Derivatives of benzocycloheptene or benzocaine, the retrieval method, intermediate compounds and pharmaceutical composition

 

(57) Abstract:

Invention are new compounds of General formula I where X is oxygen or the group CHR; R1- R4(indetity or different) is hydrogen or C1-C7-alkyl, with advanced R1together with R forms a bond; R5is hydrogen or a hydroxy-group, or R5together with R7forms a bond or a group-O-; R6- group where R10and R11together with the carbon atom to which they are linked, form azotosoderjashchig a heterocycle, and their N-oxides and pharmaceutically acceptable salts. These compounds are potent activators of potassium channels. On the basis of the obtained pharmaceutical composition having a relaxing effect on smooth muscles. Also described is a method of obtaining compounds of formula (I) on the basis of the interaction of the corresponding ketone with the ORGANOMETALLIC compound with the subsequent removal of the protective groups to obtain the corresponding intermediate products in the presence of acid or carboxylic acid. 4 C. and 9 C.p. f-crystals, 2 tab.

The object of the present invention are new heterocyclic compounds having pharmacological activity, which is to promote the potassium channels of cell membranes, opening these channels or extending their open state. This leads to the movement of ions through the membrane and to a decrease in free intracellular Ca ions++that cause relaxation of smooth muscle fibers.

Therapeutic capabilities allow today to lay high agonists potassium. Among the most studied areas should be mention of hypertension, angina and asthma. Large collection activators potassium channels already known for their relaxant properties.

The family of derivative benzpyrene is the subject of many publications in this area. These compounds meet the following General formula A:

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EP 0076075 describes compounds of General formula A, where the group-pyrrolidone. Patent DE 3726261 describes compounds of General formula A, where the group - pyridone.

Another family benzpyrene corresponds to the formula B below; it corresponds to the compounds described in EP 0298452:

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Patents WO 89/11477 and EP 0360131 refer to benzocaine General formula C:

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in which X is a nitrogen-containing ring linked through the nitrogen atom in position 5 benzocaine, for example 2-oxo-1-pyrrolidinyl and 2-oxo-1-pyridyl for the first patent and 2 is d or lower alkyl; and R1and R2is hydrogen or nitrile, arylsulfonyl, cyano - or nitro-group.

Now open a new connection with a system of rings of benzocycloheptene or benzocaine, which show a noticeable effect on the activation of potassium channels.

The subject invention are compounds of General formula I,

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in which X is oxygen or the group CHR, where R is hydrogen, or R together with R1form a bond, R1, R2R3and R4- which may be the same or different is hydrogen or C1-C7-alkyl, or R1together with R form a bond; R5is hydrogen or a hydroxy-group, or R5together with R7form a bond, or/O; R6group of the formula where R10and R11together with the carbon atom to which they are bound, form an optionally aromatic mono - or bicyclic nitrogen-containing heterocyclic 3 - to 11-membered radical with 1 to 2 nitrogen atoms, optionally substituted at carbon atoms 1 to 7 groups selected from hydroxy-, nitro-, cyano-C1-C7-alkoxygroup or C1-C7-alkyl, and it is possible that at least one of the nitrogen atoms of the heterocycle may be oxidized; R7is hydrogen or GT communication or/O group; R8and R9that may be the same or different, is hydrogen, halogen, trifluoromethyl, pentafluoroethyl, C1-C7-alkyl, C1-C7-alkylsulfonyl, C1-C7-alkylsulfonyl, hydroxy-, nitro-, cyano-, triptoreline-, C1-C7-alkoxy, C1-C7-alkylthio or C1-C7-alltihopa or a group of the formula COOR12where R12and R13may be the same or different, is hydrogen or C1-C7-alkyl, or R8and R9- C6-C10-arylsulfonyl or C6-C10-arylsulfonyl, optionally substituted by 1 to 6 substituents selected from halogen, carbamoyl, trifloromethyl, pentaborate, C1-C7-alkyl, C1-C7-alkylsulfonyl, C1-C7-alkylsulfonyl, hydroxy-, nitro-, cyano-, carboxyl, triptoreline-, C1-C7-alkoxy, C1-C7-alkylthio or C1-C7-alltihopa, or R8and R9may be the same or different, a heterocyclic 3 - to 11-membered radical with 1 to 4 heteroatoms which may be the same or different, selected from oxygen, sulfur and nitrogen, optionally substituted by 1 to 6 substituents selected and the Nile, C1-C7-alkylsulfonyl, hydroxy-, nitro-, cyano-, carboxy-, triptoreline-, C1-C7-alkoxy, C1-C7-alkylthio or C1-C7-alltihopa, or R8and R9form a group (CH2)nwhere n is from 1 to 6, or R8and R9together form a heterocyclic 3 - to 11-membered radical with 1 to 4 heteroatoms which may be the same or different, selected from oxygen, sulfur and nitrogen, optionally substituted by 1 to 6 substituents selected from halogen, carbamoyl, trifloromethyl, pentaborate, C1-C7-alkyl, C1-C7-alkylsulfonyl, C1-C7-alkylsulfonyl, hydroxy-, nitro-, cyano-, carboxy-, triptoreline-C1-C7-alkoxy, C1-C7-alkylthio or C1-C7-alltihopa, and their N-oxides and their pharmaceutically acceptable salts.

"C1-C7-alkyl" refers to groups containing linear and branched C1-C7-chains, especially methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl and heptyl.

"C1-C7-alkoxygroup" denotes a group containing a linear or branched C1-C7-chains, especially methoxy, ethoxy, propac the AET alkyl group, containing a linear or branched C1-C6-the circuit associated with carbonyloxy, especially acetoxy - and propionyloxy.

"C1-C7-allylthiourea" denotes an alkyl group containing a linear or branched C1-C7the circuit associated with the sulfur atom, especially methylthio, ethylthio, propylthio, butylthio, pentylthio-, hexylthio and reptiliomorpha.

"C1-C7-alkylsulfonyl" means an alkyl group containing a linear or branched C1-C7-the circuit associated with sulfonium-SO2- especially methylsulfonium, ethylsulfonyl, propylsulfonyl, butylsulfonyl, intercolonial, vexillological and heptansulfonat.

"C1-C7-alkylsulfonyl" refers to alkyl groups containing linear or branched C1-C7-the circuit associated with sulfinil-SO2- especially methylsulfinyl, ethylsulfinyl, propylsulfonyl, butylsulfonyl, pentasulfide, exisulind and heptylaniline.

"C6-C10aryl" means a mono - or bicyclic carbocyclic aromatic group, particularly phenyl, naphthyl or indenyl.

The term "halogenatom, selected from oxygen, sulfur and nitrogen, may be aromatic or non-aromatic, monocyclic or bicyclic and is especially pyridium, imidazolium, fullam, tetrahydrofuryl, Puritanism, teinila, aziridinyl, oxiranyl, azetidinol, chinaillon, tetrahydroquinoline and tetrazolium.

If R8and R9together form a heterocycle with 3 - 1 members, including from 1 to 4 identical or different heteroatoms selected from oxygen, sulfur and nitrogen, they are, especially with the phenyl to which they relate, hinely, ethanolic, benzimidazolyl, bankfull, Bastiani or benzoxadiazole.

R6- preferably 2-pyridyl, N-oxido-2-pyridyl, 3-pyridine, N-oxido-3-pyridyl, 4-pyridyl, 3-hydroxy-4-pyridyl, 2-pyrimidyl, N-oxido-2 pirimidil, 6 pirimidil, N-oxido-6 pirimidil, 2-chinolin, N-oxido-2-chinolin, 1-ethanolic and N-oxido-1-ethanolic, optionally substituted at carbon atoms 1 to 3 substituents, selected from hydroxy-, nitro-, cyano-, C1-C7-alkoxygroup and C1-C2-alkyl.

Physiologically acceptable salts of the compounds of formula I are salts formed with metals such as sodium, potassium, calcium and magnesium, or with the slots.

N-Oxely formula I are compounds in which one or more nitrogen atoms in the group R6oxidized.

The term "TRANS" is used for compounds that contain asymmetric carbon atoms in the rings, shows that two deputies are on opposite sides of the Central plane of the ring, and the term "CIS" is used for two deputies are on one side of the Central plane of the ring.

Preferred compounds of General formula I are those compounds in which X is an oxygen atom.

Mainly R1and R2- hydrogen atoms, and/or R5- the hydrogen atom. Mainly R7selected from hydrogen, hydroxy-, methoxy - and acetochlor.

The first preferred family of compounds of the present invention correspond to compounds of General formula II

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in which X is oxygen or the group CHR and R, R5, R6, R7, R8and R9defined above.

The carbon atoms 4 and 5 of the formula II can work together or independently to provide a chiral center. Derivatives, such as optical isomers, racemates, CIS - or transperitoneal, enantiomers and diastereoisomers form part of izopet>3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

8-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7-bromo-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

5-acetoxy-7-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin;

7-bromo-4,5-epoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin;

7-bromo-5-methoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin;

7-ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7-methoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

3,3-dimethyl-7-(1-methylpropyl) -5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3,4,5 - tetrahydro-1-benzoxazin-5-ol;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-triptoreline-2,3,4,5 - tetrahydro-1-benzoxazin-5-ol;

3,3-dimethyl-7-phenyl-5-(N-oxido-2-pyridyl)-2,3,4,5-benzoxazin-5-ol;

8-chloro-7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

3,3-dimethyl-5-(N-OK is 2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7,8-dimethoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

7,9-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol;

The second preferred family of compounds of the present invention are compounds of General formula III

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in which X is oxygen or the group CHR and R, R6, R8and R9defined above. Among the preferred compounds of formula III may be mentioned the following compounds:

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

7-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

7-chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

8-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

7-bromo-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3-dihydro-1-benzoxazin;

3,3,7-trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

7-ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-(1-methylpropyl)-5- (N-oxido-2-pyridyl)-2,3-digimatic-5- (N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl - 2,3-dihydro-1-benzoxazin;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-8-trifluoromethyl-2,3-dihydro-1-benzoxazin;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-triptoreline - 2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-methylsulfinyl-5-(2-pyridyl)- 2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-methylsulphonyl-5-(2-pyridyl)- 2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-methylsulphonyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7-cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

8-cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin;

3,3-dimethyl-5-(N-oxido-2-pyridyl)- 7-pentafluoroethyl-2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-phenyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

3,3-dimethyl-7-nitro-5-(4-nitro-N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

6,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7,9-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

8,9-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7,8-debtor-3,3-dimethyl-5-(N-oxido-2-pyridyl)- 2,33,3,7-trimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7-cyano-3,3,8-trimethyl-5-(N-oxido-2-pyridyl)- 2,3-dihydro-1-benzoxazin;

7,8-dimethoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin;

8-chloro-7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,7,8,9,10 - hexahydro-1-naphthas(2,3-b)oxepin;

8-cyano-3,3-dimethyl-1-(N-oxido-2-pyridyl)-4,5 - dihydro-3H-benzo-(4,3-f)cyclohepten;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin-7-carboxamide;

3,3-dimethyl-7-phenylsulfonyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin;

7-chloro-8-ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin;

8-bromo-3,3-dimethyl-1-(N-oxido-2-pyridyl)-3H-benzo/f/cyclohepta - 1,4-diene.

Compounds of the invention can be obtained by the method lies in

a) reaction of a ketone of formula IV,

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in which X, R1, R2, R3and R4defined above, and R'5, R'8and R'9respectively, are not necessarily protected groups R5, R8and R9as defined above, with an ORGANOMETALLIC compound of the formula R'6- RM(V) in which R'6group of the formula where R10and R11together with the carbon atom to which they are bound, form the optional aromata nitrogen and optionally substituted on carbon atoms 1 - 7 groups, optionally protected if necessary, selected from hydroxy-, nitro-, cyano-, C1-C7-alkoxygroup or C1-C7-alkyl; and b) removing the protective group to form compounds of formula VI

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in which X, R1, R2, R3, R4, R5, R6, R8and R9defined above; and optionally or c1) reaction of compounds of General formula VI with a reagent of formula R14-Y (VII) in which R14-C1-C7-alkyl or C1-C7-acyl and Y is a leaving group, to obtain compounds of the formula I, in which R7- C1-C7-alkoxy or C1-C7-alloctype respectively; or c2) by dehydration of compounds of formula VI obtained in stage (b), in the presence of acid or carboxylic acid to obtain the following compounds of General formula I:

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in which X, R1, R2, R3, R4, R5, R6, R8and R9defined above; and optionally (d) reaction of compounds of formula I, obtained in stage (c2), with the peroxide to produce compounds of the formula I, in which R5and R7together form a group; and optionally (e) reaction of compounds of the formula VI obtained in stage (b) or compounds Faure is entrusted f) reaction of compounds of General formula VI, obtained in stage (b), or compounds of General formula I obtained in stage (c1), (c2) or (d), with a pharmaceutically acceptable inorganic or organic acid to obtain the corresponding salt.

In the reaction stage (a) the compounds of formula IV, as defined above, mainly react with organolithium compounds of the formula LiR'6where R'6defined above. The compounds of formula LiR'6you can get a known way, for example by reaction of compounds of the formula R'6Br, where R'6defined above, with n-butyllithium in an organic solvent, such as diethyl ether or tetrahydrofuran, optionally in the presence of hexamethylphosphoramide or 1,3-dimethylimidazolidine at a temperature of from -110oC to the boiling point of the solvent or solvent mixture, for 4 to 24 hours.

If the compounds of formula IV or V contain the OH group, then they are protected by protective groups for hydroxy groups, for example SiMe3or SiMe2- t - Bu.

The reaction of stage (a) takes place in an inert organic solvent, particularly diethyl ether, tetrahydrofuran or hexane, at a temperature of from -78oC to -20oC followed by the addition of dilute acid to about the carry out acid treatment in an aqueous medium or a fluoride (e.g., tetrabutylammonium) in tetrahydrofuran or a temperature of -20 to 100oC, preferably at 25oC.

On stage (c1) leaving group V are especially halogen, or alkyl-or arylsulfonate, preferably mesilate or tailorshop.

Preferably allalone or alkylhalogenide used in the presence of the Lewis base in a solvent such as dimethylformamide.

The reaction of removal of H2O on stage (c2) is mainly carried out in acidic medium and in the presence of an organic solvent, such as benzene, toluene or xylene, and the acid is preferably p-toluensulfonate or sulfuric acid. Acid can also be acylchlorides, such as methanesulfonate, in the presence of a solvent, such as chloroform, dichloromethane or dichloroethane. The reaction is mainly carried out at the boiling temperature of the solvent.

The reaction of stage (d) is carried out in the presence of a peroxide, especially percolate, such as peracetic, derbentina, Perfilieva or 3-chloroperbenzoic acid. The amount of peroxide can vary from 1 to 4 equivalents, depending on oxidizable compounds. In cachestudio.net, chloroform or dichloroethane. The reaction is preferably carried out at a temperature from -20oC to the boiling point of the solvent.

