Oxathiepino[6,5-b]dihydropyridines and pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

 

The scope of the invention

This invention relates to new oxathiane[6,5-b]dihydropyridine, useful as calcium channel blockers. These compounds and related pharmaceutical compositions useful for the treatment and prevention or the prevention of a number of disorders, such as increased or hypersensitivity, Allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature birth, disorders of the urinary tract motor function of the gastrointestinal tract and cardiovascular disorders.

Background of invention

Thiacyclohexane[3,2-b]pyridine are inhibitors include calcium ions in the tissue of smooth muscle. They act by relaxing or preventing a reduction in tissue, mediated by calcium mechanisms (Dodd et al., Drug Des. Discov. 1997, 15:135-48). These compounds are active hypotensive and bronchodilatory drugs.

Thiacyclohexane[3,2-b]pyridine also useful for the treatment of cardiovascular disorders, including hypertension, ischemia, angina, congestive heart failure, migraine, myocardial infarction and stroke (stroke). Such compounds are also useful to treat other disorders such as hypersensitivity, Allergy, asthma, dysmenorrhea, esophageal spasm, disorders of motor function VC is docno-intestinal tract, glaucoma, premature childbirth and disorders of the urinary tract.

Dodd et al. estimated number thiacyclohexane[3,2-b]pyridines having the size sulfonic rings from five to deletechannel for their antagonistic activity against calcium. It was found that increasing the size sulfonic ring of 5 to 8-membered in vitro leads to increased activity two orders of magnitude. It was found that the nature of the aromatic substitution, which contributes to the effect, in relation to the box, compared to the effect on the aorta, is 2-NO2and 2-CL, 6-f was Found that lonefire side chain, which maximizes in vivo activity is N-benzyl-N-methylaminomethyl group (Dodd. et al., Drug Des. Discov. 1997, 15:135-48, and Drug. Des. Discov. 1993, 10:65-75).

Numerous connection thiacyclohexane, examples of which are given in the following publications. In U.S. patent No. 5708177 name Straub describes a method for optically active orthotamine 4-aryl - or-heteroaryl-1,4-dihydropyridine oxidation and subsequent restoration of their opposite enantiomers. In patent No. 5075440 Wustrow et al. described pyrido[2,3-f] [1,4]thiazepine and pyrido[3,2-b][1,5]benzothiazepine, which are useful as calcium channel antagonists and have cardio-vascular, anti-asthma and antibreakage activity. In patents school is No. 4879384 and 4845225, both the name Schwender and Dodd described substituted thiacyclohexane[3,2-b]-pyridine, which are useful as calcium channel antagonists and have cardio-vascular, anti-asthma and antibreakage activity. In U.S. patent No. 4285955 and 4483985 described substituted acyclic sulfona the dihydropyridines, which have antagonistic activity against calcium channels. In U.S. patent No. 4532248 describes an extensive genus of dihydropyridines including cyclic sulfones, condensed with dihydropyridine nucleus. Cardiotonic activity described for all kinds of substituted therefore of dihydropyridine. Finally, in the publication Pagani, G.P.A., J. Chem. Soc. Perkin Trans. 2, 1392 (1974), describes the 10-phenyl-2H-thiopyrano[3,2-b]quinoline. However, none of these compounds is an antagonist of calcium channels.

"Soft drugs" (also known as printcasting funds) are biologically active drugs that are metabolically inactivated after the achievements of their therapeutic role in their scene. The use of soft drugs instead of their mainactivity analogues allows you to avoid unwanted side effects. Soft drugs in General are known (see, for example, Biggadike et al., 2000, J. Med. Chem. 43:19-21; ee et al., 1998, Curr. Opin. Drug Disc. Dev. 1:235-44). However, it is not known dihydropyridine soft drugs.

Summary of the invention

This invention provides novel compounds classified by the formula I defined in the description below, as well as methods for their preparation. This invention also provides a pharmaceutical composition comprising the present compound and a pharmaceutically acceptable carrier.

