Compositions for treating inflammation and method of treating inflammation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula , or their pharmaceutically acceptable salt, which can find application for treating or preventing ophthalmic diseases.

EFFECT: invention refers to the pharmaceutical compositions and methods of treating the ophthalmic diseases with the use of the above compound.

13 cl, 7 dwg, 7 tbl, 4 ex

 

Related applications

In this application claims the priority of provisional patent application U.S. No. 61/168739, filed April 13, 2009, and provisional application for U.S. patent No. 61/174806, filed may 1, 2009, the contents of which in its entirety is included in this description by reference.

The level of technology

Supplement dietary omega-3 polyunsaturated fatty acids (ω-3 PUFA”), such as eicosapentaenoic acid, which is a component of fish oils may be beneficial for diseases such as arteriosclerosis, arthritis, and cancer, which can oposredovanie antithrombine, immunoregulatory and anti-inflammatory responses [De Caterina, R., S. Endres, S. D. Kristensen, and E. B. Schmidt, editors. (1993). n-3 Fatty Acids and Vascular Disease. Springer-Verlag, London; Lands, W. E. M., editor. (1987). Proceedings of the AOCS Short Course on Polyunsaturated Fatty Acids and Eicosanoids. American Oil Chemists' Society, Champaign, IL; Iigo, M. et al. (1997) Br. J. Cancer 75:650]. The potential of ω-3 PUFA for the prevention of cardiovascular disease confirms the recently established fact that the main dietary ω-3 PUFA such as eicosapentaenoic acid (C20:5 ω-3; EPA) and docosahexaenoic acid (C22:6 ω-3; DHA), have a significant impact on ischemia-induced ventricular fibrillation [Billman, G. E. et al. (1999)Circulation, 99:2452]. The manifestation of such a possible prophylactic and/or therapeutic action supplementation of ω-3 PUFA in infant nutrition, the ri cardiovascular diseases and mental health led to announced at the international conference appeals to recommend ω-3 PUFA for diet purposes [Simopoulous, A. P.et al. (1999)J. Am. Coll. Nutr.18:487]. In the study, which was undertaken in the Gruppo Italiano per Io Studio della Sopravvivense Nell Infarto Miocardio (GISSI) Prevenzione, was evaluated the effect of supplementation of ω-3 PUFA on 11300 patients after myocardial infarction, which daily (n=2836) was appointed ~1 g of the additive of ω-3 PUFA along with recommended preventive treatment, including aspirin, and reported significant beneficial effects while reducing mortality caused by diseases of the cardiovascular system [Marchioloi, R.et al.(1999),Lancet, 354:447]. However, the mechanisms underlying the protective effect of dietary ω-3 PUFA, which are identified in these and other studies, including research on diseases of the skin, intestines, and nervous tissues, currently remain unclear. One of the numerous hypotheses concerning the elements of the mechanism(s) of action of ω-3 PUFA, is that natural metabolites formed from these PUFA may act as mediators that support important biological functions, however, these metabolites have relatively short period half-life in terms ofin vivo.There remains a need in the new analogues, which may be more stable in terms ofin vivothan the metabolites arising naturally from ω-3 PUFA, in those conditions, when you need the longer period half-life.

The invention

The present invention features a compound of formula I

and its pharmaceutically acceptable salts, where

the double bond between the carbon atom qq' and the carbon atom rr' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom ss' and the carbon atom tt' is CIS - or TRANS stereochemical configuration;

Re and Rf are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group;

E denotes branched alkoxy, for example, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3 methylbutoxy, 2,2-DIMETHYLPROPANE or 1,1,2-trimethylpropane;

Rh and Ri are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl;

R5selected from the following groups i-iv: i) CH2CH(R6)CH2where R6denotes a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl, heteroaryl, a fluorine atom, hydroxyl or alkoxy; (ii) CH2C(R6R7)CH2where each of R6and R7independently denotes an alkyl, alkenyl, quinil, perfluoroalkyl, aryl or fluorine atom, or R6and R7connected to each other and form carbocycle or heterocycle; (iii) CH 2OCH2CH2C(O)CH2or CH2CH2; or (iv) R5denotes carbocycle, heterocycle, aryl or heteroaryl cycle; and

R8and R9independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl or R8and R9connected to each other and form carbocycle or heterocycle.

In certain embodiments of the implementation of the present invention the compound of formula I is represented by formula II

and its pharmaceutically acceptable salts, where

the double bond between the carbon atom qq' and the carbon atom rr' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom ss' and the carbon atom tt' is CIS - or TRANS stereochemical configuration;

the values of Re, Rf, R5and E above.

In certain embodiments of the implementation of the present invention the compound of formula I or II is represented by formula III

and its pharmaceutically acceptable salts, where

the values of Re, Rf and E above.

In certain embodiments implementing the present invention features a pharmaceutical preparation suitable for use for patients-people, which includes an effective amount of any of the above compounds (who, for example, compounds of the present invention, such as any of the compounds of formulas I-III) and one or more pharmaceutically acceptable inert fillers. In certain embodiments of the implementation of the present invention, the pharmaceutical preparations can be used to treat or prevent conditions or diseases specified in this description. In certain embodiments of the implementation of the present invention the pharmaceutical drugs have a low enough pyrogenic activity, so that they were suitable for intravenous patient-people.

In the present invention are also methods of treatment or prevention of bone metabolism, inflammation of the mucous membranes, cardiovascular diseases, inflammatory diseases, metabolic disorders, eye diseases, impaired immune function, lung diseases, gastrointestinal diseases, rheumatologic diseases, dermatological diseases, neurological diseases, cancer, infectious diseases, degenerative diseases, geriatric diseases and apoptotic conditions, methods of reduction, prevention or treatment of organ injury, reduce and/or prevent damage and/or death of stem cells, ways to improve the persistence and/or vyzyvaet the authorities or increase the persistence and/or survival of stem cells, as indicated in this description, which consist in the introduction of the compounds of the present invention.

Detailed description of drawings

Figure 1 shows that comparable concentrations of compound 1003 observed in the intraocular fluid (figure 1a), the vitreous body (figure 1b) and the cornea (figure 1c) when the local introduction into the eyes of rabbits compounds 1001 and 1002.

The figure 2 presents the data to determine the level of discomfort for the eyes on a 28-day study of dry eye in humans after local injection of the carrier or connection 1001 with a dose of A, B or C.

The figure 3 presents the data to determine the level of discomfort for the eyes on the 29th day (approximately one day after the last exposure) study of dry eye in humans after local injection of the carrier or connection 1001 with a dose of A, B or C.

Figure 4 shows the feeling of sand in eyes or dry eyes on the 28-day study of dry eye in humans after local injection of the carrier or connection 1001 with a dose of A, B or C.

The figure 5 presents1H NMR spectrum of compound 1001 in CDCl3.

The figure 6 presents1H NMR spectrum of compound 1002 in CDCl3.

The figure 7 presents1H NMR spectrum of compound Z in D2O.

Detailed description of the invention

The present invention features a compound of formula I

and its pharmaceutically acceptable salts, where

the double bond between the carbon atom qq' and the carbon atom rr' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom ss' and the carbon atom tt' is CIS - or TRANS stereochemical configuration;

Re and Rf are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group, preferably, a hydrogen atom, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl and alkoxycarbonyl, most preferably a hydrogen atom;

E denotes branched alkoxy, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3 methylbutoxy, 2,2-DIMETHYLPROPANE or 1,1,2-trimethylpropane, preferably isopropoxy;

Rh and Ri are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl, preferably a hydrogen atom or alkyl, most preferably a hydrogen atom.

R5selected from the following groups i-iv: i) CH2CH(R6)CH2where R6denotes a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl, heteroaryl, a fluorine atom, hydroxyl or alkoxy; (ii) CH2C(R6R7)CH2where each of R6and R7the independent is IMO denotes alkyl, alkenyl, quinil, perfluoroalkyl, aryl or fluorine atom, or R6and R7connected to each other and form carbocycle or heterocycle; (iii) CH2OCH2CH2C(O)CH2CH2or CH2CH2; or (iv) R5denotes carbocycle, heterocycle, aryl or heteroaryl cycle; preferably (CH2)3; and

R8and R9independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl or R8and R9connected to each other and form carbocycle or a heterocycle, preferably selected from a hydrogen atom and alkyl, most preferably selected from a hydrogen atom.

For example, the present invention features a compound of formula Ia

and its pharmaceutically acceptable salts, where

Re and Rf are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group, preferably a hydrogen atom, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl and alkoxycarbonyl, most preferably a hydrogen atom;

E denotes branched alkoxy, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, 3 methylbutoxy, 2,2-DIMETHYLPROPANE or 1,1,2-trimet is propoxy, preferably isopropoxy;

Rh and Ri are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl, preferably selected from a hydrogen atom or alkyl, most preferably selected from a hydrogen atom.

R5selected from the following groups i-iv: i) CH2CH(R6)CH2where R6denotes a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl, heteroaryl, a fluorine atom, hydroxyl or alkoxy; (ii) CH2C(R6R7)CH2where each of R6and R7independently denotes an alkyl, alkenyl, quinil, perfluoroalkyl, aryl or fluorine atom, or R6and R7connected to each other and form carbocycle or heterocycle; (iii) CH2OCH2CH2C(O)CH2CH2or CH2CH2; or (iv) R5denotes carbocycle, heterocycle, aryl or heteroaryl cycle; preferably (CH2)3; and

R8and R9independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl or R8and R9connected to each other and form carbocycle or heterocycle is preferably selected from a hydrogen atom and alkyl, most preferably selected from a hydrogen atom.

In certain preferred embodiments of formula Ia stereochemical configuration of carbon atoms is and, supporting the Vice-ORf and-ORe shown in formula Ia'

In certain embodiments of the implementation of the present invention the compound of formula I is represented by formula II

and its pharmaceutically acceptable salts, where

the double bond between the carbon atom qq' and the carbon atom rr' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom ss' and the carbon atom tt' is CIS - or TRANS stereochemical configuration;

the values of Re, Rf, R5and E above.

For example, the present invention features a compound of formula IIa

and its pharmaceutically acceptable salts, where

the values of Re, Rf, R5and E above.

In certain embodiments of the implementation of the present invention the compound of formula I or II is represented by formula III

and its pharmaceutically acceptable salts, where

the values of Re, Rf and E above.

In certain embodiments of formulae I-III E denotes O-R, where R denotes an alkyl group, preferably a lower alkyl group which is branched at the position where the attached oxygen atom. Examples of such fragments of R include-CH(CH3)2(isopropyl), -CH(CH2CH3)2, -CH(CH3)(CH2CH ) (sec-butyl), and-C(CH3)3(tert-butyl).

Examples of formulas I, II and III include the connection 1001,

and its pharmaceutically acceptable salts.

In certain embodiments implementing the present invention features a pharmaceutical preparation suitable for use for patients-people, which includes an effective amount of any of the above compounds (for example, the compounds of the present invention, such as any of the compounds of formulas I-III) and one or more pharmaceutically acceptable inert fillers. In certain embodiments of the implementation of the present invention, the pharmaceutical preparations can be used to treat or prevent conditions or diseases specified in this description. In certain embodiments of the implementation of the present invention the pharmaceutical drugs have a low enough pyrogenic activity, that they are suitable for patient people.

Connection with any of the above structures can be used for the preparation of drugs intended for the treatment of any disease or condition disclosed in this specification.

Bone metabolism

The present invention provides methods of treating or preventing loss to the things of the weight of the patient, which include the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention, the disease associated with bone loss, for example, include, but not limited to, any one or more of the following diseases: ankylosing spondylitis, osteodystrophy nephrogenic (for example, patients undergoing dialysis), osteoporosis caused by glucocorticoid osteoporosis, Paget's disease, abnormally increased, the process of regeneration of bone tissue, periodontic, disease of periodontal, bone fractures, rheumatoid arthritis, osteoarthritis, peripatetically of survivorship, disorders of osteogenesis, metastatic bone disease, malignant development of hypercalcemia, multiple myeloma, bone loss, related geographicaly, histiocytosis Langerhans cells (LHC), the loss of bone mass associated with disorders of the renal tubules, or bone loss associated with the condition, when the patient is bedridden.

The present invention features a method of treating or preventing osteoporosis in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention osteoporosis is a osteoporosis caused by taking the drug is to develop drugs. In certain embodiments of the implementation of the present invention osteoporosis caused by medication, represents the osteoporosis caused by glucocorticoid.

In the present invention proposes a method of treatment or prevention of diabetic osteopenia in a patient, which includes the purpose of the compounds of the present invention.

In the present invention proposes a method of treatment or prevention of metastatic bone disease in a patient, which includes the introduction of compounds of the present invention. In the present invention proposes a method of reducing the incidence of bone metastasis in a patient, which includes the introduction of compounds of the present invention. In the present invention it is also proposed a way to slow the occurrence of bone metastasis in a patient, which includes the introduction of compounds of the present invention. In certain embodiments of the implementation of the present invention, the compound of the present invention is administered in conjunction with chemotherapy or radiotherapy.

In the present invention proposes a method of treatment or prevention of periodontitis the patient, which includes the introduction of compounds of the present invention.

In the present invention proposes a method of treatment or prevent the deposits of gingivitis patients, which includes the introduction of compounds of the present invention.

In the present invention proposes a method of treatment or prevention of ankylosing spondylitis patient, which includes the introduction of compounds of the present invention.

In the present invention proposes a method of treatment or prevention of nephrogenic osteodystrophies the patient (for example, patients undergoing dialysis), which includes the introduction of compounds of the present invention.

In one embodiment, the present invention is a method of treatment or prevention of bone loss may include introducing the compound of the present invention together with additional means suitable for the treatment of bone loss. In certain embodiments of the implementation of the present invention, the compound of the present invention may be administered in conjunction with tools such as a bisphosphonate (eg, ibandronate, zoledronate, risedronate, etidronate or alendronate), a steroid, such as an anabolic steroid (e.g., testosterone, hinboun, oxymetholone, nandrolone hexylphenylpropionate, Oxandrolone, testosterone, undecanoate, mibolerone, danazol, nandrolone decanoate, trenbolone cyclohexyloxycarbonyl, Methenolone acetate, Methenolone enanthate, mesterolone, dihydrotestosterone, methandrostenolone, NAS is rolon undecanoate, boldenone undecylenate, formebolone, trenbolone acetate, fluoxymesterone, nandrolone laurate, drostanolone propionate, clostebol acetate, trestolone acetate, methandriol dipropionate, methyltestosterone, furazabol, bolasterone, norethandrolone, mepitiostane, tetrahydrogestrinone, trenbolone enanthate and stanozolol), estrogen (such as estradiol, estriol, estrone, equilin or equilenin), the compounds having estrogenic activity (for example, xenoestrogens, phytoestrogens or mycoestrogen), a selective estrogen receptor modulator (e.g., raloxifene), or be administered in conjunction with hormonal therapy (e.g., using calcitonin or teriparatide). In certain embodiments of the implementation of the present invention, the compound of the present invention may be administered in conjunction with growth factors or other therapeutic means, which have a positive effect on the growth of bone or connective tissue, such as osteoprotegerin, interleukins, MMP inhibitors, beta-glucan, integrin antagonists, calcitonin, proton pump inhibitors, protease inhibitors, insulin-like growth factor-1, platelet growth factor, epidermal growth factor, inhibitors of the transforming growth factor-alpha, transforming growth factor-beta, bone morphogenetic protein, hormone ecolomic is a prominent gland, osteoprotegerin, fibroblast growth factor, vitamin D, vitronectin, an inhibitor of plasminogen activator or inhibitor of the protease, such as an inhibitor of metalloprotease, or elements, which are known to exert beneficial effects on bone formation, such as calcium, fluoride, magnesium, boron or combinations thereof.

In one embodiment, the present invention is a method of treatment or prevention of metastatic bone lesions may include introducing the compound of the present invention in conjunction with a chemotherapeutic agent. Chemotherapeutic agents that may be administered together with the compounds of the present invention, include aminoglutetimid, amsacrine, anastrozole, asparaginase, BCG, bikalutamid, bleomycin, buserelin, busulfan, computacin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubitsin, ifosfamide, imatinib, interferon, irinotecan, irinotecan, letrozole, leucovorin, lei is solid, levamisole, lomustin, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen, temozolomide, teniposide, testosterone, tioguanin, thiotepa, dichloride titanocene, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine and vinorelbine.

For the treatment of cancer has developed a great variety of combination therapies. In certain embodiments of the implementation of the present invention compounds of the present invention can be administered together with combined therapy. Examples of combined treatment methods together with which can be compounds of the present invention, included in table 1.

Table 1
Examples of combination therapy for cancer treatment
NameA therapeutic agent
ABVdoxorubicin, bleomycin, vinblastine
ABVDdoxorubicin, bleomycin, vinblastine duck is basin
AC (breast cancer)doxorubicin, cyclophosphamide
AC (sarcoma)doxorubicin, cisplatin
AC (neuroblastoma)cyclophosphamide, doxorubicin
ACEcyclophosphamide, doxorubicin, etoposide
Acecyclophosphamide, doxorubicin
ADdoxorubicin, dacarbazine
APdoxorubicin, cisplatin
ARAC-DNRcytarabine, daunorubicin
B-CAVebleomycin, lomustin, doxorubicin, vinblastine
BCVPPcarmustine, cyclophosphamide, vinblastine, procarbazine, and prednisone
BEACOPPbleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, filgrastim
BEPbleomycin, etoposide, cisplatin

BIP bleomycin, cisplatin, ifosfamide, mesna
BOMPbleomycin, vincristine, cisplatin, mitomycin
CAcytarabine, asparaginase
CABOcisplatin, methotrexate, bleomycin, vincristine
CAFcyclophosphamide, doxorubicin, fluorouracil
CAL-Gcyclophosphamide, daunorubicin, vincristine, prednisone, asparaginase
CAMPcyclophosphamide, doxorubicin, methotrexate, procarbazine
CAPcyclophosphamide, doxorubicin, cisplatin
CaTcarboplatin, paclitaxel
CAVcyclophosphamide, doxorubicin, vincristine
CAVE ADDCAV and etoposide
CA-VP16cyclophosphamide, doxorubicin, etoposide
SScyclophosphamide, carboplatin
CDDP/VP-16cisplatin, etoposide
CEFcyclophosphamide, epirubicin, fluorouracil
CEPP(B)cyclophosphamide, etoposide, prednisone with or without bleomycin bleomycin
CEVcyclophosphamide, etoposide, vincristine
CFcisplatin, fluorouracil or fluorouracil carboplatin
CHAPcyclophosphamide or cyclophosphamide, altretamin, doxorubicin, cisplatin

ChlVPPchlorambucil, vinblastine, procarbazine, and prednisone
CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone
CHOP-BLEOthe addition of bleomycin to CHOP
CISCAcyclophosphamide, doxorubicin, cisplatin
CLD-BOMPbleomycin, cisplatin, vincristine, mitomycin
CMFmethotrexate, fluorouracil, cyclophosphamide
CMFPcyclop shamed, methotrexate, fluorouracil, and prednisone
CMFVPcyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone
CMVcisplatin, methotrexate, vinblastine
CNFcyclophosphamide, mitoxantrone, fluorouracil
CNOPcyclophosphamide, mitoxantrone, vincristine, and prednisone
COBcisplatin, vincristine, bleomycin
CODEcisplatin, vincristine, doxorubicin, etoposide
COMLAcyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine
COMPcyclophosphamide, vincristine, methotrexate, and prednisone
The treatment regimen Coopercyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone

COPcyclophosphamide, vincristine, and prednisone
COPEcyclophosphamide, vincristine, cisplatin, etoposide
COPPcyclophosphamide, vincristine, procarbazine, and prednisone
CP (chronic lymphocytic leukemia)chlorambucil prednisone
CP (ovarian cancer)cyclophosphamide, cisplatin
CTcisplatin, paclitaxel
CVDcisplatin, vinblastine, dacarbazine
CVIcarboplatin, etoposide, ifosfamide, mesna
CVPcyclophosphamide, vincristine, and prednisone
CVPPlomustin, procarbazine, and prednisone
CYVADICcyclophosphamide, vincristine, doxorubicin, dacarbazine
DAdaunorubicin, cytarabine
DATdaunorubicin, cytarabine, tioguanin
DAVdaunorubicin, cytarabine, etoposide
DCTdaunorubicin, cytarabine, tioguanin
DHAPcisplatin, CIT is the Abin, dexamethasone
DIdoxorubicin, ifosfamide
DTIC/tamoxifenthe dacarbazine, tamoxifen
DVPdaunorubicin, vincristine, prednisone
EAPetoposide, doxorubicin, cisplatin
ECetoposide, carboplatin
EFPetoposide, fluorouracil, cisplatin

ELFetoposide, leucovorin, florouracil
EMA 86mitoxantrone, etoposide, cytarabine
EPetoposide, cisplatin
EVAetoposide, vinblastine
FACfluorouracil, doxorubicin, cyclophosphamide
FAMfluorouracil, doxorubicin, mitomycin
FAMTXmethotrexate, leucovorin, doxorubicin
FAP
F-CLfluorouracil, leucovorin
FECfluorouracil, cyclophosphamide, epirubicin
FEDfluorouracil, etoposide, cisplatin
FLflutamide, leuprolide
FZflutamide, an implant of goserelin acetate
HDMTXmethotrexate, leucovorin
Hexa-CAFaltretamin, cyclophosphamide, methotrexate, fluorouracil
ICE-Tifosfamide, carboplatin, etoposide, paclitaxel, mesna
IDMTX/6-MPmethotrexate, mercaptopurine, leucovorin
IEifosfamide, etoposide, mesna
IfoVPifosfamide, etoposide, mesna
IPAifosfamide, cisplatin, doxorubicin
M-2vincristine, carmustine, cyclophosphamide, prednisone, melphalan
MC-III methotrexate, leucovorin, dactinomycin, cyclophosphamide

MACCmethotrexate, doxorubicin, cyclophosphamide, lomustin
MACOP-Bmethotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone
MAIDmesna, doxorubicin, ifosfamide, dacarbazine
m-BACODbleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, methotrexate, leucovorin
MBCmethotrexate, bleomycin, cisplatin
MCmitoxantrone, cytarabine
MFmethotrexate, fluorouracil, leucovorin
MICEifosfamide, carboplatin, etoposide, mesna
MINEmesna, ifosfamide, mitoxantrone, etoposide
mini-BEAMcarmustine, etoposide, cytarabine, melphalan
MOBPbleomycin, vincristine, CIS is Latin, mitomycin
MOPmechlorethamine, vincristine, procarbazine
MOPPmechlorethamine, vincristine, procarbazine, and prednisone
MOPP/ABVmechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine
MP (multiple myeloma)melphalan, prednisone

MP (prostate cancer)mitoxantrone prednisone
MTX/6-MOmethotrexate, mercaptopurine
MTX/6-MP/VPmethotrexate, mercaptopurine, vincristine, and prednisone
MTX-CCDPAdrmethotrexate, leucovorin, cisplatin, doxorubicin
MV (breast cancer)mitomycin, vinblastine
MV (acute military leukemia)mitoxantrone, etoposide
M-VAC methotrexatevinblastine, doxorubicin, cisplatin
MVP mitomycinvinblastine, cisplatin
MVPPmechlorethamine, vinblastine, procarbazine, and prednisone
NFLmitoxantrone, fluorouracil, leucovorin
NOVPmitoxantrone, vinblastine, vincristine
OPAvincristine, prednisone, doxorubicin
OPPAadd to procarbazine OPA
PACcisplatin, doxorubicin
PAC-Icisplatin, doxorubicin, cyclophosphamide
PA-CIcisplatin, doxorubicin
PCpaclitaxel, carboplatin or paclitaxel, cisplatin

PCVlomustin, procarbazine, vincristine
PEpaclitaxel, estramustine
PFLcisplatin, fluorouracil, leucovorin
POC prednisone, vincristine, lomustin
ProMACEprednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, etoposide
ProMACE/cytaBOMprednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin, cotrimoxazole
PRoMACE/MOPPprednisone, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, methotrexate, leucovorin
Pt/VMcisplatin, teniposide
PVAprednisone, vincristine, asparaginase
PVBcisplatin, vinblastine, bleomycin
PVDAprednisone, vincristine, daunorubicin, asparaginase
SMFstreptozocin, mitomycin, fluorouracil
TADmechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone
TCFpaclitaxel, cisplatin, fluorouracil
TIP paclitaxel, ifosfamide, mesna, cisplatin
TTTmethotrexate, cytarabine, hydrocortisone
Topo/CTXcyclophosphamide, topotecan, mesna

VAB-6cyclophosphamide, dactinomycin, vinblastine, cisplatin, bleomycin
VACvincristine, dactinomycin, cyclophosphamide
VACAdrvincristine, cyclophosphamide, doxorubicin, dactinomycin, vincristine
VADvincristine, doxorubicin, dexamethasone
VATHvinblastine, doxorubicin, thiotepa, fluoxymesterone
VBAPvincristine, carmustine, doxorubicin, and prednisone
VBCMPvincristine, carmustine, melphalan, cyclophosphamide, prednisone
VCvinorelbine, cisplatin
VCAPvincristine, cyclophosphamide, doxorubicin, and prednisone
VD vinorelbine, doxorubicin
VelPvinblastine, cisplatin, ifosfamide, mesna
VIPetoposide, cisplatin, ifosfamide, mesna
VMmitomycin, vinblastine
VMCPvincristine, melphalan, cyclophosphamide, prednisone
VPetoposide, cisplatin
V-TADetoposide, tioguanin, daunorubicin, cytarabine
5+2cytarabine, daunorubicin, mitoxantrone

7+3cytarabine with daunorubicin/ or idarubitsina, or mitoxantrone
8-in-1methylprednisolone, vincristine, lomustin, procarbazine, hydroxyurea, cisplatin, cytarabine, dacarbazine

In certain embodiments of the implementation of the present invention, the compound of the present invention may be administered in conjunction with non-chemical methods of treatment of cancer. In certain embodiments of the implementation of the present invention the connection this is the overarching invention may be administered in conjunction with radiotherapy. In certain embodiments of the implementation of the present invention, the compound of the present invention can be administered concomitantly with surgery, with thermoablative, focused ultrasound therapy or cryotherapy.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Furthermore, such combinations can be co-administered with other therapeutic means, such as other means suitable for the treatment of metabolic disorders in the bones, such as the above agents.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms chemotherapeutic agents specified above; and (c) of the regulations relating to the introduction of the compounds of the present invention and a chemotherapeutic drug.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the contest shall be the introduction of the pharmaceutical composition, for example, for the treatment or prevention of any of the above conditions, in particular bone loss.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of bone loss (e.g., bisphosphonates), as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms), which contains the means suitable for the treatment or prevention of bone loss (e.g., a bisphosphonate), as described above.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of a pharmaceutical composition for the treatment or prevention of osteoporosis, treatment or prevention of the development of periodontitis, treat, cure or prevent the development of metastatic bone lesions, reduce the frequencies of the occurrence of bone metastasis or delay bone metastasis.

In certain embodiments of the implementation of the present invention the specified reagent kit further comprises instructions relating to the introduction of a pharmaceutical composition comprising the compound of the present invention, together with a chemotherapeutic agent listed above. In certain embodiments of the implementation of the present invention a specified set of reagents further comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a chemotherapeutic agent as defined above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of bone loss (e.g., a bisphosphonate), as described above; and

b) instructions relating to the introduction of the first pharmaceutical composition and a second pharmaceutical composition comprising the compound of the present invention, for the treatment or prevention of bone loss, treatment or prevention of osteoporosis, treatment or prevention of the development of periodontitis, treat, cure or prevent the development of metastatic lesions in bone, reducing the frequency of occurrence to the spas of metastasis or delay bone metastasis.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising a chemotherapeutic agent as defined above; and

b) instructions relating to the introduction of the first pharmaceutical composition with a compound of the present invention, for the treatment or prevention of bone loss, treatment or prevention of osteoporosis, treatment or prevention of the development of periodontitis, treat, cure or prevent the development of metastatic lesions of the bones, reducing the incidence of bone metastasis or delay bone metastasis.

Inflammation of the mucous membrane

In the present invention proposes a method of treatment or prevention of inflammation of the mucous membrane, comprising introducing the compound of the present invention. The term "inflammation of the mucous membranes" in this description refers to the defeat of the mucous membrane, caused by or associated with the use of radiation or drugs (chemotherapy) in the treatment of cancer and related diseases. Inflammation of the mucous membrane is usually manifested in the form of ulcers, necrosis and atrophy of the mucous membranes anywhere along the digestive tract, from the mouth is TVersity to the anus. For example, the methods of the present invention can be used for the treatment of swoopstake and tissue necrosis associated with radiotherapy and/or chemotherapy.

In the present invention proposes a method of preventing the development of mucosal inflammation caused by chemotherapy or radiotherapy, which includes the introduction of compounds of the present invention. In certain embodiments of the implementation of the present invention, the compound of the present invention is prescribed in conjunction with chemotherapy or radiotherapy.

In the present invention proposes a method of improving survival by reducing the incidence of inflammation of the mucous membrane, caused by therapy, which includes introducing the compound of the present invention. As expected, the level of life-threatening severe inflammation of the mucous membrane, corresponding to the 4th degree of the scale who will be reduced from the average level of 60% for non-treated patients up to 20% or less in treated patients.

In one embodiment, the present invention is a method of treatment or prevention of inflammation of the mucous membrane may include introducing the compound of the present invention together with additional means suitable for the treatment of inflammation of the mucous membrane. In opredeleniya implementation of the present invention, the compound of the present invention can be administered together with a bactericidal agent. In certain embodiments of the implementation of the present invention, the compound of the present invention can be administered together with a growth factor. In certain embodiments of the implementation of the present invention, the compound of the present invention can be administered together with an agent that inhibits the synthesis of ceramide, an agent that blocks the activity of ceramide, or agent, which decomposes ceramide.

In one embodiment, the present invention is a method of treatment or prevention of inflammation of the mucous membrane may include introducing the compound of the present invention in conjunction with a chemotherapeutic agent. Chemotherapeutic agents that may be administered together with the compounds of the present invention include any suitable chemotherapeutic agent or combination therapy as described above.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Furthermore, such combinations can be co-administered with other therapeutic means, such as other means suitable for the treatment and prevention of inflammation of the mucous membranes, such as the above agents.

In the definition is the R variants of implementation of the present invention features a kit of reagents which includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms chemotherapeutic agents specified above; and (c) of the regulations relating to the introduction of the compounds of the present invention and a chemotherapeutic drug.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, e.g. for the treatment or prevention of inflammation of the mucous membrane, preventing the development of mucosal inflammation caused by chemotherapy or radiotherapy, or to improve survival rates by reducing the incidence of inflammation of the mucous membrane, caused by therapy.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of inflammation of the mucous membrane (for example, a bactericidal agent, a growth factor, an agent, to whom that inhibits the synthesis of ceramide, an agent that blocks the activity of ceramide, or agent, which decomposes ceramide), as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms), which contains the means suitable for the treatment of inflammation of the mucous membrane (for example, a bactericidal agent, a growth factor, an agent that inhibits the synthesis of ceramide, an agent that blocks the activity of ceramide, or agent, which decomposes ceramide), as described above.

In certain embodiments of the implementation of the present invention the specified reagent kit further comprises instructions relating to the introduction of a pharmaceutical composition comprising the compound of the present invention together with a chemotherapeutic agent, as described above. In certain embodiments of the implementation of the present invention a specified set of reagents further comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a chemotherapeutic agent as defined above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more od okrutny dosage forms) including means suitable for the treatment or prevention of inflammation of the mucous membrane (for example, a bactericidal agent, a growth factor, an agent that inhibits the synthesis of ceramide, an agent that blocks the activity of ceramide, or agent, which decomposes ceramide) as described above; and

b) instructions for the introduction of the first pharmaceutical composition with a compound of the present invention, for example, for the treatment or prevention of inflammation of the mucous membrane, preventing the development of mucosal inflammation caused by chemotherapy or radiotherapy, or to improve survival rates by reducing the incidence of inflammation of the mucous membrane, caused by therapy.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising a chemotherapeutic agent as described above; and

b) instructions relating to the introduction of the first pharmaceutical composition with a compound of the present invention, for example, for the treatment or prevention of inflammation of the mucous membrane, preventing the development of mucosal inflammation caused by chemotherapy or radiotherapy, or improve survival by reducing the frequencies of the occurrence of mucosal inflammation, caused by therapy.

Cardiovascular disease

In the present invention proposes a method of treating or preventing cardiovascular disease in a patient, which includes the introduction of a specified patient compounds of the present invention. In certain embodiments of the implementation of the present invention the method includes an optional co-administration of a statin.

Cardiovascular disease refers to one or more painful conditions of the cardiovascular system (including heart). Diseases of the circulatory system and diseases of dependent bodies include, for example, but not limited to, any one or more of the following diseases:

disorders of the heart muscle (cardiomyopathy or myocarditis) such as idiopathic cardiomyopathy, metabolic cardiomyopathy which includes diabetic cardiomyopathy, alcoholic cardiomyopathy, cardiomyopathy, caused by the action of the medicinal product, ischemic cardiomyopathy, and hypertensive cardiomyopathy;

atheromatous disease of the major blood vessels (macrovascular disease) such as the aorta, coronary artery, carotid artery, cerebral artery, renal artery, iliac artery, femoral artery and popliteal artery;

p> toxicity caused by drugs and metabolic (including, but not limited to, hypertension and/or diabetes) disorders of small blood vessels (microvascular disease) such as the arterioles of the retina, the glomerular arterioles, the neurovascular bundles, the arterioles, the heart and associated capillary bed eyes, kidneys, heart and Central and peripheral nervous systems; and

associated with the rupture of atheromatous plaque lesions of major blood vessels such as the aorta, coronary artery, carotid artery, cerebral artery, renal artery, iliac artery, femoral artery and popliteal artery.

Finally, other disorders that can be treated using compounds of the present invention, include restenosis, for example, after surgery on the coronary vessels, and disorders associated with abnormal levels of cholesterol, high density and low density.

In certain embodiments of the implementation of the present invention provides methods of treatment of diseases of the blood vessels or vascular disorders. In certain embodiments of the implementation of the present invention vascular disorder may include any vascular disease and vascular disorder, which includes autoimmune component, n is the sample, component caused by an autoimmune response. Examples of cardiovascular disorders include one or more of these disorders as a disease and phenomenon, Raynaud's disease, anterior uveitis, vasculitis, peripheral vascular disease, the formation of atheroma, atherosclerosis, Takayasu (e.g., Takayasu's arteritis, temporal arteritis diagnostics/giant cell arteritis diagnostics), hyperplasia neointima (natural origin or after plastic surgery on the blood vessels), inflammatory and autoimmune intima thickening and/or muscular layer of blood vessels, inflammation of the blood vessels, atherosclerotic heart disease, reperfusion injury, cardiac conduction, myocarditis and myocardial infarction.

In certain embodiments implementing the present invention features a method of treating or preventing heart attack or myocardial infarction or arrhythmia in a patient, which includes the introduction of a specified patient compounds of the present invention. In certain embodiments implementing the present invention proposes a method of preventing death of the heart in a patient, which includes the appointment of a specified patient compounds of the present invention. In certain embodiments of the implementation of the present invention the method includes the optional joint is the first introduction with a statin.

Compounds of the present invention is able to eliminate the inflammation. Considered several aspects of cardiovascular disease, in particular the formation of atherosclerotic plaques on the walls of blood vessels, is closely associated with inflammation. Currently, it is believed that serological marker genes of inflammation, such as CRP, can just as successfully be used to predict the risk of cardiovascular disease, and elevated levels of LDL. Thus, the compounds of the present invention is suitable for treatment or prevention of cardiovascular diseases. In certain embodiments of the implementation of the present invention compounds of the present invention is suitable for treatment or prevention of inflammation of the arteries and/or atherosclerosis.

Another mechanism by which the compounds of the present invention can be effective in the treatment or prevention of cardiovascular diseases, is the suppression of structural and functional changes in HDL, which are the immediate response in the acute phase, observed in cardiovascular disease with active atherosclerotic plaques in the walls of blood vessels. Thus, the compounds of the present invention can increase the levels of HDL (or prevent the decrease is giving levels HDL) or restore the ability of HDL to bind LDL. This can lead to a lower and a better ratio of LDL/HDL in the serum.

In addition to increase HDL levels, statins also demonstrate anti-inflammatory activity, which stimulates their ability to reduce the risk of cardiovascular disease and to treat cardiovascular disease. However, the full anti-inflammatory potential of statins cannot be used in clinical trials as monotherapy, due to the need to apply large doses, which can lead to increased levels and severity of restrictive management of adverse effects, in particular, toxic effects on the liver.

Fortunately, and surprisingly the treatment or prevention of cardiovascular disease with a combination of statin and a compound of the present invention leads to the mutual reinforcement as anti-inflammatory properties of both classes of compounds, and to their ability to increase levels of HDL in the serum, while allowing to avoid the risks associated with large doses when using only one statin.

In the methods of the present invention, when the compound of the present invention is administered in conjunction with a statin (e.g., inhibitor of HMG-CoA-reductase), a statin may be selected from any statin drug, known from the field of technology. Statins are suitable for the joint shown in the introduction, include, but not limited to, mevastatin ((2S)-2-methylbutanoic acid (1S,7S,8S,8aR)-1,2,3,7,8,8 a-hexahydro-7-methyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether), atorvastatin ((βR,δR)-2-(4-forfinal)-β,δ-dihydroxy-5-(1-methylether)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-heptane acid), fluvastatin ((3R,5S,6E)-rel-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-geptanona acid), lovastatin (2(S)-2-methylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8 a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether), pravastatin ((βR,δR,1S,2S,6S,8S,8aR)-1,2,6,7,8,8 a-hexahydro-β,β,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutanoic]-1-naphthalenemethanol acid), simvastatin (2,2-dimethylbutanol acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8 a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether), rosuvastatin ((3R,5S,6E)-7-[4-(4-forfinal)-6-(1-methylethyl)-2-[methyl(methylsulphonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-geptanona acid), attestation, pitavastatin ((3R,5S,6E)-7-[2-cyclopropyl-4-(4-forfinal)-3-chinoline]-3,5-dihydroxy-6-geptanona acid), tseriwastatina ((3R,5S,6E)-7-[4-(4-forfinal)-5-(methoxymethyl)-2,6-bis(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-geptanona acid), bervastatin ((R*,S*-(E)-7-(4-(4-forfinal)Spiro(2H-1-benzopyran-2,1'-cyclopentane)-3-yl)-3,5-dihydroxyethyl ether), Dallas is Athyn ((4R,6S)-rel-6-[(1E)-2-[2-(4-fluoro-3-were)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]ethynyl]tetrahydro-4-hydroxy-2H-Piran-2-one), glenashton ((4R,6S)-6-[(1E)-2-[4-(4-forfinal)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]tetrahydro-4-hydroxy-2H-Piran-2-one), RP 61969 ([2S-[2a(E),4β]]-4-(4-forfinal)-2-(1-methylethyl)-3-[2-(tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl)ethynyl]-1-(2H)-athinaikon), assuming your-265859, BMS-180431 ((3R,5S,6E)-rel-9,9-bis(4-forfinal)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-Naydenova acid), CP-83101 ((3R,5S,6E)-rel-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienal acid methyl ester), dihydrokavain ((2S)-2-methylbutanoic acid (1S,3S,4aR,7S,8S,8aS)-1,2,3,4,4 a,7,8,8 a-octahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether) and L-669262 (2,2-dimethylbutanol acid (1S,7R,8R,8aR)-1,2,6,7,8,8 a-hexahydro-3,7-dimethyl-6-oxo-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether).

