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

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

 

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. In respect of the 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 have seen 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 when the constant is m the decrease 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 is RA is the development of 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 fats, 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, there remains a need in alternativemedicine 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 4665070 (Syntex) describes a broad class of compounds, 2-oxy-4H-3,1-benzoxazin-4-it formula

where a is an integer from 0 to 4, each R' may be selected from a large number of deputies; And - communication or C1-8Allenova group, R is hydrogen (except when And communication), phenyl, imidazolyl or3-6cycloalkyl, and each of these rings may have substituents. R' groups can preferably be in the 5 and/or 7-position of the ring. The preferred value And lowest alkylene having 1-4 carbon atoms. In the most preferred compounds And ethylene. 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 syndrome mucocutaneous lymph nodes, respira the priori disorders in adults and pancreatitis. Assumed also that the compounds may have anti-parasitic, anticoagulate and/or anti-viral action. Similar compounds are also described in U.S. patent 4745116.

In the international patent application WO 89/07639 (BP Chemicals Ltd) describes the detergents in aqueous solutions containing surface-active substance, a compound, a precursor, giving the peroxide compound in the presence of water, a substance that reduces foaming, detergent base and activator bleaching, which can have the following formula:

where R can be, among others, alkoxygroup, and R1, R2, R3and R4(which may be the same or different) selected from halogen, alkyl, alkenyl, aryl, hydroxyl, alkoxyl, amino, alkylamino-, -COOR5and carbonyl functional groups. The number of carbon atoms in the alkyl groups and groups not defined, but specific examples refer to lower alkyl or CNS groups, for example R can be ethoxypropane.

In GDR patent 246996 A1 describes a method for 2-alkoxy - and 2-aryloxy-3,1-benzoxazin-4-it formula

Where R'nrepresents one or more hydrogen atoms, and/or other substituents, such as alkyl, alkoxy, aralkyl, aryl, thiocyanato-, mercapto-, alkyl is IO-, halogen or nitro-, a R2represents alkyl, Aracely or aryl residue. It is known that such compounds are used in herbicides, fungicides have activity as inhibitors of chymotrypsin. Specific examples of R2are ethyl, benzyl and phenyl.

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 proposed the use of the compounds 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 Emesene derivative, where 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, -NCX1X2CO2R6, -N(OH)C(O)NR6R7N(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 R1must be separated from ekzoticheskogo oxygen atom at least two carbon atoms (preferably saturated), and where

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

R5represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or reset is issued by 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, C2-10and

X1and X2independently 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 value is for R 4, 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 up 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, 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, phenoxy substituted by one or more halogen, halogenoalkanes, alkyl or alkoxygroup.

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

Compounds of formula I 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 (I), as defined above, or its 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 X2takiego, 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 R1is as defined above and R2is hydrogen or R1provided that any replacement heteroatom in R1and/or R2must be separated from ekzoticheskogo the nitrogen atom at least two carbon atoms (preferably saturated).

Preferred values of R1, R8, R9, R10and R11such as that defined above for compounds of formula (IIA).

More preferably, the compound for use according to the first aspect of the invention includes a compound of formula (II), or its pharmaceutically acceptable salt, ester, amide or predecessor, where:

R1represents a branched or unbranched alkyl group with up to 25, i.e. for example, up to 20 carbon atoms, aryl (e.g., 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 atom is in carbon; 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,

R8is hydrogen or fluorine,

R9- lower branched or unbranched alkyl having from 1 to 10 carbon atoms, preferably methyl; cycloalkyl having from 3 to 6 carbon atoms, preferably cyclopropyl; halogenated, preferably trifluoromethyl; or a halogen, most preferably chlorine or fluorine;

R10- preferably hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms, preferably methyl; cycloalkyl having from 3 to 6 carbon atoms, preferably cyclopropyl, haloalkyl, preferably trifluoromethyl; or a halogen, most preferably chlorine or fluorine;

R11- preferably hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms; preferably methyl, or halogen, preferably fluorine.

In particular, R1- can be unbranched alkyl group having 12, 14, 15, 16, 17, or 18 carbon atoms in the alkyl chain. In addition to this, in particular, R1, R9maybe it is ü the stands.

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

R1arepresents a

(i) branched or unbranched10-30alkyl, possibly substituted by one or more independently selected from the group3-6cycloalkyl,3-6cycloalkenyl, aryl, heteroaryl, restored heteroaryl, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano and nitro and/or possibly interrupted by one or more oxygen atom, provided that any heteroatom in R1must be separated from ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated), or

(ii)2-25alkenyl,2-25quinil,3-6cycloalkenyl, aryl-C2-25alkenyl, heteroaryl-C2-25alkenyl, restored heteroaryl, restored heteroaryl C1-25alkyl or substituted derivative in which the Deputy is one or more independently selected from the group of C1-6alkyl, halogenating C1-6alkyl, aryl, aryl-C1-6alkyl, heteroaryl in the plant and heteroaryl, restored heteroaryl-C1-6alkyl, C1-6alkoxy-, aryl-C1-6alkoxy-, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano and nitro, provided that any heteroatom in R1must be separated from ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated),

(iii)1-9alkyl, possibly interrupted by one or more oxygen atom and possibly substituted by one or more independently selected from C3-6cycloalkenyl,3-6-cycloalkenyl, aryl, heteroaryl, restored heteroaryl, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano and nitro, provided that any heteroatom in R1must be separated from ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated),

(iv)1-9alkyl, substituted by a group selected from-C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -OR13, -SR13, -C(O)NR13R14, -NR14C(O)R13, halogen, cyano-, nitro-, bicyclo the reel, bicicletasaran, monocyclic or bicyclic restored heteroaryl and monocyclic heteroaryl other than imidazole,