The invention provides further a method of treatment of a subject suffering from disorders relief which is mediated by a reduction of the influx of calcium ions into cells, which exacerbates the disorder, which includes an introduction to the subject a therapeutically effective dose of a given pharmaceutical composition.

This invention further provides a method of inhibiting the subject of the beginning of the disorder or violation, the relief of which is mediated by a decrease in the influx of calcium ions into the cells, which contributes to the violation, which includes an introduction to the subject prophylactically effective dose of a given pharmaceutical composition.

Finally, this invention provides a device for introducing this subject a pharmaceutical composition comprising a container and a pharmaceutical composition therein, the container has the media is the primary objective for delivery to the subject a therapeutic and/or preventive dose of the pharmaceutical composition.

Detailed description of the invention

This invention provides compounds of formula I,

in which

(a) R1, R2, R3, R4and R5independently selected from the group consisting of H, HE, halogen, cyano, NO2, alkyl, C1-8-alkoxy, C1-8-alkylsulfonyl, C1-4-carbalkoxy, C1-8-alkylthio, deformedarse, deformality, trifloromethyl and oxadiazole (formed R1and R2);

(b) R6selected from the group consisting of H, an unbranched or branched C1-5of alkyl, aryl, 3-piperidyl, N-substituted 3-piperidyl, N-substituted 2-pyrrolidinedione and substituted alkyl, of which

specified N-substituted 3-piperidyl and N-substituted 2-pyrrolidinone can be substituted C1-8-alkyl with an unbranched or branched chain, or benzyl, and the specified substituted alkyl may be substituted C1-8-alkoxy, C1-8-alkanoyloxy, phenylacetylene, benzoyloxy, hydroxy, halogen, p-tosyloxy, mesilate, amino, carbalkoxy or a group NR'r R’,

in which (i) R’ and R’, independently, selected from the group consisting of H, an unbranched or branched C1-8-alkyl, C3-7-cycloalkyl, phenyl, benzyl and Venetia or (ii) R’ and R’ together form a heterocyclic ring selected and the group, consisting of piperidino, pyrrolidino, morpholino, thiomorpholine, piperazine derivatives, 2-thieno, 3-thieno and N-substituted derivatives of these heterocyclic rings, and these N-substituted derivatives of substituted N, unbranched or branched C1-8-alkyl, benzyl, benzhydryl, phenyl and/or substituted by phenyl (substituted by a group of NO2, halogen, C1-8-alkyl with an unbranched or branched chain, C1-8-alkoxy and/or trifluoromethyl);

(C) R7selected from the group consisting of H, amino, alkyl, aryl, trifloromethyl, alkoxymethyl, 2-thieno and 3-thieno;

(d) R9represents oxygen or sulfur; and

(e) n is an integer from 1 to 4;

or their pharmaceutically acceptable salts.

In one embodiment of the present compounds R6represents -(CH2)2N(CH3)CH2Ph or methyl. In another embodiment R7represents methyl. In the following embodiment R1, R2, R3, R4and R5independently selected from the group consisting of H, halogen and NO2. In the preferred embodiment R9is oxygen.

The following compounds are examples of compounds of the present invention.

Connection 1: 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl) - 5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic key is lots.

Connection 2: 1,1-dioxide methyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Connection 3: 1,1-dioxide, 2-[methyl(phenylmethyl)amino]-ethyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Compound 4: 1,1-dioxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Connection 5: 1,1-dioxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Compound 6: 1,1-dioxide methyl ester 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Compound 7: 1,1-dioxide, 2[methyl(phenylmethyl)-amino]ethyl ester 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Compound 8: 1,1-dioxide, 2-[methyl(phenylmethyl)-amino]ethyl ester 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

Compound 9: 1,1-dioxid-[methyl(phenylmethyl)-amino]ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

This invention also provides soft pharmaceutical analogues of compounds of formula I. these mild drugs are characterized by a chemically labile part associated with the ester group, in turn, is associated with the ring structure of dihydropyridines. Soft drugs allow the given medicines to show their action locally and subsequently metabolized in the bloodstream, thereby reducing unwanted systemic effects (low blood pressure). The use of such soft drug analogues allows you to enter a higher dose of the claimed compounds of the dihydropyridines, without exposing the subject intolerable levels of undesirable system actions.

