Derivatives of piperidine

 

(57) Abstract:

Usage: in medicine as a neuroprotective funds. The inventive products: derivatives of piperidine f-ly I, where A and B are taken together to represent-CH2CH2or A and B taken separately and each is H, X is CH2or O, X1Is H or OH, Z is H, F, Cl or OH, Z1Is H, F, Cl, Br or /C1-C3/alkyl, n is 0 or 1, m -0,1 or 2. Reagent: connection f-crystals 2, where all substituents have the meanings as defined for compounds I. Reagent 2: reducing agent, for example, Na, BH4or LiAlH4. Reaction conditions: inert solvent at minus 15 to plus 15oC. 3 C. and 14 C.p. f-crystals, 1 table.

The present invention relates to a neuroprotective (anti-ischemic and blocking the stimulation of amino acid receptor) derived 3-piperidino-1-chromanol and their analogues, vpisivaushiesya the following formula (1), their pharmaceutically acceptable salts, use of these compounds in the treatment of seizures or degenerative diseases of the Central nervous system such as Alzheimer's disease, Huntington's disease and Parkinson's disease, and to some of the intermediates of these compounds.

Ifenprodil represents racemize is as antihypertensives, and their properties is on a par with a number of close analogues (Carron, U.S. patent 3 509 164; Carron, Drug Res. 1971, vol. 21, p. 1992-1999). Recently it was shown that ifenprodil has anti-ischemic activity and the ability to block the stimulation of amino acid receptor (Gotti and T. Pharm. Exp. Therap. 1988, vol. 247, p. 1211-21; Carter, 1988, p. 1222-32; Cm. this plan also published European application 322361 and French patent 2546166). The present invention was to find compounds that would have the same high neuroprotective activity, and at the same time did not exert any significant or had a lower hypotensive effect.

In the literature there is evidence that some similar in structure 1-phenyl-3-/4-aryl-4-acrocephalidae/-1-propanol can also be used as analgesics (U.S. patent 3294804) and 1-[4-amino - and hydroxyalkyl/phenyl]-2-/4-hydroxy-4-callipering/-1-alkanols possess hypotensive, analgesic, psychotropic or anti-inflammatory activity Japanes Kokai 53-02474 (CA 89: 43498y; Derwent Abs. 14858A) and 53-59675 (CA 89:146938w; Derwent Abs. 48671A).

Used in this description of the item, usually described Rigaudy IUPAC Nomenclature of Organic Chemistry, 1979 Edition, Pergammon Press, new York. Chromane also called 3R>,

in which A and B together denote-CH2CH2or A and B mean each H;

X is CH2or O;

X1H or OH;

Z is H, F, Cl, Br or OH;

Z1H, F, Cl, Br or /C1-C3/-alkyl;

n is 0 or 1, and m denotes an integer equal 1-6, as well as their pharmaceutically acceptable salts.

From the viewpoint of the ease of obtaining and biological activity are preferred those compounds of formula (I) in which A and B denote each a hydrogen atom, Z denotes H, F, Cl or OH; Z1-H, and m is 0,1 or 2. If X is 0 and n is 1, the most preferred compounds are cisterciacka formula:

< / BR>
In particular, compounds in which Z denotes OH and which are substituted in the 7-position with romanovas ring system. The most preferred compounds of formula (Ia) are those in which m is 0 or 2. If X is CH2and n is 1, the most preferred are compounds vpisivaushiesya transderivational formula:

< / BR>
In particular, compounds in which Z denotes OH and which are substituted in the 6-position of the 1,2,3,4-tetrahydronaphthalene ring system. The most preferred compounds of formula (Ib) are those of n in which X is CH2X1OH X OH, and which are substituted in the 5-position with indianboy ring system, and m have equal 0.

The object of the present invention are intermediate compounds of the formula:

,

in which A and B, X, X1, Z1, m and n have the above definitions;

G and J are taken together mean an oxygen atom (forming a carbonyl group) or G and J are taken separately and G means H, and J hydroxyl group;

Z3H, F, Cl, Br or or;

R permutes H or a conventional protective group for a hydroxy-group, provided that when G and H are taken individually, Z3means OR1and R1conventional protective group for a hydroxy-group, as well as the intermediate compounds of formula:

,

in which all substituents are the above definition.

The object of the present invention are hereinafter pharmaceutical composition containing the compound of formula (I), as well as a method of treatment of seizures or degenerative diseases of the Central nervous system compound of formula (I).

Under the above expression "pharmaceutically acceptable salt" in all cases, without exception, refers to conventional acid additive salt. Thus, the compounds of formulas which do include, but however, the range of possible salts is not limited to, salts with HCl, HBr, HNO3H2SO4H3PO4CH3SO3H, n-CH3C6H4SO3H, CH3CO2H, gluconic, tartaric, maleic and succinic acids. You usually get these conventional methods, for example, by mixing the compounds of formula (I) with at least one molar equivalent of acid in the environment of a suitable solvent. The compounds of formula (I) containing a phenolic oxygraph, also capable of forming cationic salts (e.g. sodium, potassium, etc.,), and therefore the expression "pharmaceutically acceptable salts" are covered and salts of this type. These salts can also be obtained by conventional means, for example, by reacting a phenolic compound of the formula (I) with one molar equivalent of NaOH or KOH in an environment suitable solvent.

As already mentioned, obtaining possessing pharmacological activity of the compounds of formula (I) in accordance with the present invention does not cause any difficulties.

