Compounds for treating metabolic diseases

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

 

Diabetes is the leading cause of morbidity and mortality. Chronically elevated levels of glucose in the blood leads to debilitating complications: nephropathy, which often requires dialysis or a kidney transplant; peripheral neuropathy; retinopathy leading to blindness; ulceration of the legs and feet, leading to amputation; fatty liver, sometimes progressing to cirrhosis, and susceptibility to coronary artery disease and myocardial infarction.

There are two main types of diabetes. Type I or insulin-dependent diabetes mellitus (IDDM) is associated with autoimmune destruction of producing insulin by beta cells in the pancreatic islets (islets of Langerhans). This disease usually occurs in childhood or puberty period. Treatment primarily consists of multiple daily insulin injections in combination with frequent glucose in the blood to regulate the dosage of insulin, because the excess insulin may cause hypoglycemia and subsequent deterioration of brain function, and other functions.

Type II or non-insulin-dependent diabetes mellitus (NIDDM) usually develops in adulthood. NIDDM is associated with resistance (immunity) using the glucose of the tissues, such as adipose tissue, muscle, and liver, to the action of insulin. Initially, beta-CL the TCI pancreatic islets to compensate for this by secreting excess insulin. Ultimately, the failure of the island leads to decompensation and chronic hyperglycemia. On the contrary, the average failure of islet may precede or coincide with peripheral insulin resistance. There are several classes of drugs that can be used for the treatment of NIDDM: 1) stimulates insulin funds that directly stimulate the release of insulin, causing hypoglycemia risk; 2) "dining" releasing insulin means that potentiate-induced glucose insulin secretion, and which should be taken before each meal; 3) biguanides, including Metformin, which softens the liver gluconeogenesis (which paradoxically increases in diabetes); 4) insulin sensitizers, for example, derived thiazolidinedione rosiglitazone and pioglitazone, which improve peripheral response to insulin, but which have such side effects as weight gain, edema and transient toxicity liver; 5) insulin injections, which are often necessary in the later stages of NIDDM, when the islets fail in conditions of chronic overstimulation.

Insulin resistance can also occur without severe hyperglycemia and is usually associated with atherosclerosis, obesity, hyperglycemia, and with the significant increase in blood pressure. This combination of anomalies is "metabolic syndrome" or "syndrome of insulin resistance". Insulin resistance is also associated with fatty liver, which can progress to chronic inflammation (NASH; "non-alcoholic steatohepatitis), fibrosis and cirrhosis. Collectively, the syndromes of insulin resistance, including, but not limited to diabetes, underlie many of the major cases of morbidity and death in people older than 40 years.

Despite the existence of such medicines, diabetes remains a major and growing problem of human health. Diabetes complications in the later stages consume a large share of health resources. There is a need for new orally active therapeutic agents that effectively addressed the primary defects of insulin resistance and damage islets, with fewer or milder side effects than existing drugs.

Currently there are no safe and effective treatments for fatty liver disease. Therefore, such treatment could be valuable for the treatment of such diseases.

Summary of the invention

This invention relates to a biologically active agent, where the agent is a compound is ormula:

where n is 1 or 2; m is 0 or 1; q is 0 or 1; t is 0 or 1; R5represents alkyl containing from 1 to 3 carbon atoms; R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms; A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon are independently monosubstituted by stands or ethyl; or a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring, selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula I via a ring carbon atom; and X represents-CH2-, Q represents-OR1and R1represents ethyl; or X represents-CH2CR12R13or CH2CH(NHAc)-, where each R12and R13independently represents hydrogen or methyl, Q is a OR1and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; or X represents-CH2CH2-, and Q presented yet a NR 10R11where one of R10and R11represents hydrogen, alkyl containing from 1 to 3 carbon atoms, or hydroxy and the other represents hydrogen or alkyl containing from 1 to 3 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; t is 0 or 1; m is 0 and r is 1, or m is 1 and r is 0; A is phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted the stands or ethyl; or a 5-or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula II with the aid of a ring carbon atom; Z represents a

R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms;R 4represents hydrogen; -NHCOOC(CH3)3; -NHCH3or-NHCH2CH3; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where one or two ring carbon are independently monosubstituted by stands or ethyl; or a 5 or 6 membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring covalently linked to the remainder of the compounds of formula III via a ring carbon atom.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound.

This invention relates is biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; R14represents hydroxy or hydrogen; and A is phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl; or a 5-or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula V' with the aid of a ring carbon atom;

or pharmaceutically acceptable salt of the compound.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 3 carbon atoms; and A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 and the Ohm carbon, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl; or a 5-or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula XCI with the aid of a ring carbon atom; or a pharmaceutically acceptable salt of the compound.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 3 carbon atoms; and A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl; or a 5-or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring, wybran the x of N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula CXVI with the aid of a ring carbon atom; or a pharmaceutically acceptable salt of the compound.

This invention relates to a biologically active agent, where the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 3 carbon atoms; R15represents hydrogen or alkyl containing from 1 to 3 carbon atoms; R9represents hydrogen, halogen, hydroxy or alkoxy containing from 1 to 3 carbon atoms; and A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl; or a 5-or 6-membered heteroaromatic ring, containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula CXVII with the aid of a ring carbon atom; or a pharmaceutically acceptable salt of the compound.

About vannie above biologically active agents have activity in one or more of the following tests for biological activity, in which animal models of diabetes man syndrome and insulin resistance. Thus, such agents may be useful for the treatment of diabetes and syndrome of insulin resistance. All tested illustrative compounds have demonstrated activity in the study of the biological activity or the analyses performed.

This invention relates to the use of the above-described biologically active agents to obtain drugs for the treatment of syndrome of insulin resistance, diabetes, cachexia, hyperlipidemia, fatty liver disease, obesity, atherosclerosis or arteriosclerosis. This invention also relates to methods of treatment of the subject is a mammal susceptible to the syndrome of insulin resistance, diabetes, cachexia, hyperlipidemia, fatty liver, obesity, atherosclerosis or arteriosclerosis, comprising an introduction to the subject an effective amount of a biologically active agent according to the invention. This invention also relates to pharmaceutical compositions comprising a biologically active agent according to the invention and a pharmaceutically acceptable carrier.

This invention also relates to certain new intermediate compounds that can be used to obtain biologically active agents of this is bretania. The invention also relates to methods of producing biologically active compounds and intermediate products.

Brief description of drawings

Figure 1: Levels of insulin in the serum of mice C57B1/6J receiving a high calorie diet kotkorye received media (negative control), Compound BI, Compound BL, Wyl4643 or rosiglitazone.

Figure 2: Levels of leptin in the serum of mice C57B1/6J receiving a high calorie diet kotkorye received media (negative control), Compound BI, Compound BL, Wyl4643 or rosiglitazone.

Detailed description of the invention

Definition

In this description, the term "alkyl" means a linear or branched alkyl group. An alkyl group that is specified as containing a certain number of carbon atoms refers to any alkyl group having the specified number of carbon atoms. For example, alkyl having three carbon atoms, may represent propyl or isopropyl; and alkyl having four carbon atoms, may represent an n-butyl, 1-methylpropyl, 2-methylpropyl or tert-butyl.

In this description, the term "halogen" refers to one or more of fluorine, chlorine, bromine and iodine.

In this description, the term "PERFLUORO", as for example in performative or performatce, means that the group is fluorine atoms instead of all atoms in Dorada.

As used herein, "AC" refers to a group of CH3C(O)-.

The following are examples of biologically active compounds of the present invention. These compounds are referred to in the present description by their chemical names or by using the following two-letter code.

AA 4-(4-(2-Forbindelse)phenyl)-4-oxobutanoic acid;

AB 4-(4-(2-Methoxybenzyloxy)phenyl)-4-oxobutanoic acid;

AC 3-[(4-(2-Forbindelse)phenyl)-methylthio]propionic acid;

AD 4-(4-(3-Forbindelse)phenyl)-4-oxobutanoic acid;

AE 4-(4-(4-Forbindelse)phenyl)-4-oxobutanoic acid;

AF 4-(4-((2-Pyridyl)methoxy)phenyl)-4-oxobutanoic acid;

AG 4-(4-(Benzyloxy)phenyl)-4-oxobutanoic acid;

AH 4-(4-(2,6-Deferasirox)phenyl)-4-oxobutanoic acid;

AI 4-(4-(2-Chlorobenzoyloxy)phenyl)-4-oxobutanoic acid;

AJ 4-(4-(2-(2-Forfinal)ethoxy)phenyl)-4-oxobutanoic acid;

AK Ethyl 4-(4-(2-forbindelse)phenyl)-4-oxybutyrate;

AL 4-(4-(2-Methylbenzylamino)phenyl)-4-oxobutanoic acid;

AM 4-[4-(2-(N-(2-terbisil)-N-methylamino)ethoxy)phenyl]-4-oxobutanoic acid;

AN 4-(3-(2-Methylbenzylamino)phenyl)-4-oxobutanoic acid;

JSC Ethyl 4-(3-(2-forbindelse)phenyl)-4-oxybutyrate;

AP Ethyl 4-(4-(2-methylbenzylamino)phenyl)-4-oxybutyrate;

AQ Ethyl 4-(4-(2,6-deferasirox)phenyl)-4-oxybutyrate;

AR 4-(4-(2-(2-Tie the Il)ethoxy)phenyl)-4-oxobutanoic acid;

AS 4-(2,6-Differenl)-4-oxobutanoic acid;

At 4-(4-(2,5-Dimethylbenzylamine)phenyl)-4-oxobutanoic acid;

AU 4-(4-(2,5-Deferasirox)phenyl)-4-oxobutanoic acid;

AV 4-(4-(2,4-Deferasirox)phenyl)-4-oxobutanoic acid;

AW 4-(3-(2,6-Deferasirox)phenyl)-4-oxobutanoic acid;

AX 4-(4-((Cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid;

AY 4-(4-(2-Triftormetilfosfinov)phenyl)-4-oxobutanoic acid;

AZ 3-[(4-(2,6-Deferasirox)phenyl)methylthio]propionic acid;

BA 4-(2-(2,6-Deferasirox)phenyl)-4-oxobutanoic acid;

BB Ethyl 4-(4-(2,6-deferasirox)phenyl)methyl-3-oxybutyrate;

SU 3-(2-(4-(2,6-Deferasirox)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole;

BD 5-[(4-(2,6-Deferasirox)phenyl)-methyl]-1H-tetrazol;

BE (2RS) 2-(N-Boc)-3-[2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl]thiopropionate acid;

BF Ethyl 2-hydroxy-4-oxo-4-(4-(2,6-deferasirox)phenyl)but-2-ENOAT;

BG (2RS) 2-(N-Acetyl)-4-(4-(2,6-deferasirox)phenyl)-4-oxobutanoic acid;

BH 4-(3-((Cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid;

BI 4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxobutanoic acid;

BJ 4-(3-(2-Fluoro-6-methylbenzoate)phenyl)-4-oxobutanoic acid;

BK Ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate;

BL Sodium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acids;

BM 4-(4-(2,6-Dimethylsiloxy)phenyl-4-oxobutanoic acid;

BN Potassium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acids;

BO 4-(3-(2,6-Dimethoxybenzoate)phenyl)-4-oxobutanoic acid;

BP 4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxo-2,2-dimethylbutanoate acid;

BQ 4-(3-(4-Triftormetilfosfinov)phenyl)-4-oxobutanoic acid;

BR 4-(3-((Cyclobutyl)methoxy)phenyl)-4-oxobutanoic acid;

BS 4-(3-(2,6-Dimethylsiloxy)phenyl)butane acid;

BT 4-[[4-(2,6-Dimethylsiloxy)-3-methoxy]phenyl]-4-oxobutanoic acid;

BU 4-{3-[((4-Triphtalocyaninine)carbonyl)--4-methoxy}phenyl]-4-oxobutanoic acid;

BV 4-{3-[((2,6-Dimethylbenzylamine)carbonyl)-4-methoxy]phenyl}-4-oxobutanoic acid;

BW 4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oksobutiltrimyetilolova acid;

BX 4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxobutanamide;

BY 4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxo-2-butane acid; and

BZ 4-(3-(2,6-Dimethylsiloxy)phenyl)-3-butenova acid.

In this description, the term "including" means an open set. The claim, in which the term is used, it may contain elements in addition to those identified in this paragraph.

DETAILED DESCRIPTION of ACTIVE CONNECTIONS

In one embodiment, the implementation agent of the formula I, the agent is a compound of the formula:

where n is 1 or 2; m is 0 or 1; q is avno 0 or 1; t is 0 or 1; R5represents alkyl containing from 1 to 3 carbon atoms; A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl; or a 5-or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula I with the aid of a ring carbon atom; and X represents-CH2-, and R1is ethyl; or X is-CH2CH2-or-CH2CH(NHAc)-, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound.

In other embodiments, the implementation of the agent of formula I, Rlrepresents hydrogen or ethyl; q is 0; or X represents-CH2CH2-.

In another embodiment, the agent of formula I, A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from halogen, of alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce, each halogen independently represents fluorine or chlorine. In a particular embodiment, each halogen substituent in the phenyl ring And represents fluorine. In a more specific embodiment, the phenyl ring And the substituted 2 groups of fluorine. In a specific embodiment, alkyl, perfluoroalkyl, alkoxy or performace has one carbon atom.

In another embodiment, the agent of formula I, A represents cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms are independently monosubstituted by stands or ethyl. In a specific embodiment, cycloalkyl is unsubstituted or one or both of the ring carbon atoms adjacent to the ring carbon that is covalently bound to the remainder of the compounds of formula I are independently monosubstituted by stands or ethyl. In a more specific embodiment, And represents the unsubstituted cyclopropyl.

In another embodiment, the agent of formula I, q is 1, and R5represents methyl.

In another embodiment, the agent is a compound of the formula:

where n is 1 or 2; m is 0 or 1; q is 0 or 1; t is 0 or 1; each of R2and R3independently selected from hydrogen, halogen, alkyl having 1 or 2 carbon atoms, performative, alkoxy having 1 or 2 carbon atoms, and performatce; R5represents alkyl containing from 1 to 3 carbon atoms; and X represents-CH2-, and R1represents ethyl; or X represents-CH2CH2- or-CH2CH(NHAc)-, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound. In a more specific embodiment, R1represents hydrogen or ethyl. Examples of compounds of formula IA include connection AM and BG connection.

In a specific embodiment, the agent is a compound of the formula:

where n is 1 or 2; m is 0 or 1; p is 1, and R1represents ethyl; or p is 2, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; each of R2and R3independently selected from hydrogen, halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or when R1represents odor is d, pharmaceutically acceptable salt of the compound. In a more specific embodiment, R1represents hydrogen or ethyl. In another more specific embodiment, one of R2and R3represents a hydrogen or halogen and the other is halogen. Examples of such compounds include compound AD, the connection AE and the connection AI. In another even more specific embodiment, R2represents fluorine, and R3represents hydrogen. Examples of such compounds include compound AA, connection AJ, AK connection and connection AO. The following more specific embodiment, R2represents fluorine, and R3represents fluorine. Examples of such compounds include compound AU, AV connection and the BB connection.

In a more specific embodiment, the agent is a compound of the formula:

where n is 1 or 2; m is 0; R1represents H or alkyl containing from 1 to 7 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound. Examples of such compounds include compound AH, AQ connection, the connection AW and connection BA. In another more specific embodiment, one of R2and R3represents methyl, methoxy or perf ormetal, and the other represents hydrogen or methyl. In one embodiment, R2represents methyl, methoxy or performer and R3represents hydrogen. Examples of such compounds include compound AB, AL connection, the connection'AN, the AP connection and connection AY. In another embodiment, R2represents methyl, and R3represents methyl. Examples of such compounds include compound and AT connection BI. In the following embodiment, R2represents hydrogen, and R3represents hydrogen. Examples of such compounds include compound AG.

In another embodiment, the agent is a compound of the formula:

where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound. In a specific embodiment, R1represents hydrogen or ethyl. Examples of such compounds include compound AX and connection BH. In another embodiment, the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; and Het represents a 5 or 6-membered heteroaromatic ring, containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula IC with the aid of a ring carbon atom. In a specific embodiment, R1represents hydrogen or ethyl. Examples of such compounds include compound AF and connection AR.

In the embodiment, the agent of formula II, A is cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atom adjacent to the remainder of the compounds of formula II are monosubstituted by stands or ethyl. In another embodiment, the agent of formula II, A is phenyl, unsubstituted or substituted 1 or 2 groups selected from: fluorine, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce.

In another embodiment, the agent is a compound of the formula:

where m is 0 or 1; r is 0 or 1; Z represents a

R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; R4represents hydrogen; -NHCOOC(CH3)3; -NHCH3or-NHCH2CH3; R3represents hydrogen or Galaga is; or when R1represents hydrogen, a pharmaceutically acceptable salt of the compound. In a specific embodiment, R1represents hydrogen or ethyl. Examples of such compounds include AC connection, the connection AZ, connection BC and the connection will BE.

In the embodiment, the agent of formula III, A is phenyl, unsubstituted or substituted 1 or 2 groups selected from: halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce. Examples of such compounds include compound BD.

In the embodiment, the agent of the formula IV, R1represents hydrogen or ethyl. Examples of such compounds include compound AS.

In the embodiment, the agent of formula V', the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; A represents a phenyl, unsubstituted or substituted 1 or 2 groups selected from halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce; or cycloalkyl having from 3 to 6 ring carbon atoms, where cycloalkyl is unsubstituted or one or two ring carbon atoms independently researched the Simo are monosubstituted by stands or ethyl; or 5 or 6-membered heteroaromatic ring containing 1 or 2 heteroatoms in the ring selected from N, S and O and the heteroaromatic ring is covalently linked to the remainder of the compounds of formula I with the aid of a ring carbon atom; or a pharmaceutically acceptable salt of the compound.

In the embodiment, the agent of formula V, the agent is a compound of the formula:

where n is 1 or 2; R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms; each of R2and R3independently selected from hydrogen, halogen, alkyl containing 1 or 2 carbon atoms, performative, alkoxy containing 1 or 2 carbon atoms, and performatce, or pharmaceutically acceptable salt of the compound. In a specific embodiment, R1represents hydrogen or ethyl. Examples of such compounds include compound BF.

Use in methods of treatment

This invention relates to a method of treatment of a subject mammal suffering from a disease selected from the group consisting of a syndrome of insulin resistance and diabetes (both the main important of diabetes, such as diabetes type I or diabetes type II, and secondary neadiabaticheskie diabetes), including introduction to the subject effective to treat the condition number of the above-described biological and active agent. In accordance with the method of the present invention can decrease the symptoms of diabetes or develop symptoms of diabetes, such as atherosclerosis, obesity, high blood pressure, hyperlipidemia, fatty liver, nephropathy, neuropathy, retinopathy, ulceration of the feet and cataracts, each a symptom associated with diabetes. This invention also relates to a method of treating hyperlipidemia, comprising an introduction to the subject of the biologically active agent described herein in a quantity effective to treat the disease. As shown in the examples, the compounds lower the triglycerides and free fatty acids in the blood serum of hyperlipidemics animals. This invention also relates to a method for treatment of cachexia, including the introduction of the subject of the biologically active agent described herein, in amounts effective for the treatment of cachexia. This invention also relates to a method of treating obesity, comprising administration to the subject of the biologically active agent described herein in a quantity effective to treat the disease. This invention also relates to a method of treatment of a disease selected from atherosclerosis or arteriosclerosis, comprising an introduction to the subject of the biologically active agent described herein in a quantity effective DL the treatment of the disease. The active agents of this invention are effective for treatment of hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis or arteriosclerosis, regardless of whether the subject has diabetes or syndrome of insulin resistance. The agent can enter any normal by systemic injection. Preferably the agent is administered orally. Other routes of administration that can be used in accordance with the invention, include rectal, parenteral injection (e.g. intravenous, subcutaneous, intramuscular or intraperitoneal injection) or nasal route.

Further embodiments of each of the applications and methods of treatment according to this invention include the introduction of any one of the above biologically active agents. In order to avoid unnecessary congestion, each agent or group of agents are not repeated, but they are included in this description of the uses and methods of treatment, as if they were repeated.

Many of the diseases or disorders, which addressed the compounds according to the invention fall into two broad categories: the syndromes of insulin resistance and consequences of chronic hyperglycemia. Violation of the regulation of energy metabolism, especially insulin resistance, which can occur in the absence of diabetes (constant is hyperglycemia) itself is associated with many symptoms, including hyperlipidemia, atherosclerosis, obesity, idiopathic hypertension, fatty liver (NASH, nonalcoholic steatohepatitis) and, especially in the context of cancer or systemic inflammatory disease, cachexia. Cachexia may also occur in diabetes type I or late stage diabetes type II. By improving energy metabolism in tissues of the active agents according to the invention are useful for prevention and / or alleviate the occurrence of diseases and symptoms associated with insulin resistance, as shown in animal studies. Although individual patient a set of signs and symptoms associated with insulin resistance, can coexist, in many cases can dominate only one symptom due to individual differences in the vulnerability of many physiological systems are affected by insulin resistance. However, since insulin resistance is a major contributor to many painful conditions, drugs, which are aimed at this cell and molecular defect, useful for the prevention or relief of almost any symptom in any organ system, which is the result of or exacerbated by resistance to insulin.

When insulin resistance or associated inadequately the production of insulin by the pancreatic islets are sufficiently serious, occurs chronic hypoglycemia that defines the beginning of diabetes mellitus type II (NIDDM). In addition to metabolic disturbances associated with the above insulin resistance in patients with NIDDM also occur secondary to hyperglycemia symptoms. They include nephropathy, peripheral neuropathy, retinopathy, a disease of capillaries, ulceration of the extremities and the consequences of non-enzymatic glycosylation of proteins, i.e. the damage of collagen and other connective tissue. The attenuation of hyperglycemia reduces the speed of onset and the severity of such consequences of diabetes. Since, as is demonstrated in the examples, the active agents and compositions of the invention help to reduce hyperglycemia in diabetes, they are useful for prevention and relief of complications of chronic hyperglycemia.

Subjects mammals, both humans and animals, can be treated in accordance with the method of treatment according to this invention. The optimal dose of a particular active agent according to the invention for a specific subject can be determined in clinical practice by a qualified physician. In the case of oral administration to man for the treatment of diseases associated with insulin resistance, diabetes, hyperlipidemia, fatty liver, cachexia or obesity, Ah the NT is usually administered in a daily dose of from 1 mg to 400 mg, which is injected once or twice a day. For oral administration to a person intended the preferred daily dose of the compounds of the Academy of Sciences is from 100 to 400 mg; compound AW - from 30 to 300 mg and connections BI - from 10 to 200 mg. In the case of oral administration to mice, the agent is usually administered in a daily dose of from 1 to 300 mg of agent per kilogram of body weight. The active agents according to the invention is used as monotherapy diabetes or syndrome of insulin resistance, or in combination with one or more other drugs, which are used for these types of diseases, for example, releasing insulin agents, "dining" releasing insulin means, the biguanides, or by insulin. Such additional drugs administered in accordance with standard clinical practice. In some cases, the agents according to the invention will improve the efficiency of certain classes of drugs, allowing the introduction of a patients lower (and therefore less toxic) doses of such agents with satisfactory therapeutic results. Set a safe and effective dosage ranges for men illustrative compounds are: Metformin - 500 up to 2550 mg/day; glyburide from 1.25 to 20 mg/day; Glucovance (GLUCOVANCE) (combined drug metform is on and glyburide) - from 1.25 to 20 mg/day of glyburide and from 250 to 2000 mg/day of Metformin; atorvastatin 10 to 80 mg/day lovastatin from 10 to 80 mg/day; pravastatin 10 to 40 mg/day and simvastatin - 5-80 mg/day; clofibrate - 2000 mg/day; gemfibrozil - 1200-2400 mg/day; rosiglitazon from 4 to 8 mg/day; pioglitazone 15 to 45 mg/day; acarbose - 75-300 mg/day; Repaglinide from 0.5 to 16 mg/day.

