Derivatives of n-substituted 3-azabicyclo[3.2.0]heptane

 

(57) Abstract:

Describes new derivatives of N-substituted 3-azabicyclo[3.2.0]heptane of formula I, where R1is phenyl or thienyl, unsubstituted or monosubstituted by halogen, a nitro-group, amino group, monomethylamine, dimethylaminopropoxy: A group of formula II, where R2is hydrogen, R3is hydrogen or R2and R3together denote oxygen, R4- thienyl or naphthyl, unsubstituted or substituted by fluorine or chlorine, R5is hydrogen or methyl, R6- phenyl, disubstituted by fluorine, chlorine, monosubstituted amino group, alkylamino c 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms in each alkyl part, or unsubstituted or substituted by fluorine, chlorine, nitro-group is thienyl, naphthyl, benzofuran, benzothiazyl, indolyl, N-methylindole or indenyl, cycloalkyl with 3 to 6 carbon atoms, R7is hydrogen, fluorine, chlorine, alkyl with 1 to 4 carbon atoms, amino, R8is hydrogen, methyl, R9is hydrogen, methyl, or R8and R9together with the ring carbon atom represent spirocyclopropane ring, R10is phenyl or benzyl, cyano, n = 1, 2, 3, 4, and their salts with physiologically tolerated acids. Derivatives of N for which you can apply as an adjunct means and means for protecting brain. 1 C.p. f-crystals, 1 table.

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes.

Known derivatives of 1,3,4-triple-substituted piperidine derivatives, which can be used as a neuroleptic funds or funds for protection of the brain (see application WO N. 9218480, publ. 29.10.1992 year).

Object of the invention is the expansion of the range of nitrogen-containing heterocyclic compounds which can be used as an adjunct means and means for protection of the brain, in particular, represent a receptor antagonist D4dopamine.

The problem is solved proposed derivatives of N-substituted of azabicycloalkanes the General formula

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where R1is phenyl or thienyl, unsubstituted or monosubstituted by halogen, a nitro-group, amino group, monomethylamine, dimethylaminopropoxy,

A group

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< / BR>
R2is hydrogen,

R3is hydrogen or

R2and R3together denote oxygen,

R4- thienyl or naphthyl, unsubstituted or substituted by fluorine or chlorine,

R5is hydrogen or IU the volumes of carbon dialkylamino with 1-4 carbon atoms in each alkyl part, or unsubstituted or substituted by fluorine, chlorine, nitro-group is thienyl, naphthyl, benzofuran, benzothiazyl, indolyl, N-methylindole or indenyl, cycloalkyl with 3-6 carbon atoms,

R7is hydrogen, fluorine, chlorine, alkyl with 1-4 carbon atoms, amino,

R8is hydrogen, methyl,

R9is hydrogen, methyl, or

R8and R9together with the ring carbon atom represent spirocyclopropane ring,

R10is phenyl or benzyl, cyano,

n- 1, 2, 3, 4,

and their salts with physiologically tolerated acids.

In the formula (I), the radicals R1-R10and n preferably have the following values:

R1- phenyl, thienyl, unsubstituted or substituted by fluorine, chlorine, iodine, nitro group,

R2is hydrogen,

R3is hydrogen,

R4- 1-naphthyl,

R5is hydrogen,

R6- o-AMINOPHENYL, o-N-methylaminophenol, 5-chlortan-1-yl, 1-naphthyl, 3-indanyl, cyclohexyl, 3-chloro-1-benzothieno-2-Il,

R7is hydrogen,

R8is hydrogen, methyl,

R9is hydrogen, methyl,

R10- phenyl,

n - 1,2.

The proposed compounds of formula (I) receive at the expense of the hat is nucleofuge remove the group subjected to interaction with the derived 3-azabicyclo[3.2.0.]heptane of the formula (III)

< / BR>
where R1is phenyl or thienyl, unsubstituted or monosubstituted by halogen, a nitro-group, amino group, monomethylamine, dimethylaminopropoxy, and thus obtained compounds translated, if necessary, in their acid additive salts with physiologically tolerated acids.

B as nucleofuge removed using preferably halogen, in particular bromine or chlorine.

The reaction is expediently carried out in the presence of an employee as an acid binding agent inert base, such as, for example, triethylamine or potassium carbonate, in an inert solvent such as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or an aromatic hydrocarbon, like toluene or xylene.

The reaction is carried out usually at temperatures of from 20 to 150oC and is completed usually within 1 to 10 hours.

The proposed compounds of formula (I) can precrystallization of the usual organic solvents, preferably lower alcohols, such as ethanol, or clear column chromatography. water wine to the CLO[3.2.0]heptane of the formula (I) can be translated in the usual reception in additive salt of the pharmacologically tolerable acid, preferably added to the solution of the equivalent of the appropriate acid. As pharmaceutically tolerated acid is used, for example, hydrochloric, phosphoric, sulfuric, maleic, fumaric, oxalic, tartaric, citric acid, and methansulfonate and amidosulfonic.