The reaction of stage (e) is carried out in the presence of an oxidant, especially proximity from among those mentioned above (for example, 3-chloroperbenzoic acid) in a solvent such as dichloromethane.

The following ketones:

7-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 117 - 121oC;

7-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. to 66.5 PA = 0.5 mm RT. Art.) = 80 - 100oC;

7-cyano-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. 114oC;

7-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (39.9 PA = 0.3 mm RT. Art.) = 97 - 104oC;

7-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he; so bales. cases (53.2 PA = 0.4 mm RT. Art.) = 102-108oC;

7-isopropyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 112-122oC;

7-methoxy-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (33,25 PA = 0.25 mm RT. Art.) = 122-126oC;

3,3, -dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (103,4 PA = 0.8 mm RT. Art.) = 90oC;

3,3,7-trimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 90-104oC;
< 7-methylthio-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he so Kip. (79,8 PA = 0.6 mm RT. Art.) = 125-135 mAoC;

7-pentafluoroethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5 - he;

7-phenyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (to 26.6 PA = 0.2 mm RT. Art.) = 135-140oC;

7 phenylthio-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he;

7 triptoreline-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin - 5-he, so Kip. (2128 PA = 16 mm RT. Art.) = 135-138oC;

7-trifluoromethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5 - he, so Kip. (133 PA = 1 mm RT. Art.) = 80-100oC;

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo/f/cyclohepten-1 - it, so pl. = 94oC;

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (39.9 PA = 0.3 mm RT. Art.) = 108-112;

8-trifluoromethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5 - he, so Kip. (39.9 PA = 0.3 mm RT. Art.) = 85-110oC;

9-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he; so pl. 86oC;

7-(2-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin - 5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 128-138oC;

7-(2-methoxypropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin - 5-he, so Kip. = 128-136oC;

7-bromo-8-methyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 120-130oC;

6,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (106,4 PA = 0.8 mm RT.3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he so Kip. (79,8 PA = 0.6 mm RT. Art.) = 120-130oC;

8,9-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he,

7-chloro-8-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 108-112oC;

7-chloro-3,3,8-trimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 115-122oC;

7,8-debtor-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. = 84oC;

7-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. = 82oC;

7-fluoro-9-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so Kip. (79,8 PA = 0.6 mm RT. Art.) = 102 to 106oC;

7,8-dimethoxy-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. = 110oC;

7-methyl-8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5 - he, so Kip. to 66.5 PA = 0.5 mm RT. Art.) = 125-130oC;

7,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. 95oC;

3,3-dimethyl-2,3,4,5,7,8,9,10-octahydro-1-naphthas/2,3-b/oxepin-5-he, so Kip cases (53.2 PA = 0.4 mm RT. Art.) = 135-150oC;

7-(2-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin - 5-he, so pl. = 128-136oC;

8-chloro-3,3-dimethyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1 - benzoxazin-5-he, so pl. = 80oC;

7-bromo-8-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-he, so pl. = 94oC;

3,3-dimethyl-8-phenylthio-2,3,4,5-tetrahed C;

8-bromo-4,4-dimethyl-2,3,4,5-tetrahydro-1H-benzo/f/Cycloheptane-1 - it;

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo/f/Cycloheptane-1 - it, so pl. = 94oC;

Ketones of the formula IV can be obtained by cyclization of the acid of formula VIII

< / BR>
in which X, R1, R2, R3, R4, R5, R8and R9defined above, by way of Fontaines (Ann. Chem. , 1968, 3, N 3, p. 180) receiving benzocaine the cyclization proximally acids in the presence of phosphoric acid, alone or in a mixture with an organic solvent, such as xylene, toluene or benzene, or by reaction of the Friedel-from aluminofluoride and acid chlorides of the corresponding 4-Phenoxyethanol, 4-phenylthiourea or 5-phenylpentane acid in a solvent such as carbon disulfide or nitrobenzene.

You can also use another way of synthesis, in particular the condensation of Dickman.

Acids of formula VIII can be obtained, if X is oxygen, the reaction of compounds of formula IX

< / BR>
in which R8and R9defined above, with compounds of the formula X

< / BR>
in which R1, R2, R3, R4and R5defined above, in accordance with the method of Rappe (Ann. Chem., 1955, 596, c.158-224). The reaction proceeds under heating in butanol in which use, with compounds of the formula XI

< / BR>
in which R1, R2, R3, R4, R5defined above, A is halogen and B is lower alkyl or phenyl, in a solvent such as dimethylformamide, in the presence of K2CO3or in acetone in the presence of K2CO3and KI.

If X is a group CHR, acids of formula VIII can be obtained by the Matura and Minghu (Proc. Natl. Acad. Dci. India. Sect. A, 1981, 51 (2), S. 177-180) or Klaus and Mohr (EP 0315071) a) reaction of compounds of formula XII

< / BR>
with compounds of the formula XIII or XIV

< / BR>
in which R1, R2, R3, R4, R5defined above, A is halogen and B is lower alkyl or phenyl, in the presence of AlCl3in a solvent such as carbon disulfide or nitrobenzyl, or without solvent to form compounds of formula XV

< / BR>
in which R1, R2, R3, R4, R5, R6, R8and R9and B are defined above b) hydrolysis of the resulting compounds of formula XV in a basic environment, such as a water-alcohol solution of NaOH, KOH or NaHCO3or in an acid environment with formation of compounds of formula XVI

< / BR>
in which R1, R2, R3, R4, R5, R8and R9defined above, and (C) the reduction of carbonyl group connection is N, in diethylene glycol or polyethylene glycol at elevated temperature.

The following acids of formula VIII:

4 phenoxy-3,3-dimethylbutanoate acid, so Kip. (13.3 PA=0.1 mm, RT.CT.) = 130oC;

4-(4-bromophenoxy)3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT. Art.) = 154 - 162oC;

4-(4-chlorphenoxy)3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 145oC;

4-(4-pertenece)3,3-dimethylbutanoate acid, so Kip.cases (53.2 PA = 0.4 mm RT.CT.) = 128 - 134oC;

4-(4-methylphenoxy)3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 136oC;

4-(4-ethylenoxy)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 132 - 136oC;

4-(4-isopropylphenoxy)3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 142oC;

4-[4-(1-methylpropyl)phenoxy] -3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.article ) = 155 - 165oC;

4-(4-methoxyphenoxy)-3,3-dimethylbutanoate acid, so Kip. = 69oC;

4-(4-triftormetilfosfinov)-3,3-dimethylbutanoate acid. so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 100 - 120oC;

4-(4-methylthiophene)-3,3-dimethylbutanoate acid, so Kip. (106,4 PA = 0.8 mm RT.CT.) = 150 - 170oC;

4-(4-phenyleneoxy)-3,3-dimethylbutanoate acid, so Kip. = 124oC;

4-(3-br methylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 150oC;

4-(3,4-dichlorophenoxy)-3,3-dimethylbutanoate acid, so pl. = 66oC;

4-(2,4-dichlorphenoxy)-3,3-dimethylbutanoate acid, so Kip. to 66.5 PA = 0.5 mm RT.CT.) = 150 - 160oC;

4-(2,3-dichlorophenoxy)-3,3-dimethylbutanoate acid, so Kip. to 66.5 PA = 0.5 mm RT.CT.) = 130 - 160oC;

4-(3,4-divergence)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 110 - 134oC;

4-(3-chloro-4-pertenece)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 145oC;

4-(2-ethyl-4-pertenece)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 123 - 136oC;

4-(3,4-dimethoxyphenoxy)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 150 - 170oC;

4-(4-bromo-3-methylphenoxy)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 130 - 135oC;

4-(3-bromo-4-methylphenoxy)-3,3-dimethylbutanoate acid, so Kip. a 53.2 PA = 0.4 mm RT.CT.) = 155 - 160oC;

4-(5,6,7,8-tetrahydro-2-naphthyloxy)-3,3-dimethylbutanoate acid so pl. = 85oC;

4-[4-(2-methylpropyl)phenoxy] -3,3-dimethylbutanoate acid, and instrumentation. (665 PA = 5 mm RT.CT.) = 160 - 180oC;

4-(4-chloro-3-ethylenoxy)-3,3-dimethylbutanoate acid, so Kip. cases (53.2 PA = 0.4 mm RT.CT.) = 160 - 166oC;

4-(4-chloro-3-methylphenoxy)-3,3-dimethylbutan, the.the TRC. cases (53.2 PA = 0.4 mm RT.CT.) = 150 - 170oC;

5-(4-bromophenyl)-3,3-dimethylpentane acid, so pl. = 72oC;

5-(3,4-dichlorophenyl)-3,3-dimethylpentane acid;

5-(4-bromophenyl)-4,4-dimethylpentane acid, so pl. = 106 - 108oC.

The connection of the invention have excellent properties, activation of potassium channels and increased relaxing effect on smooth muscles. Therefore, they can be used as bronchodilators in diseases of the respiratory system, especially in asthma and obstruction of the upper respiratory tract. They also have the advantage in the treatment of hypertension and in the case of spasms of smooth muscles of the gastrointestinal tract, uterus, urinary tract and phenomena incontinence. They are useful in the case of cardiovascular disease other than hypertension, especially heart failure, angina pectoris, vascular pathology of the brain and peripheral vascular and pulmonary hypertension. The compounds are also active in the treatment of alopecia (baldness).

Activity activation of potassium channels was measured by the rate of output of the rubidium-86 cells from tracheal smooth muscle according to the method described by Allen, Br.J. Pharmac., 1986, 87, p. 117 - 127 and 89, p. 395 - 405.

Soon rowlevel through an incision in the jugular vein. The trachea was quickly freed and cleaned in situ. The removed parts were placed on a support in oxygenated modified Krebs solution Henseleit (M. K. H.). When all of the trachea removed every enrich smooth muscle. The trachea is placed in a crystallization Cup containing solution M. K. H. and flow O2/CO2at 37oC. On both sides of the muscle strips carefully make two longitudinal cuts at a distance of 1 mm from each other. Trachea invention result in an equilibrium state in a beaker containing 30 ml of solution M. K. H., for 30 min, then add radioactively charged rubidium-86. During operations support permanent and withstand the velocity of the gas stream.

The glass then replace the other, containing 25 ml oxygendemanding solution M. K. H. and 125 microcure86Rb, for 3 hours. The trachea was washed twice successively in the beaker containing approximately 100 ml of solution M. K. H., for 3 minutes.

The trachea is placed individually in the number of free 10 ml test tubes. The fill tube for 30 seconds to dive trachea 4 ml oxygendemanding solution M. K. H. Then perform the immersion of the box for 5 minutes, 5 washes for 10 minutes and the interval expires for 3 minutes. The first group of tubes isagroup tubes makes it possible for the contacting of the sample with the concentration of the test product, lasting seven intervals for 3 minutes. Products used in the form of mother solutions containing 40.1 per mmol of pure DMSO, and then diluted with the same solvent and injected into a specified number of 10 ál (product) in 4 ml M. K. H. Calculation is performed based on the Cherenkov effect.

Determination of the effective concentration of the product, which increases the speed of the main outflow of 25% (EC25%).

The speed of the labeled expiration of an atom expressed as the% discharge per minute in relation to the total number of labeled atoms in the present time.

EC25%expect a linear regression of the relationship: the maximum expiration in the presence of the product relative to the main outflow as a function of logarithm of concentration.

The results obtained with representative compounds of the invention are presented in table 1.

Bronchodilatory activity was measured in vivo by the method Concetta and Rosslare (Arch. Exp. Pathoi. Pharmak. , 1940, 195, S. 71 - 74) and Dyuo and others (Arzneim. Forsch./Drug. res., 1987, 37 S. 1353 - 1362).

Measurement bronchodilatory activity

Guinea pigs Dakine-Hartley (400 - 500 g) was prepared according to the method described by Concetta and Rosslare. Animals were exposed tidal volume 10 ml/kg). Animals were attached to the respiratory pump, which is adjusted to supply a volume of 1 ml per 100 g of body weight of the Guinea pig. Through the pressure sensor was connected recording device. In the jugular vein is injected with a catheter for intravenous injection.

Performed intravenous injection gallamine and propanolol. After stabilization of pulmonary pressure during the 30 minute details intravenous injection of histamine every 10 minutes to achieve reproducibility. 10 minutes after the last spasm injection injected product. Histamine was determined after 5 and 15 minutes after injection of the product and the expected effective dose for 50% inhibition.

The results obtained with representative compounds of the invention are presented in table 2.

Compounds of the invention are active for humans and animals, especially mammals, especially dogs, Guinea pigs, rabbits, rats and mice.

Compounds of the invention are not toxic.

Another object of the invention is Francesca preparations containing as active ingredient compounds of the invention described above, in a mixture with a pharmaceutically acceptable carrier. Pharmaceuticals used the maintenance or as aerosols. Moreover, these new products have long lasting effects, whatever the route of administration.

The products of General formula will be combined in a pharmaceutical form with fillers, flavoring agents and dyes, suitable for forming, for example, of tablets, which (products) can be optionally attached liposomal, microcapsule or nanocapsule form or in the form of tablets, coated gelatin capsules, solutions, injectable solutions, suppositories, sprays or creams. As fillers are used, for example, microcrystalline cellulose, lactose, polyvidone, brahmacharinis, talc or magnesium stearate. Fillers for liposomal or microcapsule forms can be poly(alkylcarboxylic) or phospholipids.

Coated tablets may be made by adding, for example, hydroxypropylmethylcellulose, various acrylic polymers of propylene glycol and titanium dioxide.

Preparations for oral administration may contain artificial flavoring and sweeteners such as sugar or aspartame.

Drugs injection solutions must be water containing stabilizers, soljubilizatory

For preparing suppositories can use media such as semi-synthetic glycerides.

Drugs creams should be made with the addition of nonionic surfactants.

Drugs aerosol appointments can be made of very finely ground active ingredient in a mixture with surface-active substance, such as sarbatorile, in the raw gas, such as CFC-11 or -12, or any other replacement gas.

Compounds of the invention can be used in combination with other therapies such as diuretics, beta-blockers, antagonists of platelet activating factor, antagonists TxA2, inhibitors of the converting enzyme, beta-adrenergic inhibitors, antiarrhythmic agents.

A daily dose of the active component, is entered only once or a few times, can be between 0,0001 and 100 mg/kg body weight, preferably between 0.001 and 1 mg/kg, However, these limits can be extended if necessary.

Examples of formulations of tablets and gelatin capsules in accordance with the invention is shown below.

An example of a tablet formulation

Link is 10 mg

Magnesium stearate 1 mg- --- - 250 mg

An example of the composition of the gelatin capsules

The compound of formula III - 10 mg

Microcrystalline cellulose - 109 mg

Lactose 100 mg

Starch 30 mg

Magnesium stearate 1 mg- --- - 250 mg

The following examples illustrate the invention without limiting it. In the description of the spectra of the proton nuclear magnetic resonance (1H PMR) use the following abbreviations: ppm-part per million (million-1); S, singlet (s); D-doublet (d); t-triplet (t); q, Quartet (K); b-broad (W); J is the interaction constant, expressed in Hertz (Hz), dd-doublet of doublets (DD); Hz - Hertz; MM, molecular mass (MM).