Diabetes mellitus type I: the Patient with diabetes type I in control of their disease in the first place by way of self-introduction from one to several doses of insulin per day, with frequent monitoring of glucose levels in the blood, which is the appropriate way to regulate the dosage and time of administration of insulin. Chronic hyperglycemia leads to complications, such as nephropathy, neuropathy, retinopathy, ulceration of the feet and premature death; hypoglycemia due to excessive doses of insulin may cause cognitive dysfunction or unconsciousness. The patient suffering from diabetes type I receives from 1 to 400 mg/day of active agent in this invention, for example, from 50 to 400 mg/day connections Academy, in the form of tablets or capsules as a single dose or divided doses. The expected effect would be a decrease in the dose or frequency of insulin required to maintain satisfactory range of glucose levels in the blood, and reducing the proportion and severity of GI is glycemically cases. The clinical result is controlled by the measurement of glucose and glycated hemoglobin in the blood (the index of the adequacy of glycemic control, integrated over a period of several months), and also to reduce the proportion and severity of typical complications of diabetes. The biologically active agent in this invention can be introduced in combination with transplantation of pancreatic islets to maintain the antidiabetic efficacy of transplantation of islets.

Diabetes mellitus type II: a Patient with type II diabetes control their disease with nutrition programs and physical exercise, and medications, such as Metformin, glyburide, Repaglinide, rosiglitazone or acarbose, all of which lead to some improvement in glycemic control for some patients, but none of which is devoid of side effects or treatment failure due to the development of the disease. Dysfunction of the Islands occurs over time in patients with NIDDM, leading to the need for insulin injections in a large proportion of patients. It is expected that daily treatment with the active agent according to the invention (with or without the use of additional classes of antidiabetic drugs) will improve glycemic control, reduce SC is the rate of renal function islets and reduce the proportion and severity of common symptoms of diabetes. In addition, the active agents according to the invention will reduce elevated levels of triglycerides and fatty acids in the serum, thus reducing the risk of cardiovascular diseases, the leading cause of death in patients with diabetes. Suitable daily dosage ranges for selected compounds of the invention for the treatment of NIDDM (either as monotherapy or in combination with other antidiabetic medicines) are from 50 to 400 mg/day connections Academy, from 15 mg to 300 mg of compound AW and from 5 mg to 200 mg of compound BI. As in the case of all other therapeutic agents for diabetes, dose optimization is carried out for an individual patient in accordance with necessity, clinical effect, and susceptibility to side effects.

Hyperlipidemia: Elevated levels of triglycerides and free fatty acids in the blood affect a significant proportion of the population and represent an important risk factor for atherosclerosis and myocardial infarction. The active agents according to the invention can be used to reduce circulating triglycerides and free fatty acids in hyperlipidemics patients. Suitable daily dosage ranges for selected compounds of the invention for the treatment of hypertriglyceridemia range from 50 to 400 mg/day connections Academy, from 15 mg to 300 mg is connected to the I AW and from 5 mg to 200 mg of compound BI. Patients suffering from hyperlipidemia, often also seen an increased level of cholesterol in the blood, which increases the risk of cardiovascular disease. Reducing the level of cholesterol drugs, such as inhibitors of HMG-CoA reductase, you can enter suffering from hyperlipidemia patients in addition to the agents according to the invention, it is not necessarily included in the same pharmaceutical composition.

Fatty liver: a large proportion of the population susceptible to this disease as fatty liver, also known as nonalcoholic steatohepatitis (NASH; NASH often associated with obesity and diabetes. Hepatic steatosis, the presence of droplets of triglycerides together with the liver cells (hepatocytes), leads to the susceptibility of the liver to chronic inflammation (detected in samples for biopsy in the form of infiltration of inflammatory leukocytes), which can lead to fibrosis and cirrhosis. Fatty liver is usually found through observation of increased levels of serum liver-specific enzymes such as transaminases ALT and AST, which serve as indicators of damage to the liver cells, and presence of symptoms that include fatigue and pain in the liver, although an accurate diagnosis often requires a biopsy. As shown in the example is, compounds according to the invention, for example, compound AW, reduce the amount of hepatic transaminases in serum and fat in the liver, as it was found in animal models of NASH (prone to obesity mouse ob/ob), and therefore useful for the treatment of fatty liver disease. A suitable dosage range for the compounds AW for the treatment of fatty liver disease ranges from 15 to 300 mg/day. The expected benefit is the reduction of inflammation and liver fat content, which will lead to a weakening of the termination or reversal of the progression of NASH to fibrosis and cirrhosis.

The PHARMACEUTICAL COMPOSITION

This invention relates to a pharmaceutical composition comprising a biologically active agent as described herein, and a pharmaceutically acceptable carrier. The following embodiments of the pharmaceutical compositions of this invention include any of the embodiments described above biologically active agents. In order to avoid unnecessary excessive information, each agent or group of agents are not repeated, but they are included in this description of pharmaceutical compositions as if they were repeated.

Preferably the composition is adapted for oral administration, for example, in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, RA is down, emulsion or suspension. Usually oral composition will comprise from 1 mg to 400 mg of this agent. The subject will be convenient to swallow one or two tablets, coated tablets, coated tablets or gelatin capsules a day. Accordingly, the preferred oral compositions for the treatment of people include from 50 mg to 400 mg of compound AH, from 15 mg to 300 mg of compound AW, or from 5 mg to 200 mg of compound BI. However, the composition can also be adapted for administration by any other conventional method of system introduction, including rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of solutions for injection or nasal.

Biologically active compounds can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions.

As such carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active ingredient in the case of soft chelation is new capsules carriers, different from the soft gelatin, are not usually required. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, glycerine, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, covering agents and antioxidants. They can also contain other therapeutically valuable substances, especially antidiabetic or lipid-lowering agents, the mechanism of action is different from the mechanism, which are compounds of the invention. Agents, which mainly can be combined with the compounds according to the invention in a single composition, include, but are not limited to: biguanidine, such as betterman, insulin-releasing agents, such as releasing insulin, a sulfonylurea, glyburide and other insulin-releasing sulfonylureas drugs that lower cholesterol, such as "satinowye" inhibitors of HMG-CoA reductase, such to the to atrovastatin, lovastatin, pravastatin and simvastatin, PPAR-alpha agonists such as clofibrate, and gemfibrozil, PPAR-gamma agonists, such as preparations of thiazolidinediones (such as rosiglitazone and pioglitazone, alpha-glucosidase inhibitors, such as acarbose (which inhibits the digestion of starch) and "dining" insulin-releasing agents, such as Repaglinide.

The number of additional agents, combined with the compounds according to the invention in a single composition that correspond to the dosages used in standard clinical practice. Developed a safe and effective dosage ranges for some illustrative of the compounds described above.

Schema reactions

Biologically active compounds according to the present invention can be obtained in accordance with the following scheme of reactions:

The compound of formula I'where X represents-CH2CR12R13-, q and m are 0, t is 0 or 1, and n is 1 or 2, R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, i.e. the compounds of formula:

where A is as described above, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, R12The R 13independently represent hydrogen or methyl, can be obtained from compounds of formula VI by reaction scheme shown in Scheme 1.

To the reaction scheme shown in Scheme 1, A, t, n, and R9are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms, R12and R13independently represent hydrogen or methyl, and Y is a leaving group.

The compound of formula VI is converted into the compound of formula VIII by reaction stage (a) using a condensation Mitsunobu VI VII using triphenylphosphine and diethylazodicarboxylate. For carrying out this reaction stage (a) you can use any terms that are commonly used in reactions of Mitsunobu.

The compound of formula VIII can also be obtained terifically or by alkylation of compounds of formula VI, a compound of formula IX, as in the reaction stage (b). In the compound of formula IX, Y can be any common leaving group, such as mesilate, tosyloxy or halide. For the reaction stage (b) can be used any conventional method of etherification of hydroxyl groups using reaction with a halide or leaving group. If the compound of formula IX is readily available, the reaction of stage (b) is more preferable than the reaction of stage (a).

the Compound of formula VIII is converted into the compound of formula XI by reaction stage (c) by alkylation of compounds of formula VIII compound of formula X. This reaction is carried out using a conventional Foundation that converts acetophenone 3-keto ester (i.e. gamma-keto ester). For these purposes, in the reaction stage (C) you can use any regular basis. In carrying out this reaction is usually preferable to use as the basis of salts of alkali metals hexamethyldisilazane, such as bis(trimethylsilyl)amide and lithium. Typically this reaction is carried out in an inert solvent, for example, a mixture of tetrahydrofuran:1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5:1). For the reaction stage (C) you can use any of the conditions conventional for such reactions alkylation.

The compound of formula XI is a compound of formula I', where Rlrepresents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XI can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of the ester group. Any conventional method of hydrolysis of ester will lead to the compound of formula I', where R1represents H.

The compound of General formula VII can be obtained by restoring the appropriate acid of the formula A-(CH2)t+n-CO2H. the Reaction is carried out initially by conducting the esterification of compounds of formula A-(CH2 )t+n-CO2H idestam the stands, followed by reduction using a conventional Foundation, for example, socialwise hydride or the like, in an inert organic solvent, for example tetrahydrofuran or the like. For carrying out this reaction, you can use any of the conditions conventional for such reactions recovery.

Scheme 1

Compound of formula VII, where A represents a 2,6-dimetilfenil can be obtained from compounds of formula XCI, according to the reaction scheme shown in scheme 2.

In scheme 2, the compound of formula XCI can be converted to the compound of formula VII by etherification using iodotope bromide, followed by reduction socialwise hydride by the reaction of stage (r"). Reaction stage (r") can be performed using conventional reducing agent. In carrying out this reaction is generally preferred to use as a reductant socialwise hydride. Any conditions conventional for the reactions of recovery, can be used for carrying out this reaction.

Scheme 2

The compound of formula I, where X represents-CH2-, q is 0, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is t is Kim, as described above, R1represents ethyl, and R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, can be obtained from compounds of formula XII where m is the same as earlier, according to the reaction scheme shown in scheme 3.

In scheme 3, A is the same as above, Y represents a leaving group such as halide, mesilate or tosyloxy. Y1represents chlorine.

In scheme 3, the compound of formula XII in turn ethyl ester of formula XIII with ethanol by the reaction of stage (d). For carrying out this reaction it is possible to use any conventional way of turning acid ethyl ester.

The compound of formula XIII can be converted to the compound of formula XIV the same way as previously described in connection with the reaction of stage (a) or (b).

At stage (f), the compound of formula XIV hydrolyzing, receiving compound of formula XV. For carrying out this reaction it is possible to use any conventional method of alkaline hydrolysis for hydrolysis of esters.

The compound of formula XV is converted into the acid chloride of the acid of formula XVI by reaction stage (g) through interaction with chloride tiomila. For carrying out this reaction stage (g) you can use any generally accepted method of transforming acid in chloramide the acid.

The compound of formula XVII interacts with the acid chloride of the acid of formula XVI with the formation of compounds of formula XVIII by reaction stage (h). For carrying out this reaction, you can use any regular basis, with the preferred base is pyridine. Obtained acylated acid Meldrum was not provided, and instead of handling them was heated in boiling absolute ethanol with polucheniem 2-ketoesters. For the reaction of stage (h) you can use any common conditions.

The compound of formula XVIII is a compound of formula I, where R1represents ethyl.

Scheme 3

The compound of formula I'where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, where X represents-CH2CR12R13-, m is 0, t is 0 or 1, and n is 1 or 2, i.e. the compounds of formula:

where A is as above, R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, and R12and R13independently represent hydrogen or methyl, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 the volume of carbon can be obtained from compounds of formula XIX, where t and A are as described above, according to the reaction scheme presented in figure 4.

In figure 4, t, n, A, R1, R9, R12, R13and R5are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms. Y1represents chlorine.

In scheme 4, the compound of formula XIX Mailroot to obtain the compounds of formula XX by reaction stage (i). For metilirovaniya you can use any normal conditions. The compound of formula XX is then heated with the compound of the formula XXI to obtain the compounds of formula XXII. For the reaction of stage (j) you can use any of the conditions conventional for receiving amerosport.

In the compound of formula XXII, alcohol group is then replaced by chlorine by treatment of compounds of formula XXII chloride tiomila, receiving the compound of formula XXIII by reaction stage (k). For carrying out this reaction it is possible to use any method to replace the alcohol group to a halogen.

Then spend the interaction of the compounds of formula XXIII with a compound of formula VI in the presence of a base using dimethylformamide as solvent for the reaction of stage (l), obtaining the corresponding compound of formula XXIV. The position of substituents in the compound of formula VI is determined by the position the of the substituents in the compound of formula XXIV. For the reaction of stage (l) can be used any conventional method of etherification of a hydroxyl group, a halide in the presence of a base (the preferred base is potassium carbonate). The compound of formula XXIV is converted into a compound of formula XXV reaction stage (m) using the alkylation of compounds of formula XXIV compound of formula X in the presence of silylated metal (for example, hexamethyldisilane lithium or hexamethyldisilane sodium). This reaction is carried out in the same manner as described for the reaction of stage (c) scheme 1.

The compound of formula XXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XXV can be converted to the free acid i.e. the compound of formula I, in which R1represents H, by hydrolysis of ester. Any conventional methods of hydrolysis of the ester group will lead to the compound of formula I', where R1represents H.

Scheme 4

The compound of formula I'where X represents-CH2CH(NHAc)-, m is 0, q is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is as above, R1represents hydrogen or alkyl containing from 1 to 7 at the MOU carbon and R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, can be obtained from compounds of formula VIII by reaction scheme presented in figure 5.

In scheme 5, t, n, A, R9and R1are as described above. R7represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula VIII receive the same manner as previously described in connection with the reaction of stage (a) or (b) in scheme 1.

The compound of formula VIII is converted into a compound of formula XXVI selective bromirovanii methylketones fragment reaction stage (n) treatment of compounds of formula VIII CuBr2. For the reaction of stage (n) you can use any of the conditions selective synthesized for the conversion of ketone 1-Bratton.

The compound of formula XXVI can be converted to the compound of formula XXVIII reaction stage (o) treatment of compounds of formula XXVI sodium salt of the compounds of formula XXVII in ethanol. For carrying out this reaction it is possible to use any conventional reaction conditions for the alkylation.

The compound of formula XXVIII is converted into a compound of formula XXIX reaction stage (p), representing deesterification using 4 equival new sodium hydroxide. Watched the original mono deesterification followed by slow hydrolysis of the remaining ethyl ether complex. Removing the solvent and curing of the residue in acetic acid leads to the compound of formula XXIX.

The compound of formula XXIX is a compound of formula I'in which R1represents H.

The compound of formula XXIX can be converted to the compound of formula XXXI, where R7represents an alkyl chain containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction stage (q), you can use any of the conditions suitable for this reaction.

The compound of formula XXXI is a compound of formula I', where Rlrepresents an alkyl chain containing from 1 to 7 carbon atoms.

Scheme 5

The compound of formula I'where X represents-CH2-, q and m are 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where t, n and A are as described above, R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, and R1represents ethyl, can be obtained from the compounds the formula ia LX in the reaction scheme, presented in figure 6.

In the reaction scheme presented in figure 6, A, t, R9and n are such as defined above, Y represents a leaving group and Y1represents chlorine.

In scheme 6, the compound of formula LX is converted into a compound of formula LXI in the same manner as previously described in connection with reaction stages (a) or (b) in scheme 1.

On stage (q') a compound of formula LXI hydrolyzing to obtain the compounds of formula LXII in the same manner as described in connection with the reaction of stage (f) in scheme 3.

The compound of formula LXII is converted into a compound of formula LXIII reaction stage (r') in the same manner as described in connection with the reaction of stage (g) in scheme 3.

The compound of formula LXIV initially treated with 2 equivalents of n-utility at low temperature and then add the compound of formula LXIII to obtain the compounds of formula LXV (Weirenga, W.; Skulnick, H.I, J. O. C. 1979, 44, 310-311). The compound of formula LXV is a compound of formula 1, where R1represents ethyl.

Scheme 6

The compound of formula I, where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, where X represents-CH2-, m is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is the same as described is use, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, and R1represents ethyl, can be obtained from the compounds of formula LX according to the reaction scheme presented in figure 7.

In the reaction scheme presented in figure 7, A, t, R9and n are such as defined above, Y1represents chlorine. R5represents an alkyl group containing from 1 to 3 carbon atoms.

In scheme 7, the compound of formula LX interacts with the compound of the formula XXIII (produced in the same manner as described in scheme 4) to obtain the compounds of formula LXVI by the reaction of stage (t'). This reaction is carried out in the same manner as previously described in connection with the reaction of stage (l) in figure 4.

On the stage (u') the compound of formula LXVI hydrolyzing to obtain the compounds of formula LXVII in the same way as described for the reaction of stage (f) in scheme 3.

The compound of formula LXVII is converted into a compound of formula LXVIII by the reaction of stage (v') in the same manner as described in connection with the reaction of stage (g) in scheme 3.

The compound of formula LXIV initially treated with 2 equivalents of n-utility at low temperature and then add the compound of formula LXIII to obtain the compounds of formula LXV (Weirenga, W.; Skulnick, H.I, J. O. C. 1979, 44, 310-311). The compound of formula LXIX is a compound of formula I, where 1represents an alkyl group containing 2 carbon atoms.

Scheme 7

The compound of formula I'where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, X represents-CH2CH(NHAc)-, m is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where t, n, A and R1are as described above, can be obtained from compounds of formula VI by reaction scheme presented in figure 8.

Figure 8 t, n, A, R9and R1are as described above. R7represents an alkyl group containing from 1 to 7 carbon atoms. R5represents an alkyl group containing from 1 to 3 carbon atoms. Y1represents chlorine.

The compound of formula XXIV receive the same manner as previously described in connection with the reaction of stage (l) in figure 4.

The compound of formula XXIV is converted into a compound of formula LXX selective bromirovanii methylketones fragment on which eacli stage (x') by treating compound of formula XXIV CuBr 2. For the reaction stage (x'), you can use any of the conditions selective synthesized for the conversion of ketone 1-Bratton.

The compound of formula LXX can be converted to the compound of formula LXXI by the reaction of stage (y') by treating compound of formula LXX sodium salt of the compounds of formula XXVII in ethanol. For the reaction of alkylation you can use any common conditions.

The compound of formula LXXI is converted into a compound of formula LXXII by the reaction of stage (z') by deesterification using 4 equivalents of sodium hydroxide. This indicates that the initial mono-deesterification followed by slow hydrolysis of the remaining ethyl ester groups. Removing the solvent and curing of the residue in acetic acid leads to the compound of formula LXXII.

The compound of formula LXXII is a compound of formula I', where R1represents N.

The compound of formula LXXII can be converted to the compound of formula LXXIII, where R7represents an alkyl group containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction stage (a) you can use any terms that are appropriate for given the Oh reaction.

The compound of formula LXXIII is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms.

Scheme 8

The compound of formula I'where X represents-CH2CH(NHAc)-, R9represents hydrogen, halogen or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, m is 1, q is 0, t is 0 or 1, and n is 1 or 2, i.e. the compound of the formula:

where A is as above, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, can be obtained from the compounds of formula LXXIV according to the reaction scheme shown in scheme 9.

In scheme 9, t, n, A, R9and R1are as described above. R7represents an alkyl group containing from 1 to 7 carbon atoms. R5represents an alkyl group containing from 1 to 3 carbon atoms.

The compound of formula LXXIV can be obtained in accordance with the method described by Murphy et al. J.C..Perkin 1, 1980, 1555-1566.

The compound of formula LXXIV can be preaccelerated to obtain the compounds of formula LXXV by the reaction of stage (b) using either the compounds of formula VII using is the same way, as described in connection with the reaction of stage (a) in figure 1, or the compounds of formula IX using potassium carbonate as a base for alkylation. The reaction is carried out in the same manner as previously described in connection with the reaction of stage (l) in figure 4.

The compound of formula LXXV then selectively bromilow at 0°C using 30 wt.% HBr in acetic acid is added dropwise, to obtain the compounds of formula LXXVI by the reaction of stage (c). For carrying out this reaction stage (c) can be used any conventional method for the selective conversion of substituted acetone 1-bromoacetone.

The compound of formula LXXVI converted into the compound of formula LXXVII by the reaction of stage (d) in the same manner as previously described in connection with the reaction of stage (o) figure 5.

The compound of formula LXXVII converted into the compound of formula LXXVIII by the reaction of stage (e) by deesterification using 4 equivalents of sodium hydroxide. Watched the original mono-deesterification followed by slow hydrolysis of the remaining ethyl ester groups. Removing the solvent and curing of the residue in acetic acid leads to the compound of formula LXXVIII.

The compound of formula LXXVIII is a compound of formula I', where R1represents N.

The compound of formula LXXVIII can be converted to the compound of formula LXXIX, where R 7represents an alkyl group containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction of stage (f), you can use any of the conditions conventional for this reaction.

The compound of formula LXXIX is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms.

Scheme 9

The compound of formula I'where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, X represents-CH2CH(NHAc)-, m is 1, t is 0 or 1, and n is 1 or 2, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, i.e. compounds of formula:

where A is as above, and R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, can be obtained from the compounds of formula LXXIV according to the reaction scheme shown in scheme 10.

In scheme 10, t, n, A, R9and R1are as described above. R7the stand is made by an alkyl group, containing from 1 to 7 atoms .R5represents an alkyl group containing from 1 to 3 carbon atoms. Y1represents chlorine.

The compound of formula LXXIV can be obtained by the method described by Murphy et. al. J. C. Sracp 1, 1980, 1555-1566.

In scheme 10, the compound of formula LXXIV interacts with the compound of the formula XXIII (produced in the same manner as described in scheme 4) to obtain the compound of formula LXXX by the reaction of stage (g). This reaction is carried out in the same manner as previously described in connection with the reaction of stage (l) in figure 4.

The compound of formula LXXX then selectively bromilow at 0°C using 30 wt.% HBr in acetic acid is added dropwise, to obtain the compounds of formula LXXXI by the reaction of stage (h). For the reaction of stage (h') can be used any conventional method for making substituted in acetone 1-bromoacetone.

The compound of formula LXXXI is converted into the compound of formula LXXXII by the reaction of stage (i) in the same manner as previously described in connection with the reaction of stage (o) figure 5.

The compound of formula LXXXII converted into the compound of formula LXXXIII by the reaction of stage (j) in the same manner as described for the reaction of stage (p) in scheme 5.

The compound of formula LXXXIII is a compound of formula I', where R1represents N.

The compound of formula LXXXIII may convert Sovana in the compound of formula LXXXIV where R 7represents an alkyl chain containing from 1 to 7 carbon atoms by esterification of carboxylic kiislamu compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction of stage (k), you can use any of the conditions suitable for the interaction.

The compound of formula LXXXIV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms.

Scheme 10

The compound of formula I'where X represents-CH2CR12R13-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, q is 0, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is the same as described above, R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, and R12and R13independently represent hydrogen or methyl, can be obtained from the compounds of formula LXXIV according to the reaction scheme shown in scheme 11.

In the reaction scheme presented in figure 11, A, t, R9, R12, R and n are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms, and Y represents a leaving group.

The compound of formula LXXV is obtained from the compounds of formula LXXIV in the same manner as previously described in connection with the reaction of stage (b) figure 9.

