Derivatives of 2-amino-4h-3,1-benzoxazine-4-one for prophylaxis or treatment of obesity or accompanying disorder

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

 

The present invention relates to known and new compounds, their use in the inhibition of the enzyme, the primary effect of which is to catalyze the hydrolysis of ester functional groups (in vivo, because the enzyme natural origin), their application in medicine, and, in particular, in the prevention and/or treatment of obesity or obesity-related diseases. Proposed methods of preventing and/or treating obesity or obesity-related diseases and promotion/promote weight loss without the use of medicines and use of compounds in the manufacture of medicinal products specified above purpose. For new compounds according to the invention proposed methods for their preparation, compositions containing them, and methods for producing such compounds.

In the last 20 years, there has been a growing tendency to fullness in the developed world. The increase in the number of cases of obesity is partly due to the wide availability of food in numerous retail outlets and Western diets using a highly saturated fat low fiber content, i.e. energy-dense foods. In addition, the way of life of the population in developed countries is becoming more and more sedentary with increasing mechanization and helpless the reduction in the number of enterprises with high labour costs of manual labor. Thus, there is an energy imbalance between energy intake with picocuries food and reduce power consumption when a sedentary lifestyle. A certain amount of excess energy is stored as fat in adipose tissue, the accumulation of which in the course of some period of time leads to obesity and can be an important factor in the development of other diseases and disorders.

Currently, obesity is considered a metabolic disorder. In the United States, an estimated 25% of the adult population is affected clinical obesity (BMI >30). Obesity can be a debilitating condition, which reduces the quality of life and increases the risk of comorbidities such as diabetes, cardiovascular disease and hypertension. Estimated at US $ 45 billion, or 8% of the annual health costs comprise costs associated with the direct results of obesity. The traditional approach to long-term weight control, such as diet and exercise, has been found to be ineffective to control the growth of obesity. Today, more than ever, there is considerable interest in the development of safe, effective drugs for the treatment of obesity.

Pharmacological approach to the treatment of obesity lies in p is this the drugs, or contributing to the increase in energy consumption, or to reduce energy consumption. One approach to reducing energy consumption is to reduce the body's ability to digest and absorb food, particularly fats. The main enzymes involved in the breakdown of fat are enzymes hydrolysis. The most important enzymes for the breakdown of fats are lipase, primarily, but not exclusively, pancreatic lipase, which are secreted by the pancreas in the digestive tract. Enzyme inhibitor lipstatin was the basis of drug against obesity - orlistat. Orlistat is the subject of the published application in the European patent EP 129748, which relates to the compound of the formula:

Where a represents -(CH2)5-or:

And their use in the inhibition of pancreatic lipase and hyperlipidemia, and obesity. Orlistat has as main active group of beta lactoovo group, which reacts with the formation of ester with the hydroxyl group of the side chain of serine 152 in the region of the active site of pancreatic lipase. Even despite the fact that orlistat is an effective agent for the treatment of obesity remains a need for alternative Lech is only a preparation and method for control and treatment of obesity, comorbidities and non-medical weight loss. The proposed inhibitors of enzymes involved in the breakdown of fats, and also shown their effectiveness in the prevention and/or treatment of obesity related diseases and/or for cosmetic weight loss.

In U.S. patent 466576893 (Syntex) describes a broad class of compounds 2-amino-4H-3,1-benzoxazin-4-it formula:

where R1is hydrogen or lower alkyl, R2and R3each independently hydrogen, halogen, lower alkyl, gotoxy, lower alkoxyl, lower thioalkyl, NO2N(R1)2, NR1COR1, NHCON(R1)2, NHCOOR1, a X - inter alia-other, where R is lower alkyl, lower alkenyl, lower quinil, possibly substituted lower cycloalkyl or possibly substituted phenyl lower alkyl. The compounds are useful as serine protease inhibitors and for the treatment of physiological conditions and diseases, in which, as far as is known, involves the serine protease, or as a contraceptive. In the description of the invention describes various conditions and diseases involving fermentation processes, including inflammation, arthritis, metastasis of cancer cells, emphysema, symptoms of skin and mucous membranes, lymph nodes, respiratory disorders in adults and pancreatitis. Assumed that the connection mo is ut to have antiparasitic, anticoagulate and/or anti-viral action. Similar compounds are also described Krantz et al., J.Med. Chem. 1990, 33: 464-479.

Compounds 2-amino-4H-3,1-benzoxazin-4-it is as serine protease inhibitors are also described Hays et al., in J. Med. Chem. 1998 41: 1060-1067. In this work, described amongst the compounds 2-(substituted phenyl) amino of benzoxazinone, where the phenyl substituents include halogen, methyl, SMe, and F3and some 2-(heterocycle)aminobenzamidine. Some of these compounds are also described in U.S. patent 5,652,237 (Warner Lambert).

In the application Germany OLS 2315303 (Bayer AG) describes the formation of compounds of the formula

where R is an alkyl or aryl residue which may be substituted by a nitro-group, halogen, alkyl, alkoxy or aryl group, and R’ and R’ each independently represents hydrogen, halogen, a nitro-group, possibly substituted alkyl, cycloalkyl, aralkyl, aryl, alkoxy or aryloxy group. The only examples of R is nitrophenyl, and mono - and di-course. It is known that such compounds are used as an intermediate for pharmaceuticals and plant protection products.

We found that one of the classes of compounds of benzoxazinone active as a lipase inhibitor.

Thus, according to the first aspect of the present invention p is edlozano compound of formula (I)

or its pharmaceutically acceptable salt, ester, amide or the precursor in the manufacture of a medicinal product for the treatment of conditions requiring inhibition of the enzyme, the primary effect of which is to catalyze the hydrolysis of the ether functional groups, where in the formula (I)

A - six-membered aromatic or heteroaromatic ring,

R1branched or unbranched alkyl (the carbon chain of which may interrupted by one or more oxygen atoms), alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, restored arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic restored aryl, restored heteroaryl, restored heteroaromatic or substituted derivative in which the Deputy is one or more independently selected from the group of halogen, alkyl, substituted with halogen alkyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, restored heteroallyl, Allakaket-, cyan-, nitro-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X 2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7C(O)NHNR6R7, -C(O)N(OR5R6or lipid or steroid (natural or synthetic), provided that any replacement heteroatom in R1or R2must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated), and

R2is hydrogen or a group as defined for R1and where

R4represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or restored heteroaromatic, OR6, NHCX1X2CO2R6or NR6R7,

R5represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or restored heteroallyl,

R6and R7independently selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, heteroaromatic, restored heteroallyl or -(CH2)n(OR5)m, where n is from 1 to 12, preferably from 2 to 10, a m is 1 to 3, and R5most preferably alkyl With2-10,

X1and X 2independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, heteroaromatic, or restored heteroallyl.

In the compounds of formula I, any alkyl, Alchemilla or Alchemilla group or the group may be a linear (unbranched) or branched chain. Linear chain alkyl, alkenyl or etkinlik groups or groups can contain from 1 to 30 carbon atoms, for example, from 1 to 25 carbon atoms, preferably from 1 to 20 carbon atoms. Branched chain alkyl, alkenyl or etkinlik groups or groups can contain from 1 to 50 carbon atoms, preferably from 1 to 30 carbon atoms.

Preferred values for R1, R4, R5, R6, R7X1and X2the same as that defined above for formulas (I) and (IIA). In particular, the preferred values for R4, R5and R6are the same as for R13and preferred values for R7are the same as for R14. In this context, "restored", for example, "restored heteroaryl"means a fully or partially saturated.

Aryl groups include, for example, possibly substituted unsaturated monocyclic or bicyclic ring, containing the E. to 12 carbon atoms, such as phenyl and naphthyl, and partially saturated bicyclic ring, such as tetrahydronaphthyl. Examples of substituents that may be present in the aryl groups include one or more halogen, amino, nitro, alkyl, halogenated, alkoxy, phenoxy, and phenoxy substituted by one or more halogen, alkyl or alkoxy.

Heteroaryl group or the group may represent, for example, possibly substituted 5 - or 6-membered heterocyclic aromatic ring which may contain 1 to 4 heteroatoms selected from O, N and S. the Heterocyclic ring may possibly be associated with the phenyl ring. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, thiazolyl, triazinyl, pyridil, pyrimidinyl, pyrazolyl, indolyl, indazoles, benzofuranyl, benzothiazol, benzimidazolyl, benzoxazolyl, benzoxazines, honokalani, hintline, indolinyl, benzothiazolyl, iridoviral. Suitable substituents include one or more halogen, oxo, amino, nitro, alkyl, halogenated, alkoxy, phenoxy, and phenoxy substituted by one or more halogen, halogenoalkanes, alkyl or alkoxygroup.

Retrieved heteroaryl group or groups can be represented, for example, fully or frequent is a rule saturated derivatives of the above-mentioned heteroaryl groups. Examples of restored heteroaryl groups include pyridinyl, tetrahydrofuryl, tetrahydrothieno and piperidinyl.

Compounds according to the first aspect of the invention are useful inhibitors of enzymes involved in the breakdown of fats. Preferably, therefore, the first aspect of the invention includes the use of compounds of formula (1) as described above, or

pharmaceutically acceptable salt, ester, amide or its predecessor, in the manufacture of a medicinal product for control or treatment of obesity and related disorders or to facilitate non-medical weight loss.

Preferably the connection according to the first aspect of the invention is a compound of formula (II):

or its pharmaceutically acceptable salt, ester, amide or predecessor

where R1, R4, R5, R6, R7X1and X2are the same as defined above for formula (I), R2represents hydrogen or a group such as defined for R1and R8, R9, R10, R11each independently represent hydrogen, halogen, hydroxy-, amino-, nitro-, cyano - or group, R1as defined above, or a group R12Q, where Q represents O, CO, CONH, NHCO, S, SO, SO2, SO2NH2and R12is ogorodili group, R 1as defined above, or a group R1R2N, where R1or R2as defined above, provided that any replacement heteroatom in R1and/or R2must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated).