The biological activity of the proposed compounds were determined as follows.

The experiments were carried out in transfected Cos7 cells, exprimarea cloned D4receptors person. After lysis of the cells re-suspended in incubation buffer (50 mmol Tris-HCl, pH 7,4) containing 5 mmol of sodium salt of ethylenediaminetetraacetic acid, 1.5 mmol of calcium chloride, 5 mmol potassium chloride, 120 nmol of sodium chloride and 5 mmol of magnesium chloride, at a concentration of 105cells/experience. Incubation was carried out at a temperature of 25oC using 50 pmol of [125J] spiperone in the presence or absence of the proposed compounds. Non-specific ability to bind was determined using galoppatoio, taken in the quantity of 10-6mol. After 60-minute incubation, bound and free radioactivity were separated by high-speed filtering through the stack is karolneu filtration through glass filters GF/B British firm of Watman using satanowski harvester cells Norwegian company Lear. Filters were washed in cold buffer Tris-HCl, pH 7.0, containing 20 mmol Tris, 20 mmol magnesium chloride and 7% of polyethylene glycol with a molecular weight of 6000. Bound radioactivity was determined using a scintillation counter brand Packard 2200 CA. The activity of Ki in nmol/l of the studied compounds was determined by the method of nonlinear regression using the program Ligand.

The results of the experiments are summarized in table.

The proposed connection is introduced into the body in the usual ways, i.e. through the mouth, parenterally, intravenously or intramuscularly.

The dosage depends on the growth, condition, weight of the patient, and the method of drug administration. Generally, a daily dose of about 1-100 mg/kg body weight for oral introduction, and 0.1 to 10 mg/kg body weight at parenteral administration.

New connections can be applied in solid or liquid state as the active principle normal galenically dosage forms, e.g. tablets, which may be provided with a film, capsules, powders, granules, pills, suppositories, solutions, ointments, creams or sprays. Dosage forms get conventional ways with conventional galenically auxiliary substances, such as, for example, St is ligatory, solvents that provide prolonged action of agents, antioxidants and/or working gases (see X. Sucker and others, "Pharmazeutische Technologie", in Time-Verlag, 1978). Thus obtained preparations generally contain the active principle in an amount of from 1 to 99 wt.%.

Proposed connections (most of them) are of low toxicity.

The initial compounds of the formula (II) are known or are obtained by known literature methods.

The compounds of formula (III) can be obtained due to the fact that the amine of formula (IV)

< / BR>
where R1have the above meanings and R11means hydrogen, acetyl, benzyl, TRIFLUOROACETYL,

subjected to photochemical 2+2-cyclopentadienyl, if necessary, followed by removal of the acyl or benzyl.

Photoreactive well is carried out in an inert solvent, preferably acetone, at temperatures from 20 to 80oC. as a light source is particularly suitable mercury lamp high pressure. If necessary, it is advantageous to carry out photocycloaddition in the quartz device in the atmosphere of nitrogen, if necessary, with addition of about 1 mol of hydrochloric acid per mole of amine.

In most the m receive bicyclic compounds of the formula (III), with the Exo-configuration with respect to the radicals R1and R', where R1has the above value, a R' means hydrogen:

< / BR>
By separation of the racemate, for example, by using optically active derivatives of tartaric acid may clean the allocation of both enantiomers.

Cleavage of the acyl (R12), and the appropriate benzyl is carried out by saponification by known methods.

Amines of formula (IV) are known in the literature or they get due to the fact that the aldehyde of the formula R1CHO is subjected to interaction with chloride vinylmania obtaining allyl alcohol of formula (V)

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which is subjected to interaction with hydrogen chloride and the resulting allylchloride formula (VI)

< / BR>
subjected to interaction with the corresponding allylamino formula (VII)

< / BR>
or due to the fact that cinnamic aldehyde of formula (VIII)

< / BR>
subjected to direct restorative aminating allylamino formula (VII).

The following examples explain the invention.

A) obtaining a parent compounds

1. Exo-6-(p-fluoro)-phenyl-3-azabicyclo[3.2.0]heptane

In a solution of 19.4 r (102 mmol) of N-allyl-N-[3-(4-forfinal)allyl]amine in 130 ml of acetone at what omashu mercury lamps high pressure power 150W quartz apparatus at room temperature for 55 hours. Then the reaction mixture was concentrated and the residue partitioned between methylene chloride and water. The mixture is alkalinized water ammonia solution and the aqueous phase is additionally extracted two times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. Output: 19,3 r (99%), melting point: 165-166oC (malaikat).

For the separation of the antipodes in 15 g (about 78.5 mmol) of the racemate submit a solution of 31.7 g (78.5 per mmol) of (-)-di-O-toluoyl-L-tartaric acid in 300 ml of boiling ethanol. 13.8 g of precipitated upon cooling by mixing the crystals are sucked off by additional washing with ethanol and recrystallized from 200 ml of ethanol with the addition of 200 ml of water. Result in the release of the Foundation receive 5.5 g of (+)-antipode. The refractive index [a]D: +97,0o(ethanol, c = 0,969).