(v) phenyl, substituted by a group selected from OR17, -COR13, -CO2R13, -SOR13, -SO2R13, -CONR13R14, -NR13C(O)R13, halogen-substituted C1-6alkyl, aryl, aryl (C1-9alkyl, heteroaryl or heteroaryl C1-9alkyl, or

(vi) bicycloalkyl, bicicletasaran, monocyclic or bicyclic restored heteroaryl and monocyclic heteroaryl other than imidazole, possibly substituted by a group selected from OR17, -COR13, -CO2R13, -SOR13, -SO2R13, -CONR13R14, -NR14C(O)R13, halogen-substituted C1-6alkyl, aryl, aryl (C1-9alkyl, heteroaryl or heteroaryl1-9alkyl,

where R13and R14each independently represent hydrogen, C1-10alkyl, C2-10alkenyl,3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl C1-10alkyl, restored heteroaryl, or restored heteroaryl - C1-10alkyl, and R17represents hydrogen or C2-10alkenyl,2-10quinil,3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl C1-1 alkyl, restored heteroaryl, or restored heteroaryl-C1-10alkyl,

R8A, R9aR10Aand R11aeach independently represents hydrogen, halogen, hydroxy-, amino-, nitro-, cyano, thiol, C1-10alkyl, C1-10alkoxy, C1-10cycloalkyl, C1-10cycloalkane, C(O)R15C(O)NR15R16, S(O)R15or halogeno1-10alkyl,

R15and R16each independently represent hydrogen or C1-10alkyl.

In the compounds of formula (IIA).

If R1arepresents a group as defined in (i), it is preferably a branched or unbranched10-25alkyl, for example branched or unbranched10-20alkyl, mainly With12-18alkyl, for example branched or unbranched14-18alkyl, possibly substituted by one or more oxygen atom. Possible substituents of the alkyl groups preferably selected from one or more arrow, for example phenyl, heteroaryl, for example trienyl; aryloxy, for example, phenoxy; heteroaromatic, for example, benzoxazinone; -CO2R13for example COOH; -NR13R14for example NH2; -CONR13R14for example, N3, cyano, nitro, halogen and HE. R13and R14each independently represent hydrogen or C1-6alkyl.

If R 1arepresents a group as defined in (ii), it is preferably10-25alkyl, for example branched or unbranched of alkenyl or quinil, mainly C14-18branched or unbranched of alkenyl or quinil.

If R1arepresents a group as defined in (iii), C1-9the group preferably contains one or two oxygen atom. Preferred possible substituents, such as defined for groups (i) and (ii).

If R1arepresents a group as defined in (iv), preferred substituents such as defined for groups (i) to(iii).

If R1arepresents a group as defined in (v), the preferred substituents selected from OR17, -CO2R13C(O)NR13R14, -NR14C(O)R13and aryl With1-10alkyl. Phenyl group, R1aany other phenyl group or grouping the Deputy may also be substituted by one or more halogen, alkyl or halogenoalkanes.

If R1arepresents a group as defined in (vi), it is preferably selected from naphthyl, pyridyl, pyrrolyl and piperidinyl.

Preferably R1aselected from groups (i) and (v)as defined above.

R1apreferably represents a branched or unbranched10-20alkyl, possibly interrupted the first one or more oxygen atom, and/or possibly substituted by one or more aryl, such as phenyl, aryloxy, for example, phenoxy, where the phenyl group may be substituted by alkyl, halogenoalkanes, halogen or phenoxy, heteroaryl, such as tanila, heteroaromatic, for example, benzoxazinone (which may bear an oxo-Deputy), cyano-, nitro-, -C(O)R13, -NR13R14,-C(O)NR13R14HE or halogen.

R1aalso preferably phenyl, substituted by one or more, but preferably one-OR17, -CO2R13, -C(O)NR13R14, -NR14C(O)R13and arils1-10the alkyl,

where R13and R14preferably each independently represent hydrogen, C1-6alkyl,

where R17preferably represents phenyl, possibly substituted by alkyl, halogenoalkanes, halogen or phenoxy, and the phenyl group may be substituted by alkyl, halogenoalkanes or halogen.

Most preferably, R1arepresents an unbranched alkyl chain of 14,15,16,17 or 18 carbon atoms.

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, preferably from 1 to 6 carbon atoms, before occhialino methyl, cycloalkyl having from 3 to 6 carbon atoms, preferably cyclopropyl, halogeno C1-6alkyl, preferably trifluoromethyl or halogen, preferably chlorine or fluorine;

R10a- preferably hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, preferably methyl, cycloalkyl having from 3 to 6 carbon atoms, preferably cyclopropyl, halogeno C1-6alkyl, preferably trifluoromethyl or halogen, preferably chlorine or fluorine;

R11a- preferably hydrogen, halogen, for example fluorine, or a branched or unbranched alkyl having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, for example methyl.

Preferably in compounds of formula (IIA) at least one of R8a, R9a, R10aand R11ais a Deputy other than hydrogen. So, for example, R8amay be a hydrogen atom, a R9a, R10aand R11asuch as defined above. In another preferred example implementation, each of R8aand R11arepresents a hydrogen atom, a R9ais a Deputy, such as defined above, a R10arepresents a hydrogen atom or a substituent. In another preferred example of realization of ka which each of R 8a, R9aand R10arepresent a hydrogen atom, a R11ais a Deputy, such as defined above, for example methyl. Most preferably each of R8a, R10aand R11arepresent a hydrogen atom, a R9ais a Deputy, such as defined above, preferably C1-6alkyl, for example methyl.