In that case, if the compound of formula (I) Z denotes OH, the immediate predecessor it is an appropriate compound of the above formula (II), in which G and Nicou protective group for actigraphy. This protective group is removed at the last stage by conventional methods. These groups are preferably protected, translating connection in the usual simple Silovye esters, i.e., R means, for example, triisopropylsilyl or tributylammonium. The preferred method deletes such silyl groups is the treatment of compound 1-1,1 molar equivalents of tetrabutylammonium fluoride in an inert in the reaction conditions solvent, such as tetrahydrofuran. The reaction is usually carried out at a temperature of about 0-50oC, preferably at ambient temperature, in order to avoid the cost of heating or cooling of the reaction mixture.

As in the previous paragraph and elsewhere in the future, under the expression "inert under the reaction conditions solvent" refers to any solvent which does not react with the starting materials, reagents, intermediate compounds or products having any negative influence on the yield of the target product.

The compounds of formula (I) in which Z is other than OH, a value, and the intermediate compounds of formula (II) in which Z3means a protective group for actigraphy, as is Tate which usually produces a mixture of CIS - and TRANS-isomers, for example, respectively:

< / BR>
Of course, in some cases in the mixture will be dominated by one or the other of these CIS - and TRANS-isomers.

These reactions hydride recovery is carried out using conventional hydrides-reducing agents, for example, NaBH4or LiAlH4. The last of these hydrides is usually taken in excess (e.g., mol per mole). The reaction is carried out in an inert solvent, e.g. tetrahydrofuran, at low temperatures (e.g.,- 15-15oC). Alternatively the intermediate ketones, in particular containing complex ester group, restore using softer hydride reducing agent, for example, NaBH4, which is also typically taken in excess. The reaction in this case is carried out in the environment of the proton solvent, for example methanol or ethanol, at a somewhat elevated temperature, for example, when 15-45oC. All protective groups still remaining after recovery of the ketone, then remove the above-described method.

The above intermediate compounds of type (A) are usually obtained by reacting the corresponding monobromide compounds with substituted accordingly with the amine by the reaction of:2CH3). This reaction is carried out under the conditions customary for reactions of nucleophilic substitution. If both of the reagent at about the same distance, you can take in approximately molar equivalent ratio. If one of them more affordable, it is usually desirable to take in excess, in order to complete this bimolecular reaction in a shorter period of time. The reaction is usually carried out in the presence of at least one molar equivalent of base is usually, if it is readily available, the derivative of piperidine more often, however, the tertiary amine is at least comparable in strength of the base used with the nucleophilic piperidine, and inert in the reaction conditions solvent, for example ethanol. If desired, to accelerate the reaction, to the reaction mixture as a catalyst to one molar equivalent or more Sol iodine (such as NaI or KI). Temperature is not significant, however it is usually a little boost to make the reaction was completed in a shorter period of time. However, it should not be so high that occurred n titelnoj is the boiling temperature of the reaction mixture.

The above-mentioned periods of compounds of type (B) are usually obtained by reacting the corresponding alpha, alpha-dibromo-substituted compound with an appropriately substituted amine according to the reaction:

< / BR>
Except that the base charge in at least one molar equivalent of more (to neutralize the HBr formed in the competitive reaction of dehydrohalogenation), other reaction conditions similar to the above when describing obtain compounds of type (A) by the reaction of nucleophilic substitution.

The compounds of formula (I) contains two asymmetric carbon atoms, in accordance with what has two racemate and four optically active compounds. One of these racemates is above CIS-and other - transisomer. Each of these racemates by adding diastereoisomeric acid additive salts with optically active acid can be divided into a pair of enantiomers. Another option for this purpose racemic alcohol is transferred to the appropriate diastereoisomeric esters or urethanes using as starting material an optically active acid or isocyanate. Such derived from the covalent link to nomernye esters derived from alcohol and an optically active acid by standard methods, usually involving activation of the acid, for example, by transferring it to the acid chloride or mixed anhydride with alkylphosphonate or dehydrating combining reagent, for example, dicyclohexylcarbodiimide. After the separation of the thus obtained diastereoisomeric esters, for example, by chromatographic methods, hydrolyzing them in the usual ways, for example, an aqueous solution of acid or base, receiving the enantiomeric, optically active alcohol of formula (1). In the applicant's intention is not to present application is limited to the following specific examples of racemic CIS - and Transmediale.

Starting materials and reagents required for the synthesis of compounds in accordance with the present invention, are readily available; they are produced by the industry or can be obtained are described in the literature or below as examples of methods.

The inventive compounds of the above formula (1) have a selective neuroprotective activity, based on their anti-ischemic activity and the ability to block the stimulating amino acid receptors. At the same time they do not have substantially the of soedinenii in accordance with the present invention was determined by one or more of the previously described Gotti, Carter (see above) or similar methods. The ability of compounds in accordance with the present invention to block the stimulating amino acid receptors shown, for example, blocking or induced by N-methyl-D-aspartic acid (NMDA) increase of cGMP in the cerebellum of newborn rats by the following method. Dissected quickly the cerebellum ten 8-14-day-old rats of the Wistar breed and put them in 4oC in Krebs (bicarbonate buffer with a pH of 7.4, and then cut into pieces 0,h,5 mm using a knife for preparative processing of fabrics McIlvain /The Nickle Laboratory Engineering Co. Gomshall, Surrey, England). Thus prepared slices of cerebellum was transferred into a 100 ml Krebs (bicarbonate buffer at 37oC, through which continuously missed a mixture of O2and CO2in the ratio 95:5. Pieces of the buffer was kept in these conditions for 90 min, three times during this time changing the buffer, then the buffer decantation, and the fabric was separated by centrifugation (1 min, 3200 rpm) and re-suspended in 20 ml of Krebs bicarbonate buffer. After that was selected aliquot of sample 250 ál (approximately 2 mg) and placed them in microcentrifuge tubes 1.5 ml tubes were added 10 μl of the test compounds from the initial solution and after in what amounted to 100 μm. The tube was kept for one minute at 37oC shake a water bath, and then added to 750 μl of a solution of 50 mm Tris-Cl, 5 mm EDTA to stop the reaction. After that the tube was immediately placed in a boiling water bath and kept at it for 5 minutes the Contents of all tubes were then processed for 15 with ultrasound by the ultrasonic probe at the position of the switch power level "three". Was collected from the tubes of the sample 10 ál and determined in their protein content by the method of Lowry, Anal. Biochem. 100: 201-220,1979. The tubes then were centrifuged (5 min, 10000 xg), samples were taken of the supernatant liquid 100 µl and determined the content of cyclic guanosine monophosphate (cGMP) using radioimmunoassay on cGMP New England Nuclear (Bost on, Mass a chusetts) method suppli er. Data were represented as PM cGMP generated per mg of protein. Unwanted hypotensive activity were also determined by known methods, for example, by the techniques Carron (see above).