For example, statins, suitable for use in the methods of the present invention, include statins formula 200:

,

where

R201selected from alkyl, alkenyl, quinil, cycloalkyl or aralkyl;

R202, R203and R204independently selected from a hydrogen atom, halogen atom, alkyl, alkenyl or quinil;

R205and R206independently selected from a hydrogen atom, halogen atom, alkyl, alkenyl, quinil, cycloalkyl, aralkyl, alkoxy or Alcoxy; and

R240selected from a hydrogen atom, R241or M;

R241about the means of physiologically acceptable and can either hydrolyzed ester group; and

M denotes a pharmaceutically acceptable cation;

or their enantiomers, or their salts or their hydrates.

Other statins, suitable for use in the methods of the present invention, include statins formula 201:

A-B

where

And selected from the

B is selected from

C1 and C2 are connected in a simple or a double bond;

R207selected from CO2R215, CONR211R212or CH2OR213or R207and R209can form a lactone;

R215selected from H or a fragment cationic salt, or CO2R215forms a fragment of a pharmaceutically acceptable complex ether;

R208, R209and R210independently selected from H, C(O)R214or C(O)NR211R212;

R211and R212independently selected from H, alkyl, alkenyl or quinil;

R213selected from H or C(O)R214; and

R214selected from alkyl, alkenyl or quinil.

Other statins, suitable for use in the methods of the present invention, include statins formula 202:

,

where

R222selected from the

R216selected from OH, C6H5CO2or R221CO2;

R221represents C1-C5alkyl, C2-C5alkenyl or 2-C5quinil branched or straight chain;

R217, R218and R219independently selected from H, C1-C5of alkyl, C2-C5alkenyl, C2-C5the quinil or C1-C5acyl; and

R220selected from H or CH3.

Other statins, suitable for use in the methods of the present invention, include statins formula 203:

,

where

R227denotes-CH2-, -CH2-CH2-, -CH2-CH2-CH2- or-CH2-CH(CH3)-;

R223represents 1-naphthyl; 2-naphthyl; cyclohexyl; norbornene; 2-, 3 - or 4-pyridinyl; phenyl; phenyl substituted by a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl; trifluoromethyl; alkyl, alkenyl or quinil containing from one to four carbon atoms; alkoxy containing from one to four carbon atoms; or alkanoyloxy containing from two to eight carbon atoms;

or R224or R225means-CONR228R229where R228and R229independently represent a hydrogen atom; alkyl, alkenyl or quinil containing from one to six carbon atoms; 2-, 3 - or 4-pyridinyl; phenyl; phenyl substituted by fluorine atom, chlorine atom, bromine atom, cyano, trifluoromethyl or carbalkoxy containing from three to eight carbon atoms; and the other of R224/sub> or R225denotes a hydrogen atom; alkyl, alkenyl or quinil containing from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; or phenyl substituted by a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl; trifluoromethyl; alkyl, alkenyl or quinil containing from one to four carbon atoms; alkoxy containing from one to four carbon atoms; or alkanoyloxy containing from one to eight carbon atoms; and

R226denotes alkyl, alkenyl or quinil containing from one to six carbon atoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl;

or hydroxyacids, and their pharmaceutically acceptable salts obtained by disclosure lactoovo cycle.

Other statins, suitable for use in the methods of the present invention, include statins formula 204:

,

where

one of R230and R231means

,

and the other denotes a primary or secondary C1-6alkyl, alkenyl or quinil, not containing an asymmetric carbon atom, C3-6cycloalkyl or phenyl-(CH2)m-;

R234selected from a hydrogen atom, a C1-3of alkyl, C2-C4alkenyl, C2-C4the quinil, n-butyl, isobutyl, tert-is utila, C1-3alkoxy, n-butoxy, isobutoxy, trifloromethyl, fluorine atom, chlorine atom, phenoxy or benzyloxy;

R235selected from a hydrogen atom, a C1-3of alkyl, C2-C3alkenyl, C2-C3the quinil, C1-3alkoxy, trifloromethyl, fluorine atom, chlorine atom, phenoxy or benzyloxy;

R236selected from a hydrogen atom, a C1-2of alkyl, C2alkenyl, C2the quinil, C1-2alkoxy, fluorine atom or chlorine atom;

m is selected from 1, 2 or 3, provided that both R235and R236must denote a hydrogen atom when R234denotes a hydrogen atom, R236must denote a hydrogen atom when R235denotes a hydrogen atom, not more than one of R234and R235denotes trifluoromethyl, not more than one of R234and R235indicates phenoxy and not more than one of R234and R235means benzyloxy;

R232selected from a hydrogen atom, a C1-3of alkyl, C2-C4alkenyl, C2-C4the quinil, n-butyl, isobutyl, tert-butyl, C3-6cycloalkyl, C1-3alkoxy, n-butoxy, isobutoxy, trifloromethyl, fluorine atom, chlorine atom, phenoxy or benzyloxy;

R233selected from a hydrogen atom, a C1-3of alkyl, C2-C3alkenyl, C2-C3the quinil, C1-3alkoxy, trifloromethyl, fluorine atom, chlorine atom, the dryer is XI or benzyloxy, under the conditions that R233must denote a hydrogen atom when R232denotes a hydrogen atom, not more than one of R232and R233denotes trifluoromethyl, not more than one of R232and R233indicates phenoxy and not more than one of R232and R233means benzyloxy;

R237selected from -(CH2)n- or-CH=CH-, when n is 0, 1, 2 or 3;

R238selected from the

R239selected from hydrogen or C1-3of alkyl, C2-C3alkenyl or C2-C3the quinil;

R240selected from a hydrogen atom, R241or M;

R241denotes a physiologically acceptable and can either hydrolyzed ester group; and

M denotes a pharmaceutically acceptable cation.

Other statins, suitable for use in the methods of the present invention, include statins formula 205:

,

where

R242selected from the

,

or from lactones with a closed cycle, their salts and their esters.

Other statins, suitable for use in the methods of the present invention, include statins formula 206:

,

where

R243selected from H or CH3;

R244selected from 1,1-dimethylpropyl; C3-10the CEC is oprofile; C2-10alkenyl; CF3-substituted C1-10of alkyl; phenyl; halogen-substituted phenyl; phenyl-C1-3of alkyl; substituted phenyl-C1-3the alkyl, the substituent in which a is a halogen atom, a C1-3alkyl or C1-3alkoxy;

the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when they are present, are either a combination of X and Z, or individual X, Y, or Z;

or appropriate dihydroxyindole formula 206a

,

or pharmaceutically acceptable salt of the specified acid, C1-4the alkyl ether of the specified acid or phenyldimethylsilane or acetyliminodibenzyl C1-4the alkyl ether of the specified acid.

Other statins, suitable for use in the methods of the present invention, include statins formula 207:

,

where

R245denotes lower alkyl, alkenyl, quinil, aryl or aralkyl, each of which may have one or more substituents;

R246and R247independently selected from a hydrogen atom, lower alkyl, alkenyl, quinil or aryl, where each of the above lower alkyl, alkenyl, quinil or aryl may have one or more substituents;

R248denotes a hydrogen atom, lower alkyl, alkenyl, al is inil or a cation, able to form non-toxic pharmaceutically acceptable salt;

R249denotes a sulfur atom, oxygen or sulfonyl or amino, which may have a Deputy; and the dotted lines indicate the presence or absence of a double bond; or denotes the corresponding lactone with a closed loop.

The synthesis of various statins in document US RE37314 E, U.S. patent No. 4444784, 4346227, 5354772, 4681893 and the application for U.S. patent No. 2005/0228042.

In another embodiment, the present invention proposes a method of increasing the concentration of HDL in the serum (or prevent a decrease in the concentration of HDL in serum) or decrease relationship LDL/HDL in the serum of the patient, while this method includes the introduction of a specified patient compounds of the present invention optionally in combination with a statin. Patients who are treated in this way, the total cholesterol level in serum may be more than 189 mg/DL, preferably greater than 200 mg/DL, and most preferably greater than 240 mg/DL; and/or the concentration of LDL in the serum may be greater than 130 mg/DL, preferably greater than 160 mg/DL, and most preferably more than 189 mg/DL. In addition to levels of cholesterol and LDL in serum, other factors to consider are the presence or absence of disease cor is stationary arteries and risk factors such as age (45 or older for men and 55 years or more for women), family history of coronary heart disease, Smoking, high blood pressure, HDL serum cholesterol or diabetes.

In certain embodiments implementing the present invention proposes a method of reducing the levels of triglycerides in a patient, while this method includes the introduction of a specified patient compounds of the present invention optionally in combination with a statin.

In certain embodiments of the implementation of the present invention, the patient is treated by the method according to the present invention, can obtain a tool for reducing the level of cholesterol. In one preferred embodiment of the present invention, the patient is already receiving a statin, such as the one described above statins; and will continue to take the drug together with the compound of the present invention. Alternatively, the compound of the present invention can be used as a replacement for the previously used drug that lowers cholesterol.

In related embodiments, the implementation of the present invention proposes a method of reducing statin dose needed to achieve the desired increase in the content of HDL in savor is TCE, reduction relations LDL/HDL in serum or total cholesterol in serum and/or reduce the level of triglycerides. Reducing the dose of statins while maintaining effective ability to lower lipid levels in serum is highly desirable due to side effects associated with certain statins. Well-known side effects include harmful changes in liver function, muscle pain, weakness, muscle weakness, myopathy. Other side effects of statins include cognitive decline, memory impairment, depression, irritability, second pain, peripheral neuropathy, sleep disorders, sexual dysfunction, fatigue, dizziness, swelling, shortness of breath, vision changes, changes in the regulation of temperature, weight change, hunger, breast enlargement, changes in the concentration of sugar in the blood, dry skin, rash, changes in blood pressure, nausea, stomach upset, bleeding and ringing in the ears or other noises.

In this embodiment of the present invention, the dose of the statin reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% or more. The actual dose reduction is Tatina will depend on the type of connection according to the present invention, the number of used compounds of the present invention and the desired reduction in the level of lipid and/or triglyceride in serum, as well as other factors listed in this description, which is usually considered when the disease or condition. Used in a specified way a number of compounds of the present invention will also depend on the above factors, as well as the type and amount used of the statin. In certain embodiments of the implementation of the present invention is assigned in the present invention, the number of compounds of the present invention is 5% less 10% less 15% less 20% less 25% less, 30% less, 40% less 50% less 60% less 70% less 80% less, or 90% less than the dose of a compound of the present invention, required to cause anti-inflammatory effects. In other embodiments, implementation of the present invention, the number of assigned compounds of the present invention is more than 110%, more than 120%, greater than 130%, greater than 140%, greater than 150%, more than 160%, more than 170% greater than 180%, more than 190%, or even more than 200% of the dose of the compounds of the present invention, desired to provide an anti-inflammatory effect.

In one embodiment, the present invention methods for the treatment or prevention of cardiovascular diseases according to the present invention may include the additional step of joint injection, the patient is another tool, suitable for the treatment of cardiovascular diseases, such as, for example, an inhibitor of cyclooxygenase, receptor antagonist of thromboxane, prostacyclin mimetic, a phosphodiesterase inhibitor, a vasodilator agent, a means of protecting the brain, a drug that increases the functional activity of the brain, an anticoagulant, an antiplatelet drug, a thrombolytic drug, antihypertensive agent, a calcium channel blocker, a drug against angina, a diuretic, a cardioplegic solution, a cardiotonic agent, an antiarrhythmic drug, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a donor of nitric oxide, a blocker of potassium channels blocker of sodium channels, antihyperlipidemic drug, an immunosuppressant or a natriuretic agent.

Examples of the inhibitor of cyclooxygenase include, but not limited to, celecoxib, rofecoksib, meloxicam, valdecoxib, aspirin or indomethacin.

An example of a receptor antagonist of the thromboxane is petrobas.

Examples of vasodilators include, for example, bencyclane, Cinnarizine, citicoline, cyclandelate, cyclonical, erumananen, phenoxetol, flunarizin, ibudilast, ifenprodil, lomerizine, NAF is ol, nikomat, nicergoline, nimodipine, Praveen, peniillin, noferin, vincamine, Vinpocetine, vagisil, pentoxifylline, derived prostacyclin (such as prostaglandin E1 and prostaglandin I2), a drug that blocks the receptor for endothelin (such as bosentan), diltiazem, nicorandil and nitroglycerin.

Examples of medicinal remedies of the brain include the acceptors radicals (such as edaravone, vitamin E and vitamin C), antagonists of glutamate, AMPA antagonists, antagonists kainate, NMDA antagonists, GABA agonists, growth factors, opioid antagonists, the precursor of phosphatidylcholine, serotonin agonists, drugs that inhibit Na+/Ca2+feeds, and medicines, the opening of K+channels.

Examples of medicinal substance that increases the functional activity of the brain include amantadine, tiaprid and gamma-aminobutyric acid.

Examples of the coagulant include heparins (such as heparin sodium, heparin, potassium, dalteparin sodium, dalteparin calcium, heparin calcium, parnaparin sodium, reviparin sodium and danaparoid sodium), warfarin, enoxaparin, argatroban, batroxobin and sodium citrate.

Examples of antiplatelet drug include ticlopidine hydrochloride, dipyridamole, Cilostazol, ethyl icosapentate, sarpogrelate hydrochloride, dilazep hydrochloride,trapidil, non-steroidal anti-inflammatory drug (such as aspirin), beraprost sodium, iloprost, indobufen.

Examples of thrombolytic drugs include tissue plasminogen activator (tPA), recombinant tPA, tissue plasminogen activators (such as alteplaza, isocynate, nameplate, pamiteplase, monteplase and reteplase), streptokinase, urokinase, PUK, replaced by antilam activator complex of streptokinase and plasminogen (APSAC, Eminase, Beecham Laboratories), plasminogen activators salivary glands of animals and naturopathy.

Examples of antihypertensive drugs include angiotensin converting enzyme inhibitors (such as captopril, alacepril, lisinopril, imidapril, inapril, temocapril, delapril, benazepril, cilazapril, trandolapril, enalapril, ceronapril, fosinopril, imidapril, Mobitel, perindopril, ramipril, spirapril, zofenopril, pentopril, trandolapril and salts of such compounds), antagonists of angiotensin II (such as losartan, candesartan, valsartan, eprosartan and irbesartan), drugs that block calcium channels (such as aranidipine, efonidipine, nicardipine, benidipine, benidipine, manidipine, cilnidipine, nisoldipine, nitrendipin, nifedipine, nilvadipine, felodipine, amlodipine, diltiazem, bepridil, clentiazem, fendilin, gallopamil, mibefradil, prenilamin, emotional, terodiline, verapamil, cilnidipine, elhadidy, isradipine, lacidipine, lercanidipine, nimodipine, Cinnarizine, flunarizin, lidoflazine, lomerizine, benzilan, athenon and perhexiline), drugs that block β-adrenaline receptor (propranolol, pindolol, indenolol, carteolol, bunitrolol, atenolol, acebutolol, metoprolol, timolol, nipradilol, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, bopindolol, bevantolol, labetalol, alprenolol, amosulalol, arotinolol, befunolol, Bogomolov, buretrol, bufuralol, bupranolol, butylidene, butoverall, carazolol, atemolol, carnosol, dilevalol, epanolol, levobunolol, mepindolol, metipranolol, moprolol, ngoxolo, nebivolol, oxprenolol, Proactol, pronethalol, sotalol, supinely, talinolol, chertala, celiprolol, xianya and esmolol), drugs that block α-receptor (such as amosulalol, prazosin, terazosin, doxazosin, bunazosin, urapidil, phentolamine, arotinolol, dapiprazole, fenspirid, indoramin, labetalol, naftopidil, nicergoline, tamsulosin, tolazoline, trimazosin and yohimbin), sympathetic nerve inhibitors (such as clonidine, guanfacine, guanabenz, hydrochlorothiazide methyldopa and reserpine, hydralazine, cadralazine, betalain and cadralazine.

Examples of drugs against angina include nitrate drugs is ATA (such as amyl nitrate, nitroglycerin and isosorbide), drugs that block the receptor β-adrenaline (above), drugs that block calcium channels (see above), Trimetazidine, dipyridamole, athenon, dilazep, trapidil, nicorandil, enoxaparin and aspirin.

Examples of the diuretic include thiazide diuretics (such as hydrochlorothiazide, methyclothiazide, bendrofluazide, chlorothiazide, trichlormethiazide, benzylhydroxylamine, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, polythiazide, benzthiazide and panflute), loop diuretics (such as furosemide, ethacrynic acid, bumetanide, piretanide, azosemide and torasemide), K+-saving diuretics (spironolactone, triamterene, amiloride and canrenoate potassium), osmotic diuretics (such as isosorbide, D-mannitol, and glycerin), nithiazine diuretics (such as metakron, tripamide, chlorthalidone and mefruside) and acetazolamide.

Examples cardiotonic tools include compositions based on digitalis (such as digitoxin, digoxin, methyldigoxin, deslanoside, vesnarinone, lanatoside C and proscillaridin), compounds based on xanthine (such as aminophylline, choline theophylline, diprophylline and proxyphylline), structures on the basis of catecholamine (such as dopamine, dobutamine and doerpen), inhibitors of PDE III (such as amrinone, olprinone and mi is rinon), denopamine, ubidecarenone, pimobendan, "levosimendan", aminoacyltrna acid, vesnarinone, carperitide and colforsin daropate.

Examples of antiarrhythmic agent include aymalin, pirmenol, procainamide, cibenzoline, disopyramide, quinidine, aprindine, meksiletin, lidocaine, Fenelon, pilsicainide, propafenone, flecainide, atenolol, acebutolol, sotalol, propranolol, metoprolol, pindolol, amiodaron, nifekalant, diltiazem, bepridil, moricizine, tocainide, enkainid, propafenone, esmolol, artile, brutily, clofely, isobutylic, sotalol, azimilide, dofetilide, dronedarone, percentile, ibutilide, tedisamil, treatise, digitalis, adenosine, chloride of Nickel and magnesium ions and verapamil.

Examples of the antihyperlipidemic tools include atorvastatin, simvastatin, pravastatin sodium, fluvastatin sodium, clinofibrate, clofibrate, simfibrate, fenofibrate, bezafibrat, colestimide, cholestyramine, mevastatin ((2S)-2-methylbutanoic acid (1S,7S,8S,8aR)-1,2,3,7,8,8 a-hexahydro-7-methyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether), fluvastatin ((3R,5S,6E)-rel-7-[3-(4-forfinal)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-geptanona acid), lovastatin (2(S)-2-methylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8 a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether), pravastatin ((βR,δR,1S,2S,6S,8S,8aR)-1,2,6,,8,8 a-hexahydro-β,β,6-trihydroxy-2-methyl-8-[(2S)-2-methyl-1-oxobutanoic]-1-naphthalenemethanol acid), rosuvastatin ((3R,5S,6E)-7-[4-(4-forfinal)-6-(1-methylethyl)-2-[methyl(methylsulphonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-geptanona acid), attestation, pitavastatin ((3R,5S,6E)-7-[2-cyclopropyl-4-(4-forfinal)-3-chinoline]-3,5-dihydroxy-6-geptanona acid), the tseriwastatina ((3R,5S,6E)-7-[4-(4-forfinal)-5-(methoxymethyl)-2,6-bis(1-methylethyl)-3-pyridinyl]-3,5-dihydroxy-6-geptanona acid), bervastatin ((R*,S*-(E)-7-(4-(4-forfinal)Spiro(2H-1-benzopyran-2,1'-cyclopentane)-3-yl)-3,5-dihydroxyethyl ether), dalvastatin ((4R,6S)-rel-6-[(1E)-2-[2-(4-fluoro-3-were)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl]ethynyl]tetrahydro-4-hydroxy-, 2H-Piran-2-one), glenashton ((4R,6S)-6-[(1E)-2-[4-(4-forfinal)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]ethynyl]tetrahydro-4-hydroxy-2H-Piran-2-one), RP 61969 ([2S-[2a(E),4β]]-; 4-(4-forfinal)-2-(1-methylethyl)-3-[2-(tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl)ethynyl]-1-(2H)-athinaikon), assuming your-265859, BMS-180431 ((3R,5S,6E)-rel-9,9-bis(4-forfinal)-3,5-dihydroxy-8-(1-methyl-1H-tetrazol-5-yl)-6,8-Naydenova acid), CP-83101 ((3R,5S,6E)-rel-3,5-dihydroxy-9,9-diphenyl-6,8-nonadienal acid methyl ester), dihydrokavain ((2S)-2-methylbutanoic acid (1S,3S,4aR,7S,8S,8aS)-1,2,3,4,4 a,7,8,8 a-octahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ester) and L-669262 (2,2-dimethylbutanol acid (1S,7R,8R,8aR)-1,2,6,7,8,8 a-hexahydro-3,7-dimethyl-6-oxo-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-Piran-2-yl]ethyl]-1-naphthalenyloxy ether).

When the minimum level of immunosuppressant include azathioprine, mizoribine, cyclosporine, tacrolimus, gusperimus and methotrexate.

In one embodiment, the present invention is a method of treatment or prevention of cardiovascular diseases in accordance with the present invention may include introducing the compound of the present invention in conjunction with non-chemical methods of treating or preventing cardiovascular disease as part of a treatment regimen that includes physical intervention (e.g., percutaneous transluminal coronary angioplasty, surgery on the coronary arteries or vascular surgery). In certain such embodiments, the implementation of the present invention regimens, including physical intervention may additionally enable simultaneous introduction of other means suitable for the treatment or prevention of cardiovascular diseases, such as the tools listed above.

It should be understood that the methods of treatment or prevention of cardiovascular diseases according to the present invention can include co-administration of one or more of the above-mentioned funds in a separate dosage form or as part of a composition that also contains a statin, the compound of the present invention, and optionally further include a statin. In addition, use the W in the treatment of cardiovascular diseases of the composition, including both a statin and a compound of the present invention, in accordance with the present invention does not exclude separate, but co-administration of another statin.

The method of increasing the concentration of HDL in serum, reduce relations LDL/HDL in serum, reducing the total concentration of cholesterol in serum and/or reduce the level of triglycerides in a patient in accordance with the present invention may further include inserting the indicated patient a different active ingredient than the statin. Such additional active ingredient may be selected from other than statins means to lower cholesterol, such as substances that increase the excretion of bile acids (colesevelam, cholestyramine and colestipol), Niacin, fibrates (gemfibrozil, probucol and clofibrate).

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other agents suitable for the treatment or prevention of cardiovascular diseases, such as the above-mentioned tools.

In certain embodiments of the implementation of the present invention p is alagaesia set of reagents, which includes

a) one or more single dosage forms of the compounds of the present invention;

b) one or more single dosage forms of the statin, above; and

c) instructions concerning the introduction of the compounds of the present invention and statin.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent cardiovascular disease, increasing the concentration of HDL in the serum (or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or decrease levels of triglycerides.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of cardiovascular diseases, increasing the concentration of HDL in the serum (or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or the decrease in triglyceride levels (in particular, with a statin or other agent suitable for the treatment or prevention of cardiovascular diseases, such as, for example, an inhibitor of cyclooxygenase, receptor antagonist of thromboxane, prostacyclin mimetic, a phosphodiesterase inhibitor, a vasodilator agent, a means of protecting the brain, the medicinal substance that increases the functional activity of the brain, an anticoagulant, an antiplatelet drug, a thrombolytic drug, antihypertensive agent, a calcium channel blocker, a drug against angina, a diuretic, a cardioplegic solution, a cardiotonic agent, an antiarrhythmic drug, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a donor of nitric oxide, blocker of potassium channels blocker of sodium channels, antihyperlipidemic drug, an immunosuppressant or natriuretic tool), which is listed above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising an agent suitable for treating or preventing cardiovascular disease, increasing the concentration of HDL in serum or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or decrease levels of triglycerides (in particular, a statin or other agent suitable for the treatment or prevention of cardiovascular diseases, such as, for example, an inhibitor of cyclooxygenase, receptor antagonist of thromboxane, prostacyclin mimetic, a phosphodiesterase inhibitor, a vasodilator agent, a drug to protect the brain, the medicinal substance that increases the functional activity of the brain, an anticoagulant, an antiplatelet drug, a thrombolytic drug, antihypertensive agent, a calcium channel blocker, a drug against angina, a diuretic, a cardioplegic solution, a cardiotonic agent, antiarrhythmic drug, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a donor of nitric oxide, a blocker of potassium channels blocker of sodium channels, antihyperlipidemic drug, an immunosuppressant or natriuretic tool), which is specified above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention with techno disease, increasing the concentration of HDL in the serum (or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or decrease levels of triglycerides (in particular, a statin or other agent suitable for the treatment or prevention of cardiovascular diseases, such as, for example, an inhibitor of cyclooxygenase, receptor antagonist of thromboxane, prostacyclin mimetic, a phosphodiesterase inhibitor, a vasodilator agent, a means of protecting the brain, the medicinal substance that increases the functional activity of the brain, an anticoagulant, an antiplatelet drug, a thrombolytic drug, antihypertensive agent, a calcium channel blocker, drug against angina, a diuretic, a cardioplegic solution, a cardiotonic agent, an antiarrhythmic drug, a fibrinolytic agent, a sclerosing solution, a vasoconstrictor agent, a donor of nitric oxide, a blocker of potassium channels blocker of sodium channels, antihyperlipidemic drug, an immunosuppressant or a natriuretic agent); and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of cardio-soudi the condition increasing the concentration of HDL in the serum (or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or decrease levels of triglycerides.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising a statin, as described above; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of cardiovascular diseases, increasing the concentration of HDL in the serum (or prevent the reduction of the concentration of HDL in serum), reduction relations LDL/HDL in the serum and/or decrease levels of triglycerides.

Common inflammatory disease

In the present invention proposes a method of treating or preventing an inflammatory disease in a patient, which includes the introduction of a specified patient compounds of the present invention.

Examples of inflammatory diseases that can be treated or prevented by the introduction of the compounds of the present invention, include, but not limited to, inflammation of the lungs, joints, connective tissue, eyes, nose, intestines, kidneys, liver, skin, Central nervoussystem, vascular system and heart. In certain embodiments of the implementation of the present invention inflammatory diseases that can be treated in accordance with the present invention include inflammation caused by infiltration of cells or other effector cells of the immune system in the affected tissue. Other relevant examples of inflammatory diseases that can be treated in accordance with the present invention include inflammation caused by infectious agents, including, but not limited to, viruses, bacteria, fungi, and parasites.

Inflammatory lung disease include, but not limited to, asthma, respiratory distress syndrome in adults, bronchitis, pneumonia, pulmonary fibrosis and cystic degeneration (which may additionally or alternatively cover the gastrointestinal tract or other(s) tissue(s)). Inflammatory joint diseases include rheumatoid arthritis, rheumatoid spondylitis, juvenile rheumatoid arthritis, osteoarthritis, gouty arthritis and other arthritic condition. Eye diseases with an inflammatory component include, but not limited to, uveitis (including iritis, conjunctivitis, scleritis, keratoconjunctivitis sicca and retina diseases, including, but these is not limited to, diabetic retinopathy, retrolental retinopathy, pigmentary degeneration of the retina and dry and wet age-related macular degeneration. Inflammatory bowel disease includes Crohn's disease, ulcerative colitis and distal proctitis.

Inflammatory diseases of the skin include, but not limited to, conditions associated with cell proliferation, such as psoriasis, eczema and dermatitis (e.g., eczematous dermatitis, local and seborrheic dermatitis, or allergic caused by irritation, contact dermatitis, eczema elderly, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis and chronic dermatitis). Other inflammatory diseases of the skin include, but not limited to, scleroderma, ulcers and erosion as a result of trauma, burns, bullous disease or ischemia of the skin or mucous membranes, several forms of diffuse keratitis, bullous congenital a bullosa, hypertrophic scars, keloids, skin changes due to aging caused by the internal state of the organism, photoaging, friction blisters caused by mechanical cutting of the skin, and skin atrophy caused by local application of corticosteroids. Additional inflammatory skin conditions include inflammation of the mucous membranes, such to the to cheilitis, cracks in the lips, irritation of nose, inflammation of the mucous membrane and vulvovaginitis.

Inflammatory diseases of the endocrine system include, but not limited to, autoimmune thyroiditis (Hashimoto's disease), diabetes type I and acute and chronic inflammation of the adrenal cortex. Inflammatory condition of the cardiovascular system include, but are not limited to, lesions caused by myocardial infarction, peripheral vascular disease, myocarditis, vasculitis, revascularization stenosis, atherosclerosis and vascular disease associated with diabetes type II.

Inflammatory condition of the kidneys include, but not limited to, glomerulonephritis, interstitial nephritis, lupus nephritis, nephritis as a complication after an illness of Wegener, acute renal failure as a complication of acute nephritis, the syndrome?, complications of obstructive syndrome and ischemia tubules.

Inflammatory condition of the liver include, but not limited to, hepatitis (resulting from a viral infection, autoimmune reactions, medication, toxins, agents, related to the external environment, or arising as a complication after primary disease, atresia of the bile ducts, primary biliary cirrhosis and primary sclerosing cholangitis.

Vos is Alitalia state of the Central nervous system include, but not limited to, multiple sclerosis and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or dementia associated with HIV infection.

Other inflammatory condition include periodontal disease, necrosis of tissue in chronic inflammation, endotoxic shock, proliferative disease of smooth muscles, graft-versus-host tissue damage as a result of damage caused by reperfusion after ischemia, and tissue rejection after a transplant operation.

In the present invention it is also proposed a method for the treatment or prevention of inflammatory diseases associated with wound healing in a patient after surgery, which includes the introduction of a specified patient compounds of the present invention.

It should be noted that the compounds of the present invention can be used to treat or prevent any diseases that have an inflammatory component, such as the above diseases. In addition, the above diseases should be considered as examples and is not exhaustive.

Professionals should be clear that the additional condition (e.g., systemic or local disturbance or imbalance of the immune system caused by what damaged, stroke, infection, hereditary disease or the influence of intoxicant or perturbant from the external environment on the physiology of the patient can be treated or prevented using the compounds of the present invention. Thus, the methods of the present invention can be used to treat or prevent any diseases that have an inflammatory component, including, but not limited to, the above listed diseases.

In the present invention are also methods of treating or preventing arthritis, inflammatory bowel disease, uveitis, inflammation of the eyes, asthma, inflammation of the lung, cystic degeneration, psoriasis, inflammation of the arteries, cardiovascular disease, multiple sclerosis or neurodegenerative diseases by introducing an effective amount of the compounds of the present invention.

The present invention provides methods of treating ischemia by introducing an effective amount of the compounds of the present invention. In certain embodiments of the implementation of the present invention ischemia is a cardiac ischemia, cerebral ischemia, ischemia of the bowel (eg, ischemic colitis or esentially thrombosis or ischemia of the skin.

In the present invention proposes a method of treatment or before the rotation inflammatory disease in a patient, which includes the appointment of a specified patient compounds of the present invention in conjunction with a glucocorticoid.

The present invention features a method of treating or preventing an inflammatory condition (e.g., any of the above inflammatory conditions), which involves giving the patient a compound of the present invention in conjunction with a glucocorticoid.

Compounds of the present invention is able to eliminate the inflammation. Role of glucocorticoids play in the treatment of inflammation, also known. However, attempts to use only anti-inflammatory potential of glucocorticoids are often confronted with clinical restrictions when using monotherapy due to the high level and the severity of limiting treatment adverse effects that accompany the use of large or prolonged dosing schedules. For example, the introduction of glucocorticoids can cause side effects that are reminiscent of Cushing disease. These side effects and other side effects associated with the use of glucocorticoids, include increased appetite and weight gain, fat deposition on the chest, face, upper back and stomach, retention of water and salts, which leads to swelling and edema, high blood pressure, diabetes, m is glendoe wound healing, osteoporosis, cataracts, acne, muscle weakness, thinning of the skin, increased susceptibility to infection, stomach ulcers, increased sweating, sudden mood swings, mental problems such as depression and adrenal suppression and crisis. Fortunately, the treatment of inflammatory diseases using a combination of glucocorticoid and compounds of the present invention enhances the anti-inflammatory properties of both classes of compounds and reduce the effects associated with large doses, use only one of glucocorticoid.

In the methods of the present invention, which provide for the introduction of glucocorticoid together with the compound of the present invention, the glucocorticoid may be selected from any glucocorticoid known from the field of technology. Glucocorticoids, suitable for the specified joint injection include, but not limited to, alclometasone, amcinonide, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, cortisol, deflazacort, desonide, desoximetasone, detoxication, dexamethasone, diflorasone, diflucortolone, difluprednate, fluchloralin, fludroxycortide, flumetazon, flunisolide, fluotsinolon acetonide, fluocinonide, fluocortin, fluocortolone, formation, flaperon, flupredniden, flu is Cason, farmacita, halcinonide, halobetasol, hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisone balarat, hydrocortisone butyrate, loteprednol, Madison, meprednisone, methylprednisolone, methylprednisolone aceponate, mometazon furoate, paramethasone, prednicarbate, prednisone/prednisolone, prednisone, rimexolone, tixocortol, triamcinolone, WebEasy, mometazon, fluticasone propionate, beclomethasone dipropionate, fluotsinolon, flunisolide hemihydrate, mometazon furoate monohydrate, desoximetasone, diflorasone diacetate, hydrocortisone acetate, deformation, forgotson, flumetazon, flunisolide, perkantoran, prednisolone, prednisone, cortisol, 6a-methylprednisolone, alclometasone dipropionate, fluchloralin acetonide, fluotsinolon acetonide, betamethasone benzoate, fluocortin butyl, betamethasone dipropionate, drugs of fluocortolone, betamethasone valerate, flupredniden acetate, flurandrenolide, clobetasol propionate, clobetasol butyrate, hydrocortisone, hydrocortisone butyrate, methylprednisolone acetate, valerate, flumetazon pivalate or triamcinolone acetonide, or their pharmaceutically acceptable salts.

In certain embodiments of the implementation of the present invention the patient, which are going to be treated according to the method of the present invention, may already have anti-inflammatory drug environments the creation (other than glucocorticoid). In one preferred embodiment of the present invention, the patient is already taking a glucocorticoid, such as the one described above glucocorticoids, and will continue to take the drug together with the compound of the present invention. Alternatively, the compound of the present invention can be used as a replacement for the previously used anti-inflammatory drug.

In related embodiments, the implementation of the present invention proposes a method of reducing the dose of glucocorticoid required to achieve the desired anti-inflammatory effect. Dose reduction of glucocorticoid while maintaining its effective anti-inflammatory ability is highly desirable due to side effects associated with some of glucocorticoids. Side effects of corticosteroids include increased appetite and weight gain, fat deposition on the chest, face, upper back and stomach, retention of water and salts, which leads to swelling and edema, high blood pressure, diabetes, slow wound healing, osteoporosis, cataracts, acne, muscle weakness, thinning of the skin, increased susceptibility to infection, stomach ulcers, increased sweating, sudden mood swings, mental problems, still is as depression, and adrenal suppression and crisis.

In this embodiment of the present invention dose glucocorticoid reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more. The actual reduction in the dose of glucocorticoid will depend on the type and amount used of the compound of the present invention, the desired reduction of inflammation and other factors referred to in this description, which usually take into account when treating the disease or condition. A number of compounds of the present invention, assigned to the specified method will also depend on the above factors, as well as the type and quantity of input glucocorticoid. In certain embodiments of the implementation of the present invention, the number of compounds of the present invention, assigned to the specified method is less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80% or less than 90% of the dose of the compounds of the present invention, required for to provide anti-inflammatory action is without their joint introduction of glucocorticoid.

In one embodiment, the present invention is a method of treatment or prevention of inflammatory diseases in accordance with the present invention may include the additional step of joint injection, the patient is another anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drug (NSAID), a stabilizer of mast cells or leukotriene controller.

In certain embodiments of the implementation of the present invention use in the treatment of inflammatory diseases of the composition comprising the compound of the present invention, and glucocorticoid, in accordance with the present invention does not preclude the individual, but joint introduction of another corticosteroid.

In certain embodiments of the implementation of the present invention use in the treatment of inflammatory diseases of the composition comprising the compound of the present invention, and the glucocorticoid, in accordance with the present invention does not preclude the individual, but joint introduction of another glucocorticoid.

In certain embodiments of the implementation of the present invention, various compounds of the present invention may be administered in conjunction with other compounds of the present invention and provide joint is e introduction glucocorticoid. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other anti-inflammatory drugs.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of glucocorticoid specified above; and (c) of the regulations relating to the introduction of the compounds of the present invention and glucocorticoid.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, e.g. for the treatment or prevention of the above disorders or diseases, such as inflammatory diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention in conjunction with a glucocorticoid, as described above. In certain embodiments of the implementation of this izobreteniya reagent additionally comprises a second pharmaceutical composition (for example, in the form of one or more single dosage forms) comprising the above glucocorticoids.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of inflammatory diseases (e.g., nonsteroidal anti-inflammatory drug (NSAID), a stabilizer of mast cells or leukotriene regulator), as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising an agent suitable for the treatment or prevention of inflammatory diseases (e.g., nonsteroidal anti-inflammatory drug (NSAID), a stabilizer of mast cells or leukotriene regulator), as described above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of inflammatory sableman the I (for example, non-steroidal anti-inflammatory drug (NSAID), a stabilizer of mast cells or leukotriene controller as described above; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of inflammatory diseases.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising the above glucocorticoid; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of inflammatory diseases.

Diseases of metabolism

In the present invention proposes a method of treatment or prevention of complex diseases in a patient having an inflammatory component, which includes the appointment of a specified patient compounds of the present invention. In certain embodiments of the implementation of the present invention a complex disease with an inflammatory component is type 2 diabetes or obesity.

The present invention features a method of treating or preventing metabolic disorders in a patient, including the Mering introduction to the specified patient compounds of the present invention. In certain embodiments of the implementation of the present invention, the metabolic disorder is selected from an eating disorder, dyslipidemia, hypertriglyceridemia, hypertension or metabolic syndrome.

In the present invention it is also proposed a method for the treatment or prevention of type 1 diabetes in a patient, comprising the introduction of a specified patient compounds of the present invention. In certain embodiments implementing the present invention proposes a method of ridding the patient of the risk of developing type 1 diabetes, including the introduction of a specified patient compounds of the present invention. In certain embodiments implementing the present invention features a method of treating a patient who manifested one or more red flags of type 1 diabetes such as excessive thirst; frequent urination; drowsiness or lethargy; sugar in urine; sudden changes in visual acuity; increased appetite; sudden weight loss; similar to fruity, sweet or similar guilt smell when breathing; wheezing, shortness of breath; dizziness; or unconsciousness, which includes the introduction of a specified patient connection according to the present invention.