Another group of new compounds of the formula (II) are those in which R1defined by the formula (II) and at least one of R8, R9, R10and R11represents a C8-10alkyl group, preferably8-10alkyl. Most preferably in this example implementation, or R8or R9represents a C8-10alkyl group and all other substituents in the benzene ring are hydrogen.

Examples of pharmaceutically acceptable salts of this formula include organic acid salts, such as methanesulfonate, benzosulfimide and p-toluensulfonate, salts of mineral acids such as 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 established what I salts of the compounds according to the present invention include hydroxides, 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 trihydroxystilbene, 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. Salt acid accession 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 is the Rupp, 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/or second aspects of the present invention include compounds shown in table 1.

In contrast to compounds 1-3, 6, 7, and 9 compounds shown in table 1, are, according to the applicants, new, and, thus, constitute preferred examples of implementing the present invention.

The preferred joint is of the formula (II) listed in table 1 include compounds 4, 5, 8, 10, 11, 12, 13, 14, 21, 26, 27, 28, 30, 32, 33, 34, 35 and 78.

These specific compounds are, according to the applicants, new, and, thus, represent another aspect of the present invention.

Preferred compounds of formula (IIA) listed in table 1 include the compounds 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 29, 31, 36, 37, 38, 39, 79, 80, 81, 82, 84 and 85.

Particularly preferred compounds of the formula (IIA) are as follows:

15: 2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one

16: 6-methyl-2-tetradecenoic-4H-3,1-benzoxazin-4-one

18: 2-hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one

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

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), (IIA), which shall include:

method (A) the reaction of compounds of formula (IV)

with the compound of the formula (V):

or

method (C) carrying out the cyclization of compounds of formula (VI)

where R1and R8-R11is as defined above and R18represents hydrogen or C1-6alkyl, or

method (C) the reaction of compounds of formula (VII)

with the compound of the formula (VIII)

or

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

(1) recovery of the compounds of formula (IIA), where R1, R8, R9, R10and R11contain alkenylphenol or alkenylphenol group or a group corresponding alkyl or alkenylphenol group, or clique, or

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

Method (A) can be realized by carrying out the reaction of the compound (IV) with CHLOROFORMATES formula (V). The method is preferably carried out in an alkaline medium, for example, pyridine. The reaction can be carried out with cooling to avoid overheating. Received temporarily the second connection of the carbamate is then subjected to cyclization by reaction with an 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. The specialist should be clear that if for conducting the cyclization use chloroformiate, it can be accomplished by using an excess of the compounds of formula (V). Preferably, however, use low-molecular chloroformiate, because it is cheaper and easier to remove the formed alcohol.

The compounds of formula (V) can be obtained by many known in the field of methods, for example by reaction of the corresponding alcohol R1OH with phosgene in a solvent such as toluene. This product can be allocated in the traditional way by removing the solvent and volatile by-products.

Method (C) can be achieved by reaction of compounds of formula (VI), where R18is hydrogen, with a cyclization agent, such as alkylchlorosilanes, for example, as described in method (A). Alternatively, the compound of formula (VI) may be subjected to cyclization by treatment with dehydrating agent such as concentrated sulphuric acid.

Connection is by means of formula (VI), where R18is an alkyl group, can be obtained by reacting the ester corresponding to a compound of formula (VI), for example, with phosgene and a base, such as pyridine, to obtain the corresponding isocyanate, followed by treatment of the alcohol R1OH. If desired, the ether (i.e. one where R18- alkyl) can be hydrolyzed to the corresponding acid (R18- hydrogen) using, for example, lithium hydroxide, for example, in aqueous tetrahydrofuran or aqueous dioxane.

It should be noted that the method (a) is also carried out through an intermediate compound of formula (VI), and thus, it is a variant of method ().

Method (C) can be achieved by reaction of compounds of formula (VII) with an alcohol R1OH in the presence of a base, such as base Koenig (diisopropylethylamine).

The compound of formula (VII) can be obtained from the corresponding anhydride of the formula (IX)

by reaction for example with phosphorus oxychloride (l3) at elevated temperature, for example at 100°C.

The anhydride of formula (IX) can be obtained by cyclization of compounds of formula (IV), for example with phosgene or its synthetic equivalent.

In method (D) recovery alkenylphenol or alkenylphenol groups can hold, for example, catalytic hydrogenation with COI is the whether, 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 (D) (ii) is performed in the Stille method or by cross-linking catalyzed by palladium, using, for example, tetraalkyllead, such as tetramethylurea, and h2PD(PPH3)2CL in NRMA at elevated temperature, for example at 50 to 100°C. as starting substances can be used other other halide or pseudohalide, such as triflate.

According to a fourth aspect of the invention proposed connection according to the first and second aspects of the invention (i.e. compounds of formula (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 connection according to the first and/or second aspects of the invention for use in the inhibition of enzymes, the primary 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 applications, for example in industry. These enzymes catalyze the decomposition framework, containing essential fu is clonally 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-acetylserotonin esterase, hydrolase ether carboxylic acids and cholesterol 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 in the first place refer to link the m for use in the prevention and/or treatment of such medical conditions, as obesity, hyperlipemia, hyperlipidemia and related diseases, 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 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 predotvrasenie and treatment themselves. The term "treatment" means any improvement in respect of breach, disease, syndrome, condition, 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, mainly the operation 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 (i.e. lean) 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, fats in the blood and, thus, into the intestine.

The fifth aspect of the invention has an important application. 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 microorganism is), 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, diagnostics, 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 mentioned 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 is, 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 to receive any of the suitable methods, such as oral (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, for example in the form of solutions, syrups, suspensions or emulsions, tablets, capsules and patches.