Such selective neuroprotective anti-ischemic activity of the compounds in accordance with the present invention and their ability to block the stimulating amino acid receptors talking about the possibility of their use for leg Parkinson's and Huntington's disease, without causing significant harm to excessive reduction of blood pressure. The systematic treatment of such diseases neuroprotective amount of compounds of formula (I), the dosage is from about 0.02 to 10 mg/kg / day (1-500 mg/day) for a typical patient weight of 50 kg, in single or divided into several doses dose, regardless of the method of introduction. Of course, depending on the nature of the connection and a specific disease, the doctor may prescribe a dose beyond the specified interval. It is preferable to oral route of administration of drugs. However, if the patient is unable to swallow, or the oral intake is undesirable for some reason, is preferably parenteral administration (intramuscular, intravenous or topical application.

Compounds in accordance with the present invention is generally introduced in the form of pharmaceutical compositions comprising at least one compound of formula (1) in combination with a pharmaceutically acceptable carrier or diluent. Such compositions typically receive conventional methods using solid or liquid carriers or diluents, depending on the route of administration (for parenteral administration in the form of solutions or suspensions for injection, etc. for local application in the form of solutions, lotions, ointments, balms, etc).

The following examples illustrate the present invention. Last but is not limited to the details of these examples.

All reactions in nonaqueous media to avoid complications and to increase the yield was carried out in nitrogen atmosphere. All solvents and thinners were dried according to published standard methods or purchased already dried. All of the reaction mixture in the reaction stirred magnetic or mechanical stirrer.

Yarm-spectra were filmed at 300 MHz. The obtained data are given in M. D. as a solvent when removing the YOKES spectra, unless otherwise indicated, used CDCl3. Data obtained by removing the IR spectra are given in cm-1. As a rule, were recorded only strong signals. Used abbreviations: DMF dimethylformamide, THF is tetrahydrofuran, HRMS mass spectrometry high resolution.

Example 1. 3-/4-Hydroxy-4-phenylpiperidine/-7-/triisopropylsilane/chromen - 4-one.

3,3-dibromo-7-/triisopropylsilane/-4-chromanone /5.0 g, 10.5 mmole/ was dissolved in CH3CN /150 ml and was added to the obtained solution of 4-hydroxy-4-penile is ment environment then concentrated and the residue was distributed between ethyl acetate and water. The organic layer was washed with water (250 ml) and brine, dried over CaSO4concentrated and the residue was subjected to chromatographic separation with a gradient elution with a mixture of ethyl acetate and hexane, obtaining the target product as a white solid (2.3 g, 54%). Part of the obtained product was recrystallized from a mixture of ethanol and ethyl ether. Melting point 163-163,5oC; IR (KBr) 3437, 2950, 2870, 1635, 1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690.

The results of the analysis based on the formula C29H39NO4Si.

Calculated C, 70,55; H, Of 7.96; N, 2,84.

Found C, 70,44; H, 7,76; N, 2,84.

Subsequent fractions in the process of chromatographic separation were additionally 0,61 g of the product, namely 7-hydroxy-3-/4-Oki-4-phenylpiperidine/chromen-4-it, resulting from desirelove in the reaction. This connection can also be used as intermediate compounds in obtaining these products similar methods.

Example 2. CIS - and TRANS-3-/4-hydroxy-4-phenylpiperidine/-7- /triisopropylsilane/-4-chromanol.

The target product of the preds is (1.5 g, 39.7 mmole). The mixture was stirred over night at room temperature, and then thereto was added another portion of NaBH4(0.75 g, to 19.9 mmole) and continued stirring for another 5 hours and Then the reaction was stopped by adding to the mixture an excess of water, the mixture was concentrated and the residue was distributed between ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4and concentrated, resulting in the solid yellowish color, which was recrystallized from a mixture of ethyl ether and hexane. The result was obtained 1.0 g (50%) of the target product (CIS-form) in the form of a white solid. Melting point 145,5-146,5oC. IR (KBr): 3380, 2940, 2860, 1615, 1280, 1173, 1040.

The results of the analysis based on the formula C29H43NO4Si.

Calculated C, 69,98; H, 8,71; N 2,81.

Found C, 70,02; H, 8,58; N 2,81.

After chromatography on silica gel obtained by recrystallization of the filtrate with gradient elution with a mixture of ethyl acetate and hexane were obtained 70 mg of the target product (conforme) and 0.27 g (14% ) solid yellow color, which, as shown by the data of NMR spectroscopy, was a mixture of TRANS - and ziprasido synthesis transforms.