In particular, the invention provides compounds of formula II,

in which

(a) R1, R2, R3, R4and R5independently selected from the group consisting of hydrogen, HE, halogen, cyano, NO2, alkyl, C1-8-alkoxy, C1-8-alkylsulfonyl, C1-4-carbalkoxy, C1-8-alkylthio, deformedarse, deformality, trifloromethyl and oxadiazole (formed R1and R2);

(b) R7selected from the group consisting of hydrogen, amino, alkyl, aryl, thrift is rotela, alkoxymethyl, 2-thieno and 3-thieno;

(c) R8selected from the group consisting of-alkyl-HE, alkylamine, lactone, cyclic carbonate, alkyl substituted cyclic carbonate, arizonasonora cyclic carbonate, -aryl-C(O)or SIG’, -alkylaryl-C(O)or SIG’, -alkyl-OC(O)R’, -alkyl-C(O)R’, -alkyl-C(O)OR’, -alkyl-N(R’)C(O)R’, and-alkyl-N(R’)C(O)OR’, where

R’ and R’, independently, selected from the group consisting of hydrogen, amino, alkyl, aryl, ariconditioning of cycloalkyl and heterocyclyl, and amino, alkyl, aryl, ariconditioning cycloalkyl and heterocyclyl optionally substituted with halogen, cyano, NO2, lactone, amino, alkylamino, the aryl-substituted alkylamino, amidon, carbamate, carbamoyl, cyclic carbonate, alkyl, halogen-substituted by alkyl, arylalkyl, alkoxy, heterocyclyl and/or aryl (which aryl, optionally, replaced IT, halogen, cyano, NO2, alkyl, amino, dimethylamino, alkoxy, alkylsulfonyl, C1-4-carbalkoxy, alkylthio and/or trifluoromethyl); and

(d) R9represents oxygen or sulfur;

or their pharmaceutically acceptable salts.

Each of the preferred embodiments of the compounds of formula I, above, are also regarded as the embodiment of the compounds of formula II. In addition, in the preferred embodiment of the compounds of formula II, R8chosen as the keel-HE, the lactone, cyclic carbonate, alkyl substituted cyclic carbonate, aryl-substituted cyclic carbonate and alkyl-OC(O)R’, where R’ has the above values.

The following compounds (defined here as connection No. 10-19) are also preferred embodiments of the compounds of the present invention:

1,1-dioxide(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide(2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl ester 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-hydroxyethylamide ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiazine-[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-(2-methyl-1-oxopropoxy)ethyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-(2-methyl-1-oxopropoxy)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]-oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-[(cyclopropanecarbonyl)oxy]ethyl ester 9-(2-chloro-6-forfinal)-1,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-(atomic charges)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiazine-[6,5-b]Piri is in-8-carboxylic acid;

1,1-dioxide, 2-[(cyclohexylcarbonyl)oxy]ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid;

1,1-dioxide, 2-(benzoyloxy)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid and

1,1-dioxide, 3-(benzoyloxy)propyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiazine-[6,5-b]pyridine-8-carboxylic acid.

Unless otherwise noted, the term "alkyl" refers to an unbranched, branched or cyclic Deputy consisting only of carbon and N without nancysinatra. The term "alkoxy" refers to O-alkyl, in which alkyl has the above values. Illustrative aryl substituents include, for example, phenyl, naphthyl, diphenyl, forfinal, differenl, benzyl, benzyloxyphenyl, carbamaxepine, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, triptoreline, methoxyethanol, acetamidophenyl, tolyl, xylyl, dimethylcarbamoyl, -(CH2)2N(CH3)CH2PH, -CH2CH2-N(Me)-CH2-heteroaryl and similar. The term "halogen" means fluorine, chlorine, bromine and iodine. The symbol "Ph" refers to phenyl. "Independently" means that when there is more than one Deputy, the substituents may be different.