Liquid formulations typically consist of suspensions or solutions, or a physiologically acceptable salt in a suitable aqueous or non-aqueous liquid media, such as water, ethanol, glycerin, glycol or 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 prigot is no 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, an alternative may be prepared in dispersion or suspension with the use of any pharmaceutical carrier or carriers, such as water 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 suspension of the 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. An alternative solution may be lyophilized and then restored with a suitable solvent, directly n the ed method.

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. Alternative airtight container can 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 tablets 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 (with whom containing a series regular basis 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 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 tablet form, liquid form, in the form of capsules and powder, or in the form of food, 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 invented what I proposed is a method of prevention and/or treatment of obesity or associated disorders, moreover, the method includes 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 contraindications. 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 max is 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 can 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; 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 a 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 carrier or 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 humans and other vividly the data which 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 connection

Connection benzoxazinone used in the following tests marked with 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 PS™ catalogue 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, which has a pink color and absorbs light with a wavelength of 550 nm.

Inhibitor

Individual compounds were dissolved in DMSO (dimethyl sulfoxide) at 10 mm. DMSO was used in order to avoid about the LEM in the 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 colorimetrically 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 micron: 9, 11-16, 18-22, 23, 24-39, 77, 79-82, 84 and 85.

Determination of enzyme activity of lipase by the method of titration of NaOH

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

Logarithmic curves of the response from the logarithm of the dose were built for the interval inhibiting concentrations.

Results

Selected compounds of benzoxazinone investigated by the method of the title is of 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 IC501 μm: 1, 2, 4, 6-9, 11-16, 18, 22-25, 27-36, 37-39, 78, 82, 84, and 85.

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.

Measurement of trypsin activity

Trypsin pigs (Boeringer) was dissolved at a concentration of 1 mg/ml in 100 mm MOPS (3-[N-morpholino]propanesulfonic acid) with a pH of 7.3, containing 2 mm CaCl2. Before using the enzyme was diluted 500 times to obtain a final concentration of 2 µg/ml.

Selected compounds were stored under normal conditions in the form of a 5 mm solution in DMSO (dimethyl sulfoxide) at minus 20° C. For analysis, aliquot portions were thawed and prepared a series of solutions (× 100, × 200, × 1000, × 2000, × 10000, × 20000 × 100000) in 100 mm MOPS at pH of 7.3, containing 2 mm CaCl2. The basis of Bz-Phe-Arg-pNA (benzoyl-phenylalanine-valillinen-p-nitroanilide) was dissolved in DMSO to obtain a 10 mm solution. Immediately before use basis was diluted to 0.3 mm (30 μl/ml) in 100 mm MOPS containing 2 M l2.

The analysis was carried out 3 times on the ELISA plates with 96 wells. While sequentially added 10 μl of 2 μg/ml of trypsin, 26 ál of diluted inhibitor and 190 μl of the basics. Plates then were incubated at 37° installation BioRad BenchMark Microplate Reader. The measured rate of release of p-nitroaniline at 405 nm was exceeded for 10 min speed for the enzyme without inhibitor.

Measurement of the activity of chymotrypsin

Chymotrypsin cows (Sigma Type 11 Cat.No. C4129) was dissolved at a concentration of 1 mg/ml in 100 mm Tris with a pH of 7.8. Before using the enzyme was diluted 20 times in the same buffer.

Selected compounds were stored under normal conditions in the form of a 5 mm solution in DMSO (dimethyl sulfoxide) at minus 20° C. For analysis, aliquot portions were thawed and prepared a series of solutions (× 100, × 200, × 1000, × 2000, × 10000, × 20000 × 100000) in 100 mm Tris with a pH of 7.8. The basis of H-Ala-Ala-Phe-pNA (N-alanyl-alanyl-phenylalanine-p-nitroanilide) (Bachem Cat. No.L-1095) was dissolved in DMSO to obtain a 10 mm solution and kept at 4° until use. Immediately before use basis was diluted to 0.3 mm to a final concentration of 30 μl/ml

The analysis was carried out 3 times on the ELISA plates with 96 wells. While sequentially added 10 μl of 50 μg/ml is ametryplene, 50 ál of diluted inhibitor and 190 μl of the basics. Plates then were incubated at 37° installation BioRad BenchMark Microplate Reader. The measured rate of release of p-nitroaniline at 405 nm was exceeded for 10 min speed for the enzyme without inhibitor.

Results

In this analysis, we measured the selectivity of compound 18 in relation to the pancreatic lipase person, trypsin and chymotrypsin. Inhibitory activity of compound 18 with respect to the lipase was evaluated according to the colorimetric analysis with hendikins dye.

At 500 nm the connection 18 inhibited by 98.7% of the activity of pancreatic lipase, but only 4% of the activity of trypsin and 12.5% of the activity of chymotrypsin. Thus, the results show that the connection 18 is a selective inhibitor of lipases.

The test model mouse

Compound 18 was tested in the mouse model, 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 acids

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

The method is based on the methodology described LA.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) Oh what Adila in an 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% tO/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% tO/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, 2,7 the mol).

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; σH(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. Agsn2), 6.42 per (2H, br.s. 2 ArH), 7,74 (1H, br.s. ArH); m/z (ES+) 250 (MN+).

Synthesis of 5 - substituted Anthranilic acids

Example: obtain 5-octyl Anthranilic acid

The method is based on the methodology described B.R.Baker and others in J.Org.Chem. 17, 141 (1952).

