Substituted derivatives of n-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

 

The present invention relates to compounds that increase the activity of pyruvaldehyde (PDG), methods for their preparation, pharmaceutical compositions containing them as active ingredients, and to methods for treating disease conditions associated with reduced PDG-activity, to their use as medicaments and to their use for the production of pharmaceuticals for use in improving PDG activity in warm-blooded animals such as man, in particular, in the treatment of diabetes mellitus, peripheral vascular disease and ischemic myocardium in warm-blooded animals such as man, more specifically, to their use in the production drugs for use in the treatment of diabetes mellitus in a warm-blooded animal such as man.

Adenosine triphosphate (ATP) provides energy for the synthesis of complex molecules in tissues and muscle contractions. ATP is formed during the collapse of energy-rich substrates, such as glucose or free fatty acids with long chain. In oxidative tissues such as muscles, most ATP is formed from acetyl COA, which enters the citric acid cycle, and thus, the supply of acetyl COA is a critical parameter in the production of ATP in oxidative tissues. Acetyl COA is produced or β-oxidation of fatty acids or in d is the query result of the metabolism of glucose by the glycolytic pathway. A key regulatory enzyme that regulates the rate of formation of acetyl COA from glucose, is PDG, which catalyzes the oxidation of pyruvate to acetyl COA and carbon dioxide with concomitant restoration of nicotinamide-adenine-dinucleotide (NAD) to NADH.

For painful conditions such as leisureservices diabetes mellitus (NSSD), and insulin-dependent diabetes mellitus (IDDM), lipid oxidation increased with concomitant decrease in glucose utilization, which contributes to hyperglycemia. Reduced utilization of glucose as in IDDM and NISSL associated with a reduction of PDC activity. Furthermore, an additional consequence of the reduced PDG activity may be that the increase in the concentration of pyruvate leads to increased availability of lactate as a substrate for hepatic gluconeogenesis. There is reason to believe that the increased activity of the PDG can increase the rate of glucose oxidation and, hence, the total glucose utilization in addition to reduced release of hepatic glucose. Another factor responsible for diabetes, is the diminished secretion of insulin, which as been shown to be associated with reduced PDG-aktivnosti in β-cells of the pancreas (at the genetic model of diabetes in rodents Zhou et al. (1996) Diabetes 45: 580-586).

Oxidation of glucose production ability is to give more molecules of ATP per mole of oxygen, than the oxidation of fatty acids. When the States in which energy demand may exceed the supply of energy, such as ischemic infarction, intermittent claudication, cerebral ischemia and reperfusion (Zaidan et al., 1998; J. Neurochem. 70: 233-241), it can be expected that the shift of balance utilization of the substrate in the direction of glucose metabolism by increasing PDG activity will improve the ability to maintain the levels of ATP and, therefore, function.

You can also expect an agent that can increase PDG activity is beneficial for the treatment of conditions in which the manifest excess circulating lactic acid, such as some cases of sepsis.

It was shown that the agent dichloracetic acid (DHOC), which increases PDG activity after acute injection of animals (Vary et al., 1988; Circ. Shock, 24:3-18), has a predictable effect when blood glucose levels (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530), as a means of therapy on ischemic myocardium (Bersin and Stacpoole, 1997; American Heart Journal, 134: 841-855) and dairy acidemia (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396).

PDG is intramitochondrial mnogovershinny complex, consisting of multiple copies of several subunits, including three enzyme activity E1, E2 and E3 are required to complete the conversion of pyruvate into acetyl COA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1 catalyse is the duty to regulate irreversible destruction of CO 2from pyruvate; E2 forms acetyl COA, and E3 regenerates NAD to NADH. With the complex are two additional enzymatic activity: specific kinase, which reverses to fosforilirovanii E1 on three serine residues, and freely associated specific phosphatase that reverses phosphorylation. Phosphorylation of only one of the three serine residues makes E1 inactive. The share of SOEs in its active (dephosphorylated) state is determined by the balance between the activity of the kinase and phosphatase. The kinase activity can be regulated in vivo by the relative concentrations of metabolic substrates such as NAD/NADH, COA/acetyl-COA and adeninivorans (ADP)/ATP, as well as the availability of pyruvate.

European patent publication No. 617010 and 524781 describe compounds that are able to relax the smooth muscle of the bladder and can be used in the treatment of urinary incontinence. We have found that the compounds of the present invention are very effective in improving PDG-activity; property, which is nowhere disclosed in EP 0617010 and EP 524781.

The present invention is based on the surprising discovery that certain compounds increase PDG-activity; having a valuable property for the treatment of painful conditions associated with disorders of glucose utilization, such as diabetes is diabetes, obesity (Curto et al., 1997; Int. J. Obes. 21: 1137-1142) and dairy acidemia. Additionally, it can be expected that these compounds are useful in diseases in which limited the supply of tissue energy-rich substrate, such as peripheral vascular disease (including alternating lameness), heart failure and certain cardiac myopathy, muscle weakness, hyperlipidemia, and atherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530). The compound that activates the PDG can also be useful in the treatment of Alzheimer's disease (AD) (J.Neural Transm. (1998) 105, 855-870).

Accordingly, the present invention provides compounds of formula (I):

in which:

n is 1 or 2;

R1represents chlorine, fluorine, bromine, methyl or methoxy;

R2selected from one of the following three groups:

i) halogen, nitro, hydroxy, amino or cyano;

ii) -X1-R5in which X1represents a direct link, -O-, -S-, -SO-, -SO2-, -NR6-, -CO-, -CONR6-, -NR6CO-, -NR6SO2- or-NR6ONR7-where R6and R7independently represent hydrogen or C1-4alkyl, optionally substituted by one or more A; and R5selected from C1-6the alkyl, optionally substituted by one or more a, C3-7cycloalkyl, not necessarily umestnogo one or more A, With3-7cycloalkyl1-6the alkyl, optionally substituted by one or more a, C2-6alkenyl, optionally substituted by one or more a, C1-6the quinil, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, panels1-6the alkyl, optionally substituted by one or more D, heteroaryl ring, optionally substituted at a carbon ring by one or more D, or (heteroaryl ring)C1-6the alkyl, optionally substituted at a carbon ring by one or more D where specified heteroaryl ring is attached to a carbon atom of the 6-membered ring containing 1-2 nitrogen atom, or attached carbon atom of the 5-membered ring containing 1-3 heteroatoms, selected independently from O, N and S, and where, if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

iii) attached to the nitrogen atom 4-8-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more D, and in which, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

R3represents C1-6alkyl, optionally alseny one or more A, With3-7cycloalkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D, or attached carbon atom of the 5-membered heteroaryl ring containing 1-3 heteroatoms, selected independently from O, N and S, optionally substituted at the carbon atom of the ring by one or more D, and where, if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

And selected from hydroxy, amino, halogen, carboxy, N-(C1-4alkyl)amino, N,N-di(C1-4alkyl) amino, carbamoyl and C1-6alkoxy;

D is chosen from:

i) -Xa-Rcwhere Xarepresents a direct link, -O-, -S-, -SO-, -SO2-, -CO-, -NRdSO2-, -NRdCO-, -NRdCONRe-, -NRd- or-CONRd-; where Rdand Reindependently represent hydrogen or C1-4alkyl, optionally substituted by one or more hydroxy or1-4alkoxy; and Rcselected from hydrogen or C1-6the alkyl, optionally substituted by one or more hydroxy or1-4alkoxy;

ii) 4-8-membered Het group which is optionally substituted and is Ohm carbon ring by one or more groups, selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if the specified 4-8-membered Het group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

iii) -Xa-C1-6alkyl-Xb-Rcwhere Xaand Rchave the meanings defined above, and Xbis-S-, -SO-or-SO2-;

iv) cyano, or halogen; and

v) -Xc-Rfwhere Xcrepresents-C(O)- or-SO2-, and Rfis attached by the nitrogen atom 4-8-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more groups selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

G is selected from C1-6the alkyl, optionally substituted by one or more A, C1-6alkanoyl, optionally substituted by one or more A, C1-6alkylsulfonyl, optionally substituted by one or more A, C1-6alkoxycarbonyl, optionally substituted by one or more a, carbamoyl, N-(C1-6alkyl) carbamoyl, optionally substituted by one or more A, N-(C1-6alkyl)2carbamoyl, long is correctly substituted by one or more A, and benzoyl, optionally substituted by one or more A; and

R4represents hydrogen or fluorine;

or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

In this description, the term "alkyl" includes an alkyl group with a straight or branched chain, but the instructions on the individual alkyl groups such as "propyl" are specific only for variants with a straight chain. For example, the term "C1-6alkyl includes With1-4alkyl, C2-4alkyl, propyl, isopropyl and tert-butyl. However, information as to individual alkyl groups such as "propyl" are specific only for variants with a straight chain, and guidance to individual alkyl groups branched chain, such as "isopropyl", are specific only for variants with branched chain. The term "halogen" refers to fluorine, chlorine, bromine and idgruppo.

The appropriate values for the attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom"include pyridyl, pyrimidyl, pyrazinyl and pyridazinyl. Preferably "attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom"is pyridyl. In another aspect of the invention "attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, etc is doctitle is pyridazinyl.

The appropriate values for the attached carbon atom of the 5-membered heteroaryl ring containing 1-3 heteroatoms"include pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl and triazolyl.

"Attached nitrogen atom 4-8-membered heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic ring containing 4 to 8 atoms of which at least one is a nitrogen atom, optionally, 1-3 additional heteroatoms independently selected from O, N and S, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides. Obviously, it is clear that the formation of this communication nitrogen atom of nitrogen and stereoselectivity, i.e. forms a neutral connection. The appropriate values for "attached nitrogen atom 4-8-membered heterocyclic group" include morpholino, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl, homopiperazine, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolidine and triazolyl. More appropriate values for "attached nitrogen atom 4-8-membered heterocyclic group" include azetidine, morpholine, piperidyl, piperazinil, pyrrolidinyl, timoho the Ino, pyrrolidyl, homopiperazine, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolidine and triazolyl. Preferably "attached nitrogen atom 4-8-membered heterocyclic group" is morpholino, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl or homopiperazine. More preferably "attached nitrogen atom 4-8-membered heterocyclic group" represents azetidine, morpholine, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl or homopiperazine. More appropriate values for "attached nitrogen atom 4-8-membered heterocyclic group" include azetidine, morpholine, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, pyrrolidyl, homopiperazine, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolidine and triazolyl. Preferably "attached nitrogen atom 4-8-membered heterocyclic group" represented by morpholino, 1 Osotimehin, 1,1-dioxothiazolidine, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl or homopiperazine. More preferably "attached nitrogen atom 4-8-membered heterocyclic group" represents azetidine, morpholine, piperidyl, piperazinil, pyrrolidinyl, Timor is Olya, 1 Osotimehin, 1,1-dioxothiazolidine, pyrrolidyl or homopiperazine. In particular, Rfas the attached nitrogen atom 4-8-membered heterocyclic group" represents azetidine, morpholine or pyrrolidine. In particular, when R2is "attached nitrogen atom 4-8-membered heterocyclic group", it is thiomorpholine. In another aspect of the invention, in particular when R2is "attached nitrogen atom 4-8-membered heterocyclic group", it is thiomorpholine, piperazinil, 1 Osotimehin, 1,1-dioxothiazolidine or morpholino.

"Attached nitrogen atom 4-6-membered heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic ring containing 4-6 atoms, of which at least one is a nitrogen atom, optionally 1-3 additional heteroatoms independently selected from O, N and S, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides. Obviously, it is clear that the formation of this nitrogen regard, the nitrogen atom not quartersawn, i.e. forms a neutral connection. The appropriate values for "attached nitrogen atom 4-6-membered heterocyclic group" include AZ is tibinil, morpholino, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolidine and triazolyl. Preferably "attached nitrogen atom 4-6-membered heterocyclic group" represents azetidine, morpholine or pyrrolidine.

"Attached nitrogen atom a 5-or 6-membered heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic ring containing 5 or 6 atoms, of which at least one is a nitrogen atom, optionally 1-3 additional heteroatoms independently selected from O, N and S, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides. Obviously, it is clear that the formation of this communication nitrogen atom of nitrogen and stereoselectivity, i.e. forms a neutral connection. The appropriate values for "attached nitrogen atom a 5-or 6-membered heterocyclic group" include morpholino, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine, pyrrolidyl, pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolidine and triazolyl. Preferably "attached nitrogen atom 5-6-membered heterocyclic group" of t is made of morpholino, piperidyl, piperazinil, pyrrolidinyl, thiomorpholine or pyrrolidyl.

"Attached nitrogen atom to 6-membered heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic ring containing 6 atoms, of which at least one is a nitrogen atom with optional 1-3 additional heteroatoms independently selected from O, N and S, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides. Obviously, it is clear that the formation of this communication nitrogen atom of nitrogen and stereoselectivity, i.e. forms a neutral connection. The appropriate values for "attached nitrogen atom to 6-membered heterocyclic group" include morpholino, piperidyl, piperazinil, thiomorpholine.

"4-to 8-membered Het" group is a saturated, partially saturated or unsaturated monocyclic ring containing 4 to 8 atoms, containing 1-4 heteroatoms independently selected from O, N and S, which may be attached carbon atom or nitrogen, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides.

The appropriate values for the "4-to 8-membered Het" group include Mohali is about, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolin, thienyl, thiadiazolyl, piperazinil, diazolidinyl, pyrrolidinyl, thiomorpholine, pyrrolidyl, homopiperazine, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 4-pyridone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.

"5 or 6-membered Het" group is a saturated, partially saturated or unsaturated monocyclic ring containing 4 to 8 atoms, containing 1-4 heteroatoms independently selected from O, N and S, which may be attached carbon atom or nitrogen, where the group-CH2- may be optionally replaced by a group-C(O)-, and a nitrogen atom in the ring and/or sulfur may be optionally oxidized, forming N-oxide and/or S-oxides. The appropriate values for "5 or 6-membered Het" group include morpholino, piperidyl, pyridyl, pyranyl. pyrrolyl, isothiazolin, thienyl, thiadiazolyl, piperazinil, diazolidinyl, pyrrolidinyl, thiomorpholine, pyrrolidyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 4-pyridone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.

Examples of "C1-6alkoxycarbonyl include methoxycarbonyl, etoxycarbonyl, n - and tert-butoxycarbonyl. Examples of "C1-6alkoxy" include1-4alkoxy, methoxy, ethoxy and propoxy. Examples "1-4alkylsulfonic is and include methylsulfinyl and ethylsulfinyl. Examples of "C1-6alkylsulfonyl include1-4alkylsulfonyl, methil and ethylsulfonyl. Examples of "C1-6alkanoyl include1-4alkanoyl, propionyl and acetyl. Examples "C3-7cycloalkyl are cyclopropyl and cyclohexyl. Examples "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples "C2-6the quinil are ethinyl, 1-PROPYNYL and 2-PROPYNYL. Examples of "N-(C1-6alkyl)carbamoyl are methylaminoethanol and ethylaminoethanol. Examples of "N-(C1-6alkyl)2carbamoyl are dimethylaminoethyl and methylaminoethanol. Examples of "N-(C1-4alkyl)amino" include methylamino, ethylamino. Examples of "N-(C1-4alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "panels1-6of alkyl" include panels1-6alkyl, benzyl and phenethyl. Examples "3-7cycloalkyl1-6of alkyl" include cyclopropylmethyl, cyclopentylmethyl and 2-cyclohexylprop. Examples of "(heteroaryl ring)C1-6of alkyl" include pyridylmethyl, personality and imidazolidinyl.

According to further aspect of the present invention are provided compounds of formula (I) (as depicted above), in which:

n is 1 or 2;

R1represents chlorine, fluorine, bromine, methyl or methoxy;

R2selected from one of the following three GRU the paragraph:

i) halogen, nitro, hydroxy, amino or cyano;

ii) -X1-R5in which X1represents a direct link, -O-, -S-, -SO-, -SO2-, -NR6-, -CO-, -CONR6-, -NR6CO-, -NR6SO2-or-NR6ONR7-where R6and R7independently represent hydrogen or C1-4alkyl, optionally substituted by one or more A; and R5selected from C1-6the alkyl, optionally substituted by one or more a, C3-7-cycloalkyl, optionally substituted by one or more a, C2-6alkenyl, optionally substituted by one or more a, C2-6the quinil, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached at carbon 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D, or attached carbon atom of the 5-membered heteroaryl ring containing 1-3 heteroatoms, selected independently from O, N and S, optionally substituted at the carbon atom of the ring by one or more D, where if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

iii) attached to the nitrogen atom 4-8-membered heterocyclic group, neobythites is but substituted at the carbon atom of the ring by one or more D, and where, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

R3represents C1-6alkyl, optionally substituted by one or more a, C3-7cycloalkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D, or attached carbon atom of the 5-membered heteroaryl ring containing 1-3 heteroatoms, selected independently from O, N and S, optionally substituted at the carbon atom of the ring by one or more D, and where, if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

And selected from hydroxy, amino, halogen, carboxy and C1-6alkoxy;

D is chosen from:

i) -Xa-Rcwhere Xarepresents a direct link, -O-, -S-, -SO-, -SO2-, -CO-, -NRdSO2-, -NRdCO-, -NRdCONRe-, -NRd- or-CONRd-; where Rdand Reindependently represent hydrogen or C1-4alkyl, optionally substituted by one or more hydroxy or1-4alkoxy; and Rcselected from bodoro is a or C 1-6the alkyl, optionally substituted by one or more hydroxy or1-4alkoxy;

ii) 4-8-membered Het group which is optionally substituted at a carbon atom of the ring by one or more groups selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if the specified 4-8-membered Het group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

iii) -Xa-C1-6alkyl-Xb-Rcwhere Xaand Rchave the meanings defined above, and Xbis-S-, -SO-or-SO2-;

iv) cyano, or halogen;

G is selected from C1-6the alkyl, optionally substituted by one or more A, C1-6alkanoyl, optionally substituted by one or more A, C1-6alkylsulfonyl, optionally substituted by one or more A, C1-6alkoxycarbonyl, optionally substituted by one or more a, carbamoyl, N-(C1-6alkyl)carbamoyl, optionally substituted by one or more A, N-(C1-6alkyl)2carbamoyl, optionally substituted by one or more A, and benzoyl, optionally substituted by one or more A; and

R4represents hydrogen or fluorine;

or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

Sootvetstvenno is as an additional aspect of the present invention are provided compounds of formula (I) (as depicted above), in which:

n is 1 or 2;

R1represents chlorine, fluorine, bromine, methyl or methoxy;

R2selected from one of the following three groups:

i) halogen, nitro, hydroxy, amino or cyano;

ii) -X1-R5where X1represents a direct link, -O-, -S-, -SO-, -SO2-, -NR6-, -CO-, -CONR6-, -NR6CO-, -NR6SO2-or-NR6CONR7-where R6and R7independently represent hydrogen or C1-4alkyl, optionally substituted by one or more A; and R5selected from C1-6the alkyl, optionally substituted by one or more a, C3-7cycloalkyl, optionally substituted by one or more a, C2-6alkenyl, optionally substituted by one or more a, C2-6the quinil, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached at carbon 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted carbon atom of the ring by one or more D, or attached at carbon 5-membered heteroaryl ring containing 1-3 heteroatoms, selected independently from O, N and S, optionally substituted at the carbon atom of the ring by one or more D, where if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen mo is et to be optionally substituted by a group, selected from G;

iii) attached to the nitrogen atom 4-8-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more D, and where, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

R3represents C1-6alkyl, optionally substituted by one or more a, C3-7cycloalkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D, or attached carbon atom of the 5-membered heteroaryl ring containing 1-3 heteroatoms, selected independently from O, N and S, optionally substituted at the carbon atom of the ring by one or more D, and where, if said 5-membered heteroaryl ring contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

And selected from hydroxy, amino, halogen, carboxy, N-(C1-4alkyl)amino, N,N-di(C1-4alkyl)amino, and C1-6alkoxy;

D is chosen from:

i) -Xa-Rcwhere Xarepresents a direct link, -O-, -S-, -SO-, -SO2-, -CO-, -NRdSO2-, -NRdCO-, -NRdCONRe-, -NRd- or-CONRd-; where Rdand Reindependently represent hydrogen or C1-4alkyl, optionally substituted by one or more hydroxy or1-4alkoxy; and Rcselected from hydrogen or C1-6the alkyl, optionally substituted by one or more hydroxy or1-4alkoxy;

ii) 4-8-membered Het group which is optionally substituted at a carbon atom of the ring by one or more groups selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if the specified 4-8-membered Het group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G;

iii) -Xa-C1-6alkyl-Xb-Rcwhere Xaand Rchave the meanings defined above, and X12is-S-, -SO - or-SO2-;

iv) cyano, or halogen; and

v) -Xc-Rfwhere Xcrepresents-C(O)- or-SO2-, and Rfis attached by the nitrogen atom 4-8-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more groups selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if said heterocyclic group contains an-NH - fragment, this nitrogen may be optionally substituted by a group selected from G;

G is selected from C1- the alkyl, optionally substituted by one or more A, C1-6alkanoyl, optionally substituted by one or more A, C1-6alkylsulfonyl, optionally substituted by one or more A, C1-6alkoxycarbonyl, optionally substituted by one or more a, carbamoyl, N-(C1-6alkyl)carbamoyl, optionally substituted by one or more A, N-(C1-6alkyl)2carbamoyl, optionally substituted by one or more A, and benzoyl, optionally substituted by one or more A; and

R4represents hydrogen or fluorine;

or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

The preferred values of R1, R2, R3and R4are the following. Such values can be used when it meets any of the definitions, claims or performing above or below.