13C-NMR (TRANS) 156,7, 154,5, 148,2, 128,8, 128,4, 127,2, 117,2, 113,4, 107,2, 71,4, 64,8, 64,1, 63,4, 48,4, 43,0, 39,0, 17,9, 12,7. HRMS: calculated for MH+: 498,3041; received: 498,3011.

Example 3. CIS-3-/4-hydroxy-4-phenylpiperidine/-4,7-chromanol.

To a solution of conformi target compound from the previous example (0,94 g, 1.89 mmole) in THF was added a IM solution of tetrabutylammonium fluoride in THF (1,95 ml of 1.95 mmole). The resulting solution was stirred at ambient temperature for 1.5 h, then concentrated and subjected to chromatographic separation on silica gel with gradient elution with a mixture of ethyl acetate and hexane. The result has been the target product (0,72 g) which was recrystallized from a mixture of ethanol and ethyl ether, receiving of 0.54 g (84%) of white solids. The melting point of which is 171,5-172,5oC.

The results of the analysis based on the formula C20H23NO40,25 H2O.

Calculated C, 69,45; H, At 6.84; N, Of 4.05.

Found C, 69,26; H, 6,79; N, 3.96 Points.

Example 4. TRANS-3-/4-hydroxy-4-phenylpiperidine/-4,7-chromanol.

In the same way as in the previous example, the target product (transform) example 2 (0.27 g, 0.54 mmole) containing 15% of cisisomer translated in the crude product (0.17 g) in the form m%) of the target product in accordance with this example in the form of a white solid. The melting point of 192.5 kg-193oC.

The results of the analysis based on 2 formula C20H23No4.

Calculated C, 70,36; H, 6,79; N, 4,10.

Found C, 70,06; H, To 6.88; N, Android 4.04.

Example 5. 3-/4-Hydroxy-4-phenylpiperidine/-7-/triisopropylsilane/-4-chromanone.

7-/triisopropylsilane/-4-chromeno (2.0 g, 6.2 mmole) was dissolved in CCl4(45 ml) and was added to the resulting solution was dropwise at ambient temperature a solution of bromine (0.3 ml, 6.4 mmole) in CCl4(5 ml) for 10 minutes at the Beginning of the reaction mixture became dark red, but after stirring for 10 minutes the color was changed to yellow. This yellow solution was washed with diluted, and then a saturated solution of NaHCO3and brine, dried by filtration through patristically paper and concentrated, resulting in the oily brown liquid, which according to NMR data was a mixture of 3-bromo-7-/triisopropylsilane/-4-chromanone, 3,3-dibromo-7-/triisopropylsilane/-4-chromanone and source material in a ratio of 2.5:1:1. This mixture (2.3 g, 5.5 mmole) was mixed with 4-hydroxy-4-phenylpiperidine (1.0 g, 5.8 mmole), triethylamine (0.9 ml, 6.5 mmole) and ethanol (50 ml). The reaction mixture kipda with ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4and the residue was subjected to chromatographic separation on silica gel with gradient elution with a mixture of ethyl acetate and hexane. As a result received 80 mg (3%) of target compound as a yellow solid. Melting point 132-132,5oC.

Example 6. CIS-3-/4-hydroxy-4-phenylpiperidine/-4,7-chromanol.

The target product from the previous example (80 mg, 0.16 mmole) was dissolved in ethanol (10 ml) and was added to the obtained solution of NaBH4(7 mg, 0.2 mmole). The mixture was stirred at ambient temperature for 6 h, after which the reaction was stopped by adding water and the mixture was concentrated. The residue was distributed between ethyl acetate and water. The organic layer was washed with water and brine, dried over CaSO4and concentrated, resulting in the crude product (conforme) in accordance with example 4 in the form of an oily liquid yellow (50 mg, 63%). The obtained product was subjected to desilicious in the same manner as described in example 3, resulting in the compound (15 mg, 44%), identical to the product in accordance with example 3.

Examples 7-13.

In the same way as described in the derived piperidine, received in addition, the following compounds (with the specified outputs, and properties):

7. 3-/4-benzyl-4-oxopiperidine/-7-/triisopropylsilane/ chromen-4-one; 34% melting point 115-116oC (after recrystallization from a mixture of ethyl ether and hexane);

8. 3-/4-phenylpiperidine/-7-/triisopropylsilane/chromen-4-one; melting point 99-100oC (after recrystallization from a mixture of ethyl ether and hexane);

9. 3-/4-benzylpiperidine/-7-/triisopropylsilane/chromen-4-one; 38% oily liquid;13C-NMR: 160,7, 157,2, 143,6, 140,5, 137,0,129,2, 128,2, 127,6, 125,8, 118,4, 106,7, 50,7, 43,3, 37,8, 32,1, 17,8, 12,3;

10. 3-[4-hydroxy-4-/2-phenylethyl/piperidine]-7- /triisopropylsilane/chromen-4-one; 2% oily liquid; 13C-NMR: 174,7, 160,9, 157,4, 144,3, 142,3, 136,8, 128,5, 128,3, 127,6, 125,9, 118,7, 106,8, 69,5, 46,3, 45,0, 36,8, 29,3, 17,9 12,7;

11. 6-chloro-3-/4-hydroxy-4-phenylpiperidine/-chromen-4-one; 40% melting point 191,5-192oC (after recrystallization from a mixture of CHCl3and ethyl ether);