Compounds of the present and the gain are asymmetric in the 4-position of ring of dihydropyridines and thus, there are in the form of optical antipodes. As such, all possible optical isomers, antipodes, enantiomers or diastereomers resulting from the additional asymmetric centers may exist in the optical antipodes, racemates and racemic mixtures, are also part of this invention. Antipodes can be separated by methods known to experts in this field, such as, for example, fractional recrystallization of the diastereomeric salts enantiomerically pure acids. Alternative antipodes can be separated by chromatography on a column of type Pirkle.

Used in this description, the phrase "pharmaceutically acceptable salt" means a salt of the free base, which possesses the desired pharmacological activity of the free bases and which are neither biological nor in any other respect is not undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are chlorotoluron, nitric, Hydrobromic, sulfuric and phosphoric acid. Examples of organic acids are acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzonal, cinnamon, almond, metasolv the new, econsultancy, p-toluensulfonate, methylsulfonate, salicylic acid and similar.

These compounds may be obtained using the freely available source materials. The first stage of the synthesis, as shown below in scheme 1, is well known in this field (Shibata et al., Fuji Photo Film Co., Ltd., Jpn. Kokai Tokkyo Koho, p. 47; Japan patent 62253161, 1987; patent application Japan 86-39760 (860224); patent application Canada No. 429975, 1988).

This invention also provides a pharmaceutical composition comprising the present compound and a pharmaceutically acceptable carrier.

Pharmaceutical compositions containing the compound of the present invention as an active ingredient in a close mixture with a pharmaceutical carrier can be obtained by conventional pharmaceutical techniques. The media can have a large number of forms depending on the form of preparation desired for administration, such as systemic injection, including, but not limited to, intravenous, oral, nasal or parenteral. Upon receipt of the compositions in oral dosage form, you can use any of the usual pharmaceutical carriers, such as water, glycols, oils, alcohols, corrigentov, preservatives, coloring agents, syrup and similar in the case of oral liquid preparations (for example, suspensions, elixirs and concrete is), or devices such as starches, sugars, diluents, granulating agents, lubricants, binders, dezintegriruetsja agents to the same in the case of oral solid preparations (such as powders, capsules and tablets).

In a special embodiment of the compounds of the present invention is administered by inhalation. For inhalation therapy, the compound may be in solution, useful for the introduction using inhalers with flow measured doses, or in a form suitable for inhalation or insufflator with a dry powder. More specifically, the compounds for use in accordance with the present invention are conveniently delivered in the form of an aerosol spray from a pressurized container with a swab or spray, for example, with the use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas inside such a container. A single dose can define or limit the supply container valve for delivering metered quantities. Can be formulated capsules and cartridges made of a pharmaceutically acceptable material, such as gelatin, for use in an inhaler or insufflator containing a powder mix of the compound and a suitable powder base, such as lactose or krahm the L.

Due to their ease of administration, tablets and capsules represent the predominant oral form one dose, which use solid pharmaceutical carriers. If desired, tablets may be coated with sugar or enterococci coating using standard techniques. For parenteral administration the carrier typically includes sterile water, although it may also include other ingredients, for purposes of solubility or conservation. You can also prepare injectable suspension, in which you can use the appropriate liquid carriers, suspendresume agents and similar. Connections can also be entered in the form of an aerosol.

Data pharmaceutical compositions typically contain a single dose (e.g., tablet, capsule, powder, injection, full teaspoon, and so on) from about 0.001 to 100 mg/kg and preferably from about 0.01 to 20 mg/kg of this compound. In this area known methods for the determination of therapeutically and prophylactically effective doses for the present pharmaceutical compositions. Effective dose for administration of the pharmaceutical composition to a person, for example, can be defined mathematically by the results of animal studies.

