Method for preparation of 4=cycloalkylsubstituted pyridine derivatives or theirs hydrochlorides

专利摘要:
The invention relates to cycloalkyl-substituted 4-pyridyl derivatives of formula (I) <CHEM> wherein R is C1-C4 alkyl; each of R1 and R2 is, independently, hydrogen or C1-C4 alkyl; n is an integer of 1 to 5; and either (a) A is >C=O and B is -O-, -NH- or -CH2-; or (b) A is -CH2- and B is -O-, -NH-, -CH2- or >C=O; or (c) A is -O- and B is >C=O or -CH2-; or (d) A is -NH- and B is >C=O or -CH2-, and their pharmaceutically acceptable salts. The compounds of the invention show aromatase inhibiting activity and can be useful, e.g., in treating hormone-dependent tumors and prostatic hyperplasia.
公开号:SU1639428A3
申请号:SU874203026
申请日:1987-07-17
公开日:1991-03-30
发明作者:Кругнола Анджело；Ди Салле Энрико；Ломбарди Паоло
申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
IPC主号:

专利说明:

This invention relates to pyridine-derived chemistry, in particular, to methods for the preparation of novel 4-cycloalkyl-substituted pyridine of general formula I,
TO
v (sn2)
CHj-CH-A-B J
where R is hydrogen or C -C-alkyl; A is HC-0 or -CHHBNNH4-, -O- or -CH-;
n 3 or 4.
or their hydrochlorides, which are inhibitors of the biosynthesis of estrogens, in particular, aromatherapy inhibitors, and can be used in the treatment and prevention of various tumor diseases.
The purpose of the invention is to create, on the basis of known methods, new pyridine derivatives with valuable pharmacological properties.
The goal is achieved by those compounds of formula II
N
(sn2) l
w2 s-vcg about
where B and n correspond to the specified
values,
subjected to alkylation with methyl iodide in anhydrous tetrahydrofuran medium in the presence of diisopropyl amide lithium to give a compound of the general formula I, where A -, followed, if necessary, by reduction of the carbonyl group at B -NH- or -O- or conversion of the carbonyl group in dithioethanol and reduction in the presence of Rene nickel at B = CH С - to obtain a compound of general formula I, where A is -CHH- and the desired product is isolated in free form or as hydrochloride,
Kp r mime 1. N-Piclohexyl- 2 (4-pyridyl) propanamide fj, A B -NH-,).
To a stirred solution of lithium diisopropylamide (7.6 mmol) in anhydrous tetrahydrofuran (10 ml), add H-cyclohexyl 4-pyridylaceIC (CIIClj): 2975, 2925,
amide (750 mg, 8.45 mmol), dissolved 50 2840, 1710, 1590, 1550. ny in anhydrous tetrahydrofuran Example 2. Bis-hydrochloride
(25 ml), dropwise at -70 ° C in an atmosphere of K-cyclohexyl-2- (4-pyridyl) propylamine nitrogen. After 1 hour additional (I, RH, A -CH-, B -NH), methyl iodide (0.24 ml, 3.8 mmol) dissolved in anhydrous tetrahydrope is added at -7Q ° C. ).
its To a stirred suspension of lithium aluminum hydride (0.4 g) in anhydrous diglyme (10 ml) was added K-cyclohexyl-2- (4-pyridyl) propane-, amide (0.464 g, 2 mmol), obtained,
furan (3 ml). "The reaction mixture was stirred at -70 ° C for 30 minutes, then left to reach

