DK174189B1 - 1,1-Di:oxo-thia-cycloalkeno-(3,2-B)pyridine-carboxylate derivs. - useful as calcium channel antagonists having e.g. cardiovascular, anti-asthmatic, cyto-protective and platelet aggregating inhibiting action - Google Patents

Abstract

Thiacycloalkeno(3,2-b) pyridine derivs. of formula (I), their optical antipodes and the pharmaceutically acid and base addn. salts are new; where n = 1-12; R1 = H, NH2, alkyl, haloalkyl or CH2OR2; R2 = 1-8C alkyl, 3-7C cycloalkyl, or alkylene-X having at least 2C; X = alkoxy, OH, halo, p-tosyloxy; mesyloxy, NH2, pyridyl or NR4NR5, R4 and R5 = H, alkyl, cycloalkyl, phenyl, benzyl or phenethyl; or NR4R5 = 5- to 7-membered heterocyclyl opt. contg. an O or S or an additional N and opt. fused to a benzene ring; provided that when NR4R5 = piperazino it is substd. by R6 at the 4-position; R6 = H, alkyl, cycloalkyl, benzyl or phenyl (opt. substd. by alkoxy, halo, alkyl, NO2 or CF3); R3 = 2-pyridyl; 3-pyridyl opt. substd. at the 2,4,5 and/or 6-positions by halo, NO2, alkoxy, alkylthio, CN, alkoxycarbonyl, OCHF2, SCHF2 or alkylsulphonyl; 2-thienyl, 3-thienyl, 2, 1, 3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl or phenyl (opt. substd. by 1 or more of alkyl, alkoxy, CN, alkoxycarbonyl, alkylthio, OCHF2, alkylsulphonyl, halo, NO2 or CF3). Intermediates of formula (VIII) and (XII), their optical antipodes and the acid and base addn. salts are new. Specifically claimed are 28 cpds. (I) e.g. ethyl 2,3,4,7-tetrahydro -5-methyl-7-(3-nitrophenyl)-1,1- dioxothieno(3,2-b)pyridine -b-carboxylate.

Description

in DK 174189 B1

The present invention relates to novel dioxothiacycloal kenohydroxy dye compounds and to a process for their preparation. These compounds are partly useful intermediates in the preparation of the calcium channel antagonistic compounds of formula (I) in DK 167.021 B1, and in themselves useful as calcium channel antagonists with cardiovascular, anti-asthmatic, anti-bronchospastic, gastric antisecretory, cytoprotective and platelet. aggregate inhibitory activity. Furthermore, the compounds are useful for treating hypermotility of the digestive system and for treating diarrhea. The invention further relates to pharmaceutical compositions containing these compounds.

U.S. Patent No. 4,285,955 and U.S. Patent No. 4,483,985 disclose acyclic sulphone substituted in on on simple dihydropods exhibiting calcium channel antagonistic activity. However, the compounds concerned are chemically different from the compounds of the invention.

I G P.A. Pagani, J. Chem. Soc., Perkin Trans. 2, 1392-7 (1974) deals with 10-phenyl-2H-thiopyrano [3,2-b] quinolines. However, these compounds are not calcium channel antagonists.

U.S. Patent No. 4,532,248 discloses a wide variety of dihydro-padins comprising cyclic sulfones condensed with a dihydropyridine nucleus. The entire group is attributed to cardiotonic activity. In contrast, the compounds of the present invention are potent calcium antagonists with a pharmacological activity that is opposite to that described in U.S. Patent No. 4,532,248.

