3-methoxy-2-fluoro-18-ethyl-8α-gona-1,3,5( 10 )-trienes, having osteoprotector and hypocholesteremic activity

FIELD: chemistry.

SUBSTANCE: invention enables synthesis of 3-methoxy-2-fluoro-18ethyl-8α-gona-1,3,5(10)-trienes, having osteoprotector and hypocholesteremic activity.

EFFECT: invention has osteoprotector and hypocholesteremic activity and can be used in medicine for hormonal replacement therapy.

1 cl, 3 ex, 1 tbl, 3 dwg

 

The invention relates to the field of synthesis of biologically active analogues of steroidal estrogens. Modified steroid estrogens are widely used in medicine as a means of hormone replacement therapy (HRT) [1], though they have serious side effects. Thus, prolonged use of estrogens increases the risk of a number of malignant diseases [2, 3]. Moreover, the use of estrogen for HRT increases the risk of stroke [4]. The above demonstrates the need for search of new estrogen analogues with improved biological properties.

It is known that 2-forestration in the experiment does not show a carcinogenic effect [5, 6], although it has a uterotrophic activity. However, to reproduce the receipt of this derivative on a large scale by the method proposed earlier [7], failed [8].

It is also known that there is a correlation between the uterotrophic activity of modified estrogens and their potential Carcinogenicity [9]. So for HRT promising connection with osteoprotektornogo properties and low uterotrophic activity.

According to [10] such a range of biological properties is 3,17β-dihydroxy-2-Fergana-1,3,5(10)-triene closest to the claimed invention, compounds selected as the e prototype. However, specific data on the biological activity of this steroid in the work are not given, and the scheme of synthesis of compound (yield of the target product of the methyl ester of 2-Florestan is 5.3%).

Therefore currently remains a very topical problem of the synthesis of analogues of steroidal estrogens containing fluorine in position 2 and having osteoprotektornogo action at low uterotrophic activity. The technical result of the invention is to obtain 3-methoxy-2-fluorine-18-ethyl-8α-gona-1,3,5(10)-trienol General formula presented in figure 1.

Scheme of synthesis is presented in figure 2.

Example 1.

a) 18-Methyl-3-methoxy-2-fluoro-8,14-secuestro-1,3,5(10),9(11)-tetraen-14,17-dione (V).

To a solution of 4.8 g of isothiuronium salt (IV) [11] in 100 ml of a mixture of ethanol-water (1:1) are added under stirring 2.6 g of 2-ethyl-1,3-ciclopentadione. After 7 days the precipitation is filtered off, washed with 30 ml ethanol-water (1:1), air-dried. The filtrates are combined, the solvents removed on a rotary evaporator, the residue chromatographic on a column of 50 g silica gel, elute with a mixture of hexane-ethyl acetate (10:1). After distillation of the solvent the resulting substance combine with loose sediment, the mixture is crystallized from methanol. Obtain 3.95 g (85%), secosteroid (V), TPL 103-104°C. Found, %; 72.99; H 7.18. C20H23FO3. Calculated, %: C 72.71; is 7.02. Range1H-NMR (CDCl3, δ, ppm): 0.80 t (3H, H18aJ=7.6 Hz), 1.67 (2H, N.18), 1.75 m (4H), 2.42 t (2N, N8J=5.7 Hz), 2.55 (2H, N.12, J=8.6 Hz), 2.62-2.72 m (4H), 3.86 (3H, CH3Oh), 5.56 t (1H, H11, J=7.6 Hz), 6.63 (1H, H4,4JHF=8.6 Hz), 7.15 (1H, H1,3JHF=12.4 Hz).

b) 18-Methyl-3-methoxy-2-forestry-1,3,5(10),8,14-pentaen-17-one (VI).

To the boiling solution of 2 g of secocoeni (V) in 150 ml of toluene added 0.15 g of the monohydrate of p-toluenesulfonic acid. After 25 min the reaction mixture was cooled to room temperature, washed with 5% soda solution, water, saturated NaCl solution. The toluene is distilled off on a rotary evaporator, the residue is crystallized from methanol. Obtain 1.7 g (90%) of extrapontine (VI), TPL 108-109°C. Found, %: C 76.94; N, 6.88. C20H21FO2. Calculated, %: C 76.90; N, 6.78. An NMR spectrum1H (CDCl3, δ, ppm: 0.82 t (3H),18-CH3, J=7.5 Hz), 3.90 (1H, CH3Oh), 5.97 t (1H, WITH15H, J=2.9 Hz), 6.77 (1H, C4H,4JHF=8.4 Hz), 7.02 (1H, C1H,3JHF=12.9 Hz).

in) Acetate 18-methyl-3-methoxy-2-forestry-1,3,5(10),8,14-pentaen-17β-ol (VII).