12. 6-fluoro-3-/4-hydroxy-4-phenylpiperidine/-chromen-4-one; 40% melting point 183,5-184oC (after recrystallization from a mixture of CHCl3and ethyl ether);

13. 3-/4-hydroxy-4-phenylpiperidine/chroman-4-one; 85% of the melting temperature 168-168,5oC (after recrystallization from a mixture of atnesa as source material products in accordance with examples 7-13, received the following compounds (with the specified outputs, and properties);

14. CIS-3-/4-benzyl-4-oxopiperidine/-7-/triisopropylsilane/ -4-chromanol; 29% melting point 172,0-172,5oC (after recrystallization from a mixture of ethanol and ethyl ether) and the mixture (in the ratio 2:1) CIS - and TRANS-isomers 3-/4-benzyl-4-oxopiperidine/-7-/triisopropoxide/-4-chromanol /40% /, which can be divided into CIS - and TRANS-isomers using column chromatography;

15. CIS-3-/4-phenylpiperidine/-7-/triisopropylsilane/-4 - chromanol; 69% melting point 148-148,5oC (after recrystallization from a mixture of ethanol and ethyl ether);

16. CIS-3-/4-benzoylpiperidine/-7-/triisopropylsilane/-4 - chromanol; 55% oily liquid;13C-NMR: 157,2, 154,8, 140,4, 131,7 129,1, 128,2, 125,9, 115,3, 113,4, 107,1, 62,3, 61,7, 60,8, 51,5, 49,3, 43,1, 37,8, 32,3, 32,2 17,9, 12,7;

17. CIS-3-[4-hydroxy-4-/2-phenylethyl/piperidine]-7- /triisopropylsilane/-4-chromanol; 25% white solid;

18. CIS-6-chloro-3-/4-hydroxy-4-phenylpiperidine/-4-chromanol; 16% melting point 185-185,5oC (after recrystallization from a mixture of ethanol and ethyl ether and the mixture of CIS - and TRANS-isomers in the ratio 3:2 (37%), odorou can be separated into individual isomers by chromatography;

19. CIS-6-fluoro-3-the ethanol and ethyl ether and the mixture of CIS - and TRANS-isomers in the ratio 2:1 (28%), from which, by fractional crystallization received 80% of the net transisomer, melting point 164-168oC (total yield 4%);

20. CIS-3-/4-hydroxy-4-phenylpiperidine/-4-chromanol; 58% melting point 187,5-188oC (after recrystallization from a mixture of ethanol and ethyl ether); obtained by crystallization from the mother liquor mixture of CIS - and TRANS-isomers in the ratio 1:3; 3% melting point 170-174oC.

Examples 21-24.

In the same manner as described in example 3, using as source material the products obtained in accordance with examples 7-10 were obtained the following compounds (with the specified outputs, and properties):

21. CIS-3-/4/benzyl-4-oxopiperidine/-4,7-chromanol; 85% melting point 181-182oC (after recrystallization from a mixture of ethanol and ethyl ether);

22. CIS-3-/4-phenylpiperidine/-4,7-chromanol; 67% melting point 195,0-195,5oC (with decomposition) after recrystallization from a mixture of ethanol and ethyl ether);

23. CIS-3-/4-benzylpiperidine/-4,7-chromanol; 31% melting point 164,6-165,0oC (after recrystallization from a mixture of ethanol and ethyl ether);

24. CIS-3-[4-hydroxy-4-/2-futility/piperidino]-4,7-chromanol; 54% temperat the same way as described in example 1, using as starting material 2-bromo-6-methoxytyramine (2.8 g, 11.5 mmole), 4-hydroxy-4-phenylpiperidine (2.5 g, a 14.1 mmole) and triethylamine (4,0 ml, or 28.7 mmole), by stirring the mixture overnight in acetonitrile (75 ml) was received by the target connection. The concentrated product was subjected to chromatographic separation on silica gel with gradient elution with a mixture of ethyl acetate and hexane. The result has been to 1.33 g (33%) of target compound. The melting point of 149.5-150,5oC (after recrystallization from a mixture of ethanol and ethyl ether).

Example 26. CIS - and TRANS-1,2,3,4-tetrahydro-2-/4-hydroxy-4-phenylpiperidine/-6 - methoxy-1-naphthol.

In the same manner as described in example 2, the target product of the preceding example (1.0 g, to 2.85 mmole) were transferred into the target compounds in accordance with this example. The separation was performed using chromatography on silica gel (using a gradient elution with a mixture of ethyl acetate and hexane), and then the products obtained was recrystallized from a mixture of ethanol and ethyl ether.

Transisomer: 0,13 g (13%), more polar; melting point 155-155,5oC.

Cisisomer: 0,033 g (3% ), less polyamidimide 25, appropriately substituted 2-bromo-1-tetralone translated in the following connections:

27. 2-/4-hydroxy-4-phenylpiperidine/-1-tetralone; 21% melting point 148-151oC (Razlog.) ( after recrystallization from a mixture of ethanol and ethyl ether);

28. 2-/4-hydroxy-4-phenylpiperidine/-6-/triisopropylsilane/-1 - tetralone; the melting point of 151-153oC (after recrystallization from a mixture of ethanol and ethyl ether); 36%

Example 29. TRANS-1,2,3,4-tetrahydro-2-/4-hydroxy-4-phenylpiperidine/-1-naphthol.

In the same manner as described in example 26, the product in accordance with example 27 were transferred to the target connection. Output: 5% melting point 184-184,5oC.

Example 30. TRANS-1,2,3,4-tetrahydro-2-/4-hydroxy-4-phenylpiperidine/-6-/ triisopropylsilane/-1-naphthol.