In one aspect of the invention preferably n is 1.

In another aspect of the invention preferably n is 2.

R1preferably represents chlorine, fluorine or bromine.

More preferably R1represents chlorine or fluorine.

In particular, R1is chlorine.

In another aspect of the invention R1preferably represents methyl, chlorine, fluorine or bromine.

In another aspect of the invention more preferably R1represents methyl, chlorine or fluorine.

In another aspect of the invention R1in particular represents methyl or chlorine.

When R2selected from the group (i):

Preferably group i) is halogen or hydroxy. More preferably group i) represents a halogen. In particular, group i) represents chlorine or fluorine. More specifically, group i) is chlorine.

In another aspect of the invention, when R2selected from the group (i):

Preferably group i) represents nitro, halogen, amino or hydroxy. More preferably group i) represents nitro, amino or halogen. In particular, group i) represents nitro, bromine, iodine, amino, chlorine or fluorine.

When R2selected from the group (ii):

Preferably, group ii) X1is-S-, -SO-, -SO2-, -NR6- or-NR6CO-; preferably R6is hydrogen; and preferably R5selected from C1-6the alkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D.

More preferably, group ii) X1is-S-, -O-, -SO2- or-NR6CO-; more preferably R6is hydrogen; and more preferably R5selected from C1-4the alkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom of pyridyl, optionally substituted at the carbon atom of the ring by one or more D.

In particular, in group ii) X1is-S - or-NR6CO-; R6is hydrogen; and R5selected from methyl, optionally substituted by one or more And ethyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom of pyridyl, optionally substituted at the carbon atom of the ring by one or more D.

In another aspect of the invention, when R2selected from the group (ii):

Preferably, group ii) X1is-S-, -SO-, -SO2-, -NR6- or-NR6CO-; preferably R6is hydrogen; and preferably R5selected from C1-6the alkyl, optionally substituted by one or more A, or phenyl, optionally substituted by one or more D.

More preferably, group ii) X1is-S-, -SO-, -SO2- or-NR6CO-; more preferably R6to depict the defaults hydrogen; and more preferably R5selected from C1-4the alkyl, optionally substituted by one or more A, or phenyl, optionally substituted by one or more D.

In particular, in group ii) X1is-S-or-NR6CO-; R6is hydrogen; and R5selected from methyl, optionally substituted by one or more And ethyl, optionally substituted by one or more A, or phenyl, optionally substituted by one or more D.

In another aspect of the invention, when R2selected from the group (ii):

Preferably, group ii) X1represents-O-, -S-, -SO-, -SO2-, -NR6- or-NR6CO-; preferably R6is hydrogen; and preferably R5selected from C1-6the alkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or panels1-6the alkyl, optionally substituted by one or more D.

More preferably, group ii) X1represents-O-, -S-, -SO-, -SO2- or-NR6CO-; more preferably R6is hydrogen; and more preferably R5selected from C1-4the alkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or panels1-4the alkyl, optionally substituted by the one or more CSOs D.

When R2selected from group (iii):

Preferably group iii) is attached nitrogen atom a 5 - or 6-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more D, and where, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G.

More preferably group iii) is attached nitrogen atom to 6-membered heterocyclic group, optionally substituted at the carbon atom of the ring by one or more D, and where, if said heterocyclic group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G.

In particular, group iii) represents morpholino, optionally substituted at the carbon atom of the ring by one or more D, piperidine-1-yl, optionally substituted at the carbon atom of the ring by one or more D, or piperazine-1-yl, optionally substituted at the carbon atom of the ring by one or more D, and optionally substituted at a fragment of the-NH-group, selected from G.

In another aspect of the invention, when R2selected from group (iii):

In particular, group iii) represents morpholino, optionally substituted at the carbon atom of the ring by one or more D, thiomorpholine, optionally substituted at the atom from which laroda ring by one or more D, piperidine-1-yl, optionally substituted at the carbon atom of the ring by one or more D, or piperazine-1-yl, optionally substituted at the carbon atom of the ring by one or more D, and optionally substituted at a fragment of the-NH-group, selected from G.

More specifically, group iii) represents thiomorpholine.

In another aspect of the invention, when R2selected from group (iii):

In particular, group iii) represents morpholino, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine or piperazine-1-yl, optionally substituted from fragment-NH-group, selected from G.

Preferably a represents a hydroxy, amino, halogen, carboxy and methoxy.

More preferably a is hydroxy.

In another aspect of the invention is preferably a represents a hydroxy, amino, dimethylamino, halogen, carboxy and methoxy.

In another aspect of the invention is more preferably a represents a hydroxy, methoxy and dimethylamino.

In another aspect of the invention is preferably a represents a hydroxy, amino, dimethylamino, halogen, carboxy, methoxy and carbarnoyl.

When D is selected from group (i):

Preferably Xain group i) represents-S-, -SO-, -SO2-, -NRd-, -NRdCONRe- or-CONRd-; preferably Rdrepresents hydrogen or C1-4alkyl, optionally substituted on the him or more hydroxy; and preferably Rcselected from hydrogen or C1-6the alkyl, optionally substituted by one or more hydroxy.

More preferably Xain group i) represents-S-, -SO-, -SO2-, -NRd- or-CONRd-; more preferably Rdrepresents hydrogen, methyl or ethyl, optionally substituted by hydroxy; more preferably Rcselected from hydrogen or C1-4the alkyl, optionally substituted by one or more hydroxy.

More preferably Xain group i) represents-SO-, -SO2-, -NRd- or-CONRd-; more preferably R6represents hydrogen, methyl or ethyl, optionally substituted by hydroxy; more preferably Rcselected from hydrogen, methyl or ethyl, optionally substituted by hydroxy.

In another aspect of the invention, when D is selected from group (i):

Preferably Xain group i) represents-SO-, -SO2-, -NRd- or-CONRd-; more preferably Rdrepresents hydrogen, methyl or ethyl, optionally substituted by hydroxy; more preferably Rcselected from hydrogen, methyl, ethyl or butyl, optionally substituted by hydroxy.

When D is selected from group (ii):

Preferably group ii) is 5 - or 6-membered Het group which is optionally substituted at a carbon atom is oliza one or more groups, selected from hydroxy, halogen, C1-4alkoxy, C1-4the alkyl or cyano, and where, if said 5 - or 6-membered Het group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G.

More preferably, the group (ii) is 5-or 6-membered Het group which is optionally substituted at a carbon atom of the ring by one or more groups selected from hydroxy, halogen, methyl, ethyl, methoxy, ethoxy or cyano, and where, if said 5 - or 6-membered Het group contains an-NH-fragment, this nitrogen may be optionally substituted by a group selected from G.

In particular, the group (ii) is morpholino, morpholinyl, piperidinyl or piperazinil, optionally substituted at the fragment-NH-group, selected from G.

When D is selected from group (iii):

Preferably group iii) is-Xa-C2-4alkyl-Xb-Rcwhere Xaand Rchave the meanings defined above, and Xbpreferably represents-SO-or-SO2-.

When D is selected from group (iv):

Preferably, the group iv) represents cyano, fluorine or chlorine.

More preferably, the group iv) represents fluorine or chlorine.

In another aspect of the invention, when D is selected from group (iv):

preferably, the group iv) represents fluorine.

When D is selected from group v):

Preferably Xc/sup> represents-C(O)-, and Rfis attached by the nitrogen atom 4-6-membered heterocyclic group, optionally substituted hydroxy.

More preferably Xcrepresents-C(O)-, and Rfis azetidine, morpholine or pyrrolidinyl (optionally substituted by hydroxy).

In particular, Xcrepresents-C(O)-, and Rfis azetidine, morpholine or 3-hydroxypyrrolidine.

Preferably, G represents C1-6alkanoyl, optionally substituted by one or more A, or C1-6alkyl, optionally substituted by one or more A.

More preferably, G represents C1-4alkanoyl, optionally substituted by one or more. A, or C1-4alkyl, optionally substituted by one or more A.

Preferably, G represents acetyl or2-4alkyl, substituted by one or more A.

More specifically, G is acetyl.

Preferably R2represents chlorine, fluorine, methylthio, acetylamino, hydroxy, C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), phenylsulfonyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (long what) substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), N-(C1-4alkyl)2amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], pyridylsulfonyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2amino (optionally substituted by hydroxy), N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl) carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl) piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], N-(C1-4alkyl) amino (optionally substituted by hydroxy), morpholino, 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)-piperazine-1-yl.

More preferably R2represents chlorine, ft is R, methylthio, acetylamino, hydroxy, methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesyl, ethylsulfonyl (optionally substituted by hydroxy), phenylsulfonyl [optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy)N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], pyridylsulfonyl [optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted guide is hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl) piperazine-1-Il], methylamino, ethylamino (optionally substituted by hydroxy), morpholino, 4-acetylpiperidine-1-Il, 4 methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxyethyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-yl.

In particular, R2represents chlorine, fluorine, methylthio, acetylamino or hydroxy.

According to another aspect of the invention preferably R2represents chlorine, fluorine, bromine, iodine, nitro, amino, methylthio, acetylamino, hydroxy, C1-4alkylsulfanyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy, methoxy or dimethylamino), phenylsulfonyl (optionally substituted with halogen, amino, N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optional what about substituted by hydroxy), N-(C1-4alkyl)2amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], pyridylsulfonyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2amino (optionally substituted by hydroxy), N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetyl-piperazine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl) piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl) piperazine-1-Il], N-(C1-4alkyl)amino (optionally substituted by hydroxy), morpholino, 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-yl, thiomorpholine, phenylsulfanyl (optionally substituted N-(C1-4alkyl)2carbamoyl) or phenylsulfinyl (optional) - Rev. tion of substituted N-(C 1-4alkyl)2carbamoyl).

The following aspect of the invention R2preferably represents chlorine, fluorine, bromine, iodine, nitro, hydroxy, amino, methylthio, acetylamino,1-4alkylsulfanyl (optionally substituted by hydroxy), C1-4alkylsulfonyl,1-4alkylsulfonyl, N-(C1-4alkyl)amino (optionally substituted by hydroxy, methoxy or dimethylamino), thiomorpholine, phenylsulfanyl (optionally substituted N-(C1-4alkyl)2carbamoyl) or phenylsulfinyl (optionally substituted N-(C1-4alkyl)2carbamoyl).

In another aspect of the invention more preferably R2represents chlorine, fluorine, bromine, iodine, nitro, amino, methylthio, acetylamino, hydroxy, methylsulphonyl, ethylsulfanyl (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesyl, ethylsulfonyl (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy, methoxy or dimethylamino), phenylsulfonyl (optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optional someseni is hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetyl-piperazine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl) piperazine-1-Il,. 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], pyridylsulfonyl [optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl) piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il], methylamino, ethylamino (optionally substituted by hydroxy), morpholino, 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)Piper is Jn-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-yl, thiomorpholine or phenylsulfanyl [optionally substituted N,N-dimethyl-carbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy)].

In another aspect of the invention preferably R2represents fluorine, chlorine, bromine, iodine, nitro, amino, hydroxy, methylthio, ethylsulfinyl, mesyl, 2-hydroxyethylamino, 2-methoxyethylamine, 2-diethylaminoethylamine, 2, 3-dihydroxy-propylamino,-2-hydroxyarylalkyl, acetylamino, 4-N,N-dimethylcarbamoyl, 4-N,N-dimethylcarbamoyl or thiomorpholine.

In another aspect of the invention preferably R2represents chlorine, fluorine, bromine, iodine, nitro, amino, methoxy, acetylamino, hydroxy, C1-4alkylsulfanyl (optionally substituted by hydroxy), C1-4alkylsulfonyl,1-4alkylsulfonyl, N-(C1-4alkyl)amino (optionally substituted by hydroxy, methoxy, dimethylamino or carbamoyl), morpholino, 4-acetylpiperidine-1-yl, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, benzylamino, phenoxy, phenylsulfonyl (optionally substituted N-(C1-4alkyl)2carbamoyl) or phenyl sulfinil (optionally substituted N-(C1-4-alkyl)2carbamoyl).

In another aspect of izobreteny the R 2preferably represents chlorine, fluorine, bromine, iodine, nitro, amino, methoxy, acetylamino, hydroxy, methylthio, 2-hydroxyethylthio, methylsulfinyl, mesyl, 2-hydroxyethylamino, 2-methoxyethyl-amino, carbamoylmethyl, 2-diethylaminoethylamine, 2,3-dihydroxypropyl, morpholino, 4-acetylpiperidine-1-yl, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, benzylamino, phenoxy, 4-(N,N-dimethylcarbamoyl)phenylsulfonyl or 4-(N,N-dimethylcarbamoyl)phenylsulfonyl.

In another aspect of the invention R2preferably represents methylthio, morpholino, 4-acetylpiperidine-1-yl, 1-oxathiolane or 1,1-dioxothiazolidine.

The following aspect of the invention R2more preferably represents amino, 2-hydroxyethylamino or 2-methoxy-ethylamino.

In an additional aspect of the invention R2more preferably represents fluorine or chlorine.

Preferably R3represents C1-6alkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D.

More preferably R3is1-4alkyl, optionally substituted by one or more e, f the Nile, optionally substituted by one or more D, or attached carbon atom of the pyridyl, optionally substituted at the carbon atom of the ring by one or more D.

In particular, R3is methyl, optionally substituted by one or more And ethyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom of the pyridyl, optionally substituted at the carbon atom of the ring by one or more D.

In particular, R3represents methyl, ethyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, or attached carbon atom of the pyridyl, optionally substituted at the carbon atom of the ring by one or more D.

Therefore, in another aspect of the invention preferably R3is1-4alkyl, optionally substituted by one or more hydroxy, phenyl (optionally substituted with halogen, amino, N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), N-(C1-4alkyl)2amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optional someseni is hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-yl], or attached carbon atom of the pyridyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2amino (optionally substituted by hydroxy), N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl) piperazine-1-Il].

In particular, R3represents methyl, ethyl (optionally substituted by hydroxy), phenyl [optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylam is but (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-yl], or attached carbon atom of the pyridyl [optionally substituted with halogen, amino, N N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methyl sulfinil, ethylsulfinyl (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il].

More specifically, R3represents methyl, ethyl, optionally substituted by hydroxy, or phenyl (optionally substituted with halogen).

Particularly preferred R3p is ecstasy ethyl or 4-forfinal.

Therefore, in another aspect of the invention R3preferably represents C1-4alkyl (optionally substituted by one or more hydroxy), phenyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)amino (optionally substituted by hydroxy), N-(C1-4alkyl)2amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl, 4-(2-hydroxypropyl)piperazine-1-yl, azetidinone, morpholinoethyl or pyrrolidinylcarbonyl (optionally substituted by hydroxy)], or attached carbon atom of the pyridyl [optionally substituted with halogen, amino, N-(C1-4alkyl)2amino (optionally substituted by hydroxy), N-(C1-4alkyl)2carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl)carbamoyl (optionally substituted by hydroxy), N-(C1-4alkyl) amino (optionally substituted by hydroxy), C1-4alkylsulfonyl (optionally substituted by hydroxy), C1-4Alki what sulfonium (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)piperazine-1-Il].

The following aspect of the invention R3preferably represents C1-4alkyl (optionally substituted by one or more hydroxy), phenyl [optionally substituted with halogen, N-(C1-4alkyl)2carbamoyl, N-(C1-4alkyl) carbamoyl, N-(C1-4alkyl)amino (optionally substituted by hydroxy), C1-4alkylsulfonyl, azetidinone, morpholinoethyl or pyrrolidinecarbonyl (optionally substituted by hydroxy)], or attached carbon atom of the pyridyl [optionally substituted by amino].

In particular, R3represents methyl, ethyl (optionally substituted by hydroxy), butyl (optionally substituted by hydroxy), phenyl [optionally substituted with halogen, amino, N,N-dimethyl-carbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl the scrap (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl) piperazine-1-yl, 4-(2-hydroxypropyl)piperazine-1-yl, azetidinone, morpholinoethyl or pyrrolidinylcarbonyl (optionally substituted by hydroxy)], or attached carbon atom of the pyridyl [optionally substituted with halogen, amino, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl (optionally substituted by hydroxy), N-methyl-N-ethylcarbazole (optionally substituted by hydroxy), N-methylcarbamoyl, N-ethylcarbazole (optionally substituted by hydroxy), methylamino, ethylamino (optionally substituted by hydroxy), N,N-dimethylamino, N,N-diethylamino (optionally substituted by hydroxy), N-methyl-N-ethylamine (optionally substituted by hydroxy), methylsulfinyl, ethylsulfinyl (optionally substituted by hydroxy), mesilim, ethylsulfonyl (optionally substituted by hydroxy), 4-acetylpiperidine-1-yl, 4-methylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazine-1-yl, 4-(3-hydroxypropyl)piperazine-1-yl or 4-(2-hydroxypropyl)-piperazine-1-Il].

More specifically, R3represents methyl, ethyl, 2-hydroxyethyl, 2-hydroxybutyl, 4-forfinal, 4-methylphenyl, 4-(2-hydroxyethylamino)phenyl, 4-(N-methylcarbamoyl)phenyl, 4-(N-ethylcarbazole)phenyl, 4-(N,N-dimethyl who carbamoyl)phenyl, 4-(N-methyl-N-ethylcarbamate)phenyl, 4-(azetidinone)phenyl, 4-(morpholinomethyl)phenyl, 4-(3-hydroxypyrrolidine) phenyl or 6-aminopurin-2-yl.

In another aspect of the invention R3in particular represents methyl, ethyl (optionally substituted by hydroxy), isopropyl, butyl (optionally substituted by hydroxy), phenyl [optionally substituted with halogen, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbazole, N-methylcarbamoyl, N-ethylcarbazole, acylamino (optionally substituted by hydroxy), mesilim, azetidinone, morpholinoethyl or pyrrolidinylcarbonyl (optionally substituted by hydroxy)], or attached carbon atom of the pyridyl [optionally substituted by amino].

In another aspect of the invention R3more specifically represents methyl, ethyl, 2-hydroxyethyl, isopropyl, 2-hydroxybutyl, 4-forfinal, 4-(2-hydroxyethylamino)phenyl, 4-methylphenyl, 4-(N,N-dimethylcarbamoyl)phenyl, 4-(N-ethylcarbazole)phenyl, 4-(N-methyl-N-ethylcarbamate)phenyl, 4-(N-methylcarbamoyl)phenyl, 4-(azetidinone)phenyl, 4-(morpholinomethyl)phenyl, 4-(3-hydroxypyrrolidine)phenyl or 2-aminopurin-6-yl.

In another aspect of the invention is more specifically preferred R3represents methyl, ethyl or isopropyl.

The following aspect of the invention R3more preferably represents 4-(N-metelka bemail)phenyl or 4-(N,N-dimethylcarbamoyl)phenyl.

The following aspect of the invention R3especially preferably represents 4-(N,N-dimethylcarbamoyl)phenyl.

In one aspect of the invention R4preferably represents hydrogen.

In another aspect of the invention R4preferably represents fluorine.

When the chiral center is(HE)(Me)(CF3) preferred stereochemistry is usually the R-configuration.

Therefore, in another aspect, the invention provides compounds of formula (I)shown above in which:

n is 1 or 2;

R1represents methyl, chlorine or fluorine;

R2represents chlorine, fluorine, bromine, iodine, nitro, amino, methoxy, acetylamino, hydroxy, C1-4alkylsulfanyl (optionally substituted by hydroxy), C1-4alkylsulfonyl, C1-4alkylsulfonyl, N-(C1-4alkyl)amino (optionally substituted by hydroxy, methoxy, dimethylamino or carbamoyl), morpholino, 4-acetylpiperidine-1-yl, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, benzylamino, phenoxy, phenylsulfonyl (optionally substituted N-(C1-4alkyl)2carbamoyl) or phenyl sulfinil (optionally substituted N-(C1-4alkyl)2carbamoyl).