In the present invention proposes a method of treatment or prevention of type 2 diabetes in a patient, including the maintenance of specified patient compounds of the present invention. In certain embodiments implementing the present invention proposes a method of ridding the patient of the risk of development of type 2 diabetes, including the introduction of a specified patient compounds of the present invention. In certain embodiments implementing the present invention features a method of treating a patient who manifested one or more red flags of type 2 diabetes such as excessive thirst; frequent urination; drowsiness or lethargy; sugar in urine; sudden changes in visual acuity; increased appetite; sudden weight loss; similar to fruity, sweet or similar guilt smell when breathing; wheezing, shortness of breath; dizziness; or unconsciousness, which includes the introduction of a specified patient connection according to the present invention.

In addition, the present invention proposes a method of protection, for example, stimulating the growth and/or survival of beta cells of islets of Langerhans from provoked by lipids or glucose toxicity in a patient, comprising the introduction of a specified patient compounds of the present invention.

In certain embodiments of the implementation of the present invention, the methods of treatment or prevention of complex diseases with an inflammatory component, such as type 2 diabetes, or treatment Diab is the type 1, in accordance with the present invention may include the additional step joint appointment to another patient in the treatment of diabetes, including, but not limited to, the use of sulfonylureas (such as chlorpropamide, tolbutamide, gliburida, glipizide, acetohexamide, tolazamide, gliklazida, glikvidona or glimepiride), drugs that reduce the amount produced of glucose from the liver (e.g., Metformin), meglitinides (for example, Repaglinide or nateglinide), drugs that reduce the absorption of hydrocarbons from the intestine (for example, alpha-glucosidase inhibitors such as acarbose), medicines, that affect glycemic control (for example, pramlintide or exenatide), inhibitors of DPP-IV (for example, sitagliptin), insulin treatment, or combinations thereof, iise.

In certain embodiments of the implementation of the present invention, the methods of treatment or prevention of complex diseases with an inflammatory component, such as obesity, in accordance with the present invention may include the additional step joint appointment to another patient treatment of obesity, including, but not limited to, the use of orlistat, sibutramine, phendimetrazine, phentermine, diethylpropion, benzphetamine, mazindol, de is streampreteen, the rimonabant, cetilistat, GT 389-255, APD356, pramlintide/AC137, PYY3-36, AC 162352/PYY3-36, oxyntomodulin, TM 30338, AOD 9604, oleoyl-estrone, bromocriptine, ephedrine, leptin, pseudoephedrine, or their pharmaceutically acceptable salts.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of metabolic disorders, such as those listed above tools.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, e.g. for the treatment or prevention of complex diseases with an inflammatory component (e.g., type 2 diabetes or obesity, treatment or prevention of metabolic disorders (e.g. eating disorders, dyslipidemia, hypertriglyceridemia, hypertension or metabolic syndrome), treatment or prevention of d is of Abete type 1, deliverance of the patient from the risk of development of type 1 diabetes, treatment of the patient, which appear alarming symptoms of type 1 diabetes, or protection (for example, stimulating the growth and/or survival) of the beta-cells of islets of Langerhans from toxicity caused by lipids or glucose.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of diabetes (eg, sulfonylureas (eg, chlorpropamide, tolbutamide, gliburid, glipizide, acetohexamide, tolazamide, gliclazide, glikvidona or glimepiride), drugs that reduce the quantity produced of glucose from the liver (e.g., Metformin), meglitinides (for example, Repaglinide or nateglinide), drugs that reduce the absorption of hydrocarbons from the intestine (for example, the alpha-glucosidase inhibitors such as acarbose), drugs that affect glycemic control (for example, pramlintide or exenatide), inhibitors of DPP-IV (for example, sitagliptin), together with treatment with insulin or their combinations, as described above. In particular the s variants of implementation of the present invention a specified set of reagents comprises a second pharmaceutical composition (for example, as one or more single dosage forms) that contains a drug suitable for the treatment or prevention of diabetes (eg, sulfonylureas (e.g., hlorpropamid, tolbutamide, gliburid, glipizide, acetohexamide, tolazamide, gliclazide, glikvidon or glimepiride), medicines that reduce the amount produced of glucose from the liver (e.g., Metformin), meglitinides (for example, Repaglinide or nateglinide), drugs that reduce the absorption of hydrocarbons from the intestine (for example, alpha-glucosidase inhibitors such as acarbose), medicines that affect glycemic control (e.g., pramlintide or exenatide), inhibitors of DPP-IV (e.g., sitagliptin), the use of insulin treatment or combinations as described above.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with means suitable for the treatment or prevention of obesity, mentioned above. In certain embodiments of the implementation of the present invention a specified set of reagents comprises a second pharmaceutical composition (e.g. in the form of one or more single l is drug forms), which contains a drug suitable for the treatment or prevention of obesity, above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of obesity, as indicated above; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of complex diseases with an inflammatory component (e.g., type 2 diabetes or obesity, treatment or prevention of metabolic disorders (e.g. eating disorders, dyslipidemia, hypertriglyceridemia, hypertension or metabolic syndrome), treatment or prevention of type 1 diabetes, the deliverance of the patient from the risk of development of type 1 diabetes, treatment of the patient, which appear alarming symptoms of type 1 diabetes, or protection (for example, stimulating the growth and/or survival) beta cells of islets of Langerhans from toxicity caused by lipids or glucose.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single Le is arctonyx forms), including means suitable for the treatment or prevention of diabetes, as indicated above; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of complex diseases with an inflammatory component (e.g., type 2 diabetes or obesity, treatment or prevention of metabolic disorders (e.g. eating disorders, dyslipidemia, hypertriglyceridemia, hypertension or metabolic syndrome), treatment or prevention of type 1 diabetes, the deliverance of the patient from the risk of development of type 1 diabetes, treatment of the patient, which appear alarming symptoms of type 1 diabetes, or protection (for example, stimulating the growth and/or survival) beta cells of islets of Langerhans from toxicity caused by lipids or glucose.

Ophthalmic diseases

The present invention features a method of treating or preventing an ophthalmic disease in a patient, which includes the introduction of a specified patient compounds of the present invention (for example, compounds of any of the above formulas I-III).

The present invention features a method of treating or preventing an ophthalmic condition (such as dry eye) in pale is the which includes the introduction of a given patient, the compounds of formula IV,

or its pharmaceutically acceptable salt, where

X is selected from-C≡C-, -C(R7)=C(R7)-, -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)- and -(cyclohexyl)-;

R1selected from-ORa, -N(Ra)-SO2-Rcand-N(Ra)(Rb), where each of Raand Rbindependently selected from H, C1-C6of alkyl, aryl, aralkyl, heteroaryl and heteroalkyl, and Rcselected from C1-C6of alkyl, aryl, aralkyl, heteroaryl and heteroalkyl;

R2selected from-CH2-, -C(O)-, -SO2-, -PO(OR)- and tetrazole;

R is chosen from a hydrogen atom and alkyl;

R3selected from carbocycle, heterocycle, -(CH2)n-, CH2C(O)CH2and-CH2-O-CH2where

n denotes an integer from 1 to 3;

any hydrogen atom in R3optionally and independently replaced by a halogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl, heteroaryl, hydroxy or O-(C1-C5)-alkyl; and

any two hydrogen atoms attached to a common carbon atom in R3not necessarily combined with the carbon atom to which they are attached, to form carbocycle or heterocycle;

each of R4aand R4bindependently selected from a hydrogen atom, halogen atom, -OH, -O-(C -C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl and-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro;

each of R5aand R5bindependently selected from a hydrogen atom, halogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl and heteroaryl, preferably, hydrogen atom, halogen atom and (C1-C5)-alkyl;

R6selected from phenyl, -(C1-C5)-alkyl, -(C3-C7)-cycloalkyl, -C≡C-phenyl, -C≡C-(C3-C7)-cycloalkyl, -C≡C-(C1-C5)-alkyl and-O-phenyl, where phenyl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro; and

R6independently selected from-C≡CH, where

a) X represents-C(R7)=C(R7)- or -(cyclopropyl)-; or

b) each of R4aand R4bdenotes a hydrogen atom or halogen atom; or

c) each of R5aand R5bdenotes a halogen atom; or

d) R2denotes-CH2-;

each R7independently selected from a hydrogen atom and (C1-C5)-alkyl or present two groups of R7optional can be combined with the carbon atoms to which they are attached, with the formation of 5 - or 6-membered cycle;

each of R10aand R10bindependently selected from a hydrogen atom, (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5)-alkyl, aryl and heteroaryl, or R10aand R10bcombined with the carbon atom to which they are attached, to form carbocycle or heterocycle;

and each double bond independently is E - or Z-configuration.

In certain embodiments of the implementation of the present invention R1means-OM, where M denotes a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

In certain embodiments of the implementation of the present invention R2and R1together form.

In certain embodiments of the implementation of the present invention X is-C≡C-. In certain embodiments of the implementation of the present invention X is-C(R7)=C(R7)-, -(cyclopropyl)-, -(cyclobutyl-, (cyclopentyl)- or -(cyclohexyl)-. In certain embodiments of the implementation of the present invention X is-C(R7)=C(R7)-. In certain embodiments of the implementation of the present invention X is-C≡C-, -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)- or -(cyclohexyl)-. In certain embodiments of the implementation of the present invention X is -(cyclopropyl)-. In certain embodiments of the implementation of the present invention X is-C≡C - or-C(R7)=C(R7)-. In certain embodiments of the implementation of the present invention X is -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)- or -(cyclohexyl)-, with the olefin and the carbon atom carrying the R4aattached to adjacent atoms in the cyclic system(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)- or -(cyclohexyl)-.

In certain embodiments of the implementation of the present invention R4bdenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R4bdenotes a halogen atom, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from the atom Galaga is a, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4bdenotes a fluorine atom. In certain embodiments of the implementation of the present invention R4bdenotes a hydrogen atom, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4bselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl and-O-C(O)-N(Ra)(Rb). In certain embodiments of the implementation of the present invention R4bdenotes a hydrogen atom, halogen atom, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl or-O-C(O)--heteroaryl, where any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4bselected from a hydrogen atom, halogen atom, -OH or-O-(C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R4bdenotes-O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4bselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-het is of roarie and-O-C(O)-N(R a)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4bselected from a hydrogen atom or halogen atom.

In certain embodiments of the implementation of the present invention R4bis (R)-configuration. In certain embodiments of the implementation of the present invention R4bis (S)-configuration.

In certain embodiments of the implementation of the present invention R4adenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R4adenotes a halogen atom, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, the tsila, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4adenotes a fluorine atom. In certain embodiments of the implementation of the present invention R4adenotes a hydrogen atom, -OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4aselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl and-O-C(O)-N(Ra)(Rb). In certain embodiments of the implementation of the present invention R4adenotes a hydrogen atom, halogen atom, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl or-O-C(O)-O-heteroaryl, where any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently of wybrand the mi from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4aselected from a hydrogen atom, halogen atom, -OH or-O-(C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R4adenotes-O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl or-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4aselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl and-O-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, the independent is IMO selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro. In certain embodiments of the implementation of the present invention R4aselected from a hydrogen atom or halogen atom.

In certain embodiments of the implementation of the present invention R4ais (S)-configuration. In certain embodiments of the implementation of the present invention R4ais (R)-configuration.

In certain embodiments of the implementation of the present invention, where R4adenotes-OH, R5aselected from a hydrogen atom, or (C1-C5)-alkyl. In certain embodiments of the implementation of the present invention, where R4aselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl and-O-C(O)-N(Ra)(Rb), R5aselected from a hydrogen atom, or (C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R5adenotes a fluorine atom. In certain embodiments of the implementation of the present invention R5aselected from a hydrogen atom and (C1-C5)-alkyl.

In certain embodiments implemented the I of the present invention, where R4bdenotes-OH, R5bselected from a hydrogen atom, or (C1-C5)-alkyl. In certain embodiments of the implementation of the present invention, where R4bselected from-OH, -O-(C1-C5)-alkyl, -O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, -O-C(O)-aryl, -O-C(O)-heteroaryl, -O-C(O)-O-(C1-C5)-alkyl, -O-C(O)-O-aryl, -O-C(O)-O-heteroaryl and-O-C(O)-N(Ra)(Rb), R5bselected from a hydrogen atom, or (C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R5bdenotes a fluorine atom. In certain embodiments of the implementation of the present invention R5bselected from a hydrogen atom and (C1-C5)-alkyl.

In certain embodiments of the implementation of the present invention R2denotes-CH2-. In certain embodiments of the implementation of the present invention R2denotes-C(O)-.

In certain embodiments of the implementation of the present invention Raselected from N and C1-C6-alkyl. In certain embodiments of the implementation of the present invention Raselected from aryl, aralkyl, heteroaryl and heteroalkyl.

In certain embodiments of the implementation of the present invention Rbselected from N and C1-C6-alkyl. In certain embodiments of the implementation of the present invention Rbselected from aryl, Ara is Qila, heteroaryl and heteroalkyl.

In certain embodiments of the implementation of the present invention Rcrepresents C1-C6is alkyl, aryl or heteroaryl. In certain embodiments of the implementation of the present invention Rcselected from aryl, aralkyl, heteroaryl and heteroalkyl.

In certain embodiments of the implementation of the present invention, where R3selected from carbocycle, heterocycle, -(CH2)nand CH2C(O)CH2any hydrogen atom in R3optionally and independently replaced by a halogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl, heteroaryl, hydroxy or O-(C1-C5)-alkyl. In certain embodiments of the implementation of the present invention, where R3denotes-CH2-O-CH2any hydrogen atom in R3optionally and independently substituted by a halogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl, heteroaryl or O-(C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R3selected from -(CH2)n- and-CH2-O-CH2where n denotes an integer from 1 to 3, and up to two hydrogen atoms in R3optionally and independently replaced by (C1-C5)-alkyl. In certain embodiments of the implementation of the present invention R3selected from carbocycle, the heterocycle is CH 2C(O)CH2where n denotes an integer from 1 to 3; any hydrogen atom in R3optionally and independently replaced by a halogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl, heteroaryl, hydroxy or O-(C1-C5)-alkyl; or any two hydrogen atoms attached to a common carbon atom in R3not necessarily combined with the carbon atom to which they are attached, to form carbocycle or heterocycle.

In certain embodiments of the implementation of the present invention R10adenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R10aselected from (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5)-alkyl, aryl and heteroaryl or R10aand R10bcombined with the carbon atom to which they are attached, to form carbocycle or heterocycle.

In certain embodiments of the implementation of the present invention R10bdenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R10bselected from (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5)-alkyl, aryl and heteroaryl or R10band R10acombined with the carbon atom to which they are attached, to form carbocycle or heterocycle.

In certain embodiments of the implementation of this breath is retene R 1means-ORa. In certain embodiments of the implementation of the present invention R1selected from-N(Ra)-SO2-Rcand-N(Ra)(Rb). In certain embodiments of the implementation of the present invention R1represents-N(Ra)-SO2-Rc. In certain embodiments of the implementation of the present invention R1selected from-ORaand-N(Ra)(Rb). In certain embodiments of the implementation of the present invention R1represents-N(Ra)(Rb). In certain embodiments of the implementation of the present invention R1selected from-ORaand-N(Ra)-SO2-Rc.

In certain embodiments of the implementation of the present invention R7denotes a hydrogen atom. In certain embodiments of the implementation of the present invention R7means (C1-C5)-alkyl or present two groups of R7optional can be combined with the carbon atoms to which they are attached, with the formation of 5 - or 6-membered cycle.

In certain embodiments of the implementation of the present invention X is-C≡C-, and R4bdenotes a hydrogen atom.

In certain embodiments of the implementation of the present invention X is-C≡C-, and R4adenotes a hydrogen atom.

In certain embodiments implementing the present invention will Chobotnice-C≡C-, R4adenotes a fluorine atom, and R5adenotes a fluorine atom.

In certain embodiments of the implementation of the present invention X is-C≡C-, R4bdenotes a fluorine atom, and R5bdenotes a fluorine atom.

In certain embodiments of the implementation of the present invention X is-C≡C-, and each of R4aand R4bindependently selected from-OH, -O-(C1-C5)-alkyl, O-aryl, O-heteroaryl, -O-C(O)-(C1-C5)-alkyl, O-C(O)-aryl, O-C(O)-heteroaryl and-O-C(O)-N(Ra)(Rb).

In certain embodiments of the implementation of the present invention X is-C≡C-, and R2denotes-CH2-.

In certain embodiments of the implementation of the present invention X is -(cyclopropyl)-, -(cyclobutyl)-, -(cyclopentyl)- and -(cyclohexyl)-. In certain embodiments of the implementation of the present invention X is -(cyclopropyl)-.

In certain embodiments of the implementation of the present invention X is-C(R7)=C(R7)-.

In certain embodiments of the implementation of the present invention, each of Raand Rbindependently selected from H and C1-C6-alkyl; Rcrepresents C1-C6-alkyl; R3selected from -(CH2)n- and-CH2-O-CH2where n denotes an integer from 1 to 3, and up to two hydrogen atoms in R3optionally and independently h is changed (C 1-C5)-alkyl; each of R4aand R4bindependently selected from a hydrogen atom, halogen atom, -OH, -O-(C1-C5)-alkyl; and each of R10aand R10bdenotes a hydrogen atom.

In certain embodiments of the implementation of the present invention, each of the double bond has the E-configuration. In certain embodiments of the implementation of the present invention, each of the double bond has the Z-configuration. In certain embodiments of the implementation of the present invention one double bond has the E-configuration and the other of the double bond has the Z-configuration.

In certain embodiments implementing the present invention assumes any combination of the above options. Professionals should be understood that all specific combinations of possible individual residues in variable parts described in this description of the compounds, in particular, R1, R2, R3, R4a, R4b, R5a, R5b, R6, R7, R10a, R10b, Ra, Rb, Rcn and X, are included in the scope of the present invention. For example, various specific examples in this description options embodiments for R4acan be combined with any described in this description of the various specific choices X.

In certain embodiments of the implementation of this izobreteny the compound is selected from any of the following connections:

In the present invention it is also proposed a method for the treatment or prevention of ophthalmic diseases such as dry eye) in a patient, which includes the introduction of a given patient, the compounds of formula V,

or the compounds of formula VI,

,

or pharmaceutically acceptable salt of any of these compounds, where

R1selected from-ORa, -N(Ra)-SO2-Rcand-N(Ra)(Rb), where each of Raand Rbindependently selected from H, C1-C6of alkyl, aryl, aralkyl, heteroaryl and heteroalkyl, and Rcselected from C1-C6of alkyl, aryl, aralkyl, heteroaryl and heteroalkyl;

R2selected from-C(O)-, -SO2-, -PO(OR)- and tetrazole;

R is chosen from a hydrogen atom and alkyl;

R3selected from -(CH2)n- and-CH2-O-CH2where n denotes an integer from 1 to 3; and optionally up to two hydrogen atoms in R3independently replaced by a halogen atom, (C1-C5)-alkyl or O-(C1-C5-alkyl; and

each of R5aand R5bindependently selected from a hydrogen atom, (C1-C5)-alkyl, perfluoroalkyl, aryl and heteroaryl, preferably, a hydrogen atom and (C1-C5)-alkyl;

R6selected from-C≡CH, -phenyl, -(C1-C5)-alkyl, -(C3-C7)-cycloalkyl, -C≡C-phenyl, -C≡C-(C3-C7)-cycloalkyl, -C≡C-(C1-C5)-alkyl and-O-phenyl, where phenyl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro;

each of R8and R9independently selected from hydrogen atom, -(C1-C5)-alkyl, -aryl, -heteroaryl, -C(O)-(C1-C5)-alkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-O-(C1-C5)-alkyl, -C(O)-O-aryl, -C(O)-O-heteroaryl and-C(O)-N(Ra)(Rbwhere any alkyl, aryl or heteroaryl optionally substituted by up to 3 substituents, independently selected from a halogen atom, (C1-C5)-alkyl, O-(C1-C5)-alkyl, hydroxyl, carboxyl, complex ether, alkoxycarbonyl, acyl, complex tiefer, thioacyl, simple tiefer, amino, amido, acylamino, cyano and nitro;

each of R10aand R10bn is dependent selected from a hydrogen atom, (C1-C5)-alkyl, perfluoroalkyl, O-(C1-C5)-alkyl, aryl and heteroaryl, or R10aand R10bcombined with the carbon atom to which they are attached, to form carbocycle or heterocycle; and

where each double bond independently is E - or Z-configuration.

In certain embodiments of the implementation of the present invention R1means-OM, where M denotes a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

In certain embodiments of the implementation of the present invention R2and R1together form

In certain embodiments of the implementation of the present invention R2denotes-C(O)-. In certain embodiments of the implementation of the present invention R1means-ORawhere Radenotes a hydrogen atom or a C1-C6-alkyl. In certain embodiments of the implementation of the present invention R3represents -(CH2)n-, where n is equal to 3. In certain embodiments of the implementation of the present invention R6denotes-C≡CH. In certain embodiments of the implementation of the present invention R5adenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R5bdenotes a hydrogen atom. In certain embodiments of the implementation of this the image is placed R 10adenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R10bdenotes a hydrogen atom. In certain embodiments of the implementation of the present invention R2denotes-C(O)-, R1means-ORawhere Rarepresents C1-C6-alkyl, R3represents -(CH2)n- where n is 3, R6denotes-C≡CH, R5adenotes a hydrogen atom, R5bdenotes a hydrogen atom, R10adenotes a hydrogen atom and R10bdenotes a hydrogen atom.

In certain embodiments of the implementation of the present invention the compound is selected from any of the following connections:

The present invention also offers a method of treating or preventing an ophthalmic condition (such as dry eye) in a patient, which includes the introduction of a given patient, the compounds of formula VII

or its pharmaceutically acceptable salt, where

Re and Rf are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group;

E denotes hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino or arylamino;

Rh and Ri are independently selected from an atom of water is kind, of alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl;

R5selected from the following i-iv: i) CH2CH(R6)CH2where R6denotes a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl, heteroaryl, a fluorine atom, hydroxyl or alkoxy; (ii) CH2C(R6R7)CH2where each of R6and R7independently denotes an alkyl, alkenyl, quinil, perfluoroalkyl, aryl or fluorine atom, or R6and R7combined to form carbocycle or heterocycle; (iii) CH2OCH2CH2C(O)CH2or CH2CH2; or (iv) R5denotes carbocycle, heterocycle, aryl or heteroaryl cycle; and

R8and R9independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R8and R9combined with the formation of carbocycle or heterocycle.

In certain embodiments of the implementation of the present invention the compound of formula VII is represented by formula VIII

and its pharmaceutically acceptable salts, where

the values of Re, Rf, R5 and E above.

In certain embodiments of the implementation of the present invention the compound of formula VII or VIII is represented by formula IX

and its pharmaceutically acceptable salts, where

the values of Re, Rf and above.

Additional compounds suitable for use in the method and compositions of the present invention include compounds of formula A,

where

each of W' and Y' represents a simple bond or a bridging group selected from a loop containing in the chain of up to 20 atoms, provided that W' and Y' can independently include one or more nitrogen atoms, oxygen, sulfur, or phosphorus, and provided that W' and Y' are independently contain one or more substituents independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, aaltio, atillio, alkylsulfonate, arylsulfonate, phosphoryla or sulfonyl, and provided that W' and Y' are independently contain one or more condensed carbocycles, heterocycles, aryl or heteroaryl cycles, and provided that when a variable is o' 0 and V1means

,

then Y' is attached to V1through a carbon atom;

V1selected from the

where q' is 0, and V3represents a simple bond, then n' is 0 or 1;

V2select the n of simple communication, group

,

where

L' is selected from-C(R1003)(R1004)-, where each R1003and R1004independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R1003and R1004combined to form carbocycle and heterocycle; when V3means

,

then L' is additionally selected from W'; and n' is 0 or 1;

V3selected from a simple link or group

,

where

each of R1001and R1002independently in each instance selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, alkylaryl, alkoxy or halogen atom, where the specified alkyl - or arylesterase fragment is optionally substituted up to 3 independently selected substituents;

each of Ra'and Rb'independently in each instance selected from-OR' or-N(R')2or adjacent Ra'and Rb'combined to form the epoxide cycle, having a CIS - or TRANS-configuration, where each R' is independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl, silyl group, alkoxyaryl, aminoacyl, aminocarbonyl, alkoxycarbonyl or a protective group;

or when V1means

and V2hereafter the includes

,

R1002and Rb'both represent a hydrogen atom;

X' is selected from-CN, -C(NH)N(R') (R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O) SR", -C(O)-NH-S(O)2-R", -S(O)2-A', -S(O)2-R", S(O)2N(R")(R"), -P(O)2-A', -PO(OR")-A', -tetrazole, alliterate or-CH2OH, where

A' is selected from-OR',- N(R")(R") or-OM';

each R" is independently selected from a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic or molecules detectable label, where alkyl-, aryl - or heteroarylboronic fragment is optionally substituted up to 3 independently selected substituents; and

M' represents a cation;

G' is selected from hydrogen atom, halogen atom, hydroxy, alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido or molecules detectable label, where alkyl-, aryl - or heteroarylboronic fragment is optionally substituted up to 3 independently selected substituents;

o' is 0, 1, 2, 3, 4 or 5;

p' is 0, 1, 2, 3, 4 or 5;

q' is 0, 1 or 2 ; and

o' + p' + q' is 1, 2, 3, 4, 5 or 6;

where

if V2represents a simple bond, then q' is 0, and V3represents a simple bond;

if V3refers to a group,then o' is 0, V1refers to a group,p' RA is but 1, and V2refers to a group;

any acyclic double bond may have the CIS or TRANS configuration, or optionally replaced by a triple bond; and

either one of the land plotscompounds, if present, is optionally replaced by a group ofeither one of the land plotscompounds, if present, is optionally replaced by a group of,where Q' denotes one or more substituents, and each Q' is independently selected from a halogen atom, alkyl, alkenyl, quinil, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, alkylcarboxylic, arylcarbamoyl, alkoxycarbonyl, aryloxyalkyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyl, aryloxypropanolamine or aminocarbonyl.

In certain embodiments of the implementation of the present invention V1selected from the group

In certain embodiments of the implementation of the present invention V2selected from a simple communication groupsor.

In certain embodiments of the implementation of the present invention, when q' is 0, and V3denotes a bond, then n' is 0 or 1; otherwise, n' is 1.

In the definitely variants of implementation of the present invention p' is 0, 1, 2, 3, or 5.

In certain embodiments of the implementation of the present invention q' is 0 or 1.

In certain embodiments of the implementation of the present invention, if V1doesthen o' is 0 or 1, p' is 1 or 2, o'+p' is 1 or 2; V2doesand V3means a connection.

In certain embodiments of the implementation of the present invention, if V1doesthen o' is 3, 4 or 5, p' is 0, 1 or 2, o'+p' is equal to 4 or 5, V2means a connection.

In certain embodiments of the implementation of the present invention, if V2means a connection, then o' is 0, 3, 4 or 5, p' is 0, 1, 2 or 5, o'+p' is equal to 4 or 5, q' is 0, and V3means a connection.

In certain embodiments of the implementation of the present invention W' and Y' are independently selected from a simple communication or lower alkyl or heteroalkyl, optionally substituted by one or more substituents independently selected from alkenyl, quinil, aryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, amino, or oxo.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 1,

where

the carbon atoms a' and b' are connected by a double or triple bond;

the carbon atoms c' and d' are connected by a double or triple bond;

Re, Rf and Rg is independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group;

Rh, Ri and Rj are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl;

I selected from-C(O)-E, -SO2-E, -PO(OR)-E, where E denotes a hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or arylamino; and R denotes a halogen atom or alkyl;

J, L and H represent a bridging group independently selected from a loop containing up to 20 atoms, or a chain consisting of up to 20 atoms, provided that J, L and H can independently include one or more nitrogen atoms, oxygen, sulfur, or phosphorus, and provided that J, L and H may be independently contain one or more substituents independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, aaltio, atillio, alkylsulfonate, arylsulfonate, fostoria and sulfonyl, and provided that J, L and H may be independently contain one or more of condens the level of carbocycles, heterocycles, aryl or heteroaryl cycles, and provided that the bridging group J is attached to the adjacent group C(R)OR via a carbon atom;

G is selected from hydrogen atom, alkyl, perfluoroalkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino or carboxamido;

or their pharmaceutically acceptable salts.

In certain embodiments of the implementation of the present invention pharmaceutically acceptable salt of the compound formed by functionalization of E, where E represents-OM, where M denotes a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

In certain embodiments of the implementation of the present invention the compound of formula 1 is represented by formula 2

where

the values of E, Re, Rf and Rg are listed above.

In certain embodiments of the implementation of the present invention pharmaceutically acceptable salt of the compound formed by functionalization of E, where E represents-OM, where M denotes a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

Specific examples of compounds of formula 2 include compound 2a:

In certain embodiments of the implementation of the present invention, the connection f is rmula 1 represented by formula 3

where

the values of E, Re, Rf and Rg are listed above.

In certain embodiments of the implementation of the present invention pharmaceutically acceptable salt of the compound formed by functionalization of E, where E represents-OM, where M denotes a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

Specific examples of compounds of formula 3 include the connection 3a,

and the connection 3b

Other examples of compounds of formula 1 include connection X,

and its pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 4,

where

A stands for H or-OP4;

P1P2and P4each individually denotes a protective group or a hydrogen atom;

R1and R2each individually represents a substituted or unsubstituted, branched or unbranched alkyl, alkenylphenol or alkenylphenol group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alcylaryl group, a halogen atom, a hydrogen atom;

Z represents-C(O)ORdcRc, -C(O)H, -C(NH)NRcRc, -C(S)H, -C(S)ORd, -C(S)NRcRc, -CN, preferably, carboxylic acid, ester, amide, complex tiefer, thiocarboxamide or nitrile;

each Raif present, independently selected from a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) quinil, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkenyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6-membered heteroalkyl, 3-8-membered heterocyclyl, morpholinyl, piperazinil, homopiperazine, piperidinyl, 4-11-membered geterotsiklicheskikh, 5-10-membered heteroaryl and 6-16-membered heteroaromatic.

each Rbif present, independently selected from =O, -ORd, (C1-C3) halogenations, -OCF3, =S, -SRd, =NRd, =NORd, -NRcRc, halogen atom, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)Rd, -S(O)2Rd, -S(O)2ORd, -S(O)NRcRc, -S(O)2NRcRc, -OS(O)Rd, -OS(O)2Rd, -OS(O)2ORd, -OS(O)2NRcRc, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -C(NRa)NRcRc, -C(NOH)Ra, -C(NOH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcR c, -OC(NH)NRcRc, -OC(NRa)NRcRc, -[NHC(O)]nRd, -[NRaC(O)]nRd, -[NHC(O)]nORd, -[NRaC(O)]nORd, [NHC(O)]nNRcRc, -[NRaC(O)]nNRcRc, -[NHC(NH)]nNRcRcand -[NRaC(NRa)]nNRcRc;

each Rcif present, independently selected protecting group or Raor, alternatively, two groups of Rctogether with the nitrogen atom to which they are attached, form a 5-8-membered heterocyclyl or heteroaryl, which optionally includes one or more additional heteroatoms and optionally substituted by one or more identical or different groups Raor suitable groups Rb;

each n represents an integer from 0 to 3;

each Rdindependently denotes a protective group, or Ra;

and their pharmaceutically acceptable salts.

Specific examples of compounds of formula 4 include connection 4a,

,compound 4b

and their pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 5,

or the pharmaceutically acceptable salt, where

the relationship between the carbon atom ii' and the carbon atom jj' is CIS - or TRANS stereochemical configuration;

P3denotes a protective group or a hydrogen atom; and

values of P1P2, R1and Z are defined above in formula 4.

In certain embodiments of the implementation of the present invention, the bond between carbon atom ii' and the carbon atom jj' is TRANS-stereochemical configuration.

Specific examples of compounds of formula 5 include connection 5a,

,compound 5b

and their pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 6,

or their pharmaceutically acceptable salts, where

the relationship between the carbon atom gg' and the carbon atom hh' is CIS - or TRANS stereochemical configuration;

each X represents a hydrogen atom or together both groups X represent a substituted or unsubstituted methylene or an oxygen atom, a substituted or an unsubstituted N atom, or a sulfur atom, so that a three-membered cycle; and

values of P1P2P3, R1and Z described above.

In certain embodiments of the implementation of the present invention, the IU connection is remote carbon atom gg' and the carbon atom hh' is TRANS-stereochemical configuration.

Specific examples of compounds of formula 6 include the connection 6a,

,compound 6b

and their pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 7,

or their pharmaceutically acceptable salts, where

carbon atoms, e' and f' are connected by a double bond or triple bond, and when the carbon atom e' attached to the carbon atom f' by a double bond, it may be CIS - or TRANS-configuration;

carbon atoms g' and h' are connected by a double bond or triple bond, and when the carbon atom g' is attached to the carbon atom h' by a double bond, it may be CIS - or TRANS-configuration;

m is 0 or 1;

T' denotes a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) quinil, (C5-C14) aryl, (C6-C16) arylalkyl, 5-14-membered heteroaryl, 6-16-membered heteroaromatic or-CH=CHCH2CH3;

T represents -(CH2)q- or -(CH2)q-O-, whereqdenotes an integer from 0 to 6;

Z' denotes a (C1-C6) alkylene, optionally substituted with 1, 2, 3, 4, 5 or 6 identical or different the volumes of halogen, -(CH2)P-O-CH2- or -(CH2)m-S-CH2- wherepdenotes an integer from 0 to 4;

R11, R12and R13each individually represents a substituted or unsubstituted, branched or unbranched alkyl, alkenylphenol or alkenylphenol group, substituted or unsubstituted aryl group, substituted or unsubstituted, branched or unbranched alcylaryl group, C1-4alkoxy, a halogen atom, a group-CH2R14, -CHR14R14, -CR14R14R14or a hydrogen atom;

R14independently in each instance selected from-CN, -NO2or halogen atom;

values of P1P2P3and Z is defined above.

In certain embodiments of the implementation of the present invention the carbon atoms e' and f' are connected by a double bond, having the CIS-configuration.

In certain embodiments of the implementation of the present invention the carbon atoms g' and h' are connected by a double bond.

In certain embodiments of the implementation of the present invention the carbon atoms e' and f' are connected by a double bond, having the CIS-configuration and the carbon atoms g' and h' are connected by a double bond.

Specific examples of compounds of formula 7 include connection 7a,

,compound 7b

and their pharmaceutically who ielemia salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 8,

or their pharmaceutically acceptable salts, where

the relationship between the carbon atom i' and the carbon atom j' has a CIS - or TRANS stereochemical configuration;

m is 0 or 1;

D' denotes CH3, -CH=CHCH2U or-CH=CHCH2CH2A;

U denotes a substituted or unsubstituted, branched or unbranched alkyl, alkenylphenol, alkenylphenol, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarboxylic, arylcarbamoyl, alkoxycarbonyl, aryloxyalkyl, alkoxycarbonyl and aryloxypropanolamine;

A stands for H or-OP4;

values of P1P2P4, R1, R2and Z is defined above.

In certain embodiments of the implementation of the present invention, the bond between carbon atom i' and the carbon atom j' has a CIS-stereochemical configuration.

Specific examples of compounds of formula 8 include connection 8a,

,compound 8b,

,compound 8c,

and their pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in STRs is obah and compositions of the present invention, include the compounds of formula 9,

or their pharmaceutically acceptable salts, where

carbon atoms k' and l' are connected by a double bond or triple bond, and when the carbon atom k' attached to the carbon atom of l' by a double bond, it may be CIS - or TRANS-configuration;

the relationship between the carbon atom m' and the carbon atom n' has a CIS - or TRANS-configuration;

m is 0 or 1;

D represents-CH3or-CH=CHCH2CH3;

values of P1P2P3, R1X and Z are defined above.

In certain embodiments implementing the present invention of the double bond between the carbon atom m' and the carbon atom n' has the CIS-configuration.

In certain embodiments of the implementation of the present invention the carbon atoms k' and l' are connected by a double bond, having the CIS-configuration.

In certain embodiments implementing the present invention of the double bond between the carbon atom m' and the carbon atom n' has the CIS-configuration and the carbon atoms k' and l' are connected by a double bond, having the CIS-configuration.

Specific examples of compounds of formula 9 include connection 9a,

,compound 9b,

and their pharmaceutically acceptable salts and esters.

Additional compounds suitable DL is used in the methods and compositions of the present invention, include the compounds of formula 10,

or their pharmaceutically acceptable salts, where

values of P1P2P3, R1and Z are defined above; and

Q represents one or more substituents, and each Q individually, if present, denotes a halogen atom or a branched or unbranched, substituted or unsubstituted alkyl, alkenylphenol, alkenylphenol, cycloalkyl, aryl, alkoxy, aryloxy, alkylcarboxylic, arylcarbamoyl, alkoxycarbonyl, aryloxyalkyl, amino, hydroxy, cyano, carboxyl, alkoxycarbonyl, aryloxypropanolamine or aminocarbonyl group.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 11,

or their pharmaceutically acceptable salts, where

values of P1P2P3, R1and Z is defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 12,

or their pharmaceutically acceptable salts, where

values of P1P2P3, Q, R1and Z is defined above.

Additional compounds suitable for use in the family and compositions of the present invention, include the compounds of formula 13,

or their pharmaceutically acceptable salts, where

values of P1P2, R1, R2, U and Z are defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 14,

or their pharmaceutically acceptable salts, where

values of P1P2, R1, R2, Q and Z are defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 15,

or their pharmaceutically acceptable salts, where

values of P1P2and Z is defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 16,

or their pharmaceutically acceptable salts, where

values of P1and Z is defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 17,

or their pharmaceutically acceptable salts, where

carbon atoms o' and p' are connected with single or double tie the Yu (for example, double bonds with CIS - or TRANS-configuration);

carbon atoms, q' and r' are connected by a simple or a double bond (for example, double bonds with CIS - or TRANS-configuration); and

values of P1P1and Z is defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 18,

or their pharmaceutically acceptable salts, where

the double bond between the carbon atom s' and t' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom of u' and v' is CIS - or TRANS stereochemical configuration; and

values of P1P1, R1, R2and Z is defined above.

Additional compounds suitable for use in the methods and compositions of the present invention. include the compounds of formula 19,

or their pharmaceutically acceptable salts, where

carbon atoms w' and x' are connected by a simple or a double bond;

carbon atoms, y' and z' are connected by a simple or a double bond; and

values of P1P1and Z is defined above.

In certain embodiments of the embodiments of formulas 4-19 each Rbif present, denotes a suitable group independently selected from =O, -ORd, (C1-C3)halog is alkyloxy, -OCF3, =S, -SRd, =NRd, =NORd, -NRcRc, halogen atom, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, - S(O)Rd, -S(O)2Rd, -S(O)2ORd, -S(O)NRcRc, -S(O)2NRcRc, -OS(O)Rd, -OS(O)2Rd, -OS(O)2ORd, -OS(O)2NRcRc, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -C(NRa)NRcRc, -C(NOH)Ra, -C(NOH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc, -OC(NH)NRcRc, -OC(NRa)NRcRc, -[NHC(O)]nRd, -[NRaC(O)]nRd, -[NHC(O)]nORd, [NHC(O)]nNRcRc, -[NRaC(O)]nNRcRc, -[NHC(NH)]nNRcRcand -[NRaC(NRa)]nNRcRc.