From the mother liquor is crystallized during the night of 14.2 g of salt, which is recrystallized from 400 ml of ethanol (filtering insoluble component boiling). The mixture is then concentrated to a volume of 300 ml. result In the release of the Foundation receive 4.0 g of (-)-antipode. The refractive index [a]D: -96,0o(ethanol, c = 0,940).

Actionmovie configuration argue with rentgenostrukturnye in 1600 ml of acetone serves 300 ml of 10% hydrochloric acid and the resulting mixture is irradiated in a nitrogen atmosphere using a mercury lamp high pressure power 150W quartz apparatus at room temperature for two days. Then the reaction mixture was concentrated and the residue partitioned between methylene chloride and water. The mixture is alkalinized water ammonia solution and the aqueous phase is additionally extracted two times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated.

Output: 49,0 g (98%) of a viscous oil, melting point: 177-178oC (malaikat).

3. Exo-6,7-diphenyl-3-benzyl-3-azabicyclo[3.2.0]heptane

In the solution 70,0 g (206 mmol) of bis-(N-cinnamyl)-benzylamine in 2500 ml of acetone serves 0.8 g of michler ketone and the resulting mixture is irradiated in a nitrogen atmosphere using a mercury high-pressure lamps with a capacity of 150W apparatus made of glass brand "Duran", at room temperature for 25 hours. Then the reaction mixture was concentrated and the residue partitioned between methylene chloride and water. The mixture is alkalinized water ammonia solution and the aqueous phase is additionally extracted two times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. 65.0 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of toluene and ethanol in the ratio of 98:2. Get 58,0 g (83%) of the target product, the point of the melt is mol) Exo-6,7-diphenyl-3-benzyl-3 - azabicyclo[3.2.0]heptane in 300 ml of n-propanol and 16 ml of water serves 16.0 g (254 mmol) of ammonium formate, and 2.0 g of 10% palladium on coal and the reaction mixture is refluxed for 4 hours, forming carbon dioxide. After cooling, a certain amount of catalyst is sucked off, the mixture is optionally washed with propanol and methylene chloride and the filtrate concentrated. The residue is partitioned between methylene chloride and water, the mixture is alkalinized water ammonia solution and the aqueous phase is additionally extracted two times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated. Get 8,1 g (92%) of the desired product, melting point: 140-142oC (malaikat).

5. Exo-6-phenyl-3-benzyl-3-azabicyclo[3.2.0] heptane. In a solution of 9.2 g (35,0 mmol) N-cinnamyl-N-allyl-benzylamine in 1100 ml of acetone serves 100 mg of michler ketone and the resulting mixture is irradiated in a nitrogen atmosphere using a mercury high-pressure lamps with power of 150 W in the apparatus, made of glass brand "Duran", at room temperature for 5 hours. Then the reaction mixture is thickened. 9.4 g of a crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 98:2. Gain of 3.3 g (36%) of the target product - 3-yl] -alanon

14.0 g (51,8 mmol) of N-allyl,2,2,2 trifter-N-[3-(3-pyridyl)- allyl]-ndimethylacetamide dissolved in 140 ml of acetone, the solution serves 30 ml of 10% aqueous hydrochloric acid and the resulting mixture is irradiated in a nitrogen atmosphere using a mercury high-pressure lamps with power of 150 W in the apparatus, made of glass brand "Duran", at room temperature for two days. Then the reaction mixture is thickened, served in 150 ml water and the aqueous ammonia solution is brought to a pH equal to 8-9.

The aqueous phase is extracted twice tert-butylmethylamine ether, the combined organic phases are dried over sodium sulfate and concentrated. The remainder fractionary column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 98:2. Obtain 6.2 g (42%) of unchanged N-allyl - 2,2,2-Cryptor-N-[3-(3-pyridyl)-allyl] -ndimethylacetamide and 3.7 g (26%) of 2,2,2-Cryptor-1-[Exo-6-(3-pyridyl)-3-azabicyclo[3.2.0]hept-3-yl]-ethanone in the form of a black oil.

7. Exo-6-(3-pyridyl)-3-azabicyclo[3.2.0] heptane. In a solution of 3.7 g (13.7 mmol) of 2,2,2-Cryptor-1-[Exo-6-(3-pyridyl)-3-azabicyclo[3.2.0]hept - 3-yl]-ethanone in 50 ml of ethanol serves 2.5 g of particles of potassium hydroxide. The reaction mixture was additionally mixed at room temperature in obyedinenie the organic phase is dried over sodium sulfate and concentrated. Yield: 2.3 g (96%) yellow oil; melting point: 202-205 areoC (hydrochloride).