To a solution of 7.0 g of extrapontine (VI) in 120 ml of absolute ethanol is added 1.2 g of sodium borohydride at -5°C, the reaction mixture was stirred 1 h at -5°C and then for 12 h at room temperature. The excess reducing agent is decomposed with acetic acid, then the reaction mixture was poured in in the ice, the reaction products extracted with four portions of chloroform, 50 ml of the Extract is washed with two portions of water, 100 ml, dried over anhydrous sodium sulfate. The chloroform is removed on a rotary evaporator. The oil obtained is dissolved in 25 ml of pyridine, add 20 ml of acetic anhydride, the reaction mixture was left for 72 hours After conventional treatment [11] product acetylation is crystallized from a mixture of hexane-chloroform. The yield of the target compound 6.8 g (85%), TPL 138-139 .5°C. Found, %: C 74.09; H 7.18. C22H25FO3. Calculated, %: C 74.13; H 7.07. Range1H-NMR (CDCl3, δ, ppm): 0.94 t (3H, H18a, J=7.3 Hz), 1.39-1.47 (m 1H), 1.27-1.67 m (2N, N12), 2.13 (3H, CH3COO-), 2.16-2.36 m (2H), 2.40-2.60 m (4H), 2.68-2.88 (m 3H), 3.91 (3H, CH3Oh), 5.12 t (1H, H17J=8.7 Hz), 5.63 USS (1H, H15), 6.76 (1H, H4I , JHF=8.01 Hz), 7.02 (1H, H1I , JHF=13.1 Hz).

d) Catalytic hydrogenation of 17β-acetoxy-18-methyl-3-methoxy-2-forestry-1,3,5(10),8,14-pentaen (VII).

To a solution of 560 mg of the acetate (VII) in 20 ml of THF was added 200 mg of 10%Pd/C hydrogenation carried out 72 h at room temperature. The catalyst is filtered off and washed with methanol, the solvents are combined and removed in vacuum. The remainder chromatographic on a column of 50 g of silica gel 100/160 multiples µ, elute with a mixture of hexane-ethyl acetate (20:1). After crystallization from methanol obtain 285 mg (50%) steroid (I), TPL 153-154°C. Found, %:C 73.11; N 8.11. C22H29FO3. Calculated, %: C 73.31; H 8.11. Range13C-NMR: 116.3 (C1), 150.8 (C2), 145.3 (C3), 113.4 (C4), 132.4 (C5), 31.4 (C6), 21.8 (C7), 39.1 (C8), 41.5 (C9), 132.4 (C10), 28.8 (C11), 34.0 (C12), 43.8 (C13), 48.6 (C14), 22.4 (C15), 27.8 (C16), 84.2 (C17), 19.8 (C18), 9.8 (Sa), 56.3 (CH3CO), 21.4 (CH3WITH a), 171.2 (CH3WITH). Mass spectrum, m/z (IRel, %): 360 (100, M+), 300 (4), 271 (20), 259 (68), 244 (11), 229 (10), 217 (10), 204 (27), 192 (54), 191 (37), 190 (68), 189 (53), 179 (19), 178 (90), 177 (35), 176 (25), 165 (32).

The remaining mixture of substances chromatographic on Bond column ODS, elute in a gradient of acetonitrile - water 80-95% within 7.5 minutes After crystallization predominant substance from a mixture of chloroform-methanol (1:5) to obtain 170 mg (30%) steroid (VIII), TPL 185-187°C. Found, %: C 73.92; N, 7.01. C22H25FO3. Calculated, %: C 74.13; H 7.07. Range1H-NMR: 7.54 (H1), 7.16 (N4), 7.54 (N6), 7.12 (H7), 3.14 (H11α), 2.98 (H11β), 1.65 (H12α), 2.47 (H12β), 2.90 (H14α), 2.15 (H15α), 1.81 (15β), 1.78 (H16α), 2.45 (H16β), 4.95 (H17α), 1.09 and 1.42 (n), 0.99 (Na), 3.98 (CH3CO), 2.11 (CH3WITH). Mass spectrum, m/z (IRel, %): 356 (51, M+), 294 (10), 281 (6), 267 (100), 256 (7), 241 (41), 227 (16), 207 (10), 189 (20), 183 (18).

Example 2.

Methyl ether 18-methyl-2-fluoro-8α-estrone.