The compound of formula LXXV is converted into a compound of formula LXXXV by the reaction of stage (1") selective alkylation of compounds of formula LXXV compound of formula X. This reaction is carried out using a conventional Foundation that turns substituted ketone gamma-keto ester. In carrying out this reaction is usually preferred to use diisopropylamide lithium as the base. Alkylation will be held at the less sterically hindered methyl group. Typically this reaction is carried out in an inert solvent, such as tetrahydrofuran or 1,2-dimethoxyethane at -78°C.

The compound of formula LXXXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula LXXXV can be converted to the free acid i.e. the compound of formula I'in which R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula I', where R 1represents N.

Scheme 11

The compound of formula I'where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, where X represents-CH2-, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is as above, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, and R1represents ethyl, can be obtained from compounds of formula XIII, where m is as described above in reaction scheme shown in scheme 12.

In figure 12, A is the same as described above. Y1represents chlorine.

The compound of formula XIII (produced in the same manner as previously described in connection with the reaction of stage (d) in scheme 3) can be converted to the compound of formula LXXXVI by the reaction of stage (m) in the same manner as described above for the reaction of stage (1) in figure 4.

At stage (n), the compound of formula LXXXVI hydrolyzing to obtain the compounds of formula LXXXVII. For carrying out this reaction it is possible to use any conventional method basic hydrolysis to hydrolyze the ester group.

The compound of formula LXXXVII converted into the acid chloride of the acid of formula LXXXVIII by the reaction of stage (o) using the interaction of the chloride tiomila. For the reaction, you can use any normal way of turning the acid into gelegenheid acid.

The compound of formula XVII is subjected to interaction with the compound of the formula LXXXVIII to obtain the compounds of formula LXXXIX by the reaction of stage (p"). For carrying out this reaction, you can use any regular basis, with the preferred base is pyridine. For the reaction stage (p") can be any suitable conditions.

The compound of formula LXXXIX is a compound of formula I, where R1represents ethyl.

Scheme 12

The compound of formula I'where q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, where X represents-CH2CR12R13-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, Q represents OR1where R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where A is the same as described above, R1represents hydrogen or alkyl containing from 1 to 7 carbon atoms, and R12and R13independently represent hydrogen or methyl, can be floor is told from the compounds of formula LXXIV in the reaction scheme, presented in figure 13.

To the reaction scheme shown in scheme 13, R9, R12, R13, A, t, and n are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula LXXX obtained from the compounds of formula LXXIV in the same manner as previously described in connection with the reaction of stage (g) figure 10.

The compound of formula LXXX converted into the compound of the formula XC reaction stage (q) using the alkylation of compounds of formula LXXX compound of formula X. This reaction is carried out using a conventional Foundation, which converts the ketone 3-keto ester. In carrying out this reaction is usually preferable to use diisopropylamide lithium as the base. Alkylation will occur at the less sterically hindered methyl group. Typically this reaction is carried out in an inert solvent, such as tetrahydrofuran or 1,2-dimethoxyethane at -78°C.

The compound of formula XC is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XC can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of complex e the Ira will lead to the compound of formula I', where R1represents N.

Scheme 13

The compound of formula II, where Z is a

m is 0, r is 1, q is 0, t is 0 or 1, and n is 1 or 2, R4represents-NHCO2C(CH3)3, -NHCH3or-NHCH2CH3i.e. compounds of formula:

where A and R1are as described above, can be obtained from compounds of formula XXVI by the reaction scheme shown in scheme 14.

In figure 14, t, n, A and R1are as described above. R7represents an alkyl group containing from 1 to 7 carbon atoms. R8represents an alkyl group containing 1-2 carbon atoms. Y1represents a halogen, preferably bromine.

In figure 14, the compound of formula XXVI (produced in the same manner as previously described in connection with the reaction of stage (n) in figure 5) is subjected to interaction with the compound of the formula XXXII in the presence of a base to obtain a compound of formula XXXIII by the reaction of stage (r). In carrying out this reaction is generally preferred to the use of triethylamine as the base. For carrying out this reaction it is possible to use any suitable way interaction Boc-cys-OEt with halide.

The compound of formula XXXIII is predstavljaet a compound of formula II, where R4represents-NHCO2C(CH3)3and R1represents ethyl.

The compound of formula XXXIII can be converted to the free acid i.e. the compound of formula II, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula II where R1represents N, and R4represents-NHCO2C(CH3)3

The compound of formula XXXIII is converted into a compound of formula XXXV initially by the reaction of stage (s) by removing the protective tert-butoxyphenol group using triperoxonane acid substitution on the lower alkyl having 1 to 2 carbon atoms, by the reaction of stage (t). For carrying out this reaction it is possible to use any conventional method of condensing an amine with alkylhalogenide.

The compound of formula XXXV is a compound of formula II, where R4is an amine having 1 to 2 carbon atoms, and R1represents an alkyl group having 2 carbon atoms. The compound of formula XXXV can be converted to the free acid i.e. the compound of formula XXXVI, where R1represents N, the basic hydrolysis reaction stage (u). The compound of formula XXXVI is a compound of formula II, where R4is a-NHCH3or NHCHsub> 2CH3and R1represents N.

The compound of formula XXXVI can be converted to the compound of formula XXXVII, where R7represents an alkyl group containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction of stage (v) you can use any of the conditions conventional for this reaction.

The compound of formula XXXVII is a compound of formula II, where R1represents alkyl containing from 1 to 7 carbon atoms, and R4is a-NHCH3or-NHCH2CH3.

Scheme 14

The compound of formula II, where Z is a

m and q is 0, r is 1, t is 0 or 1, n is 1 or 2, i.e. compounds of formula:

A is the same as described above, can be obtained from compounds of formula VIII, where t, n and A are as described above for reaction scheme presented in figure 15.

In scheme 15, the compound of formula VIII (produced in the same manner as previously described in connection with the reaction of stage (a) or (b) in scheme 1) is converted into a compound of formula XXVI in the same way as described for the reaction of stage (n) figure 5.

The compound of formula XXVI is subjected to interaction with the compound of the formula XXXVIII in the presence of a base, with the preferred base is triethylamine, to obtain the compound of formula XXXIX. For the reaction stage (w) you can use any generally accepted method for interaction of the thiol with the halide.

The compound of formula II, where Z is a

m is 0, r is 1, t is 0 or 1, and n is 1 or 2, R4represents H, i.e. compounds of formula:

where t, n, A and R1are as described above, can be obtained from compounds of formula VIII by reaction scheme presented in figure 15.

To the reaction scheme shown in scheme 15, t, n, A and R1are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula VIII receive the same manner as previously described in connection with the reaction of stage (a) or (b) in scheme 1.

The compound of formula XXVI is obtained from the compounds of formula VIII in the same manner as previously described in connection with the reaction of stage (n) figure 5.

The compound of formula XXVI is subjected to interaction with the compound of the formula XL in the presence of a base, with the preferred base is triethylamine to obtain the is a group of formula XLI. For the reaction stage (x) you can use any normal way to interact with thiol 1-bromoketones.

The compound of formula XLI is a compound of formula II, where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XLI can be converted to the free acid i.e. the compound of formula II, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula II, where R1represents N.

Scheme 15

The compound of formula II, where Z is a

r is 0, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where n, t and A are as indicated above, can be obtained from compounds of formula XIII by reaction scheme presented in figure 16.

In scheme 16 t, n, and A are the same as described above. Y represents a leaving group such as halide, mesilate or tosyloxy. Y1represents a halogen, preferably bromine.

In scheme 16, the compound of formula XXXVIII is converted into a compound of formula XLIII reaction stage (y) by selective substitution of the hydroxyl group of the primary alcohol to the halogen. Took the I this reaction can be used any conventional halogenation agent, while the preferred halogenation agent is tribromide phosphorus. This reaction is carried out at a low temperature. Any conditions that are suitable for this method can be used for the reaction stage (y). The compound of formula XLIII is used immediately without further purification.

The compound of formula XLIII is subjected to interaction with the compound of the formula XXXVIII in the presence of a base to obtain a compound of formula XLIV. For the reaction stage (z) can be used any conventional method of condensation of the thiol with the halide. For carrying out this reaction, you can use any regular basis, with the preferred base is triethylamine.

The compound of formula XLIV is converted into a compound of formula XLV reaction with the compound of the formula VII by reaction stage (a'). This reaction is carried out in the same manner as previously described in connection with the reaction of stage (a) in scheme 1.

The compound of formula II, where Z is a

r is 0, m is 1, t is 0 or 1, and n is 1 or 2, R4represents H, i.e. compounds of formula:

where A and R1are as described above, can be obtained from compounds of formula XIII by reaction scheme presented in figure 16.

In scheme 16, t, n, and A are as indicated above. Y represents a leaving group such as halide, mesilate or tosyloxy. Y1represents a halogen, preferably bromine. R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula XXXVIII is converted into a compound of formula XLIII in the same manner as previously described in connection with the reaction of stage (y).

The compound of formula XLIII interacts with the compound of formula XL by the reaction of stage (b'), as described in connection with the reaction of stage (x) in scheme 15.

The compound of formula XLVI is converted into a compound of formula XLVII by the reaction of stage (c'). This reaction is carried out in the same manner as described for the reaction stages (a) or (b) in scheme 1.

The compound of formula XLVII is a compound of formula II, where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XLVII can be converted to the free acid i.e. the compound of formula II, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula II, where R1represents N.

Scheme 16

The compound of formula II, where Z is a

r is 0, m ravno, t is 0 or 1, and n is 1 or 2, i.e. the compounds of formula:

where t, n, A and R1are as above, R4represents-NHCO2C(CH3)3, -NHCH3, -NHCH2CH3can be obtained from compounds of formula XLIII in reaction scheme shown in scheme 17.

Figure 17 t, n, A and R1are as described above. Y represents a leaving group such as halide, mesilate or tosyloxy. R7represents an alkyl group containing from 1 to 7 carbon atoms, and R8represents an alkyl group containing from 1 to 2 carbon atoms. Y1represents a halogen, preferably bromine.

In scheme 17, the compound of formula XLIII (get in the same way as described previously for the reaction of stage (y) in scheme 16) is subjected to interaction with the compound of the formula XXXII in the presence of a base to obtain the compounds of formula XLVIII by the reaction of stage (d'). In carrying out this reaction is generally preferred to the use of triethylamine as the base. For carrying out this reaction it is possible to use any conventional way interaction Boc-cyst-OEt with halide.

The compound of formula XLIX is produced by interaction of the compounds of formula XLVIII with the compound of the formula VII or IX. This reaction is carried out in the same manner as described for the reaction stages (a) or (b) in scheme 1.

Connection fo the mules XLIX is a compound of formula II, where R4represents-NHCO2C(CH3)3and R1represents an alkyl group containing 2 carbon atoms.

The compound of formula XLIX can be converted to the free acid i.e. the compound of formula II, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula II, where R1represents N and R4represents-NHCO2C(CH3)3.

The compound of formula XLIX is converted into a compound of formula L initially, the reaction of stage (f) removing the protective tert-butoxyphenyl group using triperoxonane acid and then replacing it on the lower alkyl containing from 1 to 2 carbon atoms by the reaction of stage (g'). For carrying out this reaction it is possible to use any conventional method of condensing an amine with alkylhalogenide.

The compound of formula L is a compound of formula II, where R4is an amine having 1-2 carbon atoms, and R1represents an alkyl group containing 2 carbon atoms.

The compound of formula L can be converted to the free acid i.e. the compound of formula LI wherein R1represents N, the main hydrolysis in the reaction stage (h').

The compound of formula LI is a compound of formula I, where R4is a-NHCH3or-NHCH2CH3and R1represents N. Any conventional method of hydrolysis of ester will lead to the compound of formula II, where R1represents N.

The compound of formula LI can be converted to the compound of formula LII, where R7 is an alkyl group containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. For the reaction of stage (i'), you can use any normal reaction conditions.

The compound of formula LII is a compound of formula II, where R1represents an alkyl group containing from 1 to 7 carbon atoms, and R4is a-NHCH3or-NHCH2CH3.

Scheme 17

The compound of formula III

where n is 1 or 2 and A is as above, can be obtained from the compounds of formula LIII, according to the reaction scheme shown in scheme 18, where n, A and Y are as described above.

In figure 18 the compound of formula LIII is converted into a compound of formula LIV in the same manner as described in connection with reaction stages (a) or (b) in Scheme 1.

The connection f is rmula LIV is converted into a compound of formula III by reaction stage (k') by heating the compounds of formula LIV with sodium azide in the presence of ammonium chloride in dimethylformamide. For carrying out this reaction it is possible to use any conventional method for converting a nitrile to tetrasol.

Scheme 18

The compound of formula IV

where R1so, as stated above, can be obtained from 2',6'-defloration according to the reaction scheme shown in scheme 19.

In figure 19, R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula LV is converted into a compound of formula LVI by the reaction of stage (l') in the same manner as previously described in connection with the reaction of stage (c) in figure 1.

The compound of formula LVI is a compound of formula IV, where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula LVI can be converted to the free acid i.e. the compound of formula IV, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula IV, where R1represents N.

Scheme 19

The compound of formula V

where n, A and R1are as above, R14represents hydroxy, can be obtained from compounds of formula VI by reaction scheme, performance is undertaken in figure 20.

Figure 20 n, A are as indicated above. Y represents a leaving group such as halide, mesilate or tosyloxy. R7represents an alkyl group containing from 1 to 7 carbon atoms, and R8represents an alkyl group containing from 1 to 2 carbon atoms.

The compound of formula VI into a compound of formula VIII in the same manner as previously described in connection with reaction stages (a) or (b) in scheme 1.

The compound of formula VIII is subjected to interaction with the compound of the formula LVII by the reaction of stage (m') in the presence of freshly prepared sodium alkoxide at room temperature to obtain the compound of formula LVIII. For the reaction, you can use any of the usual conditions for such alkylation.

The compound of formula LVIII is a compound of formula V, where R1represents an alkyl group containing from 1 to 2 carbon atoms. The compound of formula LVIII can be converted to the free acid i.e. the compound of formula V, where R1represent H, hydrolysis of ester by the reaction of stage (n'). Any conventional method of hydrolysis of ester will lead to the compound of formula V, where R1represents N.

The compound of formula LVIII can be converted to the compound of formula LIX, where R7is own the th alkyl group, containing from 1 to 7 carbon atoms by esterification of carboxylic acid with compound of formula XXX using N,N-dicyclohexylcarbodiimide as dehydrating condensing agent. Any conventional conditions for such reactions can be used for the reaction stage (o').

The compound of formula LIX is a compound of formula V, where RIrepresents an alkyl group containing from 1 to 7 carbon atoms.

Scheme 20

The compound of formula I'where X represents-CH2CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, q and m are 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where Q represents NR10R11where R10represents hydrogen, and R11represents a hydroxyl group; t, n, A, and R9are as described above, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 21.

In reaction scheme 21, A, t, R9, R6and n are as described above.

The compound of formula XI receive the same manner as described for reaction scheme presented in figure 1.

The compound of formula XI can be convert Sovana in the compound of formula XCII in the reaction stage (s) by treating compound of formula XI with hydroxylamine hydrochloride in an organic solvent, for example, ethanol, tetrahydrofuran or the like. The reaction is carried out using an organic base, for example potassium hydroxide or the like. For carrying out this reaction, you can use any of the conditions conventional for obtaining hydroxamic acids.

The compound of formula I'where X represents-CH2-CH2-, q and m are 0, t is 0 or 1, and n is 1 or 2, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, i.e. compounds of formula:

where t, n, A, and R9are as described above. Q represents NR10R11where R10and R11represent hydrogen, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 21.

In the reaction scheme presented in figure 21, A, t, R9and n are as described above. R1represents H, R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XI receive the same manner as described for reaction scheme shown in scheme 1. The compound of formula XI is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XI can the be converted into the free acid, i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula XI can be converted to the compound of formula XCIII in the reaction stage (t) by the initial activation using, for example, hexaflurophosphate benzotriazol-1-electroporation or the like in an organic solvent, e.g. methylene chloride, N,N-dimethylformamide or the like, followed dobavleniem aqueous ammonium hydroxide or ammonia. The reaction is carried out using an organic base, such as triethylamine, diisopropylethylamine or the like. For the reaction stage (t") you can use any standard for amide synthesis conditions.

The compound of formula I'where X represents-CH2-CH2-, q and m is 0, t is 0 or 1, and n is 1 or 2, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, i.e. compounds of formula:

where t, n, A, and R9are as described above. Q represents NR10R11where R10and R11independently represent hydrogen or alkyl containing from 1 to 3 carbon atoms, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme is e 21.

In the reaction scheme presented in figure 21, A, t, R9and n are as described above. R1represents H, and R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XI receive the same manner as described for reaction scheme shown in scheme 1. The compound of formula XI is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XI can be converted to the free acid, i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula XI can be converted to the compound of formula XCIV or initial interaction with gloriouse reagent, for example, chloride tiomila or the like, and then the interaction of gelegenheid acid with the appropriate amine. For the reaction stage (u"), you can use any suitable method of condensation of the amine with galogenangidridy acid. Or you can use the condensation of the corresponding amine with a compound of formula XI using 1,3-dicyclohexylcarbodiimide as a condensing agent.

For the reaction stage (u") can be used any conventional method of condensing an amine with an acid.

Scheme 21

The compound of formula I'where X represents-CH2-CH2-, q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where Q represents NR10R11where R10represents hydrogen, and R11represents a hydroxyl group; A, t, n, and R9are as described above, can be obtained from the compounds of formula

according to the reaction scheme presented in figure 22.

In reaction scheme 22, q, A, t, R5, R9and n are as described above. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XXV get in the same way as described for reaction scheme presented in figure 4.

The compound of formula XXV can be converted to the compound of the formula XCV in the reaction stage (v) in the same manner as described for the reaction stage (s) scheme 21.

The compound of formula I'where X represents-CH2-CH2-, q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, R9represents hydrogen, Gal is gene or alkoxy containing from 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, R1represents H, i.e. compounds of formula:

where q, t, n, A, R5and R9are as described above; Q represents NR10R11where R10and R11represent hydrogen, can be obtained from the compounds of formula

according to the reaction scheme presented in figure 22.

To the reaction scheme shown in scheme 22, q, A, t, R5, R9and n are as described above. R1represents H, and R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XXV get in the same way as described for reaction scheme presented in figure 4. The compound of formula XXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XXV can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula XXV can be converted to the compound of formula XCVI in the reaction stage (w") in the same manner as described for stage (t) of the reaction scheme 21.

The compound of formula I'where X represents-CH 2-CH2-, q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, m is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where q, t, n, A, R5and R9are as described above; Q represents NR10R11where R10and R11independently represent hydrogen or alkyl containing from 1 to 3 carbon atoms, can be obtained from the compounds of formula

according to the reaction scheme presented in figure 22.

In reaction scheme 22, q, A, t, R5, R9and n are as described above. R6represents alkyl containing from 1 to 7 carbon atoms. R1represents H.

The compound of formula XXV get in the same way as described for reaction scheme presented in figure 4. The compound of formula XXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XXV can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester. The compound of formula XXV can be converted to compound f is rmula XCVII in the reaction stage (x") in the same way, as described for stage (u") of reaction scheme 21.

Scheme 22

The compound of formula I'where X represents-CH2-CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where Q represents NR10R11where R10represents hydrogen, R11represents a hydroxyl group. t, n, A and R9are as described above, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 23.

In reaction scheme 23, A, t, R9and n are as described above. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula LXXXV receive the same manner as described in reaction scheme shown in scheme 11.

The compound of formula LXXXV can be converted to the compound of formula XCVIII in the reaction stage (y) in the same manner as described for the reaction stage (s) scheme 21.

The compound of formula I'where X represents-CH2-CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1, and n Rav is about 1 or 2, i.e. compounds of formula:

where t, n, A and R9are as described above; Q represents NR10R11where R10and R11represent hydrogen, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 23.

In the reaction scheme presented in figure 23, A, t, R5, R9and n are as described above. R1represents H. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula LXXXV get in the same way as described for reaction scheme presented in figure 11. The compound of formula LXXXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula LXXXV can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula LXXXV can be converted to the compound of formula XCIX in the reaction stage (z) in the same manner as described for the reaction stage (t) of the reaction scheme 21.

The compound of formula I'where X represents-CH2-CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, m is 1, q is 0, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where t, n, A, and R9are as described above, Q represents NR10R11where R10and R11independently represent hydrogen or alkyl containing from 1 to 3 carbon atoms, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 23.

In reaction scheme 23, A, t, R9and n are as described above. R1represents H. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula LXXXV get in the same way as described for reaction scheme presented in figure 11. The compound of formula LXXXV is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula LXXXV can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula LXXXV can be converted to the compound of formula C in the reaction stage (a'") in the same manner as described for stage (u") of reaction scheme 21.

Scheme 23

The compound of formula I'where X represents-CH2-CH2-, 9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e. the compounds of formula:

where Q represents NR10R11where R10represents hydrogen, and R11represents a hydroxyl group; t, n, A, R5and R9are as described above, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 24.

In reaction scheme 24, q, A, t, n, R5, R9and R6are as described above.

The compound of formula XC receive the same manner as described for reaction scheme presented in figure 13.

The compound of formula XC can be converted to the compound of formula CII in the reaction stage (b') in the same manner as described for the reaction stage (s) scheme 21. The compound of formula I'where X represents-CH2-CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, q is 1, R5represents an alkyl group containing from 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where q, t, n, A, R5and R9are as described above. Q represents NR10R11where R10and R11represent hydrogen, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 24.

To the reaction scheme shown in scheme 24, q, A, t, R5, R9and n are as described above. R1represents H. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XC receive the same manner as described for reaction scheme presented in figure 13. The compound of formula XC is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XC can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula XC can be converted to the compound of formula III by reaction stage (c'") in the same manner as described for stage (t) of the reaction scheme 21.

The compound of formula I'where X represents-CH2-CH2-, R9represents hydrogen, halogen, or alkoxy containing from 1 to 3 carbon atoms, q is 1, R5represents an alkyl group, the soda is containing from 1 to 3 carbon atoms, m is 1, t is 0 or 1, and n is 1 or 2, i.e. compounds of formula:

where q, t, n, A, R5and R9are as described above, Q represents NR10R11where R10and R11independently represent hydrogen or alkyl containing from 1 to 3 carbon atoms, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 24.

In reaction scheme 24, A, t, R5, R9and n are as described above. R1represents H. R6represents alkyl containing from 1 to 7 carbon atoms.

The compound of formula XC receive the same manner as described for reaction scheme presented in figure 13. The compound of formula XC is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XC can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester.

The compound of formula XC can be converted to the compound of formula IV by reaction stage (d') in the same manner as described for stage (u") of reaction scheme 21.

Scheme 24

The compound of formula V', where n is 1 or 2, t is 0, R1/sup> , R9and R14represent H, i.e. compounds of formula:

where t, n, A, R9, R14and R1are as described above, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 25.

In the reaction scheme presented in figure 25, A and n are as described above. R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula XI receive the same manner as described for reaction scheme presented in figure 1.

The compound of formula XI can be converted to the compound of formula CV in the reaction stage (e'"), treatment of compounds of formula XI, bromine or the like in an organic solvent, for example ether, carbon tetrachloride, where the preferred organic solvent is a simple ether.

As for the reaction temperature, the reaction may provodit at a temperature of from cooling with ice to room temperature, while it is preferable cooling with ice.

The compound of formula CV can be converted to the compound of formula VI by reaction stage (f) dehydrobrominated. The reaction is carried out using a conventional Foundation, while it is preferable triethyl is in and the like, in an organic solvent, for example, carbon tetrachloride or the like. For the reaction of stage (f"') you can use any of the conditions conventional for dihydrobromide.