Similarly receive the following connections:

8. Exo-6-(o-forfinal)-3-azabicyclo[3.2.0] heptane, melting point: 118-120oC (malaikat),

9. Exo-6-(p-chlorophenyl)-3-azabicyclo[3.2.0] heptane, melting point: 152-154oC (malaikat),

10. Exo-6-(m-chlorophenyl)-3-azabicyclo[3.2.0] heptane, melting point: 130-132oC (malaikat),

11. Exo-6-(p-nitrophenyl)-3-azabicyclo[3.2.0] heptane, melting point: 158-160oC (malaikat),

12. Exo-6-(p-triptoreline)-3-azabicyclo[3.2.0] heptane, melting point: 155-156oC (malaikat),

13. Exo-6-(3,5-dichlorophenyl)-3-azabicyclo[3.2.0]heptane, melting point above 250oC (hydrochloride),

14. Exo-6-(p-t-butylphenyl)-3-azabicyclo[3.2.0] heptane, melting point above 255oC (hydrochloride),

15. Exo-6-(p-cyanophenyl)-3-azabicyclo[3.2.0] heptane, melting point: 168-170oC (malaikat),

16. Exo-6-Tien-2-yl-3-azabicyclo[3.2.0] heptane, melting point: 180-182oC (hydrochloride),

17. Exo-6-Tien-3-yl-3-azabicyclo[3.2.0] heptane, melting point: 143-145oC (hydrochloride),

18. Exo-6-(5-chlortan-2-yl)-3-azabicyclo[3.2.0]heptane, melting point: 156-157oC (malaikat).

B. Obtaining the target product

To a solution of 3.0 g (15.7 mmol) of Exo-6-p-forfinal-3 - azabicyclo[3.2.0] heptane in 60 ml of xylene serves 3.5 g (15.7 mmol) of N-(2-chloroethyl)-benzosulfimide, 2.2 g (15.7 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide and the resulting mixture is refluxed with thorough mixing for 4 hours.

After cooling, the mixture is concentrated in a rotary evaporator and the residue partitioned between methylene chloride and water (pH: 10).

The aqueous phase is additionally extracted two times with methylene chloride and then the organic phase is optionally washed with water, dried over sodium sulfate and concentrated. 7.6 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 98: 2. The free base is served in 30 ml of ester acetic acid, insoluble flakes filtered off and the solution is simple ether serves excess ethereal hydrochloric acid. After 1 hour of mixing in the solution serves 150 ml simple ether and left to stand over night. Then the solid is sucked off in a cold state and hydrochloride optionally washed with copious amounts of simple ether. Allocate 4.1 g (64%) 2. N-(2-[Exo-6-phenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- benzosulfimide, melting point: 116-118oC (hydrochloride),

3. N-(2-[Exo-6-p-forfinal-3-azabicyclo-[3.2.0]heptane-3-yl]-ethyl)- N-methylbenzenesulfonamide, melting point: 63-65oC (hydrochloride),

4. 3-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -1 - phenoxypropan, melting point: 128-130oC (hydrochloride),

5. 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-1-p - fortunecity, melting point: 177-178oC (hydrochloride),

6.3-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - 1-(1-naphthyloxy)-propane, melting point: 79oC (hydrochloride), decomp.

Example 8

Toilet N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-t-benzamide

Into a solution of 2.4 g (7.1 mmol) of N-(2-[Exo-6-p-forfinal-3 - azabicyclo-[3.2.0] heptane-3-yl]-ethylbenzamide (see application DE N 4219973) in 50 ml of toluene serves 1.5 g (3.6 mmol) of the reagent Lawesson and the resulting mixture is refluxed with thorough mixing for 3 hours. After cooling, the mixture is concentrated in a rotary evaporator and the residue is partitioned between methylene chloride and water and the mixture is alkalinized 10% sodium clicking. The aqueous phase is additionally extracted two times with methylene chloride and Oh on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio, equal to 99:1. The purified free base was dissolved in 150 ml of simple ether while cooling with ice and mix in the mixture dotted slowly a solution of 1.0 g of p-toluenesulfonic acid in a complex ester of acetic acid. Osadovskaya salt sucked off in a nitrogen atmosphere, additionally simple washed with ether and dried in nitrogen atmosphere. Emit 2.7 g (72%) of the desired product as tosilata, melting point: 119-122oC.

Example 9.