Example 1.

7-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula I). C17H18BrNO2, MM=348.239

< / BR>
A solution of n-utility (1.6 mol/h) in hexane (93 ml, 0.15 mol) in anhydrous diethyl ether (200 ml) cooled to -78oC in a stream of dry nitrogen. A solution of 2-bromopyridine (14,3 ml, 0.15 mol) in diethyl ether (100 ml) added dropwise within 1 hour and the mixture is then stirred for an additional 0.5 hour at -78oC. a Solution of 7-bromo-3,3 - dimethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-she (13.5 g, 0.05 mol) in dry benzene is added dropwise within 1 hour at -78oC. Mixing prodoljayut diethyl ether. The organic phase is washed with water and dried over anhydrous sodium sulfate. The solution is concentrated under reduced pressure with the formation of a brown oil. The product is a yellow solid, 14 g, 80%, so pl. 124 - 128oC (hexane).

IR (cm-1: 3340, 2950, 1595, 1580.

1H NMR (CDCl3in million-1: 8.50 (1H, DD, J=4.5 Hz), 7,20 (6H, m), of 5.75 (1H, s) 4,08 (1H, d, J=1 Hz), 3,80 (1H,d, J=11 Hz), 2,34 (1H, d, J=13.5 Hz), of 1.66 (1H, d, J=13.5 Hz), of 1.06 (3H, s) 0,86 (3H, s).

Elemental analysis for C H Br N O

Found (%) 58,56 5,28 was 4.02 22, 95mm

Calculated (%) 58,63 to 5.21 22, 95mm was 4.02 9,19

This way, we obtained the following compounds.

7-Chloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 2), C17H18ClNO2, MM = 303.788

< / BR>
(Flash chromatography: CH2Cl2; So pl. = 118oC (hexane); 83%).

IR (cm-1: 3340, 2950, 1595, 1570.

1H NMR (CDCl3in million-1: 8.54 (1H, DD, J=1.5 Hz), 7,22 (6H, m), of 5.75 (1H, s), 4,11 (1H, d, J=11 Hz), 3,85 (1H, d, J=11 Hz), is 2.37 (1H, d, J=13.5 Hz), 1,71 (1H, d, J=13.5 Hz), with 1.07 (3H, s) to 0.88 (3H, s).

7-Fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 3), C17H18FNO2, MM = 287.333

< / BR>
(So pl. = 110oC(hexane); 64%)

IR (cm-1: 3320, 2960, 1595, 1580

1H NMR (CDCl3in ml the x2">

3,3-Dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol(formula 4), C17H19NO2, MM = 269.343

< / BR>
(chromatography on silica gel, CH2Cl2; oil, 87%)

IR (cm-1: 3360, 2950, 1595, 1580

1H NMR (CDCl3in million-1: (8.46 (1H, dd, J = 4.5 Hz), 7.15 (6H, m), 5.75 (1H, m), 4.15 (1H, d, J = 12 Hz), 3.85 (1H, d, J = 12 Hz), 2.37 (1H, d, J = 13.5 Hz), 1.70 (1H, d, J = 13.5 Hz), 1.10 (3H, s), 0.92 (3H, s).

3,3,7-Trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 5), C18H21NO2MM = 283.369

< / BR>
(So pl. = 125oC (hexane); 66%)

IR (cm-1: 3910, 2960, 1595, 1575, 1500

1H NMR (CDCl3in million-1: 8.52 (1H, dd, J = 4.5 Hz), 7.05 (6H, m), 5.63 (1H, m), 4.07 (1H, d, J = 11 Hz), 3.85 (1H, d, J = 11 Hz), 2.41 (1H, d, J = 13.5 Hz), 2.10 (3H, s), 1.74 (1H, d, J = 13.5 Hz), 1.09 (3H, s), 0.88 (3H, s).

7-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 6), C19H23NO2, MM = 297.396

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2; So pl. 84oC (hexane); 76%)

IR (cm-1: 3350, 2970, 1595, 1565, 1500

7-Isopropyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 7), C20H25NO2, MM = 311.423

< / BR>
(So pl. = 72oC (pentane); 72%)

IR (cm-1: 3310, 2960, 1585, 1495

1H NMR (CDCl3in million-1: 8.50 (1H, m), 7.53 (1H, m),)-5-(2-pyridyl-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 8), C21H27NO2, MM=325.450

< / BR>
(chromatography on silica gel, dichloromethane/heptane: 80/20; 33%).

IR (cm-1: 3370, 2970, 1600, 1580, 1500

1H NMR (CDCl3in million-1: 8.46 (1H, m), 7.05 (6H, m), 5.65 (1H, s), 4.09 (1H, d, J = 11 Hz), 3.79 (1H, d, J = 11 Hz), 2.35 (1H, d, J = 13.5 Hz), 2.22 (1H, m), 1.65 (1H, d, J = 13.5 Hz), 1.06 (14 H, m).

7-Methoxy-3,3-dimethyl-5-(2-pyridyl(-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 9), C18H21NO3, MM = 299.369

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 95/5; So pl. 98oC (hexane), 68%)

IR (cm-1: 3270, 2970, 1595, 1575, 1500

1H NMR (CDCl3in million-1: 8.50 (1H, dd, J = 4.5 Hz), 7.05 (6H, m), 5.53 (1H, s), 3.89 (2H, s), 3.55 (3H, s), 2.42 (1H, d, J = 13.5 Hz), 1.76 (1H, d, J = 13.5 Hz), 1.04 (3H, s), 0.80 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-triptoreline-2,3,4,5-tetrahydro-1 benzoxazin-5-ol (formula 10), C18H18F3NO3, MM=353.340

< / BR>
(chromatography on silica gel, dichloromethane; So pl. = 76oC (heptane); 62%)

IR (cm-1: 3290, 2950, 1590, 1485

1H NMR (CDCl3in million-1: 8.52 (1H, m), 7.13 (6H, m), 5.78 (1H, s), 4.16 (1H, d, J = 11 Hz), 3.84 (1H, d, J = 11 Hz), 2.39 (1H, d, J = 13.5 Hz), 1.73 (1H, d, J = 13.5 Hz), 1.10 (3H, s), 0.90 (3H, s).

3,3-Dimethyl-7-methylthio-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 11), C18H21NO2S, MM = 315.435

< / BR>
8.53 (1H, m), 7.23 (6H, m), 5.70 (1H, s), 4.10 (1H, d, J = 11 Hz), 3.81 (1H, d, J = 11 Hz), 2.36 (1H, d, J = 14 Hz), 2.25 (3H, s), 1.71 (1H, d, J = 14 Hz), 1.09 (3H, s), 0.89 (3H, s).

3,3-Dimethyl-7-phenyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 12), C23H23NO2, MM=345.440

< / BR>
(chromatography on silica gel, dichloromethane; So pl. = 140-150oC (heptane); 95%)

IR (cm-1; 3290, 2930, 1600

1H NMR (CDCl3in million-1: 8.50 (1H, m), 7.22 (11H, m), 5.82 (1H, m), 4.20 (1H, d, J = 11 Hz), 3.89 (1H, d, J = 11 Hz), 2.41 (1H, d, J = 14 Hz), 1.75 (1H, d, J = 14 Hz), 1.13 (3H, s), 0.95 (3H, s).

8-bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 13). C17H18BrNO2, MM = 348.239

< / BR>
(chromatography on silica gel, dichloromethane,

so pl. = 110oC (hexane), 85%)

IR (cm-1: 330, 2950, 1595, 1565, 1480

1H NMR (CDCl3in million-1: 8.55 (1H, m), 7.55 (1H, dd, J = 1.5 Hz, J = 7.5 Hz), 7.07 (4H, m), 6.57 (1H, d, J = 8 Hz), 5.81 (1H, m), 4.20 (1H, d, J = 11 Hz), 3.90 (1H, d, J = 11 Hz), 2.37 (1H, d, J = 13.5 Hz), 1.71 (1H, d, J = 13.5 Hz), 1.12 (3H, s), 0.92 (3H, s).

6,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 14), C17H17Cl2NO2, MM = 338.233

< / BR>
(So pl. = 156oC (heptane), 76%)

IR (cm-1: 3350, 3060, 2950, 1585, 1550

1H NMR (CDCl3in million-1: 8.49 (1H, m), 7.12 (5H, m), 5.81 (1H, m), 4.16 (1H, d, J = 10.5 Hz), 3.92 (1H, d, J = 10.5 Hz), 2.12 (1H, d, -ol (formula 15), C17H17Cl2NO2, MM = 338.232

< / BR>
(So pl. = 128oC (hexane); 73%)

IR (cm-1: 3350, 2970, 1595, 1585, 1550

1H NMR (CDCl3in million-1: 8.51 (1H, m), 7.35 (3H, m), 7.08 (1H, s), 6.83 (1H, s), 5.77 (1H, s), 4.12 (1H, d, J = 11 Hz), 3.83 (1H, d, J = 11 Hz), 2.34 (1H, d, J = 13.5 Hz), 1.70 (1H, d, J = 13.5 Hz), 1.06 (3H, s), 0.88 (3H, s).

7,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 16), C17H17Cl2NO2, MM = 338.233

< / BR>
(chromatography on silica gel, dichloromethane, 83%)

IR (cm-1: 3300, 2950, 1590, 1570, 1560

1H NMR (CDCl3in million-1: 8.52 (1H, m), 7.25 (5H, m), 5.70 (1H, s), 4.00 (2H, s), 2.39 (1H, d, J = 14 Hz), 1.76 (1H, d, J = 14 Hz), 1.05 (3H, s), 0.86 (3H, s).

8,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 17), C17H17Cl2NO2, MM = 338.233

< / BR>
(yellow oil; 37%)

IR (cm-1: 3300, 2960, 1595, 1585, 1560

1H NMR (CDCl3in million-18.52 (1H, m), 7.15 (5H, m), 5.76 (1H, s), 4.07 (2H, s), 2.37 (1H, d, J = 13.5 Hz), 1.72 (1H, d, J = 13.5 Hz), 1.10 (3H, s), 0.90 (3H, s).

7,8-Debtor-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 18), C17H17F2NO2, MM = 305.324

< / BR>
(So pl. 93oC (pentane); 61%)

IR (cm-1: 3320, 2990, 1660, 1575, 1505

1H NMR (CDCl3in million-1: 8.52 (1H, m), 7.61 (1H, mTOR-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 19). C17H17ClFNO2, MM = 321.778

< / BR>
(So pl. = 100oC (hexane); 77%)

IR (cm-1: 3310, 2965, 1595, 1585, 1485

1H NMR (CDCl3in million-1: 8.55 (1H, m), 7.61 (1H, m), 7.10 (3H, m), 6.63 (1H, d), 5.70 (1H, s), 4.08 (1H, d, J = 6 Hz), 3.83 (1H, d, J = 6 Hz), 2.40 (1H, d, J = 13.5 Hz), 1.75 (1H, d, J = 13.5 Hz), 1.08 (3H, s), 0.86 (3H, s).

9-Ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 20), C19H22FNO2, MM = 315.387

< / BR>
(So pl. = 100oC (pentane); 68%)

IR (cm-1: 3260, 2965, 1590

-1H NMR (CDCl3in million-1: 8.53 (1H, m), 7.04 (5H, m), 5.45 (1H, s), 3.85 (2H, s), 2.70 (2H, q), 2.40 (1H, d, J = 13.5 Hz), 1.75 (1H, d, J = 13.5 Hz), 1.19 (3H, t), 1.02 (3H, s), 0.78 (3H, s).

7,8-Dimethoxy-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 21), C19H23NO4, MM = 329,395

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2;

So pl. = 90oC (heptane); 63%)

IR (cm-1: 3370, 2950, 1610, 1590, 1505

1H NMR (CDCl3in million-1: 8.52 (1H, m), 7.56 (1H, m), 7.06 (3H, m), 6.54 (1H, s), 6.31 (1H, s), 5.50 (1H, m), 4.08 (1H, d, J = 10 Hz), 3.81 (3H, s), 3.80 (1H, d, J = 10 Hz), 3.55 (3H, s), 2.38 (1H, d, J = 13 Hz), 1.73 (1H, d, J = 13 Hz), 1.08 (3H, s), 0.85 (3H, s).|

7-Bromo-3,3,8-trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 22), C18H20BrNO2, MM = 362.266

< / BR>
(chromatography on silica gel, di is B> in million-1: 8.54 (1H, m), 7.60 (1H, m), 7.05 (4H, m), 5.70 (1H, m), 4.10 (1H, d, J = 11 Hz), 3.81 (1H, d, 11 Hz), 2.35 (1H, d, J = 13.5 Hz), 2.27 (3H, s), 1.69 (1H, d, J = 13.5 Hz), 1.07 (3H, s), 0.88 (3H, s).

8-Bromo-3,3,7-trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 23), C18H20BrNO2, MM = 362.266

< / BR>
(chromatography on silica gel, dichloromethane;

So pl. = 129oC (hexane); 70%).

IR (cm-1: 3320, 2950, 1595, 1560

-1H NMR (CDCl3in million-1: 8.52 (1H, m), 7.55 (1H, m), 7.14 (1H, s), 7.04 (2H, m), 6.62 (1H, s), 5.64 (1H, s), 4.05 (1H, d, J = 11 Hz), 3.80 (1H, d, J = 11 Hz), 2.32 (1H, d, J = 13.5 Hz), 2.11 (3H, s), 1.67 (1H, d, J = 13.5 Hz), 1.05 (3H, s), 0.66 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3,4,5,7,8,9,10-octahydro-1-naphthas/2,3-b)-oxepin-5-ol (formula 24), C21H25NO2, MM = 323.434

< / BR>
(chromatography on silica gel, dichloromethane,

So pl. = 134oC; 67%)

IR (cm-1: 3330, 3060, 2930, 1620, 1595, 1570, 1500

1H NMR (CDCl3in million-1: 8.50 (1H, m), 7.54 (1H, m), 7.08 (2H, m), 6.66 (1H, s), 6.50 (1H, s), 5.50 (1H, s), 4.02 (1H, d, J = 10.5 Hz), 3.77 (1H, d, J = 10.5 Hz), 2.56 (4H, m), 2.36 (1H, d, J = 13.5 Hz), 1.74 (5H, m), 1.05 (3H, s), 0.83 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 25), C18H18F3NO2, MM = 337.341

< / BR>
(chromatography on silica gel, dichloromethane; So pl. = 116oC (isooctane); 29%)

IR (cm-10 (1H, d, J = 11 Hz), 2.35 (1H, d, J = 13.5 Hz), 1.72 (1H, d, J = 13.5 Hz), 1.10 (3H, s), 0.92 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 26), C18H18F3NO2, MM = 337.341

< / BR>
(chromatography on silica gel, dichloromethane,

So pl. = 78oC; 31%)

IR (cm-1: 3330, 2970, 1595, 1575, 1500

1H NMR (CDCl3in million-1: 8.55 (1H, dd, J = 4.5 Hz), 7.25 (6H, m), 5.94 (1H, s), 4.22 (1H, d, J = 11 Hz), 3.90 (1H, d, J = 11 Hz), 2.40 (1H, d, J = 14 Hz), 1.72 (1H, d, J = 14 Hz), 1.12 (3H, s), 0.95 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-pentafluoroethyl-2,3,4,5-tetrahydro - 1-benzoxazin-5-ol (formula 27), C19H18F5NO2,

MM = 387.349

< / BR>
(chromatography on silica gel, dichloromethane; 42%)

IR (cm-1: 3330, 2950, 1620, 1595, 1575, 1500

1H NMR (CDCl3in million-1: 8.55 (1H, dd, J = 4.5 Hz), 7.28 (6H, m), 6.00 (1H, s), 4.33 (1H, d, J = 11 Hz), 3.94 (1H, d, J = 11 Hz), 2.38 (1H, d, J = 14 Hz), 1.75 (1H, d, J = 14 Hz), 1.15 (3H, s), 0.97 (3H, s).