The compound of formula VI is a compound of formula V', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula VI can be converted to the free acid i.e. the compound of formula V', where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester to yield the compounds of formula V', where R1represents H.

Scheme 25

The compound of formula CXVI, where X represents-CH2-CH2-, t is 0 or 1, and n is 1 or 2, R1and R9represent H, i.e. compounds of formula:

where t, n, A, and R9are as described above, R1represents H, can be obtained from the compounds of formula

according to the reaction scheme shown in scheme 26.

In reaction scheme 26, A, t, n, and R9are as described above. R1represents H. R6represents an alkyl group containing from 1 to 7 carbon atoms.

The compound of formula XI gender is given in the same way, as described for reaction scheme shown in scheme 1. The compound of formula XI is a compound of formula I', where R1represents an alkyl group containing from 1 to 7 carbon atoms. The compound of formula XI can be converted to the free acid i.e. the compound of formula I', where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula I', where R1represents H.

The compound of formula XI is converted into a compound of formula VII by reaction stage (g"') restoring the wolf-Kizaru treatment of compounds of formula XI hydrazine hydrate and potassium hydroxide in an organic solvent, for example, ethylene glycol or the like. Any conditions conventional for the reactions of recovering wolf-Kijner, can be used for carrying out the reaction stage (g"').

Scheme 26

The compound of formula XCI, where n is 1 or 2, R9represents H, and R1represents hydrogen or alkyl containing from 1 to 3 carbon atoms, i.e. compounds of formula:

where n, A, R9and R1are as described above, can be obtained from the compounds of formula

in the reaction scheme, the performance is allenou in scheme 27.

To the reaction scheme shown in scheme 27, R9represents a hydrogen atom, t is 0, R6represents an alkyl group containing from 1 to 7 carbon atoms, A and n are as described above.

The compound of formula XI receive the same manner as operands the reaction scheme shown in scheme 1.

The compound of formula XI can be converted to the compound of formula VIII by reaction stage (h') selective recovery of the ketone group to an alcohol. This reaction is carried out using conventional reducing agents, for example, sodium borohydride in ethanol, bis-3-methyl-2-butyl-borane in tetrahydrofuran and the like. For the reaction of stage (h') you can use any of the conditions conventional for such reactions selective recovery.

The compound of formula VIII can be converted to the compound of formula CIX in the reaction stage (i"') bromirovanii the compounds of formula VIII using pomeroyi agents, for example, trichromate phosphorus in tetrahydrofuran or dioxane, hydrogen bromide in acetic acid or dioxane, chetyrehpostovye carbon and bis(1,2-diphenylphosphino)ethane or the like. Any conditions conventional for such reactions, synthesized, can be used for the reaction of stage (i"').

The compound of formula CIX can be conversions is held in the compound of the formula CX in the reaction stage (j"') dehydrobrominated. The reaction is carried out using a conventional Foundation, the preferred base is triethylamine or the like, in an organic solvent, for example, carbon tetrachloride or the like. Any conditions conventional for such reactions dihydrobromide, can be used for carrying out the reaction stage (j"').

The compound of the formula CX is a compound of formula XCI, where R1represents an alkyl group containing from 1 to 3 carbon atoms. The compound of the formula CX can be converted to the free acid i.e. the compound of formula XCI, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula XCI, where R1represents H.

Scheme 27

The compound of formula CXVII, where X represents-CH2-CH2-, and n is 0 or 2, R15represents hydrogen or a lower alkyl group containing from 1 to 3 carbon atoms, R9represents hydroxy, hydrogen, CNS group containing from 1 to 3 carbon atoms, halogen atom, R1represents hydrogen or alkyl containing from 1 to 3 carbon atoms, i.e. compounds of formula:

where n, A, R9and R15are such as OPI is ANO above, can be obtained by the coupling of compounds of formula

with the compound of the formula

according to the reaction scheme shown in scheme 28.

In the reaction scheme presented in figure 28, A, n, R9, R15are as described above, R6represents alkyl containing from 1 to 3 carbon atoms.

The compound of formula XI can be converted to the compound of formula CXIII in the reaction stage (k') by treating compound of formula CXI condensing agent, for example, diethylthiophosphate, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide or the like, in an organic solvent, e.g. methylene chloride, N,N-dimethylformamide, followed by addition of the compounds of formula CXII.

The reaction temperature may be from 0°C to room temperature.

The compound of formula CXIII can be converted to the compound of formula CXIV in the reaction stage (l') by alkylation of compounds of formula CXIII compound of formula X. This reaction is carried out in the same manner as described for the reaction stage (c) of the reaction scheme 1.

The compound of formula CXIV is a compound of formula CXVII, where R9is a CNS group containing from 1 to 3 carbon atoms, halogen atom. Deputy R9you can convert the preferred into a hydroxyl group by demethylation using, for example, trichromate boron in methylene chloride or the like. For the reaction, you can use any of the conditions conventional for such reactions demethylation.

The compound of formula CXIV is a compound of formula CXVII, where R1represents an alkyl group containing from 1 to 3 carbon atoms, the Compound of formula CXIV can be converted into the free acid, i.e. the compound of formula CXVII, where R1represent H, hydrolysis of ester. Any conventional method of hydrolysis of ester will lead to the compound of formula CXVII, where R1represents N.

Compounds of General formula XI can be obtained by esterification of compounds of formula CI using alkyl halide, followed by hydrolysis of ester.

where R16represents a lower alkyl group containing from 1 to 3 carbon atoms, R9represents a hydroxyl group.

The interaction between the compound of the formula (CI) and the alkyl halide can be carried out in an organic solvent, e.g. N,N-dimethylformamide or the like, using a base, for example potassium carbonate, cesium carbonate or the like. For carrying out this reaction, you can use any of the conditions conventional for such reactions alkiline the project. Hydrolysis of ester can be carried out in acidic conditions, for example, using acid or hydrochloric acid, mixed with an organic solvent, for example ethanol, or acetic acid or the like. The reaction can be conducted at a temperature from room temperature up to the boiling point of the solvent. For carrying out this reaction it is possible to use any conventional conditions for acid hydrolysis of ester. In addition, if necessary, hydrolysis is difficult ester can be carried out using basic conditions, for example, in aqueous sodium hydroxide solution or the mixed solution of sodium hydroxide in an organic solvent, for example, ethanol or the like. For carrying out this reaction it is possible to use any conventional for the basic hydrolysis conditions.

Compounds of General formula CXII can be obtained by the coupling of compounds of formula VII with gloriouse agent, for example, trimethylsilylpropyne, chloride tiomila or the like, in an organic solvent, for example dimethyl sulfoxide, N,N-dimethylformamide or the like. The reaction temperature may be from room temperature to the boiling point organic solvent. Any customary for reactions of chlorination conditions can be used for the reaction.

Scheme 28

The invention will be better understood by reference to the following examples, which illustrate but do not limit the invention described here.

EXAMPLES of CHEMICAL SYNTHESIS

Example 1: Synthesis of 4-(4-(2-forbindelse)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-forbindelse)acetophenone:

A solution of 4-hydroxyacetophenone (2,80 g of 20.6 mmol) in anhydrous DMF (15 ml) was added at room temperature to a suspension of NaH (60% in oil, 794 g) in anhydrous DMF (20 ml). After cessation of hydrogen was added dropwise 2-terbisil bromide (3 g, 15.8 mmol). The reaction mixture was stirred at room temperature for 6 hours, reduce saturated aqueous NH4Cl and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified flash games is by chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the title compound in the form of not-quite-white solid.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H); 7,2-7,3 (m, 1H); to 7.4 (t, 1H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(2-forbindelse)phenyl)-4-oxybutyrate:

To a stirred solution of 4-(2-forbindelse)acetophenone (stage A, 1.5 g, 6.1 mmol) in anhydrous THF (20 ml) and DMPU (5 ml) solution was added bis(trimethylsilyl)amide lithium (1,0 M, 7 ml) at -60°C in argon atmosphere. After 10 minutes stirring at -60°C was rapidly added tert-butyl bromoacetate and 4.75 g, 24.4 mmol). The reaction mixture was stirred additionally for 10 minutes and then heated to room temperature within 4 hours. The crude mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.7 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,1 (m, 4H); 7,2-7,3 (m, 1H); to 7.4 (t, 1H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-forbindelse)phenyl)-4-oxobutanoic acid:

A solution of tert-butyl 4-(4-(2-forbindelse)phenyl)-4-oxybutyrate (stage B, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated tripto the acetic acid (5 ml). The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuum. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white powder.

1H NMR (270 MHz, CDCl3:CD3OD): 2,6 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,1 (m, 4H); 7,2-7,3 (m, 1H); to 7.4 (t, 2H); to 7.9 (d, 2H).

Example 2: Synthesis of 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-methoxybenzyloxy)acetophenone:

A solution of 2-methoxybenzamido alcohol (2,99 g, and 21.7 mmol) in anhydrous THF (5 ml) and anhydrous DMF (5 ml) was added to a stirred solution of 4-hydroxyacetophenone (3.25 g, to 23.8 mmol), triphenylphosphine (of 7.36 g of 28.0 mmol) and diethylazodicarboxylate (4,51 g of 25.9 mmol) in anhydrous THF (20 ml) at 5-10°C. the Reaction mixture was stirred at 0°C for 2 hours, heated to room temperature and concentrated in vacuum. The residue was placed in EtOAc and washed twice with saturated solution of NaHCO3. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol, 99:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H; of 3.9 (s, 3H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H); and 7.3 (m,1H); to 7.4 (d,1H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxybutyrate:

To a stirred solution of 4-(2-methoxybenzyloxy)acetophenone (stage A, 1.22 g, 4.7 mmol) in anhydrous THF (20 ml) and DMPU (5 ml) solution was added bis(trimethylsilyl)amide lithium (l,0 M, 5 ml) in an argon atmosphere at -60°C. After 10 minutes stirring at -60°C was rapidly added ethylbromoacetate (2,59 g, 15.6 mmol). The reaction mixture was stirred additionally for 10 minutes and then heated to room temperature within 2 hours. The crude mixture was placed in EtOAc and washed with water. The aqueous layer was extracted one more time, EtOAc and the combined organic layers were dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,6 (t, 2H); 3,2 (t, 2H); and 3.8 (s, 3H); to 4.1 (q, 2H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 4H); 7,1-7,3 (m, 2H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxobutanoic acid: a Solution of ethyl 4-(4-(2-methoxybenzyloxy)phenyl)-4-oxybutyrate (stage B, 1,49 g, 4.3 mmol) in absolute ethanol (20 ml) was treated with 1N NaOH (6 ml). The reaction mixture was stirred at room temperature for 2 hours and then acidified using 1M HCl. P the obtained white solid was filtered, washed with cold water and dried in vacuum, obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,6 (t, 2H); 3 2 (t, 2H); and 3.8 (s, 3H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 4H); 7,2-7,3 (m, 2H); 7,8 (d, 2H).

Example 3: Synthesis of 3-[(4-(2-forbindelse)phenyl)methylthio]propionic acid

Stage A: Getting 4-hydroxybenzyl bromide:

To mix the solution PBr3(to 1.38 g, 5.0 mmol) in anhydrous THF (2 ml) at -5°C was added a solution of anhydrous pyridine (0,201 ml) in anhydrous THF (0.4 ml). To the reaction mixture was added dropwise a solution of 4-hydroxybenzoato alcohol (1.89 g, of 15.2 mmol) in anhydrous THF (23 ml). The reaction mixture was left at room temperature for 18 hours, then diluted with THF and filtered through a layer of celite. The filtrate was evaporated, the obtained semi-solid substance was re-dissolved in anhydrous toluene (16 ml). The solution was kept at -20°C for 2 hours and then filtered through a layer of celite, getting mentioned in the title compound as light-yellow solution, which was used without further purification.

Stage B: Obtain ethyl 3-((4-hydroxyphenyl)methylthio)propionate:

To a solution of NaH (60% dispersed in oil, 0,731 g, and 21.7 mmol) in anhydrous DMF (15 ml) was added ethyl 3-mercaptopropionate (2.66 g, and 19.8 mmol). After cessation of hydrogen was added 4-hydroxybenzo the l bromide from step A. The reaction mixture was stirred for 16 hours at room temperature, extinguished a saturated solution of NH4Cl and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was washed once EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (dichloromethane:ethyl acetate, 95:5), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2.4 to a 2.6 (m, 4H); 3,6 (s, 2H); to 4.1 (q, 2H); 6,7 (d, 2H); to 7.2 (d, 2H).

Stage C: Obtain ethyl 3-((4-(2-forbindelse)phenyl)methylthio)propionate:

To a solution of NaH (60% dispersed in oil, 0,054 g, 1.3 mmol) in anhydrous DMF (10 ml) was added ethyl 3-((4-hydroxyphenyl)methylthio)propionate (stage B, 2.5 g, 1.0 mmol). After cessation of hydrogen was added 2-terbisil bromide (to 0.263 g, 1.3 mmol). The reaction mixture was stirred for 4 hours at room temperature, extinguished a saturated solution of NH4Cl, and concentrated in vacuum. The crude residue was placed in EtOAc and washed twice with water and saturated salt solution. The aqueous layer was washed once EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on Colo is ke silica gel (hexane:ethyl acetate, 4:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2.4 to a 2.6 (m, 4H); 3,6 (s, 2H); to 4.2 (q, 2H); further 5.15 (s, 2H); to 6.9 (d, 2H); of 7.2 to 7.4 (m, 5H); 7.5 (t, 1H).

Stage D: 3-((4-(2-forbindelse)phenyl)methylthio)propionic acid:

To a solution of ethyl 3-((4-(2-forbindelse)phenyl)methylthio)propionate (stage C, 0,122 g, 0.35 mmol) in ethanol (5 ml) was added 1N NaOH (0.5 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified using 1M HCl and concentrated in vacuum, obtaining a white substance, which was purified flash chromatography on a column of silica gel (chloroform:methanol, of 92.5:7.5 to enriched acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 2,4-2,6 (m, 4H); 3,7 (s, 2H); to 5.1 (s, 2H); to 6.9 (d, 2H); of 7.2 to 7.4 (m, 5H); 7.5 (t, 1H).

Example 4: Synthesis of 4-(4-(3-forbindelse)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(3-forbindelse)acetophenone:

Using the method described in example 1, step A, using 3-terbisil bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s, 2H); 7,0 (m, 3H); 7,2-7,3 (t, 2H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(3-forbindelse)phenyl)-4-oxybutyrate:

Using the method described in p is the iMER 1, Stage B has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.7 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 7,0 (m, 3H); to 7.2 (t, 2H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Stage C: Obtain 4-(4-(3-forbindelse)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,1 (m, 3H); 7,2-7,3 (m, 2H); 7,4 (kV, 1H); to 7.9 (d, 2H).

Example 5: Synthesis of 4-(4-(4-forbindelse)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(4-forbindelse)acetophenone:

Using the method described in example 1, step A, using 4-terbisil bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s, 2H); 7,0 (d, 2H); and 7.1 (t, 2H); to 7.4 (m, 2H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(4-forbindelse)phenyl)-4-oxybutyrate:

Using the method described in example 1, stage B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 7,0 (m, 2H); to 7.2 (t, 2H); to 7.4 (m, 2H); 8.0 a (d, 2H).

Stage C: Obtain 4-(4-(4-forbindelse)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, DCl 3): or 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,1 (m, 2H); 7,2-7,3 (d, 2H); to 7.4 (m, 2H); to 7.9 (d, 2H).

Example 6: Synthesis of 4-(4-((2-pyridinyl)methoxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-((2-pyridinyl)methoxy)acetophenone:

A solution of 4-hydroxyacetophenone (1,99 g, 14.6 mmol) in anhydrous DMF (5 ml) was added at room temperature to a suspension of NaH (60% in oil, 604 g) in anhydrous DMF (20 ml). After cessation of hydrogen was added the hydrochloride of 2-picolylamine (2 g, 12.1 mmol). The reaction mixture was stirred at room temperature for 16 hours, reduce saturated aqueous NH4Cl and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was twice washed with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 1:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); 7,0 (d, 2H); to 7.2 (m, 1H); 7.5 (d, 1H), and 7.7 (t, 1H); to 7.9 (d, 2H); and 8.6 (s, 1H).

Stage B: Obtain tert-butyl 4-(4-((2-pyridinyl)methoxy)phenyl)-4-oxybutyrate:

To a stirred solution of 4-((2-pyridinyl)methoxy)acetophenone (stage A, 0,968 g, 3.6 mmol) in anhydrous THF (16 ml) and DMPU (4 ml) solution was added bis(trimethylsilyl)amide whether the Oia (1,0 M, 5 ml) at -60°C in argon atmosphere. After stirring for 10 minutes at -60°C was rapidly added tert-butylbromide (2.64 g, 13.5 mmol). The reaction mixture was stirred additionally for 10 minutes and then heated to room temperature within 4 hours. The crude mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.7 (t, 2H); 3,2 (t, 2H); 5,3 (s, 2H); 7,0 (d, 2H); to 7.2 (m, 1H); 7.5 (d, 1H), and 7.7 (t, 1H); to 7.9 (d, 2H); and 8.6 (s, 1H).

Stage C: Obtain 4-(4-((2-pyridinyl)methoxy)phenyl)-4-oxobutanoic acid:

A solution of tert-butyl 4-(4-((2-pyridinyl)methoxy)phenyl)-4-oxybutyrate (stage C, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated triperoxonane acid (5 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuum. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3:CD3OD): or 2.7 (t, 2H); 3,2 (t, 2H); 5,3 (s, 2H); 7,0 (d, 2H) and 7.3 (m, 1H); 7.5 (d, 1H); to 7.9 (m, 3H); and 8.6 (s, 1H).

Example 7: Synthesis of 4-(4-(benzyloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(benzyloxy)acetophenone:

Using the method described in example 1, step A, using benzylbromide as an initial matter, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s, 2H); 7,0 (d, 2H); 7.3 to 7.5 (m, 5H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(benzyloxy)phenyl)-4-oxybutyrate:

Using the method described in example 1, stage B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); 7,0 (d, 2H); 7.3 to 7.5 (m, 5H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(benzyloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 7,0 (d, 2H); 7.3 to 7.5 (m, 5H); to 7.9 (d, 2H).

Example 8: Synthesis of 4-(4-(2,6-deferasirox)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

A solution of 4-hydroxyacetophenone (3,61 g of 26.5 mmol) in anhydrous DMF (5 ml) was added at room temperature to a suspension of NaH (60% in oil, to 1.21 g) in anhydrous DMF (40 ml). After cessation of hydrogen was added to ply 2,6-diferensial bromide (5 g, 24,1 mmol). The reaction mixture was stirred at room temperature for 6 hours, reduce saturated aqueous NH4Cl and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(2,6-deferasirox)phenyl)-4-oxybutyrate:

To a stirred solution of 4-(2,6-deferasirox)acetophenone (stage A, 0.6 g, of 22.8 mmol) in anhydrous THF (60 ml) and DMPU (12 ml) solution was added bis(trimethylsilyl)amide lithium (1,0 M, 30 ml) at -60°C in argon atmosphere. After stirring for 10 minutes at -60°C was rapidly added tert-butyl bromoacetate (8,97 g, 46 mmol). The reaction mixture was stirred additionally for 10 min. / and then heated to room temperature within 4 hours. The crude mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated the Ali and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2,6-deferasirox)phenyl)-4-oxobutanoic acid:

A solution of tert-butyl 4-(4-(2,6-deferasirox)phenyl)-4-oxybutyrate (stage B, the value of 4.76 g, 12.6 mmol) in dichloromethane (40 ml) was treated triperoxonane acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuum. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white powder.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Example 9: Synthesis of 4-(4-(2-chlorobenzoyloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-chlorobenzoyloxy)acetophenone:

Using the method described in example 1, step A, using 2-Chlorobenzyl bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); 7,0 (d, 2H); 7,2-7,5 (m, 4H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(2-chlorobenzoyloxy)phenyl)-4-oxybutyrate:

Using the method described in example 1, stage has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); 7,0 (d, 2H); 7,2-7,5 (m, 4H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-chlorobenzoyloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); 7,0 (d, 2H); to 7.2 (m, 2H); and 7.3 (m, 1H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Example 10: Synthesis of 4-(4-(2-(2-forfinal)ethoxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-(2-forfinal)ethoxy)acetophenone:

Using the method described in example 2, step A, using 2-fortunately alcohol as the starting material, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,3 (s, 3H); 2,9 (t, 2H); 4,2 (t, 2H); to 6.9 (d, 2H); and 7.1 (m, 2H); and 7.3 (m, 2H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(2-(2-forfinal)ethoxy)phenyl)-4-oxybutyrate:

Using the method described in example 2, step B, using tert-butyl bromoacetate as an initial matter, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); 2,6 (t, 2H); 3,2 (m, 4H); 4,2 (t, 2H); to 6.9 (d, 2H); and 7.1 (m, 2H); and 7.3 (t, 2H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-(2-forfinal)ethoxy)phenyl)-4-oxobutanoic acid:

A solution of tert-butyl 4-(4-(2-(2-forfinal)e is the hydroxy)phenyl)-4-oxybutyrate (stage 2, 1.2 g, 3.2 mmol) in dichloromethane (25 ml) was treated triperoxonane acid (10 ml). The reaction mixture was stirred at ambient temperature for 4 hours and concentrated in vacuum. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): or 2.8 (t,2H); 3,3 (t, 2H); 4,2 (t, 2H); to 6.9 (d, 2H); and 7.1 (m, 2H); and 7.3 (t, 2H); to 7.9 (d, 2H).

Example 11: Synthesis of ethyl 4-(4-(2-forbindelse)phenyl)-4-oxybutyrate

Stage A: Obtain 4-(4-(2-forbindelse)acetophenone:

Using the method described in example 1, stage A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H); 7,2-7,3 (m, 1H); to 7.4 (t, 1H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(4-(2-forbindelse)phenyl)-4-oxybutyrate:

To a stirred solution of 4-(2-forbindelse)acetophenone (7,26 g, 29.7 mmol) in anhydrous THF (80 ml) and DMPU (16 ml) solution was added bis(trimethylsilyl)amide lithium (1,0 M, 35 ml) at -60°C in argon atmosphere. After stirring for 10 minutes at -60°C was rapidly added ethylbromoacetate (10, 12 grams of 60.5 mmol). The reaction mixture was stirred additionally for 10 minutes and then heated to room temperature within 4 hours. Neo is sennou the mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining mentioned in the title compound as a white powder.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); and 2.7 (t, 2H); 3,2 (t, 2H); to 4.2 (q, 2H); to 5.1 (s, 2H); to 6.9 (d, 2H); to 7.2 (m, 2H); to 7.4 (m, 1H); 7.5 (m, 1H); to 7.9 (d, 2H).

Example 12: Synthesis of 4-(4-(2-methylbenzylamino)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-methylbenzylamino)acetophenone:

Using the method described in example 1, step A, using 2-methylbenzyl bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 3H); 2,5 (s, 3H); and 5.2 (s, 2H); to 6.9 (d, 2H); 7,2-7,3 (m, 3H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain tert-Butyl 4-(4-(2-methylbenzylamino)phenyl)-4-oxybutyrate:

Using the method described in example 1, stage B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3receive: 1.5 (s, 9H)and 2.4 (s, 3H); 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); to 6.9 (d, 2H); 7,2-7,3 (m, 3H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-methylbenzylamino)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, CDCl ): of 2.4 (s, 3H); and 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); to 6.9 (d, 2H); 7,2-7,3 (m, 3H); to 7.4 (m, 1H); to 7.9 (d, 2H).

