87,2 mg, 0,568 mmol) and PS-DIEA (supplied Argonoto Corporation, 0.31 g, 1,19 mmol). After stirring for two days add MP-isocyanate and PS-carbonate. Then stirring is continued for three hours, then the reaction mixture is filtered and the solvent is removed by distillation under reduced pressure. The residue is purified on a column for flash chromatography and obtain colorless crystals of III-005 (0,1496 g, 76%).

Example 41. Synthesis of [(1-cyclog Kilmer-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]butyric acid (III-013)

Methyl[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]butyrate (III-005, 56,5 mg, 0,136 mmol)obtained in example 40, dissolved in methanol (1.5 ml)and add 2M aqueous sodium hydroxide solution (of 0.27 ml, 0.54 mmol) and stirred at room temperature. After 2.5 hours, the solution acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, the solvent is removed by distillation under reduced pressure and get colorless amorphous III-013 (51.9 mg, 95%).

Example 42. Synthesis formativos ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid (I-311)

[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid (I-355, 0.15 g, 0.40 mmol)obtained in example 39, dissolved in 1,1,2-trichloroethane, in a nitrogen atmosphere add floridana (47 μl, 0.80 mmol) and concentrated sulfuric acid (20 μl, 0.40 mmol) and heated to 80°C. After 22 hours, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, the solvent is removed by distillation under reduced pressure, the residue is purified column of HRO what ecografia on silica gel and get colorless crystals I-311 (101 mg, 60%).

IR (KBr): 3235, 2925, 2855, 1763, 1665, 1618, 1580, 1529, 1446, 1212.

Example 43. Synthesis cryptomaterial ether [(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]acetic acid (I-312)

In nitrogen atmosphere of 60% sodium hydride, washed with hexane (3,05 g of 76.3 mmol), suspended in diethyl ether (60 ml), add triptoreline (5,56 ml of 76.3 mmol) and stirred for 10 minutes while cooling on ice. Then add triphenylphosphine (10.0 g, 38,1 mmol) and the suspension continue to mix for another 5 minutes. Then slowly added bromine (1,95 ml of 38.1 mmol) and stirred for 1.5 hours. Then, the insoluble matter is removed by filtration through a glass filter and the solvent is removed by distillation under reduced pressure. After adding dichloromethane (30 ml) to the residue receive 1,27M solution dateformat.gettimeinstance. 1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-355, 0.10 g, 0,267 mmol)obtained in example 38, dissolved in dichloromethane (1 ml) and add previously obtained solution dateformat.gettimeinstance (0.25 ml, 0.32 mmol), the mixture is then stirred at room temperature. After 1.5 hours, add the same amount of dateformat.gettimeinstance. After stirring for 18 hours the solvent is removed from R. the promo mixture by distillation under reduced pressure, the residue is purified column chromatography and receive a colorless amorphous I-312 (45,4 mg, 37%).

Example 44. Synthesis of methyl 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino]-2-methylpropionate (I-084)

In nitrogen atmosphere 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01, 500 mg, 1.57 mmol)obtained in example 1 was dissolved in methylene chloride (5 ml), add oxalicacid (164,9 μl, 1,89 mmol) and DMF (three drops), the mixture is then stirred at room temperature for 1 hour. Then add the hydrochloride of the methyl ester of dimethylglycine (290,3 mg, 1,89 mmol) and triethylamine (658,5 μl, 4,72 mmol) and the mixture continued to stir for 2 hours. Then add water, the mixture acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure and get a pale yellow solid I-084 (607 mg, 93%, TPL: 177-178°C).

NMR: (CDCl3) 1,00-of 1.95 (m, 25H), 2,61 (t, 2H, J=5,7), of 2.92 (t, 2H, J=5,7), 3,76 (s, 3H), 4,00 (width, 2H), of 8.27 (s, 1H), 10.30 a.m. (s, 1H).

Example 45. Synthesis of 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-358)

Methyl-2-[(1-cyclohexyl the Teal-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate (I-084, 597 mg of 1.43 mmol)obtained in example 44, dissolved in a solvent mixture containing THF (6 ml) and methanol (6 ml)and the solution is stirred in the presence of 2M aqueous sodium hydroxide solution (1,79 ml, 3.58 mmol) at 60°C for 1 hour. After concentrating the mixture, the aqueous layer washed with diethyl ether, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure and get colorless solid I-358 (446 mg, 77%, TPL: 260-263°C).

Example 46. Synthesis of 2-dimethylaminoethanol ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro[b]pyridine-3-carbonyl)amino]-2-methylpropionate (I-325)

In nitrogen atmosphere 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 600 mg, 1,49 mmol)obtained in example 45, was dissolved in DMF (12 ml) and the solution is stirred in the presence of WSCD (325 mg, to 1.79 mmol) and HOBt (40,2 mg, 0,298 mmol) at 80°C for 30 minutes. Then add N,N-dimethylaminoethanol (300 μl, 2,98 mmol) and the mixture is heated and stirred at 80°C for 7 hours. Then add water, the mixture extracted with ethyl acetate, the organic layer washed with water and dried over anhydrous sodium sulfate. The solvents are removed PE is Agency under reduced pressure, the residue is purified column chromatography on silica gel (5 g) (chloroform-methanol in the ratio 9:1) and receive a colourless solid I-325 (629 mg, 76%, TPL: 101-103°C).

Example 47. Synthesis of (2-{2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionate}ethyl)trimethylammonium (I-326)

To the combined acetonitrile solution (10 ml) 2-dimethylaminoethanol ether cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydro[b]pyridine-3-carbonyl]amino]-2-methylpropanoic acid (I-325, 200 mg, 0,422 mmol)obtained in example 46, add methyliodide (262 μl), then the mixture is heated and stirred at 85°C for 1 hour in a sealed tube. Then the solvent is removed by distillation under reduced pressure and obtain a pale yellow oily I-326 (244 mg, 94%).

Example 48. Synthesis of(2-methanesulfonamido-1,1-dimethyl-2-oxoethyl)amide 1-cyclohexyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-003)

In a nitrogen atmosphere to a solution of 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-358, 402 mg, 1.00 mmol)obtained in example 45, in methylene chloride (4 ml) add oxalicacid (104,7 μl, 1.20 mmol) and DMF (three drops), the mixture is then stirred at room temperature during 1 hour. Then add methanesulfonamide (114 mg, 1.20 mmol) and DBU (448 μl, 3.0 mmol) and the mixture is stirred at room temperature for 7 hours. To the reaction mixture, water is added, the mixture acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (10 g) (ethyl acetate-hexane in the ratio 1:1) and receive a colourless solid I-003 (381 mg, 79%, TPL: 186-187°C).

Example 49. Synthesis of (1-benzylcarbamoyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-005)

In a nitrogen atmosphere to a solution of 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-358, 150 mg, 0,373 mmol)obtained in example 45, in methylene chloride (3 ml) add oxalicacid (39 μl, 0,447 mmol) and DMF (one drop), then the mixture is stirred at room temperature for 1 hour. Then add benzylamine (203 ml of 1.86 mmol) and the mixture continued to stir at room temperature for 5 hours. To the reaction mixture, water is added, then the mixture is acidified with chloritoid the native acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (5 g) (ethyl acetate-hexane in the ratio 3:1) and receive a colourless solid I-005 (158 mg, 86%, TPL: 132-134°C).

Example 50. Synthesis of [1-(methoxymethylethoxy)-1-methylethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid and (I-024)

In a nitrogen atmosphere to a solution of 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-358, 150 mg, 0,373 mmol)obtained in example 45, in methylene chloride (3 ml) add oxalicacid (39 μl, 0,447 mmol) and DMF (one drop), then the mixture is stirred at room temperature for 1 hour. Then add the hydrochloride of N,O-dimethylhydroxylamine (40 mg, 0,409 mmol), triethylamine (208 μl, 1,49 mmol) and the mixture is stirred at room temperature for 3 hours. Then add water to the mixture, the mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and water, then dried over anhydrous sodium sulfate. The solvents are removed Perego is coy under reduced pressure, the residue is purified column chromatography on silica gel (5 g) (ethyl acetate) and receive a colourless solid I-024 (110 mg, 65%, TPL: 166-168°C).

Example 51. Synthesis of methyl 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2,3-Dimethylbutane (I-211)

To a solution of 1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carboxylic acid (AA03, 425 mg, to 1.60 mmol)obtained in example 3, in anhydrous THF (4 ml) add oxalicacid (147 μl, was 1.69 mmol) and DMF (8 ml), the mixture is then stirred at room temperature for 1 hour. Then to a solution of methyl ester hydrochloride L-tert-leucine (349 mg, 1.92 mmol) in anhydrous DMF (4 ml) under stirring and cooling on ice sequentially added triethylamine (0,89 ml, 6.38 mmol) and the previously obtained solution of the acid chloride. Then the solution was stirred at room temperature for 90 minutes. The reaction mixture is acidified, pouring into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (52 g) (ethyl acetate-hexane (2:1)) and obtain a pale yellow oily I-211 (572 mg, 92%)

IR (CHCl3): 3236, 1738, 1666, 1617, 1578, 1528, 1465, 1437, 1404, 1371, 1323; [α]D22+28,7±0,7° (c=1,014 registered, MeOH).

Elemental analysis: (C22H36N2O4·0,1MeOH)

Calculated (%): C, 67,07; H, 9,27; N, 7,08.

Found(Percent): C, 66,99; H, 9,27; N, 7,21.