R3represents methyl, ethyl (optionally substituted by hydroxy), isopropyl, butyl (optionally substituted by hydroxy), phenyl [optionally substituted Gal the genome, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbazole, N-methylcarbamoyl, N-ethylcarbazole, acylamino (optionally substituted by hydroxy), mesilim, azetidinone, morpholinoethyl or pyrrolidinylcarbonyl (optionally substituted by hydroxy)], or attached carbon atom of the pyridyl [optionally substituted amino; and

R4represents hydrogen.

or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

Therefore, in another aspect, the invention provides compounds of formula (I)above in which:

n is 1 or 2;

R1is chlorine;

R2represents methylthio, morpholino, 4-acetylpiperidine-!-Il, 1 Osotimehin or 1,1-dioxothiazolidine;

R3represents methyl, ethyl or isopropyl;

R4represents hydrogen;

or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

The preferred compound of the invention is any connection examples, or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

More preferred compounds of the invention are compounds of examples 7, 8, 22, 23, 24, 28, 48, 64, 69, 70, 74, 75, or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

In another aspect of the invention more predpochtite lname compounds of the invention are compounds of examples 32, 35 and 61, or its pharmaceutically acceptable salt or hydrolyzable in vivo esters.

The following aspect of the invention preferred compounds of the invention are compounds of examples 17, 18 and 58, or their pharmaceutically acceptable salts or hydrolyzable in vivo esters.

Preferred aspects of the invention are aspects that relate to the compound and its pharmaceutically acceptable salts.

In the present invention should be understood that the compound of formula (I) or its salt can exhibit the phenomenon of tautomerism and that the formulas in this specification can represent only one of the possible tautomeric forms. It should be understood that the invention covers all tautomeric forms, which increase the PDG-activity, and is not limited to any one tautomeric form, used when displaying formulas. Image of the formulas in this specification can represent only one of the possible tautomeric forms, and it should be understood that the description covers all possible tautomeric form of the depicted compounds, not only the forms that are shown here graphically.

Specialists evidently clear that some of the compounds of formula (I) contain one or more assymetrically substituted carbon atoms and/or sulfur, and accordingly may exist and be selected is in the form of enantiomerically pure, or in the form of a mixture of diastereoisomers, or in the form of racemates. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, enantiomerically pure forms, mixtures of diastereoisomers, polymorphic or stereoisomeric form, or mixtures thereof, which possess properties that are useful for improving PDG activity, and is well known in the art how to obtain optically active forms (for example, separation of the racemic form by the methods of recrystallization, by synthesis from optically active starting materials, by chiral synthesis, enzymatic separation (e.g., WO 9738124), biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine the effectiveness of increasing PDG-activity standard tests described hereafter.

It should also be understood that certain compounds of formula (I) and their salts may exist in solvated, and resolutiony forms, such as, for example, hydrated forms. It should be understood that the invention encompasses all such solvated forms that increase PDG activity.

The compound of formula (I) or its salt and other compounds of the invention (defined herein below) may be obtained by any method, which is first known for producing chemically related compounds. Such methods include, for example, the methods illustrated in the publication of European patent applications 0524781, 0617010, 0625516 and GB 2278054, WO 9323358 and WO 9738124,

Another aspect of the present invention provides a method for obtaining compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo of ester, which (in this way variable groups have the meanings defined for formula (I), unless otherwise noted) include:

(a) unprotect a protected compound of formula (II):

in which Rd represents a protective group of the alcohol;

(b) oxidation of compounds of formula (III):

(C) a combination of compounds of the formula (IV):

with the acid of formula (V):

in which X represents IT;

(d) a combination of aniline of formula (IV) with an activated derivative of the acid of formula (V);

and then, if necessary:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removing any protective groups; or

iii) formation of pharmaceutically acceptable salts or hydrolyzable in vivo complex ether.

Suitable values for Rd are benzyl group, a silyl group (for example, trialkylsilyl group or alkyldiphenylamine groups who) or the protective acetyl group.

If the formula (V) is activated derivative of the acid, suitable values for X include halogen (e.g. chlorine or bromine), anhydrides, aryloxy (for example, 4-nitrophenoxy or Pantothenate) or imidazol-1-yl.

Specific conditions for the above reactions are as follows:

Process (a)

Examples of suitable reagents for Unprotecting the alcohol of formula (II) are:

1) when Rd is benzyl:

(i) hydrogen in the presence of a catalyst of palladium/charcoal, i.e. hydrogenolysis; or

(ii) hydrogen bromide or hydrogen iodide;

2) where Rd represents a silyl protective group:

(i) fluoride or tetrabutylammonium

(ii) aqueous hydrofluoric acid;

3) when Rd is acetyl:

(i) mild aqueous base, such as lithium hydroxide; or

(ii) ammonia or amine, such as dimethylamine.

The reaction can be carried out in a suitable solvent, such as EtOH, MeOH, acetonitrile or DMSO, and conveniently can be carried out at a temperature in the range from -40 to 100°C.

The compounds of formula (II) can be obtained according to the following scheme:

E represents a protective group carboxypropyl. Appropriate values for E include C1-6alkyl, such as methyl and ethyl.

The compounds of formula (IIA) are industrially available, or they are known which are from the literature, or get them by standard means known in the art. The synthesis of compounds of formula (IV) described below.

Process (b)

Suitable oxidizing agents include potassium permanganate, OXONE, periodate potassium, Gidropress tert-butyl (in the form of a solution in toluene), percolate (such as, for example, 3-chloroperoxybenzoic acid), hydrogen peroxide, TRAR (perruthenate of tetrapropylammonium) or oxygen. The reaction can be carried out in a suitable solvent, such as diethyl ether, DCM (DHM), Meon, EtOH, water, acetic acid or a mixture of two or more of these solvents. The reaction can be conveniently carried out at a temperature in the range from -40 to 100°C.

The compounds of formula (III) can be obtained in accordance with the following schema:

Specialist evidently clear that the order of stages 1 and 2 in scheme 2 may be reversed.

where M is alkali metal. The appropriate values for M include lithium, sodium or potassium.

X represents a leaving group, suitable values for X include halogen, mesyl and tosyl.

X represents a leaving group, suitable values for X include halogen, mesyl and tosyl.

The compounds of formula (IIIa) and (IIId) are industrially available or known the s from the literature, or can be obtained by standard methods known in the art.

Process (C)

The reaction can be carried out in the presence of a suitable agent combinations. Suitable agents of the combination can be used are known in the art standard peptide agents of the combination, for example, such as described above for combination (IId) and (IV), or, for example, dicyclohexylcarbodiimide, optionally in the presence of a catalyst, such as dimethylaminopyridine or 4-pyrrolidinedione, optionally in the presence of a base, such as triethylamine, pyridine or 1, 6-dialkylamino (such as 2,6-lutidine or 2,6-di-tert-butylpyridinium) or 2,6-diphenylpyridine. Suitable solvents include DMA, DHM, benzene, THF and DMF. The reaction mix can be conveniently carried out at a temperature in the range from -40 to 40°C.

The compounds of formula (IV) are industrially available or known from the literature or receive them by standard means known in the art, for example, they can be obtained by oxidation of compounds of formula (IIIf) with aniline, protected with suitable protecting group under standard conditions of oxidation, for example, hydrogen peroxide or meta-chloroperoxybenzoic acid (with subsequent removal of the protection), or they can be obtained according to the following scheme:

Compounds of the formulas (IVa) and (V) are industrially available or known from the literature or receive them by standard means known in the art.

If you want to split the acid of formula (V), it can be obtained by any of the known methods for obtaining optically active forms (for example, by recrystallization, chiral salt (for example, WO 9738124), enzymatic separation or chromatographic separation using a chiral stationary phase). If, for example, require a dedicated (R)-(+) acid, it can be obtained by the method of scheme 2 of international publication of patent application WO 9738124 to obtain (S)-(-) acid, i.e. using the classical method of separation described in EP publication 0524781 to obtain (S)-(-) acid, except that instead of (S)-(-)-1-phenethylamine can be used (1S,2R)-norephedrine. Chiral acid can also be obtained using the enzymatic method of separation described in Tetrahedron Assymetry, 1999, 10, 679.

Process (d)

This combination can be carried out optionally in the presence of a base, such as triethylamine, pyridine or 2,6-dialkylphenol (such as 2,6-lutidine or 2,6-di-tert-butyltin) or 2,6-diphenylpyridine. Suitable solvents include DMA, DHM, benzene, THF and DMF. The reaction mix mo is but conveniently carried out at a temperature in the range from -40 to 40° C.

The necessary starting materials for such procedures, as described above, if they are not available industrial, can be obtained using a procedure selected from standard techniques of organic chemistry, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above procedure, or procedures described in the examples.

For example, it is obvious clear that some of the optional aromatic substituents in the compounds of the present invention can be introduced by standard reactions of aromatic substitution or obtained from a conventional modification of functional groups or internal conversion, or before, or directly after the above procedures, and as such is included in the aspect of the method of the invention. Such reactions and modifications include, for example, introduction of a substituent by reaction of aromatic substitution, restoration of substituents, alkylation of substituents and oxidation of substituents. Reagents and reaction conditions for such procedures well known in the field of chemistry. Specific examples of reactions of aromatic substitution include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, allhelgona and Lewis acid (such as dichlorid aluminum) under the reaction conditions of Friedel -, and the introduction of halogenlampe. Specific examples of reactions modifications include the restoration of the nitro group to the amino group, for example, catalytic hydrogenation with a Nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio in alkylsulfonyl or alkylsulfonyl using, for example, hydrogen peroxide in acetic acid when heated or 3-chloroperbenzoic acid. Specific examples of internal transformations of functional groups are, for example, the conversion of aniline in halogenfree, for example, by diazotization in the presence of halides of copper.

It is noted that many of the source materials for the above-described synthetic methods are industrially available and/or widely known from the literature or can be prepared from commercial available compounds using adaptation methods known from the literature.

Obviously, it is also clear that in some of these reactions may be necessary/desirable to protect any sensitive groups in the connection. Examples of when protection is necessary or desirable, and appropriate ways of protection of well-known experts in this field. So, if the reagents include groups such as amino, carboxy or hydroxy, it may be desirable to protect the Rupp in some of these reactions.

A suitable protecting group for amino or alkylamino group is, for example, acyl group, for example, alcoolica group, such as acetyl, alkoxycarbonyl group, for example, methoxycarbonyl, ethoxycarbonyl or tert-butylcellosolve group, armletaccessory group, such as benzyloxycarbonyl, or arolina group, for example benzoyl. Conditions unprotect for the above protective groups necessarily vary depending on the choice of protective groups. So, for example, acyl group, such as alkanoyl, or alkoxycarbonyl group, or arolina group may be removed, for example, by hydrolysis with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium hydroxide. Alternatively, the acyl group, such as tert-butylcellosolve group may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or TFOC and armletaccessory group, such as benzyloxycarbonyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-charcoal, or by treatment with a Lewis acid, for example, Tris(trifurcation)boron. A suitable alternative protecting group for a primary amino group is, for example, phthaloyl the group, which can be removed by treatment with alkylamines, for example, dimethylaminopropylamine or hydrazine.

A suitable protecting group for a hydroxy-group is, for example, acyl group, for example, alcoolica group, such as acetyl, arolina group, for example benzoyl, or arylmethylidene group, for example, benzyl. Conditions unprotect for the above protective groups will vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica or arolina group may be removed, for example, by hydrolysis with a suitable base, such as alkali metal hydroxide, e.g. lithium hydroxide or sodium hydroxide. Alternatively, allmerica group such as benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-charcoal grill.

A suitable protecting group for a carboxy group is, for example, tarifitsiruyutsya group, for example methyl or ethyl group, which may be removed, for example, by hydrolysis with base, such as sodium hydroxide, or, for example, tert-bucilina group that can be removed, for example, by treatment with an acid such as organic acid, such as TFUK, or, for example, benzyl group, which may be removed, for example, by hydrogenation catalyst, so the m as palladium-on-charcoal grill.

Protective groups can be removed at any convenient stage of the synthesis using conventional techniques well known in the field of chemistry.

In the cases where the compounds of formula (I) are sufficiently basic or acidic to formation of a stable acidic or basic salts, may be an appropriate introduction connection in the form of salts, and pharmaceutically acceptable salts can be obtained by conventional methods, such as described below. Examples of suitable pharmaceutically acceptable salts are salts of the accession of organic acids formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, α-Ketoglutarate and α-glycyrrhizinate. Can also be formed of suitable inorganic salts such as sulfate, nitrate and hydrochloride.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by the reaction of a sufficiently basic compound of formula I (or of ester) with a suitable acid, producing a physiologically acceptable anion. With most of the compounds of the invention are also possible formation of salts of the corresponding alkali metal (e.g. sodium, potassium or lithium) or deliciosum the high metal (for example, calcium) treatment of compounds of formula (I) (and in some cases its complex ester with one equivalent of hydroxide or alkoxide (e.g. methoxide or ethoxide) alkali metal or alkaline earth metal in the aquatic environment with subsequent conventional purification methods.

The compounds of formula (I) may be introduced in the form of a prodrug which is broken down in the human or animal, forming a compound of formula (I). Examples of prodrugs include hydrolyzable in vivo esters of compounds of formula (I).

Hydrolyzable in vivo complex ester compounds of formula (I)containing a carboxy or hydroxy group is, for example, pharmaceutically acceptable ester which is hydrolysed in the human or animal, giving the original acid or alcohol.

Suitable hydrolyzable in vivo esters for the compounds of formula (I)containing carboxypropyl include C1-6alkoxymethyl esters, for example, methoxymethyl; C1-6alkanoyloxy esters, for example, pivaloyloxymethyl; palidrome esters; C3-8cycloalkylcarbonyl1-6alkalemia esters, for example, 1-cyclohexyloxycarbonyloxy; 1,3-dioxolan-2-animecrave esters, for example 5-methyl-1,3-dioxolan-2-animationy; and (C1-6alkoxycarbonylmethyl esters, for example, 1-methoxycarbonylethyl the first, and they can be formed by any carboxylate compounds of the present invention.

Suitable hydrolyzable in vivo esters for the compounds of formula (I)containing a hydroxy-group includes inorganic esters such as phosphate esters, and α-aryloxyalkyl esters. Examples α-aryloxyalkyl esters include acetoxymethyl and 2,2-dimethylphenylacetate. Other groups forming hydrolyzable in vivo ester for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (forming alkalicarbonate esters), dialkylamino and N-(dialkylaminoalkyl)-N-allylcarbamate (forming carbamates), dialkylaminoalkyl and carboxyethyl. Examples of substituents for benzoyl include morpholine, piperazine derivatives, attached from the nitrogen atom of the ring via a methylene group in the 3-or 4-position sensornogo rings.

Degradable in vivo prodrugs of compounds of formula (I) also include hydrolyzable in vivo amides of compounds of formula (I)containing carboxypropyl, for example, N-C1-6alkyl-or N-di-C1-6alkylamide, such as N-methyl, N-ethyl-N-propyl-, N-dimethyl-, N-ethyl-N-methyl - or N-diethylamide.

Identification of compounds that increase PDG-activity, is the subject of the present invention. These properties may be assessed, for example, to use what Itanium one or more procedures, below.

(a) Increase PDG activity in vitro

This test determines the ability of the test compound to increase PDG activity. Coding PDG-kinase with DNA can be obtained from the polymerase chain reaction (PCR) and subsequent cloning. It can be expressed in a suitable system expresii with obtaining the polypeptide from the PDG-kinase activity. For example, it was found that Paginate rats (rPDHKII)obtained by expression of recombinant protein in Escherichia coli (E.coli), shows Parkinso activity.

If rPDHKII (Genbank accession No U10357) 1,3 TPN fragment encoding the protein, were isolated by PCR from cDNA of rat liver and cloned into a vector (for example, pQE32-Quiagen Ltd). The recombinant construct was transformed in E. coli (for example, M15pRep4 - Quiagen Ltd.). Recombinant clones were identified, were isolated plasmid DNA and perform the analysis of DNA sequences. For the expression of selected one clone, which had the expected sequence of nucleic acid. Details of the methods of recombinant DNA molecules and expression of recombinant proteins in a bacterial system can be found in the standard works, for example, in Sambrook et al., 1989, Molecular Cloning - A Laboratory Manual, 2ndEdition, Cold Spring Harbour Laboratory Press. Other known Paginate for use in the tests can be cloned and expressed and the illogical way.

For expression rPDHKII activity of cells of the strain E. coli M15pRep4 transformed vector pQE32 containing rPDHKII cDNA. This vector enters into the protein at its N-end label 6-His. E. coli were grown to an optical density of 0.6 (600 nm) and induced the expression of the protein by adding 10 μm isopropylthio-β-galactosidase. Cells were grown for 18 hours at 18°C and collected by centrifugation. The re-suspended cell paste was literally homogenization and insoluble material was removed by centrifugation at 24000×g for 1 hour. Labeled with 6-His protein was removed from the supernatant, using a matrix (Quiagen) chelated Nickel resin nitryltriacetic acid (Ni-NTA: Quiagen Ltd.), which were washed in 20 mm Tris(hydroxymethyl) aminoethanethiol, 20 mm imidazole, 0.5 M sodium chloride, pH 8.0, before elution of the bound protein using a buffer containing 20 mm Tris(hydroxymethyl) aminomethanesulfonic, 200 mm imidazole, 0.15 M sodium chloride, pH 8.0. Erwerbende fractions containing the 6-His protein were merged together and stored in aliquot at -80°With 10%glycerol.

Each new batch of the starting solution of the enzyme in the analysis was titrated to determine the concentration, giving about 90% inhibition of PDG in terms of experience. For a typical batch of the original enzyme solution was diluted to 7.5 mcg/ml

DL shall evaluate the activity of new compounds, compounds were diluted with 10% DMSO and 10 μl was transferred into individual wells of 96-well test plates. Control wells contained 20 μl of 10% DMSO instead of compound. 40 μl of buffer containing 50 mm potassium phosphate buffer, pH 7.0, 10 mm ethylene glycol-bis (β-aminoacylase ether)-N,N-tetraoxane acid (EGTA), 1 mm benzamidine, 1 mm phenylmethylsulfonyl (PMSF), 0,3 mm tosyl-L-disinheritance (TLCK), 2 mm dithiothreitol (DTT), recombinant rPDHKII and compounds were incubated in the presence Paginate at room temperature for 45 minutes. In order to determine the maximum reaction rate PDG, was included in the second series of control wells that contained instead of compound (10% DMSO without rPDHKII. Then initiated activity PDG-kinase by adding 5 μm ATP, 2 mm of magnesium chloride and 0.04 u/ml PDG (PDG pork hearts Sigma P7032) with a total volume of 50 μl and the plates were incubated at ambient temperature for a further 45 minutes. Then determined the residual activity PDG addition of substrate (2.5 mm coenzyme A, 2,5 mm tiaminpirofosfata (kokarboksilaza), 2.5 mm sodium pyruvate, 6 mm NAD with a total volume of 80 μl and the plates were incubated for 90 minutes at ambient temperature. Production recovered NAD (NADH) was determined by measuring optical density at 340 nm using a spectrophotometer reading from a tablet. The value of the ED50for the test compounds was determined in the usual way, using the results dla concentrations connection.

(b) Increase PDG activity in vitro in isolated primary cells

This test determines the ability of compounds to stimulate the oxidation of pyruvate in primary rat hepatocytes.

Hepatocytes were isolated using a two-stage procedure cleavage by collagenase described by Seglen (Methods Cel. Biol. (1976) 13, 29-33) and placed in 6-hole culture tablet (Falcon Primaria) no 600000 viable cells per well in a modified method of Dulbecco environment Needle (DMEM, Gibco BRL)containing 10% fetal bovine serum (FBS), 10% of a mixture of penicillin/streptomycin (Gibco BRL) and 10% nonessential amino acids (NEAA, Gibco BRL). After 4 hours incubation at 37°With 5% CO2the medium was replaced with minimal medium (MEM, Gibco BRL)containing, as the previous one, NEAA and penicillin/streptomycin in addition to the 10 nm dexamethasone and 10 nm insulin.