In the compounds of formula (II):

R1preferably represents phenyl substituted by a group selected from OR13, -COR13, -CO2R13, -SOR13, -SO2R13, -C(O)NR13R14, -NR14C(O)R13C1-10alkyl, C1-10alkoxy, halogeno C1-10alkyl, aryl, aryl C1-10alkyl, heteroaryl or heteroaryl1-10alkyl, where R13and R14each independently represent hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-6cycloalkyl,3-6cycloalkenyl, aryl, arils1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl or restored heteroaryl C1-10alkyl.

More preferably R1represents phenyl substituted by a group OR13or-COR13where R13preferably represents an aryl, more preferably phenyl, phenyl, substituted CO2R13where R13represents a C1-10alkyl, preferably C1-6alkyl or phenyl, substituted C1- the alkyl.

R2preferably is hydrogen or C1-10the alkyl,

R8R9R10and R11each preferably independently represents hydrogen, halogen, hydroxy-, amino-, nitro-, cyano, thiol, C1-10alkyl, C1-10alkoxy, C1-10cycloalkyl,1-10cycloalkane, C(O)R15C(o)nr15r16, S(O)R15or halogeno1-10alkyl,

R15and R16each independently represent hydrogen or C1-10alkyl,

R8represents hydrogen or halogen, such as fluorine, most preferably hydrogen,

R9- preferably hydrogen or lower branched or unbranched alkyl having from 1 to 10 carbon atoms: cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogeno1-6alkyl, for example trifluoromethyl, or halogen, for example chlorine or fluorine;

R10- preferably hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms, for example, ethyl, butyl or octyl: cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogeno1-6alkyl, for example trifluoromethyl, or halogen, for example chlorine or fluorine;

R11- preferably hydrogen, halogen, e.g. fluorine, or lower branched or unbranched alkyl having from 1 to 10 atoms is of glared.

Preferably, in compounds of formula (II) at least one of R8, R9, R10and R11is a Deputy other than hydrogen. So, for example, R8may be a hydrogen atom, and R9, R10and R11such as defined above. In a preferred example implementation, each of R8and R11represents a hydrogen atom, and one or both of R9and R10is a Deputy, such as defined above.

Preferably, the compound for use according to the first aspect of the invention contains a compound of the formula (II) or a pharmaceutically acceptable salt, ester, amide or predecessor, where

R1represents aryl, for example, possibly substituted phenyl or 2-naphthyl, or arylalkyl the group in which the aryl group has up to 25 carbon atoms, for example, up to 20, or aryl-aryl group, where arylalkyl group or aryl-aryl group can be separated by a spacer, where the spacer may be ether, amidon, O, CH2or ketone, and where the aryl group preferably represents phenyl, possibly substituted by alkyl, halogenoalkanes, or halogen,

R2preferably is hydrogen or a group as defined for R1,

R8is hydrogen or fluorine,

R9- lower branched or ner is sweetlenny alkyl, having from 1 to 10 carbon atoms: cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogeno C1-6alkyl, for example trifluoromethyl, or halogen, for example chlorine or fluorine;

R10- lower branched or unbranched alkyl having from 1 to 10 carbon atoms, for example, ethyl, butyl or octyl: cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogenoalkane, for example, trifluoromethyl, or halogen, for example chlorine or fluorine;

R11is hydrogen, halogen, for example fluorine, or lower branched or unbranched alkyl having from 1 to 10 carbon atoms;

Most preferably, R1represents unsubstituted phenyl or phenyl substituted by a group selected from C1-8of alkyl, for example butyl, pentyl, hexyl or heptyl, Gialos1-8alkyl, for example, CF3, OR6where R6- phenyl, or COR4where R4- phenyl, or C1-8alkyl.

According to the second aspect of the present invention proposed a compound of formula (IIA):

or its pharmaceutically acceptable salt, ester, amide or predecessor, where

R1ais:

(1) a branched or unbranched10-30alkyl, C2-30alkenyl,2-30quinil, cycloalkenyl, aryl-C10-30alkyl, aryl-C10-30alkenyl, heteroaryl, hetaeras is aryl-C 1-30-alkyl, heteroaryl-C2-30alkenyl restored aryl, restored heteroaryl, restored heteroaryl C1-30alkyl or substituted derivative in which the Deputy is one or more independently selected from the group: halogen, C1-10alkyl, aryl, aryl-C1-30alkyl, heteroaryl, restored heteroaryl, restored heteroaryl C1-10alkyl, aryl-C1-10alkoxy-, cyan-, nitro-, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13provided that any replacement heteroatom in R1must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated), or

(2) aryl, substituted by one or more Deputy independently selected from the group comprising halogenosilanes C1-10alkyl, aryl, aryl-C1-10alkyl, heteroaryl restored

heteroaryl, restored heteroaryl-C1-10alkyl, aryl-C1-10alkoxy-, cyano-, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13(provided that in this case, R13not an aryl or alkyl), -SR13, -C(O)NR13R14and-NR14C(O)R13,

where R13and R14each independently pre whom represent hydrogen, With1-10alkyl, C2-10alkenyl,2-10quinil,3-10cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl, or restored heteroaryl-C1-10alkyl,

R2ais hydrogen or a group such as defined above for R1and

R8a, R9a, R10aand R11a.

Such as defined above for formula (II).

In the compound of formula (IIA):

R1apreferably represents phenyl substituted by a group selected from OR13(provided that in this case, R13is not alkyl or aryl), COR13, -CO2R13, -SOR13, -SO2R13, -CONR13R14, -NR14C(O)NR13halogeno-C1-10alkyl, aryl, aryl-C1-10alkyl, heteroaryl, or heteroaryl C1-10alkyl.

Most preferably, R1Arepresents phenyl, substituted COR13where R13preferably aryl, most preferably phenyl; or phenyl substituted-CO2R13where R13represents a C1-10alkyl, preferably C1-6alkyl.

R2apreferably represents hydrogen or C1-10alkyl,

R8a, R9a, R10aand R11aeach preferably independently represents hydrogen, halogen, Hydra is XI, amino, nitro, cyano, thiol,1-10alkyl, C1-10alkoxy, C1-10cycloalkyl, C1-10cycloalkane, C(O)R15C(O)NR15R16, S(O)R15or halogeno1-10alkyl,

R15and R16each independently represent hydrogen or C1-10alkyl,

R8arepresents hydrogen or halogen, such as fluorine, most preferably hydrogen,

R9a- preferably hydrogen or lower branched or unbranched alkyl having from 1 to 10 carbon atoms:

cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogeno1-6alkyl, for example trifluoromethyl, or halogen, for example chlorine or fluorine;

R10a- preferably hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms, for example, ethyl, butyl or octyl; cycloalkyl having from 3 to 6 carbon atoms, for example, cyclopropyl, halogeno1-6alkyl, for example trifluoromethyl, or halogen, for example chlorine or fluorine;

R11a- preferably hydrogen, halogen, e.g. fluorine, or lower branched or unbranched alkyl having from 1 to 10 carbon atoms.

Preferably, in compounds of formula (IIA) at least one of R8a, R9a, R10aand R11ais a Deputy other than hydrogen. So, for example, R8a9a,R9a, R10aand R11asuch as defined above. In a preferred example implementation, each of R8aand R11arepresents a hydrogen atom, and one or both of R9aand R10ais a Deputy, such as defined above.

According to another example implementation of the invention proposed compound of formula (IIb),

where R8-R11asuch as defined above,

R20represents a C1-20alkyl, C1-20alkoxy, or perhaps replaced phenoxy.

Preferred substituents of phenoxy include one or more of halogen, CF3, lower alkyl or lower alkoxygroup.

When R20represents an alkyl or alkoxygroup, it preferably contains from 6 to 12 carbon atoms.

In this example, the implementation of R20- preferably represents fenoxaprop.

Preferred values of R8-R11asuch as defined above.

The compounds of formula (IIb) is a new selection on the basis of their pre-emptive action as lipase inhibitors.

Examples of pharmaceutically acceptable salts of this formula include organic acid salts, such as methanesulfonate, benzosulfimide and p-toluensulfonate, salt of the mineral acid is t, for example, hydrochloric and sulfuric and similar, with the formation of methansulfonate, bansilalpet, p-toluensulfonate, chloride, sulfate and the like, respectively, or derived from bases, such as organic and inorganic bases. Examples of suitable inorganic bases for the formation of salts of the compounds according to the present invention include hidroxide, carbonates and bicarbonates of ammonium, lithium, sodium, calcium, potassium, aluminum, magnesium, zinc and others. Salt can also be formed with suitable organic bases. Such grounds suitable for the formation of pharmaceutically acceptable salts obtained by the addition of bases to the compounds of the present invention include organic bases which are non-toxic and are strong enough for the formation of salts. Such organic bases are well known in the art and may include amino acids, such as arginine and lysine, mono-, di - and tri-hydroxyethylamine, such as mono-, di - and triethanolamine, choline, mono-, di - and trialkylamines, such as methylamine, dimethylamine and trimethylamine, guanidine, N-methylglucamine, N-methylpiperazine, morpholine, Ethylenediamine, N-benzylpenicillin, Tris(hydroxymethyl) aminomethan, and others.

Salt can be prepared in traditional ways well known ways. Salicyclates attach to these basic compounds can be prepared by dissolving the compounds with the free bases according to the first or second aspects of the present invention, in aqueous or aqueous-alcohol solution or other suitable solvent containing the desired acid. If the compound of formula (I) contains an acidic functional group, the basic salt of the compounds can be prepared by reacting this compound with a suitable base. Acidic or basic salt can be allocated directly or can be obtained by concentration of the solution, for example, by evaporation. Compounds according to the invention may exist in solvated or hydrated forms.