Chloral hydrate (of 3.97 g, 24 mmol) was dissolved in water (50 ml). To this solution was added sequentially anhydrous sodium sulfate (5.5 g, 39 mmol), 4-octylaniline (5 ml, 22 mmol), water (15 ml), concentrated hydrochloric acid (2.3 ml) and an aqueous solution of hydroxylamine hydrochloride (4.5 g, 22 ml, 65 mmol). A heterogeneous mixture of load, the Wali to 95° C for 2 h, then to 110° another hour. The reaction mixture was then cooled to room temperature, the brown precipitate was filtered and washed with water. The result was dissolved in dichloromethane, dried (MgSO4) and concentrated to yield 5,6 crude material, which was purified flash chromatography on silica gel (20% tO/hexane) to give the desired material (2 g, 7.2 mmol).

The oxime (1.8 g, 6.5 mmol) was added to a mixture of concentrated sulfuric acid (13 ml) and water (1 ml) at 60° C for 15 minutes the Mixture then was heated to 80° C for 2 h and left overnight. Then spent the extraction with ethyl acetate (× 3), combined organic layers were washed with saturated aqueous sodium bicarbonate and water until neutral reaction of wash water. The organic phase was then dried (MgSO4) and concentrated with the release of isatin in the form of a red sludge (1.5 g, 5.8 mmol)which was used without further purification.

A mixture of isatin (1.5 g, 5.8 mmol) and 1.5 M sodium hydroxide (13 ml) was heated to 50° C. Heating was stopped and the solution was added 35% aqueous hydrogen peroxide (1.5 ml), at a speed which provides a temperature of 50-55° C. Then the reaction mixture was left to cool, and stirred at room temperature for the of 30 minutes Adding concentrated hydrochloric acid to pH 2 resulted in the deposition of sediment. Liquid decantation, the precipitate washed with water. The residue was separated between water and dichloromethane, the organic phase was washed with brine, dried (MgSO4) and concentrated to obtain the desired Anthranilic acid (1.4 g, 5.6 mmol). Further purification was not required: σH(400 MHz, CDCl3) 0,81 (3H, t, J 6.6, Me), 1,20-of 1.23 (10H, m, 5× CH2), for 1.49 (2H, br.s., Agsn2CH2), 2,41 is 2.44 (2H, m, ArCH2), 6,55 (1H, d, J 8.3, AGN), the 7.65 (1H, s, ArH); m/z (ES+) 250 (MN+).

Getting allformats:

Example: 4-phenoxyphenylacetic

4-phenoxyphenol (1.68 g, 9 mmol), 1,4-dimethylimidazolidin-2-he (0,051 ml, 0.45 mmol) and a solution of phosgene (4,5 ml of 20%solution in toluene, 9 mmol) was heated to 40° C for 30 minutes and Then the temperature was raised to 80° and added 5 more portions of a solution of phosgene (2,25 ml each, 4.5 mmol) at intervals of 30 minutes After 30 minutes after the last addition, the solution was left to cool to room temperature and kept in an throughout the night. Aliquot portion was added to the Meon/pyridine with the formation of stable methylcarbamate, after which thin layer chromatography (10% tOA/hexane) showed almost complete disappearance of the starting material. The solution chloroformiate used directly in the sentence is allenii connection 29 to the method described in example 4 below.

The synthesis of new compounds according to the invention

Example 1

Synthesis of 6-methyl-2-octyloxy-4H-3,1-benzoxazin-4-it (room 11)

A solution of 2-amino-5-methylbenzoic acid (302 mg, 2 mmol) in pyridine (10 ml) was cooled to 0° and added drop by drop ochiltree (1,15 ml, 6 mmol). The resulting mixture was left to warm to room temperature and was stirred during 4 h of the Pyridine is then removed under vacuum and the residue was dissolved in ethyl acetate (50 ml). This solution was washed in 1 M HCl (10 ml) and brine (5 ml), dried (MgSO4) and the solvent removed under vacuum to obtain a pale orange oily residue. Recrystallization from hexane gave the desired product as an almost white solid residue. (144 mg, 25%); σH(400 MHz, DMSO-d6) to 0.68 (3H, t, J7, CH2CH3), 1,26-of 1.40 (10H, m, 5× CH2), is 1.73 (2H, tt, J, J'7, och2CH2CH3), to 2.35 (3H, s, CH3), 4,35 (2H, t, J7, co2), 7,34 (1H, d, J 8, Ph), the 7.65 (1H, d, J8, Ph), 7,83 (1H, s, Ph); m/z (ES+) 290 (MH+).

Example 2

6-methyl-2-phenoxy-4H-3,1-benzoxazin-4-one (compound No. 8)

A solution of 2-amino-5-methylbenzoic acid (302 mg, 2 mmol) in pyridine (10 ml) was cooled to 0° C and added drop by drop phenylcarbamate (3,3 ml, 26 mmol). The resulting mixture was left to warm to room temp the atmospheric temperature with stirring for 16 h, then the pyridine was removed under vacuum. The residue was washed with water (20 ml) and dried under vacuum. Recrystallization from toluene gave the desired product as a pale brown solid residue (692 mg, 41%); σH(400 MHz, DMSO-d6) to 2.40 (3H, s, CH3), 7,33 was 7.45 (3H, m, PH), of 7.48-of 7.55 (3H, m, PH), 7,63 (1H, d, J8, PH), 7,89 (1H, s, PH-H5), m/z (ES+) 254 (MN+).