The product in accordance with example 28 (0.75 g, of 1.61 mmole) in solution in tetrahydrofuran (25 ml) was added dropwise over 10 min to a stirred suspension of LiAlH4(0,065 g, 1,71 mmole) in tetrahydrofuran (75 ml). The resulting gray-green mixture was stirred for 30 min at ambient temperature, after which the reaction was stopped by adding to the mixture an excess of Na2SO410H2O. After stirring for 15 mimeographing separation on silica gel by gradient elution with a mixture of ethyl acetate and hexane. The result was obtained 0.45 g (60%) of target compound. Melting point 171,0-which is 171,5oC (after recrystallization from a mixture of ethanol and ethyl ether).

Example 31. TRANS-1,2,3,4-tetrahydro-2-/4-hydroxy-4-phenylpiperidine/-1,6 - naphthalenediol.

In the same manner as described in example 3, the product in accordance with example 30 (0.35 g, 0.75 mmole) was transferred into the target connection. Yield: 0.12 g (46%); melting point 181-183oC (after recrystallization from a mixture of ethanol and ethyl ether); IR (KBr): 3380, 3230, 2950, 2850, 1610, 1495, 1240, 1110, 1045, 7706 705.

Example 32. 5-/Triisopropylsilane/-2-/4-hydroxy-4-phenyl-piperidino/- 1-indanone.

In the same manner as described in example 1, 2-bromo-5- /triisopropylsilane/-1-indanone translated in the target connection. Yield: 41% (in the form of a foamy solid product):13C-NMR: 203,3, 163,2, 154,9, 148,1, 129,8, 128,5 128,4, 127,0, 125,9, 124,5, 120,5, 116,7, 71,0, 69,4, 46,2, 44,5, 42,0, 38,2, 37,3, 27,3, 18,0 12,7.

Example 33. CIS - and TRANS-5-/triisopropylsilane/-2-/4-hydroxy-4 - phenylpiperidine/-1-indanol.

In the same manner as described in example 2, the target product from the previous example is translated into the target compounds in accordance with this example, which was separated by chromatography on sealed 27% melting point 169, 5mm-170oC (after recrystallization from a mixture of ethyl ether and hexane); IR (KBr): 3467, 2959, 2894, 2867, 1610, 1490, 1294, 1138, 964, 883, 698.

Transisomer: exit 43% melting point 143-144oC; IR (KBr): 3321, 2945, 2867, 1613, 1490, 1465, 1291, 1265, 1135, 966, 702, 681.

Examples 34-35.

In the same manner as described in example 3, the target product from the previous example is translated to

34. CIS-2-/4-hydroxy-4-phenylpiperidine/-1,5 - indanyl; 54% melting point 212,5-213,5oC;13C-NMR: 157,7, 150,2, 143,3, 134,8, 127,9, 126,2, 126,1, 124,8, 113,5, 111,2, 71,5, 69,7, 69,6, 47,8, 47,1 38,0, 37,9, 34,2;

35. TRANS-2-/4-hydroxy-4-phenylpiperidine/-1,5-indanyl; 71% melting point 196,0-197,0oC;13C-NMR: 157,1, 150,3, 140,8, 135,6, 127,8, 126,1, 124,9, 124,8, 113,8, 110,7, 76,7, 75,2, 69,7, 47,3, 38,1, 33,9.

Method 1. 7-/Triisopropylsilane/-4-chromanone.

7-hydroxy-4-chromanone (1.2 g, 7.3 mmole; Dann and others Ann. 587, 16, 1954) and imidazole (1.0 g, 14.7 mmole) was dissolved in DMF (10 ml). To the resulting solution was added dropwise over 10 min at ambient temperature the solution triisopropylsilane (1.8 ml, 8.2 mmole) in DMF (2 ml). After stirring for 3 h the mixture was poured into 100 ml of ice water and subjected to extraction with diethyl ether (2100 ml). The combined ether extracts were washed in 1 M LiCl and then brine, visus is estce by distillation with ball reflux (0,5 Thor, 70-90oC). This impurity was removed colorless viscous oily liquid, and in the distillation flask remained the product as a brown oily liquid (2.0 g, 85%). IR (KBr) 2945, 2867, 1685, 1605, 1268, 1163. HRMS: calculated for MN+: 320, 1807, received: 320, 1842.

Method 2. 3,3-Dibromo-7-/triisopropylsilane/-4-chromanone.

The target product of the previous techniques (7,1 g, 22,1 mmole) was dissolved in carbon tetrachloride (170 ml) and was added to the resulting solution at ambient temperature is added dropwise over 20 min a solution of bromine (2.5 ml, 48.5 mmole) in CCl4(30 ml). The reaction mixture was stirred for 0.5 hours to obtain a dark red solution, which is then successively washed with diluted aqueous NaHCO3(100 ml), a saturated solution of NaHCO3(275 ml) and brine (100 ml), dried by filtration through patristically paper and concentrated to obtain a dark orange oily liquid (9,9 g, 94%).

13C-NMR: 179,0, 164,3, 161,9, 131,3, 116,6, 109,9, 107,5, 78,0, 60,9, 17,8, 12,7. HRMS: calculated for MH+: 479,0076; received: 479,0066.

Methods 3-5.

In the same way as described in the previous method, using as starting material the appropriate of melting point 128-129oC (after recrystallization from a mixture of ethanol and diethyl ether); IR (KBr): 3060, 2930, 1710, 1475, 1137, 838;

4. 3,3-dibromo-6-fluoro-4-chromanone; 70% of the melting point 90-91oC (after recrystallization from a mixture of diethyl ether and hexane); IR (KBr): 3380, 3080, 1705, 1690, 1485, 1275, 1235, 1170, 1127, 850, 727;

5. 3,3-dibromo-4-chromanone; 90% of the melting point of 67-68oC (after recrystallization from a mixture of diethyl ether and hexane); IR (KBr): 3380, 1705, 1610, 1480, 1300, 818.