Maleinate O-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl)-benzoate

a) In a solution of 11.5 g (142 mmol) of chloroethanol in 200 ml of tetrahydrofuran with thorough mixing at room temperature dotted 20,0 g (142 mmol) of benzoyl chloride and then to 14.4 g (142 mmol) of triethylamine (exothermic reaction). After 1 hour of mixing, the mixture is concentrated in a rotary evaporator and the residue is partitioned between methylene chloride and water and the mixture acidified with 10% hydrochloric acid. The aqueous phase is additionally extracted two times with methylene chloride and then the organic phase is dried over sodium sulfate and concentrated. Allocate 26,0 g (99%) 2-chlorethylene.

b) a solution of 3.0 g (15.7 mmol) of Exo-6-(p-forfinal)-3 - azabicyclo[3.2.0]heptane in 50 ml of toluene serves 6.0 g (32 mmol) of 2-chlorethylene ATiM refrigerator with thorough mixing for 15 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methylene chloride and water. The aqueous phase is brought to pH 10, and additionally extracted two times with methylene chloride. Then the organic phase is dried over sodium sulfate and concentrated. 8,9 g crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 99:1. 2.8 g of purified free base, dissolved in 150 ml of simple ether while cooling with ice and mix in the mixture dotted slowly a solution of 1.0 g of maleic acid in 10 ml of acetone. Osadovskaya salt sucked off in a nitrogen atmosphere, additionally simple washed with ether and dried in nitrogen atmosphere. Allocate a 3.9 r (53%) of the desired product as maleinate, melting point: 139-141oC.

Example 10.

N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] ethyl)-1H - benzo[c,d]indol-2-he

In a solution of 2.5 g (of 13.1 mmol) of Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane in 50 ml of xylene serves 3.0 g (of 13.1 mmol) of 1-(2-chloroethyl)-1H-benzo-[c,d] indol-2-Ana, 1.9 grams (to 13.1 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide and the resulting mixture is boiled with reverse holodilnik partitioned between methylene chloride and water, moreover, the pH is 10. The aqueous phase is additionally extracted two times with methylene chloride and the organic phase is dried over sodium sulfate and concentrated. 6.0 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 98:2.

3.4 g of the free base is dissolved in a small amount of complex ethyl ester of acetic acid and cooled with ice in the mixture serves excess ethereal hydrochloric acid. Add diethyl ether followed by mixing at a temperature of 0oC for 10 minutes. Usageprice when this hydrochloride is sucked off in the atmosphere of nitrogen, optionally washed with diethyl ether and dried in a vacuum drying Cabinet at a temperature of 40oC. Obtain 2.7 g (49%) of a light powder, melting point above 250oC (hydrochloride).

Similarly receive the following connections:

11. N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-1H-benzo[c,d]indol-2-it, melting point: 233-235oC (hydrochloride),

12. N-(2-[Exo-6-m-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-1H-benzo[c,d]indol-2-it, melting point: 230-233oC (hydrochloride),

13. N-(2-[Exo-6-m-chlorophenyl-3-Isabel is 2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl)-indoline-2, melting point: 198-200oC (hydrochloride),

15. 3,3-dimethyl-1-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl)-indoline-2 decomposition: 102oC (malaikat),

16. 3,3-dimethyl-1-(2-[Exo-6-m-chlorophenyl-3-azabicyclo[3.2.0]heptane - 3-yl]-ethyl)-indoline-2,

17. 1-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- 3,3,5-trimethyl-indoline-2, melting point 227-229oC (hydrochloride),

18. 3,4-dichloro-N-(2-[Exo-6-p-nitrophenyl-3-azabicyclo[3.2.0] heptane-3 - yl]-ethyl)-benzamide, melting point: 146-147oC (hydrochloride),

19. 2.5-debtor-N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl)-benzamide, melting point: 182-183oC (hydrochloride),

20. 2-amino-N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-benzamide, melting point: 138-139oC,

21. 2-amino-N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-benzamide, melting point: 127-128oC,

22. N-(2-[Exo-6-p-forfinal-3-asabia, yclo[3.2.0]heptane-3-yl]- ethyl)-2-methylaminoethanol, melting point: 105-110oC (dihydrochloride),

23. N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl)-2-methylaminoethanol decomposition: 107oC (dihydrochloride),

24. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-thiophene-2-carboxylic amide acid is l]-ethyl)-thiophene-2-carboxylic acid amide, melting point: 129-131oC,

26. 5-chloro-N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl)-thiophene-2-carboxylic acid amide, melting point: 136-138oC,

27. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-benzo[b] furan-2-carboxylic acid amide, melting point: 250-251oC (hydrochloride),

28. 3-chloro-N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane - 3-yl]-ethyl)-benzo[b]thiophene-2-carboxylic acid amide, melting point: 104-106oC,

29. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-inden-3-carboxylic acid amide, melting point: 107-109oC,

30. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- cyclopropane carboxylic acid, melting point: 104-105oC,

31. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-cyclopentane carboxylic acid, melting point: 78-82oC,

32. N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-cyclopentane carboxylic acid, melting point: 84-86oC,

33. N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-cyclohexane carboxylic acid, melting point: 111-113oC,

34. N-(2-[Exo-6-p-chlorophenyl-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-cyclohexane carboxylic acid, torbonosa acid, melting point: 202-204oC (hydrochloride).