Example 13: Synthesis of 4-[4-(2-(N-(2-terbisil)-N-methylamino)ethoxy)phenyl]-4-oxobutanoic acid

Stage A: Getting 2-terbisil methansulfonate:

To a solution of 2-fermentelos alcohol (10 g, 79,28 mmol) in anhydrous dichloromethane (200 ml) was added triethylamine (a 12.03 g, 118,9 mmol) in an argon atmosphere at room temperature. To the above reaction mixture at 0°C was added methanesulfonamide (10,71 g of 93.5 mmol) and stirring continued for another 3 hours. To the reaction mixture were added water (100 ml) and the mixture was twice extracted with dichloromethane. The combined organic layers were washed with water and saturated salt solution. The reaction mixture was dried over Na2SO4was filtered and concentrated, obtaining mentioned in the title compound as a yellow oil which was used without further purification.

1H NMR (270 MHz, CDCl3): 1,3 (t, 3H); 2.4 to a 2.6 (m, 4H); a 5.25 (s, 2H); and 6.9-7.5 (m, 4H).

Stage B: Obtain 2-(N-(2-terbisil)-N-methylamino)ethanol:

A mixture of 2-forbindelsesanalyse (stage A, 5 g, 24.5 mmol) and 2-(methylamino)ethanol (18,4 g, 244,9 mmol) was heated in an argon atmosphere at 120°C with stirring for 7 hours. The mixture was cooled to room temperature and concentrated. The crude residue was purified flash what cromatografia on a column of silica gel (chloroform:methanol, 90:10 enriched with triethylamine), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,3 (s, 3H); 2,6 (m, 2H); 3,6 (m, 4H); and 6.9-7.5 (m, 4H).

Stage C: Obtain 2-(N-(2-terbisil)-N-methylamino)ethylchloride:

To a solution of 2-(N-(2-terbisil)-N-methylamino)ethanol (stage B, 7.51 g, 41 mmol) in anhydrous toluene (50 ml) was added chloride thionyl (16 ml). The reaction mixture was stirred at room temperature for 16 hours and concentrated. The crude mixture was diluted with chloroform and washed with aqueous solution of NaHCO3, water and saturated salt solution. The organic layer was dried over Na2SO4was filtered and concentrated, obtaining mentioned in the title compound, which was used without further purification.

1H NMR (270 MHz, CDCl3): 2,3 (s, 3H); and 2.8 (t, 2H); 3,6 (t, 2H); 3,7 (s, 2H); 7,0-to 7.15 (m, 2H); 7,25 (m, 1H), and 7.4 (t, 1H).

Stage D: Obtain 4-(2-(N-(2-terbisil)-N-methylamino)ethoxy)acetophenone:

To a solution of 2-(N-(2-terbisil)-N-methylamino)ethylchloride (stage C of 7.48 g, 37 mmol) and 4-hydroxyacetophenone (10,07 g, 74 mmol) in anhydrous DMF (10 ml) was added K2CO3(to 7.77 g, 56.2 mmol). The mixture was heated at 80°C for 6 hours, cooled and extinguished with water and twice was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified flash chromatograph is she on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining mentioned in the title compound as a pale yellow oil.

1H NMR (270 MHz, CDCl3): 2,35 (s, 3H)and 2.4 (s, 3H); and 2.8 (t, 2H); 3,7 (s, 2H); 4,2 (t, 2H); to 6.9 (d, 2H); 7,0-to 7.15 (m, 2H); 7,25(m, 1H), and 7.4 (t,1H); to 7.9 (d, 2H).

Stage E: Obtain tert-butyl 4-[4-(2-(N-(2-terbisil)methylamino)ethoxy)phenyl]-4-oxybutyrate:

Bis(trimethylsilyl)amide lithium (l,0M, 20 ml) was slowly added over 10 minutes to a stirred solution of 4-(2-(N-(2-terbisil)-N-methylamino)ethoxy)acetophenone (stage D, 4,91 g, 16.3 mmol) in anhydrous THF (60 ml) and DMPU (15 ml) at -65°C in argon atmosphere. After stirring for 15 minutes quickly added tert-butyl bromoacetate (6,35 g, a 32.6 mmol). Stirring was continued for additional 10 minutes at -65°C and then the reaction mixture was heated to room temperature within 2 hours, extinguished with water and twice was extracted with EtOAc. The combined organic layers was purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 1:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3receive: 1.5 (s, 9H)and 2.4 (s, 3H); 2,6 (t, 2H); and 2.8 (t, 2H); 3,2 (t, 2H) 3,7 (user., 2H); 4,2 (user., 2H); and 6.9 (d, 2H); 7,0-to 7.15 (m, 2H); 7,25 (m, 1H), and 7.4 (t, 1H); to 7.9 (d, 2H).

Stage F: Obtain 4-[4-(2-(N-(2-terbisil)-N-methylamino)ethoxy)phenyl]-4-oxobutanoic acid:

A solution of tert-butyl 4-[4-(2-(N-(2-terbisil)-N-methylamine)ethoxy)phenyl]-4-oxybutyrate (stage E of 2.23 g, 5.3 mol) in dichloromethane (20 ml) was treated triperoxonane acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours and concentrated in vacuum. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, of 92.5:7.5 to 90:10 enriched acetic acid), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,5 (t, 2H); 2,6 (s, 3H); 3,0 (t, 2H); 3,4 (t, 2H); from 4.2 to 4.5 (m, 4H); and 6.9 (d, 2H); 7,0-to 7.15 (m, 2H); and 7.3 (m, 1H), 7.5 (t, 1H); to 7.9 (d, 2H).

Example 14: Synthesis of 4-(3-(2-Methylbenzylamino)phenyl)-4-oxobutanoic acid

Stage a: 3-(2-methylbenzylamino)acetophenone:

Using the method described in example 12, step A, using 3-hydroxyacetophenone as an initial matter, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,3 (s, 3H); 2,5 (s, 3H); to 5.1 (s, 2H); 7,2-7,3 (m, 4H); to 7.4 (m, 2H); 7,6 (m, 2H).

Stage B: Obtain tert-butyl 4-(3-(2-methylbenzylamino)phenyl)-4-oxybutyrate:

Using the method described in example 1, stage B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3receive: 1.5 (s, 9H)and 2.4 (s, 3H); 2,6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); 7,2-7,3 (m, 4H); to 7.4 (m, 2H); 7,6 (m, 2H).

Stage C: Obtain 4-(3-(2-methylbenzylamino)phenyl)-4-oxobutanoic acid:

Using the method described in example 1, stage C has been specified in the header of the connection.

1H NMR (270 MHz, CDCl ): of 2.4 (s, 3H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); 7,2-7,3 (m, 4H); to 7.4 (m, 2H); 7,6 (m, 2H).

Example 15: Synthesis of ethyl 4-(3-(2-forbindelse)phenyl)-4-oxybutyrate

Stage a: 3-(2-forbindelse)acetophenone:

Using the method described in example 1, step A, using 3-hydroxyacetophenone as an initial matter, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); and 7.1 (m, 4H); and 7.3 (m, 2H); 7,6 (m, 2H).

Stage B: Obtain ethyl 4-(3-(2-forbindelse)phenyl)-4-oxybutyrate:

Using the method described in example 11, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,3 (s, 9H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (t, 2H); to 7.2 (d, 2H); to 7.4 (m, 1H); 7.5 (t, 1H); and 7.6 (d, 2H).

Example 16: Synthesis of ethyl 4-(4-(2-methylbenzylamino)phenyl)-4-oxybutyrate

Stage A: Obtain 4-(2-methylbenzylamino)acetophenone:

Using the method described in example 12, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 3H); 2,5 (s, 3H); and 5.2 (s, 2H); to 6.9 (d, 2H); 7,2-7,3 (m, 3H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Stage B: Obtain ethyl 4-(4-(2-methylbenzylamino)phenyl)-4-oxybutyrate:

Using the method described in example 11, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (who, 3H); and 2.7 (t, 2H); 3,2 (t, 2H); to 4.2 (q, 2H); to 5.1 (s, 2H); 7,0 (d, 2H); 7,2-7,3 (m, 3H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Example 17: Synthesis of ethyl 4-(4-(2,6-deferasirox)phenyl)-4-oxybutyrate

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

Using the method described in example 8, step A, has been specified in the header of the connection

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(4-(2,6-deferasirox)phenyl)-4-oxybutyrate:

To a stirred solution of 4-(2,6-deferasirox)acetophenone (stage A, 6 g of 22.8 mmol) in anhydrous THF (60 ml) and DMPU (12 ml) solution was added bis(trimethylsilyl)amide lithium (1,0 M, 30 ml) at -60°C in argon atmosphere. After stirring for 10 minutes at -60°C was rapidly added ethylbromoacetate (to 7.61 g of 45.6 mmol). The reaction mixture was additionally stirred for 10 minutes and then heated to room temperature within 4 hours. The crude mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3 ): 1,3 (t, 3H); 2,8 (t, 3H); 3,2 (t, 2H); to 4.1 (q, 2H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Example 18: Synthesis of 4-(4-(2-(2-thienyl)ethoxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-(2-thienyl)ethoxy)acetophenone:

Using the method described in example 2, step A, using 2-(2-thienyl)ethanol as the starting material, and after purification with flash chromatography on a column of silica gel (hexane:ethyl acetate, 3:1)were specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); 3,3 (t, 2H); 4,2 (t, 2H); 6,9-7,1 (m, 4H); to 7.2 (d, 1H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(4-(2-(2-thienyl)ethoxy)phenyl)-4-oxybutyrate:

Using the method described in example 2, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,3 (t, 3H); and 2.8 (t, 2H); 3,3 (m, 4H); to 4.1 (q, 2H); 4,2 (t, 2H); 6,9-7,1 (m, 4H); to 7.2 (d, 1H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-(2-thienyl)ethoxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 2, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,3 (m, 4H); 4,2 (t, 2H); 6,9-7,1 (m, 4H); to 7.2 (d, 1H); to 7.9 (d, 2H).

Example 19: Synthesis of 4-(2,6-differenl)-4-oxobutanoic acid

Stage A: Obtain tert-butyl 4-(2,6-differenl)-4-oxybutyrate:

To a stirred solution of 2,6-defloration(5 g, 32 mmol) in anhydrous THF (40 ml) and DMPU (8 ml) solution was added bis(trimethylsilyl)amide lithium (1,0 M, 45 ml) at -60°C in argon atmosphere. After stirring for 10 minutes at -60°C was rapidly added tert-butylbromide (6,99 g, 35.8 mmol). The reaction mixture was stirred additionally for 10 minutes and then heated to room temperature within 4 hours. The crude mixture was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was extracted once more EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.8 (t, 2H); 3,2 (t, 2H); 6,9-7,0 (m, 2H); to 7.4 (m, 1H).

Stage B: the connection is obtained AS:

A solution of tert-butyl 4-(2,6-differenl)-4-oxybutyrate (stage A, 9,52 g of 35.2 mmol) in dichloromethane (30 ml) was treated triperoxonane acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); 6,9-7,0 (m, 2H); to 7.4 (m, 1H).

Example 20:Synthesis of 4-(4-(2,5-dimethylbenzylamine)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2,5-dimethylbenzylamine)acetophenone:

Using the method described in example 8, step A, using 2.5-dimethylbenzyl chloride as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,3 (s, 3H); 2,5 (s, 3H); to 5.1 (s, 2H); 6,9-7,2 (m, 5H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(4-(2,5-dimethylbenzylamine)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); 2,3 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); 7,0 (d, 2H); 7,2-7,3 (m, 3H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2,5-dimethylbenzylamine)phenyl)-4-oxobutanoic acid:

To a solution of ethyl 4-(4-(2,5-dimethylbenzylamine)phenyl)-4-oxybutyrate (stage B, 2,62 g, 7.7 mmol) in absolute ethanol (30 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 hours and was then acidified using 1M HCl. The resulting white precipitate was filtered, washed with water and dried in vacuum, obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 2,3 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 7,0 (d, 2H); 7,2-7,3 (m, 3H); to 8.0 (d, 2H).

Example 21: Synthesis of 4-(4-(2,5-deferasirox)phenyl)-4-oxobutanoic acid

Stage A: On the doctrine of 4-(2,5-deferasirox)acetophenone:

Using the method described in example 8, step A, using 2.5-diferensial bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 3H); to 7.2 (m, 2H); 8.0 a (d, 2H).

Stage B: Obtain ethyl 4-(4-(2,5-deferasirox)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 3H); to 7.2 (m, 2H); 8.0 a (d, 2H).

Stage C: Obtain 4-(4-(2,5-deferasirox)phenyl)-4-oxobutanoic acid:

To a solution of ethyl 4-(4-(2,5-deferasirox)phenyl)-4-oxybutyrate (stage B, 16,51 g, with 47.4 mmol) in absolute ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified using 1M HCl and concentrated in vacuum. The crude mixture was placed in chloroform and washed with water. The aqueous layer was washed once with chloroform. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 95:5 enriched acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H);6,9-7,0 (m, 3H); to 7.2 (m, 2H); 8.0 a (d, 2H).

Example 22: Synthesis of 4-(4-(2,4-deferasirox)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2,4-deferasirox)acetophenone:

Using the method described in example 8, step A, using 2,4-diferensial bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s,2H); 6,9-7,0 (m, 2H); and 7.1 (d, 2H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Stage B: Obtain ethyl 4-(4-(2,4-deferasirox)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); and 2.8 (t,2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); 6,9-7,0 (m, 2H); and 7.1 (d, 2H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Stage C: Obtain 4-(4-(2,4-deferasirox)phenyl)-4-oxobutanoic acid:

Using the method described in example 21, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,0 (m, 2H); and 7.1 (d, 2H); to 7.4 (m, 1H); 8.0 a (d, 2H).

Example 23: Synthesis of 4-(3-(2,6-deferasirox)phenyl)-4-oxobutanoic acid

Stage a: 3-(2,6-deferasirox)acetophenone:

Using the method described in example 8, step A, using 3-hydroxyacetophenone as an initial matter, has been specified in the zag is lowke connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); 6,9-7,0 (m, 2H); to 7.2 (m, 1H); to 7.4 (m, 2H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 4-(3-(2,6-deferasirox)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); 6,9-7,0 (m, 2H); to 7.2 (m, 1H); to 7.4 (m, 2H); to 7.9 (d, 2H).

Stage C: Obtain 4-(3-(2,6-deferasirox)phenyl)-4-oxobutanoic acid:

Using the method described in example 21, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); 6,9-7,0 (m, 2H); to 7.2 (m, 1H); to 7.4 (m, 2H); to 7.9 (d, 2H).

Example 24: Synthesis of 4-(4-((cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-((cyclopropyl)methoxy)acetophenone:

Using the method described in example 8, step A, using cyclopropylmethyl bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (m, 1H); 2,5 (s, 3H); and 3.8 (d, 2H); to 6.9 (d, 2H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-((cyclopropyl)methoxy)phenyl)-4-oxybutyrate:

Using the method described in example 8, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (who, 1H); and 1.4 (s, 9H); 2,6 (t, 2H); 3,2 (t, 2H); and 3.8 (d, 2H); to 6.9 (d, 2H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-((cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 8, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (m, 1H); and 2.8 (t, 2H); 3,2 (t, 2H); and 3.8 (d, 2H); to 6.9 (d, 2H); to 7.9 (d, 2H).

Example 25: Synthesis of 4-(4-(2-triftormetilfosfinov)phenyl)-4-oxobutanoic acid

Stage A: Obtain 4-(2-triftormetilfosfinov)acetophenone:

Using the method described in example 8, step A, using 2-(trifluoromethyl)benzyl bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); 5,3 (s, 2H); to 6.9 (d, 2H); to 7.4 (t, 1H); to 7.6 (t, 1H); 7.7 (d, 2H); to 7.9 (d, 2H).

Stage B: Obtain tert-butyl 4-(4-(2-triftormetilfosfinov)phenyl)-4-oxybutyrate:

Using the method described in example 8, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (s, 9H); and 2.7 (t, 2H); 3,2 (t, 2H); 5,3 (s, 2H); to 6.9 (d, 2H); to 7.4 (t, 1H); to 7.6 (t, 1H); 7.7 (d, 2H); to 7.9 (d, 2H).

Stage C: Obtain 4-(4-(2-triftormetilfosfinov)phenyl)-4-oxobutanoic acid:

Using the method described in example 8, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,2 (t, 2H); 5,3 (s, 2H) 6,9 (d, 2H); to 7.4 (t, 1H); to 7.6 (t, 1H), and 7.7 (t, 2H); to 7.9 (d, 2H).

Example 26: Synthesis of 3-[(4-(2,6-deferasirox)phenyl)methylthio]propionic acid

Stage A: Getting 4-hydroxybenzyl bromide:

Using the method described in example 3, step A, was received is indicated in the title compound, which was used without further purification.

Stage B: Obtain ethyl 3-[(4-hydroxyphenyl)methylthio]propionate:

Using the method described in example 3, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2.4 to a 2.6 (m, 4H); 3,6 (s, 2H); to 4.1 (q, 2H); 6,7 (d, 2H); to 7.2 (d, 2H).

Stage C: Obtain ethyl 3-[(4-(2,6-deferasirox)phenyl)methylthio]propionate:

Using the method described in example 3, step C, using 2,6-diferensial bromide as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2.4 to a 2.6 (m, 4H); 3,6 (s, 2H); to 4.2 (q, 2H); further 5.15 (s, 2H); 6,9 (d, 4H); of 7.2 to 7.4 (m, 3H).

Stage D: 3-[(4-(2,6-deferasirox)phenyl)methylthio]propionic acid:

Using the method described in example 3, step D, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 to 2.6 (m, 4H); 3,7 (s, 2H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 4H); of 7.2 to 7.4 (m, 3H).

Example 27: Synthesis of 4-(2-(2,6-Deferasirox)phenyl)-4-oxobutanoic acid

Stage A: Getting 2-(2,6-deferasirox)acetophenone:

Using the method described in example 8, step A, using 2-hydroxyacetophenone as an initial matter, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 3H); and 7.1 (d, 1H); to 7.4 (m, 1H); 7.5 (t, 1H); 7,8 (d, 1H).

Stage B: Obtain ethyl 4-(2-(2,6-deferasirox)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); 2,6 (t, 2H); 3,2 (t, 2H); to 4.1 (q, 2H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 3H); and 7.1 (d, 1H); to 7.4 (m, 1H); 7.5 (t, 1H); 7,8 (d, 1H).

Stage C: Obtain 4-(2-(2,6-deferasirox)phenyl)-4-oxobutanoic acid:

Using the method described in example 21, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.6 (t, 2H); 3,2 (t, 2H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 3H); and 7.1 (d, 1H); to 7.4 (m, 1H); 7.5 (t, 1H); 7,8 (d, 1H).

Example 28: Synthesis of ethyl 4-(4-(2,6-deferasirox)phenyl)methyl-3-oxybutyrate

Stage A: Obtain ethyl 4-hydroxybenzoate:

To a stirred solution of 4-hydroxybenzoato alcohol (4 g, 26,28 mmol) in anhydrous DMF (15 ml), pyridine (1 ml) and N,N-dicyclohexylcarbodimide (6.50 g, to 31.5 mmol) was added absolute EtOH (3,26 g, 78,84 mmol). The reaction mixture was stirred for 18 hours at on the th temperature and then filtered. The filtrate was concentrated under reduced pressure and was purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,5 (s, 2H); to 4.1 (q, 2H); 6,7 (d, 2H); and 7.1 (d, 2H).

Stage B: Obtain ethyl 4-(2,6-deferasirox)benzilate:

To a solution of NaH (60% dispersed in oil, 0,393 g, 9.8 mmol) in anhydrous DMF (20 ml) was added ethyl 4-hydroxybenzoate (stage A, 1,59, y, 8,8 mmol). After cessation of hydrogen was added 2,6-diferensial bromide (1.64 g, 7.9 mmol). The reaction mixture was stirred for 4 hours at room temperature, extinguished a saturated solution of NH4Cl and concentrated in vacuum. The residue was placed in EtOAc and washed twice with water and saturated salt solution. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,5 (s, 2H); to 4.1 (q, 2H); to 5.1 (s, 2H); to 6.9 (m, 4H); of 7.2 to 7.4 (m, 3H).

Stage C: Obtain 4-(2,6-deferasirox)benzyl acid:

To a stirred solution of ethyl 4-(2,6-deferasirox)benzilate (stage B, 2.14 g, 6,9 mmol) in absolute EtOH (30 ml) was added 1N NaOH (10 ml) at room temperature. The reaction mixture was stirred for 3 h, the owls, was acidified using 1M HCl and filtered. A white precipitate was washed with water and dried in a high vacuum, getting listed at the beginning of the connection.

1H NMR (270 MHz, CDCl3): of 3.6 (s, 2H); to 5.1 (s, 2H); to 6.9 (m, 4H); of 7.2 to 7.4 (m, 3H).

Stage D: Obtain 4-(2,6-deferasirox)benzylcarbamoyl chloride:

Thionyl chloride (10 ml) To 4-(2,6-deferasirox)benzyl acid (stage C, to 1.61 g, 5,79 mmol) was added chloride thionyl (10 ml). The reaction mixture was heated at the boil under reflux for 3 hours and then concentrated in vacuum, obtaining a light yellow oil which was used without further purification.

Stage E: Ethyl 4-(4-(2,6-deferasirox)phenyl)methyl-3-oxybutyrate:

To a solution of acid Meldrum (0,846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) for 10 minutes at 0°C. To this solution was added 4-(2,6-deferasirox)benzylcarbamoyl chloride (stage D, 1,71 g, 5.7 mmol) in dichloromethane (5 ml), which led to the formation of an orange solution. Dark orange solution was stirred for 1 hour at 0°C, was left to warm to room temperature and was further stirred for one hour. The reaction mixture was diluted with dichloromethane and poured into 2M HCl and ice. the phases were separated and the aqueous phase was twice extracted with dichloromethane. The combined organic layers washed twice 2M HCl and a saturated solution of salt, sushi and above Na 2SO4was filtered and concentrated, obtaining a solid substance. The solid is suspended in absolute EtOH (15 ml) and was heated at the boil under reflux for 2.5 hours. The solvent was removed in vacuum, obtaining a dark oil. The residue was purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,4 (s, 2H); 3,7 (s, 2H); to 4.2 (q, 2H); to 5.1 (s, 2H); to 6.9 (m, 4H); and 7.1 (d, 2H); and 7.3 (m, 1H).

Example 29: Synthesis of 3-(2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

Using the method described in example 8, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain 2-bromo-1-(4-(2,6-deferasirox)phenyl)-1-ethanone:

To a mixed solution of copper bromide(2) (3,70 g of 16.6 mmol) in ethyl acetate (20 ml) was added a solution of 4-(2,6-deferasirox)acetophenone (stage A, to 2.74 g, 10.4 mmol) in chloroform (20 ml) at room temperature. The reaction mixture was heated at the boil under reflux for 16 hours and then added water. The crude mixture was twice extracted with EtOAc. Organic layers of the volume of inali and washed with water, saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining mentioned in the title compound as white flakes.

1H NMR (270 MHz, CDCl3): 4,4 (s, 2H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H), and 7.3 (m, 1H); 8.0 a (d, 2H).

Stage C: 3-(2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl)thio-1H-1,2,4-triazole:

To a solution of 1H-1,2,4-triazole-3-thiol (0,250 g, 2.4 mmol) and triethylamine (2.50 g, 2.4 mmol) in anhydrous dichloromethane (20 ml) was added 2-bromo-1-(4-(2,6-deferasirox)phenyl)-1-Etalon (stage B, 0,851 g, 2.4 mmol) in anhydrous dichloromethane (5 ml) at room temperature. The reaction mixture was stirred for 50 minutes and then concentrated in vacuum. The crude residue was placed in EtOAc and washed with 1M HCl and saturated salt solution. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol, 9:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 4,5 (s, 2H); to 5.1 (s, 2H); 6,8-7,0 (m, 4H), 7,2 (m, 1H); to 7.9 (d, 2H); 8.0 a (s, 1H).