Methodology 6. 2-Bromo-6-methoxytyramine.

6-methoxytyramine (2.0 g, 11.4 mmole) and bromine (0.6 ml, an 11.7 mmole) was boiled for 30 min in diethyl ether (50 ml) under reflux. The reaction mixture was then cooled, concentrated and the residue was distributed between ethyl acetate and diluted aqueous NaHCO3. The organic layer was washed with saturated solution of NaHCO3and water, dried over CaSO4and concentrated to obtain oily liquid (2.83 g, 100%);1H-NMR: 8,03 /d, J 9.0 Hz, 1H/, 6,84 /LW. d J1=9,0 Hz, J2=2.7 Hz, 1H/, 6,69/d, J=2.3 Hz, 1H/, 4,66 /t, J=4,1 Hz, 1H/, 3,84 /c, 3H/, 3,20-3,30 /m 1H/, 2,82-2,90 /m 1H/, 2,34-2,50 /m, 2N/.

Methodology 7. 2-Brotherhood.

In the same way as in the previous method, the tetralone (2.0 g, 13.7 mmole) was transferred into the target compound (236 /m, 1H/, 2,92-2,97 /m 1H/, 2,40-2,58 /m, 2N/.

Methodology 8. 1-/Benzyloxycarbonyl/-4-hydroxy-4-/2-phenylethyl/piperidine.

Shavings of magnesium (1.7 g, 70.0 mmol) suspended in diethyl ether (10 ml) and was added to the resulting suspension is added dropwise a solution /2-bromacil/benzene (11.8 g, 63,8 mmole) in diethyl ether (15 ml), slowly at first, before the beginning of the reaction, and then faster, to provide heat. After heating the reaction mixture over night at 60oC it was cooled to 0oC, diluted with diethyl ether (200 ml) was added thereto dropwise a solution of piperidinylcarbonyl (14.9 g, 62.9 mmole) in diethyl ether (100 ml). It was becoming a white precipitate, and the mixture was intensively stirred at room temperature for 8 h, after which the reaction was stopped by adding water and continued stirring for another hour. The aqueous layer was then separated, subjected to extraction with ethyl acetate (3100 ml), the organic layers were combined, washed with brine, dried on CaSO4and concentrated, resulting in the transparent oily liquid. Pure product was obtained by chromatography on silica gel (25% ethyl acetate/hexane), which was a transparent oily liquid (9,2 g, 43%). IR (CHCl3

IR /CHCl3/: 3539, 2930, 1715, 1620, 1600, 1452, 1372, 1351, 1322, 1042.

The method 10. 6-/Triisopropylsilane/-1-tetralone.

In the same way as described in method 1, 6-hydroxy - 1-tetralone (5.0 g, 30,83 mmole; Durden, J. Agr. Food Chem. so 19, page 432, 1971) translated into the target compound in the form of oily liquid (after purification by distillation with ball reflux). IR /CHCl3/: 2937, 2889, 2862, 1666, 1593, 1349, 1333, 1319, 1274, 1226, 1109, 969, 898.

Technique 11. 2-Bromo-7-/triisopropylsilane/-1-tetralone.

In the same way as described in method 6, the target product of the previous techniques (8,3 g of 26.1 mmole) were transferred to the target connection in accordance with this methodology (9.7 g, 94%), which according to the1H-NMR contained, in addition, some amount of 2,2-dibromo-derivative. The resulting product be the-indanone.

In the same way as described in method 1, 5-hydroxy-1-indanone translated into the target compound with a 100% output. Melting point 63,0-63,5oC.

Methodology 13. 2-Bromo-5-/triisopropylsilane/-1-indanone.

In the same way as described in method 6, the target product of the previous techniques were transferred to the target connection in accordance with this method, contaminated corresponding dibromo product. Output 100%1H-NMR: 7,72 /l, 1H/, 6,89 /LW. d, 1H/, 6,83 /m 1H/, 4,62 /LW.D. 1H/, 3,74 /LW. d, 1H/, 3,34 /LW. d, 1H/, 1,22-1,34 /MB 3H/, 1,10 /A. N/. The product received without further purification directly used at a later stage of the synthesis (see example 32).

Example 36. CIS-3-(4-hydroxy-4-phenylpiperidine)-7-(triisopropylsilyl)- 4-chromanol.

N-tert-butoxycarbonyl-d-alanine (0,190 g, 1,004 of millimole) and carbonyldiimidazole (0,165 g, 1,018 of millimole) was dissolved in methylene chloride (8 ml) and stirred for 1 h at room temperature. Added coproduct example 2 (0,250 g, 0,50 millimole), and the resulting mixture stirred overnight. The reaction product was concentrated, and the residue was distributed between ethyl acetate and water. The organic phase was washed with water and saline solution(h inches /may be 25 x 200 mm), gradient elution with a mixture (diethyl ether/methylene chloride) gave the first stereoisomer in the form of a foamy white solid (0,115 g). This substance was precrystallization from a mixture of diethyl ether/petroleum ether, giving a powdery white solid (88 mg, 26%), the melting point of 152.5-153oC.1H NMR /CDCl3/ 7,46 /A. J 7,3 Hz, 2H/, 7,34 /so J 7.4 Hz, 2H/, 7,22-7,27 /m 1H/, 7,15 /Shir.D. J 8,2 Hz, 1H/, 6.42 per /DD. J 8.1 Hz, J 2.6 Hz, 1H/, 6,34 /A. J 2.2 Hz, 1H/, 6,18 /Shir.with. 1H/, 5,12 /A. J 6.5 Hz, 1H/, 4,30 was 4.42 /m 2N/, 4,18 /so J of 10.9 Hz, 1H/, 2,88-2,94 /m 2N/, 2,61-2,83 /m 3N/, 2,02 /square D. J 12.1 Hz, J 4,2 Hz, 2H/, 1,71-1,79 /m 2N/, 1,53 /C. 1H/, 1,35-1,42 /m N/, 1,10-1,31 /m 3N/, 1,07 /A. J 6.9 Hz, N/.