Example 52. Synthesis of 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2,3-dimethylmaleic acid (I-438)

Methyl-2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]-2,3-Dimethylbutane (I-211, 313 mg, 0,797 mmol)obtained in example 51, dissolved in methanol (8 ml) and the solution is stirred in the presence of 4M aqueous sodium hydroxide solution (0.8 ml) at 50°C for 25 hours. The reaction mixture was poured into water and the aqueous layer washed with ethyl ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, then the solvent is removed by distillation and obtain a colorless solid (331 mg). The obtained solid is recrystallized from a mixture of ethyl acetate-hexane and get colorless prismatic crystals I-438 (271 mg, 88%).

TPL: 140-141°C

IR (nujol): 2607, 1727, 1657, 1577, 1533, 1467, 1406, 1374, 1334; [α]D22+31,2±0,7° (c=1,007, MeOH).

Elemental analysis: (C21H34N2O4·0.2H2O)

Calculated (%): C, 66,15; H, 9,11; N, 7,8.

Found(Percent): C, 66,17; H, 9,12; N, 7,40.

Example 53. Synthesis of 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]ethylcyclohexylamine (II-029)

To the solution obtained in example 3, 1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carboxylic acid (AA03, 451 mg, 1.70 mmol) in anhydrous THF (4 ml) add oxalicacid (156 μl, to 1.79 mmol) and DMF (8 ml), the mixture is then stirred at room temperature for 1 hour. Then triethylamine (0.95 ml, for 6.81 mmol) and the above solution of the acid chloride are added to a solution of the hydrochloride of 2-amino-1-ethylcyclohexylamine (424 mg, 2.04 mmol) in anhydrous DMF (4 ml) under stirring and cooling on ice. Then the resulting solution was stirred at room temperature for 90 minutes. The reaction mixture is acidified, pouring into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (57 g) (ethyl acetate-hexane (2:1)) and obtain a pale yellow oily II-029 (694 mg, 96%).

IR (CHCl3): 3252, 1724, 1664, 1615, 1578, 1529, 1464, 1406, 1378, 1312;

Elemental analysis: (C24H32N2O4 ·0,2MeOH)

Calculated: C, 68,39; H, 9,20; N, 6,59.

Found: C, 68,32; H, 9,39; N, 6,79.

Example 54. Synthesis of 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]cyclohexanecarbonyl acid (II-056)

To a methanol solution (9 ml) of 2-[(1-butyl-5-ethyl-2-oxo-6-propyl-1,2-dihydropyridines-3-carbonyl)amino]ethylcyclohexylamine (II-029, 368 mg, 0.88 mmol)obtained in example 53, added 4M aqueous sodium hydroxide solution (0,66 ml of 2.66 mmol) and the mixture was stirred at 50°C in a period of 25.5 hours. The reaction mixture was poured into water and washed with ethyl ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, then the solvent is removed by distillation and obtain a colorless foamy substance (359 mg). The resulting material is recrystallized from a mixture of ethyl acetate-hexane and get colorless elongated crystals of II-056 (296 mg, 86%).

TPL: 167-169°C

IR (nujol): 3190, 3060, 1724, 1656, 1599, 1582, 1538, 1482, 1462, 1409, 1377, 1348, 1319.

Elemental analysis: (C22H34N2O4)

Calculated: C, 67,66; H, 8,78; N, 7,17.

Found: C, 67,61; H, 8,76; N, 7,32.

Example 55. Synthesis of methyl-1-{[(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropionate (I-240)

To a solution of 1-(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA22, 425 mg, 1.19 mmol)obtained in example 22, in anhydrous THF (4 ml) add oxalicacid (109 μl, 1.25 mmol) and DMF (6 ml), the mixture is then stirred at room temperature for 1 hour. Then to a solution of methyl ester hydrochloride of dimethylglycine (220 mg, 1,43 mmol) in anhydrous DMF (4 ml) under stirring and cooling on ice sequentially added triethylamine (of 0.67 ml, 4,80 mmol) and the above solution of the acid chloride, the mixture is then stirred at room temperature for 16 hours. The reaction mixture is acidified, pouring it into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (48 g) (ethyl acetate-hexane (1:1) and then ethyl acetate) and receive a colorless foamy substance (544 mg). The resulting material is recrystallized from a mixture of ethyl acetate-methanol-hexane and get colorless elongated crystals of I-240 (499 mg, 92%, TPL: 156-157°C).

NMR: (CDCl3) 1,32-and 1.54 (m, 4H), 1.60-to of 1.84 (m, 4H), of 1.62 (s, 6H), 1,95-to 2.06 (m, 2H), 2,60-of 2.64 (m, 2H), 2,88 of 2.92 (m, 2), of 2.97 (s, 3H), 3,06-3,18 (m, 2H), 3,76 (s, 3H), 4,24 is 4.36 (m, 2H), 5,74 (t, 1H, J=6,0), 8,30 (s, 1H), 10,17 (s, 1H).

IR (chloroform): 3257, 1738, 1667, 1619, 1577, 1529, 1484, 1458, 1439, 1408, 1384, 1363, 1329.

Elemental analysis: (C21H33N3O6S)

Calculated: C, 55,36; H, 7,30; N, Which 9.22; S,? 7.04 Baby Mortality.

Found: C, 55,25; H, 7,39; N, 9,14; S 6,98.

Example 56. Synthesis of 1-{[(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropanoic acid (I-506)

To a methanol solution (7 ml) of methyl 1-{[(3-methanesulfonylaminoethyl)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropionate (I-240, 269 mg, 0.59 mmol)obtained in example 55, added 4M aqueous sodium hydroxide solution (0.45 ml, is 1.81 mmol) and the mixture was stirred at 50°C for 17 hours. Then the reaction mixture was poured into water and washed with ethyl ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and receive a colorless foamy substance (282 mg). The resulting material is recrystallized from a mixture of ethyl acetate-hexane and get colorless prismatic crystals I-506 (226 mg, 87%, TPL: 183-184°C).

NMR: (DMSO-d6) 1,25-of 1.88 (m, 10H)to 1.48 (s, 6H), 2,60-2,70 (m, 2H), 2,90-a 3.01 (m, 2H), 2,93 (s, 3H), 3,03-of 3.12 (m, 2H), 4,07-4,18 (m, 2H), 7,15 (t, 1H, J=6,0), of 8.09 (s, 1H), 10,22 (s, 1H), 12,40 (Sirs, 1H.

IR (nujol): 3171, 3029, 1736, 1657, 1581, 1537, 1485, 1460, 1413, 1377, 1364, 1334, 1318.

Elemental analysis: (C20H31N3O6S)

Calculated: C, 54,40; H, Was 7.08; N, 9,52; S, 7,26.

Found: C, 54,37; H, 7,02; N, 9,29; S, 7,16.

Example 57. Synthesis of methyl-1-{[(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropionate (I-251)

1-(3-Acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA23, 240 mg, 0.71 mmol)obtained in example 23, dissolved in anhydrous THF (3 ml) and add oxalicacid (65 μl, 0.75 mmol) and DMF (5 ml), the mixture is then stirred at room temperature for 1 hour. Hydrochloride methyl ester dimethylglycine (131 mg, 0.85 mmol) was dissolved in anhydrous DMF (3 ml) and with stirring and cooling on ice, add triethylamine (and 0.40 ml, 2,87 mmol) and the above solution of the acid chloride. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is acidified, pouring into dilute hydrochloric acid, then extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, then the residue purified column chromatography on silica gel (46 g) (tracecut-hexane (2:1) and ethyl acetate) and receive a colorless foamy substance (296 mg). This substance is recrystallized from a mixture of ethyl acetate-methanol-hexane and get colorless mineral postadoptive crystals I-251 (273 mg, 88%, TPL: 135-136°C).

NMR: (CDCl3) 1,32-of 1.53 (m, 4H), 1,60-1,80 (m, 4H), and 1.63 (s, 6H), of 1.97 (m, 2H), 2,59-2,63 (m, 2H), 2,86-2,90 (m, 2H), 3,18 to be 3.29 (m, 2H), 3,69 (s, 3H), 3,76 (s, 3H), 4,15-4,27 (m, 2H), 5,50 (m, 1H), 8,28 (s, 1H), 10,24 (, 1H).

IR (chloroform): 3453, 3256, 1723, 1667, 1619, 1577, 1528, 1484, 1439, 1409, 1384, 1364, 1333.

Elemental analysis: (C22H33N3O6)

Calculated: C, 60,67; H, Of 7.64; N, 9,65.

Found: C, 60,49; H, 7,60; N, 9,59.

Example 58. Synthesis of 1-{[(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropanoic acid (I-518)

Methyl-1-{[(3-acetylaminophenol)-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl]amino}methylpropionate (AA24, 153 mg, 0.35 mmol)obtained in example 24 was dissolved in methanol (3 ml), added 4M aqueous sodium hydroxide solution (of 0.26 ml, 1.05 mmol) and the mixture was stirred at 50°C for 5 hours. The reaction mixture is allowed to cool, then poured into water and the aqueous layer washed with ethyl ether. The aqueous layer was acidified with 2M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, then the solvent is removed by distillation and obtain colorless oily I-518 (148 m is, 96%).

NMR: (DMSO-d6) 1,24-to 1.82 (m, 10H)to 1.48 (s, 6H), 2,60 of 2.68 (m, 2H), 2,86-2,96 (m, 2H), 3,05-and 3.16 (m, 2H), 3,53 (s, 3H), 4,00-to 4.14 (m, 2H), 7,27 (m, 1H), 8,08 (s, 1H), of 10.21 (s, 1H), 12,42 (Sirs, 1H).

IR (KBr): 3391, 1726, 1665, 1620, 1577, 1530, 1456, 1409, 1382, 1362, 1315.