8-Bromo-3,3-dimethyl-1-(2-pyridyl)-2,3,4,5-tetrahydro-1H-benzo/f/ cyclohepten-1-ol (formula 28), C18H20BrNO, MM = 346.266

< / BR>
(chromatography on silica gel, dichloromethane; oil; 78%)

IR (cm-1: 3340, 2860, 1590, 1570

1H NMR (CDCl3in million-1: 8.50 (1H, m), 7.54 (1H, m), 7.04 (5H, m), 5.39 (1H, s), 2.90 (2H, m), 2.32 (1H, d, J = 14 Hz), 1.77 (1H, d, J = 14 Hz), 1.70 (2H, m), 1.02 (6H, m).

7-Bromo-3,>/BR>Obtained by the method described above, using 3-bromopyridine instead of 2-bromopyridine.

(So pl. = 170oC (ethyl acetate); 46%)

IR (cm-1: 3120, 2950, 1585, 1475

1H NMR (CDCl3in million-1: 8.37 (2H, m), 7.14 (4H, m), 6.88 (1H, d, J = 9 Hz), 3.76 (2H, s), 3.74 (1H, m), 2.35 (1H, d, J = 13.5 Hz), 2.00 (1H, d, J = 13.5 Hz), 1.01 (3H, s), 0.62 (3H, s).

7,8-Dichloro-3,3-dimethyl-5-(3-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 30), C17H17Cl2NO2, MM = 338.233

< / BR>
(so pl. = 166oC (heptane); 44%)

IR (cm-1: 3100, 2930, 1595, 1585

1H NMR (CDCl3in million-1: 8.41 (2H, m), 7.34 (4H, m), 3.76 (3H, s), 2.35 (1H, d, J = 13.5 Hz); 2.00 (1H, d, J = 13,5 Hz), 1.00 (3H, s), 0.61 (3H, s).

Example 2.

7-Bromo-5-methoxy-3,3-dimethyl-5-(2-pyridyl)-1-benzoxazin (formula 31), C18H20BrNO2, MM = 362.265

< / BR>
A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-1-benzoxazin-5-ol (5 g, 0.014 mol) in anhydrous dimethylformamide (50 ml) is added dropwise to a suspension of sodium hydride (50% dispersion in oil, 0.8 g, 0,0168 mol) in anhydrous dimethylformamide (25 ml), the temperature rises to 88oC, the stirring is continued for 1 hour at 80oC. and Then added dropwise to the solution under the conditions (1.9 g, 0.014 mol) in anhydrous dimethylformamide at 25oC. the Mixture is stirred for 16 hours ol the ABC washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

(Pasty product; 5 g, 98%)

IR (cm-1: 2960, 1590, 1565

1H NMR (CDCl3in million-1: 8.55 (1H, dd, J = 4.5 Hz), 7.33 (6H, m), 3.91 (1H, s), 3.88 (1H, s), 3.16 (3H, s), 2.26 (2H, s), 1.11 (3H, s), 0.43 (3H, s).

Example 3.

7-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-yl acetate (formula 32), C19H20BrNO3, MM = 390.276

< / BR>
A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-1-benzoxazin-5-ol (5 g, 0.014 mol) in anhydrous dimethylformamide (50 ml) is added dropwise at 60oC to a suspension of sodium hydride (50% dispersion in oil, 0.8 g, 0,0168 mol) in anhydrous dimethylformamide (25 ml). The suspension is stirred for 1 hour at 60oC and then cooled. Dropwise at 25oC add acetylchloride (1 g, 0.014 mol) and stirred at 25oC 16 hours. The mixture is then hydrolized 600 ml of ice water. Received beige paste dissolved in 200 ml of dichloromethane, the organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil purified by chromatography on silica gel, eluent - dichloromethane/methanol : 98/2.

(So pl. = 140oC (hexane); 22%)

IR (cm-1: 2950, 1745, 1590, 1570, 1485<), 1.05 (3H, s), 0.37 (3H, s).

Example 4.

7-Bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 33), C17H18BrNO3; MM = 364.238

< / BR>
A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (3.5 g, 0.01 mol) and 3-chloroperbenzoic acid (2.8 g, to 0.016 mol) in dichloromethane (50 ml) is stirred for 16 hours at 25oC. the Resulting precipitate is filtered off, the filtrate is washed with 5% solution of sodium bisulfite, 5% sodium bicarbonate solution and then with water. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Get a thick yellow oil. After recrystallization from hexane obtain 2.6 g, so pl. = 139 - 140oC (hexane).

IR (cm-1: 3240, 3050, 2950, 1480

1H NMR (CDCl3in million-1: 8.18 (1H, m), 7.88 (1H, d), 7.13 (5H, m), 6.03 (1H, m), 3.81 (1H, m), 3.49 (1H, m), 3.31 (1H, m), 1.94 (1H, d, J = 13.5 Hz), 0.86 (3H, s), 0.51 (3H, s).

Elemental analysis for C H Br N O

Found(%) 56,07; 5,02; - ; 3,73; 13,42

Calculated(%) 56,05; 4,98; 21,94; 3,85; 13,18

This way, we obtained the following compounds.

7-Chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 34), C17H18ClNO3, MM = 319.787

< / BR>
(So pl. = 138-140o(ethyl acetate); 34%)

Elemental analysis for C H Cl N O

Found (%) 63,58 5,71 11,04 4,47

Calculated (%) 63,85 5,67 11,09 of 4.38 15,01

7-Fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 35), C17H18FNO3; MM = 303.332

< / BR>
(So pl. = 110-112oC (hexane); 78%)

IR (cm-1: 3390, 3110, 2950, 1485

1H NMR (CDCl3in million-1: 8.19 (1H, m), 7.30 (7H, m), 3.80 (1H, m), 3.48 (1H, m), 3.34 (1H, m), 1.93 (1H, d, J = 14 Hz), 0.85 (6H, s).

Elemental analysis for C H F N O

Found (%) 67,14 6,04 6,16 4,53

Calculated (%) 67,31 5,98 6,26 4,62 15,82

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 36), C17H19NO3, MM = 285.342

< / BR>
(chromatography on silica gel, ethyl acetate/chloroform/methanol: 60/30/10; So pl. = 127-128oC (cyclohexane); 41%)

IR (cm-1: 3180, 3070, 2950, 1605, 1575, 1480

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.75 (1H, m), 7.05 (6H, m), 3.81 (1H, m), 3.52 (1H, m), 3.32 (1H, m), 1.97 (1H, d, J = 14 Hz), 0.88 (3H, s), 0.60 (3H, s).

Elemental analysis C H N O

Found (%) of 71.58 6,88 4,85

Calculated (%) 71,56 of 6.71 4,91 16,82

7-Ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 37), C19H23NO3, MM = 313.396

< / BR>
(chromatography on silica gel, dichloromethane/methane is(CDCl3in million-1: 8.20 (1H, m), 7.60 (1H, m), 7.11 (5H, m), 6.50 (1H, m), 3.80 (1H, m), 3.50 (1H, m), 3.30 (1H, m), 2.64 (2H, q), 1.93 (1H, d, J = 13.5 Hz), 1.21 (3H, t), 0.83 (3H, s), 0.54 (3H, s).

Elemental analysis C H N O

Found (%) 73,03 7,49 4,57

Calculated (%) 72,82 7,40 of 4.44 15,32

3,3-Dimethyl-7-(1-methylpropyl)-5-(N-oxido-2-pyridyl)-2,3,4,5 - tetrahydro-1-benzoxazin-5-ol (formula 38), C21H27NO3; MM = 341.449

< / BR>
(chromatography on silica gel, dichloromethane; So pl. = 131-133oC (diisopropyl ether); 39%)

IR (cm-1: 3150, 2960, 1610, 1495

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.20 (7H, m), 3.77 (1H, d, J = 11 Hz), 3.48 (1H, d, J = 11 Hz), 3.28 (1H, d, J = 14 Hz), 2.58 (1H, q), 1.92 (1H, d, J = 14 Hz),1.10 (14H, m).

Elemental analysis C H N O

Found (%) 73,66 7,97 4,39

Calculated (%) 73,87 7,97 4,10 14,06

7-Methoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro - 1-benzoxazin-5-ol (formula 39), C18H21NO4; MM = 315.368

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2; So pl. = 109-110oC (isooctane))

IR (cm-1: 3200, 3080, 2950, 1605, 1495

1H NMR (CDCl3in million-1: 8.19 (1H, m), 7.15 (7H, m), 3.74 (3H, s), 3.58 (3H, m), 1.90 (1H, d, J = 13.5 Hz), 0.82 (3H, s), 0.55 (3H, s).

Elemental analysis C H N O

Found (%) 68,52 6,55 4,48

Calculated (%) 68,55 of 6.71 of 4.44 20,29

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-7-triptorelin ografia on silica gel, dichloromethane; So pl. = 114-116oC (heptane); 50%)

IR (cm-1: 3400, 3130, 3060, 2970, 2490

1H NMR (CDCl3in million-1: 8.21 (1H, m), 7.64 (1H, m), 7.01 (6H, m), 3.80 (1H, d, J = 11 Hz), 3.49 (1H, d, J = 11 Hz), 3.30 (1H, d, J = 14 Hz), 1.91 (1H, d, J = 14 Hz), 0.84 (3H, s), 0.52 (3H, s).

Elemental analysis for C H F N O

Found (%) with 58.33 4,95 15,31 3,86

Calculated (%) 58,53 4,91 15,43 3,79 17,33

3,3-Dimethyl-7-phenyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin - 5-ol (formula 41), C23H23NO3, MM=361.440

< / BR>
(chromatography on silica gel, methanol; so pl. = 175oC (diisopropyl ether/ethyl acetate: 50/50); 25%)

IR (cm-1: 3200, 2960, 1610

1H NMR (CDCl3in million-1: 8.14 (2H, m), 7.27 (10H, m), 3.85 (1H, d, J = 11 Hz), 3.55 (1H, d, J = 11 Hz), 3.34 (1H, d, J = 14 Hz), 2.02 (1H, d, J = 14 Hz), 0.90 (3H, s), 0.60 (3H, s).

Elemental analysis C H N O

Found (%) 76,57 6,37 3,90

Calculated (%) 76,43 6,41 3,88 13,28

7-Bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin - 5-ol (formula 42), C17H18BrNO3, MM = 364.238

< / BR>
(So pl. = 137-138oC (ethyl acetate); 20%)

IR (cm-1: 3090, 2950, 1590, 1560, 1475

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.65 (1H, m), 7.62 (1H, d, J = 8 Hz), 7.03 (5H, m), 3.81 (1H, d, J = 11 Hz), 3.50 (1H, d, J = 11 Hz), 3.29 (1H, d, J = 14 Hz), 1.92 (1H, d, J = 14 Hz, 0.88 (3H, s), is 0.53 (3H, s).

6,8-Dichloro-3,3-dimethyl-5-(N-oxido-2-Piri is = 220oC (ethyl acetate); 35%)

IR (cm-1: 3065, 2970, 1585, 1550

1H NMR (CDCl3in million-1: 8.15 (1H, m), 6.92 (5H, m), 4.00 (2H, s), 2.18 (2H, s), 1.28 (3H, s), 1.00 (3H, s).

Elemental analysis for C H Cl N O

Found (%) 57,54 4,84 on 20, 23 4,04

Calculated (%) 57,64 4,84 20,02 3,95 13,55

7,9-Dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin - 5-ol (formula 44), C17H17Cl2NO3, MM=354.232

< / BR>
(So pl. = 134-136oC (diisopropyl ether); 18%)

IR (cm-1: 3250, 3050, 2970, 1480

1H NMR (CDCl3in million-1: 8.21 (1H, m), 7.85 (1H, s), 7.08 (5H, m), 3.80 (1H, d, J = 11 Hz), 3.38 (2H, m), 1.90 (1H, d, J = 14 Hz), 0.88 (3H, s), 0.55 (3H, s).

Elemental analysis for C H Cl N O

Found (%) 57,80 4,70 19,73 was 4.02

Calculated (%) 57,64 4,82 20,02 3,95 13,55

7,9-sodium dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 45), C17H17Cl2NO2, MM=354.232

< / BR>
(So pl. = 150,5oC (diisopropyl ether); 33%)

IR (cm-1: 3230, 3070, 2970, 1570

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.70 (1H, m), 7.09 (4H, m), 3.89 (1H, dd, J = 1.5 Hz, J = 11 Hz), 3.40 (1H, d, J = 11 Hz), 3.31 (1H, dd, J = 1.5 Hz, J = 13.5 Hz), 1.82 (1H, d, J = 13.5 Hz), 0.81 (3H, s), 0.59 (3H, s).

Elemental analysis for C H Cl N O

Found (%) 57,38 4,89 20,02 3,99

Calculated (%) 57,64 4,84 20,02 3,95 13,55

8-Chloro-7-fluoro-3,3-dimethyl-5-(N-oxido-2-P3oC (diisopropyl ether); 24%)

IR (cm-1: 3290, 3070, 1485

1H NMR (CDCl3in million-1: 8.23 (1H, m), 7.87 (1H, s), 7.60 (1H, d), 7.08 (4H, m), 3.58 (3H, m), 1.90 (1H, d, J = 14 Hz), 0.84 (3H, s), 0.55 (3H, s).