The substituted thiacycloalkeno [3,2-b] pyridines of DK 167,021,251 have the following general formula O (CH 2

30 H I

wherein n is an integer from 2-6, R 1 is alkyl, is straight or branched alkyl of 1-8 carbon atoms, benzyl, cycloalkyl of 3-7 carbon atoms or alkylene-X of at least 2 carbon atoms wherein X is alkoxy, hydroxy, pyridyl or -NR 1 R 6 wherein R 4 and R 5 are the same or different and selected from hydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenyl ethyl, or R 2, R 9 and the nitrogen atom to which they are attached form a A 5- or 6-membered heterocyclic ring optionally containing an oxygen or sulfur atom or an additional nitrogen atom, or the heterocyclic ring may be fused with a benzene ring, R 1 is 3-pyridyl, 3-pynyl substituted in the 2-, 4-, 5- or 6-membered sequence with one or more groups selected from halogen, nitro, alkoxy, alkylthio, cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or any alkyl sulfonyl, or phenyl optionally is substituted at the 2- to 6-position by one or more groups selected from the group consisting of alkyl, alkoxy, cyano, carbal coxy, alkylthio, difluoromethoxy, difluoromethylthio, alkyl, sulfonyl, halogen, nitro or trifluoromethyl, or pharmaceutically acceptable acid addition salts thereof.

The compounds of the invention are characterized by the characterizing part of claim 1 and have an asymmetric carbon atom in the pyridine ring, which is bonded to the ring, and thus exist as optical antipodes which as such are encompassed by the present invention. The antipodes can be separated by methods known to those of skill in the art, such as e.g. fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes may be separated by chromatography on a Pirkle column.

The present invention further encompasses a process for preparing the compounds of formula VIII, which process 20 will be described in more detail below.

The compounds of the invention are potent inhibitors of calcium ion uptake in smooth muscle tissue and have the effect of relaxing or counteracting contraction of tissue mediated by calcium mechanisms. The compounds of the invention can find therapeutic use in the treatment of cardiovascular diseases, including hypertension, ischemia, angina, arrhythmia, congestive heart failure, peripheral vascular diseases such as claudication, intermittent seizures, myocardial infarction, and platelet aggregation. The compounds of the invention can also be used against other diseases such as hypersensitivity, allergy, asthma, dysmenorrhea, bronchoconstriction, oesophageal spasm, premature veins as well as urinary tract disorders, gastric hypersecretion and disorders of membrane integrity. The compound, composition and method of the invention will be described in more detail below.

35 The terms used herein have the following meanings:

Unless otherwise indicated, the term "alkyl" means a saturated, straight-chain or branched substituent consisting only of carbon and hydrogen and containing from 1-8 carbon atoms. The term "lower alkoxy" refers to a lower alkyl chain as described above with no more than 4 carbon atoms. The term "halogen" means fluorine, chlorine, bromine and solder.

The term "pharmaceutically acceptable salts" refers to salts of the free base which exhibit the desired pharmacological activity of the free base and are neither biologically nor otherwise undesirable. These salts can be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric, nitric, hydrochloric, sulfuric or phosphoric. Examples of organic acids are acetic, propionic, glycolic-10, lactic, pyruvic, malonic, succinic, malic, malic, fumaric, cinnamon acid, almond acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

Pharmaceutical compositions containing a compound of the invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to the present invention. conventional pharmaceutical manufacturing techniques. The carrier may take a large number of forms depending on the form of preparation desired for administration, e.g., aerosol, intravenous, sublingual, oral or topical administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be used, such as e.g. water, glycols, oils, alcohols, flavoring agents, preservatives, dyes and the like. in the case of oral liquid preparations such as e.g. suspensions, elixirs and solutions, or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like. in the case of oral solid compositions such as e.g. powders, capsules and tablets. P.g.a. the ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are naturally used. If desired, tablets may be sugar-coated or enteric coated by standard methods. For parenteral administration, the carrier usually comprises sterile water, although other components, e.g. to promote solubility or for preservation purposes may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like. can be used. For aerosol use, suspensions or solutions may be used. The pharmaceutical compositions generally contain per unit dose, e.g. tablet, capsule, powder, injection, teaspoon and the like, from approx. 0.001 to approx. 100 mg / kg and preferably from ca. 0.001 to approx. 20 mg / kg of active ingredient.

The novel compounds of the invention can be synthesized according to the invention. the following reaction scheme in which R 1, R 2, R 1 R 2 and R 9 have the meanings given above, MCPBA means m-chloroperoxybenzoic acid and Y represents p-methylphenyl or alkyl.