Elemental analysis: (C21H31N3O6·0,1AcOEt·0,4H2O)

Calculated: C, 58,75; H, 7,51; N, 9,60.

Found: C, 58,81; H, 7,35; N, 9,59.

Example 59. Synthesis of 5-methyl-2-oxo[1,3]dioxol-4-Eletropaulo ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-308)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 250 mg, 0,621 mmol)obtained in example 45, 4-methyl bromide-5-methyl[1,3]dioxol-2-he (180 mg, 0,933 mmol) and potassium bicarbonate (150 mg, 1.50 mmol) suspended in DMF (2.5 ml), then the suspension is stirred at room temperature for 15 hours. Then add 5% aqueous citric acid solution and the suspension is extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution and dried over sodium sulfate, then the solvent is removed by distillation. The residue is purified column chromatography on silica gel (hexane-ethyl acetate (30-34%)and receive I-308 in the form of a colorless foamy substance (318 mg, 99%).

Example 60. Synthesis of TRANS-2-phenyl[1,3]dioxane-5-silt ester 2-[(1-cycle is exility-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-302)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 200 mg, 0,497 mmol)obtained in example 45, converted into the acid chloride in the traditional way, using a solution of oxalicacid in DMF, then added pyridine (1 ml) and TRANS-2-phenyl[1,3]dioxane-5-ol (180 mg, 1.00 mmol), the mixture is then left to interact at room temperature for one hours, then at 50°C for 1 hour. Then to the reaction mixture was added diluted hydrochloric acid, the mixture is then extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and saturated saline solution in this order, then dried. Then the solvent is removed by distillation, the residue is purified column chromatography on silica gel (hexane-ethyl acetate (40-50%)and recrystallized from methanol, receiving I-302 in the form of colorless needle-like crystals (57 mg, 20%, TPL: 166-168°C).

Example 61. Synthesis of 2-hydroxy-1-hydroxymethylcellulose ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-303)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid Tran is-2-phenyl[1,3]dioxane-5-silt ether (I-302, 255 mg, 0,451 mmol)obtained in example 60, dissolved in a mixture of methanol (1 ml), THF (2 ml) and 2M hydrochloric acid (1 ml), then the solution is stirred at room temperature for 3 hours. Then the solution was diluted with water and extracted with ethyl acetate. The organic layer is washed with water and dried, then the solvent is removed by distillation. The residue is purified column chromatography on silica gel (hexane-ethyl acetate (35-80%)), recrystallized from hexane and receive I-303 in the form of colorless crystals (85 mg, 40%, TPL: 123-125°C).

Example 62. Synthesis of 2-oxo[1,3]dioxolane-4-silt ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropanoic acid (I-309)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 250 mg, 0,621 mmol)obtained in example 45, 4-chloro[1,3]dioxolane-2-he (84 μl, of 0.93 mmol), potassium bicarbonate (186 mg, of 1.86 mmol) and a small amount of potassium iodide are suspended in DMF (2.5 ml), then the suspension is stirred at room temperature for 15 hours. Then add 5% aqueous citric acid solution and the suspension is extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over sodium sulfate, then the solvent is removed by distillation. the STATCOM purified column chromatography on silica gel (hexane-ethyl acetate (30%)) and get I-309 in the form of a colorless foamy substance (96 mg, 31%).

Example 63. Synthesis of S-methyl ester 2-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylthiopropionate acid (I-001)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 250 mg, 0.621 mmol)obtained in example 45, converted into the acid chloride in the traditional way, using a solution of oxalicacid in DMF, and then the acid chloride was dissolved in DMF (2 ml). Then add thiamethoxam sodium (92 mg, 1,24 mmol) and the mixture is left to interact for 30 minutes while cooling on ice and for 2 hours at room temperature. Then carry out the processing described above, then the resulting residue is purified column chromatography on silica gel (hexane-ethyl acetate (25%)) and get I-001 in the form of colorless crystals (140 mg, 52%, TPL: 196-198°C).

Example 64. Synthesis of {1-[(2-hydroxyethyl)methylcarbamoyl]-1-methylethyl}amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-019)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 250 mg, 0,621 mmol)obtained in example 45, N-methylethanolamine (60 μl, 0,745 mmol), WSCD (143 mg, 0,683 mmol) and a small amount of HOBt was subjected to the have interaction in DMF (2.5 ml) at room temperature for 18 hours. Then carry out the processing described above, then the resulting residue is purified column chromatography on silica gel (ethyl acetate) and get I-019 in the form of a colorless solid (171 mg, 60%, TPL: 195-196°C).

Example 65. Synthesis of (2-oxitetraciclina-3-yl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-072)

1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01, 250 mg, 0,788 mmol)obtained in example 1, using the traditional method turn into the acid chloride, which is dissolved in THF. The resulting solution under cooling on ice is added dropwise to the mixture hydrobromide 3-aminopiperidin-2-it (187 mg, of 1.03 mmol) and triethylamine (0,38 ml, 2.36 mmol) in DMF (2 ml). The mixture is then stirred at the same temperature for 30 minutes and continue to stir at room temperature for 3 hours. Subsequent processing of the mixture is conducted according to the above-described method, the mixture is then purified column chromatography on silica gel (hexane-ethyl acetate (40-60%)and receive I-072 as a colourless solid (242 mg, 77%, TPL: 136-140°C).

Example 66. Synthesis of methyl ester 1-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarbonyl acid (I-149)

Toluene solution (4 ml) ethyl-1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylate (AA16, 250 mg, 0,692 mmol)obtained in example 16, hydrochloride 1 aminomethylenemalonate (174 mg, 0.90 mmol) and triethylamine (125 μl, 0.90 mmol) is refluxed for 20 hours. After cooling the reaction mixture to room temperature, the insoluble matter is removed by filtration and the filtrate concentrated. Then the resulting residue is purified column chromatography on silica gel (hexane-ethyl acetate (10-15%)and receive I-149 in the form of a colorless foamy substance (223 mg, 68%).

Example 67. Synthesis of ethyl-2-[(1-cyclohexylmethyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]cyclohexanecarboxylate (II-023)

Compound II-023 synthesized analogously to the method of example 66.

Example 68. Synthesis of (2-oxazepan-3-yl)amide 1-butyl-4-hydroxy-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-071)

Compound I-071 synthesized analogously to the method of example 66.

Example 69. Synthesis of(1-hydrazinophenyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-050)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahedrite the OCTA[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 403 mg, 1.00 mmol)obtained in example 45, suspended in anhydrous DMF (4 ml) and stirred in the presence of WSCD (422 mg, of 2.20 mmol), HOBt (27 mg, 0.20 mmol) and hydrazine monohydrate (58 μl, 1.20 mmol) at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, dried over anhydrous magnesium sulfate, then the solvent is removed by distillation under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate-methanol-hexane and obtain colorless needle crystals of I-050 (339 mg, 81%, TPL: 177-180°C).

IR (nujol): 3343, 3216, 3177, 1665, 1605, 1579, 1526, 1455, 1410, 1377, 1360, 1333.

Elemental analysis: (C23H36N4O3)

Calculated: C, 66,32; H, 8,71; N, 13,45.

Found: C, 66,11; H, 8,78; N, 13,20.

Example 70. Synthesis of (1-methylsulfonylbenzoyl-1-methylethyl)amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-052)

1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (1-geringerer-1-methylethyl)amide (I-050, 24 g, 2,98 mmol)obtained in example 69, suspended in anhydrous THF (13 ml), then with stirring and cooling on ice, add pyridine (of 0.48 ml, 5,94 mmol) and methanesulfonamide (0.35 ml, to 4.52 the mol). The mixture is then stirred at room temperature for 2 hours and 30 minutes. The reaction mixture is acidified, pouring into dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (61 g) (ethyl acetate-hexane (1:1) and then ethyl acetate) and obtain colorless crystals I-052 (1,57 g). This product is recrystallized from methanol-water and obtain colorless needle crystals (1.22 g, 80%, TPL: 177-178°C).

IR (nujol): 3543, 3287, 3249, 3137, 3037, 3011, 1670, 1618, 1579, 1517, 1484, 1454, 1408, 1389, 1377, 1365, 1341, 1321.

Elemental analysis: (C24H38N4O5S·0,3MeOH·0,4H2O)

Calculated: C, 57,10; H, 7,83; N, 10,96; S, 6,27.

Found: C, 57,11; H, 7,58; N, 10,95; S, 6,47.

Example 71. Synthesis of [1,1-dimethyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]amide 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (I-047)

2-[(1-Cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]-2-methylpropionic acid (I-358, 350 mg, 0.87 mmol)obtained in example 45, suspended in anhydrous DMF (5 ml), added WSCD (200 mg, 1.04 mmol), HOBt (24 mg, 0.18 to which mol) and N-methylpiperazine (116 μl, 1.05 mmol), the mixture is then stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and again with water, then dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, the residue is recrystallized from a mixture of ethyl acetate-methanol-hexane and obtain colorless needle crystals I-047 (313 mg, 74%, TPL: 183-184°C).

IR (nujol): 3179, 2791, 2761, 2745, 1668, 1639, 1621, 1581, 1548, 1519, 1459, 1442, 1419, 1378, 1360, 1335, 1317.

Elemental analysis: (C28H44N4O3)

Calculated: C, At 69,39; H, 9,15; N, To 11.56.

Found: C, 69,27; H, 9,10; N, 11,53.