Example 36

Exo-6-p-forfinal-3-[2-(1-naphthyl)-ethyl]-3-azabicyclo[3.2.0]heptane

In a solution of 2.5 g (of 13.1 mmol) of Exo-6-p-forfinal-3 - azabicyclo[3.2.0] heptane in 50 ml of xylene serves 3.2 g (to 13.6 mmol) 1-(2-bromacil)-naphthalene, 1.9 grams (to 13.1 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide and the resulting mixture is refluxed with thorough mixing for 2 hours. After cooling, it is condensed in a rotary evaporator and the residue is distributed between methylene chloride and water, and the pH is 10. The aqueous phase is additionally extracted two times with methylene chloride, the organic phase is dried over sodium sulfate and concentrated. 6.7 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 97.5:2.5 to.

3.3 grams of the free base was dissolved in diethyl ether and a small amount of complex ethyl ester of acetic acid and cooled with ice in the mixture serves excess ethereal hydrochloric acid. Usageprice hydrochloride sucked off in the atmosphere of nitrogen, optionally washed with diethyl ether and then dried in a vacuum sushilnomoC (hydrochloride).

Similarly, get:

37. Exo-6-p-chlorophenyl-3-[2-(1-naphthyl)-ethyl]-3-azabicyclo[3.2.0]heptane, melting point: 215-216oC (hydrochloride),

38. Exo-6-m-chlorophenyl-3-[2-(1-naphthyl)-ethyl]-3-azabicyclo[3.2.0]heptane, melting point: 185-187oC (hydrochloride),

39. Exo-6-(5-chloro-2-thienyl)-3-[2-(1-naphthyl)-ethyl]-3 - azabicyclo[3.2.0] heptane, melting point: 209-210oC (hydrochloride),

40. Exo-6-p-forfinal-3-[2-(2-naphthyl)-ethyl]-3-azabicyclo[3.2.0]heptane, melting point: 163-164oC (hydrochloride),

41. Exo-6-p-forfinal-3-[1-naphthylmethyl]-3-azabicyclo[3.2.0]heptane, melting point: 114-116oC(malaikat),

42. Exo-6-p-forfinal-3-[2-naphthylmethyl]-3-azabicyclo[3.2.0]heptane, melting point: 153 to 155oC (hydrochloride),

43. 4-(6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl)-1-(thiophene - 2-yl)-butane-1-he, melting point: 197-199oC (hydrochloride),

44. 4-(6-p-chlorophenyl-3-azabicyclo[3.2.0]heptane-3-yl)-1-(thiophene - 2-yl)-butane-1-he, melting point: 176-177oC (hydrochloride).

Example 45

Tartrate N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.01 heptane-3-yl] - ethyl)-4-phenylpyrrolidine-2

a) In a solution of 25.0 g (131 mmol) of Exo-6-(p-forfinal)-3 - azabicyclo[3.2.0] heptane in 350 ml of tetrahydrofuran serves 74,0 g (523 mmol) 1-bromo-2-chloration with thorough mixing for 15 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methyl tert.-butyl ether and water.

The aqueous phase is brought to pH 10, and additionally extracted two times with methyl-tert.-butyl ether. Then the organic phase is dried over sodium sulfate and concentrated. 34,8 g crude product was then purified column chromatography on silica gel using as eluent methylene chloride. Allot of 21.9 g(66%) 3-( (- -chloroethyl)-Exo-6-(p-forfinal)-3-azabicyclo[3.2.0]heptane as a light yellow oil.

b) In a solution of 1.56 g (9.9 mmol) of 4-phenyl-pyrrolidinone-2 in 30 ml of dimethylformamide serves to 0.30 g (9.9 mmol) of 80% sodium hydride in a nitrogen atmosphere and at room temperature and the resulting mixture is heated with thorough mixing at a temperature of 120oC for 1 hour. After cooling, the mixture was fed 2.5 g (9.9 mmol) of 3-( (- -chloroethyl)-Exo-6-(p-forfinal)-3-azabicyclo[3.2.0] heptane and the mixture was additionally mixed with 140oC for 2 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methyl tert.-butyl ether and water. The aqueous phase is brought to pH 10, and additionally extracted two times with methyl-tert.-butyl is th chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio, equal to 97:3. 2.5 g of the purified free base was dissolved in 150 ml of simple ether while cooling with ice and mix in the mixture dotted slowly a solution of 1.0 g of tartaric acid in 10 ml of ethanol. Osadovskaya salt sucked off in a nitrogen atmosphere, additionally simple washed with ether and dried in nitrogen atmosphere. Allocate 3.2 g (61%) of the desired product as tartrate, melting point: 74-77oC.