Additional compounds suitable for use in the methods and compositions of the present invention, include compounds

formula 20

formula 21

formula 22

formula 23

formula 24

formula 25

formula 26

formula 27or

formula 28

or pharmaceutically reception is going salts of these compounds, where

each P is individually selected from H or a protective group; and

R denotes H, C1-6alkyl (in particular methyl, ethyl, glycerol), C2-6alkenyl or C2-6quinil.

Specific examples of compounds of formula 21 include connection 21a,

and its pharmaceutically acceptable salts and esters.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 29,

and their pharmaceutically acceptable salt, hydrate and solvate, where

D1-E1and F1-G1independently denoteCISorTRANS- -C=C - or-C≡C-;

R101, R102and R103independently selected from a hydrogen atom, (C1-C4) alkyl straight or branched chain, (C2-C4) alkenyl, (C2-C4) quinil, (C1-C4) alkoxy, -CH2R104, -CHR104R104and-CR104R104R104;

each R104independently selected from CN, -NO2and halogen atom;

W1selected from R105, -OR105, -SR105and-NR105R105;

each R105independently selected from a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil, optionally substituted by one or more of Odin is new or different groups R, (C5-C14) aryl, optionally substituted by one or more identical or different groups R, phenyl, optionally substituted by one or more identical or different R groups, (C6-C16) arylalkyl, optionally substituted by one or more identical or different groups R, 5-14-membered heteroaryl, optionally substituted by one or more identical or different groups R, 6-16-membered heteroaromatic, optionally substituted by one or more identical or different groups R, and a molecule containing a label that can be detected;

A1selected from (C1-C6) alkylene, optionally substituted 1, 2, 3, 4, 5 or 6 identical or different halogen atoms, -(CH2)m-O-CH2- and -(CH2)m-S-CH2- wheremdenotes an integer from 0 to 4;

X1selected from -(CH2)n- and -(CH2)n-O-, wherendenotes an integer from 0 to 6;

Y1selected from a hydrogen atom, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil, optionally substituted by one or more identical or different groups R100, (C5-C14) aryl, optionally substituted by one or more identical or different groups R100the dryer is La, optionally substituted by one or more identical or different groups R100, (C6-C16) arylalkyl, optionally substituted by one or more identical or different groups R100, 5-14-membered heteroaryl, optionally substituted by one or more identical or different groups R100, 6-16-membered heteroaromatic, optionally substituted by one or more identical or different groups R100and from a molecule that contains a label that can be detected;

each R100independently selected from the electronegative group, =O, -ORa1, (C1-C3) halogenations, =S, -SRa1, =NRa1, =NONRa1, -NRc1Rc1, halogen atom, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)Ra1, -S(O)2Ra1, -S(O)2ORa1, -S(O)2NRc1Rc1, -OS(O)Ra1, -OS(O)2Ra1, -OS(O)2ORa1, -OS(O)2NRc1Rc1, -C(O)Ra1, -C(O)ORa1, -C(O)NRc1Rc1, -C(NH)NRc1Rc1, -OC(O)Ra1, -OC(O)ORa1, -OC(O)NRc1Rc1, -OC(NH)NRc1Rc1, -NHC(O)Ra1, -NHC(O)ORa1, -NHC(O)NRc1Rc1and-NHC(NH)NRc1Rc1;

each Ra1independently selected from a hydrogen atom, (C1-C4) alkyl, (C2-C4) alkenyl or (C2-C4) Alki the sludge; and

each Rc1independently denotes an Ra1or, alternatively, Rc1Rc1together with the nitrogen atom to which they are attached, form a 5 - or 6-membered cycle.

In certain embodiments of formula 29, when X1-Y1denotes-CH2CH3at least one of R101, R102or R103different from the hydrogen atom.

In certain embodiments of the implementation of the present invention the compound of formula 29 is represented by formula 30,

and its pharmaceutically acceptable salt, hydrate and solvate, where

D1-E1and F1-G1independently denoteCISorTRANS- -C=C - or-C≡C-; and

values of R101, R102, R103, R104, W1, R105, A1X1, n, Y1, R100, Ra1and Rc1defined above.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 31-37,

and their pharmaceutically acceptable salt, hydrate and solvate, where

R106represents-OH, -OCH3, -OCH(CH3)2or-NHCH2CH3; and

R107refers to a group

Additional compounds suitable on what I use in the methods and compositions of the present invention, include the compounds of formula 38,

where

carbon atoms aa' and bb' are connected by a double or triple bond;

carbon atoms cc' and dd' are connected by a double or triple bond;

Re, Rf and Rg is independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, acyl (for example, alkoxyaryl, aminoacyl), aminocarbonyl, alkoxycarbonyl or silyl group;

E denotes hydroxyl, alkoxy, aryloxy, amino, alkylamino, dialkylamino or arylamino;

Rh, Ri and Rj are independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl or heteroaryl;

R4selected from a hydrogen atom, alkyl, perfluoroalkyl, alkenyl, quinil, aryl, heteroaryl, fluorine atom, hydroxyl, alkoxy, aryloxy;

R5selected from the following i-iv: i) CH2CH(R6)CH2where R6denotes a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, aryl, heteroaryl, a fluorine atom, hydroxyl or alkoxy; (ii) CH2C(R6R7)CH2where each of R6and R7independently denotes an alkyl, alkenyl, quinil, perfluoroalkyl, aryl or fluorine atom, or R6and R7combined to form carbocycle or heterocycle; (iii) CH2OCH2CH2C(O)CH2or CH2CH2; or (iv) R5denotes carbocycle, heterocycle, aryl or heteroalicyclic; and

R8and R9independently selected from a hydrogen atom, alkyl, alkenyl, quinil, perfluoroalkyl, alkoxy, aryl or heteroaryl, or R8and R9combined with the formation of carbocycle or heterocycle;

or their pharmaceutically acceptable salts.

In certain embodiments of the implementation of the present invention R8and R9represent a hydrogen atom.

In certain embodiments of the implementation of the present invention pharmaceutically acceptable salt of the compound formed by functionalization of E, where E represents-OM, where M is a cation selected from ammonium, tetraalkylammonium, ions Na, K, Mg and Zn.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 39-44,

and their pharmaceutically acceptable salts, where

the values of Re, Rf, E, Ri, R5, R8and R9defined above.

Specific examples of compounds of formula 39, 41 and 43 include

and its pharmaceutically acceptable salts and esters.

In certain embodiments of the implementation of the present invention pharmaceutically acceptable salt of the compound formed by functionalization of E, where E represents-OM, where M is a cation selected from ammonium, tetraalkylammonium, and the new Na, K, Mg and Zn. Examples of such compounds include compound Z,

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 46,

or their pharmaceutically acceptable salts, where

each signindependently represents a double or triple bond;

R1, R2and R3independently represent OR OX1, SR, SX2N(R)2, NHX3, NRC(O)R, NRC(O)N(R)2C(O)OR, C(O)N(R)2, SO2R, NRSO2R, C(O)R or SO2N(R)2;

each R is independently selected from a hydrogen atom or an optionally substituted group selected from C1-6aliphatic, a 3-8-membered saturated, partially saturated, or aryl cycle having 0-4 heteroatoms independently selected from nitrogen atom, oxygen atom or sulfur atom; or

two R when one nitrogen atom is combined with the indicated nitrogen atom and form a 5-8-membered heterocycle or heteroaryl cycle, including 1-3 heteroatoms independently selected from nitrogen atom, oxygen or sulfur;

each X1independently represents a suitable protective group for hydroxyl:

each X2independently represents a suitable protective group for a thiol:

each X3independently denotes K is included aminosidine group; and

R4represents NRC(O)R, NRC(O)N(R)2C(O)OR, C(O)N(R)2, SO2R, NRSO2R, C(O)R or SO2N(R)2.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 47:

or their pharmaceutically acceptable salt or prodrug,

where

the double bond between the carbon atom kk' and the carbon atom'll have the CIS or TRANS stereochemical configuration;

the double bond between the carbon atom mm' and the carbon atom nn' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom oo' and the carbon atom pp' is CIS - or TRANS stereochemical configuration;

Y' represents a simple bond or a bridging group selected from a loop containing up to 20 atoms, or a chain consisting of up to 20 atoms, provided that Y' can include one or more nitrogen atoms, oxygen atoms, sulfur atoms or phosphorus atoms, and provided that Y' can contain one or more substituents independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, arieti is, atillio, alkylsulfonate, arylsulfonate, phosphoryla or sulfonyl, and provided that Y' can contain one or more condensed carbocycles, heterocycles, aryl or heteroaryl cycles;

Z' is selected from-CN, -C(NH)N(R') (R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O) SR", -C(O)-NH-S(O)2-R", -S(O)2-A', -S(O)2-R", S(O)2N(R")(R"), -P(O)2-A', -PO(OR")-A', -tetrazole, alliterate or-CH2OH, where A' is selected from-OR',- N(R")(R") or-OM';

each R" is independently selected from a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic or molecules, which can be used to detect where any alkyl-, aryl-, or heteroarylboronic fragment is optionally substituted up to 3 independently selected substituents; and M' represents a cation.

In certain embodiments of the implementation of the present invention the compound of formula 47 is represented by the formula 48,

or its pharmaceutically acceptable salts or esters, where

the double bond between the carbon atom kk' and the carbon atom'll have the CIS or TRANS stereochemical configuration;

the double bond between the carbon atom mm' and the carbon atom nn' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom oo' and the carbon atom pp' is CIS - or TRANS stereochemical configuration;

In particular the x variants of implementation of the present invention the double bond between the carbon atom kk' and the carbon atom'll have TRANS-stereochemical configuration.

In certain embodiments implementing the present invention of the double bond between the carbon atom mm' and the carbon atom nn' is TRANS-stereochemical configuration.

In certain embodiments implementing the present invention of the double bond between the carbon atom oo' and the carbon atom pp' has a CIS-stereochemical configuration.

In certain embodiments implementing the present invention of the double bond between the carbon atom kk' and the carbon atom'll have TRANS stereochemical configuration, the double bond between the carbon atom mm' and the carbon atom nn' is the TRANS stereochemical configuration, and the double bond between the carbon atom oo' and the carbon atom pp' has a CIS-stereochemical configuration.

In certain embodiments of the implementation of the present invention the compound of formula 47 is represented by the connection 48a,

connection 48b,

compound 48c,

or their pharmaceutically acceptable salts or esters.

In certain embodiments of the implementation of the present invention the compound of formula 47 is represented by the formula 48d,

or its pharmaceutically acceptable salts or esters, where

the double bond between the carbon atom kk' and the volume of carbon'll have the CIS or TRANS stereochemical configuration;

the double bond between the carbon atom mm' and the carbon atom nn' is CIS - or TRANS stereochemical configuration;

the double bond between the carbon atom oo' and the carbon atom pp' is CIS - or TRANS stereochemical configuration.

Additional compounds suitable for use in the methods and compositions of the present invention include compounds of formula 49,

or their pharmaceutically acceptable salt or prodrug,

where

Y' represents a simple bond or a bridging group selected from a loop containing up to 20 atoms, or a chain consisting of up to 20 atoms, provided that Y' can include one or more nitrogen atoms, oxygen atoms, sulfur atoms or phosphorus atoms, and provided that Y' can contain one or more substituents independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, aaltio, atillio, alkylsulfonate, arylsulfonate, phosphoryla or sulfonyl, and provided that Y' can contain one or more condensed carbocycles, heterocycles, aryl or heteroaryl cycles;

Z' is selected from N, -C(NH)N(R') (R"), -C(S)-A', -C(S)R", -C(O)-A', -C(O)-R", -C(O) SR", -C(O)-NH-S(O)2-R", -S(O)2-A', -S(O)2-R", S(O)2N(R")(R"), -P(O)2-A', -PO(OR")-A', -tetrazole, alliterate or-CH2OH, where A' is selected from-OR',- N(R")(R") or-OM';

each R" is independently selected from a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroaromatic or molecules, which can be used to detect where any alkyl-, aryl-, or heteroarylboronic fragment is optionally substituted up to 3 independently selected substituents; and

M' represents a cation; and

each of Ra'and Rb'independently in each instance selected from-OR'; or adjacent Ra'and Rb'combined to form the epoxide cycle, having a CIS - or TRANS-configuration, where each R' is independently selected from a hydrogen atom, alkyl, alkenylphenol, Salcininkai, aryl, heteroaryl, acyl, silyl, alkoxyamino, aminoaniline, aminocarbonyl, alkoxycarbonyl or a protective group.

Specific examples of compounds of formula 49 include connection 49a,

,compound 49b,

or their pharmaceutically acceptable salts or esters.

It is known that the above compounds (in particular, the compounds of formula a or formulae 1-49) are suitable for treating or preventing inflammation or an inflammatory disease. Por the action of such compounds are disclosed in the following patents and patent applications: US 2003/0191184, WO 2004/014835, WO 2004/078143, US 6670396, US 2003/0236423, US 2005/0228047, US 2005/0238589 and US2005/0261255. These compounds are suitable for use in the methods and compositions of the present invention.

Additional compounds suitable for use in the methods and compositions of the present invention, are compounds that are chemically similar varieties of any of the compounds of formula A, or of formulae 1-49 or I-III, above. The term “chemically similar species include, but not limited to, replacement of various fragments of known biostrome; replacement of the limit group of one of the above compounds corresponding end any other group of the above compounds, changing the orientation of any double bond in the compound, replacement any double bond triple bond in any connection, and replacing one or more existing substituents in one of the above compounds appropriate Deputy of any other connection.

Derivative compounds lipoxin, suitable for use in the methods and compositions of the present invention include compounds of formula 50:

where

X denotes R301OR301or SR301;

R301means

(a) a hydrogen atom;

(b) alkyl containing from 1 to 8 atoms of plastics technology: turning & the Yes inclusive, which may be a straight or branched chain;

(c) cycloalkyl containing from 3 to 10 carbon atoms;

(d) aralkyl containing from 7 to 12 carbon atoms;

(e) phenyl;

(f) substituted phenyl,

where each of Zi, Zii, Ziii, ZiVand Zvindependently selected from-NO2, -CN, -C(=O)-R301, -SO3H, hydrogen atom, halogen atom, methyl, -ORxwhere Rxcontains from 1 to 8 carbon atoms inclusive, and can be straight or branched chain, and hydroxyl, where, when any of Zi, Zii, Ziii, ZiVor Zvdenotes C(=O)-R301this Zi, Zii, Ziii, ZiVor Zvnot replaced by another group C(=O)-R301;

(g) a molecule that contains detektiruya group; or

(h) alkenyl straight or branched chain, containing from 2 to 8 carbon atoms, inclusive;

Q1means (C=O), SO2or (CN), provided that when Q1denotes CN, then X is absent;

Q3and Q4each independently denotes O, S or NH;

one of R302and R303denotes the hydrogen atom and the other denotes

(a) H;

(b) alkyl containing from 1 to 8 carbon atoms, inclusive, which may be straight or branched chain;

(c) cycloalkyl containing from 3 to 6 carbon atoms inclusive is;

(d) alkenyl containing from 2 to 8 carbon atoms, inclusive, which may be straight or branched chain; or

(e) RkQ2R1where Q2denotes-O - or-S-; where Rkdenotes alkylene containing from 0 to 6 carbon atoms, inclusive, which may be straight or branched chain, and where R1denotes alkyl containing from 0 to 8 carbon atoms, inclusive, which may be straight or branched chain, with the proviso that when R1takes the value 0, R1denotes a hydrogen atom;

R304means

(a) H;

(b) alkyl containing from 1 to 6 carbon atoms, inclusive, which may be straight or branched chain;

R305refers to a groupwhere the values of Zi, Zii, Ziii, ZiVand Zvspecified above;

R306means

(a) H;

(b) alkyl containing from 1 to 4 carbon atoms, inclusive, which may be straight or branched chain;

where Y301denotes-OH, methyl, -SH, alkyl containing from 2 to 4 carbon atoms, inclusive, which may be straight or branched chain alkoxy, which contains from 1 to 4 carbon atoms, inclusive, or (CH)p(Z)qwhere p+q=3, p=0-3, q=0-3 and Z represents cyano, nitro or halogen atom; and

T denotes O or S, and their farm is citiesi acceptable salt.

Derivative compounds lipoxin suitable for use in the methods and compositions of the present invention include compounds of formula 51, 52, 53 or 54:

where

each R307independently selected from hydrogen and straight, branched, cyclic, saturated or unsaturated alkyl containing from 1 to 20 carbon atoms;

R308, R309, R310, R319and R320independently selected from

(a) a hydrogen atom;

(b) straight, branched, cyclic, saturated or unsaturated alkyl containing from 1 to 20 carbon atoms;

(c) substituted alkyl having from 1 to 20 carbon atoms, where the alkyl substituted by one or more substituents selected from halogen atom, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino, alkylthio, aaltio, carboxy, carboxamido, carbalkoxy, aryl and heteroaryl;

(d) substituted aryl or heteroaryl, where the aryl or heteroaryl substituted by one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen atom, aryl, heteroaryl, carboxyl, carboxamido; and

(e) Z-Y, where

Z is selected from hydrogen and unbranched, branched, cyclic, saturated or unsaturated alkyl containing the t 1 to 20 carbon atoms; substituted lower alkyl, where alkyl substituted by one or more substituents selected from halogen atom, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, arylamino, hydroxyamino, alkoxyamino, alkylthio, aaltio, carboxy, carboxamido, carbalkoxy, aryl and heteroaryl; and substituted aryl and heteroaryl, where aryl and heteroaryl substituted by one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen atom, aryl, heteroaryl, carboxyl, carboxamido; and

Y is selected from hydrogen; alkyl; cycloalkyl; carboxyl; carboxamido; aryl; heteroaryl; substituted aryl or heteroaryl, where the aryl or heteroaryl substituted by one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen atom, aryl, heteroaryl, carboxyl, carboxamido; and

groups from R311to R318independently selected from

(a) a hydrogen atom;

(b) halogen atom;

(c) an unbranched, branched, cyclic, saturated or unsaturated alkyl containing from 1 to 20 carbon atoms;

(d) substituted alkyl having from 1 to 20 carbon atoms, where the alkyl substituted by one or more substituents selected from halogen atom, hydroxy, lower alkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, arylamino, g is taxiline, alkoxyamino, alkylthio, aaltio, carboxy, carboxamido, carbalkoxy, aryl and heteroaryl;

(e) substituted aryl or heteroaryl, where the aryl or heteroaryl substituted by one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen atom, aryl, heteroaryl, carboxyl, carboxamido; or

groups from R308to R320independently represent a bond, which forms a double carbon-carbon bond, a triple carbon-carbon bond or a cycle with the skeleton lipoxin; or

any two groups from R307to R320combined with the atoms to which they are attached and optionally from 1 to 6 oxygen atoms, 1 to 6 nitrogen atoms, or both 1 to 6 oxygen atoms and 1 to 6 nitrogen atoms with the formation of a loop containing from 3 to 20 atoms.

Derivative compounds lipoxin, suitable for use in the methods and compositions of the present invention include compounds of formula 55:

where

R401selected from the

R402selected from the

X10denotes the R411OR411or SR411;

R411means

(a) a hydrogen atom;

(b) alkyl containing from 1 to 8 carbon atoms, inclusive, which may be straight or branched chain;

(c) cycloalkyl, containing the rd from 3 to 10 carbon atoms;

(d) aralkyl containing from 7 to 12 carbon atoms;

(e) phenyl;

(f) substituted phenyl,

where each of Zi, Zii, Ziii, ZiVand Zvindependently selected from-NO2, -CN, -C(=O)-R411, -SO3H, hydrogen atom, halogen atom, methyl, -ORxwhere Rxcontains from 1 to 8 carbon atoms inclusive, and can be straight or branched chain, and hydroxyl, where, when any of Zi, Zii, Ziii, ZiVor Zvdenotes C(=O)-R411this Zi, Zii, Ziii, ZiVor Zvnot replaced by another group C(=O)-R411;

(g) a molecule that contains detektiruya group; or

(h) alkenyl straight or branched chain, containing from 2 to 8 carbon atoms, inclusive;

Q1means (C=O), SO2or (CN);

Q3means O, S or NH;

one of R412and R413denotes the hydrogen atom and the other denotes

(a) H;

(b) alkyl containing from 1 to 8 carbon atoms, inclusive, which may be straight or branched chain;

(c) cycloalkyl containing from 3 to 6 carbon atoms, inclusive;

(d) alkenyl containing from 2 to 8 carbon atoms, inclusive, which may be straight or branched chain; or

(e) R431Q2R432where Q2denotes-O - or-S-; RG is R 431denotes alkylene containing from 0 to 6 carbon atoms, inclusive, which may be straight or branched chain, and where R431denotes alkyl containing from 0 to 8 carbon atoms, inclusive, which may be straight or branched chain;

each of R413aand R413bindependently denotes

(a) H;

(b) alkyl containing from 1 to 8 carbon atoms, inclusive, which may be straight or branched chain;

(c) cycloalkyl containing from 3 to 6 carbon atoms, inclusive;

(d) alkenyl containing from 2 to 8 carbon atoms, inclusive, which may be straight or branched chain; or

(e) R431Q2R432where the values of R431, Q2and R432defined above;

R414means

(a) H;

(b) alkyl containing from 1 to 6 carbon atoms, inclusive, which may be straight or branched chain;

R415means

(a) alkyl containing from 1 to 9 carbon atoms which may be straight or branched chain;

(b) -(CH2)-Ri,

where n=0-4, and Rimeans

(i) cycloalkyl containing from 3 to 10 carbon atoms, inclusive;

(ii) phenyl; or

(iii) substituted phenyl

where the values of ZiZvdefined above;

(b) R431Q2R432where the values of R4312and R432defined above;

(C)- (Riii)(Riv)-Ri,

where each of Riiiand Rivindependently denotes

(i) a hydrogen atom;

(ii) (CH)p(Z)qwhere the values of Z, p and q are defined above.

(e) halogenated alkyl having 1 to 8 carbon atoms, inclusive, and 1 to 6 halogen atoms, inclusive, which has a straight or branched chain;

R416means

(a) H;

(b) alkyl containing from 1 to 4 carbon atoms, inclusive, which may be straight or branched chain;

(c) a halogen atom;

one of Y401or Y402denotes-OH, methyl, or-SH, and the other is selected from

(a) H;

(b) (CH)p(Z)qwhere p+q=3, p=0-3, q=0-3, and each Z independently represents cyano, nitro or halogen atom;

(c) alkyl containing from 2 to 4 carbon atoms, inclusive, which may be straight or branched chain; or

(d) alkoxy containing from 1 to 4 carbon atoms, inclusive,

or Y401and Y402together form

(d) =NH; or

(e) =O;

one of Y403or Y4O4denotes-OH, methyl, or-SH, and the other is selected from

(a) H;

(b) (CH)p(Z)qwhere the values of Z, p and q are defined above;

(c) alkyl containing from 2 to 4 carbon atoms, inclusive, which may be straight or branched chain; or

(d) alkoxy containing from 1 to 4 atoms is of glared inclusive,

or Y401and Y402together form

(a) =NH; or

(b) =O;

one of Y405or Y4O6denotes-OH, methyl, or-SH, and the other is selected from

(a) H;

(b) (CH)p(Z)qwhere the values of Z, p and q are defined above;

(c) alkyl containing from 2 to 4 carbon atoms, inclusive, which may be straight or branched chain; or

(d) alkoxy containing from 1 to 4 carbon atoms, inclusive,

or Y401and Y402together form

(a) =NH; or

(b) =O;

R421means

(a) H; or

(b) alkyl containing from 1 to 8 carbon atoms;

each of R422and R423independently denotes

(a) H;

(b) hydroxyl, or thiol;

(c) methyl or halogenated methyl;

(d) a halogen atom; or

(e) alkoxy containing from 1 to 3 carbon atoms;

each of R424and R425independently denotes

(a) H;

(b) hydroxyl, or thiol;

(c) methyl or halogenated methyl;

(d) a halogen atom;

(e) alkoxy containing from 1 to 3 carbon atoms; or

(f) alkyl or halogenated alkyl having 2 to 4 carbon atoms, inclusive, which may be unbranched or branched; and

R426means

(a) substituted phenyl

where the values of ZiZvdefined above;

(b) substituted phenoxy,

where the values of ZiZvdefined above; or

(c),

where the values of ZiZvdefined above.

Derivatives lipoxin, suitable for use in the methods and compositions of the present invention include compounds of formula 56:

where

E denotes a hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or-OM, where M denotes a cation selected from ammonium, and tetraalkylammonium cations of sodium, potassium, magnesium and zinc;

W represents a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, halogen atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido or sulfonamide;

each of R501-R503independently selected from a hydrogen atom, alkyl, aryl, acyl or alkoxyaryl;

n is 0, 1 or 2;

m is 1 or 2; and

two of the substituent in the phenyl cycle take ortho-, meta - or para-position.

Derivatives lipoxin, suitable for use in the methods and compositions of the present invention include compounds of formula 57:

where

I selected from-C(O)-E, -SO2-E, -PO(OR)-E, where E denotes a hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or-OM, where M is a cation selected from ammonium, tetraalkyl one, ions Na, K, Mg and Zn; and R is hydroxyl or alkoxy;

J' and K' represent a bridging group independently selected from chain containing up to 20 atoms, and the loop containing up to 20 atoms, provided that J' and K' can independently include one or more nitrogen atoms, oxygen, sulfur, or phosphorus, provided that J' and K' can independently contain one or more substituents selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, cyano, oxo, thio, alkylthio, aaltio, atillio, alkylsulfonate, arylsulfonate, fostoria and sulfonyl and, in addition, provided that J' and K' can also contain one or more condensed carbocycles, heterocycles, aryl or heteroaryl cycles, and provided that the bridging group J' and K' are connected with the adjacent group C(R)OR via a carbon atom or bond C-heteroatom, where the heteroatom is an oxygen atom, a sulfur atom, a phosphorus atom or a nitrogen atom;

G is selected from hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, chlorine atom, iodine atom, bromine atom, fluorine atom, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carbox the Mido;

Re, Rf and Rg is independently selected from a hydrogen atom, alkyl, aryl, heteroaryl, acyl, silyl group, alkoxyaryl and aminoacyl;

R601, R602and R603independently selected from a hydrogen atom, alkyl, aryl and heteroaryl, provided that R601, R602and R603can be independently attached to the bridge groups J' or K';

R604and R605independently selected from a hydrogen atom, alkyl, alkenyl, quinil, aryl, heteroaryl, fluorine atom, provided that R604and R605can be combined with the formation of carbocycle, heterocycle or aromatic cycle, and provided that R604and R605can be replaced with a simple connection with the formation of a triple bond.

Other compounds suitable for use in the methods and compositions of the present invention, are oxylipin described in international publications WO 2006/055965, WO 2007/090162 and WO2008/103753, and disclosed them in connection included in this description by reference. Examples of such compounds are compounds of formula 58-132 presented in table 2. These compounds include long chain omega-6 fatty acids, docosapentaenoic acid (DPAn-6) (connection 58-73) and docosatetraenoic acid (DTAn-6) (connection 74-83), as well as omega-3 similar DPAn-6, docosapentaenoic acid (DPAn-3) (joint who 84-97). Other compounds are docosanoid 98-115, γ-linolenic acid (GLA) (connection 116-122) and stereonova acid (SDA) (connection 123-132).

Table 2
10,17-dihydroxy DPAn-6 (58)

16,17-dihydroxy DPAn-6 (59)
4,5-dihydroxy DPAn-6 (60)
7,17-dihydroxy DPAn-6 (61)
7-hydroxy DPAn-6 (62)
10-hydroxy DPAn-6 (63)
13-hydroxy DPAn-6 (64)
17-hydroxy DPAn-6 (65)
4,5,17-trihydroxy DPAn-6 (66)

7,16,17-trihydroxy DPAn-6 (67)
8-hydroxy DPAn-6 (68)
14-hydroxy DPAn-6 (69)
13,17-dihydroxy DPAn-6 (70)
7,14-dihydroxy DPAn-6 (71)
8,14-dihydroxy DPAn-6 (72)
11-hydroxy DPAn-6 (73)
10,17-dihydroxy DTAn-6 (74)

16,17-dihydroxy DTAn-6 (75)
4,5-dihydroxy DTAn-6 (76)
7,17-dihydroxy DTAn-6 (77)
7-hydroxy DTAn-6 (78)
10-hydroxy DTAn-6 (79)
13-hydroxy DTAn-6 (80)
17-hydroxy DTAn-6 (81)
4,5,17-trihydroxy DTAn-6 (82)

7,16,17-trihydroxy DTAn-6 (83)
10,17-dihydroxy DPAn-3 (84)
10,20-dihydroxy DPAn-3 (85)
13,20-dihydroxy DPAn-3 (86)
16,17-dihydroxy DPAn-3 (87)
7,17-dihydroxy DPAn-3 (88)
7-hydroxy DPAn-3 (89)
10-hydroxy DPAn-3 (90)

13-hydroxy DPAn-3 (91)17-hydroxy DPAn-3 (92)7,16,17-trihydroxy DPAn-3 (93)16-hydroxy DPAn-3 (94)11-hydroxy DPAn-3 (95)14-hydroxy DPAn-3 (96)8,14-dihydroxy DPAn-3 (97)10,11-epoxy DHA (98)

13,14-dihydroxy DHA (99)
13,14-epoxy DHA (100)
19,20-epoxy DHA (101)
7,8-epoxy DHA (102)
4,5-epoxy-17-OH-DPA (103)
7,16,17-trihydroxy DTAn-3 (104)
16,17-dihydroxy DTAn-3 (105)
10,16,17-trihydroxy DTRAn-6 (106)

16,17-dihydroxy DTRAn-6 (107)
7,16,17-trihydroxy DTRAn-6 (108)
15-EPI-lipoxin A4 (109)
16,17-epoxy DHA (110)
7,8-epoxy DPA (111)
10,11-epoxy DPA (112)
19,20-epoxy DPA (113)
7-hydroxy DHA (114)

13,14-epoxy DPA (115)
6-hydroxy GLA (116)
10-hydroxy GLA (117)
7-hydroxy GLA (118)
12-hydroxy GLA (119)
9-hydroxy GLA (120)
13-hydroxy GLA (121)
6,13-dihydroxy GLA (122)
6-hydroxy SDA (123)

10-hydroxy SDA (124)
7-hydroxy SDA (125)
12-hydroxy SDA (126)
9-is hydroxy SDA (127)
13-hydroxy SDA (128)
15-hydroxy SDA (129)
16-hydroxy SDA (130)
6,13-dihydroxy SDA (131)
6,16-dihydroxy SDA (132)

Other derivatives of the compounds of oxylipin, which is suitable for use in the methods and compositions of the present invention include analogs of compounds listed in table 2. Such compounds include, but not limited to, such analogues where one or more substituted double bonds triple bonds, such analogues where one or more carboxyl groups converted to esters, amides or salts such analogues, where having the hydroxyl carbon atoms optionally converted (for example, using a substituted or unsubstituted branched or unbranched alkyl, alkenylphenol or Salcininkai group, substituted or unsubstituted aryl group, substituted or unsubstituted razvetvlenno is or unbranched alcylaryl group, a halogen atom) with tertiary alcohols or ethers, esters or other derivatives thereof), such analogues where one or more hydroxyl groups converted to the production of esters or protected alcohols, or such analogs that include combinations of any of the above modifications.

Other derivatives of the compounds of oxylipins, which are suitable for use in the methods and compositions of the present invention include the following compounds: selected docosanoid docosapentaenoic acid (DPAn-6); monohydroxy, dihydroxy and trihydroxypropane DPAn-6; isolated docosanoid docosapentaenoic acid (DPAn-3); monohydroxy, dihydroxy and trihydroxypropane DPAn-3; selected docosanoid docosapentaenoic acid (DTAn-6); or monohydroxy, dihydroxy and trihydroxypropane DTAn-6.

In certain embodiments of the implementation of the present invention provides methods of treating or preventing ophthalmic diseases such as dry eye), which include the introduction of an effective amount of any or several of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin), for example, in aqueous solution given in the Scripture, such as a solution, which is injected locally into the eye, for example, in the form of eye drops. In certain such embodiments, the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of more than 6 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day, for example, up to 550 nanomoles each being treated eye per day, in particular from 6 to 400 nanomoles, from 6 to 300 nanomoles, from 6 to 250 nanomoles from 6 to 200 nanomoles, from 6 to 150 nanomoles or from 6 to 100 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day. In certain such embodiments, the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of more than 7 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each subjected to the treatment of the human eye at night, for example, more than 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or 50 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day, in particular, for example, up to 100, 150, 200, 250, 300, 400 or even up to 550 nanomoles each being treated eye per day. For example, methods of treating or preventing ophthalmic diseases include introduction 7 to 550 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day, in particular from 7 to 400 nanomoles, from 7 to 300 nanomoles, from 7 to 250 nanomoles, from 7 to 200 nanomoles from 7 to 150 nanomoles or from 7 to 100 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of from 10 to 550 nanomoles of any of the above compounds (e.g. the measures compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day, in particular from 10 to 400 nanomoles, from 10 to 300 nanomoles, from 10 to 250 nanomoles, from 10 to 200 nanomoles, from 10 to 150 nanomoles or from 10 to 100 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derivative lipoxin or derivative oxylipin) in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases include introduction from 15 to 550 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day, in particular from 15 to 400 nanomoles, from 15 to 300 nanomoles, from 15 to 250 nanomoles, from 15 to 200 nanomoles from 15 to 150 nanomoles or from 15 to 100 nanomoles of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derivative oxylipin) in each affected eye treatment per day. In certain embodiments is sushestvennee of the present invention methods of treating or preventing ophthalmic diseases can include the introduction of a dose of any of the above compounds (for example, compounds of the present invention, such as compounds of any of formulas I-IX, a compound of formula A, compounds of any of formulae 1-49, derivatives lipoxin or derivatives oxylipin), as described above, in the course of the day using any suitable dosing schedules. Suitable dosing regimens can include assigning dose of the drug once a day, the doses of the medicinal product twice a day, the doses of medicines three times a day, the purpose of the dose of the medication four times a day and include any other suitable dosing regime so that the overall effect of the introduction of the drug in the course of the day would be full dose assigned in each affected eye treatment per day, as described above. In certain embodiments of the implementation of the present invention suitable dosing regimens also include the appointment of a dose of the drug once or twice a day, for example, through the day, or the appointment of a dose of the drug once in three days, for example, in two days, so that the overall effect of the introduction of the drug in the course of the day would be at least a full dose assigned in each eye per day, as specified above.

As a concrete example of the present invention pre is arranged in the treatment or prevention of ophthalmic diseases such as dry eye), which include the use of effective amounts of compound 1001, for example, in aqueous solution, as described herein, such as a solution, which is injected locally into the eye, for example, in the form of eye drops. In certain such embodiments, the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of more than 2 micrograms of compound 1001 in each affected eye treatment per day, in particular, up to 175 micrograms in each affected eye treatment per day, for example, from 2 to 150 micrograms, from 2 to 125 micrograms, from 2 to 100 micrograms, from 2 to 75 micrograms, from 2 to 50 micrograms, or from 2 to 25 micrograms of compound 1001 in each affected eye treatment per day. In certain such embodiments, the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of more than 2.5 micrograms of compound 1001 in each affected eye treatment per day, for example, more than 3; 3,5; 4; 4,5; 5; 5,5; 6; 6,5; 7; 7,5; 8; 8,5; 9; 9,5; 10; 10,5; 11; 11,5; 12; 12,5; 13; 13,5; 14; 14,5; 15; 15,5; 16; 16,5; 17; 17,5; 18; 18,5; 19; 19,5 or 20 micrograms of compound 1001 in each affected eye treatment per day, for example, up to 25, 50, 75, 100, 125, 150 or even up to 175 micrograms of compound 1001 in each affected eye treatment per day. ODA is divided variants of implementation of the present invention methods of treating or preventing ophthalmic diseases include introduction from 2.5 to 175 micrograms of compound 1001 in each affected eye treatment in the day, in particular from 2.5 to 150 micrograms, from 2.5 to 125 micrograms, from 2.5 to 100 micrograms, from 2.5 to 75 micrograms, from 2.5 to 50 micrograms, or from 2.5 to 25 micrograms of compound 1001 in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases include the introduction of from 3 to 175 micrograms of compound 1001 in each affected eye treatment per day, in particular from 3 to 150 micrograms, from 3 to 125 micrograms, from 3 to 100 micrograms, from 3 to 75 micrograms, from 3 to 50 micrograms, or from 3 to 25 micrograms of compound 1001 in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases include introduction from 4 to 175 micrograms of compound 1001 in each affected eye treatment per day, in particular from 4 to 150 micrograms, from 4 to 125 micrograms, from 4 to 100 micrograms, from 4 to 75 micrograms, from 4 to 50 micrograms, or from 4 to 25 micrograms of compound 1001 in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases include introduction from 5 to 175 micrograms of compound 1001 in each under eremy treated eye per day, in particular, from 5 to 150 micrograms, from 5 to 125 micrograms, from 5 to 100 micrograms, from 5 to 75 micrograms, from 5 to 50 micrograms, or from 5 to 25 micrograms of compound 1001 in each affected eye treatment per day. In certain embodiments of the implementation of the present invention methods of treating or preventing ophthalmic diseases may include the introduction of doses of compound 1001, as described above, in the course of the day using any suitable dosing schedules. Suitable dosing regimens can include assigning dose of the drug once a day, the doses of the medicinal product twice a day, the doses of medicines three times a day, the purpose of the dose of the medication four times a day and include any other suitable dosing regime so that the overall effect of the introduction of compound 1001 during the day would be full dose assigned in each affected eye treatment per day, as described above. In certain embodiments of the implementation of the present invention suitable dosing regimens also include the introduction of a dose of the drug once or twice a day, for example, through the day, or the dose medications once three days, for example, in two days, so that the overall effect of the introduction soedineniya during the day would be at least a full dose, assigned in each affected eye treatment per day, as specified above.

In certain embodiments implementing the present invention features a pharmaceutical composition suitable for treating or preventing ophthalmic diseases such as dry eye patients-people, which includes any one or more of any of the above compounds (for example, a compound of any of formulas I-IX, a compound of formula A, compound of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) and one or more pharmaceutically acceptable inert fillers, for example, a composition in the form of an aqueous solution, suitable for local injection into the eye, such as eye drops. In certain embodiments of the implementation of the present invention, the concentration of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) in the pharmaceutical composition is greater than 90 μm, for example, ranges from 90 to 7000 μm, in particular between 90 to 5000 μm, from 90 to 3000 μm, from 90 to 2000 μm, or from 90 to 1000 μm of any of the above substances (for example, compounds of any of formulas I-IX, the compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or produced in the water oxylipin). In certain embodiments of the implementation of the present invention, the concentration of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) in the pharmaceutical composition is greater than 100 μm, in particular greater than 150 microns, greater than 200 microns, greater than 250 microns, greater than 300 microns, greater than 350 microns, greater than 400 microns, greater than 450 μm, greater than 500 μm, more than 550 μm, greater than 600 microns, greater than 650 μm, greater than 700 microns, greater than 750 microns, or greater than 800 μm of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin), in particular, up to 1000 μm up to 2000 μm, up to 3000 microns, up to 5000 microns, or even up to 7000 μm. For example, the concentration of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) in the pharmaceutical composition may range from 100 μm to 7000 μm, in particular, to range from 100 to 5000 μm, from 100 to 3000 μm, from 100 to 2000 μm, or from 100 to 1000 μm of any of the above substances (for example, compounds of any of formulas I-IX, compound f is raly And, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin). In certain embodiments of the implementation of the present invention the concentration of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) in the pharmaceutical composition may range from 150 μm to 7000 μm, in particular ranging from 150 to 5000 μm, from 150 to 3000 μm, from 150 to 2000 μm or from 150 to 1000 μm of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin). In certain embodiments of the implementation of the present invention, the concentration of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin) in the pharmaceutical composition may range from 90 μm to 7000 μm, in particular, to range from 250 to 5000 μm, from 250 to 3000 μm, from 250 to 2000 μm, or from 250 to 1000 μm of any of the above substances (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin).