The invention also includes the predecessors of these grounds. The precursor is typically described as inactive or protected derivative of the active ingredient or drug, which is then converted into the active ingredient or drug in the patient's body.

Examples of compounds according to the first and second aspects of the present invention include the following compounds shown in table 1.

Table 1
Reference NumberStructureCompound Name
12 phenylamino-4H-3,1-benzoxazin-4-one
2 2-(4-butylaniline)-4H-3,1-benzoxazin-4-one
36-chloro-2-phenylamino-4H-3,1-benzoxazin-4-one
42 butylamino-4H-3,1-benzoxazin-4-one
56-methyl-2-phenylamino-4H-3,1-benzoxazin-4-one
62-(4-methoxybenzylamine)-4H-3,1-benzoxazin-4-one
72-(4-methylphenylimino)-4H-3,1-benzoxazin-4-one
82-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one
92-(4-chlorobenzylamino)-4H-3,1-benzoxazin-4-one
102[4(methylethyl)phenylamino]-4H-3,1-benzoxazin-4-one
112-(4-triptoreline)-4H-3,1-benzoxazin-4-one
122-(3-triptoreline amino)-4H-3,1-benzoxazin-4-one
13 6-methyl-2-(naphthas-2-ylamino)-4H-3,1-benzoxazin-4-one
142-(4-butoxycarbonylamino)-6-methyl-4H-3,1-benzoxazin-4-one
156-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one
162 ethylamino-4H-3,1-benzoxazin-4-one
177-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one
185-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one

197-methyl-2-phenylamino-4H-3,1-benzoxazin-4-one
207-ethyl-2-phenylamino-4H-3,1-benzoxazin-4-one
212-(4-hexylaniline)-6-methyl-4H-3,1-benzoxazin-4-one
222-(4-heptylaniline)-6-methyl-4H-3,1-benzoxazin-4-one
237-octyl-2-Hairdryer is a melamine-4H-3,1-benzoxazin-4-one
247-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one
252 hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one
267-butyl-2-phenylamino-4H-3,1-benzoxazin-4-one

/table>

277-methyl-2-(2-phenoxybenzamine)-4H-3,1-benzoxazin-4-one
287-methyl-2-(3-phenoxypropylamine)-4H-3,-benzoxazin-4-one
292-(4-benzoylamino)-7-methyl-4H-3,1-benzoxazin-4-one
302-(4-phenoxybenzamine)-7-methyl-4H-3,1-benzoxazin-4-one
317-methyl-2-(4-octylaniline)-4H-3,1-benzoxazin-4-one
322 phenylamino-4H-pyrido[3,4-d][1,3]oxazin-4-one
332-(2-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one
346-nitro-2-phenylamino-4H-3,1-benzoxazin-4-one
356-acetamido-2-phenylamino-4H-3,1-benzoxazin-4-one
362 phenylamino-7-trifluoromethyl-4H-3,1-benzoxazin-4-one
377-amino-2-phenylamino-4H-3,1-benzoxazin-4-one
382 phenylamino-4H-pyrido[2,3-d][1,3] oxazin-4-one
392 cyclopropylamino-4H-3,1-benzoxazin-4-one
402-(3-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one

/tr>
412-(4-cyanovinylene)-4H-3,1-benzoxazin-4-one
422-(4-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one
432-(4-carboxyphenylazo)-4H-3,1-benzoxazin-4-one
442-(4-aminophenylamino)-4H-3,1-benzoxazin-4-one
452-(4-hydroxyphenylazo)-4H-3,1-benzoxazin-4-one
462-(4-N-methylcarbamoylmethyl)-4H-3,1-benzoxazin-4-one
472,2’-(1,8-octylamine)-bis-4H-3,1-benzoxazin-4-one
482-(2-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

492-(3-phenoxypropylamine)-4H-3,1-benzoxazin-4-one
502-(naphthas-2-yl-amino)-4H-3,1-benzoxazin-4-one
512-(6-phenylendiamine)-4H-3,1-benzoxazin-4-one
522-(pyrrol-3-yl-amino)-4H-3,1-benzoxazin-4-one
532-(piperidine-4-yl-amino)-4H-3,1-benzoxazin-4-one
54 2-[6-(pyrrol-2-yl)hexylamino]-4H-3,1-benzoxazin-4-one
552-(4-ethoxycarbonylphenyl)-4H-3,1-benzoxazin-4-one
566-cyano-2-phenylamino-4H-3,1-benzoxazin-4-one

572-phenyl-6-trifluoromethyl-4H-3,1-benzoxazin-4-one
586-formyl-2-phenylamino-4H-3,1-benzoxazin-4-one
592 phenylamino-4H-3,1-benzoxazin-4-one-6-Sultanova acid
607-hydroxy-2-phenylamino-4H-3,1-benzoxazin-4-one
617-cyclopropyl-2-phenylamino-4H-3,1-benzoxazin-4-one
626,7-dimethyl-2-phenylamino-4H-3,1-benzoxazin-4-one
636-iodo-2-octylamine-4H-3,1-benzoxazin-4-one
647-butyl-2-is cholamine-4H-3,1-benzoxazin-4-one
656-methyl-2-(dodeca-7-enylamine)-4H-3,1-benzoxazin-4-one

666-methyl-2-[6-(Tien-2-yl)hexylamino]-4H-3,1-benzoxazin-4-one
678-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one
686-cyclopropyl-2-phenylamino-4H-3,1-benzoxazin-4-one
696-mercapto-2-phenylamino-4H-3,1-benzoxazin-4-one
706-cyano-2-phenylamino-4H-3,1-benzoxazin-4-one

Connection 2, 3, 5, 6, 8, 11-15 and 17-70 in table 1, according to the applicants, are new and thus, are preferred examples of implementing the present invention.

Preferred compounds of formula (II)listed in table 1 include the compounds 1, 3, 5, 9, 17, 19, 20, 23 and 26.

Preferred compounds of formula (IIA), listed in table 1 include compounds 11, 12, 14, 25, 29, and 30.

Preferred compounds of formula (IIb), listed in table 1 include the compounds 2, 6, 7, 8, 10, 15, 21 and 24

In particular, preferred compounds of the formula (IIA) and (IIb) are:

2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one;

2-(4-butoxycarbonylamino)-6-methyl-4H-3,1-benzoxazin-4-one;

6-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one;

2-(4-hexylaniline)-6-methyl-4H-3,1-benzoxazin-4-one;

7-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one;

2-(4-benzoylamino)-7-methyl-4H-3,1-benzoxazin-4-one;

2-(4-phenoxybenzamine)-7-trifluoromethyl-4H-3,1-benzoxazin-4-one.

Preferred compounds according to the present invention also include the tautomers of the above compounds, and are not limited to, pharmaceutically acceptable salts, esters, amides, or precursors of these compounds or their derivatives obtained by attaching one or more lipid groups (natural or synthetic).

According to a third aspect of the invention, a method of receiving any or several new compounds or derivatives according to the first or second aspect of the invention. Thus, in the present invention, a method of obtaining new compounds of formula (II), in particular, (IIA), which includes:

Method (A) cyclization of compounds of formula(III):

where R1and R8-R11as defined above and R18represents hydrogen or C1-6lcil,

or

Method (B), which carried out the reaction of the compound (IV):

with an amine of formula (V)

R1R2NH

or (C) the conversion of compounds of formula (I), (II), (IIA) or (IIb) in various compounds of formula (IIA) or (IIb), for example, by

(1) recovery of the compounds of formula (I), (II), (IIA) or (IIb), where R1, R8, R9, R10and R11contain alkenylphenol or alkenylphenol group or a group in a corresponding compound with an alkyl or alkenylphenol group or grouping, or

(2) alkylation of compounds of formula (I), (II), (IIA) or (IIb), where one or more of R8, R9, R10and R11represent a halogen atom.

Method (A) can be achieved by the reaction of the compound (III) with a dehydrating agent in an organic solvent. Suitable dehydrating agents include sulfuric acid, and if R18represents hydrogen, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or EDC deposited on the polymer. The reaction can be conducted at a temperature in the range from 10 to 50° C, preferably at ambient temperature, i.e. about 20-30° C. When using EDC deposited on the polymer, it can be removed by filtration at the end of the reaction, and the product is isolated from solution by standard methods such as the removal of the of astorias and purification column flashamature. Alternatively, the cyclization can be carried out with the use of concentrated sulfuric acid.

Alternatively, the cyclization according to process (A) can be done through a reaction in excess of chloroformate or by adding another agent cyclization, which promotiom ring closure. Suitable cyclization agents include, for example, methylchloroform, carbonyldiimidazole, acetic anhydride, phosgene, oxalicacid, thionyl chloride or peptide cross-linking agent, such as DICYCLOHEXYL carbodiimide (DCC). Preferably, the cyclization agent is a phosgene, triphosgene or thionyl chloride. If you use chloroformiate, it is preferable low-molecular chloroformiate, because it is cheaper and easier to remove the formed alcohol.

The compounds of formula (III) can be obtained in a variety of ways. For example, the compound of the formula:

can be subjected to reaction with the isocyanate of formula (VII):

The reaction is preferably carried out in an inert organic solvent such as an ether, e.g. tetrahydrofuran, aliphatic hydrocarbon such as pentane or hexane, a halogenated hydrocarbon, such as dichloromethane, or an aromatic hydrocarbon such as benzene or toluene, generally at room tempera is ur. Formed as an intermediate product of urea may be subjected to cyclization in the same reactor without the necessity of separation. Alternatively, if desired, urea can be separated prior to cyclization. Similarly, any unreacted promezhutochnoi urea can be subjected to cyclization at the subsequent stages of the reaction. It should be noted that the above reaction leads to the production of compound (III)if R2- hydrogen.

Alternatively, the compound of formula (III) can be obtained by reaction of the isocyanate of formula (VIII)

(where R8, R9, R10, R11and R18as indicated above)

with an amine of formula (V) R1R2NH.