394284
natal temperature. The solvent is evaporated in vacuo, and the residue is distributed between water (25 ml) and ethyl acetate, (30 ml), the organic phase is separated, and the aqueous phase is extracted with ethyl acetate (2 x 25 ml). The combined organic extracts (100 ml) are washed with water, brine, suction over sodium sulfate and evaporated in vacuo. The resulting residue is purified by flash chromatography on a silica gel column, eluting with a chloro-15 form: ethanol 95: 5. 550 mg (yield 69%) of the title compound are obtained as a yellow solid, m.p. 125-126 ° C.
Calculated (found),%: C, 72.37; 20 (72.16); K 8.68 (8.74); N 12.06 (11.98).
NMR (CDC15, 8) 1 1.50 (3N, d); 3.45 (1H, q); 3.75 (1H, m.); 5.20 (1H, tir.s.); 7.25 (2H, double d.); 25 8.57 (2H ,. double d.).
IR (SCS13, cm-): 3430, 3320,
3070 ,, 3020, 2920, 2840, 1660, 1595, 1505.
In a similar manner, starting from the 30 responding compounds of the formula II, the following compounds are obtained,
I-Cyclohexyl-3- (4-pyridyl) -2t butanone.
Calculated (found),%: C 77.88 35 (77.65); H 9.15 l (9J20); N 6.15 (6.01).
40
NMR (CDCb.f): 0.5-1.8 (1H, m.); 1.42 (3N, d); 2.15-2.30 (2H, m,); 3.77 (1H, apt.); 7.23 (2H, m.); 8.59 (2H, m.).
IR (CHQ13, cm): 3060, 2970, 2920, 2840, 1710, 1590, 1555.
1-Cyclopentyl-3- (4-pyridyl) -2-butane.
Calculated (found),%: C 77.38 45 (76.95); H 8.81 (8.80); N 6.45 (6.85).
NMR (CDClI, P: 1.40 (3N, d); 2.10-2.30 (2H, m); 3.80 (1H, q); 7.20 (2H, m); 8.58 (2H, m.).
IR (CIIClj,): 2975, 2925,
50 2840, 1710, 1590, 1550. Example 2. Bis-hydrochloride
 K-cyclohexyl-2- (4-pyridyl) propyl-amino- (I, R H, A —CH -, B —NH-,
p 4).
its To a stirred suspension of lithium aluminum hydride (0.4 g) in anhydrous diglyme (10 ml) was added K-cyclohexyl-2- (4-pyridyl) propane-, amide (0.464 g, 2 mmol), obtained,
one
in anhydrous diglyme (5 ml), dropwise under nitrogen. The reaction mixture is then heated at 85-95 ° for 6 hours. After cooling of the plasma, the lithium aluminum hydride current is decomposed by carefully adding a mixture of methanol, tert-butylmethyl egryr and water. The organic phase is separated, washed with water, dried over sodium sulfate and filtered. The filtrate is saturated with anhydrous hydrogen chloride and the resulting precipitate is filtered and recrystallized from methanol-isopropanol 1: 3. 0.48 g (yield 82%) of the title compound is obtained as bis-hydrochloride.
Calculated (found),%: C 57.73 (57.81); H 8.24 (8.19); N 9.62 (9.55 C1 24.0.g (23.91),
(KBG
1 505
): 3100-2300, 2840,
Example 3. 2- (4-Pyridyl) propyl cyclohexyl ether (I, R H, A —CH 2 -, B – 0 -; p 4).
To a stirred suspension of lithium aluminum hydride (2.5 g) in anhydrous tetrahydrofuran (50 ml) was added a mixture of cyclohexyl 2- (4-pyridyl) propionate (3.50 g, 15 mmol), prepared as described in Example 1, and boron trifluoride etherate (30 ml) in anhydrous tetrahydrofuran (50 ml) dropwise with external cooling. After 3 hours at 45 ° C, the reaction mixture is carefully decomposed by adding water, followed by the addition of a 23% hydrochloric acid solution. Most of the organic solvent was evaporated in vacuo, the aqueous solution was adjusted to pH 9 with a concentrated solution of sodium hydroxide and extracted with diethyl ether (3 times). The combined extracts are washed with water until neutral, dried over sodium sulfate and evaporated in vacuo. The resulting residue is purified with, using chromatography on a column of silica gel, eluting with benzene-ethyl acetate 95: 5 and using fractional distillation. 2.2 g (yield 65%) of the title compound are obtained. / Calculated (found),%: C 76.71 (76.82); H 9.58 (9.62); N 6.89 (6.31)
WITH -
);
ten
15
".
6394286
IR (CHC1E, cm-): 1585, 1505, 1175, FROM.
Example 4, 1-Cyclohexyl-3- (4-pyridyl) butane (I, R H, A B —CHD, p 4).
To a solution of 1-cyclohexyl-3- (4-pyridyl) -2-butanone (2.31 g, 10 mmol), prepared as described in example 1, in methylene chloride (50 ml) is added ethandithiol (2 ml) and boron trifluoride etherate (2 ml). The mixture is stirred at room temperature for 2 hours, then washed with water with 8% aqueous sodium bicarbonate solution and water, then dried over CaClg, filtered and evaporated in vacuo. The crude thioketal thus obtained (3.1 g) was dissolved in 20 anhydrous tetrahydrofuran (30 ml) and stirred in the presence of Renee nickel (10 g) (prepared according to Org. Synth. 3.181) for 2 hours at room temperature. The catalysts are filtered and washed with methylenechloride,
The combined filtrate and washings were evaporated in vacuo to give a residue, which was purified by fractional distillation. 1.3 g (60% yield) of the desired compound are obtained.
Calculated (found),%: C 82.94 (82.88); H 10.59 (10.61); N 6.45 (6.44).
Example 5. N-Iikloheksil- (2-methylpyridyl-4) propanamide (I, R 2-CHe, A, B -NH-, p 4).