Example 72. Synthesis of methyl 2-[(1-cyclohexylmethyl-2,6-dioxo-1,2,5,6,7,8-hexahydro-6-thiopyrano[4,3-b]pyridine-3-carbonyl]amino)-3-methylbutyrate (I-258)

1-Cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (AA09)obtained in example 9, was dissolved in a solution of methyl 2-[(1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-6-thiopyrano[4,3-b]pyridine-3-carbonyl)amino]-3-methylbutyrate (I-256, 350 mg, 0,832 mmol), synthesized according to the method of example 37, in chloroform (7 ml)then while cooling on ice, add methylarbutin acid (215 mg, 1.25 mmol) and the mixture is stirred at the same temperature for 12 minutes. Reactio the ing the mixture was washed with saturated aqueous sodium bicarbonate and water, then the organic layer is dried over anhydrous magnesium sulfate. The solvent is removed by distillation under reduced pressure, the residue is purified column chromatography on silica gel (42 g) (chloroform-methanol 50:1 then 25:1) and obtain a colorless oily substance (330 mg). This oily substance is recrystallized from a mixture of ethyl acetate-methanol and receive a white crystalline powder I-258 (247 mg, 68,0%, TPL: 216-218°C).

IR (nujol): 3226 (NH), 1736, 1663, 1530 (C=O)

Example 73. Synthesis of methyl 2-[(1-cyclohexylmethyl-2,6,6-trioxo-1,2,5,6,7,8,hexahydro-6-thiopyrano[4,3-b]pyridine-3-carbonyl]amino)-3-methylbutyrate (I-257)

1-Cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-2H-thiopyrano[4,3-b]pyridine-3-carboxylic acid (AA09)obtained in example 9, was dissolved in a solution of 2-[(1-cyclohexylmethyl-2-oxo-1,5,7,8-tetrahydro-6-thiopyrano[4,3-b]pyridine-3-carbonyl)amino]-3-methylmethacrylate (I-256, 350 mg, 0,832 mmol), synthesized according to the method of example 37, in chloroform (7 ml), then while cooling on ice, add methylarbutin acid (442 mg, 2.56 mmol) and the mixture is stirred at the same temperature for 10 minutes. Then the temperature was raised to room temperature and the mixture continued to stir for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, then the organic layer is dried over anhydrous Sul is blockhead magnesium. The solvent is removed by distillation under reduced pressure and get white solid I-257 (428 mg). The obtained solid is recrystallized from a mixture of ethyl acetate-hexane and get a white crystalline powder (297 mg, 78.8 per cent, TPL: 242-245°C).

IR (nujol): 3235 (NH), 1741, 1662, 1532 (C=O)

Example 74. Synthesis of methyl[(6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carbonyl)amino]thiophene-2-ilaclama (I-273)

To a solution of 6-ethyl-1-(4-terbisil)-5-methyl-2-oxo-1,2-dihydropyridines-3-carboxylic acid (289 mg, 1.00 mmol) in anhydrous THF (3 ml) at room temperature add oxalicacid (0.10 ml, 1.15 mmol) and DMF (10 μl), the mixture is then stirred for 15 minutes. The resulting solution in THF is added dropwise to a solution of methyl ester hydrochloride N-α-(2-thienyl)glycine (208 mg, 1.00 mmol), synthesized according to the method of example 25, in anhydrous DMF (3 ml), followed by cooling on ice, add triethylamine (of 0.56 ml, 4.00 mmol). The mixture is then warmed to room temperature and stirred for another four hours. To the reaction mixture add water, 2M hydrochloric acid (2 ml) and the mixture extracted with ethyl acetate. The organic layer is washed twice with water and dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure, and receives a yellow solid. According to the scientists, the solid is recrystallized from a mixture of ethyl acetate-hexane and get pale yellow crystalline powder I-273 (365 mg, 82,5%, TPL: 182-184°C).

IR (nujol): 3151 (NH), 1748, 1668, 1510 (C=O)

Example 75. Synthesis of (-)-[(1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carbonyl)amino]phenylacetic acid (I-195)

To the solution obtained in example 1, 1-cyclohexylmethyl-2-oxo-1,2,5,6,7,8,9,10-octahydrocyclopenta[b]pyridine-3-carboxylic acid (AA01, 317 mg, 1.00 mmol) in anhydrous THF (3 ml) at room temperature add oxalicacid (0.10 ml, 1.15 mmol) and DMF (10 μl), the mixture is then stirred for 15 minutes. The resulting solution in THF while cooling on ice is added dropwise to a solution of ester (-)-α-phenylglycinonitrile and paratoluolsulfonata (514 mg, 1.05 mmol) and triethylamine (of 0.56 ml, 4.00 mmol) in anhydrous DMF (3 ml). The mixture is stirred at the same temperature for 50 minutes and acidified by the addition of ice water and then 2M hydrochloric acid (2 ml). The mixture is then extracted with ethyl acetate (15 ml). The organic layer is washed twice with water and dried over anhydrous magnesium sulfate. The solvents are removed by distillation under reduced pressure and get the ether as colourless solids (629 mg). The obtained ester is recrystallized from a mixture of ethyl acetate-hexane and get a white crystalline powder (439 mg, 71.2 percent).

TPL: 178-180°C

IR (nujol): 3196(NH), 1745, 1667, 1532 (C=O).

NMR: (CDCl3) 0,98-of 1.92 (m, 19H), 2,60 (t, 2H, J=6,0), 2,0 (t, 2H, J=6,3), 4,01 (width, 2H), 5,90 (d, 1H, J=to 6.19), 6.87 in (s, 1H), 6,97-7,46 (m, 15H), 8,24 (s, 1H), 11,04 (d, 1H, J=6,9);

[α]D-5,2±0,5° (22°C, C=1,002, CDCl3).

Then triperoxonane acid (0.4 ml) under cooling on ice are added to a solution of ester (391 mg, 0,634 mm) and anisole (0.8 ml) in dichloromethane (4 ml), the mixture is then stirred at the same temperature for one hour and 30 minutes. The mixture is then warmed to room temperature and stirred for 4 hours and 30 minutes, then the solvent is removed by distillation under reduced pressure. To the residue add hexane, causing solidification of the residue, then the solid is washed with hexane and get a white powder (255 mg). The resulting powder was recrystallized from a mixture of ethyl acetate-hexane and get a white crystalline powder (I-195, 218 mg, 76,2%, optical purity of 100%ee).

TPL: 208-211°C.

Conditions for the measurement of optical purity: HPLC column CHIRALCEL OD (Daicel), 4,6ϕ×250; movable layer: acetonitrile (0.1% TFUC):water (0.1% TFUC)=60:40; flow rate: 1 ml/min; detection: UV 254 nm; retention time: 11.6 minutes.

IR (nujol): 3254 (NH), 1742, 1671, 1518 (C=O).

NMR, (DMSO-d6) 1,00-of 1.84 (m, 19H), 2,64 (shirt, 2H), 2.95 and (shirt, 2H), 4,00 (width, 2H), 5,48 (d, 1H, J=6,9), 7,31-7,44 (m, 5H), 8,10 (s, 1H), 10,71 (d, 1H, J=6,9), 13,07 (width, 1H);

[α]D-5,4±0,5° (22°C, C=1,006, CH3OH).

Structure and NMR spectra of the compounds synthesized using the methods described above, are shown in tables 4-287 (the m at the end of the description).

Examples of testing described above, compounds of the present invention is given below.

Example test 1. Analysis of inhibition of binding of human cannabinoid receptor

Use of the human cannabinoid receptor membrane preparation (membrane fraction) of CHO cells, stably exhibiting receptor CB1 or CB2. The obtained membrane preparation, test the connection and [3H] CP55940, 38,000 dpm (final concentration 0.5 nm: supplied NEN Life Science Products Corp.) incubated in a buffer solution for assay (50 mm buffer solution of Tris-HCl (pH 7,4)containing serum albumin bovine, 1 nm EDTA, 3 mm MgCl2) at 25°C for 2 hours. After incubation, the reaction mixture was filtered through a glass filter, treated with a 1% polyethylenimine, and washed with 50 mm buffer solution of Tris-HCl (pH 7,4), then using a liquid scintillation counter to measure the radioactivity on the glass filter. Nonspecific binding measured in the presence of 10 μm WIN55212-2 (cannabinoid receptor, is described in U.S. 5081122 is Sigma Corp.), and determine the concentration of test compound providing 50% inhibition (IC value50) specific binding. The value of Ki for the tested compounds calculated from the obtained values IC50 and the values of Kd 3H CP55940. The results are shown in the table.

Example of test 2. Analysis of the inhibition of the formation of the cyclic amp-mediated cannabinoid receptor

The test compound is added to the CHO cells, which exhibit human receptor CB1 or CB2, and incubated for 15 minutes, then add Forskolin (final concentration of 4 μm, is SIGMA Corp.) and the mixture is incubated for 20 minutes. The reaction stopped by the addition of 1M hydrochloric acid and then measure the amount of camp in the supernatant using a kit for measuring cyclic AMP (supplied CIS Diagnostic Corp.). Education camp as a result of stimulation by Forskolin take over 100% compared to the value obtained in the absence of stimulation by formalism, and determine the concentration of the test compound (the value of the IC50), providing 50% inhibition. Compounds with agonistic effect in relation to the receptor CB1 or CB2 shown in the table.

The results of the sample test 1 sample test 2 are shown in tables 288 and 289.