Elemental analysis for C H Cl F N O

Found (%) 60,44 5,30 10,56 5,69 4,16

Calculated(%) 60,45 5,07 10,50 5,63 4.15 14,21

7,8-Dimethoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 47), C19H23NO5, MM=345.394

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2;

So pl. = 174oC (ethyl acetate))

IR (cm1: 3220, 3090, 2970, 1615, 1510

1H NMR (CDCl3in million-1: 8.22 (1H, m), 7.18 (4H, m), 6.62 (1H, s), 3.87 (3H, s), 3.80 (3H, s), 3.76 (1H, d, J = 10 Hz), 3.50 (1H, d, J = 10 Hz), 3,29 (1H, d, J = 13 Hz), 1.92 (1H, d, J = 13 Hz), 0.87 (3H, s), 0.55 (3H, s).

Elemental analysis C H N O

Found (%) 66,35 6,87, 4,20

Calculated (%) 66,07 of 6.71 4,06 23,16

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3,4,5 - tetrahydro-1-benzoxazin-5-ol (formula 48), C18H18F3NO3, MM = 353.340

< / BR>
(so pl. = 106-107oC (hexane); 76%)

IR (cm-1: 3400, 3110, 2950, 1615, 1590, 1500, 1480

1H-NMR (CDCl3in million-1: 8.05 (2H, m), 7.13 (6H, m), 3.80 (1H, m), 3.50 (1H, m), 3,29 (1H, m), 1.95 (1H, d, J = 13,5 Hz), 0.86 (3H, s), of 0.54 (3H, s).

Elemental analysis for C H F N O

Found (%) 61,40 5,08 16,01 4,01

Vice ormula 49), C18H18F3NO3, MM = 353.340

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2; So pl. = 102-105oC (cyclohexane); 27%)

IR (cm-1: 3400, 3050, 2950, 1585, 1480

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.37 (7H, m), 3.86 (1H, m), 3.55 (1H, m), 3.32 (1H, m), 1.95 (1H, d, J = 14 Hz), 0.88 (3H, s), 0.56 (3H, s).

7-Bromo-5-methoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5 - tetrahydro-1-benzoxazin (formula 50), C18H20BrNO3, MM = 378.265

< / BR>
(So pl. = 178-180o(ethyl acetate); 33%)

IR (cm-1: 2960, 1595, 1560, 1480

1H NMR (CDCl3in million-1: 8.06 (1H, m), 7.14 (6H, m), 3.98 (1H, d, J = 11 Hz), 3.70 (1H, d, J = 11 Hz), 3.33 (1H, d, J = 14 Hz), 3.05 (3H, s), 1.61 (1H, d, J = 14 Hz), 1.11 (3H, s), 0.95 (3H, s).

Elemental analysis for C H Br N O

Found (%) 56,96 5,50 21,10 to 3.58

Calculated (%) 57,15 5,33 21,13 3,70 12,69

Example 5.

7-Bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ylacetic (formula 51), C19H20BrNO4, MM = 406.275

< / BR>
(So pl. = 145-146oC (isooctane/ethyl acetate: 80/20))

IR (cm-1: 2958, 1730, 1605, 1480

1H NMR (CDCl3in million-1: 8.05 (1H, m), 7.17 (6H, m), 3.58 (3H, m), 2.19 (3H, s), 2.07 (1H, d, J = 14 Hz), 0.93 (3H, s), 0.60 (3H, s).

Elemental analysis for C H Br N O

Found (%) 56,20 of 5.05 19,75 3,40

Calculated (%) 56,17 4,96 19,67 3,45 of 15.75

7-Br is 62.222

< / BR>
(chromatography on silica gel, ethyl acetate; So pl. = 186-187oC (ethanol); 20%)

IR (cm-1: 3060, 2970, 1560, 1480

1H NMR (CDCl3in million-1: 8.05 (1H, m), 7.22 (6H, m), 3.75 (2H, s), 2.98 (1H, s), of 1.46 (3H, s), 1.17 (3H, s).

Elemental analysis for C H Br N O

Found(%) 56,14 4,51 22,27, 3,76 13,07

Calculated (%) 56,37 4,45 representing 22.06 a 3.87 13,26

7-Bromo-3,3, -dimethyl-5-(N-oxido-3-pyridyl)-2,3,4,5-tetrahydro-1 - benzoxazin-5-ol (formula 53), C17H18BrNO3, MM = 364.233

< / BR>
(So pl. = 200oC (ethanol); 38%)

IR (cm-1: 3180, 2950, 1595, 1560, 1485

1H NMR (DMCO) in million-1: 8.07 (2H, m), 7.14 (5H, m), 6.31 (1H, s), 3.78 (2H, s), 2.30 (1H, d, J = 13.5 Hz), 1.88 (1H, d, J = Hz), 0.94 (3H, s), 0.69 (3H, s).

Elemental analysis for C H Br N O

Found (%) 56,03 5,03 21,71 3,85

Calculated(%) 56,05 to 4.98 21,94 3.85 13.18

7,8-Dichloro-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin-5-ol (formula 54), C17H17Cl2NO3, MM = 354.232

< / BR>
(so pl. = 226 - 228oC (isopropanol); 23%)

IR (cm-1: 3160, 2950, 1590

1H NMR (DMCO) in million-1: 8.05 (2H, m), 7.17 (4H, m), 6.32 (1H, s), 3.81 (2H, s), 2.30 (1H, d, J = 14 Hz), 1.86 (1H, d, J = 14 Hz), 0.96 (3H, s), 0.71 (3H, s).

Elemental analysis for C H Cl N O

Found (%) 57,75 5,12 19,84 4,06

Calculated (%) 57,64 4,84 20,02 3,95 13,55

Example 6.

7-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3-di is,5-tetrahydro-1-benzoxazin-5-ol (13,9 g, 0.04 mol) and concentrated sulfuric acid (3.3 ml) in benzene (170 ml) is heated 3 hours at boiling to remove water. The solution is washed with 25oC 1% solution of sodium hydroxide and then with water. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Get 13,2,

So pl. 113 - 114oC (hexane); 70%

IR (cm-1: 2950, 1580, 1560, 1480

1H NMR (CDCl3in million-1: at 8.62 (1H, m), 7.30 (6H, m), 5.90 (1H, s), 3.93 (2H, s), 1.20 (6H, s).

Elemental analysis for C H Br N O

Found (%) 61,61 4,96 24,03 or 4.31

Calculated (%) 61,83 4,88 24,20 4,24 4,85

The same way we obtain the following compounds.

7-Chloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 56), C17H16ClNO, MM = 285.773

< / BR>
(So pl. = 100oC (hexane); 79%)

IR (cm-1: 2960, 1585, 1565, 1490

1H NMR (CDCl3in million-1: at 8.62 (1H, m), 7.28 (6H, m), 5.92 (1H, S), 3.91 (2H, s), 1.15 (6H, s).

7-Fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 57), C17H16FNO, MM = 269.318

< / BR>
(thick yellow oil; 38%)

IR (cm-1: 2970, 1590, 1565, 1495

1H NMR (CDCl3in million-1: 8.55 (1H, m), 7.02 (6H, m), 5.89 (1H, s), 3.90 (2H, s), 1.16 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 58), C) m-1: 8.56 (1H, m), 7.20 (7H, m), 5.83 (1H, s), 3.94 (2H, s), 1.18 (6H, s).

3,3,7-Trimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 59), C18H19NO, MM = 265.354

< / BR>
(oil; 98%)

IR (cm-1: 2960, 1590, 1565, 1500

1H NMR (CDCl3in million-1: 8.58 (1H, m), 7.10 (6H, m), 5.83 (1H, s), 3.91 (2H, s), 2.10 (3H, s), 1.18 (6H, s).

7-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 60), C19H21NO, MM = 279.381

< / BR>
(yellow oil; 97%)

IR (cm-1: 2960, 1590, 1505, 1500

1H NMR (CDCl3in million-1: 8.58 (1H, m), 7.14 (6H, m), 5.84 (1H, s), 3.91 (2H, s), 2.40 (2H, q), 1.16 (6H, s), 1.03 (3H, t).

7-Isopropyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 61), C20H23NO, MM = 293,408

< / BR>
(yellow oil; 98%)

IR (cm-1: 2960, 1585, 1565, 1495

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.64 (1H, m), 6.90 (5H, m), 5.84 (1H, s), 3.91 (2H, s), 2.68 (1H, m), 1.10 (12H, m).

3,3-Dimethyl-7-(1-methylpropyl)-5-(2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 62), C21H25NO2, MM = 307.435

< / BR>
(yellow oil; 77%)

IR (cm-1: 2965, 1585, 1565, 1500

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.29 (5H, m), 6.54 (1H, s), 5.86 (1H, s), 3.92 (2H, s), 2.31 (1H, m), 1.09 (14H, m).

7-Methoxy-3,3-dimethyl-5-(2-pyridyl)-2,5-dihydro-1 - benzoxazin (equation 63), C18H19NOm-1: 8.54 (1H, m), 7.00 (6H, m), 5.85 (1H, s), 3.88 (2H, s), 3.50 (3H, s), 1.03 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-triptoreline-2,3-dihydro-1 - benzoxazin (equation 64), C18H16F3NO2, MM = 335.325

< / BR>
(So pl. = 112oC (cyclohexane), 85%)

IR (cm-1: 3070, 3045, 2960, 1585, 1560

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.66 (1H, m), 7.13 (4H, m), 6.59 (1H, s), 5.91 (1H, s), 3.91 (2H, s), 1.17 (6H, s).

3,3-Dimethyl-7-methylthio-5-(2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 65), C18H19NOS, MM = 297.420

< / BR>
(So Kip. = 0.8 mm RT.article = 140 - 180oC; 60%)

IR (cm-1: 2970, 2870, 1585, 1560

1H NMR (CDCl3in million-1: 8.58 (1H, m), 7.65 (1H, m), 6.96 (5H, m), 5.87 (1H, s), 3.90 (2H, s), 2.22 (3H, s), 1.19 (6H, s).

3,3-Dimethyl-7-phenyl-5-(2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 66), C23H21NO, MM = 327.425

< / BR>
(So pl. = 115 - 120oC (heptane/; 42%)

IR (cm-1: 3050, 2950, 1600

1H NMR (CDCl3in million-1: 8.60 (1H, m), 7.30 (11H, m), 5.91 (1H, s), 3.99 (2H, s), 1.21 (6H, s).

8-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 67), C17H16BrNO, MM = 330.224

< / BR>
(yellow oil; 90%)

IR (cm-1: 3060, 2950, 1585, 1555, 1485, 1465

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.62 (1H, dd), 7.11 (4H, m), 6.61 (1H, d, J = 8 Hz), 5.90 (1H, s), 3.95 (2H, s), 1.18 (6H, s).

R> (chromatography on silica gel, cyclohexane/chloroform/methanol: 56/33/11; So pl. = 155 - 157oC (ethyl acetate); 57%)

IR (cm-1: 2960, 2220, 1590, 1570, 1495

1H NMR (CDCl3in million-1: 8.55 (1H, m), 7.37 (6H, m), 5.90 (1H, s), 3.95 (2H, s), 1.20 (6H, s).

Elemental analysis C H N O

Found (%) 78,06 5,94, 10,14

Calculated (%) 78,23 of 5.84, 10,14 5,79

8-Cyano-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 69), C16H16N2O, MM = 276.337

< / BR>
(chromatography on silica gel, dichloromethane; so pl. = 132oC (heptane); 30%)

IR (cm-1: 2950, 2210, 1585, 1565, 1540, 1500

1H NMR (CDCl3in million-1: 8.56 (1H, m), 7.66 (1H, m), 7.16 (4H, m), 6.83 (1H, d, J = 8 Hz), 6.01 (1H, s), 3.95 (2H, s), 1.19 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-trifluoromethyl-2,3-dihydro-1-benzoxazin (equation 70), C18H16F3NO, MM = 319.326

< / BR>
(So pl. = 90oC (isooctane); 60%)

IR (cm-1: 2960, 1585, 1565, 1500

3,3-Dimethyl-5-(2-pyridyl)-8-trifluoromethyl-2,3-dihydro-1-benzoxazin (equation 71), C18H16F3NO, MM = 319.326

< / BR>
(oil; 85%)

IR (cm-1: 2960, 1585, 1565, 1500

1H NMR (CDCl3in million-1, 8.60 (1H, m), 7.34 (6H, m), 6.00 (1H, s), 3.98 (2H, s), 1.19 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-pentafluoroethyl-2,3-dihydro-1-benzoxazin (equation 72), C19H16F5 is hydro-1-benzoxazin (equation 73), C17H15Cl2NO, MM = 320.218

< / BR>
(oil)

IR (cm-1: 2960, 1585, 1545

1H NMR (CDCl3in million-1: 8.47 (1H, m), 7.22 (5H, m), 6.50 (1H, s), 4.05 (2H, s), 1.10 (6H, s).

7,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 74), C17H15Cl2NO, MM = 320.218

< / BR>
(So pl. = 98oC (hexane); 81%)

IR (cm-1: 2960, 1580, 1475

1H NMR (CDCl3in million-1: 8.58 (1H, m), 7.40 (5H, m), 5.88 (1H, s), 3.90 (2H, s), 1.15 (6H, s).

7,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 75), C17H15Cl2NO, MM = 320.218

< / BR>
(So pl. = 124oC (heptane); 66%)

IR (cm-1: 2970, 1585, 1470

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.45 (4H, m), 6.62 (1H, d, J = 1.5 Hz), 5.95 (1H, s), 4.00 (2H, s), 1.21 (6H, s).

8,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 76), C17H15Cl2NO, MM = 320.218

< / BR>
(So pl. = 112oC (heptane); 55%)

IR (cm-1: 2970, 1580, 1475

1H NMR (CDCl3in million-1: at 8.62 (1H, m), to 7.67 (1H, m), 7.15 (2H, m), 6.92 (1H, d, J = 8 Hz), 6.57 (1H, d, J = 8 Hz), of 5.92 (1H, s), 4.02 (2H, s), 1.22 (6H, s).

7,8-Debtor-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 77), C17H15F2NO, MM = 287.308

< / BR>
(So pl. = 86oC (pentane); 86%)

IR (cm-1: 3070, 2970, or-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 78), C17H15ClFNO, MM = 303.763

< / BR>
(So pl. = 86oC; 94%)

IR (cm-1: 2950, 1585, 1560, 1485

1H NMR (CDCl3in million-1: 8.63 (1H, m), 7.68 (1H, m), 7.18 (3H, m), 6.55 (1H, d), 5.90 (1H, s), 3.92 (2H, s), 1.15 (6H, s).

9-Ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 79), C19H20FNO, MM = 297.372

< / BR>
(chromatography on silica gel, dichloromethane; 95%)

IR (cm-1: 2950, 1585

1H NMR (CDCl3in million-1: 8.60 (1H, m), 7.64 (1H, m), 7.15 (2H, m), 6.70 (1H, dd, J = 2 Hz, J = 8 Hz), 6.30 (1H, dd, J = 2 Hz, J = 10 Hz), 5.90 (1H, s), 3.90 (2H, s), 2.69 (2H, q), 1.20 (9H, m).