The compounds of formula (III) can also be obtained from compounds of formula (IX)

by reaction with an amine of formula R1R2NH.

The compounds of formula (IX) can also be obtained by reaction of compound (VI) with an amine of formula (V) in the presence of trichloromethyl of chloroformiate and in a solvent such as tetrahydrofuran or dimethylformamide.

Method (C) can be achieved by reaction of compounds of formula (IV) with the amine R1R2NH in the presence of a base, e.g. sodium hydroxide, followed by cyclization, for example, as described in method (A).

The compounds of formula (IV) can b the th obtained by cyclization of compounds of formula (VI), where R18- hydrogen, using for example, phosgene or its synthetic equivalent.

In method (C), the recovery alkenylphenol or alkenylphenol groups can hold, for example, catalytic hydrogenation using, for example, deposited on activated carbon 10% palladium in an alcohol solvent such as ethanol, at a hydrogen pressure of 1 atmosphere.

The alkylation according to method (C) (ii) is performed in the Stille method or by cross-linking catalyzed by palladium, using, for example, tetraalkyllead, such as tetramethylurea, and phCh2Pd(PPH3)2Cl in NRMA at elevated temperature, for example, 50-100° C. as starting substances you can use other halide or pseudohalide, for example, triflate.

Other methods of obtaining derivatives of 2-amino-1,3-benzoxazin-4-it is described in J. Med. Chem., 1990, 33(2), 464-479, and J.Med. Chem, 1998, 41, 1060-1067, as well as U.S. patent 4, 657, 893.

According to a fourth aspect of the invention the application of the compounds according to the first and/or second aspects of the invention (i.e., compounds of formulas (I), (II) and (IIA)) in medicine. The preferred characteristics of the first and second aspects of the invention also fair to the fourth aspect. Other features of the fourth aspect set forth herein.

According to the fifth aspect of the invention proposed paragraph is the changes of the compounds according to the first and/or second aspects of the invention for the inhibition of enzymes the predominant effect of which is to catalyze the hydrolysis of ester groups. This application includes the application of in vivo and in vitro, as well as other fields of application, e.g. in industry. These enzymes catalyze the decomposition bases containing ether functional group, by adding water, resulting in the cleavage of chemical bonds. Such enzymes are also involved in key processes in the body. The enzymes according to the invention include lipases (hydrolysis of esters of fatty acids), esterase (hydrolysis of esters), and phosphatase (hydrolysis of esters of phosphoric acid).

The preferred enzymes are lipases. Lipases include pancreatic lipase, gastric lipase, lipoprotein lipase, lingual lipase, the lipase of adipose tissue, hormonecontaining the lipase, phospholipase A1, A2, b, C, D, etc, hepatic lipase and other triazol-, diacyl - and monoacylglycerol lipase in mammals. Many other similar lipase is also known in plants, fungi and microorganisms.

According to the invention also considered such enzymes as esterase and phosphatase. Esterase include esterase pig liver, cholesterol esterase, retinyl esterase, 1-alkyl-2-glycerophosphocholine esterase, hydrolase ether carboxylic acid, and x is lesterol esterase. Vospitanie enzymes include phosphatase PP1, PP2 and RR serine/threonine-phosphatase of phosphoprotein, phosphatase myosin light chain phosphatase 2C protein phosphatase protein tyrosine.

Compounds according to the invention for use in medicine, primarily relate to compounds for use in preventing and/or treating such medical conditions as obesity, hyperlipemia, hyperlipidemia, and comorbidities, such as hyperglycaemia (type II diabetes), hypertension, cardiovascular disease, stroke, gastrointestinal diseases and conditions. Compounds according to the first and/or second aspect of the invention is applicable in these and other conditions because of their ability to inhibit the enzymes, the primary effect of which is to catalyze the hydrolysis of the ether functional groups. The invention relates also to a non-medical weight loss, such as cosmetic weight reduction, and includes an improved appearance. In the context of this description, prevention and/or treatment of any disorder means any action that reduces any damage or health violation, in any degree, and includes the prevention and treatment of them. The term "treatment" means any improvement in respect of breach, disease, syndrome, condition is of, pain or a combination of two or more of these factors.

Obviously, an important application of the invention relates to weight loss (any of the above types) person. However, the invention also applies to medical and non-medical weight loss of any animal, in which the metabolism of fats and derivatives fat occurs with the participation of enzymes, premontane the action of which is to catalyze the hydrolysis of the ether functional groups. Thus, the invention also has veterinary use and particularly useful for animal companions of man, such as domestic cats and dogs, as well as the animals that provide the needs of man meat. In the latter case, application of the present invention is to reduce the fat content with getting depleted fat meat.

Presumably, the compounds according to the present invention can also be helpful in reducing the content of toxins (e.g., dioxins and PCBs), which are deposited in fatty tissues. Not wishing to be bound by any one theory, the authors suggest that the increase in the amount of undigested fat passing through the body improves the diffusion of toxins from the fat stored in the body, blood fats, and thus, in the intestines.

The fifth aspect of the invention has the important p is the applicatio. This application includes testing and diagnostic methods and control and inhibition of unwanted enzymes, preferably lipases, in any process or product. Processes or products, which preferably involves lipases include the processing of agricultural products (for example, fat-containing seeds), the selection and extraction of enzymes of biotechnological processes (e.g., lysis of microorganisms), the production and extraction of crude oil (in particular, oil and plastics), industrial production of triglycerides and other fats, the production of items for the care of the body, which include surface-active substances, Soaps or detergents (e.g., bath oils, creams), production and processing of liposomes (e.g., subjects, body care, diagnosis, in gene therapy), processing of industrial waste (e.g. recycling of waste paper), and the prevention of decomposition of food products containing fats (for example, processing of chocolate). Thus, the invention relates also to the products and processes, such as foods high in fat such as cakes, cookies, pastries, etc., and chocolate products.

Preferred features of the invention according to the fifth aspect including the preferred enzymes are the same as b the lo is specified for the previous aspects of the invention.

According to the sixth aspect of the invention is proposed, comprising the new compounds according to the first and second aspects of the invention, in combination with a pharmaceutically acceptable carrier or diluent. Suitable carriers and/or diluents are well known in the art and include pharmaceutically pure starch, mannitol, lactose, manganese stearate, saccharin sodium, talc, cellulose, glucose, sucrose or other sugars), manganese carbonate, gelatin, oil, alcohol, detergents, emulsifiers, or water (preferably sterile). The composition can be a mixed drug composition or combined preparation for simultaneous, separate or sequential use (including the reception).

Compounds according to the invention for use according to the above assignments can be assigned for reception by any suitable means, for example, orally (including inhalation), parentline, through mucous membranes (for example, through the mouth or cheek or under the tongue, through the nose), rectal or transdermal and accordingly adapted.

For oral administration the compounds can be produced in liquid and solid form, e.g. as solutions, syrups, suspensions or emulsions, tablets, capsules and patches.

Liquid formulations typically consist of suspensions or solutions or physiologically priemlimyh salts in a suitable aqueous or non-aqueous liquid media, for example, water, ethanol, glycerin, poliatilenglikole or in oil. The composition may also contain suspiciouse agent, preservative, flavoring or coloring agent.

The composition in the form of tablets can be prepared using any suitable pharmaceutical carrier or carriers customarily used in the preparation of solid compositions. Examples of such carriers include manganese stearate, starch, lactose, sucrose, and microcrystalline cellulose.

The composition in the form of capsules can be prepared using conventional methods of encapsulation. For example, powders, granules or tablets containing the active ingredient, can be prepared using standard carriers and then placed in a hard gelatin capsule, alternatively, may be prepared in dispersion or suspension with the use of any pharmaceutical carrier or carriers, for example, aqueous resins, cellulose, silicates or oils, and then the dispersion or suspension is placed in a soft gelatin capsule.

Compositions for oral administration can be designed to protect the active ingredient from degradation as it passes through the digestive tract, for example, by coating the outer shell on the composition of the tablet or capsule.

Conventional parenteral compositions consist of a solution or susp is nsii compound or physiologically acceptable salt in a sterile aqueous carrier or non-aqueous or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or Kungaeva oil. Alternatively, the solution may be lyophilized and then restored with a suitable solvent immediately before the reception.

Compositions for nasal or oral administration can be obtained in the form of a spray, drops, gel or powder. Aerosol formulations typically contain a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in one or more doses in a sterile form in a sealed container made in the form of a cartridge or fill of container used with the spray device. Alternatively, the sealed container may be made in the form of a single junction device, such as a nasal aspirator that is designed for one dose, or aerosol dispenser equipped with a metering valve, which is designed to release after the contents of the container will be spent. If the dosage form is in an aerosol dispenser, it also includes pharmaceutically acceptable propellant. Aerosol dosage forms may also be in the dispenser with compressed gas.

Formulations suitable for reception through the mouth or the cheek or under the tongue, include tablets, pellets and p is stilke, in which the active component is composed with the addition of media, such as sugar and acacia, tragakant, or gelatin and glycerin.

Compositions for rectal or vaginal application is usually prescribed in the form of suppositories containing the usual base for suppositories, such as coconut oil), uterine rings, vaginal tablets, foams, or enemas.

The formulations for percutaneous reception include ointments, gels and patches, and injections, including powder injection.

Typically, the compositions are in a unit dosage form such as tablets, capsules or ampoules.

The compositions according to the sixth aspect of the invention is useful for prevention and/or treatment of obesity and related disorders, other forms of medical weight loss and non-medical weight loss. Preferred features of this aspect of the invention are the same as described for the first to fifth aspects of the invention.