Analysis. Calculated for C37H56N2O7Si: C: 66,43, H: 8,44, N: 4,19.

Found: C: 66,14, H:8,66, N 4,18. /alpha/D-112,3oC 1,020 in chloroform.

Later fractions from the chromatography gave the second stereoisomer in the form of a foamy white solid (of 0.133 g). This substance was precrystallization from a mixture of ethyl ether/petroleum ether, giving a powdery white solid (73 mg, 22%), melting point 146-147,5oC.

1H NMR /CDCl3/ 7,51 /A. J 7.9 Hz, 2H/, 7,33 /so J 7.5 Hz, 2H/, 7,14 /A. J 8,2 Hz, 1H/, 6,41 /DD. J 8.1 Hz, J 2.2 Hz, 1H/, 6,34 /A. J 2.3 Hz, 1H/, 6,25 /C. 1H/, 5,03 /A. J 7,/SUB>+by 115.7oC 1,065 in chloroform.

Example 37. Optical active (-)-CIS-3-(4-hydroxy-4-phenylpiperidine)- 4,7-chromanol.

(-)-diastereomeric ester product of the preceding example (0,080 g, 0.12 millimole) was dissolved in 10 ml of 0.32-norms. solution of sodium methoxide (0.15 g Na dissolved in 20 ml of methanol). The mixture is stirred over night at normal temperature and then concentrated. To the residue was added 1 standards. HCl (2 ml) and then saturated NaHCO3(5 ml). The aqueous phase was extracted with ethyl acetate (320 ml). The combined extracts were washed with saline, dried over magnesium sulfate and concentrated, giving a milky oil (39 mg).

The oil was precrystallization from a mixture of absolute ethanol and ethyl ether, giving the product as a cream solid color (17.9 mg, 44% ), melting point 166-168oC (decomp.) /alpha/D-87,6oC 0,25 in methanol. The enantiomeric excess was 98% according to the1H NMR using chiral reagent shift, R-(-)-2,2,2-Cryptor-1-(9 - antrel) ethanol.

Example 38. Optically active (+)-CIS-3-(4-hydroxy-4-phenylpiperidine)- 4,7-chromanol.

According to the method of the previous example, /+/- diastereomeric ester about logo solids (0,039 g), which was precrystallization from a mixture of ethanol/ether, yielding the purified product specified in the header (16,7 mg) as a cream solid color, melting point 163,5-166oC /alpha/D+76,7oC 0,27 in methanol. Method1H NMR of the previous example, it is determined that the enantiomeric excess was 93%

Neuroprotective test are shown in table.

1. Derivatives of piperidine derivatives of the formula

< / BR>
in which A and B are taken together to represent-CH2CH2or A and B taken separately and each represents H;

X-CH2or O;

X1H or OH;

Z is H, F, Cl or OH;

Z1H, F, Cl, Br or C1-C3-alkyl;

n is 0 or 1;

m is 0, 1 or 2.

2. Connection on p. 1, in which A and B are taken separately; Z is H, F, Cl or OH; Z1H; m is 0, 1 or 2.

3. Connection on p. 2, where X 0 and n 1, having a CIS relative stereochemical formula

< / BR>
4. Connection on p. 3, in which Z is substituted in the 7-position with romanovas ring system and is OH.

5. Connection on p. 4, in which X1OH; and m is 0.

6. Connection on p. 4, in which X1OH; m 2.

7. Connection on p. 4, in which X1H; m is 0.

8. Connection on p. 4, in which X1< formula

< / BR>
10. Connection on p. 9 in which Z is substituted in 6-position tetrahydronaphthalene ring system and represents OH.

11. Connection on p. 10, in which X1OH; and m is 0.

12. Connection on p. 2, in which X is CH2; n 0.

13. Connection on p. 12, in which Z and X1each OH; m is 0, having formula

< / BR>
14. Connection on p. 13, having the relative stereochemical formula

< / BR>
15. Connection on p. 13, having the relative stereochemical formula

< / BR>
16. A derivative of piperidine derivatives of the formula

< / BR>
in which A and B are taken together to represent-CH2CH2or A and B taken separately and each represents H;

G and J are taken together to represent oxygen or G and J are taken separately and G is hydrogen, and J is hydroxy;

X-CH2or O;

X1H or OH;

Z1H, F, Cl, Br or C1C3-alkyl;

Z3H, F, Cl or or;

R hydroxy protecting trialkylsilyl group;

n is 0 or 1;

m is 0, 1 or 2,

provided that when G and J, taken separately, Z3OR, and R is a hydroxy protecting trialkylsilyl group.

17. Derivatives of piperidine derivatives of the formula

< / BR>
in which A and B are taken together to represent-CH2CH2Z3H, F, Cl or or;

R hydroxy protecting trialkylsilyl group;

m is 0, 1 or 2.

 

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