The next day cells were washed in phosphate-saline buffer (PBS) and replaced the medium with a solution of buffered Krebs HEPES (25 mm HEPES, 0.15 M sodium chloride, 25 mm sodium bicarbonate, 5 mm potassium chloride, 2 mm calcium chloride, 1 mm magnesium sulfate, 1 mm potassium dihydrophosphate)containing the test compound with the required concentration of 0.1% DMSO. Control wells contained only 0.1% DMSO, and the maximum response was determined by application of 10 µm known active compounds. After a period of preincubation in t is an increase of 40 minutes at 37° With 5% CO2cells within 12 minutes were exposed to sodium pyruvate to a final concentration of 0.5 mm (containing 1-14C sodium pyruvate (product of Amersham CFA85) 0,18Ci/mmol). Then the medium was removed and transferred into a test tube, which immediately hermetically closed tube containing suspended from the center well. Absorbent inside the center of the well fed 50% of the phenethylamine, and adding 0.2 µl of 60% (wt./about.) perchloro acid (PCA) of the environment allocated WITH2. Released14CO2captured by the absorbent was determined by the method of liquid scintillation counting. The value of the ED50for the test compounds was determined in the usual way using the results of 7 concentrations connection.

(C) Increase PDG activity in vivo

The ability of compounds to increase the activity of the PDG in the corresponding tissues of rats can be measured using the following test. Typically, the increase in the share of SOEs in its active nefosfaurilirovanna form can be found in muscle tissue, heart, liver and adipose tissue after a single administration of the active compounds. It can be expected that this leads to a reduction of glucose in the blood after repeated administration of the compound. For example, a single introduction of 150 mg/kg intraperitoneally DCA, compounds known as activating PDG by inhib the simulation PDG-kinase (Whitehouse, Cooper and Randle (1974) Biochem.J. 141, 761-774) increased the proportion of SOEs in its active form (Vary et al., (1988) Circ. Shock 24, 3-18) and after repeated administration resulted in a significant decrease of glucose in plasma (Evans and Stacpoole (1982) Biochem. Pharmacol. 31, 1295-1300).

A group of rats (weight interval 140-180 g) was treated with a single dose or multiple doses of the compounds of interest, feeding through the mouth in a suitable carrier. The control group of rats was treated with only the carrier. At a fixed time after the final introduction of the compounds of the animals were completely anestesiology, tissues were removed and frozen in liquid nitrogen. To determine PDG-activity samples of muscle tissue were digested in an atmosphere of liquid nitrogen before homogenization pulse in one-thirtieth of a second in the homogenizer transmitter station in 4 volumes of buffer containing 40 mm potassium phosphate, pH 7.0/0.5 mm EDTA, 2 mm DTT, 1% Triton X-100, 10 mm sodium pyruvate, 10 μm of phenylmethylsulfonyl (PMSF), and 2 μg/ml each of leupeptin, pepstatin and Aprotinin. The extracts were centrifuged before analysis. A portion of the extract was treated with PDG-phosphatase derived from porcine hearts by the method of Siess and Wieland (Eur.J.Biochem (1972) 26, 96): 20 μl of extract, 40 ál phosphatase (dilution 1:20) in a final volume of 125 μl containing 25 mm magnesium chloride, 1 mm calcium chloride. The activity of the untreated sample was compared with the activity of the thus prepared dephosphorylating extract. PDG-activity was determined by the method Stansbie et al. (Biochem.J. (1976) 154, 225). 50 μl of extract were incubated with 0.75 mm NAD, 0.2 mm COA, 1.5 mm of tiaminpirofosfata (RTR) and 1.5 mm sodium pyruvate in the presence of 20 μg/ml p-(p-aminophenylthio) benzosulfimide acid (AABS) and 50 IU/ml arylnitrenes (AAT) in buffer containing 100 mm Tris(hydroxymethyl)aminomethane, 0.5 mm EDTA, 50 mm sodium fluoride, 5 mm 2-mercaptoethanol and 1 mm of magnesium chloride, pH of 7.8. AAT was obtained from the liver of pigeons by the method of Tabor et al. (J.Biol. Chem. (1953) 204, 127). The rate of formation of acetylcoa was determined by the rate of decrease AABS, which was determined by the decrease in optical density at 460 nm.

The liver samples were prepared by almost the same method except that the sodium pyruvate was excluded from the extraction buffer and introduced by incubation with phosphatase to a final concentration of 5 mm.

Treatment of animals active connection led to increased activity PDG-complex in tissues. This is indicated by the increase in the number of active PDG (as determined by the activity of the raw extract in% of total PDG activity in the same extract after treatment with phosphatase).

According to further aspect of the invention features a pharmaceutical composition that includes a compound of formula (I)defined above, or its pharmaceutically acceptable salt, or it is gidrolizuemye in vivo ester in combination with a pharmaceutically acceptable excipient or the media.

The composition may be in a form suitable for oral administration, for example, in the form of a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example, in the form of a sterile solution, suspension or emulsion, for topical administration, for example, in the form of ointment or cream or for rectal administration, for example, in the form of suppository. In General, the above compositions can be prepared in the usual manner using conventional excipients.

Compositions of the present invention is preferably presented in the form of a unit dose. The connection is normally introduced warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body of the animal, i.e. approximately 0.1-100 mg/kg Provided a single dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg, and it is usually a therapeutically effective dose. The form of a unit dose, such as a tablet or capsule usually contains, for example, about 1-250 mg of the active ingredient.

According to further aspect of the present invention proposed a compound of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo ester, as defined above, for use in the method of treatment of the human or animal therapy.

B is lo be found, the compounds of the present invention increase PDG-activity and therefore are of interest due to their lower content of glucose in the blood action.

The next aspect of the present invention are the compounds of formula (I), or pharmaceutically acceptable salt or hydrolyzable in vivo esters for use as a medicine.

Mostly it is a compound of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo ester for use as a medication that causes the increase in PDG activity in warm-blooded animals such as man.

In particular, it is a compound of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo ester for use as medications for treating diabetes mellitus in a warm-blooded animal such as man.

In another aspect of the invention, in particular, is a compound of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo ester for use as drugs for the treatment of diabetes mellitus, peripheral vascular disease and ischemic myocardium in warm-blooded animals such as man.

According to further aspect of the invention features the use of the compounds of formula (I)or its pharmaceutically acceptable the salt, or hydrolyzable in vivo of ester in the manufacture of drugs used to enhance PDG activity in warm-blooded animals such as man.

According to further aspect of the invention features the use of the compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo of ester in the manufacture of medicaments for use in treating diabetes mellitus in a warm-blooded animal such as man.

According to further aspect of the invention features the use of the compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo of ester in the manufacture of medicaments for use in the treatment of diabetes mellitus, peripheral vascular disease and ischemic myocardium in warm-blooded animals such as man.

According to the following characteristic of the invention proposes a method of improving PDG activity in warm-blooded animals such as man, in need of such treatment, which includes the introduction of specified animal an effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo complex ester as defined above.

According to the following characteristic of the invention features a method of treating diabetes mellitus in a warm-blooded animal, such as man, those in need of such treatment, which includes the introduction of specified animal an effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo complex ester as defined above.

According to the following characteristic of the invention features a method of treating diabetes mellitus, peripheral vascular disease and ischemic myocardium in warm-blooded animals such as man, in need of such treatment, which includes the introduction of specified animal an effective amount of the compounds of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo complex ester as defined above.

As mentioned above, the size of the dose required for therapeutic or prophylactic treatment of a specific painful conditions, necessarily will vary depending on the patient, the route of administration and the severity of the disease under treatment. Preferably use the daily dose in the range of 1-50 mg/kg, However, the daily dose will vary depending on the patient, the specific route of administration and the severity of the disease. Accordingly, the optimal dosage can be determined by the attending physician of the patient.

This increase PDG activity can be used as the sole therapy and may involve, in addition to the subject matter of the present invention one or more other substances and/or treatments. Such joint treatment may be achieved by simultaneous, sequential or separate introduction of individual components of the treatment. For example, in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment:

i) insulin;

ii) agents that increase insulin secretion, intended to stimulate insulin secretion (e.g. glibenclamide, tolbutamide, other sulfonylureas);

iii) oral hypoglycemic agents such as Metformin, thiazolidinedione;

iv) agents designed to reduce the absorption of glucose from the intestine (for example acarbose);

v) agents designed to treat the complications of prolonged hyperglycemia;

vi) other agents used to treat dairy acidemia;

vii) inhibitors of fatty acid oxidation;

viii) agents lipid-lowering;

ix) agents used to treat coronary heart disease and peripheral vascular disease, such as aspirin, pentoxifylline, Cilostazol; and/or

x) thiamin.

As mentioned above, the compounds described in this invention are of interest because of their ability to increase the activity PDG. Such compounds of the invention, therefore, may be useful in the case of a number of illnesses, including diabetes, disease is the development of peripheral vessels (including alternating lameness), heart failure and certain cardiac myopathy, ischemic heart disease, ischemic brain disease and reverse perfusion, muscle weakness, hyperlipidemia, Alzheimer's disease and/or atherosclerosis. Alternatively, such compounds can be useful in a number of painful conditions, including peripheral vascular disease (including alternating lameness), heart failure, and some cardiac myopathy, ischemic heart disease, ischemic brain disease and reverse perfusion, muscle weakness, hyperlipidemia, Alzheimer's disease and/or atherosclerosis, in particular peripheral vascular disease and ischemic heart disease.

In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools for the development and standardisation of test systems in vitro and in vivo to assess the effectiveness of means of improving PDG activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

The invention is illustrated further by the following non-limiting examples in which, unless otherwise indicated:

(i) temperatures are given in degrees Celsius (°C); operations were carried out at room temperature, and the ambient temperature, i.e. at a temperature in the range 18-25°and in the atmosphere of inert gas, such as argon;

(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was performed, using a rotary evaporator, under reduced pressure (600-4000 PA; a 4.5-30 mmHg) with a bath temperature of up to 60°C;

(iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was performed on silicagel plates; if the reference to the column with silica Honey Bond Elut, this means a column containing 10 or 20, or 50 g of silicon dioxide with a particle size of 40 microns, and the silicon dioxide contained in a 60 ml disposable syringe and supported by a porous disc, produced Varian, Harbor City, California, USA, under the name "Honey Bond Elut SI"; "Honey Bond Elut" is a trademark; if you specify a Biotage cartridge, it means a cartridge containing silica KP-SIL™, 60A, particle size 32-63 μm, supplied by Biotage, a division of Dyax Corp., 1500 Avon Street Extended, Charlottesville, VA 22902, USA;

(iv) if the specified column Chem Elut, this means the extraction cartridge "Hydromatrix" for the water absorption of the material, i.e. a polypropylene tube containing a special grade of calcined in the melt of high purity inert hard-shelled land, pre-buffered to pH 4.5 or 9.0, including the filter material to separate the AZ, used according to the manufacturer's instructions, manufactured by Varian, Harbor City, California, USA, under the name "Extube, Chem Elut", "Extube" is a registered trademark of International Sorbent Technology Limited;

(v) if the specified column ISOLUTE, it means "ion exchange" extraction cartridge for absorption of either acidic or basic material, i.e. a polypropylene tube containing a special grade ion exchange sorbent of high purity with a pH~7, comprising a filter material for separation of phases used according to the manufacturer's instructions, manufactured by Varian, Harbor City, California, USA, under the name "Extube, Chem Elut, ISOLUTE"; "Extube" is a registered trademark of International Sorbent Technology Limited;

(vi) usually over the course of the reaction is monitored by TLC and reaction times are given for illustration only;

(vii) final products had satisfactory proton spectrum data of nuclear magnetic resonance (NMR) or mass spectrum;

(viii) the outputs are given for illustration only and are not necessarily what can be obtained with careful improve the way; if you wanted more material, obtaining repeated;

(ix) if the NMR data are given in the form of Delta values for major diagnostic protons in ppm (ppm) relative to tetramethylsilane (TMS) as internal standard, determined is at 300 MHz, using as solvent predeterminado dimethyl sulfoxide (DMSO-δ6), unless otherwise stated; other solvents (when they appear in the text) include deuterated chloroform - CDCl3; constants combinations (J) are given in Hz; Ah, when you specify a symbol, means an aromatic proton;

(x) chemical symbols have their usual meanings; used units and symbols of SI units;

(xi) reduced pressures are given as absolute pressures in Pascals (PA); increased pressure is provided in the form of excess pressures in bars;

(xii) the ratio of the solvents are given in volume: volume value (about./vol.);

(XII) mass spectra (MS) were removed at an energy of 70 electron e-In using chemical ionization (CI), using a probe direct exposure; if the indicated ionization was carried out by electron impact (EI), fast atom bombardment (FAB) or spray of electrons (ESP), given the values of m/z; they are usually only ions which indicate the source mass, and, if not stated otherwise, the given values of (M-N);

(xiv) Oxone is a trademark of E.I. du Pont de Nemours & Co., Inc. and refers to peroxymonosulfate potassium;

(xv) used the following abbreviations:

ether - diethyl ether;

DMF - N,N-dimethylformamide;

DMA N,N-dimethylacetamide;

TFUC - triperoxonane the acid;

NMP - N-methylpyrrolidine-2-he;

THEY are the raw materials;

DMSO - dimethyl sulfoxide;

EtOAc is ethyl acetate;

Meon - methanol;

EtOH - ethanol;

DHM (DCM) - dichloromethane; and

THF - tetrahydrofuran; and

(xvi) if at the beginning of the name indicates the stereochemistry of (R) or (S), if there is no further explanation, it should be understood that the specified stereochemistry refers to the center-NH-C(O)-S*(Me)(CF3)(HE), as shown in the formula (I).

Example 1

(R)-N-(2,3-Dichloro-4-ethylsulfinyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

Gidropress tert-butyl (2,4 ml of a 5.5 M solution in decane) was added to a solution of (R)-N-[2,3-dichloro-4-ethylsulfanyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method I) (0,23 g) and d-10-camphorsulfonic acid (0,018 g) in chloroform (10 ml) and the mixture was stirred for 18 hours. Volatiles were removed by evaporation and the residue was purified by chromatography on a column of silica gel Honey Bond Elut when elution with a mixture of 0-50% EtOAc/isohexane, getting mentioned in the title compound (0,22 g) as a white solid. NMR (Dl3+ 1 drop DMSO): 1,21 of 1.28 (m, 3H), 1,71 (s, 3H), 2.77-to 2,89 (m, 1H), 3.04 from-and 3.16 (m, 1H), 7,14 (s, 1H), 7,78 (d, 1H), 8,66 (d, 1H), 9,73 (s, 1H); m/z: 376.

Examples 2-8

Following the procedure of example 1 and using the appropriate initial matter, received the following connections:

1Product recip is n by adding DHM to the residue after evaporation with subsequent filtering.

2The product was a mixture of the two diastereoisomers, example 4 is less polar diastereoisomer.

3The residue was purified in a Biotage cartridge with 8 g of silica with elution 3% Meon/DHL.

4The residue was purified in a Biotage cartridge with 8 g of silica with elution with 10% MeOH/EtOAc.

Example 9

(R)-N-(2,3-Dichloro-4-ethylsulfonyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

Hydrogen peroxide (15 ml 30%solution in water) was added to a solution of (R)-N-[4-ethylsulfanyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method I) (1.88 g) in glacial acetic acid (26 ml) and the mixture was heated at 95°C for 1.5 hours and then cooled. Added EtOAc (200 ml) and the mixture was washed with saturated aqueous sodium bicarbonate solution (4×200 ml) and brine (250 ml), then dried. Volatiles were removed by evaporation and the residue was purified by chromatography with elution with a mixture of 0-50% EtOAc/isohexane, getting mentioned in the title compound (1,11 g) as a white solid. NMR: 1,1 (t, 3H), of 1.61 (s, 3H), 3,5 (square, 2H), 8,02 (d, 1H), 8,31 (d, 1H); m/z: 392.

Examples 10-26

Following the procedure of example 9 and using appropriate initial matter, received the following connections:

#x0200A; 1To the cooled reaction mixture was added water and the product was obtained by filtering.

Example 27

(R)-N-(2-Chloro-4-ethylsulfonyl-3-hydroxyphenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

Following the procedure of method I and using as starting material 2-chloro-4-ethylsulfonyl-3-hydroxyanisol (method 9)has been specified in the header of the communication (10% yield) as a solid. NMR: to 0.92 (t, 3H), 1,45 (s, 3H), of 3.25 (q, 2H), 7,55 (d, 1H), 7,79 (d, 1H), a 7.85 (d, 1H), 9,67 (s, 1H); m/z: 374.

Example 28

(R)-N-[2-Chloro-4-ethylsulfonyl-3-methylsulfinylphenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Meantioned sodium (0.16 g) was added with stirring to a solution of (R)-N-[2,3-dichloro-4-ethylsulfanyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (Example 9) (0,60 g) in anhydrous DMA. The reaction mixture was heated at the boil under reflux for 3 hours, then was added meantioned sodium (0.27 g) and heating continued for a further 18 hours. The reaction mixture was allowed to cool, added EtOAc (150 ml), the mixture was washed with brine (4×100 ml) and dried. Volatiles were removed by evaporation and the residue was purified on a column of silica gel Honey Bond Elut when elution with a mixture of 0-40% EtOAc/isohexane, getting mentioned in the title compound (0,114 g) in the form of a resin. NMR (Dl3): of 1.26 (t, 3H), of 1.78 (s, 3H), of 2.50 (s, 3H), of 3.64 (q, 2H), 3,75 (s, 1H), 8,13 (d, 1H), 8,67 (d, 1H), 9,44 (s, 1H); m/z:404.

Example 29

(R)-N-[3-Acetamido-2-chloro-4-[4-(2-hydroxyethylamino)phenyl-sulfonyl]phenyl-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[3-Acetamido-2-chloro-4-(4-perpenicular)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (683 mg) (Example 10), ethanolamine (177 mg, 2 EQ.) and acetonitrile (6 ml) were mixed and heated (85° (C) in argon atmosphere for 24 hours. The solvent was removed, the remaining resin was again dissolved in Meon (10 ml) and poured on deactivated silica (5 g). The mixture was concentrated, obtaining free flowing powder, which is carried in the upper part of the ISOLUTE column (50 g silica). Was carried out by the chromatography was carried out during the elution with a mixture of Meon/DHM, getting mentioned in the title compound (247 mg) as a brown solid. NMR (400 MHz): 1,59 (s, 3H), of 1.95 (s, 3H), is 3.08-3,19 (m, 2H), 3,53 (kV, 2H), 4,66-to 4.73 (t, 1H), 6,62 (d, 2H), to 6.67 (t, 1H), 7,0 (Sirs, 1H), 7,44 (d, 2H), of 8.06 (d, 1H), 8,29 (d, 1H), being 9.61 (Sirs, 1H), 9,82 (Sirs, 1H); m/z: 524 (M+N)+.

Example 30

(R)-N-[2-Chloro-3-(2-hydroxyethylamino)-4-(4-perpenicular)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Ethanolamine (47 mg, 2.5 EQ.) was added to a solution of (R)-N-(2-chloro-3-fluoro-4-[4-perpenicular]phenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 11) (135 mg) in NMP (1 ml), the mixture was stirred and heated (oil bath, 120° (C) in argon atmosphere for 24 hours. The reaction mixture is cooling and was distributed between saturated aqueous ammonium chloride (10 ml) and ether (3× 20 ml). The combined ether extracts were washed with water (50 ml), dried and concentrated, obtaining a resin. The residue was dissolved in Meon/DHM and poured on deactivated silica (1 g). Then the mixture was concentrated, obtaining free flowing powder, which was transferred in ISOLUTE column (10 g silica) and chromatographically, while elution with mixture of EtOAc/isohexane, getting mentioned in the title compound (50 mg) in the form of a resin. NMR: 1,65 (s, 3H), 3,2 (m, 2H), 3,42 (m, 2H), 4.92 in (t, 1H), 5,91 (t, 1H), 7,47 (t, 2H), 7,89 (d, 1H), of 7.96-8,08 (m, 3H), 9,85 (Sirs, 1H); m/z: 483.

Example 31

(R)-N-{2-Chloro-3-(2-hydroxyethylamino)-4-[4-(2-hydroxyethyl-amino)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

Specified in the title compound was also isolated from the mixture obtained in example 30, in the form of a yellow foam. NMR (400 MHz): 1,6 (c, 3H), 3,2 (m, 4H), 3,52 (m, 4H), 4,74 (t, 1H), 4.95 points (t, 1H), 5,98 (t, 1H), 6,69 (d, 2H), 6,76 (t, 1H), 7.62mm (d, 2H), 8.0 a (Sirs, 1H); m/z: 524.