Example 30: Synthesis of 5-((4-(2,6-deferasirox)phenyl)-methyl)-1H-tetrazole

Stage a: Getting (4-(2,6-deferasirox)phenyl)acetonitrile:

To a solution of 4-hydroxybenzylated (5 g, 37.5 mmol) and K2 CO3(6,74 g, 48.8 mmol) in anhydrous DMF (20 ml) was added 2,6-diferensial bromide (to 7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hours at room temperature and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was washed once EtOAc. The combined organic layers were dried over Na2SO4was filtered and concentrated, obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): the 3.65 (s, 2H); to 5.1 (s, 2H); the 6.9 to 7.0 (m, 4H); of 7.2 to 7.4 (m, 3H).

Stage B: Obtain 5-((4-(2,6-deferasirox)phenyl)methyl)-1H-tetrazole

A mixture of (4-(2,6-deferasirox)phenyl)acetonitrile (stage A, 5 g, and 19.3 mmol), NaN3(1.3 g, 20 mmol) and NH4Cl (1.06 g, 20 mmol) in anhydrous DMF (60 ml) was heated at 90°C for 16 hours. The solvent was removed in vacuum and the oily residue was distributed between EtOAc and water (acidified to pH 1 with concentrated HCl). The organic layer was washed with water, dried over Na2SO4was filtered and concentrated, obtaining a brown semi-solid substance. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol, 9:1), obtaining mentioned in the title compound as a pale cream solid.

1H NMR (270 MHz, CDCl3): 4,0 (s, 2H); to 5.1 (s, 2H); 6,7-6,9 (m, 4H); 7, (d, 2H); to 7.2 (m, 1H).

Example 31: Synthesis of (2RS) 2-(N-Boc)-3-[2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl]thiopropionic acid

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

To a solution of 4-hydroxyacetophenone (3.28 g, 24 mmol) and K2CO3(4,33 g, 31,3 mmol) in anhydrous DMF (15 ml) was added 2,6-diferensial bromide (5 g, and 24.1 mmol). The reaction mixture was stirred at room temperature for 5 hours, extinguished with water and concentrated in vacuum. The crude residue was placed in EtOAc and washed with water and saturated salt solution. The aqueous layer was twice extracted with EtOAc. The combined organic layers were dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain 2-bromo-1-(4-(2,6-deferasirox)phenyl)-l-ethanone:

Using the method described in example 29, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 4,4 (s, 2H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H), and 7.3 (m, 1H); 8.0 a (d, 2H).

Stage C: Obtain ethyl (2RS) 2-(N-Boc)-3-[2-(4-(2,6-deferasirox)phenyl)2-oxoethyl]thiopropionate:

To a stirred solution of 2-bromo-1-(4-(2,6-deferasirox)phenyl)-1-ethanone (stage B 2,07 g, 8.3 mmol) in anhydrous dichloromethane (20 ml) and triethylamine (8,39 g, 83 mmol) was added Boc-Cys-OEt (2,94 g, 8.6 mmol). The reaction mixture was stirred at room temperature for one hour and concentrated in vacuum. The crude residue was placed in EtOAc, washed with 1M HCl, and saturated salt solution. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol, 97,5:2,5), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 1,4 (s, 9H); 3,0 (m, 2H); and 3.8 (s, 2H); to 4.2 (q, 2H); 4,5 (user., 1H); and 5.2 (s, 2H); 5,4 (d, 1H); 6,9-7,1 (m, 4H); and 7.3 (m, 1H); to 7.9 (d, 2H).

Stage D: Obtain (2RS) 2-(N-Boc)-3-[2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl]thiopropionic acid:

To a solution of ethyl (2RS) 2-(N-Boc)-3-[2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl]thiopropionate (stage C, 0,761 g, 1.5 mmol) in absolute EtOH (10 ml) was added 1N NaOH (3 ml). The reaction mixture was stirred at room temperature for 4 hours, acidified using 1M HCl and concentrated in vacuum. The crude residue was placed in chloroform and washed with water and saturated salt solution. The organic layer was dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol, 92,7:7,5), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4, 9H); 3,0 (t, 2H); 4.0 a (q, 2H); 4,5 (user., 1H); and 5.2 (s, 2H); 5,4 (d, 1H); 6,9-7,1 (m, 4H); and 7.3(m, 1H); to 7.9 (d, 2H).

Example 32: Synthesis of ethyl 2-hydroxy-4-oxo-4-(4-(2,6-deferasirox)phenyl)but-2-enoate

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

Using the method described in example 31, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain ethyl 2-hydroxy-4-oxo-4-(4-(2,6-deferasirox)phenyl)but-2-enoate:

A mixture of 4-(2,6-deferasirox)acetophenone (stage A, 5,64 g, 21.5 mmol) and diethyloxalate (3,14 g, 21.5 mmol) was added to a cooled with ice to a solution of NaOEt (0,490 g of 22.4 mmol metal Na) in absolute EtOH (25 ml). After keeping the mixture overnight at room temperature, the mixture was diluted with water (50 ml), acidified 10%HCl, three times and was extracted with EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,4 (t, 3H); 4,4 (q, 2H); and 5.2 (s, 2H); 6,9-7,1 (m, 5H); 7.3 to 7.4 (m, 1H); 8.0 a (d, 2H).

Example 33: Synthesis of (2RS) 2-(N-acetyl)-4-(4-(2,6-deferasirox)phenyl)4-oxobutanoic acid

Stage A: Obtain 4-(2,6-deferasirox)acetophenone:

Using the method described in example 31, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); and 5.2 (s, 2H); the 6.9 to 7.0 (m, 4H); 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage B: Obtain 2-bromo-1-(4-(2,6-deferasirox)phenyl)-1-ethanone:

Using the method described in example 29, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 4,4 (s, 2H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H); and 7.3 (m, 1H); 8.0 a (d, 2H).

Stage C: the Receipt of diethyl (N-Acetyl)-(2-(4-(2,6-deferasirox)phenyl)-2 - oxoethyl)propanoate:

To a solution of Diethylenetriamine (0,949 g, 4.3 mmol) and NaOEt (0,301 g, 4.4 mmol) in absolute EtOH (25 ml) was added 2-bromo-l-(4-(2,6-deferasirox)phenyl)-l-Etalon (stage B, 1.42 g, 4.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuum. The crude residue was distributed between EtOAc and 0,01H NaOH. The organic layer was washed with water and 0,01M HCl, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 6H); 2,0 (s, 3H); 4,2-4,3 (m, 6H); and 5.2 (s, 2H); 6,9-7,1 (m, 4H), 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Stage D: Obtain (2RS) 2-(N-acetyl)-4-(4-(2,6-differentiality)-4-oxobutanoic acid:

To a solution of diethyl (N-acetyl)-(2-(4-(2,6-deferasirox)phenyl)-2-oxoethyl)propanoate (stage C, 1.28 g, 2.6 mmol) in water (20 ml) was added NaOH (0,529 g, 13,2 mmol). The reaction mixture was heated at the boil under reflux for 16 hours, then was added glacial acetic acid (18 ml) and heated at boiling was continued for additional 3 hours. The mixture was concentrated in vacuo, and purified flash chromatography on a column of silica gel (chloroform:methanol, 9:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,0 (s, 3H); 3,5(m, 2H); and 4.8 (t, 1H); from 5.1 (s, 2H); 6,9-7,1 (m, 4H), 7.3 to 7.4 (m, 1H); to 7.9 (d, 2H).

Example 34: Synthesis of 4-(3-((cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid

Stage a: 3-((cyclopropyl)methoxy)acetophenone:

Using the method described in example 31, step A, using cyclopropylmethyl bromide and 3-hydroxyacetophenone as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (m, 1H); 2,5 (s, 3H); and 3.8 (d, 2H); and 7.1 (m, 1H); to 7.4 (m, 1H); 7.5 to about 7.6 (m, 2H).

Stage B: Obtain tert-butyl 4-(3-((cyclopropyl)methoxy)phenyl)-4-oxybutyrate:

Using the method described in example 8, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (m, 1H); 1,4 (s, 9H); 2,6 (t, 2H); 3,2 (t, 2H); and 3.8 (d, 2H); and 7.1 (m, 1H); to 7.4 (m, 1H); 7.5 to about 7.6 (m, 2H).

Stage C: Obtain 4-(3-((cyclopropyl)methoxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 8, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 0,4 (m, 2H); 0,6 (m, 2H); 1,2 (m, 1H); and 2.8 (t, 2H); 3,2 (t, 2H); and 3.8 (d, 2H); and 7.1 (m, 1H); to 7.4 (m, 1H); 7.5 to about 7.6 (m, 2H).

Example 35: Synthesis of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

To a solution of 2,6-dimethylbenzoic acid (10 g, with 66.5 mmol) and potassium carbonate (9,18 g, with 66.5 mmol) in dimethylformamide (67 ml) was added modesty methyl (8,28 ml, 133,16 ml) under cooling in an ice bath and the mixture was stirred for 16 hours. To the reaction mixture were added toluene and water and the organic layer washed with 3%solution of K2CO3, 1N HCl and saturated salt solution. The organic layer was dried over Na2SO4, filtered and concentrated. Oily residue was re-dissolved in anhydrous THF (135 ml)was added to (3,79 g, and 99.8 mmol) and was stirred for 4 hours in an ice bath. To the reaction mixture was slowly added 1N HCl, followed by addition of ethyl acetate and the organic layer was washed with saturated salt solution, dried over Na2SO4, filtered and concentrated. Oily residue used is ovali without additional purification.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

To a stirred solution of 3'-hydroxyacetophenone (8,07 g, 59,24 mmol) and triphenylphosphine (16,93 g, and 64.5 mmol) in anhydrous THF (180 ml) was added dropwise 2,6-dimethylbenzylamine alcohol (8,05 g, 59,24 mmol) and diethylazodicarboxylate (11,24 g, 64,57 mmol) in anhydrous THF (45 ml) and anhydrous DMF (18 ml) at ambient temperature. After stirring for 1.5 hours at ambient temperature, the reaction mixture was diluted with ether and washed twice with water, 1N NaOH and saturated salt solution, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (hexane:ethyl acetate, 2:1), obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-exabot the rata (stage C, 12,31 g, and 36.2 mmol) in absolute ethanol (160 ml) was added 1N NaOH (50 ml) at room temperature. The reaction mixture was stirred for 3 hours and was then acidified using 1M HCl. The resulting white precipitate was filtered, washed with water and dried in vacuum, obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Example 36: Synthesis of 4-(3-(2-fluoro-6-methylbenzoate)phenyl)-4-oxobutanoic acid:

Stage A: Getting 2-fluoro-6-methylbenzoic acid:

Synthesized as described in example 89 (d) International patent publication No.WO 97/34893, p.43.

Stage B: Obtain 2-fluoro-6-methylbenzylamino alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 3H); 4.7 in (s, 2H); 6,85 (t, 1H); to 6.95 (d, 1H); to 7.15 (m, 1H).

Stage C: 3-(2-fluoro-6-methylbenzoate)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 3H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (m, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain ethyl 4-(3-(2-fluoro-6-methylbenzoate)phenyl)-4-oxybutyrate:

Using the method described in example 17, the Stud is I B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 3H); and 2.8 (t, 2H); 3,3 (t, 2H); and 4.4 (q, 2H); and 5.2 (s, 2H); 6,9-7,1 (m, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage E: Obtain 4-(3-(2-fluoro-6-methylbenzoate)phenyl)-4-oxobutanoic acid:

To a solution of ethyl 4-(3-(2-fluoro-6-methylbenzoate)phenyl)-4-oxybutyrate (stage D, 8,56 g, 24,9 mmol) in absolute ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified using 1M HCl and concentrated. The residue was placed in chloroform and washed with 1M HCl, saturated salt solution, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (chloroform: methanol, 95:5 by addition of acetic acid), getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 3H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); 6,9-7,1 (m, 2H); to 7.2(m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Example 37: Synthesis of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

IP is the use of the method, described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Example 38: Synthesis of sodium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); 4,4 (kV, 2); a 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage E: obtain the sodium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxobutanoic acid (stage D, 5.5 g, 17.6 mmol) was dissolved in absolute ethanol (20 ml) with gentle heating and then adding NaOH (0,705 g) at 0°C. the Reaction mixture was stirred for one hour, concentrated in vacuo and was liofilizovane, receiving the product as a white solid.

1H NMR (270 MHz, D2O): 2,0 (s, 6H); 2,5 (t, 2H); 3,0 (t, 2H); and 4.8 (s, 2H); to 6.8 (d, 2H); to 6.9 (m, 2H); to 7.2 (t, 1H); 7.5 (d, 2H).

Example 39: Synthesis of 4-(4-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: Obtain 4-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); 7,0-7,2 (m, 5H); and 8.0 (d, 2H).

Stage C: Obtain ethyl 4-(4-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); 7,0-7,2 (m, 5H); and 8.0 (d, 2H).

Stage D: Obtain 4-(4-(2,6-Dimethylsiloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); 7,0-7,2 (m,5H); and 8.0 (d, 2H).

Example 40: Synthesis of potassium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,3 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); was 7.45 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the receiving method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); was 7.45 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,5 (t, 2H); 3,2 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); was 7.45 (t, 1H); 7,6 (m, 2H).

Stage E: obtain the potassium salt of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

4-(3-(2,6-Dimethylsiloxy)phenyl)-4-oxobutanoic acid (stage D, 6.0 g, with 19.4 mmol) was dissolved in absolute ethanol (20 ml) with gentle heating, followed by addition of KOH (1,21 g) at 0°C. the Reaction mixture was stirred for one hour, concentrated in vacuo and was liofilizovane, getting mentioned in the title compound as a white solid.

1H NMR (270 MHz, D2O): 2,3 (s, 6H); 2,5 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); was 7.45 (t, 1H); 7,6 (m, 2H).

Example 41: Synthesis of 4-(3-(2,6-dimethoxybenzoate)phenyl)-4-oxobutanoic acid:

Stage A: Obtaining 2,6-dimethoxybenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection

1H NMR (270 MHz, CDCl3): of 3.9 (s, 6H); and 4.8 (s, 2H); 6.5 in (d, 2H); 7,25 (m, 1H).

Stage B: 3-(2,6-dimethoxybenzoate)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 2,6 (s, 3H); 3.9 to (s, 6H); and 5.2 (s, 2H); and 6.6 (d, 2H); and 7.3 (m, 3H); 7.5 (d, 1H); 7.7 (d, 1H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethoxybenzoate)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); and 2.8 (t, 2H); 3,3 (t, 2H); and 3.8 (s, 6H); to 4.1 (q, 2H); and 5.2 (s, 2H); 6.5 in (d, 2H); 7.3 to 7.4 (m, 3H); to 7.6 (d, 1H); 7.7 (d, 1H).

Stage D: Obtain 4-(3-(2,6-dimethoxybenzoate)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.8 (t, 2H); 3,3 (t, 2H); and 3.8 (s, 6H); and 5.2 (s, 2H); 6.5 in (d, 2H); 7.3 to 7.4 (m, 3H); to 7.6 (d, 1H); 7.7 (d, 1H).

Example 42: Synthesis of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2,2-dimethylbutanol acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

IP is the use of the method, described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2,2-dimethylbutanoate:

To a stirred solution of 3-(2,6-dimethylbenzylamine)acetophenone (stage B, 4.11 g, 16,1 mmol) in anhydrous THF (60 ml) and DMPU (12 ml) solution was added bis(trimethylsilyl)amide lithium (1,0M, 17,74 ml) at -60 °C in argon atmosphere. After stirring for 10 minutes at -60 °C was rapidly added ethyl 2-bromoisobutyrate (4,73 g, and 24.2 mmol)Reaktsionnuyu the mixture was stirred additionally for 10 minutes and then heated to room temperature within 4 hours. The crude reaction mixture was placed in EtOAc and washed with water. The aqueous layer was extracted once more EtOAc. The combined organic layers were washed with saturated salt solution, dried over Na2SO4was filtered , concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate, 4:1), obtaining mentioned in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 1,3 (s, 6H); 2,3 (s, 6H); 3,3 (s, 2H); to 4.1 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2,2-dimethylbutanol acid:

By using a method that is written in example 36, Stage E has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,3 (s, 6H); 2,3 (s, 6H); 3,3 (s, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Example 43: Synthesis of 4-(3-(4-(trifluoromethyl)benzyloxy)phenyl)-4-oxobutanoic acid:

Stage a: 3-(4-(trifluoromethyl)benzyloxy)acetophenone:

Using the method described in example 31, step A, using 4-(trifluoromethyl)benzyl bromide and 3-hydroxyacetophenone as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 3H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,4-7,6 (m, 6H).

Stage B: Obtain ethyl 4-(3-(4-(trifluoromethyl)benzyloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,3 (t, 3H); and 2.7 (t, 2H); 3,3 (t, 2H); to 4.1 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,4-7,6 (m, 6H).

Stage C: Obtain 4-(3-(4-(trifluoromethyl)benzyloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): or 2.7 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,4-7,6 (m, 6H).

Example 44: Synthesis of 4-(3-((cyclobutyl)methoxy)phenyl)-4-oxobutanoic acid:

Stage a: 3-((cyclobutyl)methoxy)acetophenone is:

Using the method described in example 31, step A, using cyclobutylamine and 3-hydroxyacetophenone as starting substances, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,9 (m, 4H); 2,1 (m, 2H); 2,5 (s, 3H); to 2.7 (m, 1H); 4,0 (d, 2H); and 7.1 (DD, 1H); to 7.4 (t, 1H); 7.5 to about 7.6 (m, 2H).

Stage B: Obtain ethyl 4-(3-((cyclobutyl)methoxy)phenyl)-4-butyrate:

Using the method described in example 35, step C, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 1,9 (m, 4H); 2,1 (m, 2H); to 2.7 (m, 1H); and 2.8 (t, 2H); 3,3 (t, 2H); 4.0 a (d, 2H); to 4.1 (q, 2H); and 7.1 (DD, 1H); to 7.4 (t, 1H); 7.5 to about 7.6 (m, 2H).

Stage C: Obtain 4-(3-((cyclobutyl)methoxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,9 (m, 4H); 2,1 (m, 2H); to 2.7 (m, 1H); and 2.8 (t, 2H); 3,3 (t, 2H); 4.0 a (d, 2H); and 7.1 (DD, 1H); to 7.4 (t, 1H); 7.5 to about 7.6 (m, 2H).

Example 45: Synthesis of 4-(3-(2,6-dimethylsiloxy)phenyl)butane acid:

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method opisanog is in example 35, Stage B has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage E: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)butane acid:

A solution of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid (stage D, 3 g, 9.6 mmol), hydrazine (1,41 ml, 28.8 mmol) and potassium hydroxide (1,61 g, 28.8 mmol) in ethylene glycol (12 ml) was heated at boiling under reflux for 4 hours, the reaction mixture was added water (18 ml) and 6N HCl (10 ml). The crude reaction mixture was concentrated and the residue was dissolved in EtOAc, washed with water and saturated salt solution, dried over Na2SO4, filtered, and concentrated. Purification was performed flash chromatography on Colo is ke silica gel (chloroform: methanol 95:5 by adding acetic acid), getting listed in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 2,4 (m, 8H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Example 46: Synthesis of 4-[[4-(2,6-dimethylsiloxy)-3-methoxy]phenyl]-4-oxobutanoic acid:

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: Obtain 4-(2,6-dimethylsiloxy)-3-methoxyacetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); of 3.9 (s, 3H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-[[4-(2,6-dimethylsiloxy)-3-methoxy]phenyl]-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); from 3.9 (s, 3H); 4,4 (q, 2H); to 5.1 (s, 2H); 7,0-7,2 (m, 4H); 7,6 (m, 2H).

Stage D: Obtain 4-[[4-(2,6-dimethylsiloxy)-3-methoxy]phenyl]-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H; the 2.8 (t, 2H); 3,3 (t, 2H); from 3.9 (s, 3H); to 5.1 (s, 2H); 7,0-7,2 (m, 4H); 7,6 (m, 2H).

Example 47: Synthesis of 4-[5-[[N-(4-trifloromethyl)aminocarbonyl]-2-methoxy]phenyl]-4-oxobutanoic acid:

Stage A: Obtain methyl 2-methoxy-5-acetylbenzoate:

To a stirred solution of methyl 2-hydroxy-5-acetylbenzoate (12 g, of 61.7 mmol) in DMF (200 ml) was added cesium carbonate (24,15 g, 74,1 mmol) and MeI (for 9.64 g, 68 mmol). The reaction mixture was stirred for 16 hours at 0°C and then was diluted with ethyl acetate, washed with an aqueous solution of Na2S2O5saturated salt solution, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (ethyl acetate:hexane 1:2), receiving specified in the title compound in the form of not-quite-white solid.

1H NMR (270 MHz, DMSO): 2,6 (s, 3H); and 3.8 (s, 3H); of 3.9 (s, 3H); and 7.3 (d, 1H); 8,1 (DD, 1H); or 8.2 (s, 1H).

Stage B: Getting 2-methoxy-5-acetylbenzoic acid:

Methyl 2-methoxy-5-acetylbenzoate (stage A, 3 g, 14.4 mmol) was dissolved in acetic acid (80 ml) and then treated with concentrated HCl (28 ml). The reaction mixture was heated at the boil under reflux for 4 hours, concentrated under reduced pressure and was liofilizovane, getting mentioned in the title compound in the form of a cream solid color that COI is litovali without additional purification.

1H NMR (270 MHz, DMSO): 2,6 (s, 3H); of 3.9 (s, 3H); and 7.3 (d, 1H); 8,1 (DD, 1H); or 8.2 (s, 1H).

Stage C: Obtain 5-acetyl-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide:

To a stirred solution of 2-methoxy-5-acetylbenzoic acid (stage B, 2.5 g, 12.8 mmol), HOBt·H2O (2,08 g of 15.4 mmol) and EDC (3,70 g, and 19.3 mmol) in CH2Cl2(20 ml) and DMF (5 ml) was added 4-(trifluoromethyl)benzylamine (2,48 g, 14.1 mmol) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in ethyl acetate. The organic layer is washed with 3%solution of K2CO3, 1N HCl and saturated salt solution, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol 95:5), receiving specified in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): 2,6 (s, 3H); 4.0 a (s, 3H); and 4.8 (d, 2H); 7,0 (d, 1H); 7.5 (d, 2H); and 7.6 (d, 2H); 8,1 (DD, 1H); of 8.8 (s, 1H).

Stage D: Obtain ethyl 4-[5-[[N-(4-trifloromethyl)aminocarbonyl]-2-methoxy]phenyl]-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H); 2,6 (t, 2H); 3,3 (t, 2H); 4.0 a (s, 3H); 4,4 (q, 2H); and 4.8 (s, 2H); 7,0 (d, 1H); to 7.4 (d, 2H); and 7.6 (d, 2H); 8,1 (DD, 1H); of 8.8 (s, 1H).

Stage E: Getting 4-5-[[N-(4-trifloromethyl)aminocarbonyl]-2-methoxy]phenyl]-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,6 (t, 2H); 3,3 (t, 2H); 4.0 a (s, 3H); 4.7 in (s, 2H); 7,0 (d, 1H); to 7.4 (d, 2H); and 7.6 (d, 2H); 8,1 (DD, 1H); of 8.8 (s, 1H).