Example 3

2-propoxy-6-methyl-4H-3,1-benzoxazin-4-one (compound No. 9)

A solution of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mol) in pyridine (10 ml) was cooled to 0°C. and added drop by drop propylchloride (3.0 ml, 26 mmol). The resulting mixture was left to warm to room temperature while stirring for 4 h, after which the pyridine was removed under vacuum. The residue was washed with water (25 ml) and dried under vacuum to give the desired product as an almost white solid residue (0.96 g, 66%); σH(400 MHz, DMSO-d6) of 1.03 (3H, t, J7, CH2CH3), is 1.82 (2H, tq, J, J'7, CH2CH3), the 2.46 (3H, s, CH3), was 4.42 (2H, t, J7, co2), 7,40 (1H, d, J8, PH), 7,71 (1H, d, J8, PH), 7,89 (1H, s, PH); m/z (ES+) 219 (MN+).

Example 4

2 hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one (18)

The method of obtaining 1

Step 1:

1-hexadecanol (0,78 g, 3.2 mmol, 1 EQ.) was dissolved in minimum amount of THF (tetrahydrofuran) in the atmosphere AZ is the same. The result has added a 20%solution of phosgene in toluene (2,34 ml, 5.5 mmol, 1.5 EQ.). After 45 min added a second identical portion of a solution of phosgene. After another 45 min, the apparatus was purged with nitrogen (which output was passed through a scrubber with 5 M sodium hydroxide) to remove excess phosgene.

Step 2:

2-amino-5-methylbenzoic acid (100 mg, 0.64 mmol, 0.2 EQ.) dissolved in pyridine (10 ml). Drop added chloroformiate pipette, and the mixture was stirred at room temperature for 2 hours Then the mixture was diluted with ethyl acetate (100 ml) and washed 10%citric acid solution (100 ml x2), saturated sodium bicarbonate solution (100 ml x2), water, and saturated brine (100 ml). The organic phase was dried (MgSO4) and concentrated under vacuum.

The residue was purified flash chromatography on silica gel, eluent 1:5:94 diisopropylethylamine/ethyl acetate/hexane to obtain a white solid residue (40 mg, 15%); σH(400 MHz, CDCI3) of 0.87 (3H, t, J6.8, CH2CH3), 1,24-1,45 (N, m, 13× CH2), a 1.75-to 1.82 (2H, m, och2CH3), is 2.41 (3H, s, Agsn3), to 4.41 (2H, t, J6.7, co2), 7,30 (1H, d, J8, ArH), 7,51 (1H, dd, J8.5, 2.0, ArH), of 7.90 (1H, d, J1.1, ArH); m/z (ES+) 402 (MH+); MPt. 72-73°C.

Thin-layer chromatogram (solvent 1% Diisopropylamine/5% ethyl acetate/94% hexane) was observed in UV light and phosphomolybdenum acid in which canola (Rf connection 18 or=0.6).

The method of obtaining 2

Step 1:

1-hexadecanol (5,01 g of 20.6 mmol, 1 EQ.), dissolved in THF (10 ml) under nitrogen atmosphere and added a 20%solution of phosgene in toluene (29 ml, 62.5 mmol, 3 EQ.). The mixture was stirred at room temperature for 2 h, and then the apparatus was purged with nitrogen (which output was passed through a scrubber with 5 M sodium hydroxide) to remove excess phosgene.

Step 2:

2-amino-5-methylbenzoic acid (2,71 g of 17.9 mmol, 0.87 for EQ.) dissolved in pyridine (24 ml) and added to a solution of chloroformate, prepared as described above. The mixture was stirred at room temperature for about 1.75 hours and Then slowly added methylchloroform (to 13.6 ml, 176 mmol, 8.5 equiv.) and the mixture was allowed to mix at room temperature overnight. Then the mixture was diluted with ethyl acetate (20 ml) and washed with water (15 ml) and 10%citric acid solution (20 ml). The combined organic phases were extracted with ethyl acetate (20 ml). The organic extracts were collected and washed with water (20 ml) and brine (20 ml) and then concentrated to obtain the precipitate. Sediment suspended in pentane (5 ml), filtered, and purified flash chromatography on silica gel (1.5% diisopropylethylamine in dichloromethane) to give a white solid residue (of 2.51 g, 31%); σH(400 MHz, CDCl3) of 0.87 (3H, t, J.8, CH2CH3), 1,24-1,45 (N, m, 13× CH2), a 1.75-to 1.82 (2H, m, och2CH3), is 2.41 (3H, s, Agsn3), to 4.41 (2H, t, J6.7, OCH2), 7,30 (1H, d, J8, ArH), 7,51 (1H, dd, J8.5, 2.0, ArH), of 7.90 (1H, d, J1.1, ArH); m/z (ES+) 402 (MH+); MPt. 72-73° C.

Example 5

The remaining compounds of table 1 can be obtained similarly to examples 1-4. In particular, the following compounds were obtained using the original substances are shown in table 2.

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 Il the 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, -N1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -N(O)NR6R7,

C(O)NNR6R7-C(O)N(or SIG5R6or lipid or steroid (natural or synthetic), provided that any replacement heteroatom in R1or R2must be separated from ekzoticheskogo atom is of ikorodu at least two carbon atoms (preferably saturated),

and where

R4represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, restored heteroaryl or restored heteroaromatic, or SIG6, NX1X2CO2R6or 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, and m is from 1 to 3, and R5most preferably alkyl With2-10and

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

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, NH, N, S, SO, SO2, SO2NH2and R12represents hydrogen or the group R1as defined above,

or group, R1R2N, where R1as defined above, and R2is hydrogen or R1provided that any replacement heteroatom in R1or R2must be separated from ekzoticheskogo oxygen atom at least two carbon atoms (preferably saturated).

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

R1represents a branched or unbranched alkyl group having up to 25 carbon atoms; aryl group; arylalkyl group in which the alkyl group has up to 25 carbon atoms; or aryl-aryl group, with arylalkyl group or aryl-aryl group can be separated by a spacer, where the spacer may be one or more of ester, amide, O, CH2or ketone,

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;

R10is hydrogen, 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, lower branched or unbranched alkyl having from 1 to 10 carbon atoms; or halogen.