Table 288
Rooms compoundsActivity binding (nm) Agonistic activity (nm)
CB1CB2CB1CB2
I-001<2<2<2
I-002487,1114,4
I-0192,9<28,1
I-0387,1<234<2
I-0481182,632817
I-052327,3498,1
I-0541165115
I-084<2 <2<2<2
I-089<2<2<2<2
I-094<2<29,0<2
I-1113,5<2<2
I-1243,6<2<2
I-1335,0<24,0
I-134<2<2<2
I-196<2<2<2
I-203<2<2<2
I-2112,4<2<2
I-252<2<2<2
I-253<2<2<2
I-2552,1<2<2
I-263<2<2<2
I-26612<2to 12.0
I-300<2<2<2
I-301<2<2<2
I-305<2<2 <2
I-306<2<2<2
I-40234<2>2000the 5.7
I-411>2000382>2000556
I-4243573>20005,9
I-493>200036>200024
I-5307<2305
I-53321<2>2000<2
I-551502,2135<2
I-556 8,1<23573,5
I-570681170912
I-572394,43972,4
I-5791587,343127
I-580247,44148
I-588411072the 5.7
I-5906616512,4
I-5953549,5120830
I-5963412231230
I-5993743713
I-60147a 3.91866,3
I-604162,5554,8
I-606604,41188,7

Table 289
Rooms compoundsActivity binding (nm)Agonistic activity (nm)
CB1CB2CB1CB2
I-60852711>20003,5
I-6172956,67 18
II-031>20002,59,9
II-067>200013685a 4.9
II-069883,45,62,1
II-073886,2110,2
II-075652482904,6
II-076>200041>20001,2
II-078145227252<2
III-0171491532235
IV-023 4252239811
IV-02913184360622
X-2117673,3>200030
X-5493<2>20003,7
X-645801845415
X-66>20009254950
X-67>200096>200040
X-11512163,3>20008,6
X-1268733113135
X-128608101523
X-133>20005,5>2000<2
X-138>200042>200030
X-1572703,4268<2
X 174>20008,9>20009,8
X-196>200031>200045
X-1971264417087,2
X-202118246>200081
X-2161767 3,3>200030
X-220555181550231
X-222162143>200057
X-2294821236927
X-231>200038>200035
X-232>200015>200029
X-233>200024>200015
X-23448243756,1
X-2359503,7270the 4.7
X-239142010>20003,6
X-2407936,2468<2
X-241>200057>200026
XI-0174416,612711
XI-025136154>2000209
XI-027136154>2000209
XI-035>200031>200047
Connection comparison
4-101*18901,9
10-035*1190,2

*1: the Numbers of the compounds described in WO 02/053543.

Example test 3. Analysis antipruritic activity when the outer coating compounds

1. Obtaining preparations of compounds and reagents: the Test compound was dissolved in acetone (SIGMA). Compound 48/80 (SIGMA) dissolved in saline solution (supplied by Otsuka Pharmaceutical Co., Ltd.) obtaining a concentration of 60 µg/ml.

2. Animals: Female Crj: as a laboratory animal use mice CD-1 (ICR) aged 6 to 10 weeks (Japan Charles Liver). Animals are kept in a special room with anti-infective barrier at room temperature 23±3°C, humidity 30 to 70%, with alternating periods of light and darkness every 12 hours, with free access to food (CE-2: Japan Crea) and drinking water. The hair on the back from the neck to mid back) animals clip out using the clippers for two days or more prior to the assessment antipruritic activity and choose animals that on the day of the experiment do not have wounds, redness and thickening of the skin on the shaven area.

3. The experiment: a 50 μl solution of the test the connection has been created in acetone pipette is applied on the shaven area of the back of the mouse. After 15 minutes with a syringe for subcutaneous injection (Terumo Corporation) injected intradermally with 50 μl (corresponding to 3 μg) solution of compound 48/80 in areas that bear the connection immediately after the mice are placed separately in each of five cells for observation, made of acrylate polymer, and determine the frequency of pokusyvanii (pokusyvanii plot introduction connections hind paw) for 30 minutes. The measurements are carried out in one group, containing from 5 to 7 mice.

4. Treatment results: the results of the experiment lead in the form of averages. The significance of the differences of the results obtained in the group treated with the compound, and the results obtained in the control group, determined using a t-test of Welsh, significant consider the results if p<0,05.

The results are shown in table 290.

Table 290
Rooms connect.The degree of suppression of itchingRooms connect.The degree of suppression of itchingRooms connect.The degree of suppression of itching
% (concentration in %) % (concentration in %)% (concentration in %)
I-00153 (0,5)I-00268 (2,5)I-01974 (1,0)
I-03867 (3,0)I-04858 (3,0)I-05280 (3,0)
I-05463 (2,0)I-08460 (0,1)I-08965 (0,5)
I-09460 (0,5)I-11155 (0,1)I-12449 (0,5)
I-13356 (0,5)I-13491 (0,5)I-19647 (0,5)
I-20386 (0,5)I-21170 (1,5)I-25296 (1,5)
I-25370 (1,5) I-25593 (1,5)I-26357 (1,5)
I-26664 (2,0)I-30041 (0,5)I-30139 (0,5)
I-30561 (0,5)I-30683 (0,5)I-40259 (3,0)
I-41180 (0,5)I-42462 (3,0)I-53074 (2,0)
I-53373 (3,0)I-55151 (2,0)I-55676 (3,0)
I-57084 (3,0)I-57297 (1,0)I-57999 (3,0)
I-58098 (3,0)I-58881 (1,0)I-59075 (3,0)
I-595108 (3,0 I-59660 (3,0)I-59967 (0,5)
I-60167 (1,0)I-60495 (3,0)I-60686 (1,0)
I-60875 (3,0)I-61796 (1,0)II-03155 (2,0)
II-06768 (3,0)II-06984 (3 0)II-07358 (3,0)
1I-07595 (3,0)II-07686 (3 0)II-07894 (3,0)
III-01776 (3,0)IV-023116 (3,0)IV-02993 (1,0)
X-21106 (1,0)X-54100 (1,0)X-6499 (1,0)
X-66 71 (1,0)X-6779 (1,0)X-11567 (0,5)
X-216106 (1,0)X-22097 (0,5)X-229105 (0,5)
XI-03569 (0,5)
Connection comparison4-101*17,5 (5,0)10-035*122 (5,0)
*1: the Numbers of the compounds described in WO 02/053543.

The above compounds of the present invention, except 4-101 and 10-035 described in WO 02/053543 demonstrate significant differences with p<0,05.

Example test 4. Analysis antipruritic activity when orally administered compounds

1. Obtaining preparations of compounds and reagents: Test the connection, suspen irout 0.5% aqueous solution of methylcellulose (Kanto Chemicals Co., Ltd.). Compound 48/80 (SIGMA) dissolved in saline solution (supplied by Otsuka Pharmaceutical Co., Ltd.) obtaining a concentration of 60 µg/ml.

2. Animals: Female Crj: as a laboratory animal use mice CD-1 (ICR) aged 6 to 10 weeks (Japan Charles Liver). Animals are kept in a special room with anti-infective barrier at room temperature 23±3°C, humidity 30 to 70%, with alternating periods of light and darkness every 12 hours, with free access to food (CE-2: Japan Crea) and drinking water. The hair on the back from the neck to mid back) animals clip out using the clippers for two days or more prior to the assessment antipruritic activity and choose animals that on the day of the experiment do not have wounds, redness and thickening of the skin on the shaven area.

3. The experiment: a Suspension of the test compound is administered orally in an amount of 5 ml/kg with oral probe. The control group mice orally administered solution of methylcellulose in an amount of 5 ml/kg Over 30 minutes using a syringe for subcutaneous injection (Terumo Corporation) in clipped plots back intradermally injected with 50 μl (corresponding to 3 μg) solution of compound 48/80, immediately after that, the mice are placed separately in each of five cells for observation, made of acrylate polymer, and determine the frequency of pokusyvanii (p is sesivany plot introduction connections hind paw) for 30 minutes. The measurements are carried out in one group, containing from 4 to 8 mice.

4. Treatment results: the results of the experiment lead in the form of averages. The significance of the differences of the results obtained in the group treated with the compound, and the results obtained in the control group, determined using a t-test of Welsh, significant consider the results if p<0,05.

Example test 5. Testing using a rat model of asthma OVA

Egg albumin (OVA) in a concentration of 0.1 mg/ml and 1 mg gel aluminum hydroxide is introduced into the abdominal cavity of the rat, Brown Norway (BN), and thus rats sensibiliser to these compounds. 12, 19, 26 and 33 days after sensitization of rats placed in a chamber and introducing them 1% solution of OVA in the form of an aerosol by inhalation using an ultrasonic nebulizer (NE-U17) for 30 minutes. The compound of the present invention is administered orally at a dose of 10 mg/kg once a day continuously for three days, starting one hour before the fourth antigen exposure. The control group instead of the compounds of the present invention introduce a 0.5% solution of methylcellulose.

Three days after the fourth antigen exposure, when anesthesia pentobarbital (80 mg/kg, V.B.), in a vein in the neck rats administered doses of acetylcholine(3,9, 7,8, 15,6, 31,3, 62,5, 125, 250 and 500 µg/kg) one by one, starting with the lowest, and measure the reduction in respiratory the ways (increasing pressure insufflation), occur immediately after the injection, using a partially modified method Konnzett & Rossler. The degree of suppression of deterioration, associated with Hyper-reactive Airways, compared with the control group, calculated from the values of the area under the curve (AUC) according to the concentration-response to acetylcholine.

After the measurement is finished hyperresponsiveness of the Airways to the alveoli bronchi of rats washed three times with physiological saline in a volume of 5 ml using hemocytometer under an optical microscope consider the total number of cells in flushing and then determine the degree of suppression of inflammatory cell infiltration compared with the control group. In addition, the ELISA method to determine the content of mucin in the rinse after washing the Airways using jacalin, which is a mucin-binding lectin, and determine the degree of suppression of secretion of mucus in comparison with the control group.