Example 48: Synthesis of 4-[5-[[N-(2,6-dimethylbenzyl)aminocarbonyl]-methoxy]phenyl]-4-oxobutanoic acid:

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: Obtaining N-(2,6-dimethylbenzyl)phthalimide:

To a stirred solution of 2,6-dimethylbenzyl alcohol (stage A, 6,59 g of 48.4 mmol) in DMSO (20 ml) was added chlorotrimethylsilane (of 15.75 ml, 145 mmol) at room temperature, and the mixture was stirred for one hour. To this reaction mixture were added ethyl acetate and water, the organic layer was washed with saturated salt solution, dried over Na2SO4was filtered and concentrated, obtaining oil. Oily residue was re-dissolved in DMF (100 ml) was added phthalimide potassium (of 10.76 g, to 58.1 mmol). The reaction mixture was stirred for 16 hours at room temperature, was added ethyl acetate and the organic layer washed with 3%solution of Na2CO3, 1N HCl, dried over Na2SO 4was filtered and concentrated, obtaining white solid. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol 95:5), receiving specified in the title compound as a white solid.

1H NMR (270 MHz, DMSO): 2,3 (s, 6H); and 4.8 (s, 2H); 7,0 (m, 3H); 7,8 (s, 4H).

Stage C: Obtaining 2,6-dimethylbenzylamine:

To a stirred solution of N-(2,6-dimethylbenzyl)phthalimide (stage B, to 7.77 g of 29.3 mmol) in ethanol (80 ml) was added hydrazine monohydrate (2,16 ml, 44,52 mmol) and the reaction mixture was heated at the boil under reflux for 3.5 hours. To this reaction mixture was added concentrated HCl to bring the pH to 1 and the boiling continued for another 3.5 hours, was added water and the reaction mixture was filtered, the filtrate was concentrated and the pH was brought to 10 with 2n NaOH. The residue was placed in methylene chloride and washed with saturated salt solution, dried over Na2SO4was filtered and concentrated, obtaining an oil which was used without further purification.

1H NMR (270 MHz, DMSO): 2,3 (s, 6H); and 3.8 (s, 2H); 7,0 (m, 3H).

Stage D: Obtain 5-acetyl-2-methoxy-N-[[2,6-dimethyl)phenyl]methyl]benzamide:

To a stirred solution of 2-methoxy-5-acetylbenzoic acid (example 47, step B, 2.5 g, 12.8 mmol), HOBt (2,08 g of 15.4 mmol) and EDC (3,70 g, and 19.3 mmol) in CH2Cl2(20 ml) and DMF (5 ml) is obavljale 2,6-dimethylbenzylamine (stage C, 1,72 g, 12.8 mmol) and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in ethyl acetate. The organic layer is washed with 3%solution of K2CO3, 1N HCl and saturated salt solution, dried over Na2SO4, filtered and concentrated. Purification was performed flash chromatography on a column of silica gel (chloroform:methanol 95:5), receiving specified in the title compound as a white solid.

1H NMR (270 MHz, CDCl3): of 2.5 (s, 6H); 2,6 (s, 3H); of 3.9 (s, 3H); 4.7 in (s, 2H); 7,0 (d, 1H); to 7.2 (m, 3H); 7,6 (user., 1H); 8,1 (DD, 1H); of 8.8 (s, 1H).

Stage E: Obtain ethyl 4-[5-[[N-(2,6-dimethylbenzyl)aminocarbonyl]methoxy]phenyl]-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (s, 6H); and 2.7 (t, 2H); 3,3 (t, 2H); from 3.9 (s, 3H); 4,4 (q, 2H); 4.7 in (s, 2H); 7,0 (m, 3H); to 7.2 (m, 1H); 8,1 (DD, 1H); to 8.7 (s, 1H).

Stage F: Obtain 4-[5-[[N-(2,6-Dimethylbenzyl)aminocarbonyl]-2-methoxy]phenyl]-4-oxobutanoic acid:

Using the method described in example 36, step E, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3:CD3OD): 2,4 (s, 6H); and 2.7 (t, 2H); 3,3 (t, 2H); from 3.9 (s, 3H); 4.7 in (s, 2H); 7,0 (m, 3H); to 7.2 (m, 1H); 8,1 (DD, 1H); to 8.7 (s, 1H).

Example 49: Synthesis of 4-(3-(2,6-emotivision)phenyl)-4-ox is butocarboxim acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oksobutilfosfonovoi acid

To a solution of hydroxylamine hydrochloride in anhydrous ethanol was added a solution of potassium hydroxide in anhydrous ethanol at 35°C. the Mixture was cooled and was added ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate (stage C) and powdered potassium hydroxide.

After several hours, the reaction mixture can be diluted with water and neutralized with hydrochloric acid, filter, and recrystallized, getting listed in the title the connection information.

Example 50: Synthesis of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanamide:

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid:

Using the method described in example 35, step D, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); and 2.8 (t, 2H); 3,3 (t, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); 7,2-7,3 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage E: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanamide:

To a solution of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxobutanoic acid (stage D) in DMF, obavljale the triethylamine and BOP, after approximately 2 hours of stirring to the reaction mixture, you can add liquid ammonia at -40°C and the resulting mixture can be heated for 16 hours, giving specified in the header of the connection.

Example 51: Synthesis of 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2-butenova acid

Stage A: Obtaining 2,6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-3-bromo-butyrate:

It chilled with ice to a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate (stage C, 3 g, 9 mmol) in anhydrous diethyl ether (70 ml) was added until the NML bromine (0,7971 g, 9.9 mmol), diluted with ether (30 ml). After 4 hours stirring, the reaction mixture was concentrated and purified flash chromatography on a column of silica gel (EtOAc:hexane, 1:4), receiving specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); 3,1 (m, 1H); 3,5 (m, 1H); to 4.2 (q, 2H); to 5.1 (s, 2H), and 5.5(m, 1H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage E: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2-butenoate:

The triethylamine (5,95 g of 58.9 mmol) was added to a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-3-bromo-butyrate (stage D, 2,47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for 4 hours at room temperature the reaction mixture was filtered several times through a layer of silica gel and concentrated, obtaining specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); to 4.2 (q, 2H); to 5.1 (s, 2H); 6,9 (DD, 1H); and 7.1 (d, 2H); to 7.2(m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H); 7,9 (DD, 1H).

Stage F: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2-butenova acid:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxo-2-butenoate (stage E) in absolute ethanol at low temperature was added aqueous sodium hydroxide solution, after one hour the mixture was concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol 95:5 enriched acetic acid).

Example 52: Synthesis of 4-(3-(2,6-di is ethylbenzylamine)phenyl)-3-butenova acid:

Stage A: Getting 2, 6-dimethylbenzyl alcohol:

Using the method described in example 35, step A, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); of 4.7 (s, 2H); 7,0-to 7.15 (m, 3H).

Stage B: 3-(2,6-dimethylbenzylamine)acetophenone:

Using the method described in example 35, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): of 2.4 (s, 6H); 2,6 (s, 3H); to 5.1 (s, 2H); and 7.1 (DD, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage C: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-butyrate:

Using the method described in example 17, step B, has been specified in the header of the connection.

1H NMR (270 MHz, CDCl3): 1,2 (s, 3H)and 2.4 (s, 6H); and 2.8 (t, 2H); 3,2 (t, 2H); and 4.4 (q, 2H); to 5.1 (s, 2H); and 7.1 (d, 2H); to 7.2 (m, 2H); to 7.4 (t, 1H); 7,6 (m, 2H).

Stage D: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-hydroxy-butyrate:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-oxybutyrate (stage C) in tetrahydrofuran was added sodium borohydride dissolved in water. After 3-4 hours of stirring at room temperature, the mixture was suppressed acid. The organic layer can be extracted with dichloromethane, washed with water, aqueous sodium bicarbonate solution and saturated salt solution, dried over Na2SO4, filtered and concentrated. If it is Timoti, the connection can be purified flash chromatography on a column of silica gel (EtOAc:hexane).

Stage E: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-bromo-butyrate:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-hydroxy-butyrate (stage D) in dioxane was added dropwise tribromide phosphorus in dioxane. After stirring at room temperature for 16 hours, the mixture is extinguished with water and chloroform. After a few minutes the reaction mixture may be neutralized soft water base, the organic layer dried over Na2SO4filtered, concentrated and purified flash chromatography on a column of silica gel (EtOAc:hexane).

Stage F: Obtain ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-3-butenoate:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-4-bromobutyrate (stage E) in carbon tetrachloride add triethylamine. After stirring for about 4 hours the mixture can be filtered several times through a layer of silica gel and concentrated, giving specified in the header of the connection.

Stage G: Obtain 4-(3-(2,6-dimethylsiloxy)phenyl)-3-butenova acid:

To a solution of ethyl 4-(3-(2,6-dimethylsiloxy)phenyl)-3-butenoate (stage F) in absolute ethanol at low temperature, add aqueous sodium hydroxide solution, after one hour the mixture was concentrated and purified flash x is matography on a column of silica gel (chloroform:methanol 95:5 by addition of acetic acid).

To a solution of ethyl 4-(3-(2,b-dimethylsiloxy)phenyl)-3-butenoate (stage F) in absolute ethanol at low temperature, add aqueous sodium hydroxide solution, after one hour the mixture was concentrated and purified flash chromatography on a column of silica gel (chloroform:methanol 95:5 by addition of acetic acid).

Example 53: Synthesis of 3-(2,6-Dimethylbenzylamine)phenylacetic acid

Stage a: 3-hydroxyphenylacetate ethyl

To a stirred solution of 3-hydroxyphenylacetic acid (10 g, and 65.7 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 16,27 g of 78.8 mmol) in DMF (30 ml) is added pyridine (2.5 ml) followed by the addition of absolute ethanol (15 ml, 255,5 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 2:1) to obtain specified in the connection header.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 3,5 (s, 2H); 4,1 (square, 2H); of 6.6 to 7.2 (m, 4H).

Stage b: 3-(2,6-dimethylbenzylamine)of ethyl phenylacetate

A solution of 2,6-dimethylbenzyl alcohol (5,25 g, and 38.6 mmol) and azodicarboxylate diisopropyl (DIAD, 8,49 g, 42 mmol) in THF (30 ml) and DMF (13 ml) is added dropwise to a solution of 3-hydroxyphenylacetate ethyl (stage And, of 6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction semipermissive at room temperature for 4 h, diluted simple ether and washed with water. The organic layer is dried over Na2SO4, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 1:1) to obtain specified in the connection header.

1H NMR (270 MHz, CDCl3): 1,2 (t, 3H); 2,4 (C, 6N); 3,5 (s, 2H); 4,1 (square, 2H); to 5.1 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

Stage C: 3-(2,b-dimethylbenzylamine)phenylacetic acid

To a stirred solution of 3-(2,6-dimethylbenzylamine)of ethyl phenylacetate (stage b, 4 g of 13.6 mmol) in absolute ethanol (30 ml) was added IN NaOH (20 ml) at room temperature. The reaction mixture was stirred for 3 h, acidified with 1N HC1 and concentrated. The residue is transferred into chloroform and washed with 0,1N HCl, dried over Na2SO4, filtered, concentrated and purified flash chromatography on a column of silica gel (hexane:ethyl acetate 1:1) to obtain specified in the connection header.

1H NMR (270 MHz, CDCl3): 2,4 (C, 6N); the 3.65 (s, 2H); to 5.1 (s, 2H); to 6.9 (m, 2H); 7,15-to 7.35 (m, 5H).

EXAMPLES of BIOLOGICAL ACTIVITY

Example A. the Connection AH improves metabolic abnormalities with insulin-dependent diabetes.

Streptozotocin (STZ) is a toxin that selectively destroys producing insulin pancreatic beta cells and is widely used to induce insulin-dependent diabetes in the experience is imentally animals.

Female Balb/C mice (age 8 weeks; body weight 18-20 g) were treated with streptozotocin (STZ) (50 mg/kg I.P. Pavlova.(intraperitoneally) in each of five consecutive days). Fourteen days after the last dose STZ, changed the level of glucose in the blood to ensure that animals developed diabetes, and the mice were divided into two groups, 5 animals in each; the animals of one group received the Compound AH (250 mg/kg) daily orally using gastric probe, and in another group of animals received the vehicle (0,75% hypromellose, suspendisse agent in water). Also monitored for a group neadiabaticheskikh mice from the same set of mice that had not received STZ. For determination of the concentration of glucose in the blood was periodically collected blood samples and also recorded body weight.

After a few weeks of treatment the concentration of glucose in the blood of mice that were treated orally with compound AH, began to decline relative to the baseline, whereas the level of glucose in the blood of control animals, which received media continued to rise. Table 1 shows body weight, concentrations of glucose, triglycerides and cholesterol in the blood after 14 weeks after the start of treatment with the medication.

Table 1
The chemical composition of the blood serum and body weight at streptozotocin-diabetic mice treated orally with Compound AH for 14 weeks.
GroupGlucose mg/decilitreTriglycerides mg/decilitreCholesterol mg/decilitreBody weight (g)
Neadiabaticheskie+media138±688±988±621+0.6
Diabetic+media615±46154±16133±617,5+1,0
Diabetic+Connection EN207±1262±7*82±2*21,7+0,8*
* = significantly different from STZ diabetic group, P<0,001

Oral administration of compound AH has led to a substantial improvement metabasic abnormalities associated with insulin-dependent diabetes.

Example B. oral administration of Compound AH improves survival in mouse on the th death with insulin dependent diabetes

Female Balb/C mice (age 14 weeks) were treated with a single dose of streptozotocin (175 mg/kg I.P. Pavlova.) to induce severe insulin-dependent diabetes. After 7 days the mice were divided into three groups: Connection AH, pioglitazone and media.

Mice were treated daily by oral administration and control survival time.

Table 2
Survival after 12 weeks
GroupSurvivors
Media0/5
Pioglitazone 30 mg/kg/day2/5
Connection EN 250 mg/kg/day4/5

All diabetic animals receiving oral carrier, died of severe uncontrolled diabetes. Two out of five animals were treated with pioglitazone, antidiabetics insulin sensitizer used for the treatment of people with non-insulin-dependent diabetes, remained alive after 12 weeks, but lost 15-20% of body weight. Four of the five animals receiving oral Connection AH, remained alive after 12 weeks, and their body weight return is the very and maintained in the normal range.

Example C: oral introduction Connection AA reduces mortality in severe insulin dependent diabetes

Female balb/C mice (age 19 weeks to the beginning of the experiment) was repeatedly injected a high dose of STZ (75 mg/kg RV for 5 consecutive days). Then the animals were divided into two groups (20 mice/group), matched for severity of diabetes. Four days after the last dose STZ started processing. In one group of animals received the vehicle (0.4 ml of 0.75% HPMC, p.o. (oral)), and in another group of animals were treated orally with compound AA (30 mg/kg/day). After three weeks of daily treatment cumulative mortality in the control group, the media was 19/20 mice. In contrast, only 5/20 mice in the group treated with compound AA, died during this period of time.

Example D: the Connection AH reduces the rate of spontaneous diabetes and mortality in NOD mice.

A significant portion of NOD ("non-obese diabetic) mice insulin-dependent diabetes develops as a consequence of spontaneous autoimmune destruction of pancreatic islet cells. Two groups of 20 NOD mice (aged 6 weeks) were treated daily or oral media (0.4 ml of 0.75% hypromellose in water; HPMC), or a connection EN (200 mg/kg/day)suspended in HPMC. Within seven months of supervised cases smart the STI due to the spontaneous development of insulin-dependent diabetes. At the end of this period of time 13/20 mice, which were treated with media, died from uncontrolled diabetes, whereas only 5/20 mice that were treated with compound Academy of Sciences, died.

Example E. the Compound AW decreases hyperglycemia and hyperlipidemia and facilitates the flow of obesity liver in ob/ob obese diabetic mice.

Mouse ob/ob are defective gene for leptin, a protein that is included in the regulation of appetite and energy metabolism, and are hypervolume suffering from obesity and resistance to insulin. They develop hyperglycemia and fatty liver.

Male lean (ob/+heterozygous) and thick (ob/ob homozygous) C57BL/6 mice aged approximately 8 weeks were obtained from Jackson Labs (Bar Harbor, ME) and randomly distributed into groups of 5 animals, so that the body weight and glucose concentrations in the blood were similar between groups. All animals were kept under controlled temperature (23°C), relative humidity (50+5%) and light period (7:00-19:00)and the animals had free access to water and nutrition laboratory (Formulab Diet 5008, quality Lab Products, Elkridge, MD).

Glucose in the blood was determined in a routine manner using the strips for the determination of glucose and device-glucometer Elite XL (Bayer Corporation). At selected time points were taken blood samples (~100 microlitres) using heparinised the bath capillary tube from the retro-orbital sinus for chemical analysis of blood serum. Analyses of the chemical composition of the blood serum (glucose, triglycerides, cholesterol, BUN, creatinine, AST, ALT, SDH, CPK and free fatty acids) was performed using the analyzer Hitachi 717 and pancreatic insulin was measured electrochemiluminescent by immunoassay (Origen Analyzer, Igen, Inc., Gaithersburg, MD).

A group of mice ob/ob distributed on group processing, as described below, and daily was administered oral dose of compound AW (10, 30, 100, 150 or 300 mg), rosiglitazone (1, 3, 10 or 30 mg) or pioglitazone (30 or 100 mg). The last two compounds are insulin-sensitizing drugs used to treat people with non-insulin-dependent diabetes mellitus, and they were used for comparison of efficacy and safety with the compounds according to the invention. The dosage range for the compounds in this experiment were chosen in such a way as to include both suboptimal and potentially Soroptimist dose.

As shown in table 3, compound AW resulted in lowering blood glucose, comparable to that achievable with the use of pioglitazone and rosiglitazone. In doses of 100 to 300 mg/kg/day of compound AW reduced the level of triglycerides and fatty acids in the serum better than rosiglitazone, or pioglitazone, in their optimal antihyperglycemics doses.

Table 3
The effect of compound AW, pioglitazone (PG) and rosiglitazone (RSG) on the level of serum glucose, triglycerides and free fatty acids in ob/ob mice
Glucose ± standard deviation from the meanTriglycerides ± standard deviation from the meanFree fatty acids ± standard deviation from the mean
Groupmg/decilitremg/decilitrethe micromol/l
ob/+268,6±12,9111,6±12,02216±197,4
ob/ob384,2±53,8is 106.6±2,9093399±345,6
AW-10to 369.6±62,5115,6±7,83697,4±357,8
AW-30280,2±46,796,4±7,32552,2±334,7
AW-100286±47,1 66,2±5,91476±82,1
AW-150RUR 188.6±28,872,6±5,61481±158,8
AW-300128,4±8,863,6±3,41452,6±111,1
PG-30188,2±21,4of 111.2±7,52606,±139,2
PG-100174,6±11595,2±4,81983,4±66,1
RSG-1142,75±8,8109,75±4,42090,75±67,7
RSG-3190,2±12,7to 107.8±3,82317,6±85,3
RSG-10188,2±21,4of 111.2±7,52606,4±139,2
RSG-30174,6±11,595,2±4,81983,4±66,1

In mice ob/ob develops a chronic inflammatory fatty liver, and consider them as an animal model of non-alcoholic steatohepatitis (NASH), a painful condition that can lead to progress the dominant cirrhosis and liver dysfunction. When NASH accumulation of fat increases the susceptibility of the liver inflammatory damage. One characteristic of NASH patients are, in the absence of viral infection or alcohol abuse, elevated levels of serum enzymes, which are released from damaged liver cells (hepatocytes), for example, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH). The content of these enzymes increased in mice ob/ob due to fatty liver disease and secondary inflammation. Table 4 presents ALT, AST, and SDH in samples of serum obtained from mice that were treated with compound AW, pioglitazone and rosiglitazone, and the levels of enzymes in the serum obtained from normal lean mice and in diabetic control mice that were treated with only the carrier. ALT, AST, and SDH significantly elevated in obese diabetic ob/ob mice compared to lean mice. Treatment of compound AW in doses ranging from 30 mg/kg/day up to 300 mg/kg/day resulted in dose-dependent decrease in liver enzymes in the serum. In contrast, pioglitazone (30 and 100 mg/kg/day) and rosiglitazone (1 to 30 mg/kg/day) induced an increase in ALT and AST and did not change the content of SDH. Profiles of liver enzymes in serum correlated with the histology of the liver. I suffered from obesity diabeticheskaya ob/ob, which was treated by the media, there has been an accumulation of fat in the liver in separate intracellular droplets. Daily administration of compound AW for 4 weeks caused a marked reduction of fat droplets in the liver, whereas either pioglitazone or rosiglitazone did not reduce either the size or density of fat droplets in hepatocytes.

Table 4
The effect of compound AW, pioglitazone and rosiglitazone on serum enzyme indicators of liver damage
GroupALT (M.E. Ter-Minassian/l)(standard deviation from the meanAST (M.E. Ter-Minassian/l)(standard deviation from the meanSDH(M.E. Ter-Minassian/l)(standard deviation from the mean
Skinny106,4±16,325,6±2,723,2±4,5
Diabetic447,2±63,4645,6±104,8745,8±102,4
2022-10483,8±81,9653,4±104,8626,8±93,8
AW-30 320,2±46,2399,6±74,4333,0±66,9
AW-100202,8±38,0143,8±30,4121,2±14,1
AW-150149,2±15,6185,8±26,0to 166.2±20,0
AW-300188,2±10,3335,4±44,8207,0±29,3
PG-30713,6±80,61024±88,7782,0±70,6
PG-100646,0±56,1901,0±49,3603,0±27,3
RSG-1668,8±42,9798,0±73,8644,5±51,6
RSG-3716,6±56,6853,8±43,8615,4±38,6
RSG-10713,6±80,51024,0±88,7782,0±70,6
RSG-30646,0±56,1901,2±49,3603,0±27,3

Mouse ob/ob gained weight during Euro is renedering processing period. As shown in table 5, pioglitazone and rosiglitazone increased weight gain relative to mice treated by the media, while the connection AW induced a dose-dependent attenuation of weight gain.

Table 5
The effect of compound AW, pioglitazone and rosiglitazone on the gain of body weight in ob/ob mice
GroupThe average increase in body weight (grams)
A receiver array (medium)+7,4
AW-3 mg/kg/day+7,3
AW-10 mg/kg/day+6,7
AW-30 mg/kg/day+6,4
AW-100 mg/kg/day+3,4
AW-150 mg/kg/day+4,6
AW-300 mg/kg/daya-0.7
PG-30 mg/kg/day+10,0
PG-100 mg/kg/day+13,6
RSG-1 mg/kg/day+8,2
RSG-3 mg/kg/day+8,5
RSG-10 mg/kg/day+11,0
RSG-30 mg/kg/day+12,0

Example F: a Strong hypoglycemic effect of the compounds according to the invention in diabetic mice: experiment 1

Compounds according to the invention exhibit a strong antihyperglycemic activity in animals with insulin-independent diabetes

Male diabetic mice ob/ob randomly distributed into groups of five animals each. Body weight was 50-55 g, and the level of glucose in the blood was approximately 300 mg/decilitre in the fed state. Using a gastric probe was administered a single oral dose of the studied substance, suspended in 0.5% karboksimetilcelljuloza media. The level of glucose in the blood was measured in a drop of blood obtained by using the tail vein with a razor, using glycolytically test strips and device Glucometer Elite XL (Bayer) after 0, 0.5, and 2, 4, 6 and 18 hours after administration of the initial dose. 10%reduction in blood glucose relative to the administered orally media was seen as a positive screening result. The decrease in blood glucose was maximum at 6 hours after administration of the drug.