Compounds of the present invention inhibit the capture of calcium ions smooth muscle and, therefore, operate on a budget who blaa or preventing mediated by calcium ions reduced tissue smooth muscle.

Thus, the invention further provides a method of treatment of a subject suffering from disorders relief which is mediated by the reduction of inflow into the cells of calcium ions, which contributes to the violation, which includes an introduction to the subject a therapeutically effective dose of a given pharmaceutical composition. As an example, for a subject suffering from asthma, the Airways are compressed due to the contraction of the smooth muscle cells of the Airways ("SMC"). It can be expected that the reduction of flow in SMC calcium, which contributes to the violation, will ease the symptoms of the disorder.

This invention further provides a method of inhibiting the subject of the beginning of the disorder, the relief of which is mediated by the reduction of inflow into the cells of calcium ions, which contributes to the violation, which includes an introduction to the subject prophylactically effective dose of a given pharmaceutical composition.

In one embodiment of the violation refers to a group consisting of hypersensitivity, Allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature birth, and disorders of the urinary tract, disorders of motor function of the gastrointestinal tract and cardiovascular disorders. In the preferred embodiment of infringement is asthma. A heart condition is about-vascular disorders may be, for example, hypertension, ischemia, angina, congestive heart failure, myocardial infarction or stroke.

Used in this description, the term "treatment" violation means removing or otherwise weakening the reasons for his and/or his actions. "Inhibition" of the beginning of violation means the prevention, slowing or reducing the likelihood of such a beginning.

The term "subject" includes, without limitation, any animal or artificially modified animal. In the preferred embodiment the subject is a person.

This invention further provides a device for introducing this subject a pharmaceutical composition comprising a container and a pharmaceutical composition therein, and the container has a means for delivery to the subject a therapeutic and/or preventive dose of the pharmaceutical composition. In the preferred embodiment the device is a device with aerosol spray for the treatment and/or prevention of asthma with the help of local respiratory injection.

Finally, as described in more detail below, the invention provides a method for obtaining compounds of formula I:

The invention can be better understood with reference to the experimental details below, but expert in this area of evide freely understands that they are merely illustrative for the invention, described more fully in the claims, below. In addition, throughout this application are cited in various publications. The content of these publications is included for information in this application to more fully describe the state of the art to which this invention relates.

Experimental details

A. Schematic and synthesis

Procedures for obtaining dihydropyridines are widely described in the field, as shown in publications Eistert et al. (Chem. Weg. 110, 1069-1085, 1977), G.A.Pagani (J.Chem. Soc., Perkin Trans 2, 1392-7, 1974), Mason et al. (J.Chem. Soc. (C) 2171-76, 1967), E.A.Fehnel (J.Amer. Chem. Soc. 74, 1569-74, 1952) and M.Seiyaku (application for Japan patent No. 58201764, 1984).

Scheme I shows the formation of compounds of the formula I:

The compounds of formula II can be obtained in accordance with scheme II (which compound 2A can be obtained through stages similar to the stages in scheme I, and R1-9have the values indicated above), preferably in the presence of K2CO3or s3in organic solvents, such as dimethylformamide (DMF).

The compounds of formula II can also be obtained in accordance with scheme III (which compound 3A can be obtained through stages similar to the stages in scheme I, and R 1-9have the values indicated above), preferably in the presence of formic acid or NaOH (aqueous), respectively.

The following examples describe in more detail the chemical synthesis of representative compounds of the present invention. The rest of the described compounds can be obtained analogously in accordance with one or more of these ways. There have not been any attempts to optimize the yields obtained in these reactions, but expert in this area, of course, it is clear that varying the time, temperature, solvents and/or reagents reactions can increase the output.