Example test 6. Testing using a model of nasal congestion in Guinea-pig

Methods of measurement of nasal resistance and evaluation reduce nasal congestion by using Guinea pigs as described below. Male Hartley Guinea pigs sensibiliser egg albumin (OVA) by inhalation of an aerosol, derived from a one percent p is the target egg albumin (OVA), within ten minutes two times a week. Seven days later the animals exposed to antigen with getting a response. Guinea pigs anaesthetize pentobarbital (30 mg/kg, V.B.), then cut through the trachea, insert the cannula from the side of the nasal cavity and from the lungs, respectively, then pulmones connect the ventilator that delivers air 60 times per minute to 4 ml each time. Spontaneous breathing Guinea pigs stop by aluminum (2 mg/kg, I.V), then in nasal rostrum through the cannula to the side of the nasal cavity with the help of artificial ventilation to deliver air at 70 times per minute for 4 ml and using a probe inserted into the side branch, measure the pressure required for the air supply, which is indicative of nasal resistance. Antigen influence in the form of a 3% solution of OVA within three minutes between artificial ventilation and cannula nasal cavity. The compound of the present invention is injected into a vein for ten minutes before exposure to the antigen. Nasal resistance was measured continuously for 30 minutes, starting with 0, and the degree of suppression compared with the medium is calculated on the basis of AUC (nasal resistance (cm H2O) lay on the vertical axis and time (from 0 to 30 minutes) - horizontally on the axis).

Example test 7. The deterioration of the respiratory function of the Guinea pig (model COPD) under the influence of cigarette smoke

Primary current smoke commercially available filter cigarette (Highlight, the content of 1.4 mg nicotine, tar 17 mg, Japan Tabaco Inc.) use for influence over the nose and mouth Hartley Guinea pigs (obtained from Japan SLC Co., Ltd.) with an intensity of 30 cigarettes a day, five days a week for 30 days using the device for exposure to cigarette smoke in animals (produced Thinker N Co., Ltd.). (Wright JL, Churg A. Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig Am. Rev. Respir. Dis. 1990 142:1422-8.).

Connection (1) suspended in 0.5% solution of methylcellulose and administered orally at a dose of 10 mg/kg three times a day. The group treated with the environment, three times a day orally administered 5 ml/kg of 0.5% solution of methylcellulose. After 16-24 hours after the last exposure to cigarette smoke under anesthesia with urethane (100 mg/kg, VB.) cut through the trachea of the Guinea pig and the cannula inkubiruut and inserted into the device for measuring the respiratory function (manufactured Baxco Co., Ltd.) in small animals. Respiratory function Guinea pigs measured in accordance with the instructions provided with the device.

Compare the number of functional residual air, the increase in the total volume of the lungs and a decrease in dynamic lung compliance under the influence is the influence of cigarette smoke in the group, receiving environment, and in the group treated with the drug, and then analyze the significance of differences. The results are shown as mean value±standard deviation. Statistical analysis is performed using two-sided student's criterion, the difference is considered significant if P<0,05.

It is shown that the introduction of the compound (1) in a dose of 30 mg/kg / day, increasing the number of functional residual air is significant, P<0,05.

It is shown that the introduction of the compound (1) in a dose of 30 mg/kg / day, the increase in the total volume of the lungs is significant, P<0,05.

Example test 8. The inhibition effect of formalin nociceptive stimulus in mice ICR

For analysis of the inhibitory effect of compounds of the present invention on the effect of formalin nociceptive stimulus using male ICR mice (age five weeks). The test compound dissolved in sesame oil and the resulting solution was orally administered to mice for two hours before injection of formalin, and then subcutaneously in the right hind paw injected with formalin (2%, 20 ml). In this experiment, the dimension that should be performed within 30 minutes after injection of formalin, divided into two phases: 5 minutes immediately after injection of formalin (first phase) and 20 minutes from the 10-th to 30-th minute after injection (second phase). Measure the decrease in pain intensity under de is the effect of the test compound, using the metric associated with a total length of lizania and biting allowed the right hind paws, and calculate the ED50 value.

Example test 9. The model of dermatitis induced by DNFB

In this experiment using female BALB/c mice. 30 μl of a 0.5% solution of 1-fluoro-2,4-dinitrobenzene (DNFB) in acetone is applied to the abdomen of the mouse once a day for two days. 6, 8 and 10 days after the first sensitization 10 μl of 0.3% DNFB solution in acetone is applied on the inner and outer sides of both ears. Compound suspended in 0.5% solution of methylcellulose and administered orally once daily for 6-12 day after the first sensitization. The thickness of the outer ear of the mouse (degree of swelling) measure stangen-compass (micrometer) every day during the experiment, starting from the sixth day after sensitization. All results are shown as mean value ± standard error. Statistical analysis is performed using t-test, Welsh, the difference is considered significant if P<0,05.

Examples of compositions

The following examples of compositions 1-10 are given only as an illustration and in no way limit the scope of the invention. The term “active ingredient” refers to the compound of the present invention, its pharmaceutically acceptable salt or MES.

Example composition 1. Hard gelatin capsules get, using the following shall ingredienti:

Dose
(mg/capsule)
The active ingredient250
Starch (dry)200
Magnesium stearate10
Only460 mg

Example composition 2. Tablets get, using the following ingredients:

Dose
(mg/capsule)
The active ingredient250
Cellulose (microcrystalline)400
Silicon dioxide (dust)10
Stearic acid5
Only665 mg

The ingredients are mixed and compressed to obtain tablets weighing 665 mg each.

Example of composition 3. Aerosol solution get, using the following ingredients

Weight
The active ingredient0,25
Ethanol25,75
Propellant (Chlorodifluoromethane)74,00
Only100,00

The active ingredient is mixed with ethanol, the mixture is added to the portion of the propellant 22 and cooled to -30°C, then the mixture is fed to a device for filling containers. Then the required amount of the mixture is placed in a stainless steel container and diluted with the remaining amount of propellant. Then in the container is injected gas bubbles.

Example of composition 4. Tablets containing 60 mg of active ingredient, receive the following way:

The active ingredient60 mg
Starch45 mg
Microcrystalline cellulose35 mg
Polyvinylpyrrolidone (10% aqueous solution)4 mg
Soda is carboximetilkrahmal 4.5 mg
Magnesium stearate0.5 mg
Talc1 mg
Only150 mg

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and stirred until a sufficient degree of homogeneity. An aqueous solution containing polyvinylpyrrolidone, mixed with the obtained powder and the mixture is then passed through sieve No. 14 mesh U.S. dollars. The obtained granules are dried at 50°C and passed through sieve No. 18 mesh U.S. dollars. To the pellet add natrocarbonatite, magnesium stearate and talc, previously passed through sieve No. 60 mesh U.S., stirred, and then the mixture is pressed through the machine for tabletting and receive tablets weighing 150 mg each.

Example of composition 5. Capsules containing 80 mg of the active ingredient, receive the following way:

The active ingredient80 mg
Starch59 mg
Microcrystalline cellulose59 mg
Magnesium stearate2 mg
Only200 mg

The active ingredient, starch and cellulose are mixed and passed through sieve No. 45 mesh U.S., then place the mixture into hard gelatin capsules of 200 mg each.

An example of the composition 6. Suppositories containing 225 mg of active ingredient, receive the following way:

The active ingredient225 mg
The glycerides of saturated fatty acids2000 mg
Only2225 mg

The active ingredient is passed through sieve No. 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, which previously melted by heating to the minimum required temperature. Then the mixture is placed in a mold, which can accommodate 2 g, and cool.

Example of composition 7. The suspension containing 50 mg of active ingredient, receive the following way:

The active ingredient50 mg
The sodium carboxymethyl cellulose50 mg
Syrup 1.25 ml
A solution of benzoic acid0.10 ml
Perfumeq.v.
Dyeq.v.
Only5 ml

The active ingredient is passed through a sieve No. 45 mesh U.S. and mixed with the sodium carboxymethyl cellulose and syrup to obtain a homogeneous dough. A solution of benzoic acid and the odorant diluted with a part of water, add to the dough and mix. Then add a quantity of water sufficient to achieve the desired volume.

An example of the composition 8. Drug for intravenous receive the following way:

The active ingredient100 mg
The glycerides of saturated fatty acids1000 ml

The solution containing the above ingredients, usually administered to the patient intravenously at a rate of one ml per minute.

Example of composition 9. The gel will receive the following way:

The active ingredient100 the g
Isopropanol500 mg
Partially hydrophobic, hydroxymethylcellulose150 mg
Just after adding purified water10000 mg

The active ingredient is dissolved in isopropanol and the resulting solution was added to the partially hydrophobic hydroxymethylcellulose obtaining a homogeneous dispersion. Then, water is added, then the mixture is uniformly stirred with a stirrer to dissolve all ingredients.

An example of the composition 10. Ointment with the distribution of droplet sizes receive the following way:

The active ingredient100 mg
Benzyl alcohol : 400 mg
Sesquistearate sorbitan400 mg
Liquid paraffin500 mg
White petrolatum8600 mg
Only10000 mg

The active ingredient is dissolved in benzyl alcohol, the resulting solution was added to the mixture is of sesquistearate sorbitan, liquid paraffin and white vaseline and mix with mixer until the desired state.

Industrial applicability

Found that 3-carbarnoyl-2-Spiridonova derivatives, which are active agonists of cannabinoid receptor, have low inhibitory activity against the enzyme (CYP), minor side effects, associated with the Central nervous system, excellent photostability and/or remarkable absorption dermal or oral administration. Moreover, it was found that a pharmaceutical composition which contains the compound as an active ingredient, has an antipruritic effect, which is particularly effective when applied externally.