Table 6
Strong hypoglycemic effect of the compounds according to the invention in ob/ob diabetic mice, obese
Processing groupGlucose levels after 6 hours% reduction relative to the control
Media297±350,0±11,8
The connection AA242±25is 18.5±8,4
Connection AB181±19-39,1±6,4
Connection AF314±32-24,6±7,7*
Connection AG222±23-25,3±7,7
Connection AH223±11-24,9±3,7
The connection AI255±9-14,1±3,0
Connection AJ190±14-36,0±4,7
Connection AK210±10 -29,3±3,4
Connection AL168±13-43,4±4,4
* Initial glucose level in this group was $ 416±29 mg/decilitre and the value after 6 hours normalized to the given initial value. All groups in this experiment, the average initial concentration of glucose in blood was ≤ 300 mg/l

Example G: a Strong hypoglycemic effect of the compounds according to the invention in diabetic mice: experiment 2

Compounds according to the invention exhibit a strong antihyperglycemic activity in animals suffering from non-insulin-dependent diabetes.

Male mice ob/ob (50-55 grams; the glucose level of 300 mg/decilitre) were divided into groups of five animals each, and were given a single dose of the test drug (250 mg/kg), suspended in medium, representing a 0.5% carboxymethylcellulose; a control group received only the carrier.

Six hours after oral administration of test drugs or media (control) from the tail vein were collected blood samples and determined the concentration of glucose using glucometer.

Table 7
Strong hypoglycemic effect of the compounds according to the invention in ob/ob diabetic mice, obese
Processing groupGlucose levels after 6 hours% reduction relative to the control
Media (control)305±200,0±5,0
Connection'AN152±11-50,2±4,5%
Connection AQ220±17-27,9±4,2%
Connection AR179±14-41,3±4,2%
Connection AS167±28-45,2±2,0%
The connection AT198±28-35,1±2,3%
Connection AU224±26-26,6±2,8%
The AV connection207±23-32,1±3,0%
Connection AW143±15-3,1±3,1%
Connection AX165±23-45,9±2,4%
Connection AY185±21-39,3±2,9%
Connection AZ186±10-39,0±6,1%

Oral administration of the compounds according to the invention showed strong antihyperglycemic effect in diabetic mice suffering from obesity.

Example H: anti-diabetic effect of the compounds according to the invention in mice db/db

Mouse db/db have a defect in latinboy signal transmission, which leads to hyperphagia, obesity and diabetes. Moreover, in contrast to mice, ob/ob, which are relatively healthy islet cells, producing insulin, islet cells of the pancreas are susceptible to damage during chronic hyperglycemia, which leads to the transition from hyperinsulinemia (associated with peripheral resistance to insulin) to hypoinsulinemic diabetes.

The male mice db/db daily oral injected media (0,75% hypromellose) or anti-diabetic compounds, as listed below. Blood samples were obtained from the retro-orbital sinus for chemical analysis of serum or blood from the tail vein to measure glitch the system using test strips and glucometer.

After four weeks of daily oral dosing of compound AW and connection BH demonstrated a significant reduction in blood glucose. Walking pioglitazone really initially reduced the level of blood glucose during the first 3 weeks, its activity was strongly decreased at 4 weeks after that. The dose of pioglitazone used in this experiment, in the literature it was reported as the most effective dose for treatment of mice db/db (Shimaya et al. (2000), Metabolism 49:411-7).

Table 8
GroupGlucose mg/decilitreGlucose (% of control)
Media (control)562±24100±4
Connection AW - 150 mg/kg313±34*56±6*
The connection of HV - 150 mg/kg229±49*41±9*
Pioglitazone 100 mg/kg558±2899±5
* Less than the reference value for the media, p<0,05

In the second experiment, n is the mice db/db compared antidiabetic activity of compound BI and rosiglitazone. After 8 weeks of treatment glucose and triglycerides in the blood was significantly decreased in animals treated with or connection BI or rosiglitazone compared with the treated carrier animals. Dose rosiglitazone used in this study in the published literature is known as the optimal dose for a later stage for db/db mice (Lenhard et al., (1999) Diabetologia 42: 545-54). The group consisted of 6-8 mice each.

Table 9
GroupGlucose (mg/decilitre)Triglycerides (mg/decilitre)
Media (control)686±47147±13
Rosiglitazone - 20 mg/kg343±38*89±16*
The connection of HV - 150 mg/kg254±30*99±8*
*Less than the reference value for the media, p<0,05 (one-way ANOVA)

Example I: the anti-diabetic action of the compounds according to the invention on mice db/db

Mouse db/db have a defect in latinboy signal transmission, which leads to hyperphagia, obesity and diabetes. Bo is her, unlike mice ob/ob on the basis of C57BL/6J mice db/db based on the C57BL/KS susceptible to damage producing insulin, islet cells of the pancreas that leads to the development of hyperinsulinaemia (associated with peripheral resistance to insulin) to hypoinsulinemic diabetes.

Male C57BL/Ksola mice prone to obesity (db/db homozygous), aged about 8 weeks were obtained from Jackson Labs (Bar Harbor, ME) and randomly divided into groups of 5-7 animals, so body weight (50-55 g) and glucose levels in serum (>300 mg/decilitre in fed state) were similar between groups; males skinny mice (db/+heterozygous) acted as the control grapple adaptation after arrival left at least 7 days. All animals were kept under controlled temperature (23°C), relative humidity (50+5%) and light period (7:00-19:00)and the animals had free access to laboratory food (Formulab Diet 5008, quality Lab Products, Elkridge, MD) and water.

The processing group received a daily oral dose (1% hydroxypropylmethylcellulose), compounds BI, BO, BP, BQ or BR for 2 weeks. At the end of the treatment period were collected in 100 μl of venous blood with a heparinized capillary tube from the retro-orbital sinus of mice db/db for chemical analysis of serum.

The influence of compounds from which briteney on the level of glucose in the blood, selected not on an empty stomach, are presented in table 10, the effect on triglycerides and free fatty acids in serum are shown in table 11.

Table 10
The effect of compounds BI, BO, BP, BQ or BR glucose in the blood in the mouse model db/db
GroupGlucose mg/decilitreGlucose (% of control)
Media (control)632±19100±3
BI-150 mg/kg279±35*44±6*
Bl-100 mg/kg423±53*67±8*
BO-100 mg/kg586±5893±9
BP-100 mg/kg629±8699±14
BQ-100 mg/kg473±49*75±7*
BR-82 mg/kg703±64111±10

Glucose levels in lean neadiabaticheskikh db/+are heterozygous the mice was 225 ± 15 mg/decilitre.

Table 11
The effect of compounds BI, BO, BP, BQ or BR content in serum glucose, triglycerides and free fatty acids in db/db mice.
GroupTriglycerides ± standard deviation from the mean value (mg/decilitre)Free fatty acids ± standard deviation from the average value (μm)
Skinny142,4±6,32577,6±80,8
Diabetic444,3±57,34044,9±158,5
BI-150103,6±8,32234,0±162,6
BI-100134,0±13,12999,9±98,7
BO-100261,1±24,33766,3±234,5
BP-100302,1±28,13772,6±182,5
BQ-100humidity 131.6±20,72825,9±110,9
BR-82253,0±32,0 3653,4±207,5

Example J: anti-diabetic effect of the compounds according to the invention in db/db mice

Mouse db/db have a defect in latinboy signal transmission, which leads to hyperphagia, obesity and diabetes. Moreover, in contrast to mice ob/ob on the basis of C57BL/6J mice db/db based on the line of aC57BL/KS susceptible to damage producing insulin, islet cells of the pancreas that leads to the development of hyperinsulinaemia (associated with peripheral resistance to insulin) to hypoinsulinemic diabetes.

Male C57BL/Ksola mice prone to obesity (db/db homozygous), aged about 8 weeks were obtained from Jackson Labs (Bar Harbor, ME) and randomly divided into groups of 5-7 animals, so body weight (50-55 g) and glucose levels in serum (>300 mg/decilitre in fed state) were similar between groups; males skinny mice (db/+heterozygous) acted as the control grapple adaptation after arrival left at least 7 days. All animals were kept under controlled temperature (23°C), relative humidity (50+5%) and light period (7:00-19:00)and the animals had free access to laboratory food (Formulab Diet 5008, quality Lab Products, Elkridge, MD) and water.

The processing group received a daily oral dose of vehicle (1% hydroxypropylmethylcellulose), compounds BI, BS, BT, BU, BV, or Fe is fibrate within 2 weeks. At the end of the treatment period were collected in 100 μl of venous blood with a heparinized capillary tube from the retro-orbital sinus of mice db/db for chemical analysis of serum.

The effect of the compounds according to the invention on the level of glucose in the blood, not selected on an empty stomach, are presented in table 12, the effect on triglycerides and free fatty acids in serum are shown in table 13.

Table 12
The effect of compounds BI, BS,BT, BU, BV and fenofibrate for mice db/db
GroupGlucose mg/decilitreGlucose (% of control)
Media (control)692,5±55,4100±8
Bl-100 mg/kg347,0±43,1*50±6*
BS-93 mg/kg372,0±53,8*54±8*
BT-107 mg/kg684,3±63,699±9
BU-128 mg/kg533,3±46,777±7
BV-115 mg/kg 789,5±38,9114±6
Fenofibrat-113 mg/kg563,2±49,081±7

Glucose levels in lean neadiabaticheskikh db/+heterozygous mice was 208,5 ± 6.6 mg/decilitre.

Table 13
The effect of compounds BI, BS,BT, BU, BV and fenofibrate content in serum glucose, triglycerides and free fatty acids in db/db mice
GroupTriglycerides ± standard deviation from the mean value (mg/decilitre)Free fatty acids ± standard deviation from the average value (μm)
Skinny114,2±8,72315,8±238,3
Diabetic232,8±20,73511,8±257,6
Bl77,8±5,31997,2±196,4
BS132,0±15,22867,4±267,7
Wof 211.5±21,53897,7±291,3
BU172,5±9,93587,0±156, 3mm
BV153,2±14,23373,8±233,6
Fenofibrateto 109.3±9,13318,5±208,7

Example K: Weakening of cataractogenesis when using the compounds according to the invention in diabetic fatty Zucker rats (ZDF)

Cataracts are one of the leading causes progressive decline of vision and blindness, age-related and diabetes, and model of diabetic fatty Zucker rats (ZDF) has much in common with cataractogenesis in humans, including biochemical changes and oxidative stress in the lens. These rats, however, subject to cataractogenesis usually at the age of 14-16 weeks.

Male ZDF rats and their matched by age skinny twins - Zucker rats (ZL) (fa/+or+/+), was obtained from Genetic Models, Inc. (Indianapolis,IN) at the age of 12 weeks and acclimatized for 1 week before the study. All animals were kept under controlled temperature (23°C), relative humidity (50+5%) and light period (7:00-19:00)and the animals had free access to standard food (Formulab Diet 5008, quality Lab Products, Elkridge, MD) and tap water as needed. The treated group received a daily oral dose of media and 100 is g/kg of compounds BI or BH for 10 weeks. Body weight and glucose content in blood was determined in the usual way (once a week, usually around 10.00 a.m.), sending blood from the tail, using test strips and devices Glucometer Elite XL (Bayer Corporation). At the end of the treatment period were collected and 100 μl of venous blood (usually around 10.00 a.m.) in heparinized tube from the tail vein for chemical analysis of blood serum (Anilytics, Inc., Gaithersburg, MD). The chemical composition of the blood serum (glucose (GL), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH) and free fatty acids (FFA)) were analyzed using a Hitachi 717 Analyzer (Anilytics, Inc., Gaithersburg, MD). The content of insulin in plasma was measured electrochemiluminescent by immunoassay, ECL (Origen Analyzer, Igen, Inc., Gaithersburg, MD). Animals were killed and tissues and/or organs (lenses and liver) were removed, weighed (wet weight) and processed for biochemical analyses.

Malondialdehyde (MDA), the main product of perechisleniya fats, analyzed in the lens by the method of Ohkawa et al. (1979), Analytical Biochem 95,351-358.

Table 14 shows the proportion of visible cataracts in the eyes of ZDF rats. Table 15 provides additional quantitative indicators of cataractogenesis from the same animals.

Table 14
The weakening of cataractogenesis when using compounds BH and BI in ZDF rats
The formation of cataracts% protection
The group of animalsNLeft eyeRight eyeLeft eyeRight eye
Media control66/66/600
BI63/61/65083
BH64/65/63317
Skinny40/40/4N/AN/A

Table 1
The weakening of cataractogenesis when using compounds BH and BI in ZDF rats
Weight (mg)Size (mm)Related to the lens of the eye MDA
GroupLeft lensesThe right lensLeft lensesThe right lensnmol/g lenses
Skinny51,2±3,559,0±0,43,8±0,23,9±0,10,4±0,0
Media15,1±1,416,8±1,71,9±0,12,0±0,22,4±0,2
BI38,1±7,3**54,9±1,2*3,4±0,2*3,8±0,1*0,8±0,1‡
NR27,0±7,220,0±6,62,5±0,3 2,1±0,41,9±0,2

Data represent mean values ± standard deviation. *p<0,05 when compared with the control group media (diabetic) and process connection EXT groups, respectively; **p<0,05 when compared with control groups of media; ‡p<0,05 when compared with the control group of media and the right lens group connection HV, respectively (One Way ANOVA, Tukey Test). All pairwise multiple comparisons.

Example L: When administered orally BI and BL lowers circulating triglycerides, free fatty acids, insulin and leptin in mice C57B1/6J receiving meals with high fat content

Mice receiving a diet with high fat content, represent a model of hypertriglyceridemia and high circulating levels of fatty acids and insulin resistance and leptin that is found in people with a predisposition to obesity or obesity, diabetes, cardiovascular and other diseases.

Male mice C57B1/6J, aged approximately 8 weeks, randomly distributed into groups of 6 animals. They were kept under controlled temperature (23°C), relative humidity (50+5%) and light period (7:00-19:00)and the animals had free access to food and water as needed. Mice received a diet with high quality, is their fat content (number of diets D12451, containing 45% of calories as fat (research diets (Research Diets), New Brunswick, NJ)for 6 weeks. After 6 weeks, groups of mice were treated with either media (hydroxymethylcellulose), or BI, BL, Wyl4,643 or rosiglitazone using a gastric probe in the dose for an additional 4 weeks, while they continued to receive food high in fat. The chemical composition of the plasma (Anilytics, Inc., Gaithersburg, MD) was analyzed after 2 weeks of treatment with the medication. The plasma serum insulin (figure 1) and leptin (figure 2) was measured using electrochemiluminescence immunoassay (Origen Analyzer, Igen, Inc., Gaithersburg, MD) at the end of the 4 week period of treatment drugs.

BI and BL was effective for lowering triglycerides and free fatty acids in the serum and the levels of insulin and leptin in serum. Values in the serum obtained for mice from the same group ("lean control"), which contained on regular laboratory diet (Formulab Diet 5008, Quality Lab Products, Elkridge, MD), is shown for comparison.

Table 16
Triglycerides (mg/decilitre)Free fatty acids (which KMOL/l)
Media135±40,11686±359,3
BI (10 mg/kg)68,8±5,71227±193,7
" (30 mg/kg)66,5±14,71292±231,4
" (100 mg/kg)37,4±8,3992,8±172,1
BL (10 mg/kg)80±12,21571,8±100,9
" (30 mg/kg)66,4±13,71413,2±to 228.7
" (100 mg/kg)41±5,61133,5±132,7
Rosiglitazone (1 mg/kg)76,6±16,51537±256,3
" (3 mg/kg)103,2±10,81833,2±169,8
" (10 mg/kg)129,5±48,71810,3±595
" (100 mg/kg)88±7,21568,5±197
Wyl4643 (10 mg/kg)70,6±10,81512,2±172,9
" 30 mg/kg) 88±12,51676±237
" (100 mg/kg)to 88.4±18,81839,8±154,8
Rosiglitazone (3 mg/kg) + Wyl4643 (100 mg/kg)54,3±10,51649,7±260,5

Example M: When administered orally BI lowers circulating triglycerides, free fatty acids, insulin and leptin in rats Sprague Dawley receiving meals with high fat content

Rat receiving food high in fat, is a model of insulin resistance and leptin. Rat Sprague-Dawley possess intact latinboy system and provide a reaction to food with a high content of fat in the form of hyperinsulinemia due to dysregulation of normal insulin response in peripheral tissues such as liver, adipose tissue and muscle.

Male rats Sprague-Dawley age of approximately 17 weeks were obtained from Jackson Labs (Bar Harbor, ME) and randomly distributed into groups of 5-7 animals, where the weight between the groups was similar. All animals were kept in temperature-controlled (25°C) favorable conditions, with the exact 12-hour cycle of light/dark, and they had free access to water and food. Rats were fed a diet with a high content of fat (diet room D1245 (containing 45% of calories as fat), Research Diets, New Brunswick, NJ) for one month before treatment drug.

Groups of 6 rats Sprague-Dawley was treated with a single daily dose of media (hydroxymethylcellulose), BI (10, 30 and 100 mg/kg) or rosiglitazone (3 mg/kg) for 6 weeks while maintaining a diet with a high fat content. At these time points were selected blood samples (~100 ál) from the tail vein for chemical analysis of blood serum. BI (30 mg/kg) reduced the content of insulin and triglycerides in the serum, BI all doses reduced the content of free fatty acids.

Table 17
The influence of BI and rosiglitazone glucose, insulin, triglycerides and free fatty acids in the serum of rats, Sprague-Dawley
GroupGlucose (mg/decilitre)Insulin (ng/ml)Triglycerides (mg/decilitre)Free fatty acids (µmol/l)
Skinny123,8±7,00,72±0,1179,0±72,3743,5±57,4
Media 122,3±5,91,78±0,3200,7±39,2942,5±181,0
BI-10117,3±8,82,18±0,9183,7±58,4923,7±161,3
BI-30RUB 127.3±22,21,46±0,2to 129.3±20,0738,7±50,0
BI-10019,3±3,51,79±0,2171,7±33,1725,7±87,5
RG-3to 119.8±5,41,57±0,2134,2±15,2758,8±61,0

The compound of the formula

where m is 1; n is 1 or 2; t is 0 or 1; and
Rather it represents a phenyl, substituted by 2 alkyl groups containing 1 or 2 carbon atoms.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

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

wherein R1 represents (C2-C6)-alkyl; each radical among R2, R3 and R4 represents (C1-C6)-alkyl under condition that sum of carbon atoms in R1, R2, R3 and R4 is above 7. Also, invention relates to compound of the formula (II):

wherein R1 represents ethyl; R4 represents propyl; R5 represents hydrogen atom. Also, invention relates to a pharmaceutical composition possessing capacity for providing and maintaining anesthesia or sedative effect and comprising the effective dose of compound of the formula (I) and a pharmaceutically acceptable carrier. Also, invention relates to using compound of the formula (I) for preparing a medicinal agent used for providing and maintaining anesthesia or sedative effect in mammal, and to a method for providing or maintaining anesthesia wherein indicated method involves administration the therapeutically effective dose of compound of the formula (I) to a mammal.

EFFECT: improved and valuable medicinal properties of compounds.

12 cl, 2 dwg, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 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

The invention relates to an improved process for the preparation of ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid, which is an intermediate product, suitable for the synthesis of idebenone - drug nootropic action

The invention relates to ester compounds, method of their production and their use as a means for spooling the fiber

The invention relates to organic chemistry, namely the method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid - intermediate, suitable for the synthesis of idebenone - drug nootropic action

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of the following general formula [1a], wherein R1 represents (1) a hydrogen atom, (2) C1-C6alkyl group, (3) C2-C6alkenyl group, (4) C2-C6alkynyl group, (5) C1-C6alkoxygroup, (6) hydroxyC1-C6alkyl group, (7) C1-C6alkoxy(C1-C6)alkyl group, (8) -CONR11R12, wherein R11 and R12 are identical or different, and each represents a hydrogen atom or C1-C6alkyl group, (9) phenyl group or (10) a five-member heteroaryl group which contains at least one heteroatom specified in a group consisting of a nitrogen atom and oxygen atom, and which may be substituted by C1-C6alkyl group; R2 represents (1) a halogen atom, (2) C1-C6alkyl group, (3) hydroxy group or (4) C1-C6alkoxy group; p is equal to 0, 1, 2 or 3; X represents a carbon atom or nitrogen atom; m1 is equal to 0, 1 or 2; m2 is equal to 0 or 1; the spiro ring AB may be substituted by 1-5 identical or different, specified in a group consisting of (1) hydroxy group, (2) C1-C6alkyl group, (3) C1-C6alkoxygroup and (4) oxo group; n1 is equal to 0, 1, 2, 3 or 4; n2 is equal to 1, 2, 3 or 4; n3 is equal to 0, 1 or 2, provided n2+n3 is equal to 2, 3 or 4; and a bond presented by the symbol means a single bond or a double bond, provided the three adjoining carbon atoms forms no allene bond presented by formula: C=C=C, or a pharmaceutically acceptable salt thereof.

EFFECT: invention refers to a pharmaceutical composition possessing GPR40 agonist activity, to a GPR40 agonist drugs; to a hypoglycemic agent stimulating insulin secretion on the basis of the above compounds.

45 cl, 42 tbl, 120 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: chemistry.

SUBSTANCE: invention relates to chemistry of organochlorine compounds, and specifically to an improved method of producing chlorine-substituted aryloxycarboxylic acids through chlorination of acids of general formula

where R1 is H, haloid, C1-C4alkyl, n is an integer ranging from 1 to 3, or salts thereof with subsequent extraction of the end product, wherein the chlorinating agent used is solid calcium hyprochlorite in the absence of solvents, and the process is activated by mechanical action in form of impact or impact-shear loading the mixture of solid reagents.

EFFECT: method increases output and purity of the end product, and also simplifies the process technology.

5 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: medicine; pharmacology.

SUBSTANCE: description is provided for the derivative of phenylalcan or phenyloxyalcan acids, formula (I), or their pharmaceutically acceptable salt or hydrolysable ester, where: R1 and R2 independently present the H or С1-3alkyl; X presents the O or (СН2)n where n is 0.1 or 2; R3 and R4 independently present the H, С1-3alkyl, -ОСН3, CF3, allyl or halogen; X1 presents О, S, SO2, SO or СН2; one of R5 and R6 independently presents hydrogen, and another - С1-6alkyl (including the ramified alkyl and, probably, the substituted С1-6alkoxy); R7 presents a phenyl or hexamerous heterocycle taken from pyridine, and each of specified phenyl or heterocycles is substituted by phenyl (probably, substituted by one ore more С1-3alkyl, CN, halogen or CF3). The pharmaceutical composition is also described.

EFFECT: compounds can be used in treatment of cardiovascular and endocrine diseases.

13 cl, 145 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using compounds of (R,S)-2-arylpropionic acids of the formula (Ia) , and their (R)- and (S)-isomers as inhibitors of neutrophile (PMN leukocytes) chemotaxis induced by IL-8. These compounds elicit unexpected ability to inhibit effectively IL-8-induced chemotaxis and degranulation of neutrophiles being without significant effect on activity of cyclooxygenases. These compounds can be used in treatment of such diseases as psoriasis, ulcerated colitis, melanoma, chronic obstructive pulmonary disease, bulla pemphigus, rheumatic arthritis, idiopathic fibrosis, glomerulonephritis, and for prophylaxis and treatment of damages induced by ischemia and reperfusion.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

9 cl, 3 tbl, 43 ex

FIELD: organic chemistry, pharmacy, pharmacy.

SUBSTANCE: invention relates to novel compounds designated for delivery of active substances to tissues of the following formula: wherein values of radicals R1-R7 are determined in claim 1 of the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to compositions designated for delivery of active substances to tissues and containing: (A) active substance and (B) at least one compound designated for delivery of active substance to animal tissues of the formula: wherein values of radicals R1-R7 are determined in claims 3-5 of the invention claim. Also, proposed invention relates to a standard medicinal formulation designated for delivery of active substances to body tissues and to a method for preparing indicated compositions and administration of substances for their delivery to body tissues.

EFFECT: valuable properties of compounds.

23 cl, 11 tbl, 11 ex

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