According to the seventh aspect of the invention, a method of making a composition according to the sixth aspect of the invention. The receiving part can be done by standard methods well known in the art, and it includes the preparation of a composition comprising the compound according to the first or second aspects of the invention and a pharmaceutically acceptable carrier or diluent. The composition may be in any form, for example, in the de tablets, in liquid form, in the form of capsules and powder, or in the form of a food product, for example, food functionality. In the latter case, the food product itself can act as a pharmaceutically acceptable carrier.

According to the eighth aspect of the invention, a method for preventing and/or treating obesity or an associated disorder, the method comprises the use of compounds according to the first or second aspects of the invention, preferably in combination with a pharmaceutically acceptable carrier or diluent (as in the sixth aspect of the invention). Related obesity diseases include hyperlipemia, hyperlipidemia, hyperglycemia, hypertension, cardiovascular disease, stroke, gastrointestinal diseases and gastro-intestinal condition. Compounds or compositions are preferably administered to patients who need it, and in quantities sufficient to prevent and/or treat the symptoms of these conditions, disorders or diseases. For all aspects of the invention, in particular, medical, reception compounds or composition must be strictly controlled under mandatory supervision of a physician and taking into account such factors as the connection, the type of animal, age, weight, severity of symptoms, the route of administration, adverse reactions and/or other across the lagoon to the sanctions. Specifically prescribed dose can be determined by standard designed clinical trials, with full control over the status of the patient and the recovery. In such tests can be used increasing doses, and as a starting dose for humans can be taken low percentage of the maximum permissible dose in animals.

Physiologically acceptable compounds according to the invention can usually be administered in the form of a daily dose (for an adult patient), which may be, for example: oral doses

from 1 mg to 2000 mg, preferably from 30 mg to 1000 mg, for example, from 10 to 250 mg for intravenous, subcutaneous or intramuscular dose of between 0.1 mg to 100 mg, preferably from 0.1 mg to 50 mg, for example, from 1 to 25 mg of the compounds of formula (I) or its physiologically acceptable salts calculated as the free base, and the connection take from 1 to 4 times per day. The connection may be assigned during the period of continuous treatment, for example, in the course of a week or more.

According to the ninth aspect of the invention, a method of cosmetic maintain this weight, or cosmetic weight loss, the method includes receiving connection according to the first aspect of the invention, preferably in combination with a pharmaceutically acceptable nakateleeli diluent (as in the fifth aspect of the invention). The drug is preferably administered to a patient who needs it, and in sufficient quantity to maintain this weight or for cosmetic weight loss.

The eighth and ninth aspects of the invention relate to methods of treatment of humans and animals, in particular animal-companions of man and other animals that provide for human needs in meat, such as cattle, pigs and sheep (of any age).

The invention will be further described with reference to the following non-limiting examples.

Methods of biological testing and results.

Test the connection.

Connection benzoxazine used in the following denoted by numbers that correspond to the numbers of the compounds in table 1.

Determination of lipase activity by colorimetric analysis using inindiana dye.

Ingibiruyushee effect of selected compounds in relation to the pancreatic lipase was measured during the next analysis, the set for which is supplied by the company Sigma Ltd (Lipase PSTMcatalogue 805-A):

Glycerol allocated under the action of pancreatic and monoglyceride lipase, was oxidized with the release of H2About2. Then on stage reaction involving peroxidase is formed hinny dye, to the which has a pink color and absorbs light with a wavelength of 550 nm.

The inhibitor.

Individual compounds were dissolved in DMSO (dimethyl sulfoxide) at 10 mm. DMSO was used in order to avoid problems in case of water-insoluble compounds.

For individual compounds, IC50(the concentration at which the lipase activity is inhibited to 50% of maximum activity) was calculated by measuring the inhibitory effect on the logarithmic curve of the dependence of the logarithm of the dose in the range of inhibitory concentrations.

Results.

Method colorimetric analysis with hininden dye, which allows you to quickly measure the inhibitory activity of the lipase was investigated by a number of compounds. None of the tested compounds did not participate in the colorimetric reaction, i.e. no false positive results.

Watched the interval inhibiting concentrations of the test compounds of benzoxazinone, which indicates that these compounds are inhibitors of pancreatic lipase person. The following compounds had IC501 µm: 1-3, 5-12, 14, 15, 17, 19-21, 23-26, 28-30.

Determination of enzyme activity of lipase by NaOH titration method.

The inhibitory activity of selected compounds in relation to the pancreatic lipase was measured in the analysis described in Pasquie et al., 1986, Vol.7, Nutritional Biochemistry, 293-302.

Logarithmic to Evie according to a response from the logarithm of the dose were built for the interval inhibiting concentrations.

Results

Selected compounds of benzoxazinone investigated by the method of titration with NaOH. In this analysis, we recorded the activity of pancreatic lipase pigs in a system containing lipid micelles. These conditions are therefore similar to those observed in the gastrointestinal tract.

Watched the interval inhibiting concentrations of the test compounds of benzoxazinone, indicating that these compounds are inhibitors of pancreatic lipase pigs. The following compounds had IC502 μm: 1-3, 5, 8, 11, 12, 14-20, 24, 26, 28-30.

Thus, the results show that the tested compounds of benzoxazinone are inhibitors of lipolysis and that these compounds may be particularly suitable for the treatment of obesity.

The test mice.

Compound 24 was tested on mice, as described Isler et al., British Journal of Nutrition, 1995, 73, 851-862, it was found that this compound is a potential inhibitor of lipases.

Synthesis of intermediate compounds

Synthesis of 4-substituted Anthranilic acid

Example: 4-octyl Anthranilic acid (4-octyl-2-aminobenzoic acid)

The method is based on the methodology described L.A.Paquette et al., J.Am.Soc. 99, 3734 (1981).

A solution of 1-bromo-4-octylbenzene (9,9 g, 36 mmol) in sulfuric acid (20 ml) was cooled in the ice bath. Then added nitric acid (of 1.44 ml, 36 mmol). Removed ice bath and the mixture was stirred at room temperature for 20 minutes was Added another portion of nitric acid (0,07 ml of 1.75 mmol) and continued stirring for another 20 minutes the Mixture was poured into aqueous potassium carbonate solution, which was extracted with ethyl acetate. The organic extract was washed with saturated aqueous potassium carbonate solution, water and brine then dried (MgSO4) and concentrated. If further purification of the crude product flash chromatography (1% toac/hexane) removes unwanted (main) regioisomers with the yield of the desired product as a yellow oil (1.7 g, 5.4 mmol).

Basis (1.7 g, 5.4 mmol), copper cyanide (I) (of 0.533 g, 5.9 mmol), and pyridine (20 ml) was subjected to reflux distilled at 150° within 2 days.

Subsequent concentration under vacuum and purification with flash chromatography (10% to 20% toac/hexane) gives the yield of the desired product as a brown oil (739 mg, 2.8 mmol).

Base (694 mg, 2.7 mmol) was heated at 150° mixes with water (2 ml), Asón (1 ml) and sulfuric acid (1 ml) for 2 days. The mixture was extracted with ethyl acetate, the organic phase is washed with water (2 times), dried (Na2SO4) and concentrated to obtain the desired material (744 mg ,7 mmol).

Source material (744 mg, 2.7 mmol) was dissolved in ethanol (10 ml), and to the solution was added a suspension of 10% palladium deposited on activated carbon (40 mg) in ethanol (4 ml). The flask was purged with nitrogen and then with hydrogen (1 ATM), and then stirred overnight. Then added the following portions of the catalyst (5 mg and 25 mg)and the reaction was completed in the next 24 hours. The reaction mixture was filtered on celite, was thoroughly rinsed with methanol and ethyl acetate. Concentration gave Anthranilic acid (597 mg, 2.4 mmol) of sufficient purity for use without further purification; σn(400 MHz, CDCl3) 0,79 is 0.81 (3H, m, Me), 1,12-1,36 (10H, m, 5× CH2), of 1.52 (2H, br.s. Agsn2CH2), a 2.45 (2H, br.s. ArCH2), 6.42 per (2H, br.s. 2× ArH), 7,74 (1H, br.s. ArH); m/z (ES+) 250 (MH+).

Synthesis of substituted phenylisocyanates

Example: obtain 4-octylphenolethoxylate

A solution of 4-octylaniline (0.3 ml, 1.3 mmol) and Diisopropylamine (0,205 ml, 5.2 mmol) in THF (tetrahydrofuran) (5 ml) was cooled to minus 10° . Then added a 10% solution of phosgene in toluene (1.3 ml, 2.6 mmol)and the mixture left to warm to room temperature and kept at this temperature for 3 hours. Excess phosgene was removed in a stream of nitrogen (which output was passed through a scrubber with an aqueous NaOH) to obtain R is the target crude isocyanate which was used directly in the next stage.

4-benzoylferrocene prepared by a similar method from the corresponding aniline.

Substituted 4-phenoxyphenylacetic can be prepared with known methods from the corresponding amines.

The synthesis of compounds according to the invention

Example 1

Synthesis of 2-(4-butoxycarbonylamino)-6-methyl-4H-3,1-benzoxazin-4-it (room 14).

A solution of 2-amino-5-methylbenzoic acid (690 mg, of 4.57 mmol) in THF (2 ml) was treated with 4-n-butoxycarbonylmethylene (1.0 g, of 4.57 mmol). The mixture stood at room temperature for 24 h, during which occurred the evaporation of solvent to form a pale brown solid residue (1.7 g, quantitatively); σ h (400 MHz, DMSO-d6) of 0.93 (3H, t, J7, CH2CH3), of 1.41 (2H, tq, J, J’7, CH2CH3), to 1.67 (2H, tt, J, J’7, CH2CH2CH3), of 2.28 (3H, s, CH3), to 4.23 (2H, t, J7, co2), 7,37 (1H, d, J8, Ph), to 7.77 (1H, s, Ph), the 7.85-a 7.92 (4H, m, Ph), 8, 24 (1H, d, J8, Ph).