1. The compound of formula (I):

where R1means C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents As;
R2means C1-Salkil or C1-Salmoxis-Salkil;
R3means C1-Salkil or C1-Celecoxi; or
R2and R3taken together with the adjacent carbon atoms, may form an optionally substituted non-aromatic 5-to 10-membered carbon ring;
R4means hydrogen;
G stands for a group represented by the formula:
or
where R5means hydrogen;
X1means a single bond, C1-Salminen, optionally substituted with one to three substituents selected from the group of substituents In;
X2means C1-Salminen, which may be substituted by one or two substituents selected from the group of substituents In;
X3means a single bond, C1-Salminen, C2-Calcanean or C2-Calcinit;
the group represented by the formula:

means a group selected from groups represented by the formula:
,,
where Rameans C1-Salkil, and n is 0, 1 or 2;
the group represented by the formula:

means a group selected from groups represented by the formula:
,
where Rbmeans hydrogen or C1-Salkil; p is 0, 1 or 2;
q is an integer from 1 to 4;
Y represents-O-, -S-, -N(R6)-, where R6means hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, or a group selected from groups represented by the formula:
,and
where R7means C1-Salkil; m is 1 or 2;
Z denotes hydrogen, C1-Salkil, optionally substituted by one the three substituents, selected from the group of substituents D,
C3-Cal, optionally substituted by one or two substituents selected from the group of substituents, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C1-Sarkilarini, C6-SLR, optionally substituted with one to three substituents selected from the group of substituents F, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group optionally substituted with one to three substituents selected from the group of substituents E, a group represented by the formula: -C(NH2)-NR8-CO-NR8R9where R8and R9each independently mean hydrogen or C1-Salkil, or a group represented by the formula: -C(=W)-R10where R10means C1-Salkil, hydroxys-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, hydrazine, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted by one to three of the mandated what teli, selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents E, W denotes an oxygen atom or a sulfur atom; a group of substituents: halogen, C3-Cicloalchil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and a group represented by the formula:
-C(=O)-R11where R11means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or NEA is ematichesky heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;
the group of substituents: halogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents A, C3-Cicloalchil, C2-Salkini, C2-Salminen, which can be replaced by a group-O-, hydroxy, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, cyano, azide, nitro, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, and the group represented by formula: -C(=O)-R12where R12means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, not battelino substituted with one to three substituents, selected from the group of substituents F;
the group of substituents: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, oxo, cyano, azide, nitro and phenyl;
the group of substituents D: halogen, C1-Salkil, Halogens-Salkil, C3-Cicloalchil, hydroxy, C1-Sarcoxie, hydroxys-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, oxo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, carboxy, cyano, azide, nitro, three(C1-Salkil)ammonium, di(C1-Salkil)benzylamine, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one three substituents selected from the group of substituents F, non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F, the group represented by formula: -C(=O)-R13where R13means hydrogen, C1-Salkil, C1-Sarcoxie, C1-Saltillo, amino group, optionally substituted by one or two substituents selected from the group of substituents E, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or nonaromatic geterotsiklicheskikh, optionally substituted with one to three substituents selected from the group of substituents F, and a group represented by the formula: -O-C(O)-R14where R14means C1-Salkil, C3-Cicloalchil, C1-Sarcoxie, C3-Styleability, C6-Six, optionally substituted with one to three substituents selected from the group of substituents F, heteroaromatic, optionally substituted with one to three substituents selected from the group of substituents F, amino group, optionally substituted by one or two substituents selected from the group of substituents E, piperidino, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents F, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents F, or non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents F;
the group of substituents: C1-Salkil, (C1-Salkil)carbonyl, (C1-Celecoxi)carbonyl, (C6-Ser)carbonyl, heteroarylboronic, (amino, optionally substituted by one or two groups of C1-Salkil or C6-Ser)carbonyl, C1-Sarkilarini, C6-Sly and heteroarylboronic;
the group of substituents F: halogen, C1-Salkil, Halogens-Salkil, hydroxy, C1-Sarcoxie, Halogens-Sarcoxie, methylenedioxy, benzyloxy, carbarnoyl, neo is Astelin substituted by one or two groups of C1-Salkil, cyano, azide, nitro, oxo and phenyl;
provided that if-X1-X2-X3-C(=O)-Y-Z stands for a group represented by the formula (II):

R2and R3taken together with the adjacent carbon atoms, form a 6-membered non-aromatic carbon ring;
its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, where R1means C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents a or its pharmaceutically acceptable salt or MES.

3. The compound according to claim 1, where R1means n-butyl, 4,4,4-tripcomputer, 2-methoxyethyl, cyclohexylmethyl or phenyl, optionally substituted with one to three substituents selected from the group of substituents (F) methyl, its pharmaceutically acceptable salt or MES.

4. The compound according to claim 1, where R2means C1-Salkil or C1-Calcinosis-Salkil, and R3means C1-Salkil or C1-Calculate, its pharmaceutically acceptable salt or MES.

5. The compound according to claim 1, where R2means ethyl, n-propyl, isopropyl or methoxymethyl, and R3means methyl, ethyl or metiloksi, its pharmaceutically acceptable salt or MES.

6. The compound according to claim 1, where R2and R3taken together with the adjacent carbon atoms, form a non-aromatic 7-10-membered carbon is a ring, optionally substituted C1-Calcilo, its pharmaceutically acceptable salt or MES.

7. The compound according to claim 1, where R2and R3taken together with the adjacent carbon atoms, form a non-aromatic 8-membered carbon ring, its pharmaceutically acceptable salt or MES.

8. The compound according to claim 1, where X1and X3denote a single bond and X2means linear C1-Salminen, optionally substituted by one or two substituents selected from the group of substituents In, its pharmaceutically acceptable salt or MES.

9. The compound according to claim 1, where X1and X3each independently means a single bond or C1-Salminen and X2means C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents With, its pharmaceutically acceptable salt or MES.

10. The compound according to claim 1, where X1means a single bond, X3means C1-Sakilan or C2-Calcanean and X2means heteroaryl, optionally substituted by one or two substituents selected from the group of substituents With, its pharmaceutically acceptable salt or MES.

11. The compound according to claim 1, where Y represents-O-, Z denotes hydrogen or C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents D, its pharmaceutically p is ielemia salt or MES.

12. The compound according to claim 1, where Y represents-N(R6)-, where R6such as defined in claim 1, its pharmaceutically acceptable salt or MES.

13. The compound according to claim 1, where Y stands for a group represented by the formula:
or
where m is as defined in claim 1, its pharmaceutically acceptable salt or MES.

14. The compound of formula (II)

where R1Ameans C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents G, C3-Calcaneal or C3-Calciner;
R2Ameans C1-Salkil or C1-Salmoxis-Salkil;
R3Ameans C1-Salkil or C1-Celecoxi; or
R2Aand R3Ataken together with the adjacent carbon atoms, may form an optionally substituted non-aromatic 5-to 10-membered carbon ring;
R4Ameans hydrogen or hydroxy;
R15Ameans hydrogen or C1-Salkil;
X1Ameans a single bond or C1-Sakilan;
X2Ameans linear C1-Salminen, optionally substituted by one or two substituents selected from the group of substituents H, C3-Cicloalchil, optionally substituted by one or two substituents selected from the group of substituents I, or heteroaryl, optionally substituted by one or two to cover the firs, selected from the group of substituents I;
X3Ameans a single bond, C1-Sakilan or C2-Calcanean;
the group of substituents G: halogen, C3-Cicloalchil, C1-Sarcoxie, Halogens-Sarcoxie, cyano, azide, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents J, and heteroaryl, optionally substituted with one to three substituents selected from the group of substituents J;
a group of substituents, e.g. halogen, C1-Salkil, optionally substituted with one to three substituents selected from the group of substituents G, C3-Cicloalchil, C2-Salkini, C2-Salminen, which can be replaced by a group-O-, C1-Sarcoxie, C1-Saltillo, Halogens-Sarcoxie, C6-Ser, optionally substituted with one to three substituents selected from the group of substituents J, heteroaryl, optionally substituted with one to three substituents selected from the group of substituents J, and non-aromatic heterocyclic group, optionally substituted with one to three substituents selected from the group of substituents J;
group Deputy I: halogen, C1-Salkil and phenyl;
group Vice J: halogen, C1-Salkil, Halogens-Salkil, C1-Sarcoxie, Halogens-Sarcoxie, cyano, nitro and phenyl;
its pharmaceutically acceptable salt or MES.

15. The connection 14, where the group represented by the formula:

means a group selected from groups represented by the formula:
,,,,
,,,,
,,,
,,,,
,,,,
,,,,
or
where Me denotes methyl; Et means ethyl; n-WG means n-propyl; i-Pr means isopropyl,
the group represented by the formula:

means a group selected from groups represented by the formula:
,,,,
,,,, ,
,,,,,
,,,,,
,,,,
,and
where Me denotes methyl; R15Ais the same as defined in 14; its pharmaceutically acceptable salt or MES.

16. The connection indicated in paragraph 15, where R15Ameans hydrogen, its pharmaceutically acceptable salt or MES.

17. Pharmaceutical composition having agonistic activity towards canariense receptor containing the compound according to any one of claims 1 to 16 as an active ingredient.

18. The pharmaceutical composition according to 17, which is a tool for the treatment of atopic dermatitis.

19. The pharmaceutical composition according to 17, which represents an antipruritic agent.

20. Application of the compound and its pharmaceutically acceptable salt or MES according to any one of claims 1 to 16 for obtaining a medicinal product for the prevention and/or treatment of atopic dermati the A.