As a concrete example of this is General the invention features a pharmaceutical preparation, suitable for the treatment or prevention of ophthalmic diseases such as dry eye patients-people, which includes connecting 1001 and one or more pharmaceutically acceptable inert fillers, for example, in aqueous solution, suitable for local application to the eye, such as eye drops. In certain embodiments of the implementation of the present invention, the concentration of compound 1001 in the pharmaceutical preparation is more than 30 micrograms per milliliter (μg/ml), for example, ranging from 30 μg/ml to 2000 μg/ml, in particular from 30 ág/ml 1500 ág/ml, 30 μg/ml to 1000 μg/ml, 30 ág/ml 750 ág/ml, 30 μg/ml to 500 μg/ml, from 30 μg/ml to 400 μg/ml or 30 μg/ml to 350 mg/ml In certain embodiments implementing the present invention, the concentration of compound 1001 in the pharmaceutical preparation is greater than 40 μg/ml, for example, more than 50 μg/ml, greater than 60 μg/ml, greater than 70 μg/ml, more than 75 μg/ml, greater than 100 μg/ml, more than 125 μg/ml, greater than 150 µg/ml more than 175 μg/ml, greater than 200 μg/ml, greater than 225 mg/ml, or greater than 250 micrograms/ml, for example, up to 350 µg/ml, up to 400 µg/ml up to 500 µg/ml, up to 750 mcg/ml, up to 1000 mcg/ml, up to 1500 mcg/ml or even up to 2000 µg/ml. for Example, the concentration of compound 1001 in pharmaceutical whom whom the drug may be from 40 μg/ml to 2000 μg/ml, for example, from 40 ág/ml 1500 ág/ml, 40 μg/ml to 1000 μg/ml, 40 ág/ml 750 ág/ml, 40 μg/ml to 500 μg/ml, 40 μg/ml to 400 μg/ml or 40 μg/ml to 350 mg/ml In certain embodiments implementing the present invention, the concentration of compound 1001 in the pharmaceutical drug is 50 mcg/ml to 2000 μg/ml, for example, ranges from 50 ág/ml 1500 ág/ml, 50 μg/ml to 1000 μg/ml, 50 ág/ml 750 ág/ml, 50 μg/ml to 500 μg/ml, 50 μg/ml to 400 μg/ml or 50 μg/ml to 350 mg/ml In certain embodiments implementing the present invention, the concentration of compound 1001 in the pharmaceutical preparation is 60 μg/ml to 2000 μg/ml, for example, is 60 ág/ml 1500 ág/ml, 60 μg/ml to 1000 μg/ml, 60 ág/ml 750 ág/ml, 60 μg/ml to 500 μg/ml, 60 μg/ml to 400 μg/ml or 60 mg/ml to 350 mg/ml In certain embodiments implementing the present invention, the concentration of compound 1001 in the pharmaceutical preparation is 75 μg/ml to 2000 μg/ml, for example, ranges from 75 ág/ml 1500 ág/ml, 75 μg/ml to 1000 μg/ml, 75 ág/ml 750 ág/ml, 75 μg/ml to 500 ág/ml 750 ág/ml to 400 μg/ml or 75 mg/ml to 350 mg/ml

In certain embodiments of the implementation of the methods of treatment or prevention of ophthalmic diseases such as dry eye), which include the appointment of an effective amount of l is the God of one or more of any of the above compounds (for example, compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin), for example, in aqueous solution, as described herein, which is administered topically in the eye, for example, in the form of eye drops, the preferred connection is the connection 1001.

In certain embodiments of the implementation of any of the above pharmaceutical preparations (for example, any of the above pharmaceutical compositions comprising a compound of any of formulas I-IX, a compound of formula A, compound of any of formulae 1-49, a derivative of lipoxin or derived oxylipins, such as the connection 1001, and one or more pharmaceutically acceptable inert fillers) the pharmaceutical preparation is an aqueous solution suitable for local injection into the eye, where the solution has a pH in the range from 5.5 to 7.4, such as from 5.5 to 7.0; or from 5.5 to 6.5; or from 5.5 to 6.0. In certain embodiments of the implementation of any of the above pharmaceutical preparations (for example, any of the above pharmaceutical compositions comprising a compound of any of formulas I-IX, a compound of formula A, compound of any of formulae 1-49, a derivative of lipoxin or derived oxylipins, such as the connection 1001, and one or more pharmaceutically acceptable inert filler is) the pharmaceutical preparation is an aqueous solution, suitable for local injection into the eye, where the solution has a pH in the range from 5.0 to 7.4, such as from 5.0 to 7.0; or in the range from 5.0 to 6.5, such as from 5.0 to 6.0 or 5.0 to 5.5. In certain embodiments of the implementation of any of the above pharmaceutical solution also includes one or more surfactants, one or more funds, reduce irritation, and/or one or more emulsifiers, such as Polysorbate 80, Pluronic F-147, tyloxapol, polyvinylpyrrolidone (such as polyvinylpyrrolidone with an average molecular weight 360000, for example, polyvinylpyrrolidone K-90, Chemical Abstracts Service Registry No. 9003-39-8), mineral oil or castor oil. In certain embodiments of the implementation of the present invention, the preparation is practically no preservatives.

In certain embodiments of the implementation of the present invention is the above pharmaceutical drug (for example, having the above concentration) can be entered using any suitable dosage regimen for the treatment or prevention of ophthalmic diseases. Suitable dosing regimens aqueous eye drops include the introduction of pharmaceutical product once, twice, three times or four times a day in affected eye. In certain embodiments implementing the present invented the I appropriate modes of dose solution eye drops may include the appointment of a dose of the medication in the affected eye, twice a day, for example, every other day or every three days, for example, in two days. In certain embodiments of the implementation of the present invention to any specific case of the introduction of the above pharmaceutical drug (for example, having the above concentration) may include the introduction of one or more drops of a pharmaceutical product in each affected eye. In certain embodiments of the implementation of the present invention to any specific case of the introduction of the above pharmaceutical drug (for example, having the above concentration) may include the introduction of two, three, four or five drops of a pharmaceutical product in each affected eye. In addition, the present invention encompasses any and all of the above combinations.

Examples of ophthalmic diseases that can be treated by introducing the compounds or compositions of the present invention, include, but not limited to, due to the AIDS diseases of the retina; age-related macular degeneration; erosive-ulcerative keratoconjunctivitis, allergic keratitis; anterior ischemic optic neuropathy; anterior uveitis (iridocyclitis); Behcet's disease; blepharitis; seborrheic blepharitis; canaliculi; cataracts; Central serous the horioretinopatia; chorioidea; chronic uveitis; disease Coates; conjunctivitis (in the example, infectious conjunctivitis, conjunctivitis of the newborn, non-infectious conjunctivitis and allergic conjunctivitis); caused by contact lenses keratoconjunctivitis; contact eczema, ulcers of the cornea (for example, corroding ulcer of the cornea Morena, ulcers of the cornea, caused by chronic rheumatoid arthritis or collagen disease, marginal degeneration of Terrena, catarrhal ulcer of the cornea, infectious corneal ulcer); retinopathy lens; cycle; swelling (for example, cystic macular edema); dacryoadenitis; dacryocystitis; degenerative myopia, degenerative stratification of the retina; diabetic keratopathy; diabetic macular edema; diabetic retinopathy; a disease associated with dry eye (e.g., dry eye lacrimal system or dryness of the eyes cornea); dry age-related macular degeneration; endophthalmitis; episcleritis; exudative macular edema; Fuchs dystrophy; giant cell arteritis diagnostics; giant papillary conjunctivitis; glaucoma (e.g., primary open-angle glaucoma, primary angle-closure glaucoma, secondary open-angle glaucoma, secondary angle-closure glaucoma and pediatric glaucoma); the unfavorable outcome of surgical treatment of glaucoma, graft-versus-host during surgery on the eyes (often in the form of dryness of the eye); herpes zoster(shingles); hypertensive retinopathy; inflammation after cataract surgery; iridocorneal endothelial syndrome; iridia; iritis; keratitis (e.g., infectious keratitis, infectious keratitis and neuroparalytic keratitis); keratoconjunctivitis sicca; keratoconjunctivitis inflammatory disease; keratoconus; keratopathy; lattice dystrophy; epithelial basement membrane dystrophy of the cornea; necrotic keratitis; neovascular diseases, exciting the retina, vascular sheath of the eyeball or cornea, such as neovascular glaucoma, neovascularization of the cornea (inflammatory, transplantation, developing hypoplasia of the iris), neovascularization caused by the combined removal of vitreous body and removal of the lens, the neovascularization of the optic nerve and neovascularization due to penetration of the eye or eye damage as a result of injury; non-infectious uveitis; ocular herpes simplex; ocular rosacea; eye infections (e.g., corneal herpes, bacterial keratitis, bacterial conjunctivitis, fungal keratitis, acanthameba keratitis, infectious endophthalmitis, infectious ulcers of the cornea, inflammation of the conjunctiva or cornea caused by Staphylococcus, Streptococcus, Enterococcus, automaticcaly, b is sellami, corynebacteria, chlamydia and Neisseria); eye pemphigoid; drusen of the optic nerve; optic neuritis; proveit; swelling of the optic nerve; papilla; granulomatous uveitis flat part of the ciliary body; persistent macular edema; phacoanaphylaxis; posterior uveitis (holoendemic); postoperative inflammation (for example, inflammation of the cornea after conducting LASIK); proliferative diabetic retinopathy; proliferative sickle cell retinopathy; the proliferative vitreoretinopathy; occlusion of artery of the retina; retinal detachment; retinal vasculitis; occlusion retinal vein; retinitis pigmentosa; retrolental fibroplasia; robes iris; scleritis; syndrome Stevens-Johnson (erythema multiforme); metastatic ophthalmia; temporal Takayasu; toxic retinopathy; uveitis (e.g., anterior uveitis or posterior uveitis); vernal conjunctivitis; keratomalacia caused by lack of vitamin a; Vitrea; and wet age-related macular degeneration.

Diseases that cause dry eyes include syndrome Riley-Day, the syndrome of the Shi-Draeger, Sjogren syndrome, sarcoidosis, amyloidosis, the consequence of radiotherapy, lagophthalmus, A deficiency, a syndrome of Stevens-Johnson, ocular pemphigoid, marginal blepharitis, mabait the result of intraocular surgery, the damage caused by wearing contact if the SHL, diabetic corneal epitheliopathy, dry eye due to VDT operation, graft-versus-host etc. Disorders caused by infectious disease of the cornea include, for example, viral epitheliopathy etc. Syndromes depletion of stem cells include the syndrome of Stevens-Johnson, ocular pemphigoid, thermal or chemical burn, toxicity of drugs of idoxuridine (IDU) and therapeutic agents for the treatment of glaucoma, etc.

In the present invention proposes a method of inhibiting COX-2, or TNF in the eye of the patient, which includes the introduction of a specified patient compounds of the present invention. In the present invention it is also proposed a method of protection against loss of goblet cells in the eye of the patient, which includes the introduction of a specified patient compounds of the present invention.

Compounds described in this description can also inhibit inflammatory mediators in the cornea, such as TNF, IL-1a, IL-1b, IL-6 and IL-8. Thus, these compounds may be suitable for treatment of diseases of dry eye, age-related macular degeneration, retrolental fibroplasia, uveitis and glaucoma.

Described in this description of the compounds can also inhibit COX-2 in the cornea. Thus, these compounds may be suitable for treatment of diseases dry the STI eyes.

Described in this description of the compounds can also protect against loss of goblet cells. Thus, these compounds may be suitable for treatment of diseases of dry eye, age-related macular degeneration, retrolental fibroplasia, age pigmentosa and glaucoma. Described in this description of the compounds can also enhance the production of tears and to increase the density of superficial epithelial cells, two of the expected results that are associated with the treatment of dry eye.

Described in this description of the compounds can also reduce the transudation of fluid through the vessels. Thus, these compounds may be suitable for treatment of age-related macular degeneration.

Described in this description of the compounds can also inhibit cells CD11b+. Animal models of dry eye indicate an increase in the number of cells, CD11b+, indicating a high concentration of cells in the cornea. Thus, these compounds may be suitable for the treatment of dry eye by reducing the appearance of leukocytes induced dry eye.

Described in this description of the compounds can also prevent pigment destruction of the epithelium of the retina. Thus, these compounds may be suitable for treatment of age-related macular degeneration, retrolental fibroplasia pigmented retinitis and glaucoma.

In certain embodiments of the implementation of the present invention, various compounds of the present invention may be administered in conjunction with other agents suitable for the treatment or prevention of ophthalmic diseases. For example, the following drugs or classes of drugs may be administered with the compound of the present invention: doxicyclin; decosahexanoic acid; inhibitors of angiogenesis, such as VEGF inhibitors, such as pegaptanib sodium, bevacizumab, ranibizumab, AV-951, vandetanib, semaxanib, CBO-P11, axitinib, sorafenib, sunitinib, pazopanib and TIMP3; anaesthetics and means to relieve pain, such as lidocaine and related compounds and benzodiazepam and related compounds; anti-cancer, such as 5-fluorouracil, adriamycin and related compounds; anti-inflammatory agents, such as 6-Manasarovar; antifungal agents such as fluconazole and related compounds; anti-viral agents, such as trinary phosphonoformic, triptorelin, acyclovir, ganciclovir, DDI, DDC and AZT; means for reducing the migration/mobility of cells, such as colchicine, vincristine, cytochalasin B and related compounds; drugs against glaucoma, such as beta blockers: timolol, betasol, atenalol and so on; PR is tallandini, such as latanoprost and travoprost and so on; modulators of immunological reactions, such as muramyl-dipeptide and related compounds; peptides and proteins such as cyclosporin, insulin, growth hormones associated with insulin growth factor, nerve growth factor (optionally in further combination with docosahexanoic acid), heat shock proteins and related compounds; treatment with estrogen treatment; corticosteroids, such as dexamethasone, dexamethasone 21-phosphate, formation, Madison, betamethasone, triamcinolone, triamcinolone acetonide, criminale, prednisone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, hydrocortisone, hydrocortisone acetate, prednicarbate, deflazacort, halometasone, tixocortol, prednisone (21-diethylaminoacetate), prednesol, paramethasone, prednisolone, methylprednisolone, meprednisone, mazipredon, isoflupredone, haloperidol acetate, halcinonide, farmacita, flurandrenolide, fluprednisolone, flupredniden acetate, flaperon acetate, fluocortolone, fluocortin butyl, fluocinonide, fluotsinolon, fluotsinolon acetonide, flunisolide, flumetazon, fludrocortisone, Flocklined, formation, enoxolone, difluprednate, diflucortolone, diflorasone diacetate, desoximetasone, desonide, destinaton, cortisol, corticosterone, cortisone, cloprednol, clocortolone, clobetasol, clobetasol, chloroprednisone,cafestol, budesonide, beclomethasone, amcinonide, allopregnane acetonide, alclometasone, 21-acetoxyphenyl, taloned, diflorasone acetate, deallocate, EN-26988, budesonide and deallocate oxetane. All of these corticosteroids are known compounds. Further information on connections can be found, for example, in The Merck Index, Thirteenth Edition (2001) and in the references, the full contents of which are incorporated in this description by reference. In certain embodiments of the implementation of the present invention, the corticosteroid is selected from fluotsinolon acetonide, triamcinolone acetonide, dexamethasone, and related compounds, or any combinations thereof; and inhibitors of carbonic anhydrase.

Further examples of drugs or classes of drugs which may be administered together with a compound of the present invention, include: DE-104, PF-04217329; PF-03187207; AL 37807; OPC-12759; chemotherapeutic agents such as mitomycin C; synthetic structural analogues of prostaglandins, such as bimatoprost; agonists alpha-2, such as brimonidine; inhibitors of carbonic anhydrase, dorzolamide HCl; derivatives of prostaglandins and analogues, such as tafluprost and travoprost; NMDA antagonists such as memantine; hyaluronic acid (for example, sodium salt of hyaluronic acid); corticosteroids, such as lot is prenol etabonate, difluprednate and rimexolone; antibiotics such as doxycycline; means of increasing mucin, such as ecabet and rebamipide; lubricating agents such as a combination of sodium carboxymethyl cellulose and glycerin; receptor agonists adenosine-A3, such as CF-101; immunoregulatory, such as thalidomide; TNFα antagonists, such as etanercept; inhibitors of protein kinase C-b, such as ruboxistaurin; immunosuppressants such as sirolimus; PARP inhibitors, such as AG-014699; neuroprotective thrombolytic agents such as microplasmin; hyaluronidase; oxidizing agents, such as urea; the somatostatin analogues such as octreotide acetate; receptor antagonists angiotensin II, such as candesartan, cilexetil; basic Antirheumatic drugs that modify the course of the disease, such as Leflunomide; AEB071; TNF antagonists, such as adalimumab; antagonists CD11, such as efalizumab; inhibitors calcineurin, such as LX211; interferons such as interferon α-2a and α-fetoprotein person, such as MM 093.

In addition to these medicines, for introduction into the eye and the surrounding tissue to provide a beneficial local or systemic physiological or pharmacological effect, other suitable means. Such funds may be administered together with a compound according to the present invention. Examples of such tools include neuroprotective agents, such as nimodipine and related compounds; antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antibacterial agents such as sulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole; antivirals, such as idoxuridine; and other antibacterial additives, such as nitrofurazone and sodium propionate; antiallergic drugs, such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and propanediamine; antitumor drugs, such as phenylephrine, nafazolina and tetrahydrozoline; mitotic tools and anticholinesterase agents, such as pilocarpine, ezerin salicylate, carbachol, aminobutiramida fjortoft, phospholine iodide and demerary bromide; medicinal substances causing pupil dilation, such as atropine sulfate, cyclopentolate, gomatropin, scopolamine, Tropicamide, eucatropine and hydroxyamphetamine; sympathomimetics such as epinephrine; and prodrugs, such as prodrugs described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam, 1985. To determine other medications, you can refer to any standard textbook of pharmaceutics, such as Remington''s Pharmaceutical Sciences (Remington's Pharmaceutical ciences. Mack Publishing Company, Easton, Pa., USA 1985).

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with non-chemical methods suitable for the treatment or prevention of ophthalmic diseases. In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with laser treatment (such as, for example, photocoagulation or photodynamic therapy), macular translocation surgery or together with devices (e.g., implant tartrate of brimonidine).

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of ophthalmic diseases, such as the above medicines.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more ADNOC is the shaft dosage forms of medicines suitable for the treatment or prevention of ophthalmic diseases or medications, suitable for introduction into the eye and the surrounding tissue, with the aim of providing the above beneficial local or systemic physiological or pharmacological effect; and (c) of the regulations relating to the introduction of the compounds of the present invention and means suitable for the treatment or prevention of ophthalmic diseases or medications, suitable for introduction into the eye and the surrounding tissue, with the aim of providing the above beneficial local or systemic physiological or pharmacological effect.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, e.g. for the treatment or prevention of ophthalmic diseases, inhibition of COX-2 or TNF in the eye or protection from loss of goblet cells in the eye.

In certain embodiments of the implementation of this reagent kit further includes instructions relating to the introduction of a pharmaceutical composition that contains the compound is of the present invention, together with a drug suitable for the treatment or prevention of ophthalmic diseases, drug, suitable for introduction into the eye and the surrounding tissue, with the aim of providing a beneficial local or systemic physiological or pharmacological effect, or together with non-chemical methods suitable for the treatment or prevention of ophthalmic diseases, as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising an agent suitable for the treatment or prevention of ophthalmic diseases, or drug, suitable for introduction into the eye and the surrounding tissue, with the aim of providing a beneficial local or systemic physiological or pharmacological effect.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of ophthalmic diseases, or drug, suitable for introduction into the eye and the surrounding tissue, with the aim of an eye is beneficial project for local or systemic physiological or pharmacological effect; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, for the treatment or prevention of inflammatory diseases, inhibition of COX-2 or TNF in the eye or protection from loss of goblet cells in the eye.

In the present invention proposes a packaging pharmaceutical agents for administration of eye drops containing the compound of any of formulas I-IX, a compound of formula A, compound of any of formulae 1-49, a derivative of lipoxin or derived oxylipin, in the eye that needs treatment of ophthalmic diseases. In certain embodiments of the implementation of the present invention packaging pharmaceuticals prepared in such a way that it provides for the introduction of eye drops in the form of any of the doses (for example, any molar or weight), above, by introducing one, two, three, four or five of eye drops in the eye either once or twice or three times, or four times a day, or by introducing eye drops only once in two days, for example, every other day or every three days, for example, every two days. The specialist should be clear how to change the volume drops (for example, due to changes in surface tension and/or viscosity of the solution and/or by regulating the physical is some block configuration of dispensing drops package) the concentration of the solution and the dosage regimen (e.g., number of drops and the frequency of administration) to provide the necessary dosage.

In certain embodiments of the implementation of the present invention the pharmaceutical packaging means includes an aqueous solution (e.g., eye drops), Packed in a sealed disposable container, each container contains, for example at least 1.5 nanomoles compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin, for example at least 2, 3, or 6 nanomoles compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin, in the aqueous composition, suitable for local injection into the eye. In certain such embodiments, the implementation of the present invention, each container contains from 1.5 nanomoles to 550 nanomoles, for example, from 1.5 to 400 nanomoles or from 1.5 to 100 nanomoles compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin in an aqueous composition suitable for local injection into the eye. In certain embodiments of the implementation of the present invention the pharmaceutical packaging means includes an aqueous solution (e.g., the eye to the lip), Packed in a sealed disposable container, each container contains, for example at least 0.5 micrograms of compound 1001, for example at least 0,7; 1 or 2 micrograms of compound 1001 in an aqueous composition suitable for local injection into the eye. In certain such embodiments, the implementation of the present invention, each container contains from 0.5 to 150 micrograms micrograms of compound 1001, for example, from 0.5 to 100 micrograms, or from 0.5 to 25 micrograms of compound 1001 in an aqueous composition suitable for local injection into the eye. In certain embodiments of the implementation of the present invention the pharmaceutical packaging means includes an aqueous solution (e.g., eye drops), Packed in a sealed disposable container, each container contains, for example, a solution with a concentration of more than 90 μm of the compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin, for example, with a concentration of more than 100, 150, 200 or 250 μm of the compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, derived lipoxin or derived oxylipin in the form of an aqueous composition suitable for local injection into the eye. In certain such embodiments, the implementation of the present invention each of the first container contains a solution with a concentration of from 90 μm to 7000 μm, for example, from 90 μm to 2000 μm or 90 μm to 1000 μm of the compounds of any of formulas I-IX, compounds of formula A, compounds of any of formulae 1-49, a derivative of lipoxin or derived oxylipin in the form of an aqueous composition suitable for local injection into the eye. For example, in certain embodiments of the implementation of the present invention the pharmaceutical packaging means includes an aqueous solution (e.g., eye drops), Packed in a sealed disposable container, each container contains, for example, a solution with a concentration of more than 30 μg/ml of compound 1001, for example, with a concentration of more than 40, 50, 60, or 75 μg/ml of compound 1001, in the form of an aqueous composition suitable for local injection into the eye. In certain such embodiments, the implementation of the present invention, each container includes a solution with a concentration of 30 μg/ml to 2000 μg/ml, for example, from 30 μg/ml to 1000 μg/ml or 30 μg/ml to 350 mg/ml of compound 1001, in the form of an aqueous composition suitable for local injection into the eye.

In other embodiments, implementation of the present invention the pharmaceutical packaging means includes not contain the preservative is an aqueous solution that includes a compound of any of formulas I-IX, a compound of formula A, compound of any of formulae 1-49, a derivative of lipoxin or derived oxylipin (for example, glasny the drops) Packed in a container suitable for repeated administration of the dosage of the drug in the eye in need of treatment of ophthalmic diseases. In certain such embodiments, the implementation of the present invention the container is suitable for repeated dose not contain the preservative solution, designed so that in the interval between successive usages preserve the sterility of the solution. Suitable dosing devices include a metering device disclosed in application for U.S. patent No. 2009/294347.

Immune function

In the present invention proposes a method of deterrence immune function and/or suppressing an immune response in a patient, which includes the introduction of a specified patient compounds of the present invention.

In the present invention proposes a method of treating or preventing an autoimmune disease or autoimmune disorder in a patient, which includes the introduction of a specified patient compounds of the present invention.

In certain embodiments of the implementation of the present invention autoimmune disease or autoimmune disorder is a disease or disorder when the patient's immune system affects one or more tissues of the patient is. In certain embodiments of the implementation of the present invention autoimmune disease or autoimmune disorder is induced by something inside the patient's or anything in the surrounding of the patient environment.

In certain embodiments of the implementation of the present invention autoimmune disease or autoimmune disorder may be a disease or disorder, which occurs as a result of the initiating cause. For example, an autoimmune disease or autoimmune disorder may be a disease or disorder that is caused by infection and/or some other initiating cause. Potential initiating causes may include old age, infection (such as infection parasites), treatment with steroids, repeated vaccination with alum, pregnancy and/or types of cancer.

In certain embodiments of the implementation of the present invention autoimmune disease or autoimmune disorder may be organ-specific or not organ-specific. Examples of such autoimmune diseases or autoimmune disorders include multiple sclerosis, arthritis (such as rheumatoid arthritis or juvenile arthritis), Crohn's disease, ulcerative colitis and gipoplasticheskaya anemia in systemic lupus erythematosus, dermatomyositis, pernicious anemia, addisonova disease, Anki is serouse spondylitis, antiphospholipid syndrome, charge-Strauss, discoid lupus, fibromyalgia, graves ' disease, severe pseudoparalysis the gravis, psoriasis, Reiter syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren syndrome, syndrome muscle stiffness, thyroiditis, uveitis, vitiligo, Wegener's granulomatosis, graft rejection and vascular disorders.

In certain embodiments of the implementation of the present invention, when an autoimmune disease or autoimmune disorder is a graft rejection, graft rejection can be chronic graft rejection. In certain embodiments of the implementation of the present invention, when the compounds of the present invention is prescribed for the treatment of transplant rejection, the introduction of the compounds of the present invention regulates immune responses to transplants (e.g., allografts or xenografts) in cases where not treated rejection would have led to loss of the graft. Thus, the connection of the present invention can be used as a replacement or in addition to the usual immunosuppressant that is used before, during and/or after transplantation. In certain embodiments of the implementation of the present invention graft rejection one is camping response to transplantation of natural or artificial cells, islet cells, tissues (for example, natural or artificial skin tissue, cornea, bone marrow, organs (e.g. kidney, liver, pancreas, lung or heart), lenses or pockets of automaticity of the heart.

In the present invention it is also proposed a method for the treatment or prevention of disease, complications, or pathological condition mediated by the activation of the immune system in a patient, which includes the appointment of a specified patient compounds of the present invention. In certain embodiments of the implementation of the present invention illness, complications or pathological condition mediated by the activation of the immune system, which includes, but not limited to, increased capillary permeability, pulmonary insufficiency, sepsis, endotoxic shock or complication after tissue injury.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered in conjunction with other means suitable for the regulation of immune function, suppressing immune response, treating an autoimmune disease or autoimmune disorder, or treating disease, complications or pathological condition mediated by the activation of the immune system. For example, the following immunosuppres the sector funds may be administered together with a compound of the present invention include cyclosporin, cyclosporine A, tacrolimus, rapamycin, everolimus, FK-506, cyclophosphamide, azathioprine, methotrexate, brequinar, Leflunomide, mizoribine, mycofenolate acid, mycophenolate mofetil, 15-desoxipeganine, triamcinolone acetonide, decadron, daclizumab, basiliximab, glatiramer acetate, infliximab, muromonab, octreotide, dipeptide derivatives of murmillos acid, levamisole, niridazole, oxysure, flagyl and sirolimus.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the regulation of immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system, such as the aforementioned therapeutic agent.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one who does more single dosage forms of medicines suitable for the regulation of immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system, as described above; and (c) of the regulations relating to the introduction of the compounds of the present invention and medicines are suitable for the regulation of immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to contain immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system.

p> In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the regulation of immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system, as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the regulation of immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system, as described above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage fo the m), including means suitable for regulating immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system, as described above; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to contain immune function, suppressing immune response, treating or preventing an autoimmune disease or autoimmune disorder, or treating or preventing diseases, complications or pathological condition mediated by the activation of the immune system.

Pulmonary disease

In the present invention proposes a method of treating or preventing a pulmonary disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention pulmonary disease may be selected from inflammation of the lungs, airway inflammation, asthma, chronic bronchitis, bronchiectasis not associated with cystic fibrosis bronchiectasis, cystic fibrosis, eosinophilic lung diseases (e.g., infection, parasites, eosinophi Inoi pneumonia of unknown origin and vasculitis charge-Strauss), allergic bronchopulmonary aspergillosis, allergic inflammation of the respiratory tract (e.g., rhinitis and sinusitis, bronchiolitis, obliterating bronchiolitis, obliterating bronchiolitis with organizing pneumonia, eosinophilic granuloma, Wegener's granulomatosis, sarcoidosis, hypersensitive pneumonia, pulmonary fibrosis of unknown origin, pulmonary manifestations of diseases of the connective tissues, acute or chorionic lung damage, respiratory distress syndrome in adults, pneumonia, emphysema, pulmonary disorders or chronic obstructive pulmonary disease.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of lung diseases, such as diseases, disclosed in the present description. Examples of drugs suitable for the treatment of lung diseases include corticosteroids (eg, prednisone, beclomethasone dipropionate, fluticasone propionate, and other suitable corticosteroids), beta agonists (e.g., albuterol, IU aproaerema, pirbuterol, formoterol, terbutaline, isoetharine, levalbuterol, salmeterol xinafoate and other suitable beta-agonists and anticholinergics (e.g. ipratropium bromide, Tiotropium bromide and other suitable anticholinergics).

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for treating or preventing pulmonary diseases; and (c) of the regulations relating to the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of lung disease.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, particularly lung diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction f rmaceuticals composition, which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of lung disease. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of lung disease.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of one or more single dosage forms, each of which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of lung disease. In certain embodiments of the implementation of the present invention the kit further includes one or more single dosage forms of a means suitable for the treatment or prevention of lung disease.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for treating or preventing lung for which Alemania; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to treat or prevent the above diseases, in particular for the treatment or prevention of lung disease.

Gastrointestinal diseases

In the present invention proposes a method of treatment or prevention of gastrointestinal disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention gastrointestinal disease may be selected from inflammation of the gastrointestinal tract, ulcerative colitis, pseudomembranous colitis caused by Clostridium difficile, microscopic or lymphocytic colitis, collagenous colitis, Crohn's disease, irritable bowel syndrome, infectious enteritis, diarrhoea associated with antibiotics, colon polyps, family polyps syndrome hereditary polyposis, Gardner syndrome, a disease caused by the bacteria Helicobacter pylori, non-specific diseases accompanied by diarrhea, bowel cancer, distal proctitis, inflammatory conditions, associated with abnormal contraction of the colon (e.g., syndrome level becomes too low, colon cancer, and if the East colitis), allergic diseases of the bowel (eg, celiac disease, esophagitis, or pancreatitis.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of gastrointestinal diseases, such as diseases, disclosed in the present description. Examples of drugs suitable for the treatment of gastrointestinal diseases include immunosuppressive drugs (eg, corticosteroids, antagonists of histamine receptor-2 (e.g., cimetidine, famotidine, nizatidine, and ranitidine), sukralfat, prostaglandins (in particular, misoprostol) and proton pump inhibitors (e.g. omeprazole, lansoprazole, esomeprazole, pantoprazole and rabeprazole).

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for the treatment or prevention of gastrointestinal diseases and c) instructions on the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of gastrointestinal diseases.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, particularly gastrointestinal diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of gastrointestinal diseases. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of gastrointestinal diseases.

The present invention features a kit of reagents which contain what it

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of gastrointestinal disease; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to treat or prevent the above diseases, particularly gastrointestinal diseases.

Rheumatic diseases

In the present invention proposes a method of treatment or prevention of rheumatic disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention rheumatic disease can be selected from rheumatic diseases, rheumatoid arthritis, osteoarthritis, inflammatory conditions of joints (e.g. rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis), ankylosing spondylitis, lupus, psoriatic arthritis, myalgia or chronic lumbar pain.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds according to the present izaberete the Oia. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of rheumatic diseases, such as diseases, disclosed in the present description. Examples of drugs suitable for the treatment of rheumatic diseases include non-steroidal anti-inflammatory drugs such as salicylates (eg, aspirin, aloxiprin, benorilate, choline magnesium salicylate, diflunisal, filamin, methyl salicylate, magnesium salicylate, salicylsalicylic), arylalkenes acid (for example, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacin, nabumetone, sulindac, tolmetin), 2-arylpropionic acid (for example, ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, Ketoprofen, Ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, suprofen), N-irelandlavalife acid (for example, mefenamovaya acid and meclofenamic acid), derivatives of pyrazolidine (for example, phenylbutazone, azapropazone, Metamizole, oxyphenbutazone and sulfinpyrazone), oxicam (e.g., piroxicam, lornoxicam, meloxicam and tenoxicam), COX-2 inhibitors (e.g. celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoksib, valdecoxib) and sulfonanilide (for example, nimesulid), corticosteroid the s (for example, prednisone, cortisone, solumedrol and hydrocortisone), basic Antirheumatic drugs that modify the course of illness (e.g., Leflunomide prescribed oral gold preparations, sulfasalazin, mycophenolate, cyclophosphamide, azathioprine, chlorambucil, rheumatrex, minocycline, injection preparations of gold, cuprimine and MiniProx), analgesics (eg, acetaminophen, codeine, propoksifen, fentanyl, hydromorphone, morphine, oxycodone, pentazocine, tramadol and hydrocodone) and biological response modifiers (e.g., etanercept, adalimumab, anakinra, abatacept, efalizumab, infliximab, rituximab and natalizumab).

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for the treatment or prevention of rheumatic disease; and c) instructions concerning the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of rheumatic diseases.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single Lek is stannah forms), including a connection according to the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, in particular rheumatic diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of rheumatic diseases. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of rheumatic diseases.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of rheumatic disease; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example,to treat or prevent the above diseases, in particular, rheumatologic diseases.

Dermatological diseases

In the present invention proposes a method of treatment or prevention of dermatological disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention dermatological disease may be selected from scleroderma, psoriasis, urticaria, vasculitis, seborrheic dermatitis, pustular dermatosis, eczema, dermatitis, ulcers and erosions caused by trauma, burns, bullous disorders or ischemia of the skin or mucous membranes, ichthyosis, congenital bullous of bullosa, hypertrophic scars and keloids, skin changes due to aging caused by the internal state of the organism, photoaging, friction blistering caused by mechanical cutting of the skin, atrophy of the skin caused by local application of corticosteroids, inflammation of the mucous membranes (for example, heylita, the formation of cracks on the lips, irritation of nose or candidiasis), dandruff, sunburn, burn sumac Aganozero, allergic dermatitis, acne or rosacea.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or n is the number of other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of dermatological diseases, such as diseases, disclosed in the present description. Examples of drugs suitable for the treatment of dermatological diseases include immunosuppressive agents such as cyclosporine or calcineurin inhibitors (e.g., tacrolimus or pimecrolimus), corticosteroids (eg, prednisone and betamethasone dipropionate), antigistaminny drugs (eg, diphenhydramine, hydroxyzine, and cyproheptadine at), salicylic acid, anthralin, calcipotriene, tazarotene.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for the treatment or prevention of dermatological diseases; and c) instructions concerning the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of dermatological diseases.

The present invention features a kit that contains

a) a pharmacist shall ical composition (for example, one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, in particular, dermatological diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of dermatological diseases. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of dermatological diseases.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of dermatological diseases; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the unity of the present invention, for example, to treat or prevent the above diseases, in particular, dermatological diseases.

Neurological disorders

In the present invention proposes a method of treatment or prevention of a neurological disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention neurological disease may be selected from neurodegeneration and dementia associated with HIV infection, depression, Alzheimer's disease, Parkinson's disease, addiction, disorders associated with alcohol use disorder analysis, decision-making, degenerative neurological disorders, dementia, neurological disorders, neuromuscular disorders, psychiatric disorders, brain injury, trauma, inflammation of the nerves or multiple sclerosis.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of neurological Soboleva what I such as diseases disclosed in the present description. Examples of drugs suitable for treatment of neurological diseases include thyroid-stimulating hormone replacement, cholinesterase inhibitors (eg, donepezil and taken), neuroleptics (e.g., clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, trifluoperazine, flupentixol, loxapine, perphenazine, chlorpromazine, haloperidol, fluphenazine decanoate, and thioridazine), tranquilizers, such as benzodiazepine drugs (eg, lorazepam, clonazepam, alprazolam and diazepam) and dibenzodiazepine drugs (e.g., buspirone), drugs for treatment of Alzheimer's disease, such as acetylcholinesterase inhibitors (for example, donepezil, rivastigmine and galantamine) or NMDA receptor antagonists (e.g. memantine), antidepressants, such as selective inhibitors of serotonin reuptake (e.g., fluoxetine, paroxetine, ESCITALOPRAM, citalopram, and sertraline), inhibitors of reuptake of serotonin and norepinephrine (e.g., venlafaxine and DULOXETINE), noradrenergic and specific serotoninergicheskie antidepressants (eg, mirtazapine), inhibitors of reuptake of norepinephrine (e.g. reboxetine), inhibitors of reuptake of norepinephrine and dopamine (for example, bupropion), Tris licencie antidepressants (for example, amitriptyline and desipramine) and monoamine oxidase inhibitors (e.g. phenelzine, moclobemide and selegiline), drugs for the treatment of multiple sclerosis, such as interferons (e.g. interferon beta-1a and interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, and corticosteroids (eg, methylprednisolone or any of the above corticosteroids), and drugs to treat Parkinson's disease such as levodopa, carbidopa, benserazida, tolkapon, entacapone; dopamine agonists such as bromocriptine, pergolid, pramipexol, ropinirole, cabergoline, apomorphine, and lisuride; inhibitors of MAO-B, such as selegiline and rasagiline or a combination of both.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for the treatment or prevention of neurological diseases; and (c) of the regulations relating to the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of neurological diseases.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more od okrutny dosage forms) including a connection according to the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, particularly neurological disorders.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of neurological diseases. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of neurological diseases.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of neurological diseases; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, the purpose is ecene or prevent the above diseases, in particular, neurological disorders.