4. The method according to any one of claims 1 to 3, wherein the specified condition is selected from the following: obesity, hyperlipemia, hyperlipidemia, hyperglycemia (diabetes type II), hypertension, cardiovascular disease, stroke, gastrointestinal diseases and gastro-intestinal condition.

5. The method according to any one of claims 1 to 3, in which the specified connection serves to reduce the level of toxins in the fat body.

6. The method according to any one of claims 1 to 5, in which the specified connection is used for reception by the person.

7. The method according to any one of claims 1 to 5, in which the specified connection used for receiving animals.

8. The compound of formula (IIA)

or its pharmaceutically acceptable salt, ester, amide or predecessor

where

R1ais

(i) branched or unbranched10-30alkyl,possibly substituted by one or more independently selected from the group 3-6cycloalkyl,3-6cycloalkenyl, aryl, heteroaryl, restored heteroaryl, -C(O)R13, -CO2R13-The separator R s o13, -SO2R13, -NR13R14, -Or SIG13, -SR13-C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and nitro and/or possibly interrupted by one or more oxygen atom, provided that any heteroatom in R1must be separated from ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated), or

(ii)2-25alkenyl,2-25quinil,3-6cycloalkenyl, aryl-C2-25alkenyl, heteroaryl-C2-25alkenyl, restored heteroaryl, restored heteroaryl1-25alkyl or substituted derivative in which the Deputy is one or more independently selected from the group:1-6alkyl, halogen-substituted C1-6alkyl, aryl, aryl-C1-6alkyl, heteroaryl, restored heteroaryl, restored heteroaryl-C1-6alkyl, C1-6alkoxy-, aryl-C1-6alkoxy-, -C(O)R13, -CO2R13-The separator R s o13, -SO2R13, -NR13R14, -Or SIG13, -SR13-C(O)NR13R14, -NR14C(O)R13, halogen, cyano, and nitro, provided that any heteroatom in R1should be separated is t ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated),

(iii)2-9alkyl, possibly interrupted by one or more atom of Colorada and possibly substituted by one or more independently selected from C3-6-cycloalkenyl,3-6-cycloalkenyl, aryl, heteroaryl, restored heteroaryl, -C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -Or SIG13, -SR13-C(O)NR13R14, -NR14C(O)R13halogen, cyano, and nitro, provided that any heteroatom in R1must be separated from ekzoticheskogo oxygen atom (or from any other heteroatom) by at least two carbon atoms (preferably saturated),

(iv)1-9alkyl, substituted by a group selected from-C(O)R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -Or SIG13, -SR13, -C(O)NR13R14, -NR14C(O)R13, tetrahydronaphthyl, pyridyl, pirolli, piperidinyl, halogen, cyano-, nitro-, bicycloalkyl, bicicletasaran, monocyclic or bicyclic restored heteroaryl and monocyclic heteroaryl other than imidazole,

(v) phenyl, substituted by a group selected from or SIG17, -R13, -CO2R13, -SOR13,-SO2R13, -NR13R14, -NR14C(O)R13, halogen-substituted C1-6alkyl, aryl, aryl C1-6alkyl, heteroaryl or heteroaryl the 1-6alkyl, or

(vi) bicycloalkyl, bicicletasaran, monocyclic or bicyclic restored heteroaryl and monocyclic heteroaryl other than imidazole, possibly substituted by a group selected from or SIG17, -R13, -CO2R13, -SOR13, -SO2R13, -NR13R14, -NR14C(O)R13, halogen-substituted C1-6alkyl, aryl, aryl C1-6alkyl, heteroaryl or heteroaryl1-6alkyl,

where R13and R14each independently represent hydrogen, C1-10alkyl, C2-10alkenyl,2-10quinil, C3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl, or restored heteroaryl - C1-10alkyl, and R17represents hydrogen or C2-10alkenyl,2-10quinil,3-6cycloalkyl,3-6cycloalkenyl, aryl, aryl-C1-10alkyl, heteroaryl, heteroaryl1-10alkyl, restored heteroaryl, or restored heteroaryl-C1-10alkyl,

R8a, R9aR10aand R11aeach independently represents hydrogen, halogen, hydroxy-, amino-, nitro-, cyano, thiol,1-10alkyl, C1-10alkoxy, C1-10cycloalkyl,1-10cycloalkane, C(O)R15With(O)NR15R16, S(O)R15 or halogeno1-10alkyl,

R15and R16each independently represent hydrogen or C1-10alkyl.

9. The connection of claim 8, in which

R1ais a branched or non-branched C10-20alkyl, possibly interrupted by one or more oxygen atom and/or possibly substituted by one or more of aryl, aryloxy, heteroaryl, heteroaromatic, cyano, nitro, -CO2R13, -NR13R14, -CONR13R14HE and halogen, where R13and R14each independently represent hydrogen or C1-6alkyl.

10. The compound of claim 8 or 9, in which R1arepresents an unbranched alkyl chain containing 14, 15, 16, 17, or 18 carbon atoms.

11. The compound according to any one of p-10, in which R8arepresents a hydrogen or halogen.

12. The compound according to any one of p-11, in which R9arepresents hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, halogeno1-6alkyl or halogen.

13. The compound according to any one of p-12, in which R10ais hydrogen, lower branched or unbranched alkyl having from 1 to 10 carbon atoms; cycloalkyl having from 3 to 6 carbon atoms, halogeno1-6alkyl or halogen.