5

Sul phonetic synthesis (nj = 2 or 3) ("" ΓΊ ^ 1 "CPU * Ov 10" 1 2 Λ (CH2h | ^ II W> \ * °

15S_1 Cr ° 3-H'S ° <j I5 I

n. (CH2) A "l (CH2H, i 'OH 1 0 rv Va

Synthesis of dioxothiacycloalkeno [3,2-b] pyridines of formula VIII

and their further use in the preparation of the compounds of formula I in DK 167.021 Bl ^ o Q r Ή R.CH0 VI. ; VCVC00R2 n (cvH —-> „(ch2lX ΐ 'TV 2 ί' ^ 05? HO N R1 (H20) i> (ch2) - L iv V H H VIII N Kj

H2N ^ R1 H

la

WE

In accordance with the above reaction scheme, the compounds according to the invention are synthesized as follows:

The cyclic 3-ketosulfones of formula V can be prepared according to the one in B. tistert, P. Kuffner and T.J. Arackel, Chem. Ber. 110, 1069-1085 (1977) 5.

In the case of 3-oxotetrahydrothiophene-1,1-dioxide, i.e. where n is 2, however, the process described in the above reference is rather labor intensive. According to the present invention, it has been found that the compounds of formula Va, wherein n is 2 or 3, can be obtained in high yield in an uncomplicated manner from the respective 3-cyclic sulfides of formula II. The compounds of formula II can be prepared according to that of E.A. Fehnel, J Amer. Chem. Soc., 74, 1569-74 (1952).

The 3-keto portion of Compound II is reduced to an alcohol (Compound 15 III), preferably with sodium borohydride, although a number of other reducing agents such as diborane, lithium aluminum hydride or sodium numanoano boron can be used. Then compound III is oxidized to compound IV, preferably with m-chloroperoxybenzoic acid. Other suitable oxidizing agents are hydrogen peroxide or sodium periodate. Finally, the hydroxide portion of compound IV is reoxidized to the corresponding ketode of compound Va, preferably using Jones reagent (chromic anhydride in dilute sulfuric acid added to a solution of the alcohol in acetone). Other suitable oxidizing agents are calming dichromate or Collins reagent (chromic anhydride in pyridine).

Compounds of DK 167.021 B1 of formula I wherein n is 2-6 (called compound Ia in the above reaction scheme) can be prepared by stirring equimolar portions of, for example, 3-oxotetrahydrothiophene-1,1-dioxide, the appropriately substituted aldehyde of formula VII and the substituted 3-amino ester of formula VI in ethanol for 2 to 24 hours at room temperature (see Example 1). Each compound of formula VIII according to the invention is obtained. The present compound of formula VIII is then heated in toluene to reflux mg for 1 to 24 hours to provide dehydration, thereby preparing the aforementioned compound la (see Example 2). The various reaction schemes described above are further discussed in the following references: G.A. Pagani, J. Chem. Soc., Perkm Trans. 2, 1392-7 (1974), K.G. Hason, H A. Smith, and E.S. Stern, J. Chem. Soc. (C) 2171-76 (1967), in 6 DK 174189 B1 and Japanese Patent No. 58201764 (1984, Haruko Seiyaku).

The following examples are intended to illustrate, but not to limit, the present invention.

Example 1

Methyl 2,3,3a, 4,7,7a-hexahydro-3a-hydroxy-5-methyl-7- (2-nitrophenyl) -1,1-dioxothieno [3,2-b] pyridine-6-carboxylate

A solution of tetrahydrothiophene-3-oxo-1,1-dioxide (1.3 g, 0.01 mole), 2-nitrobenzaldehyde (1.5 g, 0.01 mole) and methyl 3-aminocrotonate 10 (1, 1 g, 0.01 mole) in ethanol (20 ml) was stirred overnight. The resulting crystals were solubilized by filtration and washed 2 times with ethanol and 2 times with diethyl ether. After drying under high vacuum for 24 hours, 2.54 g of product, m.p. 175-179 ° C (dec.).