21. The method of prevention and/or treatment of atopic dermatitis in a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the compound or its pharmaceutically acceptable salt or MES according to any one of claims 1 to 16, and facilitating thus the symptoms.

22. Application of the compound and its pharmaceutically acceptable salt or MES according to any one of claims 1 to 16 for obtaining a medicinal product for the prevention and/or treatment of itching.

23. Way relieve itching from a mammal, including humans, comprising an introduction to the specified mammal a therapeutically effective amount of the compound and its pharmaceutically acceptable salt or MES according to any one of claims 1 to 16.

24. The compound of the formula:
,,,,
,,,,
,,,,
,,,,
,,,
,,,,
,or
where Me denotes methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl, R168means hydroxy, C1-Sarkilari or a chlorine atom; and its pharmaceutically acceptable salt or MES.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , where R1 is C1-C7-alkyl; R2 is C1-C7-alkyl, C1-C7-haloalkyl, C3-C8-cycloalkyl; R3 is -NRaRb; possibly substituted phenyl, thiophenyl, furanyl, where the substitutes are selected from a group consisting of halogen, C1-C7-alkoxy, C1-C7-alkylsulphonyl and -C(O)O-C1-C7-alkyl; R4 is hydrogen or C1-C7-alkyl; R5 is hydrogen, halogen, C1-C7-alkyl, phenyl; or R5 together with R4 can form a ring selected from a group consisting of C5-C7-cycloalkyl, tetrahydrofuranyl, piperidine, tetrahydropyran, phenyl or pyridinyl, which can possibly be substituted with -C(O)O-C1-C7-alkyl; Ra and Rb together with the nitrogen atom to which they are bonded form piperidine; and to pharmaceutically acceptable salts thereof. The invention also relates to a medicinal agent based on the said compounds which has GABA-B receptor allosteric enhancement effect.

EFFECT: obtaining novel compounds and a medicinal agent based on the said compounds, which can be used in medicine for treating central nervous system disorders.

13 cl, 42 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel therapeutically suitable derivatives of pyridazin-3(2H)-one of formula and pharmaceutical compositions containing the said derivatives. These compounds are used for treating, preventing or inhibiting corresponding pathological conditions, diseases or disorders, mainly asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable colon syndrome.

EFFECT: obtaining compounds which are active and selective phosphodiesterase 4 (PDE4) inhibitors.

11 cl, 1 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), their N-oxide forms, pharmaceutically acceptable additive salts and stereochemically isomeric forms as 11-HSD1 inhibitors, to their use, a pharmaceutical composition based on the said compounds and method of obtaining the said compounds. In general formula (I) , X is C or N; Y is C or N; L is methyl or a single bond; Z1 is a single bond, C1-2alkyl or a radical of formula -CH=; Z2 is a single bond, C1-2alkyl; R1 is hydrogen, halogen, hydroxy; R2 is hydrogen, halogen or C1-4alkyloxy; A is phenyl or a monocyclic heterocycle selected from a group consisting of thiophenyl or pyrridinyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by 11-HSD1.

9 cl, 7 dwg, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of purifying thiopenes of formula (I) which are liquid at room temperature and can be used in organic synthesis to produce an electroconductive polymer or an organic semiconductor. The proposed method involves precipitation of thiophene of formula (I) , where R1 and R2 represent hydrogen, optionally broken by 1-5 O and/or S atoms C1-20alkyl, C1-20alkoxy, or R1 and R2 together represent optionally substituted C1-20dioxyalkylene or C6-20dioxyarylene group, where the thiophene is precipitated from a solution in isobutyl-methylketone, chloroform, methylene chloride, toluene, methanol, propanol, ethanol, acetone, isopropanol, n-butanol, fluorobutanol, dimethylformamide, methyl-tertbutyl ether, tetrahydrofuran, diethyl ether, hexane, pentane or mixtures thereof in ratio solvent : thiophene ranging from 0.01:1 to 10:1, cooled to temperature at least 10°C below melting point of the thiophene being purified in pure form, with subsequent separation of thiophene by filtration at low temperature.

EFFECT: design of a new efficient method of purifying low-melting thiophenes.

14 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic amine compounds of formula (1) or pharmaceutically acceptable salts thereof: . In formula (1), X is O, S, NR2 (where R2 is H, C1-C12 alkyl); when X is O, S, then R1 is H, CN, COOH, C2-C13 alkoxycarbonyl, carbamoyl group; and when X is NR2 (where R2 assumes values given above), R1 is CN; Ar1 and Ar2 are identical or different and each represents an aryl which can be substituted with 1-3 halogens; or Ar1 and Ar2 together with neighbouring carbon atoms to which they are bonded form a group with formula (b): (where ring S and ring T are identical and each is a benzene ring; Y is O); ring B is a benzene ring which can be substituted with 1-3 substitutes independently selected from a group comprising halogen, C1-C12 alkyl, C1-C8 halogenalkyl, C1-C12 alkoxy, C1-C8 halogenalkoxy group; n is an integer from 1 to 10; p, q are identical or different and each is an integer equal to 1 or 2. Formula (1) compounds are bonding inhibitors of the α2C-adrenoreceptor.

EFFECT: possibility of using compounds in pharmaceutical compositions.

7 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: medicine.

SUBSTANCE: new compounds of thienopyrazole are described with formula (1) , where R1 means non-substituted C3-C8-cycloalkyl group or tetrahydropyranyl, R2 means non-substituted C1-C3alkyl group, R3 means atom of hydrogen, R4 means various groups mentioned in invention formula. Compounds inhibit PDE 7 and, accordingly, increase cell level of cyclic adenosine monophosphate. Pharmaceutical composition is also described, as well as method for inhibition of PDE, methods for production of compound with formula (1), where R4 means CO2R7, and intermediate compounds.

EFFECT: possibility to use for treatment of various types of such diseases as allergic diseases, inflammatory diseases or immunological diseases.

20 cl, 138 tbl, 440 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: medicine.

SUBSTANCE: invention refers to new pyridine derivatives or to their pharmaceutically acceptable salts of general formula 1: wherein R1, R2, R3, R4, R5, R6 and R7 are independently chosen from the group including hydrogen atom, halogen, amino, C1-C6lower alkyl, C2-C6lower alkenyl, C1-C6lower alkoxy, C1-C10alkylamino, C4-C9cycloalkylamino, C4-C9heterocycloalkylamino, C1-C10aralkylamino, arylamino, acylamino, saturated heterocyclyl, acyloxy, aryl, heteroaryl, C1-C10aralkyl, aryloxy; X represents oxygen or sulphur atom; Y represents oxygen atom or N-R8, wherein R8 is chosen from the group including hydrogen atom; aforesaid aryl group is chosen from phenyl, naphthyl and condensed phenyl group; aforesaid heteroaryl and saturated heterocyclic groups represent pentagonal or hexagonal heterocyclic ring containing 1 to 2 heteroatoms chosen from oxygen, nitrogen and sulphur atom; or condensed heterocyclic ring; and aforesaid aryl and heteroaryl groups are those that 1 to 4 assistants chosen from group including halogen, C1-C6lower alkyl, C1-C6lower alkoxy are substituted. And specified compounds or their pharmaceutically acceptable salt of formula 1 are not compounds as follows 6-methyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 5-vinyl-3,4-dihydro-pyrano[3,4-c]pyridin-1-one, 6-methyl-8-furan-2-yl-3,4- dihydropyrano[3,4-c]pyridin-1-one, 3-tert-butyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-8-one and dimethyl ether (3S)-6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-[2,7]naphthyridine-3,5-dicarboxylic acids.

EFFECT: compounds possess inhibitory action with respect to formation of cytokines involved in inflammatory reactions, can be used as a therapeutic agent for treatment of inflammatory diseases, immune diseases, chronic inflammations; it provides antiinflammatory and analgesic action.

21 cl, 7 tbl, 144 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted of dihydropyranoindole-3,4-dione of formula I and formula II: where X stands for H, R1 stands for H, phenyl, benzyl, cycles of said phenyl and benzyl can be substituted with 1-3 substituents, selected independently on each other from group, which includes halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup; where R2 stands for H, -OH; R3 stands for H, phenyl, benzyl, benzyloxygroup, cycles of these groups can be optionally substituted with 1-3 substituents, selected independently on each other from group including phenyl, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, -O-C1-C6-perfluoroalkyl, C1-C6-alkoxygroup, pharmaceutically acceptable salts of said compounds. Compounds demonstrate activity of inhibiting plasminogene activator inhibitor (PAI-1), which allows using them for production of medication for treatment of pathological states resulting from fibrinolytic disorders.

EFFECT: obtaining compounds, demonstrating activity in inhibiting plasminogene activator inhibitor which allows using them in pharmacology.

23 cl, 1 dwg, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the agent strongly inhibiting thrombocyte aggregation, it doesn't inhibit COX-1 or COX-2. The invention offers the compounds of formula (I) or their pharmaceutically acceptable salts, where residuals and groups in the specified structure of the compounds have the values denoted in the formula of the invention. The pharmaceuticals containing any of the compounds of formula (I) or their pharmaceutically acceptable salts, and phylactic and/or therapeutic agents for coronary heart disease, which contain any of the compounds of formula (I) or their pharmaceutically acceptable salts are suggested. Moreover, application of the compounds and their pharmaceutically acceptable salts for preparation of the medicine having anti-thrombotic potency, and method of the treatment of coronary heart disease are suggested.

EFFECT: production of the medicines having anti-thrombotic potency on basis of pyrazole.

12 cl, 1 tbl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

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