14. Connect the s on any of PP-13, in which R11arepresents hydrogen, halogen or unbranched alkyl having from 1 to 10 carbon atoms.

15. The compound of formula (IIb)

where R1bdefined as R1for the compounds of formula (II) according to claim 2, and at least one of R8b, R9bR10band R11brepresents a C8-20alkyl, preferably8-10alkyl group.

16. The new compound of the formula (II), selected from

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

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

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

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

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

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

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

2-ethyl-2-hexyloxy-4H-3,1-benzoxazin-4-one

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

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

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

6-methoxy-2-octyloxy-4H-3,1-benzoxazin-4-one

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

6-iodo-2-octyloxy-4H-benzoxazin-4-one

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

6-methyl-2-(8-phenylacrylate)-4H-3,1-benzoxazin-4-one

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

5-methyl-2-o is tilox-4H-3,1-benzoxazin-4-one,

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

17. The compound of formula (IIa)selected from the

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

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

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

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

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

2-(3,7-dimethyloctyl)-6-methyl-4H-3,1-benzoxazin-4-one

2-[2-(2-hexyloxyethoxy)ethoxy] -6-methyl-4H-3,1-benzoxazin-4-one

2-(octadeca-9 enyloxy)-6-methyl-4H-3,1-benzoxazin-4-one

2-(10-phenyldecane)-6-methyl-4H-3,1-benzoxazin-4-one

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

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

6-methyl-2-(12-phenyldecane)-4H-3,1-benzoxazin-4-one

6-methyl-2-(octadeca-11 enyloxy)-4H-3,1-benzoxazin-4-one

6-methyl-2-(octadeca-11 enyloxy)-4H-3,1-benzoxazin-4-one

6-methyl-2-[-10-(Tien-2-yl)-decyloxy]-4H-3,1-benzoxazin-4-one

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

6-octyl-2-octyloxy-4H-3,1-benzoxazin-4-one

2-(5-chloropentane)-6-methyl-4H-3,1-benzoxazin-4-one

2,2'-(1,16 hexadecylamine)-bis-4H-3,1-benzoxazin-4-one

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

6-methyl-2-[6-(4-phenoxyphenoxy)hexyloxy]-4H-3,1-b is isoxazine-4-one

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

18. The compound of formula (IIa), representing

2 hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one or its pharmaceutically acceptable salt, ester, amide or predecessor.

19. The method of obtaining a new connection according to any one of p-18, which includes

carrying out the reaction of compounds of formula (IV)

with the compound of the formula (V)

20. The method of obtaining a new connection according to any one of p-18, which comprises carrying out the cyclization of compounds of formula (VI)

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

21. The method of obtaining a new connection according to any one of p-18, which includes

carrying out the reaction of compounds of formula (VII)

with the compound of the formula (VIII)

22. The method of obtaining a new connection according to any one of p-18, which includes the transformation of the compounds of formula (I), (II) or (IIa) in various compounds of formula (IIa).

23. The compound according to any one of p-18 for the prevention and/or treatment of obesity or associated disorders.

p> 24. The pharmaceutical composition containing the new compound of the formula (II) or its pharmaceutically acceptable salt, ester, amide, or precursor, in combination with a pharmaceutically acceptable carrier or diluent, for the prevention and/or treatment of obesity or associated disorders.

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

26. A method of preventing or treating obesity or associated disorders, including patient connection according to any one of claims 1 to 18 or composition according to item 23 or 24.

27. 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 18, or its pharmaceutically acceptable salt, ester, amide, or predecessor.

28. 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 18, or its pharmaceutically acceptable salt, ester, amide, or predecessor.

29. Cosmetic way to maintain this weight, or cosmetic weight loss, including reception of compounds according to any one of claims 1 to 18.

30. The method according to item 27, in which oterom these connections are used for control and inhibition of unwanted enzymes in processes or products.

31. The method according to item 27, in which the above compounds used in items to care for the body, containing surface-active agents, soap and detergents.

32. The method according to item 27 in which the said compound is used to prevent decomposition of food containing fat.

33. New intermediate compound of formula (IV), where R1and R8-R11as defined in any of PP-18, and R18represents hydrogen or C1-6alkyl.



 

Same patents:

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

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 invention relates to the field of medicine and relates to the application of metabolite of sibutramine as a new drug to treat attention deficit or attention deficit hyperactivity disorder

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

A therapeutic agent // 2234917
The invention relates to medicine, to a method of treating obesity in a human in need of such treatment, by appointing such a person a therapeutically effective amount of the compounds of formula I, including enantiomers and pharmaceutically acceptable salts, where R1and R2independently mean hydrogen or methyl, and therapeutically effective amounts of compounds of formula II, in which the compound of formula I and the compound of formula II appointed simultaneously, separately or sequentially, and farbkomposition, including the compounds of formula I and II

The invention relates to medicine, in particular to endocrinology and therapy, and for the treatment of pathological conditions associated with obesity

Inovative polymers // 2222335
The invention relates to medicine, in particular to the treatment of obesity, reducing the absorption of dietary fat and hypertriglyceridemia

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 invention relates to pharmaceutical industry and relates to inhibitors lks-channel simultaneous action as inhibitors KQT1 channel to obtain drugs for the treatment of diseases caused by helminths and ectoparasites, while inhibitors KQT1 channel have high selectivity and are non-toxic to warm-blooded animals and humans

The invention relates to new derivatives of benzoxazinone General formula (I), where R1means N or carboxyethyl, R2represents hydrogen or alkyl, and R3is a different derivatively of amino acids, dipeptides and hydrazones acid groups, respectively, their conjugates with active substances, such as residues from a number of penicillin

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

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