Examples 32-39

Following the procedure of example 30 and using the appropriate starting materials, received the following connections:

Example 40

(R)-N-[2-Chloro-3-mesyl-4-(4-perpenicular)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

The reaction of (R)-N-(2-Chloro-3-fluoro-4-{4-perpenicular}phenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 11) (222 m is) mertiolate sodium (62 mg) in NMP (2 ml) was carried out at 120° C in argon atmosphere for 18 hours. The cooled reaction mixture was distributed between saturated aqueous ammonium chloride (20 ml) and ether (40 ml), the organic layer was separated, and the aqueous layer was extracted with additional ether (2×40 ml). The combined ether extracts were washed with water (30 ml), dried and concentrated, obtaining a yellow solid (242 mg), which was a mixture of three compounds. The solid was stirred and heated (100° (C) in glacial acetic acid (2 ml) and hydrogen peroxide (100 vol., of 0.42 ml) in an argon atmosphere for 80 minutes. The reaction mixture was distributed between water (20 ml) and EtOAc (50 ml). The organic layer was washed with water, dried and concentrated, obtaining a resin. The residue was dissolved in DHM and introduced into the cartridge Biotage (40 g silica)was suirable a mixture of 50% EtOAc/isohexane, getting mentioned in the title compound (42 mg) as a white solid. NMR (CDCl3+ 1 drop DMSO; 500 MHz): 1,63 (s, 3H), 3,37 (s, 3H), to 7.09 (t, 2H), 7,49 (s, 1H), 7,76 (m, 2H), to 8.45 (d, 1H), 8,89 (d, 1H), 10,1 (Sirs, 1H); m/z: 502.

Examples 41-42

Other compounds isolated from the above mixture, shown in the following table:

Example 43

(R)-N-[4-Ethylsulfonyl-3-methylsulfinyl-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R) -N-[4-ethylsulfonyl-3-methylsulfanyl the-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 28) (0,636 g) in DHM under stirring was added meta-chloroperoxybenzoic acid (0.17 g). After 1 hour at ambient temperature was added an additional portion of meta-chloroperoxybenzoic acid (0.14 g) and continued stirring at ambient temperature for 16 hours. Added more meta-chloroperoxybenzoic acid (0.08 g) and after 30 minutes the solution was added sodium bicarbonate (50 ml). The organic layer was separated, dried and the volatiles removed by evaporation. The residue was purified by chromatography on a column of Honey Bond Elut (20 g) with elution with a mixture of 10-80% EtOAc/isohexane, getting mentioned in the title compound (0.55 g) as a white foam. NMR: 1,19 (t, 3H), of 1.62 (s, 3H), 3,14 (s, 3H), 3,52-of 3.60 (m, 2H), 8,00 (d, 1H), 8,14 (Sirs, 1H), 8,45-8,49 (m, 1H), 10,11 (Sirs, 1H); m/z: 420.

Examples 44-47

Following the procedure of example 43 using the appropriate starting materials, received the following connections:

Example 48

(R)-N-(4-Mesyl-3-methylsulfanyl-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

Meantioned sodium (48 mg) was added to deoksigenirovanii solution of (R)-N-[4-mesyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (Example 14) (0.20 g) in anhydrous NMP (1 ml). The reaction mixture was heated to 120°C in an atmosphere of argon overnight. Added another meantioned sodium (50 mg) and heating was continued for 2 hours. The reaction mixture was allowed to cool to ambient temperature cf the water. Was added saturated ammonium chloride (50 ml) and the mixture was extracted with ether (4×50 ml). The ether extracts were combined, washed with brine (50 ml) and dried. Volatiles were removed by evaporation and the residue was purified by chromatography on a Biotage cartridge with 8 g of silica gel with elution with a mixture of 3:7 EtOAc/isohexane, getting mentioned in the title compound (0.14 g) as a white foam. NMR: of 1.62 (s, 3H), 2,47 (s, 3H), with 8.05 (d, 1H), at 8.36 (d, 1H); m/z: 390.

Example 49

(R)-N-[4-Ethylsulfinyl-3-methylsulfanyl-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Specified in the title compound was obtained from (R)-N-[4-ethylsulfinyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (Example 3) (0,223 g) by the procedure described in example 48, receiving specified in the title compound as a white solid (55%). NMR: 1,03-of 1.09 (m, 3H), of 1.61 (s, 3H), 2,41 (s, 3H), 2.71 to 2,82 (m, 1H), is 3.08-3,20 (m, 1H), 7,69 (d, 1H), of 7.96 (Sirs, 1H), 8,28-8,32 (m, 1H), 9,92 (Sirs, 1H); m/z: 388.

Example 50

(R)-N-{2-Chloro-3-(2-hydroxyethylthio)-4-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

To (R)-N-{2-chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl) phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 18) (600 mg) in the form of a solution in NMP (5 ml) was added 2-hydroxilation (0.1 ml) and sodium methoxide (0.65 g) and the reaction mixture was heated to 120°C overnight in an argon atmosphere. The solution RusBusinessNews brine and was extracted with ether (3× 30 ml). The ether extracts were combined and dried. Volatiles were removed by evaporation and the residue was purified by chromatography on a column of Honey Bond Elut (20 g silica gel) with elution by the mixture hexane/EtOAc, getting mentioned in the title compound as a white solid (60 mg, 12%). NMR: 1,60 (s, 3H), 2,60-to 2.65 (m, 2H), 2,85 (s, 3H), 2.95 and (s, 3H), of 3.10-3.20 (m, 2H), and 4.75 (DD, 1H), 7,60 (d, 2H), 7,95 (d, 2H), with 8.05 (s, 1H), 8,35 (d, 1H), 8,45 (d, 1H), 9,95 (s, 1H); m/z: 553.

Example 51

(R)-N-(4-Ethylsulfonyl-3-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl]-2-chlorophenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-N-[4-ethylsulfonyl-3-[4-carboxyphenyl-sulfanyl)-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 59) (0.64 g) in DHM and DMF (3 drops) was added with stirring oxalicacid (0.25 ml). The reaction mixture was allowed to mix at ambient temperature over night. Volatile substances are evaporated, the residue was re-dissolved in DHM (20 ml) was added dimethylamine (1 ml, 5.6 M solution in EtOH). The mixture was allowed to mix at room temperature over night. Was added Hcl (2 M, 50 ml), the organic phase was separated, dried and the volatiles removed by evaporation. The residue was purified by chromatography on a column of Honey Bond Elut (50 g silica) with elution with a mixture of 1-3% Meon/DHM, getting mentioned in the title compound as a brown foam (0,67 g). NMR (CDCl3): of 1.20 (t, 3H), of 1.64 (s,3H), 2,89 (s, 3H), 3,01 (s, 3H), 3,44-of 3.48 (q, 2H), lower than the 5.37 (s, 1H), 7,03 (d, 2H), 7,22 (d, 2H), 8,18 (d, 1H), 8,72 (d, 1H), of 9.56 (s, 1H); m/z: 537.

Examples 52-60

Following the procedure of example 51 and using the appropriate starting materials, received the following connections:

1The oil obtained after chromatography was dissolved in EtOA, washed with water, brine and dried. Volatiles were removed by evaporation and then the residue triturated with ether.

2The residue was chromatographically using a gradient solvent EtOAc/hexane.

Example 61

(R)-N-{2-Chloro-3-amino-4-[4-(N,N-dimethylcarbamoyl)phenyl]-sulfanilyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a suspension of (R)-N-{2-chloro-3-nitro-4-[4-(N,N-dimethylcarbamoyl)phenyl]sulfanilyl}-2-hydroxy-2-methyl-3,3,3-tri-forprepaid (example 63) (305 mg) in water (0.25 ml) and EtOH (1 ml) was added iron (324 mg) and conc. hydrochloric acid (1 drop). The mixture was stirred for 1.5 hours at 75°and gave it to cool down to ambient temperature. Was added a saturated Panso3(10 ml) and the solution was extracted with EtOAc (100 ml). The extracts were washed with brine (40 ml) and dried.

Volatiles were removed by evaporation. The reaction was not complete, so the suspension of the residue in water (0.25 in) and EtOH (1 ml) was added iron (324 mg) and conc. hydrochloric acid is (3 drops). The mixture was stirred for 3 hours at 75°C. After the mixture was allowed to cool to ambient temperature, was added saturated Panso3(10 ml) and the solution was extracted with EtOAc (100 ml). The extracts were washed with brine (40 ml) and dried. Volatiles were removed by evaporation, getting the foam. The foam was purified by chromatography on silica gel with elution 4% Meon in DHM, getting named the title compound as a foam (250 mg). NMR: 1,58 (s, 3H), of 2.81 (s, 3H), 2.95 and (s, 3H), of 6.31 (s, 2), 7,60 (m, 3H), 7,81 (d, 1H), of 7.96 (m, 3H), 9,73 (Sirs, 1H); m/z: 492.

Example 62

(R)-N-[4-{2-Aminopurin-6-ylsulphonyl}-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[4-{2-Nitrophenyl}-6-sulfonyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate method (71) (220 mg, 0.45 mmol) was stirred and heated at 75°C for 1 hour with iron powder (272 mg), EtOH (0.3 ml), water (0,11 ml) and 1 drop of conc. HCl. The reaction mixture was allowed to cool to room temperature and the mixture was podslushivaet a saturated solution of NaHCO3. Added EtOAc and the mixture was filtered through a layer of hard-shelled land and thoroughly washed with a mixture of EtOAc/water. The combined organic layers were washed with brine, was loaded into the column, Chem Elut and suirable EtOAc. Was purified using column Honey Bond Elut and gradient elution solvent 10-80% EtOAc/hexane, getting named the title compound (115 mg) in the form of b is Loy foam. NMR: 1,6 (s, 3H), 6,4 (s, 2H), 7,0 (d, 1H), 7,9 (t, 2H), and 8.0 (s, 1H), 8.3 (the square, 2H), 9,9 (s, 1H); m/z: 456.

Example 63

(R)-N-(2-Chloro-3-nitro-4-[4-N,N-dimethylcarbamoyl]phenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-N-(2-chloro-3-nitro-4-[4-carboxypenicillins]phenyl)-2-hydroxy-2-methyl-3,3,3-tri-forprepaid (method 62) (260 mg) in DHM (15 ml) was added oxalicacid (0,07 ml) and DMF (2 drops). The mixture was stirred for 16 hours at ambient temperature. Volatiles were removed by evaporation and the residue was dissolved in DHM (15 ml). Added dimethylamine in EtOH (5.6 M, 0.6 ml) and the solution was stirred for 16 hours at ambient temperature. Volatiles were removed by evaporation and the residue was distributed between EtOAc (100 ml) and water (50 ml). The organic phase was washed with brine (50 ml) and dried. Volatiles were removed by evaporation, getting named the title compound (324 mg) as a solid. NMR: 1,58 (s, 3H), and 2.83 (s, 3H), of 2.97 (s, 3H), 7,66 (d, 2H), to 7.93 (d, 2H), 8,08 (Sirs, 1H), 8,35 (d, 1H), 8,42 (d, 1H); m/z: 522.

Example 64

(R)-N-[2-Chloro-3-(4-acetylpiperidine-1-yl)-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[2-Chloro-3-fluoro-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 15; 2.0 g) was added in an argon atmosphere to a solution of 1-acetylpiperidine (2.0 g, 3 EQ.) in anhydrous NMP (3 ml), the mixture was stirred and heated at 147°With within 24 hours. The reaction mixture was cooled and distributed between saturated aqueous ammonium chloride (80 ml) and ether (4×200 ml). The combined ether layers were washed with brine (200 ml), dried and concentrated, obtaining a resin. The residue was purified by chromatography on a column of Honey Bond Elut (50 g) with elution with a mixture of 0-4% Meon/DHM, getting named the title compound (0,895 g) as a white foam. NMR: 1.14 in (t, 3H), of 1.61 (s, 3H), of 2.05 (s, 3H), 2,75-2,82 (m, 1H), 2,94 (SIRM, 2H), 3.25 to 3,44 (m, 3H), 3,49-3,56 (square,2H), 3,85 (d, 1H), 4,39 (d, 1H), 7,94 (d, 1H), 8,07 (Sirs, 1H), compared to 8.26 (d, 1H), 9,94 (Sirs, 1H); m/z: 484.

Examples 65-76

Following the procedure of example 64 and using the appropriate starting materials, received the following connections:

1The residue was chromatographically using as eluent a mixture of 0-50% EtOAc/isohexane.

2Used ethanolamine (1/5 EQ.) at 120°C for 3 hours.

3The residue was purified in a Biotage cartridge, 8 g of silicon dioxide, while elution with a mixture of 1:1 EtOAc/isohexane.

4Used benzylamine (1.5 EQ.) at 120°C for 3 hours.

5The residue was purified using as eluent a mixture of 0-40% EtOAc/isohexane.

6Used glycinamide hydrochloride (3 EQ.) and triethylamine (3 EQ.) at 120°during the course the e 3 hours.

7The residue was purified in a Biotage cartridge, 8 g of silica with elution EtOAc.

8Source material: Example 14.

9After chromatography of the residue was filtered from hot EtOAc.

10Used methoxyethylamine (1.5 EQ.) at 120°C for 3 hours.

11The residue was purified in a Biotage cartridge, 8 g of silica with elution with a mixture of 40% EtOAc/isohexane.

12The residue was purified using as eluent a mixture of 0-50% EtOAc/isohexane.

13Source material: Example 80.

14After chromatography of the residue was recrystallized from Meon.

Example 77

(R)-N-[2-Chloro-3-phenoxy-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[2-Chloro-3-fluoro-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 15; 0,308 g) was added under stirring to a suspension of phenol (0,150 g) and anhydrous potassium carbonate (0,220 g) in anhydrous DMF (2 ml). The reaction mixture was heated to 150°C in argon atmosphere for 17 hours and gave it to cool down to ambient temperature. Added EtOAc (50 ml), the organic phase was washed with brine (4×50 ml), separated and the volatiles removed by evaporation. The residue was purified in a Biotage cartridge, 8 g of silicon dioxide, while elution with a mixture of 40% EtOAc/isohexane, getting called in the header connection,073 g) as pale yellow foam.

NMR (CDCl3): of 1.18 (t, 3H), 1.69 in (s, 3H), 3,23-3,30 (square, 2H), 3,48 (s, 1H), 6,78 (d, 2H), 7,02 (t, 1H), 7,24 (t, 2H), of 7.97 (d, 1H), and 8.50 (d, 1H), 9,24 (Sirs, 1H); m/z: 450,

Example 78

(R)-N-[2-Chloro-3-methoxy-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Named in the title compound was obtained from 2-chloro-N-methoxy-4-ethylsulfonyl (method 10) by the procedure described in method 11 with the release of 19% in the form of a white solid. NMR (CDCl3): to 1.15 (t, 3H), 1,71 (s, 3H), 3.27 to 3,34 (square, 2H), 3,57 (s, 1H), 3,98 (s, 3H), 7,81 (d, 1H), at 8.36 (d, 1H), 9,24 (s, 1H); m/z: 388.

Example 79

(R)-N-[2-Chloro-3-methylsulfanyl-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Meantioned sodium (0.16 g) was added with stirring to a solution of (2R)-N-[2-chloro-3-fluoro-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-N,3,3-tryptophanate (example 80; 0,862 g) in 1-methyl-2-pyrrolidinone (3 ml). The reaction mixture was heated to 128°C for 20 hours. The reaction mixture was allowed to cool, added EtOAc (100 ml), the mixture was washed with water (2×50 ml), brine (50 ml) and dried. Volatiles were removed by evaporation and got the oil. The oil was dissolved in ether (100 ml) and washed with brine (50 ml). Volatiles were removed by evaporation and got a foam, which was recrystallized from a mixture of EtOA/hexane, getting named the title compound (0,495 g) as a solid. NMR: 1,20 (m, 6N), to 1.60 (s, 3H), of 2.46 (s, 3H), 4,14 (m, 1H), ,00 (d, 1H), 8,39 (d, 1H); m/z: 418.

Example 80

(R)-N-[2-Chloro-3-fluoro-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Hydrogen peroxide (100 volume, 20 ml) was added to a solution of (2R)-N-[2-chloro-3-fluoro-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 80; 1,21 g) 1 glacial acetic acid (20 ml) and the mixture was stirred for 4.5 hours at 100°C. the Mixture was allowed to cool to ambient temperature and the volatiles removed by evaporation. The residue was dissolved in EtOAc (100 ml), washed with water (50 ml), brine (50 ml), dried and the volatiles removed by evaporation, getting named the title compound (1,196 g) as a solid. NMR: 1,20 (d, 6N), to 1.60 (s, 3H), 3,50 (m, 1H), 7,83 (t, 1H), 8,10 (s, 1H), 8,19 (d, 1H), 9,99 (s, 1H); m/z: 390.

Example 81

(R)-M-{2-Chloro-3-methylsulfanyl-4-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

A mixture of (R)-N-{2-chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 18; 300 mg, 0.6 mmol) and methanolate sodium (135 mg) in DMA (5 ml) was stirred for overnight at 100°C. the Mixture was allowed to cool to room temperature and distributed between EtOAc/water. The organic layers were washed with water and dried, passing through the column Chem Elut when the elution EtOAc. When standing was formed 110 mg of colorless needle-like Krista the minerals named in the title compound, which was filtered and washed with hexane. NMR: 1,6 (s, 3H), and 1.9 (s, 3H), and 2.8 (s, 3H), 3.0 a (s, 3H), and 7.6 (d, 2H), 7,9 (d, 2H), and 8.3 (d, 1H), and 8.5 (d, 1H); m/z: 523.

Example 82

(R)-N-{2-Chloro-3-methylsulfanyl-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-{2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate) phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 83; 290 mg, or 0.57 mmol) was subjected to reaction with matancilla sodium (1.5 mmol) according to the method of example 81. The residue was purified by chromatography on a column of Honey Bond Elut when elution with a mixture of 10-100% EtOAc/hexane, getting named the title compound (200 mg) as a white solid. NMR: 1,1 (m, 3H), and 1.6 (s, 3H), and 1.9 (s, 3H), 2,9 (d, 3H), 3,1 (d, 3H), 3,5 (d, 1H), and 7.6 (d, 2H), 7,9 (d, 2H)and 8.1 (s, 1H), and 8.4 (d, 1H), and 8.5 (d, 1H), 9,9 (s, 1H); m/z: 537

Example 83

(R)-N-{2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

A mixture of (R)-N-{2-chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 85; 370 mg, 0.77 mmol), glacial acetic acid (5 ml) and hydrogen peroxide (1.8 ml) was stirred at 95°C for 3 hours and allowed to cool to room temperature. The solution was extracted with EtOAc. The organic layers were washed with saturated sodium bicarbonate solution, water and brine, was transferred to a column Chem Elut and EtOAc, getting named the title compound (400 mg) as a white solid. NMR: 1,2 (m, 3H), and 1.6 (s, 3H), and 2.8 (d, 3H), 3,1 (d, 1H), 3,5 (d, 1H), and 7.6 (d, 2H), and 8.0 (d, 2H), 8,1 (t, 1H), and 8.2 (d, 1H); m/z: 509.

Example 84

(R)-N-{2-Chloro-3-fluoro-4-[4-(N-ethylcarbazole)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-{2-chloro-3-fluoro-4-[4-(N-ethylcarbazole)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 86; 90 mg), glacial acetic acid (1.3 ml) and hydrogen peroxide solution (0.45 ml) was heated with stirring at 95°C for 3 hours. The reaction mixture was allowed to cool to room temperature and was extracted with EtOAc. The organic layers were washed with saturated sodium bicarbonate solution. The organic layers was separated, washed with water and then dried, giving a column Chem Elut and suirable EtOAc. The resulting solution was evaporated to dryness and the residue was purified by chromatography on a column (Bond Elut when elution with a mixture of 20-70% EtOAc/hexane, getting named the title compound (80 mg) as a white solid. NMR: 1,1 (t, 3H), and 1.6 (s, 3H), 3,2 (m, 2H), 8,1 (m, 6N), and 8.7 (s, 1H), 9,9 (s, 1H); m/z: 495.

Obtaining raw materials

The source materials for the above examples are or industrial available or easily obtained by standard methods from known materials. For example, the following reactions are illustrative but not limiting, is the Intesa some of the original substances, used in the above reactions.