Example 46

N-(2-[Exo-6-(p-forfinal)-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- benzoxazolinone-2

a) In a solution of 10 g (74 mmol) of benzoxazolinone-2 in 150 ml of 1,2-dichloroethane serves to 7.1 g (111 mmol) of the powder of potassium hydroxide (88%), and 0.5 g of the chloride of benzyltriethylammonium and the resulting mixture is refluxed with thorough mixing for 4 hours. After cooling, the mixture is concentrated in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is additionally extracted two times with methylene chloride, the organic phase is dried over sodium sulfate and concentrated. 11,7 g crude product was then purified column chromatography on silica gel using as eluent methylene chloride. Allot of 8.2 g (56%) of N-(2-chloro)-ethylbenzothiazoline-2.

b) In a solution of 2.5 g (ozolinone-2, 1.8 g (of 13.1 mmol) of finely ground potassium carbonate and 0.3 g of potassium iodide and the resulting mixture is refluxed with thorough mixing for 7 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is brought to a pH equal to 9, and additionally extracted two times with methylene chloride. The organic phase is dried over sodium sulfate and concentrated, 6.5 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 98:2. Allocate 3.5 g (76%) of the desired product, melting point: 138-140oC (fumarate).

Example 47

N-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]-ethyl)- isoindoline

a) In a solution of 13.3 g (100 mmol) of Telemedia in 200 ml of 1,2-dichloroethane serves 9.6 g (150 mmol) of powder of potassium hydroxide (88%), and 0.5 g of the chloride of benzyltriethylammonium and the resulting mixture is refluxed with thorough mixing for 5 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is brought to pH, the volume of sodium and thicken, 15.0 g of crude product purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 97:3. Allot of 9.8 g (50%) of N-(2-chloro)-utilizandolo.

b) In a solution of 2.5 g (of 13.1 mmol) of Exo-6-(p-forfinal)-3 - azabicyclo[3.2.0] heptane in 50 ml of xylene serves to 2.75 g (14.0 mmol) of N-(2-chloro)-utilizandolo, 2.0 g (14.0 mmol) of finely ground potassium carbonate and 0.5 g of potassium iodide and the resulting mixture is refluxed with thorough mixing for 8 hours. After cooling, it is condensed in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is brought to pH 10, and additionally extracted two times with methylene chloride. Then the organic phase is dried over sodium sulfate and concentrated. 5.6 g of crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 96:4. Allocate 3.5 g (76%) of the desired product, melting point: 223-225oC (hydrochloride).

Similarly receive the following connections:

48.1-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-indazol, point placeitem, melting point: 206-208oC (hydrochloride),

50. 4-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] - ethyl)-1,4-benzoxazin-3-one, melting point: 166-168oC (toilet),

51. 1-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]heptane-3-yl]- ethyl)-cinoxacin-2-(1H)-he, melting point: 54-56oC (tartrate).

Example 52

1-(2-[Exo-6-p-forfinal-3-azabicyclo[3,2.0] heptane-3-yl]-ethyl)- indoline-2

a) In a solution of 13.3 g (100 mmol) of oxindole in 150 ml of 1,2-dichloroethane serves 11,0 g (173 mmol) of the powder of potassium hydroxide (88%), and 0.5 g of the chloride of benzyltriethylammonium and the resulting mixture is refluxed with thorough mixing for 6 hours. After cooling, the mixture is concentrated in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is additionally extracted two times with methylene chloride and then the organic phase is dried over sodium sulfate and concentrated. 15.5 g of a crude product was then purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 99:1. Allot of 7.1 g of a mixture of N-(2-chloro)-atalexandra and the corresponding derived spirocyclopropane.

b) In a solution of 3.4 g (17.8 mmol) of Exo-6-(p-fftogo potassium carbonate, and 0.5 g of potassium iodide and the resulting mixture is refluxed with thorough mixing for 9 hours. After cooling, the mixture is concentrated in a rotary evaporator and the residue partitioned between methylene chloride and water.

The aqueous phase is brought to pH 10, and additionally extracted two times with methylene chloride. Then the organic phase is dried over sodium sulfate and concentrated. of 8.4 g of crude product purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 99:1. Allocate 3.5 g of a mixture of two products in a ratio equal to 1:1. want to order fine cleaning again subjected to column chromatography on silica gel using as eluent a mixture of n-hexane and a complex ester of acetic acid in the ratio of 1:1. As polar substances are 1.9 grams(31%) 1-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)-indolinone-2, melting point: 91-93oC (tartrate).

Example 53.

1-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- Spiro[cyclopropane-1',3 indoline-2]

As a non-polar component of the mixture mentioned in example b, allocate 1.4 g (21%) is water tartrate is decomposed at a temperature of 129oC.

Example 54.

5-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- 2-phenylamino-3,6-dimethyl-4(3H)-pyrimidinone

To a solution of 3.0 g (15.7 mmol) of Exo-6-p-forfinal-7-methyl-1,5-CIS - 3,7-diazabicyclo[3.2.0] octane in 60 ml of xylene serves 4.4 g (15.7 mmol) of 5-chloroethyl-2-phenylamino-3,6-dimethyl-4(3H)-pyrimidinone derived from phenylquinoline and - acetyl-butyrolactone according to the methods described in European patent application N 110435, 2.2 g (15.7 mmol) of finely ground potassium carbonate and 0.4 g of potassium iodide, and the resulting mixture is refluxed with thorough mixing for 10 hours.