7-Dimethoxy-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 80), C19H21NO3, MM = 311.380

< / BR>
(So pl. = 86oC; 57%)

IR (cm-1: 2950, 1605, 1580, 1515

1H NMR (CDCl3in million-1: 8.61 (1H, m), 7.63 (1H, m), 7.17 (2H, m), 6.59 (1H, s), 6.25 (1H, s), 5.76 (1H, s), 3.92 (2H, s), 3.56 (3H, s), 3.50 (3H, s), 1.16 (6H, s).

7-Cyano-3,3,8-trimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazin (formula 81), C19H18N2O, MM = 290.364

< / BR>
(chromatography on silica gel, dichloromethane; So pl. = 171oC (toluene), 32%)

IR (cm-1: 3060, 2970, 2220, 1610, 1585, 1560, 1495

1H NMR (CDCl3in million-1: 8.59 (1H, m), 7.69 (1H, m), 7.19 (2H, m), 7.00 (1H, s), 6.90 (1H, s), 5.85 (1H, s), 3.95 (2H, s), 2.41 (3H, s), 1.19 (6H, s).

8-Cyano-3,3,7-t isoC (hexane), 40%)

IR (cm-1: 3070, 2980, 2230, 1590, 1500

1H NMR (CDCl3in million-1: 8.56 (1H, m), 7.66 (1H, m), 7.17 (1H, s), 7.14 (2H, m), 6.62 (1H, s), 5.96 (1H, s), 3.90 (2H, s), 2.27 (3H, s), 1.18 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3,7,8,9,10-hexahydro-1-naphthas-/2,3-b/oxepin (equation 83), C21H23NO, MM = 305.419

< / BR>
(So pl. = 75oC (hexane), 88%)

IR (cm-1: 2930, 1610, 1580, 1560, 1500

1H NMR (CDCl3in million-1: 8.56 (1H, m), 7.60 (1H, m), 7.17 (2H, m), 6.71 (1H, s), 6.40 (1H, s), 5.75 (1H, s), 3.90 (2H, s), 2.56 (4H, m), 1.70 (4H, m), 1.14 (6H, s).

8-Cyano-3,3-dimethyl-1-(2-pyridyl)-4,5-dihydro-3H-benzo/f/-cyclohepten (equation 84), C19H18N2, MM = 274.365

< / BR>
(chromatography on silica gel, ethyl acetate/hexane: 25/75; So pl. = 120oC (diisopropyl ether), 31%)

IR (cm-1: 2960, 2915, 2230, 1585, 1560

1H NMR (CDCl3in million-1: 8.55 (1H, m), 7.62 (1H, m), 7.20 (5H, m), 6.30 (1H, s), 2.80 (2H, m), 1.88 (2H, m), 0.95 (6H, m).

7-Bromo-3,3-dimethyl-5-(3-pyridyl)-2,3-dihydro-1-benzoxazin (equation 85), C17H16BrNO, MM = 330.224

< / BR>
(So pl. = 116oC (heptane); 73%)

IR (cm-1: 2950, 1560, 1485, 1465

1H NMR (CDCl3in million-1: 8.51 (2H, m), 7.35 (3H, m), 6.88 (2H, m), 5.74 (1H, s), 3.91 (2H, s), 1.17 (6H, s).

7-Cyano-3,3-dimethyl-5-(33-pyridyl)-2,3-dihydro-1-benzoxazin (equation 86), C18H16NHeptan), 38%)

IR (cm-1: 3090, 2980, 2250, 1600, 1570, 1500

1H NMR (CDCl3in million-1: 8.46 (2H, m), 7.18 (5H, m), 5.79 (1H, s), 3.95 (2H, s), 1.18 (6H, s).

7-Dichloro-3,3-dimethyl-5-(3-pyridyl)-2,3-dihydro-1-benzoxazin (equation 87), C17H15Cl2NO, MM = 320.218

< / BR>
(So pl. = 112oC (diisopropyl ether); 36%)

IR (cm-1: 3020, 2970, 1590, 1565, 1540

1H NMR (CDCl3in million-1: 8.54 (2H, m), 7.35 (2H, m), 7.10 (1H, s), 6.77 (1H, s), 5.72 (1H, s), 3.92 (2H, s), 1.17 (6H, s).

Example 7.

7-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxazin (equation 88), C19H23NO, MM=281.386

< / BR>
A solution of 7-ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxazine (75 g, 0.26 mol) in 96% ethanol (95 ml) was placed in an autoclave with a volume of 125 ml Add palladium containing 50% moisture (0.3 g at 10% on charcoal). Serves hydrogen under a pressure of 180 bar (ATM). The mixture is stirred for 4 hours at 80oC. the Suspension is filtered and concentrated under reduced pressure.

(Yellow oil; 78%).

IR (cm-1: 2960, 1590, 1570, 1495

1H NMR (CDCl3in million-1: 8.63 (1H, m), 7.30 (5H, m), 6.19 (1H, s), 4.54 (1H, dd, J = 2 Hz, J = 9 Hz), 3.89 (1H, d, J = 12 Hz), 3.48 (1H, d, J = 12 Hz), 2.42 (3H, m), 1.67 (1H, m), 1.20 (3H, s), 1.03 (3H, t), 0.85 (3H, s).

Example 8.

3,3-Dimethyl-7-nitro-5-(4-nitro-2-pyridyl)-2,3-Digue is)-1-benzoxazin-5-ol (5 g, 0.018 mol) and a solution of concentrated sulfuric acid (32 ml) cooled to 0oC. increments for 2 hours at 0oC add sodium nitrate (1.8 g, 0.02 mol) with stirring. The reaction mixture was poured into ice water (100 ml) and extracted with dichloromethane. The organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure (1.4 g, 25%; So pl. = 180oC (ethyl acetate).

IR (cm-1: 3100, 2970, 1545, 1530, 1480

1H NMR (CDCl3in million-1: 8.56 (1H, m), 8.34 (1H, d, J = 2.50 Hz), 7.90 (1H, d, J = 2.50 Hz), 7.48 (3H, m), 6.15 (1H, s), 4.15 (2H, s), 1.25 (6H, s).

The method described in example 4, the following compounds.

7-Bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 90), C17H16BrNO2, MM=346.223

< / BR>
(chromatography on silica gel, ethyl acetate; so pl. = 158-160oC (ethyl acetate); 29%)

IR (cm-1: 3040, 1960, 1480

1H NMR (CDCl3in million-1: 8.25 (1H, m), 6.98 (6H, m), 5.82 (1H, s), 3.95 (2H, s), 1.19 (6H, s).

Elemental analysis for C H Br N O

Found (%) 59,24 4,68 23,09 3,91

Calculated (%) 58,97 4,66 results were 23.08 4,05 9,24

7-Chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 91), C17H16ClNO2, MM=301.772

< / BR>
(So pl. = 168-170oC (acetone); 15s).

Elemental analysis for C H Cl N O

Found (%) 67.85 5,19 11,91 4,51

Calculated (%) 67,66 5,34 11,75 with 4.64 or 10.60

7-Fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 92), C17H16FNO2, MM=269.318

< / BR>
(So pl. = 184-185oC (ethyl acetate); 28%)

IR (cm-1: 3050, 2950, 1490

1H NMR (CDCl3in million-1: 8.23 (1H, m), 6.75 (6H, m), 5.83 (1H, s), 3.96 (2H, s), 1.19 (6H, s).

Elemental analysis for C H F N O

Found (%) 71,62 5,57 6,91 4,81

Calculated (%) 71,56 5,65 6,66 4,91 11,22

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 93), C17H17NO2, MM=265.327

< / BR>
(So pl. = 188-189oC (isopropanol); 19%)

IR (cm-1: 3050, 3010, 2960, 2870, 1605, 1570, 1490

1H NMR (CDCl3in million-1: 8.20 (1H, m), 6.91 (7H, m), 5.80 (1H, s), 4.00 (2H, s), 1.21 (6H, s).

Elemental analysis C H N O

Found (%) 76,53 6,45 of 5.05

Calculated (%) 76,38 6,41 5,24 of $ 11.97

3,3,7-Trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (equation 94), C18H19NO2, MM=281.354

< / BR>
(So pl. = 146-147oC (ethyl acetate))

IR (cm-1: 3030, 2960, 2930, 2870, 1605, 1570, 1490

1H NMR (CDCl3in million-1: 8.23 (1H, m), 7.21 (3H, m), 6.89 (2H, m), 6,34 (1H, m), 5.75 (1H, s), 3.95 (2H, s), 2.11 (3H, s), 2.11 (3H, s), 1.16 (6H, s).

Elemental analysis C H N O

Found (%) 77,04 6,75 5,07

SUB>H21NO2, MM=295.369

< / BR>
(So pl. = 126-129oC (ethyl acetate/diisopropyl ether: 2/1; 20%)

IR (cm-1: 3030, 2960, 2930, 2870, 1610, 1575, 1500

1H NMR (CDCl3in million-1: 8.28 (1H, m), 7.23 (3H, m), 6.94 (2H, m), 6.38 (1H, m), 5.78 (1H, s), 3.96 (2H, s), 2.43 (2H, q), 1.18 (6H, s), 1.04 (3H, t).

Elemental analysis C H N O

Found (%) 77,48 7,26 4,79

Calculated (%) 77,26 7,17 4,74 10,83

7-Isopropyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 96), C20H23NO2, MM = 309.407

< / BR>
(So pl. = 162 - 164oC (ethyl acetate))

IR (cm-1: 3025, 2950, 1500

1NMR (CDCl3in million-1: 8.26 (1H, m), 7.08 (5H, m), 6.38 (1H, s), 5.75 (1H, s), 3.95 (2H, s), 2.65 (1H, s), 1.10 (12H, m).

Elemental analysis C H N O

Found (%) 77.43 7.50 4.49

Calculated (%) 77.64 7.49 4.53 10.34

3,3-Dimethyl-7-(1-methylpropyl)-5-(N-oxido-2-pyridyl)-2,3-dihydro - 1-benzoxazin (equation 97), C21H25NO2, MM = 323.434

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 99/1; So pl. = 110 - 112oC (cyclohexane))

IR (cm-1: 3030, 2950, 1605, 1500, 1480

1H NMR (CDCl3in million-1: 8.28 (1H, m), 7.20 (3H, m), 6.91 (2H, m), 6.33 (1H, s), 5.77 (1H, s), 3.98 (2H, s), 2.32 (1H, m), 1.18 (6H, s), 1.05 (8H, m).

Elemental analysis C H N O

Found (%) 77.53 7.81 4.24

Calculated (%) 77.98 7.79 4.33 9.89

7-Methods < / BR>
(So pl. = 164 - 166oC (ethyl acetate)/

IR (cm-1: 3050, 2960, 1615, 1580, 1510, 1495

1H NMR (CDCl3in million-1: 8.20 (1H, m), 6.93 (5H, m), 6.14 (1H, m), 5.79 (1H, s), 3.93 (2H, s), 3.56 (3H, s), 1.15 (6H, s).

Elemental analysis C H N O

Found (%) 73.00 6.49 4.71

Calculated (%) 72.70 6.44 4.71 16.14

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-7-triptoreline-2,3 - dihydro-1-benzoxazin (equation 99), C18H16F3NO3, MM = 351.325

< / BR>
(So pl. = 157 - 159oC (ethyl acetate))

IR (cm-1: 3070, 2970, 1495

1H NMR (CDCl3in million-1: 8.24 (1H, m), 7.14 (5H, m), 6.39 (1H, s), 5.85 (1H, s), 3.96 (2H, s), 1.19 (6H, s).

Elemental analysis for C H F N O

Found (%) 61.79 4.77 16.38 3.91

Calculated (%) 61.53 4.59 16.22 3.99 13.66

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3 - dihydro-1-benzoxazin (formula 100), C19H16F3NO2, MM = 335.325

< / BR>
(So pl. = 152 - 153oC (ethyl acetate/hexane: 1/2))

IR (cm-1: 3060, 2970, 1610, 1495

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.13 (6H, m), 5.89 (1H, s), 4.00 (2H, s), 1.18 (6H, s).

Elemental analysis for C H F N O

Found (%) 64.55 4.76 17.55 4.10

Calculated (%) 64.47 4.81 17.00 4.18 9.54

3,3-Dimethyl-7-methylsulphonyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (formula 101), C18H19NO4S, MM = 345.418

< / BR>
1H NMR (CDCl3in million-1: 8.23 (1H, m), 7.65 (1H, m), 7.19 (5H, m), 5.97 (1H, s), 4.04 (2H, s), 2.91 (3H, s), 1.22 (6H, s).

Elemental analysis C H O N S

Found (%) 62.86 5.64 3.95 18.25 9.25

Calculated (%) 62.59 5.54 4.06 at 18.53 9.28

3,3-Dimethyl-7-phenyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 102), C23H21NO2, MM = 343.424

< / BR>
(chromatography on silica gel, ethyl acetate/chloroform/methanol: 60/30/11; So pl. = 165 - 168oC; 35%)

IR (cm-1: 3050, 2960, 1605

1H NMR (CDCl3in million-1: 8.24 (1H, m), 7.08 (11H, m), 5.82 (1H, s), 3.98 (2H, s), 1.16 (6H, s).

Elemental analysis C H N O

Found (%) 80.04 6.20 4.01

Calculated (%) 80.44 6.16 4.08 9.32

8-Bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 103), C17H16BrNO2, MM = 346.223

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2, so pl. = 135 - 137oC (diisopropyl ether/ethyl acetate: 60/40))

IR (cm-1: 3080, 2970, 1590, 1550, 1480

1H NMR (CDCl3in million-1: 8.21 (1H, m), 7.09 (5H, m), 6.40 (1H, d, J = 8 Hz), 5.81 (1H, s), 3.95 (2H, s), 1.17 (6H, s).

Elemental analysis for C H Br N O

Found (%) 59.23 4.70 22.04 3.97

Calculated (%) 58.97 4.66 23.08 4.05 9.24

7-Cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 104), C18H16N2OSUP>H NMR (CF3COOD) in million-1: 8.79 (1H, m), 8.05 (4H, m), 7.25 (1H, d, J = 8 Hz), 6.88 (1H, d. J = 2 Hz), 6.22 (1H, s), 4.15 (2H, s), 1.30 (6H, s)

Elemental analysis C H N O

Found (%) 74.09 5.57 9.40

Calculated (%) 73.95 5.52 9.58 10.95

8-Cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 105), C18H16N2O2, MM = 292.337

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2;

(So pl. = 195 - 197oC (ethanol))

IR (cm-1: 3090, 2970, 2230, 1550

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.18 (5H, m), 6.64 (1H, d, J = 8 Hz), 5.95 (1H, s), 3.96 (2H, s), 1.20 (6H, s).