Example 1

1,1-Dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid

Synthesis of compound 3, which is shown in the above scheme IV, carried out as follows:

24,95 g (269,7 mmol) of epichlorohydrin is added dropwise via addition funnel to a solution of 21,07 g (269,7 mmol) of 2-mercaptoethanol in 100 ml of water and 21,33 g (269,7 mmol) of pyridine at 0°C. After complete addition, the cooling bath removed and the solution stirred at room temperature for 6 hours. The reaction mixture was then acidified with 1 N. concrete is Hcl and extracted with 4× 200 ml of EtOAc. The organic layers separated, combined, dried over MgSO4, filtered and concentrated in vacuo to obtain a 40.8 g of the product as a colourless oil (yield >100%). The synthesis of this product, (2-[(oxiranylmethyl)thio]ethanol), described in detail in the literature (Benzyl alcohol-free rapid processing of silver halide color photographic print paper, Shibata et al. (Fuji Photo Film Co., Ltd., Japan); Jpn. Kokai Tokkyo Koho, pp.47; Japan patent 62253161, 1987; patent application Japan 96-39760, 860224; patent application Canada No. 429975, 1988).

12,16 g (304 mmol) of sodium hydroxide dissolved in 120 ml of water. Dropwise via addition funnel type of 40.8 g (304 mmol) of the crude epoxide. The reaction mixture is heated to boiling under reflux for 5 hours (during this time the reaction mixture becomes very dark), cooled to room temperature, acidified with 6 N. solution of Hcl and extracted with 4×400 ml EtOAc. The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo to obtain 20,08 g (150 mmol) of brown oil, which moves slightly faster than the original material, when TLC using a mixture of 1:1 hexane/ethyl acetate for the elution.

A 3-necked 1 l flask equipped with thermometer, dropping funnel and driven by air stirrer, loads of 43.5 g (214,1 mmol) of 85% 3-charprocs the benzoic acid and 260 ml l 3and then the flask was cooled in an ice bath. Dropwise via addition funnel over 1 hour add 13,06 g (97,32 mmol) of the crude sulfide in 200 ml l3. The cooling bath is then removed and the reaction suspension is stirred at room temperature for 2 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue is treated with ether and decanted. The resulting oil is then treated with warm toluene and decanted to obtain 9,07 g of light brown oil. Column chromatography using 1% Meon in EtOAc gives 7.9 g (47,53 mmol) of sulfone in the form of a light yellow oil.

7.9 g (47,53 mmol) of alcohol in 125 ml of acetone at 0°C is added dropwise through an addition funnel 20 ml (54 mmol, 1.1 equivalent) freshly 2.7 M Jones reagent. The Jones reagent prepared by careful dissolution of 5.34 g of chromium trioxide in 4.6 ml of concentrated sulfuric acid and then carefully diluted with water to 20 ml total volume. The cooling bath is removed and the resulting suspension stirred at room temperature overnight. The reaction slurry is then diluted with 200 ml of ash and extracted with 4×200 ml EtOAc. The organic layers separated, combined, washed 2×200 ml of water, dried over MgSO4, filtered and the concentration of irout in vacuum to obtain white balance. The residue is triturated with a mixture of ether/ethyl acetate and filtered with the receipt of 4.67 g (28,44 mmol) of the desired product as a white solid.

The solution 25,43 g (other 153.9 mmol) N-benzyl-N-methylethanolamine and 0.2 ml of triethylamine is heated on an oil bath to 60°C. dropwise via addition funnel type of 13.6 g (161,79 mmol) diketene maintaining the temperature of the interaction between 60-85°C. After complete addition, diketene the reaction mixture is stirred for further 30 minutes, cooled to room temperature and then cooled in an ice bath. Add 20 ml of 2-propanol. Within 2 h after the reaction mixture was bubbled ammonia gas. The orange reaction mixture is covered with a cap and leave it over night at 5°C. the Reaction mixture was then stirred in an ice bath and add 10 ml of heptane. Begins to precipitate formed. After one hour of reaction, the suspension is filtered and the precipitate washed 3×40 ml of 10% volume/volume mixture of 2-propanol/heptane with getting to 21.15 g (85,17 mmol) of a white solid.