Cancer

The present invention features a method of treating or preventing cancer in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention the cancer may be selected from breast cancer, colon cancer, leukemia, lymphoma, lung cancer or prostate cancer.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means suitable for the treatment or prevention of cancer, such as chemotherapeutic agents or combination therapy as described above.

In certain embodiments of the implementation of the present invention, the compound of the present invention can be administered together with non-chemical methods of treatment or prevention of cancer. In certain embodiments of the implementation of the present invention, the compound of the present invention can be administered together with radiotherapy. In certain embodiments of the implementation of the present invention, the connection for us is oasea the invention can be administered together with surgery, with thermoablative, with therapy focused ultrasound or cryotherapy.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to treat or prevent cancer.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a chemotherapeutic agent, as described above. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a chemotherapeutic agent, as described above.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising a chemotherapeutic agent; and

b) instructions relating to the introduction of the first pharmaceutical composition together with a connection to the present is the invention, for example, for the treatment or prevention of cancer.

Infectious diseases

In the present invention proposes a method of treating or preventing an infectious disease in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention infectious disease may be selected from a bacterial infection, parasitic diseases gram-negative bacterial infection, infection, bacteria, Salmonella typhimurium, entering through the mouth infection, fungal or viral infection.

The present invention also offers a method of treating or preventing inflammation associated with infection in a patient, which includes the purpose of the compounds of the present invention. In certain such embodiments, the implementation of the present invention compounds of the present invention can stimulate and increase the production of antimicrobial peptides expressed by epithelial cells (in particular, a bactericidal protein, increases the permeability of cell membranes).

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, p is such combinations may be administered in conjunction with other therapies such as other means suitable for the treatment or prevention of infectious diseases, such as diseases, disclosed in the present description. Examples of drugs suitable for the treatment of infectious diseases include aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin and paromomycin), ansamycins were (for example, geldanamycin and herbimycin), carbacephem (for example, loracarbef), carbapenems (e.g., ertapenem, doripenem, imipenem, and Meropenem), cephalosporins (e.g., cephalo-Smoking, Cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, Cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, Ceftriaxone, cefdinir and cefepime), glycopeptides (e.g. vancomycin), macrolides (eg, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin and spectinomycin), carbapenems (e.g., aztreonam), penicillins (eg, amoxicillin, ampicillin, azlotillin, carbenicillin, cloxacillin, dicloxacillin, Flucloxacillin, mezlocillin, nafcillin, penicillin, piperacillin, tikarcillin), polypeptides (e.g., bacitracin, colistin and polymyxin B), quinolones (eg, ciprofloxacin, enoxacin, Gatifloxacin, Le is ofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin), sulfonamides (e.g., mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilamide, sulfasalazin, sulfisoxazole and trimethoprim), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline and tetracycline), arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomicin, positieve acid, furazolidone, isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, hinopsin, dalfopristin, rifampin and tinidazole.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of drugs suitable for the treatment or prevention of infectious diseases; and c) instructions concerning the introduction of the compounds of the present invention and medicaments suitable for the treatment or prevention of infectious diseases.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) and the regulations, on the introduction of the pharmaceutical composition, for example, to treat or prevent the above diseases, in particular infectious diseases.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a drug suitable for the treatment or prevention of infectious diseases. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug suitable for the treatment or prevention of infectious diseases.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for the treatment or prevention of infectious diseases; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to treat or prevent the above diseases, in particular, infecciones the disease.

Apoptotic status

In the present invention proposes a method of suppressing apoptosis in a patient, which includes the purpose of the compounds of the present invention. The present invention also offers a method of treating or preventing a condition resulting from apoptosis in a patient, which includes the introduction of compounds of the present invention. In certain embodiments of the implementation of the present invention, the condition resulting from apoptosis, may be selected from destruction as a result of myocardial infarction, necrosis of tissue in chronic inflammation, proliferative disorders of smooth muscle (e.g., restenosis after plastic surgery on the blood vessels), inflammatory conditions associated with the contraction of the smooth muscles lining the walls of the arteries (e.g. coronary spasm, ischemia-induced lesions of the myocardium, brain spasm or cerebral ischemia and related disorders such as stroke; diseases associated with thrombosis (for example, coronary thrombosis, phlebitis or phlebothrombosis), and neurodegenerative diseases.

In certain embodiments implementing the present invention features a kit that includes a) one or more single dosage forms of the compounds of the present invention; b) one or is more single dosage forms of medicines suitable for the treatment or prevention of a condition resulting from apoptosis; and (c) of the regulations relating to the introduction of the compounds of the present invention and medicines are suitable to suppress apoptosis or treat or prevent conditions arising as a result of apoptosis.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to suppress apoptosis or treat or prevent conditions arising as a result of apoptosis.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with the drug is suitable for suppression of apoptosis or treat or prevent conditions arising as a result of apoptosis. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms), including the relevant medicinal product, suitable for suppression of apoptosis or treat or prevent conditions arising as a result of apoptosis.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for suppression of apoptosis or treatment or prevention of a condition resulting from apoptosis; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to suppress apoptosis or treat or prevent conditions arising as a result of apoptosis.

The development of blood vessels (angiogenesis)

In the present invention proposes a method of inhibiting the development of blood vessels in a patient, which includes the purpose of the compounds of the present invention. In certain embodiments of the implementation of the present invention compounds of the present invention limit the development of blood vessels, is required for metastasis of solid tumors. Since the development of blood vessels and neovascularization are critical stages in the growth of a solid tumor, the suppression of the development of blood vessels is very useful in order to prevent further growth, samedl the th or even cause reversible development of solid tumors. Examples of tumors that can be treated using the compounds of the present invention, include, but not limited to, gastrointestinal tumors and gliomas.

In certain embodiments of the implementation of the present invention additional disorders or diseases that can be treated or prevented by inhibiting the development of blood vessels (for example, by introducing the compounds of the present invention) include, but not limited to, diabetic retinopathy, rheumatoid arthritis, osteoarthritis, macular degeneration, glaucoma, formation of keloids, ulcerative colitis, Crohn's disease and psoriasis.

In certain embodiments of the implementation of the present invention, various compounds of the present invention can be administered together with one or more other compounds of the present invention. Moreover, such combinations may be administered in conjunction with other therapeutic means, such as other means, suitable for inhibiting the development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels, such as inhibitors of the development of the blood vessels, including, but not limited to, siRNA's, aptamers, angiostatin, endostatin and bevacizumab.

In the definitely variants of implementation of the present invention features a kit of reagents which includes a) one or more single dosage forms of the compounds of the present invention; b) one or more single dosage forms of medicines are suitable to suppress the development of blood vessels or for the treatment or prevention of conditions arising in the development of blood vessels; and (c) of the regulations relating to the introduction of the compounds of the present invention and medicines are suitable to suppress the development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition, for example, to suppress development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with medicinal means is om, suitable for inhibiting the development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a drug, suitable for inhibiting the development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising an agent suitable for inhibiting the development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels; and

b) instructions relating to the introduction of the first pharmaceutical composition together with the compound of the present invention, for example, to suppress development of blood vessels or treatment or prevention of conditions arising in the development of blood vessels.

When they are administered individually or as part of a treatment regimen in certain embodiments of the implementation of this and the finding of the present invention provides for the introduction of compounds of the present invention to treat or prevent specific primary disease, damage, disorder or condition. Certain embodiments of the present invention provide for the introduction of compounds of the present invention to treat or prevent secondary symptoms of primary disease, injury, disorder, or condition.

Conservation bodies

The present invention provides methods of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body, which include introducing the compound of the present invention to the patient, which is the donor organ before he would have taken the body. In the present invention proposes ways to reduce or prevent damage and/or death of stem cells or enhancing the survival and/or persistence of stem cells, which include introducing the compound of the present invention to the patient, which is the donor of the stem cells, before he will be taken stem cells. In certain embodiments of the implementation of the present invention compounds of the present invention is administered to the patient, which is the donor organ and/or stem cells, in less than 24 hours before the removal of an organ, for example, less than 12, eight, six, four or two hours before removal of the organ and/or extraction of stem cells. To identify Alannah variants of implementation of the present invention compounds of the present invention is administered to a patient, which is the donor organ and/or stem cells, immediately before the removal of the organ and/or extraction of stem cells (e.g., less than one hour before removal of the organ and/or extraction of stem cells, for example, less than 30, 15 or 10 minutes before removal of the organ and/or extraction of stem cells). In certain embodiments of the implementation of the present invention a donor organ and/or stem cells is the man.

In certain embodiments of the implementation of the present invention, a patient who is a donor organ and/or stem cell, characterized by brain death. In certain embodiments of the implementation of the present invention “brain death” is defined as the complete cessation of brain function, including the termination of the functions of the brain stem, for example, when there is no oxygen or blood flow to the brain or when none of the functions of the brain is not and never will be again.

In certain embodiments of the implementation of the present invention to the patient, which is the donor organ and/or stem cells is not preceded by a diagnosis of a chronic, transmissible or infectious ailments, for example, for which pharmacological effect is useful or could be useful. In certain embodiments of the implementation of the present invention to the patient, I had laudamus donor organ and/or stem cells, at the moment, is not and has not previously been diagnosed with the presence of diabetes, cancer, high blood pressure, kidney disease or cardiovascular disease such as atherosclerosis or heart disease.

In certain embodiments of the implementation of the present invention a method of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body, including the introduction of the compounds of the present invention to the patient, which is the donor organ before he would have taken the body further includes a stage of removal of an organ in a patient, which is the donor organ. In certain such embodiments, the implementation of the present invention, the organ is selected from one or more organs such as kidney, liver or lobe of the liver, lung or portion of a lung, part of the pancreas, part of the intestines, heart, cornea or tissue (e.g. skin, blood, bone marrow, the blood stem cells or umbilical cord blood).

In certain embodiments of the implementation of the present invention a method of reducing or preventing damage and/or death of stem cells or enhancing the survival and/or persistence of stem cells, comprising introducing the compound of the present invention to the patient, which is the donor of the stem cells, before he will be taken STW is gross cell includes next stage of the selection of stem cells in a patient, which is the donor stem cells.

In certain embodiments of the implementation of the present invention the patient is a donor organ and/or stem cells, represents any suitable patient, which is the donor organ and/or stem cells. In certain embodiments of the implementation of the present invention the patient is a donor organ and/or stem cells, is an animal other than human. For example, a patient who is a donor organ and/or stem cells may be a pig, or Primate, such as a genetically modified animal. In certain such embodiments, the implementation of the present invention the patient is a donor organ and/or stem cells, is an animal that has been genetically modified so that proteins on the surface of the organs of the animal and/or cells are considered to be compatible with the human immune system. For example, a patient who is a donor organ and/or stem cells, may be an animal that has been genetically modified so that proteins on the surface of the organs of the animal and/or cells recognized by the human immune system, so that the organs and/or cells not exposed at the ke at transplantation. In certain embodiments of the implementation of the present invention the patient is a donor organ is a pig.

The present invention provides methods of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body, which include introducing the compound of the present invention to a recipient of an organ prior to transplantation.

In certain embodiments of the implementation of the present invention a method of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body, including the introduction of the compounds of the present invention to a recipient of an organ prior to transplantation, includes next stage of removal of one or more organs of the recipient's body. In certain such embodiments, the implementation of the present invention, the compound of the present invention is administered to the recipient of the authority at any time during the operation of removal of an organ. In certain such embodiments, the implementation of the present invention the stage of removal of one or more organs of the recipient's body is carried out before introducing the compound of the present invention in the body of the recipient. In certain such embodiments, the implementation of the present invention the stage of removing one Il the several organs of the recipient authority simultaneously with the introduction of the compounds of the present invention in the body of the recipient. In certain such embodiments, the implementation of the present invention the stage of removal of one or more organs of the recipient's body is carried out after administration of the compounds of the present invention in the body of the recipient.

In certain embodiments of the implementation of the present invention a method of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body, including the introduction of the compounds of the present invention to a recipient of an organ prior to transplantation, includes next stage of the transplantation of one or more organs in the recipient organ.

In the present invention are also ways to reduce or prevent damage and/or death of stem cells or enhancing the survival and/or persistence of stem cells, comprising introducing the compound of the present invention recipient stem cells prior to stem cell transplantation.

In certain embodiments of the implementation of the present invention a method of reducing or preventing damage and/or death of stem cells or enhancing the survival and/or persistence of stem cells, comprising introducing the compound of the present invention recipient stem cells prior to stem cell transplantation, includes next stage of transplantati the stem cell recipient stem cells.

In the present invention are also ways to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the body, which include contacting the organ with a compound of the present invention.

In certain embodiments of the implementation of the present invention the body is exposed ex vivo with a compound of the present invention. In certain embodiments of the implementation of the present invention the body is in contact with the connection according to the present invention by the method other than the direct supply of the body with blood (for example, the body is in contact with the connection of the present invention beyond its circulatory system). In certain embodiments of the implementation of the present invention the body is in contact with the connection of the present invention, while the organ is still in the patient's body, in the process of removal of an organ from the patient's body, after the body is removed from the patient during the transplant organ recipient, immediately after the organ is transplanted into a recipient, or any combinations thereof.

In the present invention are also ways to reduce or prevent damage and/or death of stem cells or enhancing the survival and/or persistence of stem cells, comprising contacting ETS the business of the cells with the compound of the present invention.

In certain embodiments of the implementation of the present invention, the stem cells are contacted with the compound of the present invention ex vivo (for example, during ex vivo cultivation in a nutrient medium and/or manipulation, for example in ex vivo cultivation of stem cells or manipulate them, with a view to their reproduction and/or differentiation, in the process of cryopreservation of stem cells, in the process of thawing of stem cells after cryopreservation, or during any combination of these actions). In certain such embodiments, the implementation of the present invention, the compound of the present invention is present as a component of culture medium (for example, any culture medium suitable for ex vivo cultivation of stem cells and/or manipulation, cryopreservation of stem cells or thawing of stem cells after cryopreservation).

In certain embodiments of the implementation of the present invention, the stem cells are contacted with the compound of the present invention, while the stem cells are still in the patient's body, in the process of extracting stem cells from the patient after stem cells extracted from the patient's body, during ex vivo cultivation in a nutrient medium and/or manipulation of stem cells(for example, with a view to their reproduction and/or differentiation), in the process of cryopreservation of stem cells, in the process of thawing of stem cells after cryopreservation, stem cell transplant recipient, immediately after the stem cells are transplanted to the recipient or any of their combinations.

In the present invention are also ways to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the body, which include the contacting of the body with a preservative solution, where the preservative solution contains the compound of the present invention.

In certain embodiments of the implementation of the present invention the preservative solution contains the compound of the present invention in a quantity sufficient to reduce, prevent or reverse damage to the body or to improve the persistence and/or survival of the body. In certain embodiments of the implementation of the present invention the preservative solution contains the compound of the present invention with a concentration of from 1 nm to 1 M, for example, from 1 μm to 1 mm. In certain embodiments of the implementation of the present invention the preservative solution further comprises potassium, sodium, magnesium, calcium, phosphate, sulfate, glucose, citrate, mannitol, GI is tidy, tryptophan, alpha-ketoglutaric acid, lactobionic, raffinose, adenosine, allopurinol, glutathione, glutamate, insulin, dexamethasone, gidroxiatilkrahmal, bactrim, trehalose, gluconate or a combination thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs contains sodium, potassium, magnesium or combinations thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs does not contain or contains almost no cells, coagulation factors, nucleic acids such as DNA and/or plasma proteins. In certain embodiments of the implementation of the present invention the solution for preserving organs is sterile. In certain embodiments of the implementation of the present invention the solution for preserving organs is an aqueous solution. In certain embodiments of the implementation of the present invention the solution for preserving organs contains performancesee connection, such as a fluorocarbon or perforaciones. Examples of fluorosurfactants described in publicationsTransplantation, 74(12), 1804-1809, December 27, 2002, andAm. Assoc. of Nurse Anesthetists Journal, 74(3): 205-211, June 2007, and the compounds included in the present invention by reference.

In certain embodiments of the implementation nastojasih the invention, where the method according to the present invention is the reduction, prevention or treatment of damage to the body or increase the persistence and/or survival of an organ, which comprises contacting the organ with a preservative solution, where the preservative solution contains the compound of the present invention, the preservative solution may be any suitable solution, known from the field of technology. Examples of such preservative solutions include, but are not limited to, a solution of University of Wisconsin solution, Krebs-Henseleit, the preservative solution, celsior on®, a solution of 2 hospital St. Thomas (St. Thomas Hospital) containing lactate ringer's solution, Wednesday Collins, European modification of the environment of Collins, the preservative solution Stanford, citrate solution Ross-Marshall, phosphate buffered sucrose solution, the drug Kyoto ET Solution or containing histidine-tryptophan-Ketoglutarate (HTK) preservation solution Bretschneider.

The body may come in contact with preservative solution (or preservation solution may be) containing the compound of the present invention, at any stage of the transplant process. For example, the preservative solution containing the compound of the present invention, can be applied by carrying out the washing of the body, continuous perfusion orhaneli periodicheskoi perfusion of the body through the blood vessels of the body, while the organ is still in the patient's body, during the removal of an organ from the patient's body, after the body is removed from the patient, during an organ transplant recipient, immediately after the organ is transplanted into a recipient, or any combination of them. In certain embodiments of the implementation of the present invention, the solution for the preservation of organs, including the connection of the present invention, injected directly into the blood stream of the body until the body perpusilla blood the cardiovascular system, which may be the cardiovascular system of the donor organ or cardiovascular system of the recipient body.

In certain embodiments of the implementation of the present invention the body may be any organ suitable for transplantation, such as kidney, liver or lobe of the liver, heart, lung or part of the lung, skin, intestine or part of the intestine, cornea, pancreas or part of the pancreas, tissue (e.g., blood, bone marrow, the blood stem cells or umbilical cord blood) or any combination thereof.

In certain embodiments of the implementation of the present invention a stem cell is selected from stem cells of the adult person or stem cells of the embryo. Examples of stem cells include, but are not limited to, a totipotent stem cell, PL is ipotential stem cells, multipotential stem cells, unipotent stem cells, hematopoietic stem cells derived from adipocyte stem cells, endothelial stem cells, stem cells, muscle, stromal cells in the bone marrow (for example, stem cells of the mesenchyme), neural stem cells, stem cells and follicular stem cells. Embryonic stem cells include embryonic stem cells, which are obtained by transferring the nucleus of somatic cells and embryonic stem cells derived from the inner cell mass of the embryo, formed during fertilization. Suitable stem cells include induced pluripotent stem cells regardless of produce whether induced pluripotent stem cells using integrative or reintegrating vectors, with the purpose of expression of one or more reprogramming factors, and/or produce pluripotent stem cells using with small molecules that mimic the effects of overexpression of one or more reprogrammability factors.

In certain embodiments of the implementation of the present invention compounds of the present invention reduce, prevent or reverse damage to the body or increase the persistence of the body is due to protect the body from damage as a result of reperfusion.

In certain embodiments of the implementation of the present invention reduce, prevent or reverse damage to the body, reduce or prevent damage and/or death of the stem cells, to increase the persistence of the body or increase the persistence and/or survival of stem cells by reducing apoptosis or due to protection from apoptosis.

In the present invention proposes a method, which contributes to the survival of the recipient of the transplanted organ, including

introduction compounds of the present invention to the patient, which is the donor organ before removing the body;

introduction compounds of the present invention the recipient of the transplanted organ before transplantation authority;

the contacting of the organ ex vivo with a compound of the present invention;

the contacting of the organ ex vivo with a preservative solution, where the preservative solution contains the compound of the present invention;

or any combination of them.

In the present invention proposes a method, which contributes to the survival of the individual who is the recipient of a transplant of stem cells, including

introduction compounds of the present invention to the patient, which is the donor of the stem cells, before removing stem cells;

introduction connections n the present invention recipient stem cells before transplantation of stem cells;

contacting the stem cells ex vivo (e.g., in a suitable culture medium) with the compound of the present invention;

or any combination of them.

In the present invention proposes a method of facilitating a transaction, the transplantation of an organ and/or increase the likelihood of a successful outcome of organ transplantation, which includes

introduction compounds of the present invention to the patient, which is the donor organ before removing the body;

introduction compounds of the present invention the recipient of the transplanted organ before transplantation authority;

the contacting of the organ ex vivo with a compound of the present invention;

the contacting of the organ ex vivo with a preservative solution, where the preservative solution contains the compound of the present invention;

or any combination of them.

In the present invention proposes a method of facilitating a transaction, the transplantation of stem cells and/or increase the likelihood of a successful outcome of the operation stem cell transplant, which includes

introduction compounds of the present invention to the patient, which is the donor of the stem cells, before removing stem cells;

introduction compounds of the present invention recipient stem cells before conducting the tra is plantacii stem cells;

contacting the stem cells ex vivo (e.g., in vitro in a suitable culture medium, for example, in the process of cryopreservation and/or thawing of stem cells after cryopreservation or in ex vivo culture of stem cells and/or manipulation), with the compound of the present invention;

or any combination of them.

The success of the surgery, organ transplantation and/or stem cells can be evaluated, for example, to reduce side effects and/or symptoms associated with transplant surgery, shorter hospital stay after surgery, organ transplantation and/or stem cells, to reduce the time elapsed between organ transplantation and/or stem cells and restore normal functions and processes in the body (for example, termination needs dialysis, mechanical ventilation, the need for cardiopulmonary bypass or other prosthetic devices such as artificial hearts, and so on), or to increase life expectancy after transplant organ and/or stem cells. In certain embodiments of the implementation of the present invention the success of the surgery, transplantation of an organ can be assessed, for example, to increase the viability of the organ and/or functional long is enosti after transplantation, compared with not processed by the body (for example, can be evaluated by the delay in the needs of the transplant and/or other(CSOs) therapeutic(CSOs) interventions(a)). The presence of any of these features can be seen as increasing the likelihood of successful surgery, organ transplantation and/or stem cells.

In the present invention proposes a method of increasing the viability of the organ ex vivo, which includes

introduction compounds of the present invention to the patient, which is the donor organ before removing the body;

the contacting of the organ ex vivo with a compound of the present invention;

the contacting of the organ ex vivo with a preservative solution, where the preservative solution contains the compound of the present invention;

or any combination of them.

In the present invention proposes a method of increasing the viability of stem cells in ex vivo, which includes

introduction compounds of the present invention to the patient, which is the donor of the stem cells, before removing stem cells;

contacting the stem cells ex vivo (e.g., in vitro in a suitable culture medium, for example, in the process of cryopreservation and/or thawing of stem cells after cryopreservation or ex vivo to the litwinowii stem cells and/or manipulation, for example, when the multiplication and/or differentiation of stem cells) with the compound of the present invention;

or any combination of them.

In the present invention proposes a method of increasing the success of cryopreservation and/or thawing of stem cells after cryopreservation, which includes one or more of the following stages:

introduction compounds of the present invention to the patient, which is the donor of the stem cells, before removing stem cells;

contacting the stem cells ex vivo (e.g., in vitro in a suitable culture medium, for example, in the process of cryopreservation and/or thawing of stem cells after cryopreservation) with the compound of the present invention.

As a rule, the body of the patient can be transferred only much lower levels of chemotherapy, biotherapy and radiotherapy than many other specific organs. In this case, increased and reliable ex vivo viability of the authority would be useful and in addition to the transplantation of an organ, including the possibility of ex vivo therapy. Thus, the methods of the present invention can be applied to the body it was possible to extract the body from the body and to make the processing of the isolated body, thereby reducing the risk of damage to other parts of the body.

In the present invention is proposed to use the body, which perfusion compound of the present invention. In certain embodiments of the implementation of the present invention the body is in ex vivo. The present invention features a body that ex vivo perfusion compound of the present invention. In certain embodiments of the implementation of the present invention the concentration of the compounds of the present invention in the body is more than 1 nm, for example, ranges from 1 nm to 1 M, from 1 mm to 1 M, or from 10 mm to 1 M. In certain embodiments of the implementation of the present invention the hollow body contains a liquid with a concentration of more than 1 nm of the compounds of the present invention, for example, with a concentration from 1 nm to 1 M, from 1 mm to 1 M, or from 10 mm to 1 M.

In the present invention it is also proposed body in contact with the solution for preserving organs and, preferably, partially or fully submerged, where the solution for preserving bodies contains a compound of the present invention. In certain embodiments of the implementation of the present invention the solution for preserving organs additionally contains potassium, sodium, magnesium, calcium, phosphate, sulfate, glucose, citrate, mannitol, histidine, tryptophan, alpha-ketoglutaric acid, lactobionic, raffinose, adenosine, allopurinol, glutathione, glutamate, insulin, dexametha is he, gidroxiatilkrahmal, bactrim, trehalose, gluconate or a combination thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs contains sodium, potassium, magnesium or combinations thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs does not contain or contains almost no cells, coagulation factors, DNA and/or plasma proteins. In certain embodiments of the implementation of the present invention the solution for preserving organs is sterile. In certain embodiments of the implementation of the present invention the solution for preserving bodies contains a compound of the present invention with a concentration of more than 1 nm, for example, with a concentration of more than 10 nm, 100 nm, 1 mm, 10 mm or 100 mm. In certain embodiments of the implementation of the present invention the solution for preserving organs is an aqueous solution. In certain embodiments of the implementation of the present invention the solution for preserving bodies includes perforadora organic compound.

In the present invention proposes a solution for preserving organs, which includes the connection of the present invention. In certain embodiments of the implementation of the present invention the solution is conserved for the bodies I additionally contains potassium, sodium, magnesium, calcium, phosphate, sulfate, glucose, citrate, mannitol, histidine, tryptophan, alpha-ketoglutaric acid, lactobionic, raffinose, adenosine, allopurinol, glutathione, glutamate, insulin, dexamethasone, gidroxiatilkrahmal, bactrim, trehalose, gluconate or a combination thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs contains sodium, potassium, magnesium or combinations thereof. In certain embodiments of the implementation of the present invention the solution for preserving organs does not contain or contains almost no cells, coagulation factors, DNA or plasma proteins. In certain embodiments of the implementation of the present invention the solution for preserving organs is sterile. In certain embodiments of the implementation of the present invention the solution for preserving bodies contains a compound of the present invention with a concentration of more than 1 nm, for example, with a concentration of more than 10 nm, 100 nm, 1 mm, 10 mm or 100 mm. In certain embodiments of the implementation of the present invention the solution for preserving organs is an aqueous solution. In certain embodiments of the implementation of the present invention the solution for preserving bodies includes perfluorinated organic compound.

In this izaberete the AI offers a set of reagents, which contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition to the patient, which is the donor organ before removing the body, with the aim of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the authority, and/or instructions relating to the introduction of the pharmaceutical composition to the patient, which is the donor of the stem cells, before removing the stem cells, to reduce and/or prevent damage and/or death of stem cells or increase the persistence and/or survival of stem cells.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the introduction of the pharmaceutical composition to the recipient body before removing the body, with the aim of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the authority, and/or instructions relating to the introduction of the pharmaceutical composition to the recipient stem cells before extraction of stem cells, which reduce and/or prevent damage and/or death of stem cells or increase the persistence and/or survival of stem cells.

The present invention features a kit that contains

a) a pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention; and

b) instructions relating to the probe body with the pharmaceutical composition to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the authority, and/or instructions regarding contacting stem cells to reduce and/or prevent damage and/or death of stem cells or increase the persistence and/or survival of stem cells.

In certain embodiments of the implementation of the present invention the kit further includes instructions relating to the introduction of a pharmaceutical composition which contains a compound of the present invention, together with a second drug, such as those described above medicines. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a second drug, such as the above medicines. In certain embodiments of the implementation of the infusion is his invention, the kit additionally comprises a second pharmaceutical composition (for example, as one or more single dosage forms) comprising a second drug, suitable for the reduction, prevention or treatment of damage to the body or increase the persistence and/or survival of the body. In certain embodiments of the implementation of the present invention, the kit additionally comprises a second pharmaceutical composition (e.g. in the form of one or more single dosage forms) comprising a second drug, suitable for reducing or preventing damage and/or death of stem cells or increase the persistence and/or survival of stem cells.

The present invention features a kit that contains

a) a first pharmaceutical composition (e.g., one or more single dosage forms) comprising a drug suitable for the regulation of immune function, suppressing immune response, treating an autoimmune disease or autoimmune disorder, or treating disease, complications, or pathological condition that is mediated by the activation of the immune system, described above, or an agent suitable for the reduction, prevention or treatment of damage to the body or increase the persistence and/or survival of the authority or means, suitable for red eye reduction the treatment or prevention of injury and/or death of stem cells or increase the persistence and/or survival of stem cells; and

b) instructions relating to the introduction of the first pharmaceutical composition (e.g., one or more single dosage forms) and the second pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention, in order to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the authority, and/or instructions relating to the introduction of the first pharmaceutical composition (e.g., one or more single dosage forms) and the second pharmaceutical composition (e.g., one or more single dosage forms) comprising a compound of the present invention, to reduce or prevent injury and/or death of stem cells or increase the persistence and/or survival of stem cells.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity through the production of pharmaceutical compositions containing the compound of the present invention, or described in this description of a set of reagents and by giving health care providers the rights to the use of pharmaceutical compositions, in order to reduce, prevent, or treatment of damage to the body or increase when christemasse and/or survival of the body or to reduce or prevent injury and/or death of stem cells or increase the persistence and/or survival of stem cells.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activities by creating a trading network for the sale of compositions or compounds of the present invention or of a set of reagents given in this description, and by developing recommendations for patients or doctors regarding the use of the composition, with the aim of reducing, preventing or treatment of damage to the body or increase the persistence and/or survival of the body or to reduce or prevent injury and/or death of stem cells or increase the persistence and/or survival of stem cells.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity by selecting a suitable composition and dosages of the compounds of the present invention to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the body or to reduce or prevent injury and/or death of stem cells or increase the persistence and/or survival of stem cells by establishing therapeutic profile of the selected song from the point of view of its efficacy and toxicity in animals, and by creating a trading network for sale select the Noah song which has an acceptable therapeutic profile. In certain embodiments of the implementation of the present invention the method also includes creating a sales team for the implementation of the drug on the market for health care providers.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity by selecting a suitable composition and dosages of the compounds of the present invention to reduce, prevent, or treatment of damage to the body or increase the persistence and/or survival of the body or to reduce or prevent injury and/or death of stem cells or increase the persistence and/or survival of stem cells by establishing therapeutic profile of the selected song from the point of view of its efficacy and toxicity in animals, and by passing a third party, the rights for further development and sale of composition.

Definitions

“The development of blood vessels (angiogenesis) is defined as any extension of an existing vascular bed or the formation of a new vascular network, which creates favorable conditions for the perfusion of tissues. The development of blood vessels involves the formation of new blood vessels by sprouting of endothelial cells from existing blood southville remodeling of existing vessels, aimed at increasing the size, maturity, direction or bandwidth vessels to improve the perfusion of tissues with blood.

In this description, the term “corticosteroid” refers to any of corticosteroid hormones by the adrenal glands isolated from the adrenal cortex or obtained synthetically, as well as their derivatives, which are used for the treatment of inflammatory diseases, as specified in this description. Corticosteroids include compounds that are of natural origin, obtained by synthetic or semi-synthetic method, and the like compounds, and characterized by the presence of the steroid nucleus, composed of four condensed cycles, which can be found, for example, in the structure of cholesterol, dihydroxyprogesterone, sigmasterol and lanosterol.

The term “LASIK” in this description is used as an abbreviation to indicate a method of laser-assisted in situ Keratomileusis. It is a type of refractive surgery, which changes the shape of the cornea to change its optical power. Typically, the disk of the cornea is lifted in the form of a rag, and then use the excimer laser to reshape the middle layer of corneal tissue, thereby making surgical alignment. Surgical LASIK can be used to correct myopia, dal is sarcasti and astigmatism.

In this description, the term “immunosuppressive agent” refers to agents that inhibit the body's ability to cause an immunological reaction in response to the presence of antigen/allergen. For example, the ability to fight disease or to reject transplantirovannam body. Another term for these funds is the term “funds to prevent rejection”. They are not only used to treat rejection after transplantation, but also for the treatment of many other diseases immunologic etiology, such as Crohn's disease, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis and other diseases and disorders described in the present description.

The term “graft” in this description refers to the body part, organ, tissue or cells. Grafts may constitute all or part of one or more organs such as liver, kidney, heart or lung; parts of the body such as bone or skeletal matrix; tissue such as skin, intestines, endocrine glands; or precursor cells stem cells of various types.

The term “acyl” is common in the art and refers to a group represented by the General formula uglevodorodno(O)-, preferably alkyls ("O").

The term “acylamino” is commonly used is m in the art and refers to an amino group, substituted acyl group, and may be represented by the General formula uglevodorodno(O)NH-.

The term “acyloxy” is common in the art and refers to a group represented by the General formula uglevodorodno(O)O-, preferably alkyls(O)O-.

The term “alkoxy” refers to an alkyl group, preferably, a lower alkyl group that is attached to the oxygen atom. Examples of alkoxygroup include methoxy, ethoxy, propoxy, tert-butoxy etc.

The term “alkoxyalkyl” refers to an alkyl group substituted by alkoxygroup, and may be represented by the General formula alkyl-O-alkyl.

The term “alkenyl” in this description refers to an aliphatic group containing at least one double bond, and it is assumed that it includes both “unsubstituted of alkenyl” and “substituted alkenyl”, the latter term refers to arcenillas fragments, with the replacement of a hydrogen atom at one or more carbon atoms alkenylphenol group. Such substituents can be one or more carbon atoms, which are included or not included in one or more double bonds. In addition, such substituents include all deputies, which are assumed to alkyl groups, as defined below, except in those cases where substitution is not possible from the points of view of stability of the molecule. For example, it is assumed substitution alkenylphenol group of one or more of alkyl, carbocyclic, heterocyclic or heteroaryl groups.

The term “alkyl” refers to the radical of saturated aliphatic groups, including alkyl groups are straight chain alkyl groups, branched-chain, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl group and cycloalkylation alkyl groups. In preferred embodiments of implementing the present invention, the alkyl straight or branched chain contains in its skeleton 30 or less carbon atoms (for example, C1-C30for normal circuits, C3-C30for branched chains), and more preferably 20 or less carbon atoms. Similarly, the preferred cycloalkyl have in their ring structure from 3-10 carbon atoms and, more preferably, have 5, 6 or 7 carbon atoms in the cyclic structure.

In addition, it should be understood that the term “alkyl” (or “lower alkyl” in the present description, the examples and the formula of the present invention includes both “unsubstituted alkali” and “substituted alkali”, the latter term refers to alkyl fragments, in which the substituents replacing a hydrogen atom at one or more carbon atoms in the skeletal chain hydrocarbon. is such substituents, unless otherwise stated, may include, for example, a halogen atom, a hydroxyl, a carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as a complex tiefer, thioacetate, or thioformate), CNS, phosphoryl, phosphate, phosphonate, Phosphinates, amino, amido, ajdinovic, kinawy, cyano, nitro, azido, sulfhydryl, alkylthio, sulphate, sulphonate, sulfamoyl, sulphonamido, sulfanilyl, heterocyclic, aryl, Uralkaliy, aromatic or heteroaromatic fragment. Professionals should be clear that the fragments which are substituents in the hydrocarbon chain, themselves, if necessary, can be substituted. For example, the substituents in the substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyloxy (including sulfate, sulfonamide, sulfamoyl and sulfate), and silyl groups, as well as ethers, alkylthio, CARBONYLS (including ketones, aldehydes, carboxylates, and esters),-CF3,-CN, etc., Examples of the substituted Akilov below. Cycloalkyl can be optionally substituted by alkilani, alkenylamine, alkoxy groups, alkylthio groups, aminoalkyl, carbonization alkilani,-CF3,-CN, etc.,

It should be understood that the term “Cx-y” is when it is used in combination with chemical fragment, such as acyl, acyloxy, alkyl, alkenyl, quinil or alkoxy includes groups that contain in the chain from x to y carbon atoms. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including alkyl groups with normal chain alkyl groups, branched-chain, which contain in the chain from x to y carbon atoms, including halogen-substituted alkyl groups such as trifluoromethyl and 2,2,2-triptorelin and so0alkyl denotes a hydrogen atom, if the group has a limit position, and a simple link, if it is inside the chain. The terms “C2-yalkenyl” and “C2-yquinil” refers to substituted or unsubstituted unsaturated aliphatic groups, which are analogous in length and possible substitution to the above Akilov, but contain at least one double or triple bond, respectively.

The term “alkylamino” in this description refers to the amino group, substituted by at least one alkyl group.

The term “alkylthio” in this description refers to Tilney group, substituted alkyl group, and it can be represented by the General formula S-.

The term “quinil” in this description refers to an aliphatic group containing at least one triple bond, and it is assumed that about which includes both “unsubstituted alkinyl”, and “substituted alkinyl”, the latter term refers to alkynylaryl fragments, in which the substituents replacing a hydrogen atom at one or more carbon atoms Salcininkai group. Such substituents can be one or more carbon atoms, which includes or does not include one or more triple bonds. In addition, such substituents include all alternates considered to alkyl groups, as described above, except when not provided the necessary stability of the molecule. For example, a Deputy in Salcininkai group may be one or more alkyl, carboxyl, aryl, heterocyclic or heteroaryl groups.

The term “amide” in this description refers to a group

where each R10independently denotes a hydrogen atom or a hydrocarbon group, or two groups R10together with the N atom to which they are attached complete a heterocycle containing 4 to 8 atoms in the cyclic structure.

The terms “amine” and “amino” are conventional in the art and refer to both unsubstituted and substituted amines and their salts, in particular, to the fragments, which can be represented by the formula

where each R10regardless about who appoints a hydrogen atom or a hydrocarbon group, or two groups R 10together with the N atom to which they are attached complete a heterocycle containing 4 to 8 atoms in the ring structure.

The term “aminoalkyl” in this description refers to an alkyl group, substituted amino group.

The term “aralkyl” in this description refers to an alkyl group, substituted aryl group.

The term “aryl” includes substituted or unsubstituted monocyclic aromatic group in which each atom in the cycle is the carbon atom. Preferably, the cycle is a 5-7-membered nucleus, more preferably a 6-membered nucleus. The term “aryl” also includes multi-core cyclic system having two or more cycles in which two or more carbons are common to two adjacent loop, where at least one of the nuclei is aromatic, for example, other cycles can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocycles. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.,

The term “carbamate” is common in the art and refers to groups

where R9and R10independently represent a hydrogen atom or a hydrocarbon group such as an alkyl group, or R9and R10together with placed Ashima(UIS) between the atom(s) completing the heterocycle, containing from 4 to 8 atoms in the cyclic structure.

The terms “carbocycle”, “carbocyclic” or “carbocyclic” in this description refers to non-aromatic saturated or unsaturated cycles, in which each atom in the cycle is the carbon atom. Carbocycle preferably contains from 3 to 10 carbon atoms, more preferably contains from 5 to 7 carbon atoms.

The term “carbocyclic” in this description refers to an alkyl group, a substituted carbocyclic group.

The term “carbonate” is common in the art and refers to a group-OCO2-R10where R10is a hydrocarbon group.

The term “carboxy” in this description refers to a group represented by the formula-CO2H.

The term “ester” in this description refers to the group-C(O)OR10where R10is a hydrocarbon group.