To a solution of 0.2 g of the acetate (I) in 10 ml of benzene is added a solution of 0.6 g of sodium hydroxide in 10 ml of methanol, the reaction mixture is boiled for 2 h, and then poured into 200 ml of water. The reaction products extracted with four portions of chloroform, 50 ml combined extracts are washed with two portions of water 100ml, dried by sodium sulfate. After removal of the solvents on a rotary evaporator the residue is dissolved in 3 ml of pyridine and add the reagent Saretta prepared from 0.2 g of chromium trioxide and 3 ml of pyridine. After 12 h the reaction mixture was worked up in the usual conditions [11], the target compound (III) is obtained by crystallization from a mixture of chloroform-methanol (1:7). Yield 110 mg (63%), TPL 146-148 .5°C. Found, %: C 75.89; N, 7.96. C20H25FO2. Calculated, %: C 75.92; N, 7.96. Range13C-NMR: 9.15, 20.24, 21.19, 22.71, 28.47, 28.65, 31.32, 36.10, 39.00, 41.63, 49.67, 51.17, 56.60, 113.80, 116.48, 132.39, 133.92, 145.80, 151.10, 219.02. Mass spectrum, m/z (IRel, %): 316 (100, M+), 269 (20), 259 (22), 244 (14), 231 (7), 217 (28), 204 (29), 192 (25), 191 (24), 190 (37), 189 (32), 179 (12), 178 (64), 177 (25), 176 (12), 165 (18).

Example 3.

18-Methyl-3-methoxy-2-fluoro-17β-ethoxy-8α-östra-1,3,5(10)-triene.

To a solution of 60 mg of sodium borohydride in 4 ml of freshly diglyme was added dropwise over 2 h at -20°C. a solution of 200 mg of the acetate (I) in 4 ml of THF and 0.3 ml of epirate boron TRIFLUORIDE. After conventional treatment [12] the target compound is obtained by crystallization from a mixture of chloroform-methanol (1:5). Yield 150 mg (78%), TPL 170-173°C. Found, %: C 76.16; N, 9.09. C22H31FO2. Calculated, %: C 76.26; H 9.02. Mass spectrum, m/z (IRel, %): 346 (21, M+), 259 (100), 244 (7), 231 (6), 218 (6), 203 (9), 192 (15), 191 (19), 190 (29), 189 (20), 179 (6), 178 (31), 177 (14), 176 (11), 165 (14).

Osteoprotektornogo, hypocholesterolemic and uterotrophic effects of steroids (I), (II) and (III investigated in experiments on ovariectomised the Wistar rats according to the modified method Kalu [13] in terms proposed in [11, 14]. As a reference compound used 17α-ethinylestradiol, used in medical practice. In the table as example presents the results of a study of steroid (I), statistically processed according to the method of t-test.

The results of the study uterotrophic, osteoprotektornogo and hypocholesterolemic activities of steroids on ovariectomised rats Wistar
The experimental group of ratsChange of body weight, gWasmade, mg/ 100 g body weightThe weight of the ash from the femur / "wet" weight of the femurThe density of the mineral components in the area of the L-4 of the femur, g/cm2The cholesterol content in the serum, mg/DL
Linopirdine36.0±4.2 *190±13**0.425±0.007*0.247±0.004*46.0±2.8*
Ovariectomised43.4±3.434.2±1.10.391±0.004.220±0.003 63.2±1.1
Ovariectomized treated HER, 0.1 mg/kg8.0±3.1**207±8**0.422±0.008*0.241±0.008*31.2±2.4**
Ovariectomized treated with the drug (I), 2 mg/kg12.5±2.7**156±12**0.430±0.004*0.252±0.007*28.5±3.9**
Note: IT is 17 α-ethinylestradiol ("positive control");
*- Rovereact.<0.5; ** - Povereact.<0,1.

The data presented indicate the presence of steroid (I) osteoprotektornogo and hypocholesterolemic activity at low uterotrophic action, which is an advantage in comparison with the reference compound is 17α-ethinyl estradiol.

The claimed invention as shown by the results of the St. Petersburg state University research reaches the specified technical result and allows to synthesize 3-methoxy-2-fluorine-18-ethyl-8α-gona-1,3,5(10)-triene with osteoprotektornogo and hypocholesterolemic asset is awn. The invention is 3-methoxy-2-fluorine-18-ethyl-8α-gona-1,3,5(10)-triene with osteoprotektornogo and hypocholesterolemic activity, can be applied in medicine for hormone replacement therapy.