Method 1

(R)-N-(2,3-Dichloro-4-ethylsulfanyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

Oxalicacid (0.75 ml) was added under stirring to a suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-tryptophanol acid (method 25) (1,37 g) in DHM containing DMF (1 drop). The mixture was stirred at ambient temperature for 18 hours and then was added a solution of 4-ethylsulfanyl-2,3-dichloraniline (method 7) (1.92 g) and 2,6-diphenylpyridine (2.0 g) in DHM (50 ml). The mixture was stirred for 3 hours at room temperature, volatiles were removed by evaporation and the residue was purified by chromatography with elution with a mixture of 0-20% EtOAc/isohexane, getting named the title compound (2,12 g) as a solid. NMR (Dl3): of 1.35 (t, 3H), of 1.76 (s, 3H), 2,97 (square, 2H), 3,61 (s, 1H), 7,22 (d, 1H), 8,27 (d, 1H), 8,91 (s, 1H); m/z 360.

Methods 2-5

Following the procedure of method 1, except that instead of 2,6-diphenylpyridine used 2,6-di-tert-butylpyridinium, and using the appropriate starting materials, received the following connections:

Method 6

2,3-Dichloro-4-metilsulfonilmetane acid

The cooled sodium hypochlorite solution (120 ml with 4% free chlorine) was added to a solution of 4-ethylsulfanyl-2,3-dichloroacetophenone (10.0 g, obtained as described in European paten the Noi application EP 0195247) in dioxane (80 ml). The reaction mixture was stirred at ambient temperature for 15 minutes, then slowly heated up to 80°C for 30 minutes and heating was maintained at this temperature for 1 hour. The reaction mixture was allowed to cool to room temperature, was added aqueous hydrochloric acid (100 ml of 2 M solution)and the resulting solid is collected and dried. The solid was re-dissolved in DHM (200 ml) and Meon (20 ml), washed with sodium hydroxide (10% wt./about., 300 ml)and the aqueous phase was separated and acidified aqueous hydrochloric acid (2 M, 300 ml). The precipitate was collected and dried, obtaining mentioned in the title compound (5.4 g) as a solid. NMR: of 1.28 (t, 3H), 3,05 (square, 2H), was 7.36 (d, 1H), 7,68 (d, 1H); m/z: 249.

Method 7

2,3-Dichloro-4-ethylsulfanyl

A suspension of 2,S-dichloro-4-metilsulfonilmetane acid (method 6) (2,71 g) in tert-butanol (70 ml) and triethylamine (1.6 ml) was heated under stirring to 60°C. was Added dropwise diphenylphosphoryl (2.5 ml) and the mixture was heated at 90°C for 4 hours. The reaction mixture was allowed to cool to room temperature and the solvent evaporated under reduced pressure. Added EtOAc (150 ml) and the organic phase is washed with saturated aqueous sodium bicarbonate (2×100 ml) and then dried. Volatiles were removed by evaporation and received a mixture of 1:1 to 2.3-ALOR-4-ethylsulfanyl and tert-butylurea (of 2.51 g). This substance was added dropwise TFOC (6 ml) and the mixture was stirred at ambient temperature for 30 minutes. Was added sodium hydroxide (20% wt./about.) to bring the pH to 10-11 and the mixture was extracted with EtOAc (4×250 ml). The extracts were dried, volatiles were removed by evaporation and the residue was purified by chromatography with elution with a mixture of 10-50% EtOAc/isohexane, getting named the title compound (1.9 g) as oil. NMR (CDCl3): of 1.26 (t, 3H), 2,85 (square, 2H), 4.2V (s, 2H), of 6.65 (d, 1H), 7,21 (d, 1H); m/z: 220.

Methods 8-10

Following the procedure of method 7 using the appropriate starting materials, received the following connections:

Method 11

(R)-N-(3-Acetamido-2-chloro-4-{4-perpenicular}phenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

A solution of (S)-3,3,3-Cryptor-2-(trimethylsilyloxy)-2-methyl-propanimidamide (obtained from (R)-3,3,3-Cryptor-2-hydroxy-2-methylpropionic acid (method 25), as described in J. Med. Chem., 1999, 42, 2741-2746) (1,179 g) in DHM (10 ml) was added dropwise with stirring to a chilled ice suspension of 3-acetamido-2-chloro-4-(4-perpenicular)aniline (method 18) (1,315 g) in DHM (20 ml) and triethylamine (1,72 ml). The mixture was allowed to warmed to ambient temperature over night. Adding more triethylamine (0.8 ml) and then (S)-3,3,3-Cryptor-2-(trimethylsilyloxy)-2-methylpropanoate (0.6 g) in DHM (5 ml). From the mouths another 6 hours the mixture was concentrated by evaporation. Added Meon (50 ml) and 2M aqueous solution of Hcl (5 ml), the mixture was left overnight with stirring and then diluted with water (20 ml). Meon was removed by evaporation and added a 2M aqueous solution of Hcl (30 ml). Then the mixture was extracted with ether (2×80 ml). The extracts were washed with brine and dried. Volatiles were removed by evaporation and the residue was purified by chromatography cartridge Biotage (40 g silica) with elution with a mixture of 50% EtOAc/isohexane, getting named the title compound (1.04 g) as a foam. NMR: 1,6 (s, 3H), of 2.05 (s, 3H), 7,0 (d, 1H), 7,26 (t, 2H), 7,38-of 7.48 (m, 2H), 7,8-7,9 (m, 2H), 9,76 (Sirs, 1H); m/z: 449.

Methods 12-14

Following the procedure of method 11 and using the appropriate starting materials, received the following connections:

Method 15

3-Acetamido-2-chloro-4-(4-perpenicular)nitrobenzene

4-Fermentation (0,128 ml) was added dropwise with stirring to a suspension of sodium hydride (0,049 g 60%dispersion in mineral oil) in THF (3 ml). The mixture was stirred for 30 minutes, then added dropwise with stirring to a cooled (-65° (C) to a solution of 3-acetamido-2-amino-4-peritrabecular (0,233 g) in THF (2 ml). The mixture was stirred for 3 hours at -65°With, then she was allowed to warmed to ambient temperature. Was added a saturated aqueous solution of ammonium chloride (5 ml), then water (5 ml) and see what camping was extracted with ether (2× 25 ml). The extracts were combined, washed with water (25 ml) and brine (25 ml), then dried. Volatiles were removed by evaporation and the residue was purified on silica gel column Honey Bond Elut when elution with a mixture of 0-40% EtOAc/isohexane, getting named the title compound. Using a chromatography cartridge Biotage (40 g silica) with elution with a mixture of 40% EtOAc/isohexane has been named the title compound (0,193 g) as a solid. NMR: 2,14 (s, 3H), 6,76 (d, 1H), and 7.4 (t, 2H), 7,6 (m, 2H), 7,88 (d, 1H), 10,1 (Sirs, 1H); m/z: 339.

Methods 16-17

Following the procedure of method 15 and using 2-amino-3,4-diplomarbeit and relevant source materials were obtained the following compounds:

Method 18

3-Acetamido-2-chloro-4-(4-perpenicular)aniline

A mixture of 3-acetamido-2-chloro-4-(4-perpenicular)nitro-benzene (method 15) (0.1 g), uranyl chloride iron (0,238 g) and zinc dust (0,192 g) in DMF (1 ml) and water (1 ml) was stirred and heated (oil bath, 100°C) for 1 hour and then cooled. Was added water (15 ml) and the mixture was podslushivaet to pH 11 with saturated aqueous solution of sodium carbonate (3 ml), then was extracted with DHM (3×15 ml). The extracts were washed with brine, then was dried. Volatiles were removed by evaporation and the residue was left overnight under a deep vacuum (2 mm Hg), getting called in the header is VCE connection (0,087 g) as a solid. NMR: 1,95 (s, 3H), 5,72 (Sirs, 2H), 6.73 x (d, 1H), 7,05-7,20 (m, 5H), 9,54 (Sirs, 1H); m/z: 309.

Methods 19-21

Following the procedure of method 18 and using the appropriate starting materials, received the following connections:

Method 22

2-Chloro-3-fluoro-4-(4-perpenicular)nitrobenzene

2-Amino-3-fluoro-4-(4-perpenicular)nitrobenzene (method 16) (0,846 g) for 5 minutes was added in portions with stirring to the heated (oil bath, 100° (C) a mixture of tert-butylnitrite (0,59 ml) and ferrous chloride copper (0,484 g) in acetonitrile (12 ml). Heating was continued for 1 hour, then the mixture was left to cool and filtered. Added ether (60 ml), the mixture was washed with 20% hydrochloric acid (2×60 ml) and then dried. Volatiles were removed by evaporation and the residue was purified by chromatography cartridge Biotage (40 g silica) with elution with a mixture of 5% EtOAc/isohexane, getting named the title compound (0,57 g) as a solid. NMR: of 6.96 (t, 1H), 7,41 (t, 2H), and 7.7 (m, 2H), to $ 7.91 (d, 1H); MS (EI): 302 (M+H)+.

Methods 23-24

Following the procedure of method 22 and using the appropriate starting materials, received the following connections:

Method 25

(R)-(+)-2-hydroxy-2-methyl-3,3,3-cryptosporidia acid

Named in the title compound was isolated using the method of separation, episunago European patent application EP 524781 (listed to obtain (S)-(-)-acid), except that instead of (1R/2S)-norephedrine or (S)-(-)-1-phenethylamine was used (1S,2R)-norephedrine. NMR analysis of the acid in the presence of (R)-(+)-1-phenethylamine showed enantiomeric purity >98%; NMR (CDCl3): 1,27 (3H) for (R)-enantiomer, to 1.21(s, 3H) for (S)-enantiomer.

Method 26

2-Fluoro-3-methylsulfanyl-6-nitroaniline

To a solution of 2,3-debtor-6-nitroaniline (13.3 g) in DMF (250 ml) under stirring in an argon atmosphere was added meantioned sodium (5.7 g). The reaction mixture was allowed to cool to ambient temperature for 5 hours. Added EtOAc (500 ml), the mixture was washed with brine (6×500 ml) and dried. Volatiles were removed by evaporation, getting named the title compound (1,49 g) as a yellow solid. NMR (Dl3): of 2.51 (s, 3H), 6,09 (Sirs, 2H), 6.48 in-6,54 (m, 1H), 7,92 (d, 1H); m/z (EI+): 202 (M+).

Method 27

(R)-N-[4-Ethylsulfanyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

A suspension of (R)-N-[4-methylsulfinyl-3-fluoro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 2) (5,41 g) in triperoxonane anhydride (65 ml) was heated at the boil under reflux for 30 minutes. The reaction mixture is evaporated, the residue was re-dissolved in Meon (32 ml) and triethylamine (32 ml) was added ethyl iodide (2.2 ml). The reaction mixture was heated at the boil under reflux for 3 hours is, gave it to cool down to room temperature, and volatiles were removed by evaporation. The residue was distributed between EtOAc (150 ml) and brine (100 ml); the organic phase was separated, dried and the volatiles removed by evaporation. The residue was purified flash chromatography with elution with a mixture of 10-20% EtOAc/isohexane, getting named the title compound (2.16 g) as a yellow solid. NMR (CDCl3): of 1.27 (s, 3H), of 1.76 (s, 2H), 2,88-2,95 (square, 2H), 3,55 (s, 1H), 7,32 (m, 1H), 8,15 (d, 1H), of 8.92 (s, 1H); m/z: 344.

Method 28

(R)-N-[4-Ethylsulfanyl-3-iodine-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-N-[4-mercapto-3-iodine-2-chlorophenyl]-2-hydroxy-2-methyl-N,3,3-tryptophanate (method 29) (5,85 g) in anhydrous THF (40 ml) under stirring in an argon atmosphere was added sodium methoxide (0,44 g) and then ethyl iodide (0,65 ml). The mixture was heated at the boil under reflux for 1 hour and allowed it to cool to ambient temperature. Added EtOAc (200 ml), the organic phase was washed with brine (100 ml) and dried. Volatiles were removed by evaporation and the residue was purified flash chromatography with elution with a mixture of 5-30% EtOAc/isohexane, getting named the title compound (2,08 g) as a pale yellow solid. NMR (CDCl3): of 1.36 (t, 3H), of 1.75 (s, 3H), 2,92-2,99 (square, 2H), 7,15 (d, 1H), 8.34 per (d, 1H), 8,89 (s, 1H); m/z: 452.

Method 29

(R)-N-[4-Mercapto-3-iodine-2-chlorphen the l]-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a cooled to 0°With the solution of triphenylphosphine (6,41 g) in DHM (35 ml) and DMF (0,30 ml) was added with stirring a solution of (R)-N-[4-chlorosulfonyl-3-iodine-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 30) (4.0 g) in DHM (40 ml). The reaction mixture was stirred at ambient temperature for 45 minutes, was added Hcl (50 ml, 2M) and continued stirring for another 30 minutes. The organic phase was dried and the volatiles removed by evaporation. Added ether (70 ml) and the suspension was filtered. The filtrate is evaporated, getting named the title compound (5,85 g) as a brown foam. M/z: 452.

Method 30

(R)-N-[4-Chlorosulfonyl-3-iodine-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[3-Iodine-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 31) (to 4.92 g) was added in portions to chlorosulfonic acid (18 ml) at 0°C. the Reaction mixture was heated to 80°C for 4 hours, allowed it to cool to ambient temperature and poured into ice water (200 g). The mixture was extracted with DHM (2×250 ml), the organic phase was washed with brine (300 ml) and dried. Volatiles were removed by evaporation, getting named the title compound (4.8 g) as a brown resin. NMR (CDCl3): 1,78 (s, 3H)and 3.59 (s, 1H), 8,23 (d, 1H), total of 8.74 (d, 1H), at 9.53 (s, 1H); m/z: 490.

Method 31

(R)-N-[3-Iodine-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

<> To a cooled solution of (R)-N-[3-amino-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 32) (12.5 g) in concentrated sulfuric acid (25 ml) and water (70 ml) was added dropwise a solution of sodium nitrite (3.15 g) in water (70 ml). The reaction mixture was stirred for 10 minutes and for 1 hour at ambient temperature. Was carefully added a solution of potassium iodide (22,2 g) in water (70 ml) and the mixture was heated to 100°C for 2.5 hours. The mixture was allowed to cool to ambient temperature, was added EtOAc (500 ml), the organic phase was washed with brine (300 ml) and dried. Volatiles were removed by evaporation and the residue was purified flash chromatography with elution with a mixture of 5-20% EtOAc/isohexane, getting named the title compound (13.5 g) as a cream solid color. NMR (CDCl3): of 1.76 (s, 3H), 3,63 (s, 1H), 7,05 (t, 1H), 7,68 (d, 1H), at 8.36 (d, 1H), 8,97 (Sirs, 1H); m/z: 392.

Method 32

(R)-N-[3-Amino-2-chlorphenyl-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a stirred solution of (R)-N-[3-nitro-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 3) (14.3 g) in EtOAc (250 ml) in an atmosphere of hydrogen was added 10% palladium on coal (1.6 g). The reaction mixture was stirred at room temperature overnight; the mixture was filtered through a layer of hard-shelled land and volatiles were removed by evaporation, getting named the title compound (13 g) is the form of a brown solid. NMR (Dl3): of 1.75 (s, 3H), 4.00 points (s, 1H), 4,10 (Sirs, 2N), is 6.61 (d, 1H), was 7.08 (t, 1H), 7,72 (d, 1H), 8,77 (Sirs, 1H); m/z: 281.

Method 33

(R)-N-[4-Methylsulfanyl-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[4-Iodine-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 4) (5,17 g, 12,08 mmol) was dissolved in DMA (30 ml) and heated to 155°C for 6 hours under stirring in argon atmosphere with matancilla sodium (1.1 g, 1.3 EQ.) and chloride of monovalent copper (670 mg). The reaction mixture was allowed to cool to room temperature and snuffed out the reaction by addition of EtOAc and water. The reaction mixture was filtered through a layer of hard-shelled land and thoroughly washed with a mixture of EtOAc/water. The organic layer was washed with water and then brine, dried and evaporated to dryness. The residue was chromatographically in column Honey Bond Elut when elution with a mixture of 2-30% EtOAc/hexane, and the obtained product was washed with 10% EtzO/hexane, getting named the title compound in the form of a cream solid color (2,97 g). NMR: 1,6 (s, 3H), of 2.5 (s, 3H), and 7.3 (d, 1H), and 7.8 (d, 1H); m/z: 346.

Method 34

(R)-N-[4-(2-Hydroxybutylidene)-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

The sodium methoxide (0.075 g) was added to a stirred solution of (R)-N-[2,3-dichloro-4-mercaptophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 35) (0,44 g) in anhydrous THF (10 ml). The reaction mixture was stirred at tempera is ur environment within 5 minutes and was added 1,2-epoxybutane (0,11 ml). The mixture was heated at the boil under reflux for 2 hours and allowed it to cool to ambient temperature. Added EtOAc (150 ml) and the mixture was washed with brine (100 ml) and dried. Volatiles were removed by evaporation and the residue was purified on a column of Honey Bond Elut (20 g silica) with elution with a mixture of 1-40% EtOAc/isohexane, getting named the title compound (0,259 g) as an orange solid. NMR: from 0.88 (t, 3H), 1,35-1,49 (m, 1H), 1,58 (s, 3H), 2,97-is 3.08 (m, 1H), 3,53-3,62 (m, 1H), 5,00 (d, 1H), 7,42 (d, 1H), to 7.77 (d, 1H), 9,79 (Sirs, 1H); m/z: 404.

Method 35

(R)-N-[2,3-Dichloro-4-mercaptophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Triisopropylsilane (2.0 ml) was added under stirring in an argon atmosphere to a cooled to 0°suspension of sodium hydride (from 0.37 g, 60%dispersion in mineral oil) in anhydrous THF (30 ml). After 20 minutes at this temperature the reaction mixture was added to a stirred suspension of (R)-N-[4-iodine-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 4) (4.0 g) and tetrakis(triphenylphosphine)palladium(0) (0,86 g) in anhydrous toluene (40 ml). The mixture was heated at 85°C for 5 hours and was added DMF (10 ml)to give a clear solution. Heating was continued for another 17 hours. The mixture was allowed to cool to ambient temperature, was added EtOAc (200 ml), the mixture was washed with brine (3×100 ml) and dried. Leucaena was removed by evaporation and the residue was purified by chromatography with elution with a mixture of 1-50% EtOAc/isohexane, getting named the title compound (0,448 g) as an orange solid. NMR: 1,58 (s, 3H), at 7.55 (d, 1H), 7,66 (d, 1H), 7,73 (s, 1H), 9,80 (s, 1H); m/z: 332.

Method 36

(R)-N-[2,3-Dichloro-4-{4-(N,N-dimethylcarbamoyl)phenylsulfonyl}phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[2,3-Dichloro-4-thiocyanation]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 39) (0.5 g) in solution in DMF was treated with a solution of sodium sulfide (403 mg) in water (2 ml) and the mixture was heated at 50°C for 1 hour. Then the reaction mixture was treated with a solution of N,N-dimethylcarbamoyl-4-yogashala (0,455 g) in DMF (5 ml), and then the oxide monovalent copper (0,121 g). The reaction mixture was heated at 150°C for 4.5 hours in an argon atmosphere. The reaction mixture was extinguished with water (100 ml)was added DHM (100 ml) and the mixture was filtered through hard-shelled land. The aqueous layer was separated and washed DHM (3×50 ml). The organic extracts were combined and dried. Volatiles were removed by evaporation and the product was purified by chromatography, using a column of Honey Bond Elut (20 g silica) with elution with a mixture of 0-5% Meon/DHM, getting named the title compound as a white solid (0,53 g, 80%). NMR: 1,60 (s, 3H), 2.95 and (d, 6N), 7,30 (d, 1H), 7,30-to 7.50 (m, 4H), a 7.85 (s, 1H), of 7.90 (d, 1H), 9,90 (s, 1H); m/z: 479.

Methods 37-38

Following the procedure of method 36 and using the appropriate starting materials, produces the following connections:

Method 39

(R)-N-[2,3-Dichloro-4-thiocyanation]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-(+)-2-Hydroxy-2-methyl-3,3,3-triptocaine acid (method 25) (1 g) in suspension in DHM was treated with anhydrous DMF (1 drop). Over a period of 15 minutes was added dropwise oxalicacid (1,15 ml) in solution in DHM. The mixture was left to mix overnight in an argon atmosphere. Volatiles were removed by evaporation and the residue was re-dissolved in DHM (20 ml). This solution is used for treatment of a solution of 2,3-dichloro-4-thiocyanation (method 40) (1,37 g) and di-tert-butylpyridinium of 1.55 ml) in DHM by adding on for 15 minutes. The reaction mixture was left to mix overnight in an argon atmosphere. Volatiles were removed by evaporation and the residue was purified by chromatography on a column of Honey Bond Elut (20 g silica), getting named the title compound as a white solid, 1.08 g (48%). NMR (CDCl3): of 1.65 (s, 3H), 7,80 (d, 1H), 7,95 (s, 1H), 8,10 (d, 1H), 9,95 (s, 1H); m/z: 357.