The term “simple” air " in this description refers to a hydrocarbon group, which is connected to an oxygen atom on the other hydrocarbon group. Thus, the essential Vice of the hydrocarbon group may be a hydrocarbon-O-. Ethers can be both symmetric and asymmetric. Examples of ethers include, but not limited to, a heterocycle-O-heterocycle, and aryl-O-heterocycle. The ethers include, “oxyalkylene” group, which can be represented by the General formula alkyl-O-alkyl.

The term “halogen” in the present description means a halogen atom and includes atoms of chlorine, fluorine, bromine and iodine.

The terms “heterarchy and heteroalkyl” in this description refers to an alkyl group substituted retailnow group.

The term “heteroalkyl” in this description refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, in which no two adjacent heteroatoms.

The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structure, preferably a 5-7 membered cycles, more preferably 5-6-membered cycles, cyclic structures which include at least one heteroatom, preferably, include one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include multi-core cyclic system having two or more cycles in which two or more carbons are common to two adjoining rings, at least one of the cycles is heteroaromatic, for example, other cycles can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocycles. Heteroaryl groups include, for example, Pirro is, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazin, pyridazine and pyrimidine, etc.,

The term “heteroatom” in this description means an atom of any element other than a carbon atom or hydrogen atom. Preferred heteroatoms are nitrogen atom, an oxygen atom or a sulfur atom.

The terms “heterocyclyl”, “heterocyclyl” and “heterocyclic” refer to substituted or unsubstituted non-aromatic cyclic structures, preferably 3-10-membered cycles, more preferably, 3 to 7-membered cycles, cyclic structures which include at least one heteroatom, preferably, include one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also includes multi-core cyclic system having two or more cycles in which two or more carbons are common to two adjacent cycles, at least one of the cycles is heterocyclic, for example, other cycles can be cycloalkyl, cycloalkenyl, cycloalkenyl, arily, heteroaryl and/or heterocycles. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, etc.,

The term “geterotsiklicheskikh” in this description refers to ulcellnogouro, substituted heterocyclic group.

The term “hydrocarbon radical” in this description refers to a group attached through a carbon atom, which has no substituents =O or =S and usually has at least one bond carbon-hydrogen and skeleton, composed mostly of carbon atoms, but may not necessarily include heteroatoms. So, in this specification, the hydrocarbon radicals are groups such as methyl, ethoxyethyl, 2-pyridyl and trifluoromethyl, and such substituents as acetyl (which has a Deputy, =O when participating in bond formation carbon atom), ethoxy (which is connected via an oxygen atom, and not through a carbon atom) are not considered to be hydrocarbon radicals. Hydrocarbon radicals include, but are not limited to, aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, quinil and combinations thereof.

The term “hydroxyalkyl” in this description refers to an alkyl group substituted by a hydroxy-group.

The term “lower” when used in combination with chemical fragment, such as acyl, acyloxy, alkyl, alkenyl, quinil or alkoxy means that it includes groups, where the Deputy, contains ten or fewer atoms other than hydrogen atom, mostly six or fewer atoms. “Lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably, six or less carbon atoms. In certain embodiments of the implementation of the present invention acyl, acyloxy, alkyl, alkeline, alkyline or alkoxysubstituted listed in this description represent, respectively, lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower quinil or lower alkoxy, regardless of whether they appear individually or in combination with other substituents, such as in the above hydroxyalkyl and aralkyl (in this case, for example, the atoms in the aryl group does not take into account when calculating the carbon atoms in the alkyl Deputy).

The terms “politically”, “politics” and “polycyclic” refers to two or more cycles (in particular, cycloalkyl, cycloalkenyl, cycloalkenyl, anilam, heteroaryl and/or heterocycles), in which two or more atoms are common to two adjacent cycles, such as cycles are “condensed cycles”. Each of the cores polycycle may be substituted or unsubstituted. In certain embodiments of the implementation of the present invention, each core of politicla contains from 3 to 10 atoms in the cycle, preferably, from 5 to 7 atoms.

The term “silyl group” refers to silicon-based fragment, which includes three attached carbohydrate is adnych fragment.

The term “substituted” refers to the fragments, having the substituents that replace the hydrogen atom at one or more carbon atoms in the skeleton. It should be understood that “substitution” or “substituted”, of course, implies that such substitution complies with permitted valence of the substituted atom and the substituent, and that the substitution leads to the formation of stable compounds, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc., it is Assumed that in the present description the term “substituted” includes all permitted in organic compounds the substituents. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents in organic compounds. Permitted substituents may be present in the singular or in larger quantities and may be the same or different for the respective organic compounds. In the present invention, the heteroatoms such as nitrogen atom, may have hydrogen substituents and/or any authorised in organic compounds the substituents described herein which satisfy the valencies of the heteroatoms. Replace the and can include any substituents, described in this description, for example, halogen atom, hydroxyl, a carbonyl (such as carboxyl group, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioether, thioacetal or thioformate), CNS group, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amicin, Imin, cyano, nitro, azido, sulfhydryl, alkylthio, sulphate, sulphonate, selfamily sulfonamidnuyu, sulfanilyl, heterocyclyl, Uralkaliy, aromatic or heteroaromatic fragment. Professionals should be clear that the fragments which substituents in the hydrocarbon chain, in turn, if necessary, can be substituted. Unless specifically indicated “unsubstituted”, it should be understood that references to chemical fragments in this description includes the substituted options. For example, reference to “aryl” group, or fragment, of course, includes both substituted and unsubstituted options.

The term “sulfate” is common in the art and refers to the group-OSO3H, or its pharmaceutically acceptable salt.

The term “sulfonamide” is common in the art and refers to the groups represented by the formula

where R9and R10independently represent a hydrogen atom or a hydrocarbon group, such as Skil, or R9and R10together with(UIS) between the atom(s) enclose a heterocycle containing 4 to 8 atoms in the ring structure.

The term “sulfoxide” is common in the art and refers to the group-S(O)-R10where R10is a hydrocarbon group.

The term “sulfonate” is common in the art and refers to a group of SO3H, or its pharmaceutically acceptable salt.

The term “sulfon” is common in the art and refers to the group-S(O)2-R10where R10is a hydrocarbon group.

The term “thioalkyl” in this description refers to an alkyl group substituted Tilney group.

The term “complex tiefer” in this description refers to the group-C(O)SR10or-SC(O)R10where R10is a hydrocarbon group.

The term “simple tiefer” in this description is equivalent to the simple ether, in which the oxygen atom is replaced by a sulfur atom.

The term “urea” is common in the art and may be represented by the General formula

where R9and R10independently represent a hydrogen atom or a hydrocarbon group such as alkyl, or R9and R10together with(UIS) between the atom(s) completing g tetracycl, containing from 4 to 8 atoms in the ring structure.

“Protective group” refers to a group of atoms that when they are attached to a reactive functional group in the molecule, mask, reduce reactivity or hinder the reactivity of the functional groups. Typically, the protective group, if necessary, can be selectively removed in the process of synthesis. Examples of protective groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3rdEd., 1999, John Wiley & Sons, NY and Harrison et al.,Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Examples astonishing groups include, but are not limited to, formyl, acetyl, trifluoracetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilylethynyl ("TES"), trailing and substituted trityloxy group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitroferricyanide ("NVOC") and similar Examples hydroxyamine groups include, but are not limited to, such groups, where the hydroxyl group or allerban (etherification), or alkylated such as benzyl and triteleia esters, and alkyl ethers, tetrahydropyranyl esters, trialkylsilyl esters (for example, the TMS group or TIPS), glycol ethers such as ethylene is likely and derivative compounds propylene glycol, and allyl ethers.

The term “providers” refers to the people and organizations that provide medical services to an individual, community people, etc., Examples of healthcare providers include physicians, nursing homes, providing continuous medical care, medical facilities, providing complete care for the elderly or persons with disabilities, institutions for the care of patients after the acute phase of the disease, clinic, clinics, wide profile, independent ambulatory centers, agencies, medical care and home health maintenance organization.

The term “treating” refers to preventing a disease, disorder or condition in a cell, tissue, organism, animal or person who may be predisposed to the disease, disorder and/or condition, and the presence of such disease, disorder or condition can be diagnosed; to stabilize the disease, disorder or condition, i.e., to stop its development; and to eliminate one or more symptoms of a disease, disorder or condition, i.e., to the ability to cause regression of the disease, disorder and/or condition.

In this description of therapeutic agent, which prevents disorder or C is bolovanje, refers to a connection that, in the statistical sample, reduces the occurrence of disorder or disease receiving treatment specified statistical sample, compared with not receiving treatment statistical breakdown or delays the onset or reduces the severity of one or more symptoms of a disorder or disease in comparison with treated reference sample.

In this description, “a complex disease with an inflammatory component” means a condition in which the primary pathology/dysfunction in a specific tissue or organ, which is essential for the biological function of the body of the individual, leads to secondary systemic metabolic disorder and/or stress in the tissue that cause activation of the immune system or lead to a further strengthening of immune system activation, which leads to dysfunction of multiple organs, vital for maintaining homeostasis of the organism.

The pharmaceutical composition

Compositions and methods according to the present invention can be applied to the treatment needs of the individual. In certain embodiments of the implementation of the present invention the individual is a mammal, such as human or non-human mammal. When they are administered to an animal, such as man, is the song or the connection is preferably introduced in the form of pharmaceutical compositions which includes, for example, the compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known from the technical field and include, for example, aqueous solutions such as water or buffered saline or other solvents or carriers, such as glycols, glycerol, oils such as olive oil, or suitable for injectable organic esters. In a preferred embodiment of the present invention, when such pharmaceutical compositions intended for the introduction of man, the aqueous solution is pyrogen-free or substantially pyrogen-free. Inert fillers can be selected, for example, to implement a delayed release agent or for selective targeting of one or more cells, tissues or organs. The pharmaceutical composition may be in the form of standard dosage forms such as tablet, capsule (including small capsule and gelatin capsule, granule, powder, syrup, suppository, injection, etc., the Composition may also be contained in the delivery system through the skin, in particular applied to the skin adhesive. The composition may also be contained in the solution for local application, such as eye drops.

Pharmaceutically acceptable carrier can the soda is to press a physiologically acceptable medium, which is aimed at stabilizing or increasing the absorption of compounds such as the compound of the present invention. Such physiologically acceptable means include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or inert fillers. The choice of pharmaceutically acceptable carrier, including a physiologically acceptable medium, depends on the route of administration of the composition. Pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, which can include, for example, the compound of the present invention. For example, liposomes, which include phospholipids or other lipids, are nontoxic, physiologically acceptable and involved in the metabolism carriers, which are relatively easy to prepare and apply.

The expression “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions and/or dosage forms which are in accordance with the opinion of a doctor, made after examination of the patient, suitable for use in contact with the tissues of humans and animals without excessive toxicity and causing restage the Oia, allergic reactions or other problems or complications, commensurate with a reasonable ratio of benefit/risk.

The expression “pharmaceutically acceptable carrier” in this description means a pharmaceutically acceptable substance, composition or environment for medicines, such as liquid or solid filler, solvent, excipient, solvent or encapsulating substance. Each carrier must be “acceptable” in the sense that it is compatible with other ingredients of the composition and is not harmful impact on the patient. Some examples of substances which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; (4) powder tragakant; (5) malt; (6) gelatin; (7) talc; (8) inert fillers, such as cocoa butter and wax for suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as etiloleat and tillaart; (13) the Gar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical compositions.

Pharmaceutical composition (preparation) can be administered to a patient by any method, including, for example, oral path (for example, using devices for infusion of medication in the form of aqueous or non-aqueous solutions or suspensions, tablets, capsules (including small capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue); the absorption through the mucous membranes of the mouth (for example, sublingual); anal, rectal or vaginal route (for example, in the form of a vaginal suppository, cream or foam); parenteral (including intramuscular, intravenous, subcutaneous or vnutriobolochechnoe way of introduction, for example, in the form of a sterile solution or suspension); nasal path; intraperitoneally path; subcutaneous path; percutaneous path (for example, in the form of patches on the skin); and local application (for example, in the form of a cream, ointment or spray, which is applied to the skin, or in the form of eye drops). Of the compounds can also be prepared composition for inhalation. In certain variant of the x implementation of the present invention, the connection can simply be dissolved or suspended in sterile water. Details of the respective routes of administration and compositions suitable for such introduction can be found, for example, in U.S. patents№ 6110973, 5763493, 5731000, 5541231, 5427798, 5358970 and 4172896 and specified patents.

The composition can be cooked in a standard dosage forms, and they can be prepared by any well-known pharmaceutical methods. The amount of active ingredient which can be combined with the carrier substance for the preparation of standard dosage forms, varies depending on the patient, the treatment is carried out, and the particular route of administration. The amount of active ingredient which can be combined with the carrier substance for the preparation of standard dosage forms, usually represents such an amount that provides a therapeutic effect. In the General case, on the basis of one hundred percent, this amount is from about 1% to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably, from about 10 percent to about 30 percent.

Methods of obtaining these compositions include the stage of combining active compounds such as the compound of the present invention, with a carrier and optionally with one who does more auxiliary ingredients. In the General case, the composition is prepared by uniform and thorough mixing of the compounds of the present invention with liquid carriers, or with carefully powdered solid carriers, or both types of media, and then, if necessary, the product shape.

The compositions of the present invention suitable for oral destination can be in the form of capsules (including small capsules and gelatin capsules, sachets, pills, tablets, pellets (which use a flavored basis, usually sucrose and gum or tragakant), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquid, or as an emulsion of the type oil-in-water or water-in-oil, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and Arabian gum) and/or liquid for mouth rinses, and each of these compositions contains a certain number of compounds of the present invention as an active ingredient. Compositions or compounds can also be administered in the form of bolus, medicinal porridge and pasta.

For preparing solid dosage forms for oral administration (including small capsules and gelatin capsules, tablets, pills, pills, powders, granules, etc.,) the active ingredient is mixed is with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and/or any of the following compounds: (1) fillers or dry diluents, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or Arabian gum; (3) humectants, such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) slow dissolution of additives such as paraffin; (6) absorption accelerators, such as Quaternary ammonium base; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules (including small capsules and gelatin capsules, tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using such inert excipients as lactose or milk sugar and high molecular shall polietilenglikoli etc.

Tablets can be prepared by compressing or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using binder (for example, gelatin or hydroxymethylcellulose), lubricant, inert diluent, preservative, raising agent (such as sodium starch glycolate or Poperechnaya sodium carboxymethyl cellulose), surface-active agent or dispersing agent. Molded tablets can be made by molding in a corresponding device of a mixture of the powdered compound moistened inert liquid diluent.

Tablets and other solid dosage forms of pharmaceutical compositions such as tablets, capsules (including small capsules and gelatin capsules, pills and granules, may not necessarily have notches or they can be coated with coatings and shells, such as intersolubility coatings and other coatings well known in the field of preparation of pharmaceutical compositions. One can also prepare the compositions in such a way as to provide slow or controlled release of the active ingredient, using, for example, hypromellose in different proportions in order to obtain the desired release profile, other polymer matrices, liposomes and/or the microspheres. They can be sterilized, for example, by filtration through inhibiting bacteria filter or by incorporating sterilizing means in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environment for injection immediately before use. These compositions optionally may also contain a radio-opaque components and may be of such composition that they release the active(s) ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally, by a prolonged release. Examples of substances that can be included in the compositions include polymeric substances and waxes. The active ingredient may also be in microencapsulating form, if necessary together with one or more of the above inert fillers.

Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, soljubilizatory and emulsifiers such as ethyl alcohol, isopropyl the th alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut oil, corn oil of wheat germ, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, polyethylene glycols and esters sorbitan with fatty acids and mixtures thereof.

Besides inert diluents, the oral compositions can also include ancillary tools, such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavors, pigments, perfume and preservatives.

In addition to the active compounds, the suspension may contain suspendresume means, such as, for example, ethoxylated soteriology alcohols, polyoxyethylene sorbitol, esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

Formulations of the pharmaceutical compositions for rectal, vaginal or urethral injection can be a suppositories which can be prepared by mixing one or more active compounds with one or more suitable not irritating inert fillers or carriers, for example cocoa butter, polyethylene glycol, suppozitornyj wax or a salicylate, which are solid widestudio room temperature, but become liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Formulations of pharmaceutical compositions for administration through the mouth can be a liquid mouth rinse, or spray for the mouth, or ointment for mouth.

Alternatively or additionally can be prepared compositions for insertion through a catheter, stent, wire, or other intraluminal device. Delivery through such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum or bowel.

Formulations suitable for vaginal administration, also include vaginal suppositories, tampons, creams, gels, pastes, foams or compositions sprays containing such carriers as are known from the art are suitable for this application.

Dosage forms for local or percutaneous injection include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and drugs for inhalation. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffer additives or gases-displacers that you may need.

Ointments, pastes, creams and gels may contain, in addition to actively connected to the Yu inert fillers, such as animals and solid vegetable fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicone compounds, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to the active compound of inert fillers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary gases sprayers, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The transdermal patches have the added advantage consists in the fact that they provide a controlled release into the patient connection of the present invention. Such dosage forms can be prepared by dissolving or dispersing the active compound in an appropriate environment. To increase the flow of compounds through the skin can be used amplifiers absorption. The rate of such flux can be controlled either by using controlling membrane or by dispersing the compound in a polymer matrix or gel.

It is assumed that the ophthalmic composition, eye ointments, powders, solutions, etc. takewhat in the scope of the present invention. Examples of ophthalmic compositions are given in applications for U.S. patent No. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. patent No. 6583124, the contents of which are incorporated into this description by reference. If necessary, liquid ophthalmic compositions have properties similar to the properties of the tear fluid, aqueous humor or the vitreous body or compatible with such liquids. The preferred route of administration is the local application (for example, local introduction, such as the use of eye drops or introduction via an implant).

The phrase “parenteral administration” or “put parenteral” in this description means a route of administration other than enteral or local injection, which is carried out by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, vnutriobolochechnoe, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneally, transtracheal, subcutaneous, intradermal, intra-articular, pagkapanalo, subarachnoid, vnutrismennyh and epigastric injection and infusion.

Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile as a result of isotopically and aqueous or nonaqueous solutions, the dispersions, suspensions or emulsions, or are sterile powders which may be recovered in the form of a sterile solution or dispersion for injection immediately before use, the composition may contain antioxidants, buffer additives, antimicrobial additives, dissolved substances, which make the composition isotonic with the blood of the intended recipient, or suspendresume funds or thickeners.

Examples of suitable aqueous and nonaqueous carriers which may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.,) and their suitable mixtures of vegetable oils, such as olive oil, and suitable for injectable organic esters, such as etiloleat. The proper fluidity can be maintained, for example, by using the coating substances, such as lecithin, due to selection of the required particle size in the case of dispersions and by using surface-active substances.

These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by incorporating various antibacterial the data and antifungicide funds for example, paraben, chlorobutanol, phenol, sorbic acid, etc., it is also Desirable to include in the composition isotonic agents such as sugars, sodium chloride, etc., in Addition, prolonged absorption of the injection pharmaceutical form can be ensured by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, to extend the influence of drugs, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous substances poorly soluble in water. In this case, the rate of absorption of the drug depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenteral introduced forms of drugs is achieved by dissolution or suspension of the drug in an oil medium.

Injections of long-acting drugs are prepared, getting microencapsulation matrix of the desired compounds in biodegradable polymers such as polylactide-polyglycolides.

Depending on the relationship of the medicinal product to which alimera and the type of polymer used, you can control the rate of release of the drug. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injections of long-acting drugs are prepared by incorporating the drug in liposomes or microemulsions that are compatible with body tissues.

In the methods of the present invention the active compounds can be used individually or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with pharmaceutically acceptable carrier.

The methods of introduction may also be rechargeable or biodegradable devices. Recently been developed and tested in terms ofin vivovarious slow release polymeric devices for controlled drug delivery, including proteinopathies biopharmaceutical drugs. Can be used a variety of biocompatible polymers (including hydrogels), including biodegradable and biodegradable polymers in order to prepare the implant for sustained release of compounds in specific targeted location.

The actual dosing levels of active ingredients in the pharmaceutical compositions can various is so, to get the quantity of active ingredient which is effective to obtain a desired therapeutic response for a particular patient, compositions and mode of administration, however, they should not be toxic for the patient.

The selected dosage will depend on many factors, including the activity of the specific compound or combination of compounds, or a complex ester, salt or amide, route of administration, time management, speed of deducing of a particular(s) used(s) connection(s), duration of treatment, other drugs, compounds and/or substances used in combination with specific(and) (and) of the compound(s), age, sex, weight, condition, General health and prior medical history of the patient, the treatment is carried out, as well as factors that are well known from the field of medicine.

Normal physician or veterinarian will readily be able to identify and prescribe a therapeutically effective amount of the desired pharmaceutical composition. For example, the physician or veterinarian could start doses of the pharmaceutical compositions or compounds, the level of which is lower than required to achieve the desired therapeutic effect and gradually increase the dosage up until the desired effect is reached. Under “terap wtiches effective amount” refers to the concentration of compounds which is sufficient to elicit the desired therapeutic effect. In the General case, means that the effective number of connections will vary depending on the weight, sex, age and medical history of the patient. Other factors which influence the effective amount may include, but not limited to, the severity of the patient's condition, disorder, treatment is carried out, the stability of the connection and, if necessary, the type of the other therapeutic agent used together with the compound of the present invention. The most common dose can be administered by means of many times. The means of determining the effectiveness and dosages known in the art (Isselbacheret al.(1996) Harrison''s Principles of Internal Medicine 13th ed., 1814-1882, the document included in this description by reference).

In the General case, a suitable daily dose of the active compounds used in the compositions and methods of the present invention, will be so many connections, which is the lowest dose effective to achieve therapeutic effect. Such an effective dose in the General case will depend on the above factors.

If necessary, the effective daily dose of the active compounds can be introduced in the form of one, two, three, four, five, six or more subdot,which is administered separately at appropriate intervals throughout the day, not necessarily, in the form of a standard dosage forms. In certain embodiments of the implementation of the present invention, the active compound may be applied two or three times a day. In preferred embodiments, the implementation of the present invention the active compound is prescribed once a day.

The patient receiving said treatment is any need treatment to animals, including primates, in particular humans and other mammals, such as horses, cattle, swine and sheep; and poultry and Pets in General.

In certain embodiments of the implementation of the present invention compounds of the present invention can be used independently or be administered in conjunction with another type of therapeutic agent. In this description, the expression “joint appointment” refers to any form of introducing two or more different therapeutic compounds in such a way that the second connection is injected when the previously introduced therapeutic connection is still effectively in the body (for example, two connections at the same time effective for the patient to induce synergistic effects of the two compounds). For example, various therapeutic compounds can be administered either in the same composition or in separate compositions, both simultaneously and posledovatel the but. In certain embodiments implementing the present invention of various therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or within one week after another. Thus, the individual who receives such treatment, you may experience beneficial effects from the joint effect of various therapeutic compounds.

The present invention includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments of the implementation of the present invention corresponding salts of the present invention include, but are not limited to, alkyl, disciline, trialkylamine or tetraalkyl ammonium salts. In certain embodiments of the implementation of the present invention, the estimated salt of the present invention include, but are not limited to, salts of L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, Ethylenediamine, N-methylglucamine, geranamine, 1H-imidazole, lithium hydroxide, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)the research, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine, trom the Tamina and zinc hydroxide. In certain embodiments of the implementation of the present invention, the estimated salt of the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn and other metals.

Pharmaceutically acceptable acid additive salts may also exist in different solvate, for example, water, methanol, ethanol, dimethylformamide, etc. May also be prepared mixture of such solvate. The source of such solvate can be used in the crystallization solvent, the solvent used for crystallization or additional solvent to said solvent.

The compositions may also be available wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as pigments, agents that promote the release of medicines, covering tools, sweeteners, flavorings and flavoring, preservatives and antioxidants.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.,; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylsilane hydroxyanisol (BHA), bucillamine hydroxytoluene (BHT), lecite is, propylgallate, alpha-tocopherol, etc.,; and (3) agents that form chelates with metals, such as citric acid, ethylenediaminetetraacetic acid (edtc), sorbitol, tartaric acid, phosphoric acid, etc.,

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity through the production of compositions of the compounds of the present invention or of a set of reagents as described herein, and by giving health care providers the opportunity to use the specified composition or a specified set of reagents for the treatment or prevention of any diseases or conditions described in this description.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activities by creating a trading network for the marketing of compositions from the compounds of the present invention or of a set of reagents given in this description, and by providing instructions to patients or physicians regarding the use of a composition for the treatment or prevention of any diseases or conditions described in this description.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity by selecting a suitable HDMI is tion and dosage of the compounds of the present invention to treat or prevent any diseases or conditions, described in this description, by establishing animal therapeutic profile of selected compositions from the point of view of their toxicity and efficiency and by creating a trading network for the sale of the selected song, which has an acceptable therapeutic profile. In certain embodiments of the implementation of the present invention the method also includes creating a sales team for the implementation of the drug on the market for health care providers.

In certain variations of the present invention relate to the implementation of pharmaceutical commercial activity by selecting a suitable composition and dosages of the compounds of the present invention to treat or prevent any diseases or conditions described herein, and by passing a third party, the rights for further development and sale of composition.

EXAMPLES

Example 1. Ophthalmic pharmacokinetics (distribution) study on Dutch rabbits

Assess the tissue distribution of eye connection 1001

and the corresponding complex ester, compound 1002,

in the eye tissues Dutch rabbits after topical application to the eye surface.

Healthy young adults Dutch rabbits (he is s/females; at least 1.5 kg) will have acclimatised for at least 7 days before the start of the research. Prior to the research, conduct the examination of the eyes of rabbits to make sure that the eyes of rabbits do not have any defects that may affect the integrity of research results. Inspection carried out by competent researchers.

Animals locally through the eyes of the injected dose using the device for pipetting, which takes 30 ál of liquid in each eye. Each animal is injected dose at T=0. The right eye receives a dose of a compound 1001 with a concentration of 300 μg/ml, and the left eye receives a dose of a compound 1002 with a concentration of 300 μg/ml intervals listed in Table 3, animals kill.

Table 3
GroupThe number of animalsVolume doseTest the connection, right eyeTest the connection, the left eyeTime killing
1230 ál100110020.25 hour
2230 ál100110020,50 h
3230 ál100110021 hour
4230 ál100110022 hours
5230 ál100110026 hours

Animals subjected to euthanasia with an overdose injection of barbiturate, and each animal extract eye. Using for each eye new or vietmedia tools, eye dissect and identify the following tissues for analysis: conjunctiva, ocular fluid, the cornea, lens, vitreous body, iris/ciliary body, retina/choroid of the eye, optic nerve and sclera. Every tissue is rapidly frozen in liquid nitrogen and stored at a temperature of -80°C for further analysis.

Analysis of tissues of the eye

Not wanting to associate themselves with any of Liberia, the authors of the present invention suggest that both compounds, 1001 and 1002, the metabolism converted into the corresponding carboxylic acid compound 1003,

where M denotes N (compound 45) or a pharmaceutically acceptable cation such as ammonium, tetraalkylammonium, ion Na (compound Z), K, Mg and Zn. Not wishing to be bound by any theory, the authors present invention believe that the connection 1003 or its metabolite(s) primarily responsible for the biological activity associated with the connection 1001. Connection 1003 extracted from the tissue of the eye (cornea, retina) by homogenization and subsequent precipitation of the protein with 4 parts of acetonitrile containing internal standard. The resulting supernatant is dried in a nitrogen atmosphere and prepare a concentrated solution in mobile phase A. the Connection 1003 extracted from the aqueous humor/vitreous body by deposition of a protein using 5 parts of acetonitrile containing internal standard. The resulting supernatant is dried in a nitrogen atmosphere and restore in the form of a concentrated solution in mobile phase A.

Mobile phase And add to the rabbit cornea (~80 mg) so that the final concentration was 5% solids (wt./vol.). Corneal homogenized d is as long until you get a homogeneous suspension. To obtain homogenizate blank sample combine multiple corneas and spend homogenization.

Mobile phase And add to the rabbit retina (~75 mg) so that the final concentration was 7% solids (wt./vol.). Retinal homogenized until then, until a homogeneous suspension. To obtain homogenizate blank sample combine multiple retinas and spend homogenization.

Solutions with the exact number of standards are prepared by diluting the ethanol compound 1003 in the form of its sodium salt (in particular, M represents Na) (dissolved in ethanol) so that the range of concentrations of compounds 1003 ranged from 0,100 to 4000 ng/ml Receive two standard curves and consistently carry out their analysis before and after samples.

1 volume of homogenizate (100 μl) in the case of the samples and blank samples add 1/10 volume (10 μl) of ethanol and 1/10 volume (10 µl) of the solution with the exact amount added to the standards. Add 4 volumes of acetonitrile containing 12.5 ng/ml internal standard (400 μl) and the sample gently stirred for ~1 min, and then centrifuged for 10 min with a value of 3200 relative centrifugal force. The supernatant liquid is separated (~400 ml), dried in a nitrogen atmosphere at 0°C and again restored in 100 μl of a 5 mm solution of ammonium acetate.

Alternatively, the standards are prepared by diluting the compound 1003 in the form of its sodium salt (i.e., M represents Na) directly in the idle homogenizate so that the range of concentrations of compound 1003 ranged from 0,0100 to 400 ng/ml. This avoids further add 1/10 volume (10 μl) of ethanol in the samples and blank samples for subsequent extraction.

Connection 1003 in the samples after homogenization, extraction and recovery analyze by LC/MS/MS using D4-PGE2 as an internal standard. Detection is performed using the mass spectrometer Applied Biosystems API 4000 in the following way:

LC Predalone: Aqua C18 4×2.0 mm, 3 μm, Phenomenex # AJ0-7510

Column: Luna C18(2) 30×2.0 mm, 3 μm, Phenomenex # 00A-4251-BO

The mobile phase A: 5 mm ammonium acetate in water

The mobile phase B: 5 mm ammonium acetate in a mixture of 95:5 acetonitrile:water

Gradient:t = 05% B
t = 1 min.5% B
t = 1.5 min40% B
t = 2,0 min40% B
t = min 2,75100% B
t = 4,15 min100% B
t = 4,25 min5% B
t = min 4.75V5% B

Volumetric flow rate: 0.5 ml/min

Injection volume: 50 ál

Scan type MS:noise reduction
Polarity:negative
Ion source:elektrorazpredelenie
The transfer of the analyte:m/z from 260,95 to USD 114.9
Transfer internal standard:m/z from 355,0 to 275,3

Linear standard curve ratio of the area of concentration of compound 1003 receive, multiplying by a weighting factor 1/x2.

Analysis of ocular fluids:

Connection 1003 extracted from the aqueous humor/vitreous body by deposition of a protein using 5 parts of acetonitrile, the soda is containing the internal standard. The resulting supernatant is dried in a nitrogen atmosphere and restore in the form of a concentrated solution in mobile phase A.

Solutions with the exact number of standards are prepared by diluting the ethanol compound 1003 in the form of its sodium salt (in particular, M represents Na) (dissolved in ethanol) so that the range of concentrations of compound 1003 ranged from 0,040 up to 4000 ng/ml Receive two standard curves and consistently carry out their analysis before and after samples.

1 volume of the aqueous humor or the vitreous body (120 μl in the case of the samples and blank samples add 1/4 volume (30 μl) of ethanol, and 1/4 of the volume of the solution with the exact amount added to the standards. Add 5 volumes of acetonitrile containing 25 PG/ml internal standard (600 μl) and the sample gently stirred for ~1 min and centrifuged for 10 min with a value of 3200 relative centrifugal force. The supernatant liquid is separated (~450 ml), dried in a nitrogen atmosphere at 60°C and again restored in 90 µl of a 5 mm solution of ammonium acetate.

Alternatively, the standards are prepared by diluting the compound 1003 in the form of its sodium salt (i.e., M represents Na) directly into a blank aqueous humor or the vitreous body so that the concentration range of the is placed 1003 ranged from 0,0100 to 1000 ng/ml This avoids further add 1/10 volume (10 μl) of ethanol in the samples and blank samples for subsequent extraction.

Connection 1003 in the samples after homogenization, extraction and recovery analyze by LC/MS/MS using D4-PGE2 as an internal standard. Detection is performed using the mass spectrometer Applied Biosystems API 4000 in the following way:

LC Predalone: Aqua C18 4×2.0 mm, 3 μm, Phenomenex # AJ0-7510

Column: Luna C18(2) 30×2.0 mm, 3 μm, Phenomenex # 00A-4251-BO

The mobile phase A: 5 mm ammonium acetate in water

The mobile phase B: 5 mm ammonium acetate in a mixture of 95:5 acetonitrile:water

Gradient:t = 05% B
t = 1 min.5% B
t = 1.5 min40% B
t = 2,0 min40% B
t = min 2,75100% B
t = 4,15 min100% B
t = 4.5 min 5% B
t = min 4.75V5% B

Volumetric flow rate: 0.5 ml/min

Injection volume: 50 ál

Scan type MS:noise reduction
Polarity:negative
Ion source:elektrorazpredelenie
The transfer of the analyte:m/z from 260,95 to USD 114.9
Transfer internal standard:m/z from 355,0 to 275,3

Linear standard curve ratio of the area of concentration of compound 1003 receive, multiplying by a weighting factor 1/x2.

Figure 1 shows that comparable levels of connection 1003 observed in the intraocular fluid (Figure 1a), the vitreous body (Figure 1b) and the cornea (Figure 1c) with the introduction of compounds 1001 and 1002 using the above methods.

Ophthalmic pharmacokinetic parameters (defined connection 1003) after the introduction of any prodrugs of compound 1001 or 1002 are shown in table 4. Peak ur the downward connection 1003 after administration of compound 1001, is ~12 mm in the cornea with periodon half-life of ~1 hour and in the vitreous body peak levels are ~15 mm with a slightly longer periodon half-life, amounting to 1.3 hours.

Table 4
Connection 1001Intraocular fluidThe corneaThe vitreous body
T 1/2(h)1,181,051,3
The area under the curve (hour*ng/ml) or (hour*ng/mg)2756of 5.536,61
Cmax (ng/ml) or (ng/mg)1055of 3.564,36

Tmax (hour)0,250,250,25
Connection 1002Intraocular fluidThe corneaThe vitreous body
T 1/2(h)1,31,17/td> 1,35
The area under the curve (hour*ng/ml) or (hour*ng/mg)31463,023,74
Cmax (ng/ml) or (ng/mg)13373,351,64
Tmax (hour)0,250,250,25

Example 2: study the chemical stability

Chemical stability of the compounds 1001 and 1002 determined using HPLC analysis, the purity of these compounds over time. Analysis of purity of the active component using the percent area (% of land area) and impurities, expressed as a percentage of area (% of land area), determined by HPLC under the following conditions:

The volumetric rate of flow
Column:ACE 3, C18, 3 μm, 100×2.1 mm
The temperature of the column:35°C
The autosampler temperature:5°C
Detection:UV at 272 nm
The injected volume:30 ál
0.5 ml/min
The duration of the working cycle20 min
Flushing needle:Prolonged washing needles 100% methanol

Connection 1001
Mobile phase:A) water/triperoxonane acid (100/0,about 05./vol.), pH 3.0
B) acetonitrile/triperoxonane acid (100/0,about 05./about.)
Time (min)% A%B
08020
28020
126040
12,018020
208020
Retention time:Connection 10026,3 min
11,0 min
Connection 10032,3 min

Dilution of the sample is performed using a mixture of water/absolute ethanol (90/10 vol./about.)

Solutions comparison for connections 1001 and 1002 is prepared, weighed approximately 10 mg (±2 mg) stock solution with a concentration of 1 mg/ml of compound 1001 or 1002 in yellow volumetric flask 1 ml Add approximately 0.5 ml of the diluent and the solution vigorously stirred. The sample is diluted to the desired volume with diluent and mixed well. The comparison solution for connecting 1001 stable up to 7 days when stored at a temperature of 5±3°C protected from light. Solution comparing to connect 1002 stable up to 3 days when stored at a temperature of 5±3°C in the dark place.

Ophthalmic compositions connection 1001 (0,994 g of the solution in propylene glycol with a concentration of 52 mg/ml) or compound 1002 (to 1.034 g of the solution in propylene glycol concentration 50 mg/ml) prepared with the dose of 500 μg/ml in a buffer solution of potassium phosphate (25 mm, pH 5.5, 0.34 g) with 0.2 M sodium hydroxide solution (enough), sodium chloride (0,327 g), Polysorbate 80 (0.5% weight/vol.) and purified water (enough to 100). Samples of each is from solutions of compounds 1001 and 1002 receive, accurately weighed approximately 20 mg of the composition of compounds with a concentration of 500 μg/ml in yellow volumetric flask 1 ml Add approximately 0.5 ml of the diluent and the solution gently mixed. The resulting solution is diluted to the desired volume with diluent and mixed well.

For analysis of purity (% area) connection 1001 or 1002 in each sample using the following equation:

The content equivalent ( % ) = (Area of analog/Total area of all peaks ≥0,10% of the area)×100

Impurities, the contents of which are ≥0,10% of the area, integrate, and the number is expressed as the % of the area with accuracy to two decimal places.

In tables 5 and 6 show the results of the study of the chemical stability of the compounds 1001 and 1002, respectively, for 8 weeks at 5°C. the Compound 1001 has better chemical stability than the connection 1002, as evidenced by a higher percentage of purity over time (fewer impurities).

Initial level/tr>
Table 5
Chemical stability of compound 1001
The time point% area connection 1001% square impurities
99,550,45
1 weekNot definedNot defined
2 weeks99,030,97
4 weeks99,390,61
8 weeks99,310,69
Table 6
Chemical stability of compound 1002
The time point% area connection 1002% square impurities
Initial level98,291,71
1 week97,582,43
2 weeks97,462,55
4 weeks96,54of 3.46
8 weeks94,95of 5.05

Example 3: a Study of the connection 1001 for dry eyes

The purpose of this experiment is to compare the effectiveness of compound 1001, compared with placebo (carrier minus the active substance), the treatment of the signs and symptoms of dry eye in a multicenter, double-blind, randomized, placebo-controlled clinical study, in which 100 patients-people equally randomly selected into one of three active treatment groups or placebo group, and all subjected to the treatment group are placed in conditions with the same humidity, temperature and wind power, which exacerbate symptoms of dry eye.

During the 14-day preparatory period before randomization (i.e., from day -14 to day 0) all patients receive placebo on a bilateral basis, twice a day (BID). On the day of randomization before treatment (i.e., day 0) all patients are placed at 90 min in conditions identical with humidity, temperature and wind power, which exacerbate symptoms of dry eye, after which patients stratify irout in accordance with the following criteria: staining the Central part of the cornea after effects < 2.5 or >to 3.0. Patients who are suitable for randomization receive one of the following treatment options, which includes the introduction of approximately 30 μl drops in both eyes in BID mode: 1) connect 1001 with A dose (26,4 mg/ml) ophthalmic solution; 2) the connection 1001 with a dose of B (87,8 µg/ml) ophthalmic solution; 3) connection 1001 with a dose of C (275,6 µg/ml) ophthalmic solution; 4) placebo ophthalmic solution (carrier minus the active substance).