Sources of information

1. Gadducci, A., N. Biglia, Sismondi P., Generazzini A.R. // Gynecological Endocrinology. 2005. V.20. P.343-360.

2. Beral V. & Million Women Study Collaborators. II Lancet. 2003. V.362. P.419-427.

3. Beral V, Bull d, Reeves g & Million Women Study Collaborators. // Lancet. 2005. V.365. P.1543-1551.

4. Bushnell C.D. // Lancet Neurology. 2005. V.4. P.743-752.

5. LiehrJ. G. II Mol. Pharm. 1983. V.23 supported. P.278-281.

6. Pat. USA N4522758 (1985) - Chem. Abstr. 1985. V.103. 123790k.

7. Utne T., Jobson R.B., Babson R.D. // J. Org. Chem., 1968, 33 (6), 2469-2473.

8. Diorazio L.J., J.M. Clough J. Chem. Soc., Perkin Trans. 1. 1992. P.421-425.

9. Schafer J.I.M., Liu H., Tonetti D.A., V.C. Jordan II Cancer Research. 1999. V.59. P.4308-4313.

10. PCT Int. Appl. WO 01 32680 - Chem. Abstr. 2001. V.134. 326662h.

11. Belov VN, Dudkin V.Y., Urusova E.A., Starov GL, S. I. Selivanov, Nikolaev S.V., Eschenko N, Morozkina S.N., Savva A.G. // Bioorg. chemistry. 2007. V.33. No. 3. S-323.

12. Egorov M. R., S. Selivanov, Savva A.G. // Zhur.org.chem.. 2003. T. V.2. S-223.

13. Kalu D.N. // Bone Miner. 1991. V.15. P.175-192.

14. Morozkina S.N., Egorov, MS, Eliseev, I.I., Selivanov, S., Eschenko N, Putilina FE, Vilkova V.A., Zakharov LI, Savva A.G. // Vestnik of Saint Petersburg University. 2009. Series 4. V.2. Pagination 126-134.

3-Methoxy-2-fluorine-18-ethyl-8α-gona-1,3,5(10)-triene General formula

a) R1=H, R2=OAc;
b) R1=H, R2=OEt;
in R1+R :=O,
with osteoprotektornogo and hypocholesterolemic effect at low uterotrophic activity.



 

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7 cl, 9 dwg, 172 ex

FIELD: medicine.

SUBSTANCE: offered is application of a composition substantially consisting of trans-clomiphene or its pharmaceutically acceptable salt for preparing a drug to be introduced in a male patient in a single dose every 3-30 days for treating hypogonadism, lipodystrophy, benign prostatic hypertrophy or prostate cancer (versions). One of side effect of exogenous testosterone, namely decreased biosynthesis level of follicle-stimulating hormone causing reduced sperm formation is compensated. Contrariwise, the product is applied in treating a disorder associated with male hypogonadism and related disturbances, including reduced muscle bulk, body physical capacity limitation, decreased bone density, decreased libido, decreased potency, reduced benign prostatic hyperplasia and infertility.

EFFECT: product increases persistently total testosterone level to a normal range with no abnormal high peaks.

18 cl, 7 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of medication for reduction of fat absorption form food, containing pectin or its salts, inhibitor of gastrointestinal lipase, auxiliary components.

EFFECT: medication is used for treatment or prevention of syndrome of anal oil leks, which can take place after administration of gastrointestinal lipase inhibitor of orlistat type, with further application for treatment of obesity and hyperlipemia.

6 cl, 4 dwg, 8 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I): where: X denotes -CH2-, -CH2CH2-; R1 denotes H; R2 and R3 denote H; or one of them denotes H and the other denotes a branched or straight C1-6alkyl, C3-6cycloalkyl or phenyl; where the said C1-6alkyl is possibly substituted with one OH, NH2, C3-6cycloalkyl, phenyl; where any phenyl is possibly substituted with one or two substitutes selected from halogen or C1-6alkyl; R4 denotes H; R5 denotes H, halogen, C1-6alkyl; or a pharmaceutically acceptable salt thereof.

EFFECT: compounds inhibit cholesterol absorption, which enables their use in treating and preventing atherosclerosis.

14 cl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel polymorphous form of B-52-crystalline hemicalcium salt of atorvastatin [hemicalcium salt (βR,δR)-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methlethyl)-3-phenyl-4-{(phenylamino)carbonyl}-1H-pyrrole-1-heptanoic acid] and solvates thereof, having an X-ray diffraction pattern which is essentially identical to that given in dwg.1, with characteristics given in claim 1.

EFFECT: wider field of use of the compounds.

19 cl, 2 tbl, 3 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I): where: X denotes CH2-, -CH2CH2- ; Y denotes -CH2- or O; Y1 denotes -CH2- or O; where at least on of Y and Y1 denote -CH2-; R1 denotes H; R2 and R3 independently denote hydrogen; or one of them denotes H2 and the other denotes a branched or straight C1-6alkyl; where the said C1-6alkyl is possibly substituted with one amino, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C3-6cycloalkyl, phenyl; where any phenyl is possibly substituted with one CN; R4 denotes H; R5 denotes halogen; or its pharmaceutically acceptable salt.

EFFECT: compounds inhibit cholesterol absorption, which enables their use in treating and preventing atherosclerosis.

12 cl, 15 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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