To a stirred solution of lithium propyl amide diisoJQ (7.6 mmol) in anhydrous tetrahydrofuran (10 ml) is added dropwise at -70 ° C under a nitrogen atmosphere of M-cyclohexyl- (2-m. Methyl-pyridyl-4) acetamide (800 mg,....,
ds 3.45 mmol) dissolved in anhydrous tetrahydrofuran (25 ml). After 1 hour of additional stirring at -70 ° C, methyl iodide (0.24 ml. 3.8 mmol) is added, dissolved
50 in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred at -70 ° C for 30 minutes, then left to reach room temperature. The solvent is evaporated in
its vacuum, and the residue is distributed between me and water (25 ml) and ethyl acetate (50 ml). The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2x25 ml). United Organs
ten
The organic extracts (100 ml) are washed with water, brine, dried with sodium sulfate and evaporated in vacuo. The residue obtained is purified by flash chromatography on a column of silica gel eluted with chloroform-ethanol 95; 5. 640 mg (75% yield) of the title compound are obtained as a yellow solid.
Calculated (found),%: C 73.13 (73t27.)} H 9.00 (9.08); N 11.37 (P-, 23),
IR (CHC1 cm 1): 3430, 3320, 3070, 3020, 2920, 2840, 1660, 1595, 1505.,
Similarly, the following compounds can be prepared from the corresponding compounds of formula II.
1-Cyclohexyl-3- (3-methylpyridyl-4) - 2-butanone.
Calculated (found),%: C 7.8,32 (77,52); H 9.45 (9.48); N 5.71 (5.65).
HMR (CDC13, 6i): 1.38 (3F, d); 2.10-2.-30 (2H, m.); 2.38 (1H, s.); 3.92 (1H, q); 7.05 (W, m.); 8.30-8.50 (.N, m.).
IR (CHClg,): 2920, 2840, 1710, 1590, 1555, 1490, 1445.
Example 6, N-cycl ohex x yl- .- (2-methylpyrid yl-4) propylamine Bis-hydrochloride (I, R B -NH-, p 4).
To a stirred suspension of lithium aluminum hydride (0.4 g) in anhydrous diglyme (10 ml) was added N-cyclohexyl 2- (2-methylpyridyl-4) propand amide (0.492 g, 2 mmol) obtained, as described in example 5, dissolved in anhydrous diglyme (5 ml, dropwise under nitrogen. The reaction; the mixture is then heated at 85-95 ° C for 6 hours. After cooling, the excess lithium luminium hydride is decomposed by carefully adding methanol, tert-butyl methyl ether and water. The organic phase is separated, washed with water, dried over sodium sulfate and filtered. . The filtrate is saturated with aqueous hydrogen chloride, the resulting precipitate was filtered and transferred crystallized from methanol - isopropanol 1: 2 to give 0.450 g (yield 74%) of the title compound as bis hydrochloride.
2-CHj, A
Calculated (found) 7-: C 59.01 (59.25); H 8.58 (9.07); N 9.18 (9.07); C1 23.28 (23.02) -.
IR (KBG,): 3100-2300, 2840, 1595, 1505.
Example 7. 2- (2-Methylpyridyl-4) propylcyclohexyl ether (I, R 2-CH3, A «-CH2-, B -0-, n 4).
To a stirred suspension of lithium aluminum hydride (2.5 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise with external cooling.
75 A mixture of cyclohexyl 2- (2-methylpyridyl-4) propionate (3.70 g, 15 mmol), prepared as described in Example 10, and boron trifluoride etherate (30 ml) in anhydrous tetrahydrofur2Q (50 ml). After cooling for 3 hours at 45 ° C, the reaction mixture is carefully decomposed by the addition of water, followed by the addition of a 23% hydrochloric acid solution.
25 Most of the solvent is evaporated in vacuo, the aqueous solution is brought to pK 9 by the addition of a concentrated solution of sodium hydroxide and extracted with diethyl ether (3 times). The combined extracts are washed with water to neutrality, dried over sodium sulfate and evaporated in vacuo. The resulting residue is purified by chromatography on a silica gel column chromatography eluting with benzene and ethyl acetate (95: 5) and fractional distillation. 2.25 g (yield 65%) of the title compound are obtained.
Calculated (found),%: C 77.20, (77.35); H 9.94 (9.85); N 6.00 (5.91).
IR (CHClj, cm): 1585, 1505, 1175, FROM,
45 Example 8, 1-Cyclohexyl-3- (2-methylpyridyl-4) butane (I, R 2-CH., A B,).
To a solution of 1-cyclohexyl-3-2-methylpyridyl-4) -2-butanone (2.45 g, 10 mmol), prepared as described in Example 5, in methylene chloride (50 ml) is added ethandithiol (2 ml) and boron trifluoride etherate (2 ml). The mixture was stirred at room temperature for 2 hours, then washed with water, 8% aqueous sodium bicarbonate and water, then dried over calcium chloride and evaporated in vacuo. Received by
50
55
in this way, the crude (crude) thioketal (2.80 g) is dissolved in anhydrous tetrahydrofuran (30 ml) and stirred in the presence of Renee nickel (10 g) (prepared according to Org. Synth, 3, 181) for 2 hours at room temperature . The catalyst is filtered off and washed with methylene chloride.
The combined filtrate and washings were evaporated under vacuum, the residue was purified by fractional distillation. 1.15 g (yield 50%) of the title compound are obtained.
Calculated (found),%: C 83.05 (83.38); K 10.89 (10, 98); N 6.05 (5.85).