Elemental analysis C H N O

Found (%) 74.21 5,61 9,77

Calculated (%) 73,95 5,52 9,58 10,95

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-8-trifluoromethyl-2,3 - dihydro-1-benzoxazin (formula 106), C19H16F3NO2, MM = 335.325

< / BR>
(So pl. = 130 - 131oC (hexane); 25%)

IR (cm-1: 3060, 2960, 1570, 1485

1H NMR (CDCl3in million-1: 8.25 (1H, m), 7.03 (6H, s), 5.95 (1H, s), 4.01 (2H, s), 1.19 (6H, s)

Elemental analysis for C H F N O

Found (%) 64,74 4,93 17,00 4,18

Calculated (%) 64.47 4.81 17.00 4.18 9.54

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-7-pentafluoroethyl-2,3 - dihydro-1-benzoxazin (equation 107), C19H16F5NO2, MM = 385.333

< / BR>
(so pl. = 161 - 162oC (ethyl acetate))

IR (cm-1
Found (%) 59,52 or 4.31 24,27 3,62

Calculated (%) 59,22 4,19 24,65 to 3.64 8,30

3,3-Dimethyl-7-nitro-5-(4-nitro-N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 108), C17H15N3O6, MM = 357.322

< / BR>
(chromatography on silica gel, ethyl acetate/chloroform/methanol : 60/30/10; So pl. = 228oC (methanol))

IR (cm-1: 3100, 2970, 1545, 1530, 1480

1H NMR (CDCl3in million-1: 8.37 (1H, d, J = 2.70 Hz), 8.25 (1H, m, J = 2.50 Hz), 7.65 (1H, d, J = 2.70 Hz), 7.38 (3H, m, J = 2.50 Hz), 6.17 (1H, s), 4.21 (2H, s), 1.28 (6H, s)

Elemental analysis C H N O

Found (%) 57.35 4.25 11.49

Calculated (%) 57.14 4.23 11.76 26.86

8-Cyano-3,3-dimethyl-1-(N-oxia-2-pyridyl)-4,5-dihydro-3H - benzo/f/-cyclohepten (equation 109), C19H18N2O, MM = 290.364

< / BR>
(chromatography on silica gel, cyclohexane/chloroform/methanol : 70/20/10; so pl. = 189oC (toluene); 42%)

IR (cm-1: 2950, 2225, 1595

1H NMR (CDCl3in million-1: 8.08 (1H, m), 7.27 (5H, m), 6.85 (1H, s), 5.92 (1H, s), 2.93 (2H, m), 1.88 (2H, m), 0.95 (6H, m)

Elemental analysis C H N O

Found (%) 78,30 5,90 9,39

Calculated (%) 78,59 6,25 9,65 5,51

6,8-Dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 110), C17H15Cl2NO2, MM = 336.217

< / BR>
(So pl. = 163 - 164oC (ethyl acetate))

IR (cm-1: 3050, 2970, 1590, 1550

1
Calculated (%) 60,73 4,50 21,09 4,17 9,52

7,8-Dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 111), C17H15Cl2NO2, MM = 336.217

< / BR>
(So pl. = 173 - 174oC (ethyl acetate); 37%)

IR (cm-1: 3070, 2960, 1475

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.20 (4H, m), 6.60 (1H, s), 5.85 (1H, s), 3.95 (2H, s), 1.15 (6H, s)

Elemental analysis for C H Cl N O

Found (%) 60,47 4,46 21,11 4,12

Calculated (%) 60,73 4,50 21,09 4,17 9,52

7,9-Dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 112), C17H15Cl2NO2, MM = 336.217

< / BR>
(So pl. = 155 - 157oC (diisopropyl ether/ethyl acetate : 70/30, 30%

IR (cm-1: 3035, 1470, 1419

1H NMR (CDCl3in million-1: 8.22 (1H, m), 7.34 (4H, m), 6.42 (1H, d, J = 2 Hz), 5.88 (1H, s), 4.02 (2H, s), 1.21 (6H, s)

Elemental analysis for C H Cl N O

Found (%) 60,83 4,55 20,82 4,16

Calculated (%) 60,73 4,50 21,09 4,17 9,52

8,9-Dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 113), C17H15Cl2NO2, MM = 336.217

< / BR>
(So pl. = 168oC (ethyl acetate); 26%)

IR (cm-1: 2960, 1470, 1422

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.25 (3H, m), 6.95 (1H, d, J = 8 Hz), 6.42 (1H, d, J = 8 Hz), 5.85 (1H, s), 4.07 (2H, s), 1.24 (6H, s)

Elemental analysis for C H Cl N O

Found (%) 61,14 4,71 21,21 4, the ula 114), C17H15F2NO2, MM = 303.308

< / BR>
(So pl. = 163 - 165oC (ethyl acetate)

IR (cm-1: 3060, 2965, 1600, 1515

1H NMR (CDCl3in million-1: 8.23 (1H, m), 7.28 (3H, m), 6.80 (1H, dd, J = 7.0 Hz), 6.35 (1H, dd, J = 8.0 Hz), 5.80 (1H, s), 3.95 (2H, s), 1.18 (6H, s)

Elemental analysis for C H F N O

Found (%) at 67.36 4.56 12.73 4.05

Calculated(%) 67.32 4.99 12,53, 4,62 10,55

8-Chloro-7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 115), C17H15ClFNO2, MM = 319.762

< / BR>
(So pl. = 149 - 151oC (ethyl acetate))

IR (cm-1: 3050, 2970, 1485

1H NMR (CDCl3in million-1: 8.20 (1H. m), 7.15 (4H, m), 6.35 (1H, d), 5.85 (1H, s), 3.93 (2H, s), 1.14 (6H, s)

Elemental analysis: C H Cl F N O

Found (%) 64,04 4,82 11,16 5,91 to 4.41

Calculated(%) 63,85 4,73, 11,09 5,94 4,38 10,01

9-Ethyl-7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (equation 116), C19H20FNO2, MM = 313.371

< / BR>
(chromatography on silica gel, acetone/ethyl acetate : 50/50;

(So pl. = 120 - 122oC (diisopropyl ether))

IR (cm-1: 2960, 2940, 1610, 1590

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.20 (3H, m), 6.69 (1H, dd, J = 2 Hz, J = 8 Hz), 6.25 (1H, dd, J = 2 Hz, J = 10 Hz), 5.79 (1H, s), 3.94 (2H, s), 2.66 (2H, q), 1.19 (6H, s), 1.16 (3H, t).

Elemental analysis: C H F N O

Found (%) 73,12 6,54 6,18 4,58

Calculated (>21NO4, MM = 327,379

< / BR>
(chromatography on silica gel, dichloromethane/methanol: 98/2;

So pl. = 146oC (ethyl acetate))

IR (cm-1: 3110, 2950, 1615, 1520, 1490

1H NMR (CDCl3in million-1: 8.26 (1H, m), 7.25 (3H, m), 6.57 (1H, s), 6.08 (1H, s), 5.70 (1H, s), 3.99 (2H, s), 3.81 (3H, s), 3.56 (3H, s), 1.19 (6H, s).

Elemental analysis C H N O

Found (%) 69,86 6,70 4,12

Calculated (%) 69,70 6,47 4,28 19,55

7-Cyano-3,3,8-trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 118), C19H18N2O2, MM = 306.363

< / BR>
(chromatography on silica gel, chloroform/methanol: 98/2, so pl. = 230 - 235oC (toluene/diisopropyl ether))

IR (cm-1: 3060, 2950, 2210, 1605, 1495

Elemental analysis C H N O

Found (%) 74,39 6,00 8,93

Calculated (%) 74,49 of 5.92 9,15 10,45

8-Cyano-3,3,7-trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 119), C19H18N2O2, MM = 306.363

< / BR>
(So pl. = 182 (toluene); 30%)

IR (cm-1: 3070, 2960, 2225, 1605, 1545, 1490

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.22 (4H, m), 6.44 (1H, s), 5.90 (1H, s), 3.92 (2H, s), 2.26 (3H, s), 1.18 (6H, s)

Elemental analysis: C H N O

Found (%) 74,70 5,91, 9,04

Calculated (%) 74,49 of 5.92 9,15 10,45

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-2,3,7,8,9,10-hexahydro-1 - naphthas/2,3-b/oxepin (formula 120), C21

C (toluene))

IR (cm-1: 2930, 1610, 1550, 1500

1H NMR (CDCl3in million-1: 8.22 (1H, m), 7.22 (3H, m), 6.72 (1H, s), 6.24 (1H, s), 5.69 (1H, s), 3.95 (2H, s), 2.58 (4H, m), 1.70 (4H, m), 1.16 (6H, s).

Elemental analysis C H N O

Found (%) 78,30 7,39 4,48

Calculated (%) of 78.47 7,21 4,36 9,96

7-Ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,4,5-tetrahydro - 1-benzoxazin (equation 121), C19H23NO2, MM = 297.385

< / BR>
(So pl. = 88-89oC (diisopropyl ether))

IR (cm-1: 3060, 3020, 2960, 2930, 2870, 1610, 1490

1H NMR (CDCl3in million-1: 8.28 (1H, m), 7,16 (3H, m), 6.96 (2H, m), 6.45 (1H, m), 5.20 (1H, dd, J = 2 Hz, J = 9 Hz), 3.71 (2H, s), 2,50 (3H, m), 1.70 (1H, dd, J = 2 Hz, J = 13.5 Hz), 1.07 (3H, s), 1.06 (3H, t), 0.80 (3H, s).

Elemental analysis C H N O

found (%) 76,63 of 7.75 4,62

Calculated (%) 76,73 7,80 4,71 10,76

7-Bromo-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 122), C17H16BrNO2, MM = 346.223

< / BR>
(So pl. = 161-162oC (ethyl acetate), 50%)

IR (cm-1: 3090, 2950, 1580, 1540, 1460

1H NMR (CDCl3in million-1: 8.19 (2H, m), 7.23 (3H, m), 6.90 (2H, m), 5.77 (1H, s), 3.90 (2H, s), 1.17 (6H, s).

Elemental analysis for C H Br N O

Found (%) 59,07 4,72, 22,99 4,13

Calculated (%) 58,97 4,66 23,06 of 4.05 9,26

7-Cyano-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 123), C18H16N2O NMR (CDCl3in million-1: 8.17 (2H, m), 7.25 (5H, m), of 5.85 (1H, s), 3.92 (2H, s) and 1.15 (6H, s)

Elemental analysis C H N O

Found (%) 73,89 5,52 9,68

Calculated (%) 73,95 5,52 9,58 10,95

7,8-Dichloro-3,3, -dimethyl-5-(N-oxido-3-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 124), C17H16Cl2NO2, MM = 336.217

< / BR>
(So pl. = 137-139oC (isooctane/diisopropyl ether: 50/50), 46%)

IR (cm-1: 3120, 3030, 2950, 1590, 1540

1H NMR (CDCl3in million-1: 8.20 (2H, m), 7.16 (3H, m), 6.80 (1H, s), 5.79 (1H, s), 3,90 (2H, s), 1.19 (6H, s).

Elemental analysis for C H Cl N O

found (%) 60,70 4,54 21,24 4,05

Calculated (%) 60,73 4,50 21,09 4,17 9,52

3,3-Dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin - 7-carboxamide (formula 125), C18H18N2O3, MM = 310.352

< / BR>
(So pl. = 215-217oC (methanol); 28%)

IR (cm-1: 3400, 3200, 2970, 1665, 1605

1H NMR (DMCO) in million-1: 8.16 (1H, m), 7.35 (6H, m), 5.85 (1H, s), 3.93 (2H, s), 1.13 (6H, s).

Elemental analysis C H N O

Found (%) 69,49 of 5.84 8,80

Calculated (%) 69,66 5,85 9,03 15,47

3,3-Dimethyl-7-phenylsulfonyl-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (formula 126), C23H21NO4S, MM = 407.490

< / BR>
(So pl. = 167-169oC (diisopropyl ether), 19%)

IR (cm-1: 3060, 2950, 1600, 1560, 1490

1H NMR (CDCl3in 7,83

Calculated (%) 67,79 5,20 3,44 15,71 7,87

8-Chloro-8-ethyl-3,3-dimethyl-5-(N-oxide-2-pyridyl)-2,3-dihydro-1 - benzoxazin (equation 127), C19H20ClNO2, MM = 329.829

< / BR>
(So pl. = 144-146oC (ethyl acetate), 34%)

IR (cm-1: 3070, 2950, 1485

1H NMR (CDCl3in million-1: 8.23 (1H, m), 7.20 (3H, m), 6.87 (1H, s), 6.50 (1H, s), 5.78 (1H, s), 3.95 (2H, s), 2.62 (2H, q), 1.18 (3H, t), 1.15 (6H, s)

Elemental analysis for C H Cl N O

Found (%) 69,25 6,01 10,89 4.26 deaths

Calculated (%) 69,19 6,11 10,75 4,25 9,70

8-Bromo-3,3-dimethyl-1-(N-oxido-2-pyridyl)-3H-benzo/f/cyclohepta - 1,4-diene (formula 128), C18H16BrNO, MM = 342.235

< / BR>
(So pl. = 167oC (diisopropyl ether); 10%)

IR (cm-1: 3080, 2980, 1485

1H NMR (CDCl3in million-1: 8.11 (1H, m), to 7.15 (6H, m), 6.52 (1H, d, J = 10 Hz), 5.88 (1H, s), 5.75 (1H, d, J = 10 Hz), 1.11 (6H, s).

Elemental analysis for C H Br N O

Found (%) 63,16 4,56 23,05 4.09 to

Calculated (%) 63,17 4,71 23,35 to 4.68 4.09 to

3,3-Dimethyl-7-(2-methylpropyl)-5-(N-oxido-2-pyridyl)-2,3 - dihydro-1-benzoxazin (formula 130), C21H25NO2, MM = 323.434

< / BR>
(So pl. = 114-116oC (diisopropyl ether); 25%)

IR (cm-1: 3060, 2969, 1500, 1490

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.20 (3H, m), 6.86 (2H, m), 6.30 (1H, s), 5.76 (1H, s), 3.95 (2H, s), 2.22 (2H, d), 1.68 (1H, m), 1.16 (6H, s), 0.8 (3H, s), 0.58 (3H, s).

Elemental analysis of the Idro-1-benzoxazin (equation 131), C18H18ClNO2, MM = 315.803

< / BR>
(So pl. = 178-180oC (ethyl acetate); 20%)

IR (cm-1: 3060, 2960, 1610, 1490

1H NMR (CDCl3in million-1: 8.19 (1H, m), 7.20 (3H, m), 6.85 (1H, s), 6.49 (1H, s), 5.75 (1H, s), 3.92 (2H, s), 2.22 (3H, s), 1.15 (6H, s).

Elemental analysis for C H Cl N O

Found (%) 68,74 5,73 11,48 4,42

Calculated (%) 68,48 5,75 11,23 of 4.44 10,13

7-Bromo-8-chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 132), C17H15BrClNO2, MM = 380.672

< / BR>
(So pl. = 182-183oC (ethyl acetate); 44%)

IR (cm-1: 3060, 2950, 1580, 1540, 1470

1H NMR (CDCl3in million-1: 8.22 (1H, m), 7.22 (3H, m), 7.08 (1H, s), 6.72 (1H, s), 5.83 (1H, s), 3.95 (2H, s), 1.17 (6H, s).