To a solution of urea (185 mg, 0.5 mmol) in DMF (10 ml) was added applied to the polymer EDC (PS-EDC) (0.8 mmol/g, 1.0 g). Received 5 the mixture was stirred at room temperature for 18 h, after which the resin was filtered and washed with DMF (2× 5 ml). The filtrate and wash water were combined and evaporated in bonigen is the pressure to get the desired compound in the form of a cream solid residue (150 mg, 85%); σ h (400 MHz, DMSO-d6) to 0.94 (3H, t, J7, CH2CH3) to 1.42 (2H, tq, J, J’7, CH2CH3), was 1.69 (2H, tt, J, J’7, CH2CH2CH3), 2,39 (3H, s, CH3), 4,25 (2H, t, J7, co2), was 7.36 (1H, d, J8, Ph), 7,63 (1H, d, J8, Ph), 7,80 (1H, s, Ph), of 7.90-of 7.95 (4H, m, Ph); m/z (ES-) 351 (M-H+).

Example 2

Synthesis of 6-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-it (15)

A solution of 2-amino-5-methylbenzoic acid (172 mg, 1.10 mmol) in THF (1 ml) was treated with 4-phenoxypropionate (241 mg, 1.10 mmol). The mixture stood at room temperature for 24 h, during which occurred the evaporation of solvent to form a pale brown solid precipitate. The residue was dissolved in DMF (5 ml) and added to a suspension of PS-EDC (0.8 mmol/g, 2.8 g) in DMF (20 ml). The resulting mixture was stirred at room temperature for 18 h, after which the resin was filtered and washed with DMF (2× 5 ml). The filtrate and wash water were combined and evaporated under reduced pressure. Flash column chromatography with silica gel (eluent of 20% ethyl acetate in hexane) gave the desired compound in the form of a cream solid precipitate (153 mg, 40%); σ h (400 MHz, DMSO-d6) a 2.36 (3H, s, CH3), of 6.96 (2H, d, J8, Ph),? 7.04 baby mortality (1H, d, J8, Ph), to 7.09 (1H, t, J8, Ph), 7,26 (1H, d, J8, Ph), 7,34-7,38 (2H, m, Ph), 7,55-7,56 (1H, m, Ph), 7,76 for 7.78 (4H, m, Ph); m/z (ES+) 345 (MH+).

Example 3

2-(3-chlorpheniramine)-6-octyl-4H-3,1-benzoxa is n-4-one

Anthranilic acid (200 mg, 0.8 mmol) was dissolved in THF (1 ml) and the resulting solution was added 3-chloronicotinate (117 μl, 0.96 mmol). The mixture was stirred 3 h before concentrated. The residue is divided between water and ethyl acetate. The organic layer is washed with 5% aqueous citric acid, saturated aqueous bicarbonate, and brine then dried (MgSO4) and concentrated with the formation of an orange precipitate. The residue was purified flash column chromatography with silica gel (15% tO/hexane to 100% tO, then 10% tO/tO) with elution of benzoxazinone (18 mg, 0.05 mmol); σ h (400 MHz, CDCl3) 0,77-of 0.82 (3H, m, Me), 1,19-of 1.24 (10H, m, 5× CH2) 1,55-of 1.57 (2H, m, ArCH2CH2), 2,56-2,62 (2H, m, Agsn3), 7,00-to 7.32 (4H, m, 3× ArH, NH), 7,40-7,49 (2H, m, 2× ArH), 7,81-7,83 (2H, m, ArH); m/z (ES+) 385 (MN+) and urea (160 mg, 0.4 mmol); m/z (ES-) 401 (M-N)-.

Residual urea can be subjected to cyclization in a separate step (as described below) with the formation of a larger number of benzoxazinone, if necessary.

Example 4

7-octyl-2-phenylamino-4H-3,1-benzoxazin-4-one (compound 23).

Urea (126 mg, 0.34 mmol) suspended in dry DCM (4 ml). Added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 131 ml of 0.68 mmol) and the received mixture was stirred for 24 hours The mixture was diluted with ethyl acetate and washed with water, saturated aqueous bicarbonate and brine, then dried (Na2SO4) and concentrated with the formation of benzoxazinone, which did not require further purification; σ h (400 MHz, CDCl3) to 0.92 (3H, t, J6,7, Me), 1.30 and 1,36 (10H, m, 5× CH2) 1,68 is 1.70 (2H, m, ArCh2ch2), 2,71 is 2.75 (2H, m, ArCH2), to 6.80 (1H, br.s., NH), 7,13-7,21 (2H, m, 2× ArH), 7,28 (1H, s, ArH), 7,42-7,46 (2H, m, 2× ArH), of 7.70 (2H, d, J 8,2, ArH), of 8.04 (1H, d, J 8,1, ArH); m/z (ES+) 351 (MH+).

Example 5

7-methyl-2-(4-phenoxyphenyl)-4H-3,1-benzoxazin-4-one

2-amino-5-methylbenzoic acid (207 mg, 1.37 mmol) in THF (3 ml) was treated with 4-phenoxypropionate (289 mg, 1.37 mmol). The mixture stood at room temperature for 48 h, then was diluted with ethyl acetate and washed with 2 N HCL, water, saturated aqueous bicarbonate and brine, then dried (Na2SO4) and concentrated. The residue was purified flash column chromatography with silica gel (gradient from 50% to 100% ethyl acetate in hexane, then 1% methanol/ethyl acetate) with the formation of a white solid precipitate (217 mg, 0.6 mmol, 44%); δn(400 MHz, AMCO-d6) of 2.28 (3H, s, Me), 6,72 (1H, d, J8,0, ArH) to 6.95 (4H, m, ArH), was 7.08 (1H, t, J6,9, ArH), was 7.36 (2H, t, J7,9, ArH), 7,56 (2H, d, J7,8, ArH), 7,87 (1H, d, J7.6, ArH), 8,11 (1H, s, ArH), 9,49 (1H, s, NH), m/z (es-) 362 (m-h)-.

Urea (217 mg, 0.6 mmol who) in DCM (4 ml) was treated with (EDC, 126 mg, 0.66 mmol). After 24 h, 48 h added the following portion of EDC (115 ml each, 0.6 mmol). The mixture was diluted with ethyl acetate and washed with water, saturated aqueous bicarbonate and brine, then dried (Na2SO4) and concentrated with the formation of benzoxazinone (137 mg, 0.4 mmol, 67%); σ h (400 MHz, CDCl3) is 2.37 (3H, s, Me), 6,7 (1H, br.s, NH), 6,94-7,05 (6N, m, ArH), 7,14 (1H, s, ArH), 7,27 (2H, t, J And 7.7, ArH), 7,54 (2H, d, J 8,7, ArH), 7,89 (1H, d, J 8,1, ArH); m/z (ES+) 345 (MH+).

The remaining compounds of table 1 can be obtained similarly to examples 1-5. In particular, the following compounds were obtained using the above starting compounds (see table 2)

Table 2
No.The educt 1Starting material 2
22-aminobenzoic acid4-butylphenyl isocyanate
82-aminobenzoic acid4-phenoxyphenyl isocyanate
102-aminobenzoic acid4-(1-methylethyl)phenyl isocyanate
112-aminobenzoic acid4-triptoreline isocyanate
122-aminobenzoic acid3-triptoreline isocyanate
132-amino-5-leventina the 1-naphthyl isocyanate
142-amino-5-methylbenzene the4-butoxycarbonylmethyl isocyanate
152-amino-5-methylbenzene the4-phenoxyphenyl isocyanate
172-amino-5-Formentera thephenyl isocyanate
182-amino-6-Formentera thephenyl isocyanate
192-amino-4-methylbenzene thephenyl isocyanate
202-amino-4-ethylbenzene thephenyl isocyanate
212-amino-5-methylbenzene the4-hexylphenyl isocyanate
222-amino-5-methylbenzene the4-heptyloxybiphenyl isocyanate
232-amino-4-octylbenzene thephenyl isocyanate
242-amino-4-methylbenzene the4-phenoxyphenyl isocyanate
252-amino-5-methylbenzene thehexadecyl isocyanate
262-amino-4-butylbenzene thephenyl isocyanate
272-amino-4-methylbenzene the2-phenoxyphenyl isocyanate
282-amino-4-meth is Ventina the 3-phenoxyphenyl isocyanate
292-amino-4-methylbenzene the4-benzoylphenyl isocyanate
302-amino-4-triftorperasin the4-phenoxyphenyl isocyanate
312-amino-4-methylbenzene the4-octylphenyl isocyanate
32C-aminopyridine-4-carboxylic K-TAphenyl isocyanate
332-amino-4-methylbenzene thecyanophenyl isocyanate

In the above description in detail of specific compounds, compositions, methods and applications that can be used to implement the present invention. However, experts in this area should be clear how you can use alternative ways of implementation alternatives of the present invention covered by the claims.

1. A method of preventing or treating conditions which require inhibition of the enzyme, the primary effect of which is to catalyze the hydrolysis of the ether functional groups, where the specified condition is a obesity or a related disorder in which designate the compound of formula (I)

or its pharmaceutically acceptable salt, ester, amide or predecessor, where in the formula (I)

A - six-membered aromatic or heteroaromatic ring,

R1branched or unbranched alkyl (the carbon chain of which may interrupted by one or more oxygen atoms), alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, restored arylalkyl, arylalkyl, heteroaryl, heteroaromatic, heteroaromatic restored aryl, restored heteroaryl, restored heteroaromatic or substituted derivative in which the Deputy is one or more independently selected from the group of halogen, alkyl, substituted with halogen alkyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, restored heteroallyl, Allakaket-, cyano-, nitro-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCXlX2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7C(O)NHNR6R7, -C(O)N(OR5R6or lipid or steroid (natural or synthetic), provided that any replacement heteroatom in R1or R2/sup> must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated), and

R2is hydrogen or a group such as defined for R1and where

R4represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or restored heteroaromatic, OR6, NHCX1X2CO2R6or NR6R7,

R5represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or restored heteroallyl,

R6and R7independently selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, heteroaromatic, restored heteroallyl or -(CH2)n(OR5)mwhere n is from 1 to 12, preferably from 2 to 10, a m is 1 to 3, and R5most preferably alkyl With2-10,

X1and X2independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, restored heteroaryl, heteroaromatic, or restored heteroaryl the mud.