2.4 g (14,62 mmol) cyclic simple β-ketosulfones, of 2.06 g (14,62 mmol) 2-chlorobenzaldehyde and 3,63 g (14,62 mmol) of 2-(N-benzyl-N-methylamino)ethyl-3-amino-crotonate heated to 110°With 50 ml DMF for 3.5 hours. The reaction mixture is then cooled is, dilute 500 ml t, washed 4×200 ml of water, 1×100 ml of saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo to obtain a brown oil. Column chromatography using a mixture of 3:2 EtOAc/hexane gives equal to 4.97 g (9,42 mmol) of the desired product (compound 3) as a yellow foam.

to 4.87 g (9,42 mmol) of dihydropyridines are dissolved in 150 ml of ether containing a small amount of ethyl acetate. Through an addition funnel over 90 minutes add 1,08 g (9,42 mmol) of 85% orthophosphoric acid in 75 ml of ether. The resulting white suspension is stirred for 4 h and then filtered. The resulting white solid washed with excess ether and dried to obtain 2,68 g (5.18 mmol) of phosphate salt.

C. Analysis

Example 2

Analysis of inhibition of binding of nitrendipine

Female new Zealand white rabbits (1-2 kg) and killed by cervical displacement and immediately remove the heart, cleaned and cut into small pieces. The tissue is homogenized 5x - volume of 0.05 buffer Hs, pH 7.4. The homogenate was centrifuged at 4000 g for 10 minutes and the supernatant re-centrifuged at 42000 g for 90 minutes. The resulting membrane precipitate again suspended (0.7 ml/g weight) in 0.05 M Hs, pH 7.4 and stored at 70°s to use. Each of Roberta for analysis of binding contains 3H-nitrendipin (0,05-0,50 nm), buffer, membranes (0.10 ml) and the test compound in a total volume of 1.0 ml After incubation for 90 minutes at 4°associated With nitrendipin separated from unbound by filtration on filters Whatman GF/C After propulsive filters are dried and carry out counting using a liquid scintillation counter.

Nonspecific associated3H-nitrendipin (i.e. the number associated in the presence of excess of unlabeled nitrendipine) subtract from the total number associated to obtain specifically bound labeled radioactive isotope of nitrendipine. The amount of specifically bound nitrendipine in the presence of the test compound compared to the amount of bound of nitrendipine in the absence of connection. You can then receive a percentage of the displacement (or inhibition).

Example 3

Test for inhibition of calcinating reduce smooth muscle

The trachea and aorta of dogs, murdered by the injection of excess KCl, stored over night at 4°in oxygeneration buffered Krebs-Henseleit. Tracheal rings, the width of one segment of cartilage (5-10 mm), cut, starting with bronchial end. Prepare also a ring of tissue in the aorta of the same width. After cutting the cartilage tissue muscles of the trachea and the aortic tissue is suspended in oxygeneration buffered Krebs-Hyun is elata at 37° With 25 ml of bath tissue. After a 60-minute period equilibrium in tissue injected with 10 μm carbachol. After 5 minutes the fabric rinse and leave to rest for 50 minutes. The fabric is then treated with 50 mm KCl and 30 minutes later quantify the reduction. Cloth then rinse and again result in an equilibrium condition within 50 minutes. Then within 10 minutes add compound and the fabric is again treated with 50 mm KCl. After 30 minutes register abbreviation and is used to determine the % inhibition of control. The percentage inhibition of the contraction of smooth muscles calculate the following scapular according to the response before and after treatment with the medication:

The following table 1 presents the data of mass spectra, inhibition of nitrendipine binding and inhibition calcinating contraction of smooth muscle in the form of percentage inhibition for selected compounds of formula I.

td align="center"> 564,0589
Table 1
The connection numberMolecular weightNumberIC50binding of nitrendipine (nm)% outputIC50trachea (nm)Mass spectroscopy
10,23553927,8 M-H=528
2383,85240,17711246,1 M+Na=406
3552,510,10511291955M+N=517
4394,40520,13654634,6 M+Na=417
5394,40520,04483411,4 M+Na=418
6383,85240,16962144,2  
7553,5060,31621357,1 M+N=517
8564,05890,13278623,5 M+N=528
9633,03110,1667-13,2 M+N=535

In table 2, below, shows the mass spectra and inhibition of nitrendipine binding for selected compounds of formula IIA.