Elemental analysis for C H Br Cl N O

Found (%) 53,72 a 3.87 20,89 9,46 3,75

Calculated(%) 53,63 3,97 20,99 9,31 3,68 8.41

8-Chloro-7-cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1 - benzoxazin (formula 133), C18H15ClN2O2, MM = 326.786

< / BR>
(So pl. = 206-207oC (ethyl acetate); 53%)

IR (cm-1: 3080, 2990, 2240, 1600, 1550, 1490

1H NMR (CDCl3in million-1: 8.20 (1H, m), 7.23 (3H, m), 7.13 (1H, s), 6.83 (1H, s), 5.93 (1H, s), 4.02 (2H, s), 1.20 (6H, s).

Elemental analysis for C H Cl N O

Found (%) 65,51 4,56 10,89 8,48

Calculated (%) 66,16 4,63 10,85 to 8.57 9,79

8-Chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3 C)

IR (cm-1: 3080, 2980, 1610, 1565, 1495

1H NMR (CDCl3in million-1: 8.18 (1H, m), 7.58 (4H, m), 6.80 (1H, s), 5.88 (1H, s), 3.98 (2H, s), 1.15 (6H, s).

Elemental analysis for C H Cl F N O

Found (%) 58,42 4,24 9,99 14,79 3,83

Calculated(%) 58,46 4,09 9,59 15,42 33,79 8,65

8-Bromo-3,3-dimethyl-1-(N-oxido-2-pyridyl)-4,5-dihydro-3H-benzo/f/- cyclohepta-1-ene (formula 135), C18H18BrNO, MM = 344.250

< / BR>
(So pl. = 173-175oC (toluene); 43%)

IR (cm-1: 3070, 2960, 1590, 1490

1H NMR (CDCl3in million-1: 8.11 (1H, m), 7.18 (5H, m), 6.73 (1H, d), 5.90 (1H, s), 2.59 (2H, m), 1.85 (2H, m), 1.09 (6H, s).

Elemental analysis for C H Br N O

Found (%) 62,80 5,25 23,26 3,93

Calculated (%) 62,80 5,27 23,21 4,07 4,65

3,3-Dimethyl-8-phenylsulfonyl-1-(N-oxido-2-pyridyl)-4,5-dihydro - 3H-benzo/f/cyclohepta-1-ene (formula 136), C24H23NO3S, MM = 405.517

< / BR>
(So pl. = 191 - 192oC (isopropanol); 45%)

IR (cm-1: 3060, 2950, 1595, 1585, 1560, 1485

1H NMR (CDCl3in million-1: 8,08 (1H, m); was 7.45 (11H, m); 5,95 (1H, s); 2,92 (2H, m); a 1.88 (2H, m); 1,10 (6H, s).

Elemental analysis C H O N S

Found(%) 70,86; 5,82; 3,34; - ; 7,83

Calculated(%) 71,08; 5,72; 3,45; 11,84; 7,91

7,8-Dichloro-3,3-dimethyl-1-(N-oxido-2-pyridyl)-3H-benzo/f/-cyclohepta-1-ene (formula 137), C18H17Cl2NO, MM = 334.252

< / BR>
(So pl. = 195 - 196oC (toluene), 25%)

; ,85 (2H, m); a 1.11 (6H, s).

Elemental analysis for C H Cl N O

Found (%) 64,32 5,17 21,10 or 4.31

Calculated (%) 64,38 5,13 21,22 4,19 4,79

8-Bromo-4,4-dimethyl-1-(N-oxido-2-pyridyl)-3,4-dihydro-3H - benzo/f/cyclohepta-1-ene (formula 138), C18H18BrNO, MM = 334.250

< / BR>
(So pl. = 137 - 139oC (diisopropyl ether); 20%)

IR (cm-1: 2960, 2930, 1610, 1590, 1550, 1490

1H NMR (CDCl3in million-1: 8,12 (1H, m); for 7.12 (6H, m); 6,51 (1H, d); of 2.58 (2H, s); 1,74 (2H, d); of 1.05 (6H, s).

Elemental analysis for C H Br N O

Found (%) 62,80 5,14 23,27 4,04

Calculated (%) 62,80 5,27 23,21 4,07 4,65

Polysulfate 7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (formula 139), C17H17FNO4S0,5, MM = 334.357

< / BR>
(So pl. = 198 - 199oC (ethanol), 33%)

IR (cm-1: 3090, 2970, 1620, 1580, 1500

1H NMR (CDCl3in million-1: 10,28 (1H, s); at 8.36 (1H, m); at 7.55 (3H, m); 6,99 (2H, m); 6,07 (2H, m); 3,90 (2H, s) to 1.14 (6H, s).

Elemental analysis for C H F N O S

Found(%) 61,06; 5,45; 5,46; 4,19; - ; 5,01

Calculated(%) 61,07; 5,12; 5,68; 4,19; 19,4; 4,80

Hydrochloride 7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin (formula 140), C17H16Cl3NO2, MM = 372.690

< / BR>
(So pl. = 182 - 186oC (acetone), 60%)

IR (cm-1: 3090, 2970, 2270, 1700, 1605, 1525

1H NMR (CDCl3in million-1
Calculated (%) 54,78 4,33 28,54 3,76 8,59

Example 9.

4-(4-Pertenece)-3,3-dimethylbutanoate acid (formula 141), C12H15FO3, MM = 226.247

< / BR>
A suspension of 4-forefeel (21,3 g at 0.19 mol) and sodium hydroxide (7.6 g, to 0.19 mol) in n-butanol in a stream of dry nitrogen is heated on an oil bath at 190oC for 10 minutes with distillation of the water formed by azeotropic distillation. The heating is continued until the distillation of all n-butanol. Add 3,3-dimethylbutanoate (22,8 g 0.20 mol) and the reaction mixture is heated for 10 hours at 160oC (internal temperature of the environment), cooled to 80oC and add water (65 ml). The resulting solution was washed with dichloromethane and decanted. The aqueous phase is acidified and extracted with dichloromethane, the extract is dried with anhydrous sodium sulfate, concentrated under reduced pressure and the oily residue is distilled.

(so Kip. a 53.2 PA = 0.4 mm RT.CT.) = 130 - 134oC, 75%)

IR (cm-1: 3480, 2200, 1705, 1600, 1505

1H NMR (CDCl3in million-1: 10.75 (1H, m); 6.82 (4H, m); 3.66 (2H, s); 2.40 (2H, S); 1.11 (6H, S).

1. Derivatives of benzocycloheptene or benzocaine General formula I

< / BR>
in which X is oxygen or the group CHR, where R is hydrogen, or R together with R1form a connection;

R1, R1together with R form a connection;

R5is hydrogen, the hydroxy-group, or R5together with R7form a bond or a group-O-;

R6group of the formula

where R10and R11together with the carbon atom to which they are bound, form an optionally aromatic mono - or bicyclic nitrogen-containing heterocyclic group of 3 to 11 members, including 1 or 2 nitrogen atom, optionally substituted on the carbon atoms 1 to 7 groups selected from hydroxy-, nitro-, cyano -, or C1-C7-alkoxygroup or C1-C7-alkyl, and it is possible that at least one of the nitrogen atoms of the heterocycle is present in the form of N-oxide;

R7is hydrogen or hydroxy, C1-C7-alkoxy or C1-C7-alloctype or R5and R7together form a bond;

R8and R9the same or different and mean hydrogen, halogen, trifluoromethyl, pentafluoroethyl, C1-C7-alkyl, C1-C7-alkylsulfonyl, C1-C7-alkylsulfonyl, hydroxy-, nitro-, cyano-, triptoreline-, C1-C7-alkoxy, C1-C7-alkylthio or C1-C7-alltihopa, the group - COOR12where R12and R13the same or different and mean vpanel or C6-C10-arylsulfonyl, or R8and R9together form the group (CH2)nwhere n = 1 to 6

or their pharmaceutically acceptable salts.

2. Compounds of General formula I on p. 1, where X is oxygen.

3. Compounds of General formula I on p. 1, where R1and R2- hydrogen.

4. Compounds of General formula I on p. 1, where R5- hydrogen.

5. Compounds of General formula I on p. 1, where R6choose from 2-pyridyl, N-oxido-2-pyridyl, 3-pyridyl, N-oxido-3-pyridyl, 4-pyridyl, 3-hydroxy-4-pyridyl.

6. Compounds of General formula I on p. 1, where R7is hydrogen, hydroxy, methoxy or acetoxygroup.

7. Connection on p. 1 of General formula II

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in which X is oxygen or the group CHR;

R, R5, R6, R7, R8and R9defined above in paragraph 1.

8. Connection on p. 1 of General formula III

< / BR>
in which X is oxygen or the group CHR;

R, R6, R8and R9defined above in paragraph 1.

9. Connection on p. 1, selected from

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-triptoreline-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxa ITIL)-2,3-dihydro-1-benzoxazine;

7-ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-(1-methylpropyl)-2,3-dihydro-1-benzoxazine;

7-isopropyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7-methoxy-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-methylsulfonyl-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-methylsulphonyl-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-pentafluoroethyl-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3-dihydro-1-benzoxazine;

8-bromo-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7-bromo-3,3-dimethyl-5-(N-oxido-3-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-7-nitro-5-(N-oxido-4-nitro-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-7-phenyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

8-cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

6,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7,9-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

8,9-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7,8-dimethoxy-3,3-dimethyl-5-(N-oxido-2-p
7-chloro-8-fluoro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3,7,8,9,10-hexahydro-1-naphthas[2,3-b] oxepin;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin-5-ol;

7-chloro-8-ethyl-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine; and

8-bromo-3,3-dimethyl-1-(N-oxido-2-pyridyl)-3H-benzo(f)-cyclohepta-1,4-diene.

10. Connection on p. 1, chosen from:

7-chloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-7-trifluoromethyl-2,3-dihydro-1-benzoxazine;

7-cyano-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

8-cyano-3,3-dimethyl-1-(N-oxido-2-pyridyl)-4,5-dihydro-3H-benzo(f)of cycloheptene;

7,8-dichloro-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7,8-debtor-3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

7-cyano-3,3,8-trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

8-cyano-3,3,7-trimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine;

3,3-dimethyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazin-7-carboxamide; and

3,3-dimethyl-7-phenylsulfonyl-5-(N-oxido-2-pyridyl)-2,3-dihydro-1-benzoxazine.

11. The method of obtaining compounds of General formula I on p. 1, defined in paragraph 1;

R5', R8' and R9' - not necessarily protected groups R5, R8and R9defined in paragraph 1,

subjected to interaction with the ORGANOMETALLIC compound of General formula V

< / BR>
where R6'group of the formula

where R10and R11together with the carbon atom to which they are bound, form an optionally aromatic mono - or bicyclic nitrogen-containing heterocyclic group of 3 to 11 members, including 1 or 2 nitrogen atom, optionally substituted on carbon atoms 1 to 7 groups, optionally protected, if necessary, selected from hydroxy, nitro, cyano or C1-C7-alkoxygroup or C1-C7-alkyl;

b) with the subsequent removal of the protective groups to obtain the compounds of General formula VI

< / BR>
in which X, R1, R2, R3, R4, R5, R6, R8and R9defined in paragraph 1,

and optional c1) by the interaction of the compounds of the formula VI with a reagent of formula VII

R14-Y

where R14- C1-C7-alkyl or C1-C7-acyl and Y is a leaving group,

with the formation of compounds of formula I, where R7- C1-C7-alkoxy or C1-C7-alloctype, sootvetstvenno acid to form compounds of the formula I

< / BR>
in which X, R1, R2, R3, R4, R5, R6, R8and R9defined in paragraph 1,

and optionally (d) the interaction of the compounds of formula I, obtained in stage (c2), with the peroxide to form compounds of the formula I, in which R5and R7together form a group-O-, and optional e) the interaction of compounds of the formula VI obtained in stage (b), or compounds of the formula I, obtained in stage (c1), (c2) or (d), with the oxidizer, with the formation of the corresponding N-oxides, and/or optional (f) the interaction of compounds of the formula VI obtained in stage (b), or compounds of the formula I, obtained in stage (c1), (c2) or (d), with pharmaceutically acceptable inorganic or organic acids with formation of the corresponding salts.

12. Pharmaceutical composition having a relaxing effect on smooth muscles, including the active agent, a carrier and an excipient, wherein the active means it contains a compound of General formula I on PP.1 - 10 effective number.

13. The compounds of formula VIII

< / BR>
in which X, R1, R2, R3, R4, R5, R8and R9determine what romanucci)-3,3-dimethylbutanol acid;

4-(4-chlorphenoxy)-3,3-dimethylbutanol acid;

4-(4-pertenece)-3,3-dimethylbutanol acid;

4-(4-methylphenoxy)-3,3-dimethylbutanol acid;

4-(4-ethylenoxy)-3,3-dimethylbutanol acid;

4-(4-isopropylphenoxy)-3,3-dimethylbutanol acid;

4-[4-(1-methylpropyl)phenoxy]-3,3-dimethylbutanol acid;

4-(4-methoxyphenoxy)-3,3-dimethylbutanol acid;

4-(4-triftormetilfosfinov)-3,3-dimethylbutanol acid;

4-(4-methylthiophene)-3,3-dimethylbutanol acid;

4-(4-phenyleneoxy)-3,3-dimethylbutanol acid;

4-(3-bromophenoxy)-3,3-dimethylbutanol acid;

4-(3,5-dichlorophenoxy)-3,3-dimethylbutanol acid;

4-(3,4-dichlorophenoxy)-3,3-dimethylbutanol acid;

4-(2,4-dichlorphenoxy)-3,3-dimethylbutanol acid;

4-(2,3-dichlorophenoxy)-3,3-dimethylbutanol acid;

4-(3,4-divergence)-3,3-dimethylbutanol acid;

4-(3-chloro-4-pertenece)-3,3-dimethylbutanol acid;

4-(2-ethyl-4-pertenece)-3,3-dimethylbutanol acid;

4-(3,4-dimethoxyphenoxy)-3,3-dimethylbutanol acid;

4-(4-bromo-3-methylphenoxy)-3,3-dimethylbutanol acid;

4-(3-bromo-4-methylphenoxy)-3,3-dimethylbutanol acid;

4-(5,6,7,8-tetrahydronaphthalene)-3,3-Dimethylbutane is vulanovi acid;

4-(4-chloro-3-methylphenoxy)-3,3-dimethylbutanol acid;

4-(4-bromo-3-chlorophenoxy)-3,3-dimethylbutanol acid;

5-(4-bromophenyl)-3,3-dimethylpentane acid;

5-(3,4-dichlorophenyl)-3,3-dimethylpentane acid;

5-(4-bromophenyl)-4,4-dimethylpentane acid.

 

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< / BR>
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