A brief description of the planned medical examinations: 5 visits to the doctor for about 6 weeks study is planned as follows: visit 1 = day 14±1 day; visit 2 = day 0; visit 3 = day 14±2 days; visit 4 = day 28±2 days; visit 5 = day 29±1 hour.

The primary expected outcome of clinical research for the average value of the experience through the eyes of discomfort in conditions that increase the symptoms of dry eye, on a scale of discomfort for the eyes, made using the spectrum analyzer (ORA Ocular Discomfort Scale (within a 90-minute exposure), statistically total (n, mean, standard deviation, median, minimum and maximum) and analyzed using one-sided t-tests, comparing the best dose with placebo and taking a statistically significant value of p<0,025.

During the visit 4 (i.e., day 28) of patients who amemait 90 min in conditions with the same humidity, temperature and wind power, which exacerbate symptoms of dry eye. The discomfort of the eye within the specified period impact is determined by the scale ORA Ocular Discomfort Scale, experience eye discomfort is the average of all time points during the exposure. The discomfort of the eye determined again during the visit 5 (i.e., at day 29). Values on the scale ORA Ocular Discomfort Scale correspond to the following results: a value of 0 corresponds to no discomfort; a value of 1 indicates a momentary feeling; a value of 2 indicates a constant feeling; a value of 3 indicates a short-term discomfort and a value of 4 indicates the constant discomfort.

Figure 2 shows the discomfort of the eye, which is measured in environmental conditions at day 28 after local injection of the carrier or connection 1001 with doses A, B or C. a change in the discomfort to the eyes, compared with the media, shows approximately 27% improvement when the connection 1001 injected with a dose of C.

Figure 3 shows the discomfort of the eye, which is measured in environmental conditions at day 29 (in particular, within 24 hours after the last treatment) after local injection of the carrier or connection 1001 with doses A, B or C. a change in the discomfort to the eyes compared to the media shows approximately 36% improvement when the connection 1001 enter the t dose C, indicating that the effect observed after administration of compound 1001, persists for 24 hours after the last treatment.

Symptoms feeling of sand in the eyes, dryness of the eyes to determine the environmental conditions at day 28 by the visual analogue scale 0-5. Figure 4 indicates a significant change as the feeling of sand in eyes, and dryness of the eyes, compared with the carrier when the connection 1001 applied locally with a dose of C.

Example 4: synthesis procedures

All reactions that occur in non-aqueous environment, is carried out in dry nitrogen atmosphere. Reagents acquire from commercial sources and used without further purification. For reactions performed, unless specifically indicated in the text, use chemically pure solvents. The spectra of nuclear magnetic resonance (NMR) on protons and carbon nuclei receive spectrometer Bruker AV-300 at 300 MHz for proton and 75 MHz for carbon, using CDCl3, DMSO-d6or CD3OD as a solvent. As an internal standard for proton spectra, tetramethylsilane was used, and as the peak comparison for carbon spectra using the peak of the solvent. Mass spectra get mass spectrometer Finnigan LCQ Duo LC-MS, equipped with ion trap, when ionization elektrorazpredelenie (ESI). Thin-layer chromatography (TLC) carried out on the layer is Russia with silica gel Whatman No. 4500-101 (thickness 250 μm). Visualization of TLC plates is carried out using ultraviolet radiation (with a wavelength of 254 nm) or by staining with iodine. For determination of pH using pH meter Corning 430.

Conditions for HPLC: method a:

Column: Bond SB-CN, a 4.6×250 mm, 5 µm

The temperature of the column: environment

Sample temperature: environment

Detection: UV at 254 nm

The mobile phase A: water HPLC, containing 0.1% formic acid

The mobile phase B: acetonitrile for HPLC, containing 0.1% formic acid

Diluent: 50:50 water/acetonitrile

Volumetric flow rate: 1 ml/min

Table 7
Gradient
Time (min)% A% B
09010
200100
229010
259010

Scheme 1. Getting connection 2005

Synthesis of compound 200 In a clean dry reactor with a capacity of 100 liters, equipped with a jacket, reflux condenser, addition funnel and temperature probe, carefully add the aluminum chloride 1285 g, for 9.64 mol), and then dichloromethane (55 l). The mixture is stirred and cooled to a temperature of 0-5°C. To the obtained mixture is carefully added dropwise a solution of glutaric anhydride (1000 g, 8,76 mol) and bis(trimethylsilyl)acetylene (1643, for 9.64 mol) in dichloromethane (10 l), maintaining the temperature in the interval from 0 to 5°C. Upon completion of addition the reaction mixture is left overnight to mix at room temperature. After 12-20 hours, the reaction mixture was analyzed by the method of1H NMR (CDCl3) in the presence of glutaric anhydride. The sample for analysis by the method of1H NMR prepared by adding vials in dichloromethane (0.5 ml) and 1M HCl (0.25 ml) to the sample (0.25 ml) of the reaction mixture; dichloromethane is separated and removed in a vacuum. The residue is diluted with CDCl3and analyze1H NMR. The reaction is considered complete when less than 3% of the mass. glutaric anhydride. Then the reaction mixture is slowly added to a 1 M solution (12 l), keeping the temperature below 10°C. the Mixture is stirred for 30-60 minutes until it forms a clear solution. The two phases are separated and the organic phase is washed with saturated salt solution (12 l), dried over sodium sulfate, Phi is trout through the layer of celite on the funnel with a glass filter beds and washed thoroughly with dichloromethane. The filtrate was concentrated in vacuo at a temperature of 35-40°C and receive the connection2002(1700 g, 91%) as a dark brown oil, which was used in the next stage without further purification.

The synthesis of compounds 2003: In a clean, dry 4-necked round bottom flask with a capacity of 12 liters, equipped with a reflux condenser and a temperature sensor, put the raw acid2002(1000 g), p-TsOH•H2O (89,5 g, 0.1 EQ.) and 2-propanol (6 l). The reaction mixture is heated to 65°C for 24 hours and after a specified time, the conversion rate is approximately 90% according to HPLC. The reaction mixture was cooled and 2-propanol was concentrated in vacuo at 50-55°C. the resulting residue is added to MTBE (3 l) and washed with saturated solution of NaHCO3(3×500 ml). The organic layer is dried over Na2SO4, filtered through a layer of celite on the funnel with a glass filter bottom and carefully washed with MTBE. The filtrate was concentrated in vacuo at a temperature of 40-45°C and receive crude ester2003(1160 g, 96%) as a dark brown oil, which was used in the next stage without further purification.

The synthesis of compounds of 2005In pure purged with nitrogen 12-liter round-bottom flask equipped with a mechanical stirrer, a temperature sensor and a tube for input of nitrogen, was placed a connection2003(433 g, 1.7 mol), besod the first isopropyl alcohol (4.3 liter) and the connection 2010(20.4 g, 0,034 mol). After stirring at ambient temperature for 1 hour, as shown by TLC analysis (20% EtOAc/heptane), conversion in connection2004completely finished. Add ammonium chloride (109 g, 2.03 mol), and then add tetrabutylammonium (2,03 l, 1 M solution in THF). Leave to mix for the night, and, as shown by TLC analysis, the transformation in the connection2005completely finished. The reaction mixture was concentrated in vacuo to approximately 1/10 of the original volume, and the resulting substance redistribute between MTBE (4,3 l) and saturated aqueous ammonium chloride (2 l). The phases are separated and the aqueous phase is extracted with MTBE (2 l). The organic extracts are combined and washed with saturated aqueous salt solution (2 l), dried over sodium sulfate and concentrated, obtaining the oil is dark in color. After chromatographic purification receive the connection2005(216 g, 70% at sight of the pure fractions and 28 g 9% as mixed fractions) in the form of an orange oil.

Scheme 2. The preparation of the catalyst Noyori

The synthesis of compounds 2007: Purged with nitrogen three-neck round bottom flask with a capacity of 2 l add a hydrate of ruthenium chloride (12 g, 0,058 mol) and absolute ethanol (0.6 l), and then add p-Menta-1,5-diene (96 ml). The mixture with stirring, boil with about ATiM refrigerator for 4 hours. The suspension is cooled, stirred at 0-5°C for 30 min and filtered; the solids washed with absolute ethanol (3×1 layer volume) and get the connection2007(10.4 g, 58%) as a solid dark red. The filtrate is concentrated to 75 ml and left overnight in the refrigerator. The solids are filtered and washed with absolute ethanol (3×1 layer volume), receiving the connection2007(2 g, 11%) as a solid dark red.

The synthesis of compounds 2009: A 2-liter three-neck round bottom flask, equipped with a temperature sensor, a magnetic stirrer, a tube for supplying nitrogen and addition funnel, add (1S,2S)-(-)-1,2-diphenylethylenediamine (20 g, 0,094 mol) and dichloromethane (160 ml). The mixture is cooled to 0-3°C and added dropwise 1 M sodium hydroxide solution (160 ml), keeping the temperature below 5°C. To the mixture dropwise over 2 hours add solution toluensulfonate (17.9 g, 0,094 mol) in dichloromethane (320 ml). A two-phase mixture is stirred at a temperature of 0-5°C for 1 hour, and according to TLC the reaction is considered completed (50% EtOAc/heptane, UV). The phases are separated and the organic phase washed with water (2×320 ml) and saturated salt solution (320 ml), dried over sodium sulfate and concentrated, obtaining a solid substance. Solids are dissolved in toluene (200 ml) at 70-80°C, porci the mi add heptane (300 ml), maintaining the specified temperature. The resulting suspension is cooled and stirred at 20-25°C for 1 hour, and then cooled to 0-5°C and stirred for 10 minutes, the Solids filtered off and washed with 50% solution of toluene in heptane (3×1 layer volume), receiving the connection2009(30,24 g, 88%) as a white powder.

The synthesis of compounds of 2010: Purged with nitrogen 1-liter three-neck round bottom flask, equipped with a temperature sensor, a mechanical stirrer, addition funnel and a tube for input of nitrogen, add connection2007(10.4 g, is 0.017 mol), compound2009(12.5 g, 0,034 mol), potassium hydroxide (14,14 g, 0,252 mol) and anhydrous dichloromethane (217 ml). The mixture is stirred at 20-25°C for 10 min and then added dropwise water (217 ml), keeping the temperature below 30°C. the resulting mixture was stirred for 15 min and the phases are separated. The organic phase is washed with water (217 ml), dried over sodium sulfate and filtered. The filtrate portions dried over calcium hydride (4,2 g) and the solids filtered off through celite and washed with anhydrous dichloromethane. The filtrate was concentrated in vacuo and get the connection2010(20 g, 98%) as a solid dark pink color.

Scheme 3. Getting connection 2018

The synthesis of compounds of 2012: Trigger the th round bottom flask with a capacity of 22 l, equipped with magnetic stirrer, temperature probe, and addition funnel with a tube for supplying nitrogen, was placed (S)-(-)-glycidol (1.0 kg, 13.5 mol) and DCM (3.0 l). Add imidazole (1,01 kg 14,8 mol) and DMAP (84 g, 680 mmol) and the reaction mixture is cooled to 0°C. Add a solution of TBDMSCl (2,04 kg, 13.5 mol) in DCM (2.0 l), keeping the temperature inside the flask below 10°C. the Reaction mixture was stirred at 0°C for 2 h and analyzed by TLC (9:1 heptane/EtOAc), which shows that the reaction is complete. The reaction mixture is clear, flowing in two portions through a layer of silica gel (silica gel: 6 kg per serving), using DCM as eluent, and get the desired product as a colorless oil (2.2 kg, yield 86%). Range1H NMR consistent with the established framework for the connection2012.

The synthesis of compounds of 2013In mnogogolovy round bottom flask with a capacity of 72 litres, equipped with a mechanical stirrer, temperature probe, and addition funnel with a tube for supplying nitrogen, placed THF (5.5 l). Add n-exility (2.3 M solution in hexane, 5.3 l, 12.3 mol), keeping the temperature inside the flask below 30°C. the Solution is cooled to -20°C and added (trimethylsilyl)acetylene (1,98 l, 1.2 EQ.) at a temperature of <-50°C. the Reaction mixture is stirred at a temperature of <-55°C within 1 hour for more than 75 min add connection2012(2.2 kg, 11,66 mol) at a temperature &t; -55°C, and then at a temperature of <-55°C type BF3•Et2O (1,44 l, 1.0 EQ.) for more than 110 minutes the Reaction mixture is stirred at a temperature of <-60°C for 16 h, whereupon analysis by TLC (9:1 heptane/EtOAc) shows that the reaction is complete. The reaction is interrupted by adding 75% saturated solution of salt (11 l, 5 vol.), and diluted with MTBE (11 l, 5 vol.). The organic layer is evaporated to dryness and receive a colorless oil (3.43 kg, the yield of >100%). Range1H NMR consistent with the established framework for the connection2013.

The synthesis of compounds 2014In mnogogolovy round bottom flask with a capacity of 72 litres, equipped with a mechanical stirrer, temperature probe, and addition funnel with a tube for supplying nitrogen, was placed a raw connection2013(3.43 kg) and DCM (6.6 l). Add imidazole (1.19 kg, 17.5 mol) and DMAP (70 g, 580 mmol) and the reaction mixture is cooled to 0°C. Added TBDPSCl (4,17 kg 15,2 mol), keeping the temperature inside the flask below 10°C. the Reaction mixture was stirred at room temperature for 18 hours, after which analysis by TLC (9:1 heptane/EtOAc) shows that the reaction is complete. The reaction mixture is evaporated to dryness, diluted with heptane (11 l) and washed with water (2×11 l). The organic layer is evaporated to dryness and get the desired product2014in the form of butter, light brown (8,21 kg, the yield of >100%). Range1H NMR with Lisitsa with an established structure for the connection 2014.

The synthesis of compounds 2015In mnogogolovy round bottom flask with a capacity of 72 litres, equipped with a mechanical stirrer, temperature probe, and addition funnel with a tube for supplying nitrogen, was placed a raw connection2014(8,21 kg, approximately 11.7 mol) and DCM (15.3 litres). The reaction mixture was cooled to 0°C. and add a solution of CSA (2,72 kg, 11.7 mol) in MeOH (15.3 litres) at a temperature <10°C. the Reaction mixture was stirred at 0°C for 2 h and analyzed by TLC (9:1 heptane/EtOAc), which shows that the reaction is complete. The reaction is interrupted by adding TEA (1,18 kg, 11.7 mol) and evaporated to dryness. The residue is diluted with heptane (18.5 l) and washed with water (2×18,5 l). The organic layer is cleaned, missing four portions through a layer of silica gel (silica gel: 5 kg in each portion) using heptane to eluted impurities, and the mixture 4:1 heptane/EtOAc, to the eluted product. The fraction containing the product are concentrated to dryness and get the oil light brown (3,38 kg, 70% in three stages). Range1H NMR consistent with the established framework for the connection2015.

The synthesis of compounds 2016In mnogogolovy round bottom flask with a capacity of 72 litres, equipped with a magnetic stirrer, a temperature sensor, a mantle, and a pipe for input of nitrogen, was placed a connection2015(3,38 kg, 8.2 mol) and DCM (16 l). Cooled to 0°C and added dropwise DMSO (1,93 l) and TEA (3,79 l Add SO3•pyr (3,93 kg, 24.6 mol), keeping the temperature inside the flask below 10°C. the Reaction mixture was stirred at 0°C for 3 h and analyzed by TLC (9:1 heptane/EtOAc), which shows that the reaction is complete. The reaction mixture was washed with 10% citric acid (2×5 vol.), and the organic layer evaporated to dryness. The residue is purified in four installments through a layer of silica gel (silica gel: 7 kg in each portion), using 2% EtOAc in heptane as eluent, and get the desired product as a yellow oil (2.0 kg, yield 59%). Mixed fractions are combined and evaporated to dryness and receive a yellow oil (0.38 kg, yield 11%). Range1H NMR consistent with the established framework for the connection2016.

The synthesis of compounds 2017: In a three-neck round bottom flask with a capacity of 22 liters, equipped with a magnetic stirrer, a temperature sensor, a mantle, and a pipe for input of nitrogen, was placed a connection2016(2.0 kg, contains 1.42 kg2017according to the weight analysis of 3.48 mol), and ACN (7,1 l). The reaction mixture is heated to 30°C and portions add Ph3PCHCHO (1,38 kg, only 68.6 mmol), keeping the temperature inside the flask <35°C. the Reaction mixture is heated to 30°C for 15 h and analyse method1H NMR, which shows that the reaction is complete. The reaction mixture is evaporated to dryness and the residue is dissolved in DCM (0,71 ml). The floor is built the solution was diluted with heptane (1,42 l), the two portions are cleaned through a layer of silica gel, using a mixture of 10:1 heptane/EtOAc as eluent, and get the desired product in the form of oil, pale yellow (1.87 kg, yield 88%). Range1H NMR consistent with the established framework for the connection2017.

The synthesis of compounds 2018: a 5-liter three-neck round bottom flask heated by a dryer under vacuum (1-10 Torr) three times and rinsed with argon. Add anhydrous chromium chloride (100 g, 0,814 mol) and the flask is again three times heated in vacuum. Add anhydrous tetrahydrofuran (1000 ml) and the resulting suspension is stirred for 2 hours at room temperature. During the specified time, the suspension is heated exothermically to approximately 30-35°C and acquires a greenish color. In a separate flask connection2017(57 g, 0,131 mol) three times subjected to azeotropic distillation with toluene. Connection2017in nitrogen atmosphere add treatmetn (102 g, 0,273 mol) and anhydrous tetrahydrofuran (700 ml) and receives a yellow solution. Then the resulting solution via cannula under nitrogen is added to a suspension of chromium chloride over 30 minutes, maintaining the temperature inside the flask below 5°C. After 30 min TLC analysis shows that the reaction is complete. The reaction is interrupted portions of adding a mixture of sodium thiosulfate (10% wt., 570 ml) and a saturated solution of sodium bicarbonate (570 ml), is supporting the temperature below 15°C. Add MTBE (2000 ml); the two phases are separated and the organic phase is washed with saturated salt solution (1140 ml), dried over magnesium sulfate, filtered and concentrated give crude2018in green balance with the ratio of E/Z 8,8:1 according to the1H NMR analysis. The crude product leave be stored overnight in diethylamine (400 ml).

Scheme 4. Getting connection 1001

The synthesis of compounds 2019: 3-necked round bottom flask Tegaserod and rinsed with nitrogen. To the flask was added tetrakis(triphenylphosphine)palladium(0) (7,4 g, 6 mmol) and copper iodide (2.5 g, 13 mmol). The cannula added under nitrogen degassed solution of compound2005(24 g, 131 mol) in anhydrous tetrahydrofuran (55 ml) at ambient temperature. Then via cannula under nitrogen add a degassed solution of compound2018(0,131 mol) in diethylamine (400 ml) and anhydrous tetrahydrofuran (800 ml). The reaction mixture is left overnight to mix at ambient temperature. After that, according to HPLC, the reaction is finished. The reaction is interrupted saturated aqueous ammonium chloride (20 ml) and then concentrated, receiving the remainder. Add MTBE (700 ml), the mixture is stirred until the formation of the suspension for 10 minutes; the solid substance is filtered through a layer of celite on a glass funnel with filter bottom. The filtrate prom is provide with a saturated aqueous solution of ammonium chloride (300 ml), dried over magnesium sulfate, filtered and concentrated, obtaining2019(89 g, >100%) as a crude brown oil, in which the ratio of E/Z is 6.3:1 data1H NMR analysis; the oil is purified column chromatography on silica gel, and then combined flash chromatography.

Synthesis of compound 1001In a 5-liter three-neck flask round bottom flask is placed intermediate the connection2019(284,4 g, 0.46 mol), ammonium chloride (74,2 g of 1.39 mol) and THF (850 ml). The mixture is stirred and cooled to 5°C using baths with ice. To the mixture under stirring was added 1 M solution of tetrabutylammonium in THF (1.4 l) via addition funnel over 15 minutes so that the temperature of the reaction mixture remained below 10°C. the Mixture is stirred for 2 h, whereupon analysis by TLC (40% ethyl acetate/heptane) shows that the original substance left. The reaction mixture is diluted with tert-butylmethylamine ether (1.4 l) and saturated aqueous ammonium chloride (1.4 l) and the layers separated. The organic layer was washed with saturated aqueous ammonium chloride (1.4 l), dried over sodium sulfate and concentrated, obtaining oil (271,4 g). The oil is suspended in 20% heptane/ethyl acetate (200 ml) and dichloromethane is added slowly until, until it forms a solution (about 20 ml). The mixture is purified on silicagel the e (2 kg), elwira the following solutions: 20% ethyl acetate/heptane (16 l), 30% ethyl acetate/heptane (8 l), 40% ethyl acetate/heptane (20 l) and 50% ethyl acetate/heptane (16 l). Pure fractions are combined and concentrated, obtaining1001(128,3 g, yield 91%): HPLC of 97.7% (area under the curve), tR= a 13.3 min; Range1H NMR consistent with the established framework for the connection1001as shown in figure 5.

Scheme 5. Getting connection 1002

Synthesis of compound 1002: To a solution of1001(35 g, 115 mmol) in MeOH (350 ml) is added p-TsOH•H2O (of 4.38 g, 23 mmol). The resulting solution was stirred at room temperature for 22 h and diluted with EtOAc (700 ml). The mixture was washed with 5% aqueous sodium bicarbonate solution (3×100 ml). The aqueous extracts are combined and extracted with EtOAc (3×200 ml). The organic extracts are combined and washed with saturated salt solution (150 ml), dried over sodium sulfate and concentrated in vacuo. The oily residue is purified column chromatography (2:3 EtOAc/n-heptane) and get the connection1002(22,8 g, 71.7% of, 98,1% (area under the curve) HPLC) in the form of oil is light yellow in color. Range1H NMR consistent with the established framework for the connection1002as shown in figure 6.

Scheme 6. Getting connection Z

Synthesis of compound ZIn a three-neck cropton the second flask with a capacity of 5 l put the connection 1001(335 g, 1.1 mol), THF (5 volumes) and water (5 volumes). Add LiOH (52.7 g, 2.2 mol) and the reaction mixture stirred at ambient temperature for 4 h, and then analyzed by TLC, which shows that the reaction is complete. The reaction mixture was extracted with MTBE (2×5 volumes) and the aqueous layer is acidified to a pH of 4.4 with 2N HCl solution (900 ml). Extracted with MTBE (6×5 volumes), and the organic layers combined, washed with water (5 volumes), dried over Na2SO4, diluted with ethanol (10 volumes) and concentrate to five volumes. The resulting solution in ethanol cooled to 0°C and added 6N NaOH solution (1 EQ.). The reaction mixture is stirred for 1 hour, evaporated to dryness and dried in vacuo for 18 hours, getting a brown oil (277 g, yield 88%): HPLC 99,2% (area under the curve), tR=10,1 min; range1H NMR consistent with the established framework for the connectionZand indicates the presence of residual ethanol. Brown oil (277 g) dissolved in water (2 volumes), evaporated to dryness at 40°C, and then dried in vacuum for 18 h, receiving the requested connectionZin the form of a brown oil (279 g): HPLC 99,0% (area under the curve), tR=to 9.9 min; range1H NMR consistent with the established framework for the connectionZas shown in figure 7.

The inclusion of posredstvennyi

All publications and patents mentioned herein, in its entirety is incorporated into the present application by reference as if each individual publication or each individual patent application is specifically and individually were specified for inclusion in this application by reference. In the event of a conflict this description, including any of the definitions given here takes precedence.

Equivalents

Although in this description and discussion of specific embodiments of the present invention, the above description serves only as an explanation and does not limit the present invention. Numerous variations of the present invention will become apparent to specialists when reading this description and the following claims. The full scope of the present invention is defined by the claims, together with all equivalents, as well as the description of the invention together with the above variations.

1. The compound represented by the formula 1001
,
or its pharmaceutically acceptable salt.

2. Method for the treatment or prevention of ophthalmic diseases, including the introduction of compounds represented by formula 1001
,
or its pharmaceutically acceptable the salt.

3. The method according to p. 2, where in the eye the day enter more than 2 µg specified connection.

4. The method according to p. 3, where in the eye the day enter 2-175 µg specified connection.

5. The method according to any of paragraphs.2-4, where the specified compound is administered one, two, three or four times a day.

6. Pharmaceutical composition for treatment or prevention of ophthalmic diseases, comprising the compound represented by the formula 1001
,
or its pharmaceutically acceptable salt.

7. The pharmaceutical composition according to p. 6, where the composition is an aqueous solution suitable for local injection into the eye, the concentration of the compounds in the specified solution is greater than 30 mcg/ml

8. The pharmaceutical composition according to p. 7, where the concentration of the compound is from 30 μg/ml to 2000 μg/ml

9. A method for the treatment of ophthalmic diseases, including local injection in the eye of the pharmaceutical composition according to any one of paragraphs.6-8.

10. The method according to p. 9, where the pharmaceutical composition is administered one, two, three or four times a day.

11. The composition or method according to any of paragraphs.6, 9, 10, where the ophthalmic disease is dry eye.

12. Pharmaceutical composition for delivery of eye drops in the eye in need of treatment of ophthalmic diseases, where eye drops include with the Association, represented by the formula 1001
,
or its pharmaceutically acceptable salt.

13. The pharmaceutical composition according to p. 12, where the pharmaceutical composition does not contain preservatives.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.

EFFECT: compounds act as modulators of gamma-secretase.

31 cl, 14 tbl, 3147 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry, and represents using a biologically active agent for preparing a drug for metabolic disorders specified in a group consisting of insulin resistance syndrome and diabetes mellitus, including type I diabetes mellitus and type II diabetes mellitus, and obesity, wherein the agent represents a compound of formula

,

wherein n=1 or 2; m=0, 1, 2, 4 or 5; q=0; t=0 or 1; R3 represents hydrogen; A is phenyl, unsubstituted or substituted by 1 or 2 alkyls having 1 or 2 carbon atoms; and R1 is hydrogen or alkyl having 1 or 2 carbon atoms; or when R1 represents hydrogen - a pharmaceutically acceptable salt of the compound.

EFFECT: preparing the drug for metabolic disorders.

18 cl, 6 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

in which m equals 1; n equals 1 or 2; t equals 0 or 1; and A is phenyl, substituted with 2 alkyl groups containing 1 or 2 carbon atoms.

EFFECT: compounds of the disclosed formula can be used as intermediate compounds for producing compounds used to treat various metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidaemia, bacony liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

17 tbl, 2 dwg, 53 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing a compound of formula (I), where N equals 0, and values of substitutes R, R1 are given in claim 1, which involves: (i) esterification of a compound of formula (V) with an alcohol of formula , where m and m' are independently equal to 0 or 1; under the condition that both are not equal to 0 at the same time and values of A are given in claim 1, to obtain a compound of formula (III); (ii) reaction of the compound of formula (III) and a compound of formula (IV) to obtain a compound of formula (II); and (iii) reaction of the compound of formula (II) with L-CH2-C≡CH, wherein L is a leaving group, to form a compound of formula (I); intermediate compounds of formula (II), formula (III) and formula (XII) are also disclosed.

EFFECT: improved method.

15 cl, 19 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (I) where X is carboxylic acid, carboxylates, carboxylic anhydride, diglyceride, triglyceride, phospholipid, or carboxamides, or to any their pharmaceutically acceptable salt. The invention particularly refers to (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)-ethyl 2-ethyldocosa-4,7,10,13,16,19-hexanoate. The invention also refers to a food lipid composition and to a composition for diabetes, for reducing insulin, blood glucose, plasma triglyceride, for dislipidemia, for reducing blood cholesterol, body weight and for peripheral insulin resistance, including such compounds. Besides, the invention refers to methods for treating and/or preventing diabetes, dislipidemia, peripheral insulin resistance, body weight reduction and/or weight gain prevention, insulin, blood cholesterol, blood glucose and/or plasma triglyceride reduction.

EFFECT: higher clinical effectiveness.

61 cl, 4 tbl, 16 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: method of regioselective obtainment of 1-R1-2-R2-3-acetyl-glycerol derivative of the Formula 1 involves the following stages: Obtainment of 1-R1-3-(protective group)-glycerol of Formula 3 by adding protective group to 3rd position in 1-R1-glycerol of Formula 2; obtainment of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4 by adding R2 group to 2nd position of 1-R1-3-(protective group)-glycerol of Formula 3, where R2 group is added by reaction of R2-OH with 1-R1-3-(protective group)-glycerol in the presence of aprotic organic solvent, catalyst and dehydrating medium; aprotic organic solvent is selected out of group consisting of hexane, heptane, dichloromethane, ethyl acetate, tetrahydrofuran and mixes thereof; dimethylaminopyridine is catalyst; and dicyclohexylcarbodiimide is dehydration medium; simultaneous removal of protective group and acetylation of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4, where protective group removal reaction and acetylation reaction are performed using Lewis acid and acetic anhydride or using acetylation agent; Lewis acid is selected out of group including zink chloride (ZnC2), tin chloride (SnCl2), boron trifluoride diethyl ether (BF3Et2O) and mixes thereof; acetylation agent is selected out of group including acetylchloride, acetylbromide and mixes thereof, where compounds of Formulae 1-4 are racemic or optically active; R1 is palmitic acid group, R2 is linoleic acid group; P is trityl or trialkylsilyl as protective group; alkyl in trialkylsilyl is an alkylic group containing 1-5 carbon atoms, so that if the protective group is trityl then 1-R1-3-(protective group)-glycerol is obtained in the presence of pyridine solvent at 40-60°C or in the presence of nonpolar aprotic organic solvent and organic base within 0°C to room temperature range; nonpolar aprotic organic solvent is selected out of group including pyridine, dichloromethane, tetrahydrofuran, ethyl acetate and mixes thereof; organic base is selected out of group including triethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and mixes thereof, and if the protective group is trialkylsilyl then 1-R1-3-(protective group)-glycerol is obtained in the presence of aprotic organic solvent and organic base within 0°C to room temperature range; aprotic organic solvent is selected out of group including dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide and mixes thereof; and organic base is selected out of group including imidazole, triethylamine, and mixes thereof. [Formula 1] , [Formula 2] , [Formula 3] , [Formula 4] .

EFFECT: obtainment of glycerol derivative with high efficiency and output.

8 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining polyols, which includes the following stages: a) oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids by dinitrogen monoxide, b) interaction of product, obtained at stage a), with hydrogen with application of heterogeneous catalyst on carrier. Invention also relates to method of obtaining polyurethanes, which includes stages: a) oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids by dinitrogen monoxide, b) interaction of product, obtained on stage a), with hydrogen with application of heterogeneous catalyst on carrier with obtaining polyols, and c) interaction of polyisocyanates with polyols, obtained at stage b), as compounds, which have at least two hydrogen atoms, capable of reaction with respect to isocyanate groups.

EFFECT: simple methods make it possible to obtain broad spectrum of products without application of expensive initial raw material.

10 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining polyols, which includes the following stages: a) oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids with dinitrogen oxide; b) interaction of the product, obtained at stage a), with hydrating reagent in presence of catalyst, which contains, at least, one transition metal from groups from 6 to 11; c) interaction of the reaction product from stage b) with alkylene oxides in presence of multimetalcyanide catalyst. Invention also relates to method of obtaining polyurethanes, which includes oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids with dinitrogen oxide, interaction of the obtained product with hydrating reagent in presence of catalyst, which contains, at least, one transition metal from groups from 6 to 11, interaction of the reaction product with alkylene oxides in presence of multimetalcyanide catalyst with obtaining polyols, interaction of polyisocyanates with polyols as compounds, which have two hydrogen atoms, reactionable with respect to isocyanate groups.

EFFECT: simple methods make it possible to obtain wide spectrum of products without application of expensive initial reagents.

10 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel omega-3 lipid compounds of general formula (I) or to their pharmaceutically acceptable salt, where in formula (I): R1 and R2 are similar or different and can be selected from group of substitutes, consisting of hydrogen atom, hydroxy group, C1-C7alkyl group, halogen atom, C1-C7alkoxy group, C1-C7alkylthio group, C1-C7alkoxycarbonyl group, carboxy group, aminogroup and C1-C7alkylamino group; X represents carboxylic acid or its carbonate, selected from ethylcarboxylate, methylcarboxylate, n-propylcarboxylate, isopropylcarboxylate, n-butylcarboxylate, sec-butylcarboxylate or n-hexylcarboxylate, carboxylic acid in form of triglyceride, diglyceride, 1-monoglyceride or 2-monoglyceride, or carboxamide, selected from primary carboxamide, N-methylcarboxamide, N,N-dimethylcarboxamide, N-ethylcarboxamide or N,N-diethylcarboxamide; and Y stands for C16-C22 alkene with two or more double bonds, which have E- and/or Z-configuration.

EFFECT: described are pharmaceutical and lipid compositions, which contain said compounds, for application as medications, in particular, for treatment and/or prevention of peripheral insulin resistance and/or condition of diabetes, for instance, type 2 diabetes, increased levels of triglycerides and/or levels of non-HDL cholesterol, LDL cholesterol and VLDL cholesterol, hyperlipidemic condition, for instance, hypertriglyceridemia (HTG), obesity or condition of excessive body weight, fatty liver disease, for instance, non-alcoholic fatty liver disease (NAFLD) or inflammatory disease or condition.

60 cl, 3 tbl, 65 ex

Chemical method // 2481331

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula II from a compound of formula III: , where R1 and R2 are independently Cl, Br, F, I, via reaction thereof with an ester of formula (IV) , where R3 is C1-6alkyl; to obtain a compound of formula V: , which reacts with a hydroxyl ion in the presence of an aryl-alkyl ammonium salt or tetra-alkyl ammonium salt, to obtain a compound of formula VI , followed by treatment thereof to obtain a compound of formula VII: , which is reduced to obtain a compound of formula II.

EFFECT: high efficiency of the method.

5 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a resin used in coating and/or making shaped articles, which contains a hydroxy-aromatic compound of formula (VIII)

, where R1 R2, R4 and R5 denote H, C1-12 alkyl group, EWG denotes COOC1-12 alkyl group, which is obtained by reacting a hydroxy-aromatic compound of formula (IV) with a compound of formula (VI), if needed, in the presence of a catalyst, formula (IV), representing: , where R1 R2, R4, R3 and R5 denote H, C1-12 alkyl group, and formula (VI): , where R6 and R12 denote C1-12 alkyl group.

EFFECT: invention relates to a method of producing a hydroxy-aromatic resin, use thereof in coatings and making shaped articles, as well as a coating and shaped article containing the hydroxy-aromatic resin.

7 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), where each R1, R2 and R3 is independently selected from a group comprising H, OH, F, Cl, Br, a methoxy group and an ethoxy group; or R1 and R2 together form -OCH2O-, and R3 is selected from a group comprising H, OH, methoxy group, ethoxy group and halogens; R4 denotes OH or o-acetoxybenzoyloxy nicotinoyloxy or iso-nicotinoyloxy; R5 denotes or , and at least one of R1, R2 and R3 is not hydrogen.

EFFECT: method for synthesis of a compound of formula (I) and use of the compound of formula (I) in preparing medicinal agents for preventing or treating cerebrovascular diseases.

17 cl, 14 tbl, 5 dwg, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceutical production and a rosmarinic acid synthesis method. The method for synthesis of rosmarinic acid from plant material involves extraction with water and purification. Zosteraceae sea grass is extracted with water for 6-8 hours at room temperature while adding edible acid to pH 2.5-3.0. After extraction, the obtained solution is filtered and the grass is pressed to obtain an extra extract. The extracts are combined and purified on a membrane microfilter and then on a chromatographic column with polychrome-1. The end product is eluated with 5-7% aqueous solution of ethyl alcohol, concentrated and lyophilised.

EFFECT: method is simple and ensures high output and purity of rosmarinic acid.

2 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: method is realised by reacting C2-C4alkyl ether with pentaerythritol in the presence of a combination of reesterification catalysts consisting of (a) at least one base catalyst selected from a group consisting of compounds of a group Ia alkali metal or a compound of a group IIa alkali-earth metal, (b) at least one compound of a metal which can behave like a Lewis acid, where at least one compound of the metal which behave like a Lewis acid is different from the base catalyst and is selected from a group consisting of zinc octanoate, zinc acetate, hydrate of zinc acetylacetonate, zinc stearate, zinc p-toluene sulphonate, zinc naphthanate, zinc diethylthiocarbamate, manganese (II) acetate, manganese (II) acetylacetonate, manganese (III) acetylacetonate, gallium acetate, lanthanum acetate, hydrate of lanthanum acetylacetonate, aluminium phanate, aluminium isopropoxide, aluminium acetylacetonate, titanium tetrabutoxide, titanium oxide acetylacetonate, isopropoxide bis(acetylacetonate)titanium, zirconium (IV) acetylacetonate and a transition metal compound, and where the reaction is carried out via a first step in which there is only a base catalyst in the reaction mixture, followed by a second step which begins with addition of the said Lewis acid catalyst to the reaction mixture, when the amount of disubstituted intermediate product in the reaction mixture is reduced to less than 20% of the area from HELC analysis data.

EFFECT: design of an improved method of reesterification to produce tetrakis [3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxymethyl]methane.

9 cl, 48 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of preparing solid particles used as phenolic antioxidants and including in, in fact, crystal form compound of formula: in which one of R1 and R2 independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; and Y represents C8-C22alkoxy or groups of incomplete formulas

or in which one of R1' and R2' independently on each other represent hydrogen atom or C1-C4alkyl, and the other one represents C3-C4alkyl; x represents zero (direct bond) or number from one to three; y represents number from two to ten; and z represents number from two to six, in which homogeneous water dispersion is prepared, which includes compound (I) or mixture of such compounds, where R1, R2, R1' R2', Y, x, y and z have values given above, by addition of incomplete ether of fatty acid polyoxyethylene sorbitan and inoculating crystals, and obtained crystals are separated from dispersion and process is carried out until solid particles are obtained. Invention also relates to novel crystal forms pentaerythrite tetrakis-[3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], (µ-form) of pentaerythrite tetrakis 3-(3,5-ditret-butyl-4-hydroxyphenyl)propionate], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)], crystal form of N,N'-hexane-1,6-diyl-bis-[3-(3,5-ditret-butyl-4-hydroxyphenyl propionamide)] and crystal modification (β-form) of N,N'-hexane-4,6-diylbis-[3-(3,5-ditret-butyl-4- hydroxyphenyl propionamide)].

EFFECT: elaboration of improved method of preparing solid particles used as phenolic antioxidants.

10 cl, 2 ex

FIELD: biochemistry and enzymology.

SUBSTANCE: preparation of amorphous HMG-KoA reductase inhibitor with specified particle size comprises dissolving HMG-KoA reductase inhibitor in hydroxyl-containing solvent and removing solvent via freeze drying.

EFFECT: provided preparation of amorphous HMG-KoA reductase inhibitor using procedure, which can be implemented in industrial scale.

4 cl, 2 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves corneal impregnation with 0.1% riboflavin and ultraviolet exposure at a wave length of 365-375 nm for 30 min. Before impregnation, the cornea is coated with 40% glucose kept on the corneal surface for 9-11 min; residual glucose is removed, and the glucose-treated corneal surface is coated with 0.1% riboflavin for 30 min.

EFFECT: eliminating postoperative complications, reducing the length of the patients' rehabilitation, and achieving the high functional results of the operation.

5 ex

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