2. The method according to claim 1, in which compound (I) is a compound of formula (II)

or its pharmaceutically acceptable salt, ester, amide or predecessor

where R1, R2, R4, R5, R6, R7X1and X2are the same as defined above for formula (I),

R8, R9, R10, R11each independently represent hydrogen, halogen, hydroxy-, amino-, nitro-, cyano-,

or group, R1as defined above,

or group, R12Q, where Q represents O, CO, CONH, NHCO, S, SO, SO2, SO2NH2and R12represents hydrogen or the group R1as defined above,

or group, R1R2N, where R1or R2as defined above, provided that any replacement heteroatom in R1and/or R2must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated).

3. The method according to claim 2, in which in the compound of formula (II)

R1represents aryl or arylalkyl the group in which the aryl group has up to 25 carbon atoms, or aryl-aryl group, where arylalkyl group or aryl-aryl group can be separated by a spacer, where the spacer may be ether, amidon, With the 2or ketone,

R2is hydrogen or a group as defined for R1,

R8is hydrogen or fluorine,

R9- lower branched or unbranched alkyl having from 1 to 10 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, halogenated, or halogen,

R10- lower branched or unbranched alkyl having from 1 to 10 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, halogenated, or halogen,

R11is hydrogen, halogen, or lower branched or unbranched alkyl having from 1 to 6 carbon atoms.

4. The method according to any one of claims 1 to 3, in which

R1represents phenyl substituted by a group selected from OR13, -COR13, -CO2R13, -SOR13, -SO2R13, -C(O)NR13R14, -NR14C(O)R13C1-10alkyl, C1-10alkoxy, halogeno1-10alkyl, aryl, arils1-10alkyl, heteroaryl or heteroaryl C1-10alkyl, where R13and R14each independently represent hydrogen, C1-10alkyl, C1-10alkenyl, C2-10quinil,3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl (C1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl or restored heteroaryl1-10alkyl.

5. The method according to lubas claims 1 to 4, in which R1represents phenyl substituted by a group OR13or-COR13where R13represents phenyl, phenyl, substituted-CO2R13where R13represents a C1-10alkyl, or phenyl, substituted C6-10the alkyl.

6. The method according to any one of claims 1 to 5, in which the enzyme is a lipase.

7. The method according to any one of claims 1 to 6, in which the specified concomitant violation is selected from the following: hyperlipemia, hyperlipidemia, hyperglycemia (diabetes type II), hypertension, cardiovascular disease, stroke, gastrointestinal diseases and gastro-intestinal condition.

8. The method according to any one of claims 1 to 6, wherein said drug is used to reduce the level of toxins in the fat body.

9. The method according to any one of claims 1 to 8, wherein said pharmaceutical preparation is used for reception by the person.

10. The method according to any one of claims 1 to 8, wherein said pharmaceutical preparation is used for receiving animals.

11. The compound of formula (IIA)

or its pharmaceutically acceptable salt, ester, amide or predecessor

where

R1ais

(i) branched or unbranched10-30alkyl, C2-30alkenyl,2-30quinil, cycloalkenyl, aryl-C10-30alkyl, aryl-C10-30-alkene is l, heteroaryl, heteroaryl-C1-30-alkyl, heteroaryl-C2-30alkenyl restored aryl, restored heteroaryl, restored heteroaryl1-30alkyl or substituted derivative in which the Deputy is one or more independently selected from the group: halogen, C1-10alkyl, substituted with halogen With1-10alkyl, aryl, aryl-C1-10alkyl, heteroaryl, restored heteroaryl, restored heteroaryl1-10alkyl, aryl-C1-10alkoxy-, cyano-, nitro-, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14and-NR14C(O)R13provided that any replacement heteroatom in R1must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated), or

(ii) aryl, substituted by one or more Deputy independently selected from the group comprising halogenosilanes1-10alkyl, aryl, aryl-C1-10alkyl, heteroaryl, restored heteroaryl, restored heteroaryl-C1-10alkyl, aryl-C1-10alkoxy-, cyano-, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13(provided that in this case, R13not an aryl or alkyl), -SR13, -C(O)NR13R14That is-NR 14C(O)R13,

where R13and R14each independently represent hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil,3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl, or restored heteroaryl-C1-10alkyl,

R2ais hydrogen or a group such as defined above for R1and R8a, R9a, R10aand R11asuch as defined for R8, R9and R11in the formula (II), and R10aindependently represents halogen, hydroxy, amino, nitro, cyano or the group R1as defined for formula (II), or

the group R12Q, where Q is O, CO, CONH, NHCO, S, SO, SO2, SO2NH, and R12is hydrogen or a group as defined for R1in the formula (II).

12. Connection by claim 11, in which R8aand R11arepresents a hydrogen atom.

13. The compound of formula (IIb)

where R8-R11such as defined for R8a, R9a, R10aand R11ain item 11 or 12,

R20represents a possibly substituted fenoxaprop.

14. The compound of formula (II), selected from

2 phenylamino-4H-3,1-benzoxazin-4-one

6-chloro-2-phenylamino-4H-3,1-benzoxazin-4-one

6-methyl-2-phenylamino-4H-3,1-benzoxazin-4-one

2-(4-chlorobenzylamino)-4H-3,1-benzoxazin-4-one

6-methyl-2-(naphthas-2-ylamino)-4H-3,1-benzoxazin-4-one

7-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one

5-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one

7-methyl-2-phenylamino-4H-3,1-benzoxazin-4-one

7-ethyl-2-phenylamino-4H-3,1-benzoxazin-4-one

7-octyl-2-phenylamino-4H-3,1-benzoxazin-4-one

7-butyl-2-phenylamino-4H-3,1-benzoxazin-4-one

2 phenylamino-4H-pyrido[3,4-d][1,3]oxazin-4-one

6-nitro-2-phenylamino-4H-3,1-benzoxazin-4-one

6-acetamido-2-phenylamino-4H-3,1-benzoxazin-4-one

2 phenylamino-7-trifluoromethyl-4H-3,1-benzoxazin-4-one

7-amino-2-phenylamino-4H-3,1-benzoxazin-4-one

2 phenylamino-4H-pyrido[2,3-d][1,3]oxazin-4-one

2 cyclopropylamino-4H-3,1-benzoxazin-4-one

2-(naphthas-2-yl-amino)-4H-3,1-benzoxazin-4-one

2-(6-phenylendiamine)-4H-3,1-benzoxazin-4-one

6-cyano-2-phenylamino-4H-3,1-benzoxazin-4-one

6-trifluoromethyl-2-phenylamino-4H-3,1-benzoxazin-4-one

6-formyl-2-phenylamino-4H-3,1-benzoxazin-4-one

2 phenylamino-4H-3,1-benzoxazin-4-one-6-Sultanova acid

7-hydroxy-2-phenylamino-4H-3,1-benzoxazin-4-one

7-cyclopropyl-2-phenylamino-4H-3,1-benzoxazin-4-one

6,7-dimethyl-2-phenylamino-4H-3,1-benzoxazin-4-one

6-iodo-2-Oct is a melamine-4H-3,1-benzoxazin-4-one

7-butyl-2-octylamine-4H-3,1-benzoxazin-4-one

6-methyl-2-(dodeca-7-inyl-amino)-4H-3,1-benzoxazin-4-one

8-fluorescent-2-phenylamino-4H-3,1-benzoxazin-4-one

6-cyclopropyl-2-phenylamino-4H-3,1-benzoxazin-4-one

6-mercapto-2-phenylamino-4H-3,1-benzoxazin-4-one

6-cyano-2-phenylamino-4H-3,1-benzoxazin-4-one,

or its salt, ester, amide or predecessor.

15. The compound of formula (IIA)selected from the

2-(4-triptoreline)-4H-3,1-benzoxazin-4-one

2-(3-triptoreline)-4H-3,1-benzoxazin-4-one

2-(4-butoxycarbonylamino)-6-methyl-4H-3,1-benzoxazin-4-one

2 hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one

2-(4-benzoylamino)-7-methyl-4H-3,1-benzoxazin-4-one

2-(4-phenoxybenzamine)-7-methyl-4H-3,1-benzoxazin-4-one

2-(2-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one

2-(3-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one

2-(4-cyanovinylene)-7-methyl-4H-3,1-benzoxazin-4-one

2-(4-cyanovinylene)-4H-3,1-benzoxazin-4-one

2-(4-carboxyphenylazo)-4H-3,1-benzoxazin-4-one

2-(4-aminophenylamino)-4H-3,1-benzoxazin-4-one

2-(4-hydroxyphenylazo)-4H-3,1-benzoxazin-4-one

2-(4-N-methylcarbamoylmethyl)-4H-3,1-benzoxazin-4-one

2,2’-(1,8-octylamine)-bis-4H-3,1-benzoxazin-4-one

2-(pyrrol-3-yl-amino)-4H-3,1-benzoxazin the-4-one

2-(piperidine-4-yl-amino)-4H-3,1-benzoxazin-4-one

2-[6-(pyrrol-2-yl)hexylamino]-4H-3,1-benzoxazin-4-one

2-(4-ethoxycarbonylphenyl)-4H-3,1-benzoxazin-4-one

6-methyl-2-[6-(Tien-2-yl)hexylamino]-4H-3,1-benzoxazin-4-one,

or its salt, ester, amide or predecessor.