Example 9. Tablets, each weighing 0.150 g, containing 25 mg of active substance, can be prepared as follows.
Ingredients (for 10,000 tablets):
N-Cyclohexyl2- (4-pyridyl) propanamid250 g
Lactose 800 g
Corn
starch415 g
Talcum powder 30 g
Magnesium stearate 5 g
I-11 cyclohexyl-2- (4-pyridyl) propenamide, lactose and half of the cornstarch are mixed; the mixture is then passed through a 0.5 mm mesh sieve.
Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder. The granulation is dried, crushed on a 1.4 mm mesh sieve, then the remaining amount of starch, talc and magnesium stearate are added, carefully mixed and processed into tablets
Inhibition of aromatase activity using the compounds obtained is dismantled using the in vivo test in rats (Brodie et al, Steroides, 38, 693, 1981), slightly changed. Adult female rats are treated twice subcutaneously with 100 M, E, pregnant mares' serum gonadotropin (GSEC) with an interval of 4 days for the ovary aromatase activity and, accordingly, serum estradol levels. Four days after the second NSGP treatment, groups of 6 animals each give 163
1639478
ten
0
five
0
the vehicle (0.5% metocel) or the aromatase inhibitor in a dose of 30 mg / kg orally. After 6 hours, the animals are killed by decapitation, the resulting sera are stored at -20 ° C for estradiol analysis, Zstradiol is analyzed using radioimmunoassay kits according to the instructions of the reagent manufacturer. So, for example, when the compound N-cyclohexyl- 2- (4-pyridyl) propanamide is tested according to the described procedure, a statistically significant (, 01) decrease in estrogen levels is detected, as shown in the table. As a comparison, the activity of 4-hydroxyandrostendione (4-OH A) is investigated,
Due to their ability to inhibit aromatase and, accordingly, reduce estrogen levels, compounds of general formula I can be useful in the treatment and prevention of various diseases that depend on estrogen, such as, for example, tumors, cancers of the mammary gland, mucous membrane membranes of the uterus, ovaries and pancreas, gynecomastia, 0 benign breast disease, endometriosis, ovarian polycystic disease, early sexual maturity.
In addition, the compounds of the invention may be used in the therapeutic and / or prophylactic treatment of prostatic hyperplasia, estrogen-dependent stromal tissue disease.
Compounds of general Lormula I can also be used to treat male infertility associated with oligospermia and to regulate the fecundity of females due to their ability to inhibit egg ovulation and nidation (strengthening the fertilized egg on the wall of the uterus).
Compounds of general formula I may also be useful in veterinary medicine 0 to reduce estrogen synthesis.
Compounds of general formula I can be considered to belong to the category of low-toxic compounds.
Compounds of general formula I are administered in a variety of dosage forms, for example, orally in the form of tablets, capsules, tablets with sugar or film coating, liquid solutions or suspensions, rectally.
five
0
in the form of medical suppositories, parenteral pales, for example, intramuscularly, or by internal injection or infusion;
The dose depends on the age, weight, condition of the patient, and the method of administration for administration. For example, the dose, applicable for oral administration to adults, may vary from 10-400 mg 1-5 times a day.
Pharmaceutical compositions containing the compounds of the invention are usually prepared according to known methods and are intended for use in a pharmaceutically acceptable form.
For example, solid oral forms
very little, for example, sorbitol,
Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions
ten
For intramuscular injections, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, 15 for example propylene glycol, and, if required, a suitable amount of lidocaine hydrochloride, may be contained together with the active compound.
Solutions for internal injections or infusions may contain as a carrier, together with the active substance, a carrier, for example a sterile compound, diluents, for example, lacquer water or, preferably,
very little, for example, sorbitol,
Suspensions and emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. Suspensions or solutions
tozo, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binding agents, for example starches, Arabic gum gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolide; disaggregating agents, for example starch, elginic acid, alginates or sodium starch glycolate; gas vortex mixtures; colorants; sweetening agents; wetting agents such as lecithin, polysorbates, lauryl sulfates, as well as generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be produced in a known manner, for example, by means of blending, granulating, tabletting, sugar coating or film coating processes.