After cooling, the mixture is concentrated in a rotary evaporator and the residue partitioned between methylene chloride and water, and pH10. Insoluble cereal sucked off. The aqueous phase is additionally extracted two times with methylene chloride and then the organic phase is dried over sodium sulfate and concentrated. of 8.2 g of crude product purified column chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 93:7. Allot of 5.3 g (78%) of the desired product with a melting point 61-63oC.

Similarly, get:

55. 5-(2-[Exo-6-p-forfinal-3-Isabel is.

Example 56.

5-(2-[Exo-6-p-forfinal-3-azabicyclo[3.2.0] heptane-3-yl] -ethyl)- 2-(N-methyl-N-phenyl)-amino-3,6-dimethyl-4(3H)-pyrimidinone

In a solution of 2.9 g (6.7 mmol) of 5-[Exo-6-p-forfinal-3-azabicyclo[3.2.0]- heptane-3-yl] -ethyl)-2-phenylamino-3,6-dimethyl-4(3H)-pyrimidinone in 30 ml of dimethylformamide portions served 0.21 g (7.0 mmol) of sodium hydride (80%) with thorough mixing (exothermic reaction). The mixture was additionally mixed at a temperature of 70oC within 0.3 hours followed by the addition of 1.0 g (7.0 mmol) of methyliodide. The reaction mixture was additionally mixed at a temperature of 90oC for 2 hours and then concentrated in vacuum. The residue is partitioned between water and methyl tert-butyl ether, and pH 10, and the aqueous phase is additionally extracted two times with methyl tert-butyl ether. The organic phase is dried and concentrated. Obtain 1.2 g (40%) of the desired product, melting point: 115-117oC (hydrochloride x 2H2O).

1. Derivatives of N-substituted 3-azabicyclo[3,2.0]heptane of formula I

< / BR>
where R1is phenyl or thienyl, unsubstituted or monosubstituted by halogen, a nitro-group, amino group, monomethylamine, dimethylaminopropoxy;

A group

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
UP> and R3together represent oxygen;

R4- thienyl or naphthyl, unsubstituted or substituted by fluorine or chlorine;

R5is hydrogen or methyl;

R6- phenyl, disubstituted by fluorine, chlorine, monosubstituted amino group, alkylamino with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms in each alkyl part, or unsubstituted or substituted by fluorine, chlorine, nitro-group is thienyl, naphthyl, benzofuran, Bettany, indolyl, N-methylindole or indenyl, cycloalkyl with 3 to 6 carbon atoms;

R7is hydrogen, fluorine, chlorine, alkyl with 1 to 4 carbon atoms, amino;

R8is hydrogen, methyl;

R9is hydrogen, methyl, or R8and R9together with the ring carbon atom represent spirocyclopropane ring;

R10is phenyl or benzyl, cyano;

n= 1, 2, 3, 4,

and their salts with physiologically tolerated acids.

2. Derivatives of N-substituted 3-azabicyclo[3.2.0]heptane of formula I on p. 1, representing receptor antagonist D4dopamine.

 

Same patents:

The invention relates to 4-aryloxy - or 4-aaltio-piperidinyl derivative of the formula (I):

< / BR>
where

R1and R2each, independently of one another, signify unsubstituted or one - or twofold substituted with A, OH, OA, aryloxy with 6-10 C atoms, aralkylated with 7-11 C atoms, -O-(CH2)n-O-, Gal, CF3, NO2, NH2, NHA, NA2, NHAc, NAAc, NHSO2A and/or NASO2A phenyl residues;

X denotes O, S, SO or SO2;

"m" denotes 1, 2 or 3;

"n" represents 1 or 2;

A stands for an alkyl residue with 1-6 C-atoms;

Gal denotes F, Cl, Br or iodine;

and Ac denotes alkanoyl with 1-8 C-atoms, arkanoid with 1-10 C-atoms or aroyl with 7-11 C atoms, and their physiologically acceptable salts

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to new intermediate compounds and an improved method of producing compounds that inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular L-735524, or their pharmaceutically acceptable salts

The invention relates to new N-substituted azabicycloalkanes

The invention relates to new derivatives of hydroxamic acids, possessing valuable pharmacological properties, in particular showing the properties of an inhibitor of collagenase, which can be used to delay the development or prevention of diseases of degeneration of the joints, such as rheumatoid arthritis or osteoarthritis, or in the treatment of invasive tumors, atherosclerosis or multiple sclerosis, as well as the way they are received, intermediate products for their production, pharmaceutical preparation and method thereof

The invention relates to a new compound N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl methyl)-1H-indol-3-yl] ethylamine sulphate salt (2:1) structural formula I and its pharmaceutically acceptable hydrate

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a method for indole derivatives of General formula I, where F denotes a straight or branched C1-C4-alkylenes chain; R is a group of formula-CH2-CHR1-NR2R3where R1hydrogen; R2and R3the same and mean C1-C6-alkyl

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain
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