16. The compound of formula (IIb)is selected from the

2-(4-butylaniline)-4H-3,1-benzoxazin-4-one

2-(4-methoxybenzylamine)-4H-3,1-benzoxazin-4-one

2-(4-methylphenylimino)-4H-3,1-benzoxazin-4-one

2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

2-[4(1-methylethyl)phenylamino]-4H-3,1-benzoxazin-4-one

6-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

7-ethyl-2-phenylamino-4H-3,1-benzoxazin-4-one

2-(4-hexylaniline)-6-methyl-4H-3,1-benzoxazin-4-one

2-(4-heptylaniline)-6-methyl-4H-3,1-benzoxazin-4-one

7-methyl-2-(4-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

7-methyl-2-(2-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

7-methyl-2-(3-phenoxypropylamine)-4H-3,1-benzoxazin-4-one

7-methyl-2-(4-octylaniline)-4H-3,1-benzoxazin-4-one

2-(2-phenoxybenzamine)-4H-3,1-benzoxazin-4-one

2-(3-phenoxypropylamine)-4H-3,1-benzoxazin-4-one

or its salt, ester, amide or predecessor.

17. The method of obtaining new compounds of formula (II), in particular, the compounds of formula (IIA) or fo the formula (IIb), in any of § § 11-16, which involves the cyclization of the compounds of formula (III):

where R1and R8-R11as defined above and R18represents hydrogen or C1-6alkyl,

18. The method of obtaining new compounds of formula (II), in particular, the compounds of formula (IIA) or formula (IIb), in any of § § 11-16, which involves the reaction of compounds (IV)

with an amine of formula (V)

where R1-R2, R8-R11such as defined in claim 11 or 12.

19. The way of transformation of compounds of formula (I), (II), (IIA) or (IIb) in various compounds of formula (IIA) or (IIb) by restoring the compounds of formula (I), (II), (IIA) or (IIb), where R1, R8, R9, R10and R11contain alkenylphenol or alkenylphenol group or a group corresponding alkyl or alkenylphenol group or grouping.

20. The way of transformation of compounds of formula (I), (II), (IIA) or (IIb) in various compounds of formula (IIA) or (IIb) by alkylation of compounds of formula (I), (II), (IIA) or (IIb), where one or more of R8, R9, R10and R11represent a halogen atom.

21. The compound according to any one of § § 11-16 for preventing or treating obesity or associated disorders.

22. farmacevticheskaja composition, containing the new compound of the formula (II) according to any one of § § 11-16 or its pharmaceutically acceptable salt, ester, amide, or precursor, in combination with a pharmaceutically acceptable carrier or diluent, for preventing or treating obesity or associated disorders.

23. The food product containing the compound of the formula (II) or its pharmaceutically acceptable salt, ester, amide, or predecessor, for the prevention or treatment of obesity or associated disorders.

24. A method of preventing or treating obesity or associated disorders, including patient connection according to any one of claims 1 to 16 or a composition according to claim 19 or 20.

25. The method of inhibition of enzymes, the primary effect of which is to catalyze the hydrolysis of ester groups, which includes the use of compounds according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, ester, amide, or predecessor.

26. The way to reduce fat content in animals that provide human need in the meat, which includes the use of compounds according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, ester, amide, or predecessor.

27. Cosmetic way to maintain this weight or cosmetic weight loss, including reception of compounds according to any one of claims 1 to 16.

28. The method according A.25 in which kazaninandrey used for control and inhibition of unwanted enzymes in processes or products.

29. The method according A.25, in which these compounds are used in the manufacture of items to care for the body, containing surface-active agents, soap and detergents.

30. The method according A.25, in which these compounds are used to prevent the decomposition of food containing fat.



 

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FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states that involves inhibition of activity of enzyme that catalyzes hydrolysis of ester functional groups and wherein indicated state represents obesity or accompanying disorder, and wherein compound of the formula (1):

is prescribed, or its pharmaceutically acceptable salt, ester, amide or a precursor. Also, invention relates to a method for manufacturing the medicinal preparation used for prophylaxis or treatment of states wherein inhibition of activity of enzyme is required wherein indicated enzyme catalyzes hydrolysis of ester functional groups. In the formula (1) A means a 6-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute is taken independently among the following group: halogen atom, alkyl, alkyl substituted with halogen atom, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, nitro-group, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6 or lipid, or steroid (natural or synthetic) under condition that any substituting heteroatom in R1 or R2 must be separated from exocyclic nitrogen atom by at least two carbon atoms (preferably, saturated atoms), and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12, preferably, from 2 to 10; m = from 1 to 3; R5 means preferably (C2-C10)-alkyl; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compound of formulae (II), (IIa) and (IIb) given in the description and a method for preparing compound of formulae (II), (IIa) and (IIb), pharmaceutical composition used for prophylaxis or treatment of obesity and/or accompanying disorder, nutrition product, a method for prophylaxis or treatment of obesity or accompanying disorders, a method for inhibition of activity of enzymes, a method for reducing fat content in animals, a cosmetic method for maintaining this weight and a new intermediate compound of the formula (IV) indicated in the description. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

33 cl, 1 dwg, 2 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates in particular to derivatives of acylbenzoxazine of the formula: wherein radicals X1 and X2 are taken independently among hydrogen atom, -OR3, -CH2OR3, or taken in common they represent -OCR

42
O-, -OC2R44
O-, -OC2R42
O- wherein in each case R in residue (CR2) represents hydrogen atom, oxy-group, (C1-C6)-alkoxy; R3 represents hydrogen atom, (C1-C6)-alkyl; in each case radical R1 represents hydrogen atom or (C1-C6)-alkyl; in each case radical R4 represents hydrogen atom or (C1-C6)-alkyl; n = 1, 2, 3 or 4. Compounds elicit the higher effect as compared with corresponding benzoylpiperidines for enhancing the synaptic responses mediated by AMPA-receptors. Also, invention relates to methods for their using for treatment of patients suffering with disorders in nervous and intellectual activity as result of insufficiency in function of some excitement synapses or in some AMPA-receptors. Compounds of the present invention can be used for treatment of patients without indicated disorders for enhancing activity associated with sensomotor and cognitive tasks that depend on the brain reticular structure using AMPA-receptors and for improving the memory encoding.

EFFECT: valuable biological and medicinal properties of compounds.

13 cl, 1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: method involves administering fluoroquinolone-series antibiotic like Ciproflaxin at a dose of 100-250 mg twice a day during 3-5 days and non-steroid anti-inflammatory preparation of Diclophenac at a dose of 75-150 mg/day during 3-7 days are sequentially introduced in preparing patient to diagnostic examination.

EFFECT: enhanced effectiveness in increasing method sensitivity.

2 tbl

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation used in treatment of lung, moderate and severe infections of lower respiratory ways, organs of otorhinolaryngology sphere, urinary ways, kidneys, genital organs, skin and soft tissues caused by sensitive strains of microorganisms. The medicinal formulation consists of a core and envelope wherein a core comprises the following components, wt.-%: levofloxacin, 60-69; crospovidone, 2.9-4.5; magnesium stearate, 0.1-1.0; lauryl sulfate sodium, 0.5-2.0; polyvinylpyrrolidone, 2.0-3.5; microcrystalline cellulose, the balance; envelope comprises the following components, wt.-%: yellow iron oxide, 0.05-0.1; red iron oxide, 0.05-0.1; hydroxypropylcellulose, 35.0-42.0; polyethylene glycol, 10.0-20.0; titanium dioxide, 4.8-9.0, and hydroxypropylmethylcellulose, the balance. Also, invention discloses a method for making this medicinal formulation. Invention provides rapid release of active substance in digestive tract and high strength of the proposed medicinal formulation.

EFFECT: improved preparing method, enhanced and valuable medicinal and pharmaceutical properties of formulation.

5 cl, 1 tbl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the general formula (I) wherein R1 and R2 mean independently of on another hydrogen atom (H) or fluorine atom (F); R3 means -CH3 or -CF3 ; Ar means structural formulae (a) or (b) Invention relates also to a pharmaceutical composition possessing the modulating activity with respect to progesterone receptor and containing compound of the formula (I), adjuvants, carriers and excipents. Compounds of the formula (I) are used in preparing a medicinal agent designated for selective modulation of processes in organ-targets mediated by progesterone receptor, such as uterus/breast and for selective activation of transcription of progesterone receptor isoform A as compared with transcription of progesterone receptor isoform B, selective enhancing processes mediated by progesterone receptor isoform A as compared with processes mediated by progesterone receptor isoform B and as a contraceptive. Invention provides a compound using as a medicinal agent in hormone-substitution therapy and for control of reproductive function.

EFFECT: valuable medicinal and biological properties of compound and pharmaceutical composition.

45 cl, 4 dwg, 5 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves applying endolymphatic- and autohemochemotherapy. Stage I of choriocarcinoma involves administering Methotrexate 20 mg/m2 as endolymphatic therapy at 1, 4, 8, 11, 15 and 18-th day; Rubomycin 30 mg/m2 at 1, 4, 8, 11, 15 and 18-th day Vinblastin - 15 mg/m2 at 1, 8 and 16-th day as autohemochemotherapy. Stage II of the disease involves administering Methotrexate 200 mg/m2 at the first day as endolymphatic therapy; Vincristin - 1.5 mg/m2 at 5,11, and 17-th day, Rubomycin 30 mg/m2 at 5, 8, 11, 14, 17 and 20-th day in a 21 days long course with 3 weeks long pause as autohemochemotherapy. The number of courses is 1-3. Stage III of the disease involves administering Methotrexate 200 mg/m2 as endolymphatic therapy, Etoposide -100 mg/m2, Kosmogen - 0.5 mg as autohemochemotherapy at the first day; Kosmogen - 0.5 mg as autohemochemotherapy at the second day; Vincristin - 1.0 mg/m2 Cyclophosphane 600 mg/m2, in 8 days long courses with 3-4 weeks interval and the number of courses is equal to 2-3.

EFFECT: eliminated metastases in the region of sexual organs and lungs; repaired menstrual cycle.

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