Method 40

2,3-Dichloro-4-thiocyanation

To a cold (0-5° (C) to a solution of 2,3-dichloraniline (2 g) and sodium thiocyanate (3 g) in Meon (30 ml) was added a solution of bromine (2 g) in Meon (10 ml), saturated with sodium bromide. The solution was left to mix for 1 hour. The reaction mixture was poured into water (200 ml) and Nate who was alitwala with sodium carbonate to pH 8. The solid is collected by filtration and dried, obtaining mentioned in the title compound as a white solid (2.38 g, 88%). NMR (Dl3): 6.35mm (s, 2H), for 6.81 (d, 1H), 7,55 (d, 1H); m/z (EI+): 218.

Methods 41-42

Following the procedure of method 40 and using the appropriate starting materials, received the following connections:

Method 43

(R)-N-(2-Methyl-3-fluoro-4-[4-forfinal]sulfanilyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-N-(2-methyl-3-fluoro-4-itfinal)-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 45) (782 mg) in DMF (6 ml) was added 4-portifino (0,32 ml) and Cu2O (143 mg). The mixture was heated in argon atmosphere up to 150°C for 4.5 hours. All volatiles were removed by evaporation and the residue was dissolved in EtOAc (100 ml). The mixture was filtered through hard-shelled land and all volatiles were removed by evaporation. The residue was purified by chromatography on silica gel with elution with 15% EtOAc in isohexane, getting named the title compound (544 mg) as a solid. NMR: 1.57 in (s, 3H), of 2.06 (s, 3H), 7,15 (t, 1H), 7,26 (m, 3H), 7,39 (m, 2H), 7,52 (Sirs, 1H), 9,78 (Sirs, 1H); m/z: 390.

Method 44

Following the procedure of method 43 and using the appropriate starting materials, received the following connection:

Method 45

(R)-N-(2-Methyl-3-fluoro-4-itfinal)-2-hydroxy-2-methyl-3,3,3-cryptocrat named

Oxalicacid (0.7 ml) was added under stirring to a suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-tryptophanol acid (method 25) (1.26 g) in DHM (40 ml)containing DMF (3 drops). The mixture was stirred at ambient temperature for 4 hours and was added 2,6-di-tert-butylpyrazine (2.25 ml) and 4-iodine-3-fluoro-2-methylaniline (method 48) (1,368 g). The resulting mixture was stirred at ambient temperature for 72 hours. Volatiles were removed by evaporation and the residue was purified by chromatography on silica gel with elution with a mixture of 25% EtOAc/isohexane, getting named the title compound (1,668 g) as a solid. NMR: of 1.56 (s, 3H), of 2.08 (s, 3H), 7,03 (d, 1H), 7,66 (t, 1H); m/z: 390.

Methods 46-47

Following the procedure of method 45 and using the appropriate starting materials, received the following connections:

Method 48

4-Iodine-3-fluoro-2-methylaniline

Monochloride iodine (0.5 ml) was added to a solution of H-fluoro-2-methylaniline (1.25 g) in glacial acetic acid (15 ml). The mixture was stirred for two hours at 70°C. the Mixture was allowed to cool to ambient temperature and was added a saturated solution of sodium sulfite (50 ml). The solution was extracted with EtOAc (2×100 ml), the extracts were combined, washed with saturated sodium bicarbonate solution (100 ml) and dried. Volatiles were removed by evaporation and the residue was purified x is matography on silica gel with elution 0-10% EtOAc in hexane, getting named the title compound (1,53 g) as a solid. NMR: to 1.98 (s, 3H), 5,32 (s, 2H), 6.30-in (d, 1H), 7,20 (m, 1H); m/z: 250.

Methods 49-51

Following the procedure of method 48 and using the appropriate starting materials, received the following connections:

1Solvent for chromatography: 0-15% EtOAc/hexane. Gives a viscous dark liquid, which hardens when grinding with hexane.

Method 52

(R)-N-(2-Methyl-3-fluoro-4-[4-N,N-dimethylcarbamoyl]sulfanilyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

4-[N,N-Dimethylcarbamoyl]thiophenol (method 53) (751 mg), (R)-N-(2-methyl-3-chloro-4-itfinal)-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 45) (1,433 g) and Cu2O (250 mg) were combined in DMF (10 ml). The mixture was stirred for 4.5 hours at 150°C in argon atmosphere. The mixture was allowed to cool to ambient temperature, was added EtOAc (100 ml) and the resulting suspension was filtered through hard-shelled land before all volatiles were removed by evaporation. The residue was purified by chromatography with elution 1-5% Meon in DHM, getting named the title compound (1,02 g). NMR: 1,60 (c, 3H), 2,12 (s, 3H), 2,97 (Sirs, 6N), 7,20 (m, 2H), 7,37 (m, 4H), 9,81 (Sirs, 1H); m/z: 443.

Method 53

4-[4-N,N-dimethylcarbamoyl]thiophenol

Diphosphonates the pentoxide (923 g) was added to a solution of 4-mercaptobenzoic acid (2000 mg) in DMF (10 ml). mesh was stirred for sixteen hours at 150° C in argon atmosphere. The mixture was allowed to cool to ambient temperature, then added EtOAc (150 ml). The solution was washed with water (100 ml), brine (50 ml) and dried. Volatiles were removed by evaporation and the residue was purified by chromatography on silica gel with elution with 2.5% Meon in DHM, receiving two samples. One sample contained a mixture of thiol and disulfide, was purified by chromatography on silica gel with elution 1-2,5% Meon in DHM, getting named the title compound (760 mg) as a solid. NMR: 2,94 (C, 6N), 5,63 (s, 1H), 7,30 (m, 4H); m/z: 180.

Method 54

(R)-N-[4-(2-Hydroxyarylalkyl)-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[4-Iodine-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 4) (1.22 g) was added to deoxyribonu to a solution of 2-mercaptoethanol (0,26 ml), sodium methoxide (0.20 g) and copper chloride(I) (0.11 g) in quinoline (3 ml) and pyridine (1 ml). The mixture was stirred at 190°C in argon atmosphere for 18 hours. The mixture was allowed to cool to room temperature and was added EtOAc (200 ml). The mixture was washed with hydrochloric acid (10% vol., 2×250 ml), brine (200 ml) and dried. Volatiles were removed by evaporation and the residue was purified by chromatography on a column of Honey Bond Elut with 50 g of silica gel with elution with a mixture of 5-50% EtOAc/isohexane, getting named the title compound as an orange solid substances the. NMR: 1,59 (s, 3H), 3.15 in (t, 2H), 3,60-3,63 (m, 2H), to 4.98 (t, 1H), 7,43 (d, 1H), 7,80 (d, 1H), 9,78 (Sirs, 1H); m/z: 376.

Method 59

(R)-N-[4-Ethylsulfonyl-C(4-carboxyphenylazo)-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

Following the procedure of example 48 using 4-mercaptobenzoic acid (1.5 EQ.) and sodium methoxide instead methanolate, has been named the title compound as a brown foam. NMR: of 1.13 (t, 3H), of 1.61 (s, 3H), 3,49-3,56 (square, 2H), 7,15 (d, 2H), to 8.20 (d, 1H), 8,56 (d, 1H), 9,99 (Sirs, 1H); m/z: 510.

Methods 60-62

Following the procedure of example 9 and using the appropriate starting materials, received the following connections:

Method 63

(R)-N-(2-Methyl-3-chloro-4-[4-N,N-carboxylphenyl]phenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate

4-Mercaptobenzoic acid (308 mg) was added to a suspension of copper oxide(I) (93 mg) and (R)-N-(2-methyl-3-chloro-4-itfinal)-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 46) (530 mg) in DMF (5 ml). The mixture was heated to 150°C in an atmosphere of argon for 4.5 hours. The mixture was allowed to cool to ambient temperature, was added EtOAc (100 ml), the resulting suspension was filtered through hard-shelled land and volatiles removed by evaporation. The residue was purified by chromatography with elution of 5-10% Meon in DHM, getting named the title compound (504 mg). NMR: 1,58 (s, 3H), and 2.26 (s, 3H), 7,34 (m, 4H), 7,51 (Sirs, 1H) 7,92 (Sirs, 2H), 9,94 (s, 1H), 13,00 (Sirs, 1H); m/z: 432.

Methods 64-65

Following the procedure of method 63 and using the appropriate starting materials, received the following connections:

Method 66

(R)-N-4-[4-(4-Carboxypenicillins)-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[4-(4-Carboxypenicillins)-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 67) (a 3.83 g, to 8.45 mmol) suspended under stirring in glacial acetic acid. Was added hydrogen peroxide (19 ml). The mixture was heated with stirring to 95°C for 3 hours and allowed it to cool to room temperature. The mixture is evaporated to dryness, obtaining a solid cream color, which is triturated with hexane. The solid was filtered and washed, getting named the title compound (3,97 g) as a cream solid color. NMR: 1,6 (s, 3H), and 8.0 (d, 2H)and 8.1 (d, 2H), 8.4V (square, 2H), 9,9 (s, 1H); m/z: 484.

Method 67

(R)-N-[4-(4-Carboxypenicillins)-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-[4-Iodine-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 4) (4,58 g of 10.7 mmol) was heated with stirring in an argon atmosphere for 4 hours in DMF (30 ml) with 4-mercaptobenzoic acid (2,31 g, 14,98 mmol) and oxides of monovalent copper (765 mg) and gave the mixture to cool to room temperature. EXT is ulali EtOAc and water, the reaction mixture was filtered through a layer of hard-shelled land and washed with mixture of EtOAc/water. The organic layer was separated, washed with water, brine, dried and evaporated to dryness. The obtained solid was purified using column Honey Bond Elut when elution with a mixture of 5-50% EtOAc/isohexane, getting named the title compound (4.0 g) as a pink solid. NMR: 1,6 (s, 3H), and 7.3 (d, 2H), 7.5 (d, 1H), 7,9 (m, 3H), and 8.0 (d, 1H), 9,9 (s, 1H), 13,0 (s, 1H); m/z: 452.

Method 68

(R)-N-(2-Chloro-3-nitro-4-itfinal)-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-N-(2-chloro-3-nitro-4-itfinal)-2-trimethylsilyloxy-2-methyl-3,3,3-tryptophanate (method 69) (1150 mg) in Meon was added 2 M hydrochloric acid (2.5 ml) and the reaction mixture was stirred for 4 hours at ambient temperature. Volatiles were removed by evaporation and the residue was distributed between EtOAc (150 ml) and water (75 ml). The organic phase was separated, washed with brine (75 ml) and dried. Volatiles were removed by evaporation, getting named the title compound (943 mg). NMR: 1,58 (s, 3H), of 7.70 (d, 1H), 8,00 (d, 1H); m/z: 437.

Method 69

(R)-N-(2-Chloro-3-nitro-4-itfinal)-2-trimethylsilyloxy-2-methyl-3,3,3-tryptophanate

4-Iodine-3-nitro-2-Chloroaniline (method 70) (1269 mg) and 2,6-di-tert-butylpyrazine (1.5 ml) was added to a solution of (S)-3,3,3-Cryptor-2-(trimethylsilyloxy)-2-methylpropanamide (obtained from ()-3,3,3-Cryptor-2-hydroxy-2-methylpropionic acid (method 25), as described in J. Med. Chem., 1999, 42, 2741-2746) (6 mmol) in DHM (40 ml). The mixture was stirred for 3 days at ambient temperature. Volatiles were removed by evaporation and the residue was purified by chromatography with elution with 10% EtOAc in hexane, getting named the title compound (1160 mg). NMR: 0,27 (s, N), to 1.70 (s, 3H), of 7.70 (d, 1H), with 8.05 (d, 1H), 9,72 (Sirs, 1H); m/z: 509.

Method 70

4-Iodine-3-nitro-2-Chloroaniline

Monochloride iodide (1.25 ml) was added to a solution of 3-nitro-2-Chloroaniline (4265 mg) in glacial acetic acid (40 ml). The mixture was stirred for four hours at 70°C. After the mixture was allowed to cool to ambient temperature, was added a saturated solution of sodium sulfite (100 ml). The solution was extracted with EtOAc (200 ml), the volatiles were removed by evaporation and the residue was re-dissolved in EtOAc (150 ml), washed with saturated sodium bicarbonate solution (75 ml), brine (75 ml) and dried. Volatiles were removed by evaporation and the residue was purified by chromatography with elution with 5-15% EtOAc in hexane, obtaining a mixture named in the title compound and starting material (1,933 mg) (ratio 1:1,75). Monochloride iodine (0,28 ml) was added to a solution of the mixture (1919 mg) in glacial acetic acid (10 ml). The mixture was stirred for four hours at 70°C. After the mixture was allowed to cool to ambient temperature, was added a saturated solution of self is the sodium (50 ml). The solution was extracted with EtOAc (100 ml), the volatiles were removed by evaporation and the residue was distributed between EtOAc (100 ml) and saturated sodium bicarbonate solution (50 ml). The organic phase was separated, washed with brine (50 ml) and dried. Volatiles were removed by evaporation and the residue was purified by chromatography with elution with 5-15% EtOAc in hexane, getting named the title compound (1286 mg) as a solid. NMR: to 6.19 (s, 2H), 6.73 x (d, 1H), 7,50 (d, 1H); m/z: 297.

Method 71

(R)-N-[4-{2-Nitrapyrin-6-ylsulphonyl}-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

A mixture of (R)-N-[2,3-Dichloro-4-(chlorosulfonyl)phenyl]-2-hydroxy-2-methyl-N,3,3-tryptophanate (2 g, 5 mmol) (method 73), sodium sulfite (1,25 g) and sodium bicarbonate (1,05 g) in water (10 ml) was stirred at 75°C for 1 hour. The solution is evaporated to dryness, obtaining white solid. To it was added 2-chloro-6-nitropyridine (method 72; 713 mg) and DMF (15 ml). The mixture was heated with stirring at 75°C for 4 hours and then gave the mixture to cool to room temperature. The residue was distributed between water and EtOAc. The aqueous layer was extracted with EtOAc, the organic layers were combined, washed with brine, dried and the volatiles removed by evaporation. Purification was performed on a column of Honey Bond Elut in a gradient elution solvent 0-40% EtOAc/hexane. Thus, it has been named as header the compound (250 mg) as a pale yellow foam. NMR: 1,6 (s, 3H), and 8.1 (s, 1H), and 8.4 (q, 2H), and 8.6 (d, 1H), 8,9 (d, 1H), and 9.4 (s, 1H); m/z: 486.

Method 72

2-Chloro-6-nitropyridine

Chloride copper(II) (5.8 g) and tert-butylnitrite (6,1 ml) was stirred in THF (150 ml) in an argon atmosphere and heated to 65°C. Portions were added 2-amino-6-nitropyridine (Shurko, O.R., Mamaev, V.P., Chem. Heterocycl. Comp., 26, 1990, 1, 47-52; 5 g, 36 mmol). The reaction mixture was stirred at 65°C for 1 hour and then allowed it to cool to room temperature. Added EtOAc (200 ml), the organic layer washed with 2M Hcl, water and dried. Volatiles were removed by evaporation, getting sticky orange solid, which was triturated with hexane, getting named the title compound (3.4 g) as a brown-orange solid. NMR: 7,8 (d, 1H), and 8.6 (d, 1H), and 9.2 (s, 1H).

Method 73

(R)-N-[2,3-Dichloro-4-(chlorosulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-{2,3-Dichlorophenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (method 74) (5.0 g, of 16.6 mmol) for 15 minutes was added in portions to a cooled (0° (C) chlorosulfonic acid (5.3 ml, 81 mmol) and then the mixture was heated at 85°C for 4.5 hours. The reaction mixture was cooled in a bath with ice and then was slowly poured into a stirred mixture of ice-water (60 ml). The mixture was extracted with DHM (2×75 ml), DHM the extract was washed with brine, dried and evaporated. The residue was purified by chromatography on dioxide cream the Oia with 20% EtOAc in hexane as the eluent, getting named the title compound as a solid (3.0 g, 7.5 mmol). NMR (Dl3): 1,8 (s, 3H), 3,4 (s, 1H), 8,15 (d, 1H), 8,65 (d, 1H) and of 9.55 (Sirs, 1H); m/z: 400.

Method 74

(R)-N-{2,3-Dichlorophenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of 2,3-dichloraniline (6.85 g, 42,5 mmol) and pyridine (5.1 ml, 75 mmol) in DHM (100 ml) was added a solution of S-3,3,3-Cryptor-2-trimethylsilyloxy-2-methylpropanamide (obtained from (R)-3,3,3-Cryptor-2-hydroxy-2-methylpropionic acid (method 25), as described in J. Med. Chem., 1999, 42, 2741-2746) (12.2 g, 150 mmol) in DHM (50 ml). The mixture was stirred at ambient temperature for 24 hours, then washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine, then dried and evaporated. The residue was dissolved in Meon (50 ml)was treated with 1M hydrochloric acid (25 ml) and the mixture was stirred at ambient temperature for 18 hours. Meon evaporated, the aqueous layer was extracted with EtOAc (2×25 ml), the EtOAc extracts were washed with saturated sodium bicarbonate solution and brine, then dried and evaporated. The residue was purified by chromatography on silica with DHM as eluent, getting named the title compound as a solid (5.2 g, 17.3 mmol). NMR: 1,6 (s, 3H), and 7.4 (DD, 1H), 7.5 (d, 1H), and 7.8 (s, 1H), 7,9 (d, 1H), and 9.8 (s, 1H); m/z: 300.

Method 75

2-Chloro-3-fluoro-4-(4-N,N-dimethyl who carbamoylmethyl) nitrobenzene

Named in the title compound was obtained from 2-chloro-Z-fluoro-4-(4-carboxypenicillins)nitrobenzene (method 24) according to the procedure of example 51. NMR: 2,95 (d, 6N), 7,20 (DD, 1H), 7,50 (d, 2H), 7,60 (d, 2H), 7,95 (d, 1H); m/z (ES+): 355 (M+N)+.

Method 76

(R)-N-{2-Chloro-3-(4-carboxyphenylazo)-4-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

(R)-N-{2-Chloro-3-fluoro-4-[4-(N,N-dimethylcarbamoyl)phenylsulfonyl] phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate (example 18) was treated with 4-mercaptobenzoic acid according to the procedure of example 50, getting named the title compound as a white solid (0.39 g, 25%). NMR: 1,60 (s, 3H), 2,90 (s, 3H), of 3.00 (s, 3H), 7,55-the 7.65 (m, 4H), of 7.90-to 7.95 (m, 4H), with 8.05 (s, 1H), 8,55 (d, 1H), 8,65 (d, 1H), 9,95 (s, 1H), or 10.60 (s, 1H); m/z: 629.

Method 77

2-Fluoro-3-(isopropylphenyl)-6-nitroaniline

To a solution of 2,3-debtor-6-nitroaniline (10,04 g) in DMF (200 ml) was added 2-propandiol sodium (5,66 g). The mixture was stirred at ambient temperature for 16 hours, then diluted with EtOAc (300 ml) and washed with brine (500 ml). The wash liquid was extracted with EtOAc (300 ml). The organic phases were combined, washed with brine (500 ml), dried and the volatiles removed by evaporation, getting named the title compound (14.1 g) as a solid. NMR: 1,30 (d, 6N), 3,70 (septet, 1H), 6,70 (DD, 1H), 7,26 (s, 2H), 7,80 (DD, 1H); m/z: 229.

Method 78

2-Chloro-3-ft is R-4-(isopropylphenyl)nitrobenzene

A solution of 2-fluoro-3-(isopropylphenyl)-6-nitroaniline (method 77; 14.0 g) in acetonitrile (100 ml) was added under stirring at 65°in an argon atmosphere to a mixture of copper chloride(II) (8,95 g) and tert-butylnitrite (9,9 ml) in acetonitrile (300 ml) and the mixture was stirred for 2.5 hours. The reaction mixture was allowed to cool, added EtOAc (300 ml), the mixture was washed with 2M hydrochloric acid (2×200 ml), brine (200 ml) and dried. Volatiles were removed by evaporation and got the oil. The oil was purified by chromatography on silica gel with elution 10-25% EtOAc in hexane, getting named the title compound (10,16 g). NMR: 1,33 (d, 6N), of 3.78 (m, 1H), 7,65 (t, 1H), 7,98 (d, 1H); m/z: 249 (M+).