1. Oxathiane[6,5-b] di is hydropyridine formula I

in which

(a) R1, R2, R3, R4and R5independently selected from the group consisting of H, halogen, NR2;

(b) R6selected from the group consisting of unbranched or branched C1-5-alkyl, with the specified alkyl may be substituted for phenylacetylene, hydroxy, carbalkoxy or a group NR'r R"in which R' and R" are independently selected from the group consisting of H, an unbranched or branched C1-8-alkyl, benzyl;

(c) R7selected from the group consisting of H, alkyl;

(d) R9represents oxygen and

(e) n is an integer from 1 to 2;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R9is oxygen.

3. The compound according to claim 1, in which R6selected from the group consisting of methyl and -(CH2)2N(CH3)CH2Ph.

4. The compound according to claim 1, in which R7represents methyl.

5. The compound according to claim 1, in which R1, R2, R3, R4and R5selected independently from the group consisting of H, halogen and NO2.

6. The compound according to claim 1, which is 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

7. Connection pop, which is 1,1-dioxide methyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

8. The compound according to claim 1, which is 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

9. The compound according to claim 1, which is 1,1-dioxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9-(3-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

10. The compound according to claim 1, which is 1,1-dioxide methyl ester 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

11. The compound according to claim 1, which is 1,1-dioxide methyl ester 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

12. The compound according to claim 1, which is 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 9-(3-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

13. The compound according to claim 1, which is 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 2,3,6,9-tetrahydro-7-methyl-9-(2-nitrophenyl)-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

14. The compound according to claim 1, which is 1,1-dioxide, 2-[methyl(phenylmethyl)amino]ethyl ester 9-(2-chloro-6-fluoro-phenyl)-2,3,6,9-tetrahydro-7-m is Teal-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

15. The compound of formula (II)

in which

(a) R1, R2, R3, R4and R5independently selected from the group consisting of hydrogen, halogen, NR2;

(b) R7selected from the group consisting of H, alkyl;

(c) R8selected from the group consisting of-alkyl - OH, -alkyl-OC(O)R’, where R' is selected from the group consisting of alkyl, phenyl;

(d) R9is oxygen.

16. The connection indicated in paragraph 15, in which R9is oxygen.

17. The connection indicated in paragraph 15, in which R7represents methyl and R1, R2, R3, R4and R5independently selected from hydrogen, halogen and NO2.

18. The connection 15, which is 1,1-dioxide (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

19. The connection 15, which is 1,1-dioxide (2-oxo-5-phenyl-1,3-dioxol-4-yl)methyl ester 9-(2,3-dichlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

20. The connection 15, which is 1,1-dioxide, 2-hydroxyethylamide ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

21. The connection 15, which is 1,1-dioxide, 2-(2-methyl-1-is oxopropoxy)ethyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

22. The connection 15, which is 1,1-dioxide, 2-(2-methyl-1-oxopropoxy)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

23. The connection 15, which is 1,1-dioxide, 2-[(cyclopropanecarbonyl)oxy]ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

24. The connection 15, which is 1,1-dioxide, 2-(atomic charges)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

25. The connection 15, which is 1,1-dioxide, 2-[(cyclohexylcarbonyl)oxy]ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

26. The connection 15, which is 1,1-dioxide, 2-(benzoyloxy)ethyl ester 9-(2-chloro-6-forfinal)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

27. The connection 15, which is 1,1-dioxide, 3-(benzoyloxy)propyl ester 9-(2-chlorophenyl)-2,3,6,9-tetrahydro-7-methyl-5H-[1,4]oxathiane[6,5-b]pyridine-8-carboxylic acid.

28. Pharmaceutical composition having the property of blocking the calcium channels, comprising the compound according to claim 1 or 15, and a pharmaceutically acceptable carrier.



 

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