Liquid dispersions when administered orally may be, for example, syrups, emulsions and suspensions. Syrups may contain as a carrier, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol, in particular, for administration to patients with diabetes, may contain as a carrier only products that are not capable of metabolizing glucose or capable of metabolism may have the form of sterile, aqueous, isotonian physiological solutions,
Medical suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a surface active agent such as polyoxyethylene sorbitan fatty acid esters or lecithin.
Thus, the proposed method allows to obtain new
derivatives of 4-cycloalkyl-substituted pyridine or their hydrochloride, which have valuable pharmacological properties,

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of 4-cycloalkylamines pyridine of General formula I
N
R
1sng) p CH3-CH-A-B- J
where R is hydrogen or C C -alkyl;
A - or
B NH-, -O- or -CH2-J
 N 3 or 4
or their hydrochlorides, characterized in that the compound of general formula II
9
(sn2) „
CH2-C-B J
about
where R, b and p have the specified ena-
cheni
subjected to alkylation with methyl iodide in anhydrous tetrahydrofuran medium in the presence of lithium diisopropylate to give the compound
Aromatase inhibition of rat ovary in rats pretreated with GCBS
-. 314 + 48
30 280 ± 32 11
30 45 ± 2 86
30 28 ± 3 91
3025+ 92
30 135 ± 18 57
formula I, where A is, followed by, if necessary, by reducing the carbonyl group at B —NH or —O— or converting the carbonyl group to dithioetanal and reducing it in the presence of Rene nickel at B —CH — of general formula I, where A is CHg-, and the target product is isolated in free form or in the form of hydrochloride,
Priority as of 07/18/86 with R 11/24/86 with R

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868617596A|GB8617596D0|1986-07-18|1986-07-18|Cycloalkyl-substituted 4-pyridyl derivatives|

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GB868628029A|GB8628029D0|1986-11-24|1986-11-24|Cycloalkyl-substituted 4-pyridyl derivatives|

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