Method 79

2-Chloro-3-fluoro-4-(isopropylphenyl)aniline

A solution of uranyl trichloride iron (32.7 g) in water (100 ml) was added to a mixture of 2-chloro-3-fluoro-4-(isopropylphenyl)nitrobenzene (method 78; 10,07 g) and zinc dust (26,36 g) in DMF (100 ml). The mixture was heated to 100°C for two hours and then allowed it to cool to ambient temperature. Then the mixture was diluted with EtOAc (500 ml), filtered through hard-shelled land, washed with brine (4×250 ml), dried over magnesium sulfate and the volatiles were removed by evaporation and got the oil. The oil was purified by chromatography on silica gel with elution with 10% EtOAc in hexane, getting named the title compound (5.29 g) as a solid which CSOs substances. NMR: 1,11 (d, 6N), 3,10 (septet, 1H), of 5.92 (s, 2H), to 6.57 (d, 1H, 7,11 (t, 1H); m/z: 219 (M+).

Method 80

(2R)-N-[2-Chloro-3-fluoro-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate

To a solution of (R)-(+)-2-hydroxy-2-methyl-3,3,3-Cryptor-propanoic acid (method 25; at 4,424 g) in DHM (75 ml) was added 1,3-bis(trimethylsilyl)urea (5.73 g) and the mixture was stirred for 16 hours at ambient temperature. The solid was filtered and washed DHM (20 ml). The organic solutions were combined, cooled in a bath with ice and added oxalicacid (2.7 ml) and DMF (cat.). Then the solution was heated to ambient temperature and was stirred for 24 hours. Volatiles were removed by evaporation, the residue was dissolved in DHM (50 ml) and added to cooled in a bath with ice to a mixture of 2-chloro-3-fluoro-4-(isopropylphenyl)aniline (method 79; at 5,105 g) and triethylamine (11.7 g) in DHM (50 ml). The mixture was allowed to warmed to ambient temperature and was stirred for 18 hours. Volatiles were removed by evaporation and got the oil. The oil was purified by chromatography on silica gel with elution 10%-25% EtOAc in hexane, obtaining a solid substance. The substance was dissolved in anhydrous THF (15 ml) and cooled to -78°C. was Added 1M tetrabutylammonium (3.6 ml) and the mixture was stirred for 45 minutes at -78°C in argon atmosphere. Then the mixture was allowed to warmed up is about ambient temperature and was stirred additionally for 45 minutes. Added 2 M hydrochloric acid (50 ml) and the mixture was extracted with EtOAc (100 ml). The extract was washed with brine (50 ml), dried, volatiles were removed by evaporation and has been named the title compound (1.23 g) as a solid. NMR: 1,21 (d, 6N), was 1.58 (s, 3H), of 3.45 (m, 1H), 7,50 (t, 1H), 7,79 (d, 1H), to 7.84 (s, 1H), 9,79 (s, 1H); m/z: 358,35.

Method 81

2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfanyl]-nitrobenzene

2-Chloro-3-fluoro-4-(4-carboxypenicillins)nitrobenzene (method 24; 5.5 g, a 16.8 mmol) suspended under stirring in DHM (100 ml) was added oxalicacid (3,22 ml). Added a couple of drops of DMF to initiate the reaction and left the mixture with stirring over night. The mixture was evaporated to dryness and then dissolved in DHM (20 ml). N-Ethyl-N-methylamine (and 0.46 ml, 5,28 mmol) was dissolved in DHM (1 ml) and thereto under stirring was added a little above described solution of the hydrochloride (2.4 mmol). The solution was left under stirring overnight and then washed with water, brine and dried, was poured into the column, Chem Elut and suirable EtOAc. The resulting solution was evaporated to dryness and then purified using chromatography on a column of Honey Bond Elut when gradient elution solvent hexane/EtOAc, getting named the title compound (680 mg). NMR: 1,1 (s, 3H), 2,9 (d, 3H), 3,2 (s, 1H), 3,4 (s, 1H), 7,2 (m, 1H), 7.5 (d, 2H), and 7.6 (d, 2H), 8,0 (m, 1H); m/z: 369.

Method 82

2-Chloro-3-FPO is-4-[4-(N-ethylcarbazole)phenylsulfanyl]nitrobenzene

A solution of ethylamine (2M in absolute EtOH; 2.65 ml) were placed in a reaction vessel with DHM (1 ml). There was added a portion of a solution of the acid chloride (2.4 mmol), prepared according to the method of 81. The solution was left to mix overnight and then washed with water, brine and dried, was poured into the column, Chem Elut and suirable EtOAc. The solution was evaporated to dryness and was purified by chromatography on a column of Honey Bond Elut when gradient elution solvent hexane/EtOAc, getting named the title compound (380 mg). NMR: 1,1 (t, 3H), 3,2 (m, 2H), and 7.1 (t, 1H), and 7.6 (d, 2H), 7,9 (m, 2H), and 8.6 (s, 1H).

Method 83

2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfanyl]aniline

2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfanyl]nitrobenzene (method 81; 650 mg of 1.76 mmol) was heated with stirring at 75°C for 45 minutes with iron powder (1.06 g), EtOH (1.2 ml), water (0.5 ml) and 2 drops of conc. HCl. Then the mixture was allowed to cool to room temperature, was podslushivaet saturated sodium bicarbonate solution was added EtOAc. The reaction mixture was filtered through a layer of hard-shelled land, thoroughly washing with water and EtOAc. The organic layers were combined and washed with water, dried, filtered and evaporated to dryness, getting named the title compound (600 mg) as a pale yellow resin. NMR: 1,0 (s, 3H), AND 2.8 (S, 3H), 3,2 (d, 2H), 6,2 (s, 1H), 7,0 (m, 2H), 7,2 (m, 3H).

Method 84

2-Chloro-3-fluoro-4-[4-(N-e who ylcarbonyl)phenylsulfanyl]aniline

2-Chloro-3-fluoro-4-[4-(N-ethylcarbazole)phenylsulfanyl] nitrobenzene (method 82; 360 mg of 1.02 mmol), iron powder (617 mg), EtOH (0.68 ml), water (0,28 ml) and 1 drop of conc. HCl was heated at 75°With stirring for 45 minutes. The mixture was allowed to cool to room temperature and then was podslushivaet a saturated solution of sodium bicarbonate. Added EtOAc and the solution was poured into the column, Chem Elut and suirable EtOAc, getting named the title compound (260 mg) as a pale yellow sticky solid. NMR: 1,1 (t, 3H), 3,2 (square,2H), 6,1 (s, 1H), 7,0 (square,2H), and 7.7 (t, 2H), and 8.3 (d, 1H).

Method 85

(R)-N-{2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamate)phenylsulfanyl]aniline (method 83; 580 mg, 1.7 mmol) was dissolved in DHM (6 ml) was added pyridine (0,28 ml). S-3,3,3-Cryptor-2-(trimethylsilyloxy)-2-methylpropanoate (obtained from (R)-3,3,3-Cryptor-2-hydroxy-2-methylpropionic acid (method 25), as described in J. Med. Chem., 1999, 42, 2741-2746) (508 mg) was dissolved in DHM (1 ml) and added to aniline. The solution was stirred for 4 hours and then washed with Hcl (2M)to remove excess pyridine. The organic layer was evaporated to dryness, dissolved in Meon (17 ml) was added Hcl (2 M, 1.7 ml). The solution was left overnight under stirring at room temperature. Meon was removed and the residue was distributed m is waiting for water and EtOAc. The aqueous layer was twice extracted with EtOAc, the organic layers were combined, washed with water, brine and dried, was poured into the column, Chem Elut and suirable EtOAc. The resulting solution was evaporated to dryness and was purified by chromatography on a column (Bond Elut when elution with a mixture of 5-65% EtOAc/isohexane, getting named the title compound (390 mg) as a white solid. NMR: 1,0 (s, 3H), and 1.6 (s, 3H), and 2.8 (s, 3H), 3,2 (d, 2H), 7,2 (d, 2H), and 7.3 (d, 2H), and 7.6 (t, 1H), and 7.9 (s, 1H), 9,9 (s, 1H); m/z: 477.

Method 86

(R)-N-{2-Chloro-3-fluoro-4-[4-(N-ethylcarbazole)phenylsulfonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate

2-Chloro-3-fluoro-4-[4-(N-ethylcarbazole)phenylsulfanyl]aniline (method 84) were subjected to reaction with (S)-3,3,3-Cryptor-2-(trimethylsilyloxy)-2-methylpropanamide according to the procedure of method 85 obtaining specified in the title compound as a yellow resin. M/z: 463.

Example 85

Next illustrate representative pharmaceutical dosage forms containing the compound of formula (I)or its pharmaceutically acceptable salt or hydrolyzable in vivo ester (hereafter compound X), for therapeutic or prophylactic use people:

(a): Tablet Img tablet
Compound X100
Lactose Ph. Eur.182,75
Three is crosscarmelose to 12.0
Pasta corn starch (pasta 5% wt./about.)2,25
Magnesium stearate3,0

(b): Tablet IImg tablet
Connection X50
Lactose Ph. Eur.223,75
Nitrocresols6,0
Corn starch15,0
Polyvinylpyrrolidone (pasta 5% wt./about.)2,25
Magnesium stearate3,0

(C): Tablet IIImg tablet
Connection X1,0
Lactose Ph. Eur.93,25
Nitrocresols4,0
Pasta corn starch (pasta 5% wt./about.)0,75
Magnesium stearate1,0
 
(d): Capsulemg/capsule
Compound X10
Lactose Ph. Eur.488,5
Magnesium stearate1,5

(e): Injection I(50 mg/ml)
Connection X 5,0% (wt./about.)
1M sodium hydroxide solution15,0%vol.
0,1M hydrochloric acid solution(to bring the pH to 7.6)
The polyethylene glycol 4004.5% wt./about.
Water for injectionup to 100%

(f)Injection II10 mg/ml
Compound X1,0% (wt./about.)
Sodium phosphate BP3,6% wt./about.
0,1M sodium hydroxide solution15,0%vol.
Water for injectionup to 100%

(d): Injection III(1 mg/ml, buffered to pH 6)
Compound X0.1% wt./about.
Sodium phosphate BPof 2.26% wt./about.
Citric acid0,38% wt./about.
The polyethylene glycol 400a 3.5% wt./about.
Water for injectionup to 100%

Note:

The form above can be obtained by conventional means, well known in the field of pharmaceutical technology. The tablets (a)-(C) can be by known methods covered intersolubility coating, for example, with the teachings of the coating from acetamidoacrylate.

Table I

Increase PDG activity in vitro in isolated primary cells
Examples No.EU50(μM)
10,11
90,95
370,22
390,1
610,11
635,62
272,15
103
902
780,27
510,52
340,33
770,1
810,1
750,1
690,1
240,1
490,84
410,47
570,19
620,1
131

1. Substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3,-tryptophanate formula (I)

where n equals 1 or 2;

R1represents chlorine, fluorine, bromine, methyl or methoxy;

R2choose one of the following three groups:

i) halogen, nitro, hydroxy, amino or cyano;

ii) -X1-R5where X1represents-O-, -S-, -SO-, -SO2-, -NR6-, -CO-, -CONR6-, -NR6CO-, where R6is hydrogen; and R5choose from C1-6the alkyl, optionally substituted by one or more a, C3-7cycloalkyl, optionally substituted by one or more a, C3-7cycloalkyl1-6the alkyl, optionally substituted by one or more a, C2-6alkenyl, optionally substituted by one or more a, C2-6the quinil, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, panels1-6the alkyl, optionally substituted by one or more D;

iii) attached to the nitrogen atom 4-8-membered heterocyclic group, which is saturated monocyclic ring containing 4 to 8 carbon atoms, of which at least one is a nitrogen atom with optional additional heteroatom independently selected from O, N and S, where the sulfur atom in the ring may be optionally oxidized, and where, if said heterocyclic group contains an-NH-group, that nitrogen may be optionally substituted by a group selected from G;

R3represents C1-6alkyl, optionally substituted by one or several them And, With3-7cycloalkyl, optionally substituted by one or more A, phenyl, optionally substituted by one or more D, attached carbon atom to 6-membered heteroaryl ring containing 1-2 nitrogen atom, optionally substituted at the carbon atom of the ring by one or more D;

And are selected from hydroxy, amino, halogeno, carboxy, N-(C1-4alkyl)amino, N,N-di(C1-4alkyl) amino, carbarnoyl, and C1-6alkoxy;

D is chosen from:

i) -Xa-Rcwhere Xais-SO2-, -CO-, -NRdCO-, -NRdor-CONRd-; where Rdindependently represents hydrogen or C1-4alkyl, optionally substituted by hydroxy; and Rcselected from hydrogen or C1-6the alkyl, optionally substituted by one or more hydroxy or C1-4alkoxy;

iv) cyano or halogeno;

v) -Xwith-Rfwhere Xcrepresents-C(O)- and Rfis attached by the nitrogen atom 4-8-membered heterocyclic group,

which is a saturated monocyclic ring containing 4 to 8 carbon atoms, of which at least one is a nitrogen atom, with optional, additional heteroatom independently selected from O, optionally substituted at the carbon atom of the ring by hydroxy group, halogen, C1-4alkoxy,C 1-4alkyl or cyano;

G represents a C1-6alkanoyl;

R4represents hydrogen or fluorine;

or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

2. The compound of formula (I) according to claim 1, in which n equals 2, or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

3. The compound of formula (I) according to claim 1 or 2, in which R1represents methyl, chlorine or fluorine, or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

4. The compound of formula (I) according to any one of claims 1 to 3, in which R2represents chlorine, fluorine, bromine, iodine, nitro, amino, methoxy, acetylamino, hydroxy, C1-4alkylsulfanyl (optionally substituted by hydroxy), C1-4alkylsulfonyl,1-4alkylsulfonyl, N-(C1-4alkyl)-amino (optionally substituted by hydroxy, methoxy, dimethylamino or carbamoyl), morpholino, 4-acetylpiperidine-1-yl, thiomorpholine, 1 Osotimehin, 1,1-dioxothiazolidine, benzylamino, phenoxy, phenylsulfonyl (optionally substituted N-(C1-4alkyl)2carbamoyl), or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

5. The compound of formula (I) according to any one of claims 1 to 4, in which R3represents methyl, ethyl (optionally substituted by hydroxy), isopropyl, butyl (long what) substituted by hydroxy), phenyl [optionally substituted with halogen, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbazole, N-methylcarbamoyl, N-ethylcarbazole, acylamino (optionally substituted by hydroxy), mesilim, azetidinone, morpholinoethyl or pyrrolidinyl-carbonyl (optionally substituted by hydroxy)] or attached carbon atom of the pyridyl (optionally substituted amino), or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

6. The compound of formula (I) according to any one of claims 1 to 5, in which R4represents hydrogen, or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

7. The compound of formula (I)selected from the

(R)-N-[2-chloro-3-(1-oxathiolane)-4-(ethylsulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(1-oxathiolane)-4-(isopropylphenyl)-phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(1,1-dioxothiazolidine)-4-(methylsulphonyl)-phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(1,1-dioxothiazolidine)-4-(ethylsulfonyl)-phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(1,1-dioxothiazolidine)-4-(isopropyl-sulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(4-acetylpiperidine-1-yl)-4-(ethylsulfonyl)-phenyl]-2-hydroxy-2-methyl-3,3,3-thrift is propanamide;

(R)-N-{2-chloro-3-[1-(4-acetyl)piperazinil]-4-(methyl-sulfonyl)phenyl}-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-morpholino-4-(methylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

(R)-N-[2-chloro-3-(4-acetylpiperidine-1-yl)-4-(isopropyl-sulfonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate; and

(R)-N-[2-chloro-3-morpholino-4-(isopropylphenyl)phenyl]-2-hydroxy-2-methyl-3,3,3-tryptophanate;

or its pharmaceutically acceptable salt or hydrolyzable in vivo ester.

8. The compound of formula (I), a (R)-N-(2-chloro-4-ethylsulfonyl-3-methylsulfinylphenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate.

9. The compound of formula (I) according to claim 1, which represents the (R)-N-(4-mesyl-3-methylsulfanyl-2-chlorophenyl)-2-hydroxy-2-methyl-3,3,3-tryptophanate.

10. The method of obtaining the compounds of formula (I) according to claim 1 or its pharmaceutically acceptable salt or hydrolyzable in vivo complex of ether, where the method (in which the variable groups are as defined for formula (I), unless otherwise noted) include:

(a) unprotect a protected compound of formula (II)

in which Rd represents an alcohol protective group

(b) oxidation of compounds of formula (III)

(with the combination of compounds of the formula (IV)

with the acid of formula (V)

in which X represents IT;

(d) a combination of aniline of formula (IV) with an activated derivative of the acid of formula (V);

and after that, if necessary:

i) the conversion of compounds of formula (I) into another compound of formula (I);

ii) removal of all protective groups; or

iii) formation of pharmaceutically acceptable salts or hydrolyzable in vivo complex ether.

11. Pharmaceutical composition that increases activity of the PDG, which includes substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-tryptophanate formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt or hydrolyzable in vivo ester in combination with a pharmaceutically acceptable diluent or carrier.

12. The compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt or hydrolyzable in vivo ester for use in a method of therapeutic treatment of the human or animal.

13. The compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt or hydrolyzable in vivo ester usable in the manufacture of medicaments for use in the treatment of diabetes, peripheral vascular disease and ischemic heart disease and myocardial warm-blooded animals, such as human beings.

14. The compound of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salt or hydrolyzable in vivo ester, suitable as drugs for the treatment of diabetes mellitus, peripheral vascular disease (including alternating lameness), heart failure and certain cardiac myopathy, myocardial ischemia, cerebral ischemia, reperfusion, muscle weakness, hyperlipidemia, Alzheimer's disease and/or atherosclerosis.

Priorities for items:

claims 1 to 7, 10-14 August 30, 2000;

step 8 GB No. 9920814.2, from September 4, 1999;

9 GB No. 000641.5, dated March 21, 2000



 

Same patents:

The invention relates to new compounds, levogyrate and programada, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -4-[(were)sulfonyl]-piperazine of the formula I:

< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to stereochemical controlled way to obtain usacycling compounds of formula (Ia,), where R1R2CH-group in the 5-position of cyclic fragment and the hydroxy-group at the 3-position of cyclic element are in TRANS-position is obtained with respect to each other and where the substituent R44-polozheniii and the hydroxy-group at the 3-position of cyclic fragment are zespolony relative to each other and where n is 0 or 1, R1-R3is hydrogen, R4is hydrogen or lower alkyl, or R3andR4together mean WITH2-C6-alkylenes chain, R5-R7is hydrogen,R8is hydrogen, lower alkyl, (lower alkoxy)lower alkyl, phenyl or phenyl-lower alkyl, R6andR7together can also form a bond, and R5andR8together with the carbon atoms to which they are linked, can form an aromatic6ring system, R9is hydrogen or a protective amino group, or R8and R9together can form WITH3-C4-alkylenes chain or their salts

The invention relates to a new group of individual chemical compounds - cyclic amino compounds represented by the following formula:

< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

The invention relates to new derivatives of azetidine and pyrrolidine General formula

< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

The invention relates to a method for obtaining compounds of formula III or its salt

< / BR>
(where R1is tertbutoxycarbonyl, benzyl; R3represents C1-C6alkyl interaction of the compounds of formula I

< / BR>
(where R1shall have the meaning given above and R2is methanesulfonyl group or p-toluensulfonyl group) with a compound of formula II

< / BR>
in the presence of a base

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt
The invention relates to N-methyl-N-/(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)-ethyl/-2,2-diphenylacetamide, which can be used in the treatment of inflammatory bowel disease

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

The invention relates to a method of obtaining a mixture of Z - and E-isomers of ajoene in the ratio 2:1, namely, that the solution of the synthetic allicin in n-butanol was incubated for 6 days at a temperature of 21-23°C, followed if necessary by separation of the isomers by the method of preparative HPLC

The invention relates to thiosulfonate compounds of General formula Ia, which can be used as inhibitors of the matrix metalloprotease-13 (MMP-13)

The invention relates to an inhibitor of the activity of esterified cholesterol transport protein (HETB), comprising as active ingredient a compound represented by the formula (I), where R is a straight or branched alkyl group; a lower halogenating group; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted cycloalkylcarbonyl group; substituted or unsubstituted aryl group, or substituted or unsubstituted heterocyclic group, X1X2X3and X4may be the same or different and each represents a hydrogen atom, halogen atom, lower alkyl group, lower halogenating group; a lower alkoxygroup; a cyano; a nitro-group; Y represents-CO -, and Z represents a hydrogen atom or mercaptohexanol group, or its pharmaceutically acceptable salt, or hydrate, or MES
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