Example 2

Methyl 2,3,4,7-tetrahydro-5-methyl- 7- (2-nitrophenyl) -1,1-dioxothieno [3,2-b] pyridine-6-carboxylate (compound of formula Ia according to DK 167.021 B1)

A mixture of methyl 2,3,3a, 7,7a-hexahydro-3a-hydroxy-5-methyl-7-20 (2-methrophenyl) -1,1-dioxothieno [3,2-b] pyridine-6 carboxylate (2.5 g, 0.0065 mol) and toluene (60 ml) to reflux for 24 hours. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol. The crystals were washed twice with diethyl ether and dried at 65 ° C under high vacuum for 48 hours. This yielded 1.78 g of product, m.p. 215-25 217 ° C.

The biological properties of the compounds of the invention were investigated. Hereby, the compounds of the invention were found to influence calcium mediated processes including inhibition of the smooth muscle contraction of the trachea and vascular tissues. The screening system model used to evaluate these compounds showed the following: 1) Inhibition of nitrendipine binding to calcium channels.

2) Ability to modulate the activity of tissues dependent on calcium utilization, as in the case of trachea and vascular tissues 3) Use of the compounds as anti hypertensive and / or bronchodilatory agents for mammals.

Based on the results stated above, it is believed that the compounds may be used in hypertension, myocardial disease, ischemia, angina, congestive heart failure, migraine, myocardial infarction, platelet aggregation, stroke, hypersensitivity, allergy, asthma, gastric secretion dysmenorrhea, oesophageal spasm, premature veins and 5 urinary disorders.

The test for inhibition of nitrendipine binding is carried out as follows:

White New Zealand female rabbits (1-2 kg) are killed by cervical dislocation and the heart is immediately removed, cleansed and chopped into 1 small pieces.

The tissue is homogenized in 5X volume 0.05M Hepes buffer, pH 7.4. The homogenization is centrifuged at 4000 xg for 10 minutes, the supernatant freshly added at 42,000 xg for 90 minutes. The resulting membrane pellet is resuspended (0.7 ml / g weight) in 0.05M Hepes, pH 7.4, and stored at -70 ° C, 3 until used. Each binding test tube contains H-mtren-dipine (0.05-0.50 nM), buffer, membranes (0.10 ml) and test compound in a total volume of 1.0 ml After 90 minutes at 4 ° C, the bound is separated nitrendipine from the unbound by filtration on "Whatman GF / C" fibers After rinsing, the filters are dried and counted in a liquid scintillation counter.

Non-specific binding of H-nitrendipine (the amount bound in the presence of excess unlabeled nitrendipine) is deducted from the total binding to obtain specifically bound radiolabelled nitrendipine. The amount of specifically bound nitrendipine in the presence of a test compound is compared with that in absence of a compound bound amount. Thereafter, the percent displacement (or inhibition) can be obtained.

The test for inhibition of calcium-dependent smooth muscle contraction is performed as follows:

Trachea from dogs killed by injection of a KC1 overdose is stored overnight at 4 ° C in oxygenated Krebs-Henseleit buffer.

30 Tracheal rings with a width of one cartilage segment (5-10 mm) are excised from the bronchial end. Following excision of the cartilage, the tracheal muscle tissue is suspended in oxygenated Krebs-Henseleit buffer at 37 ° C in a 25 ml tissue bath.

After an equilibration time of 60 minutes, the tissue is treated with 10 μM carbachol. After 5 minutes, the tissue is rinsed and left for 50 minutes. The tissue is then treated with 50 mM KCl and after 30 minutes the extent of contraction is assessed. Next, the tissue is rinsed and re-equilibrated for 50 minutes. Then test compound is added for 10 minutes and the tissue is treated again with 50 mM KCl. After 30 minutes, the contraction is recorded and applied to determine the percent control inhibition.

The percentage of inhibition of smooth muscle contraction is calculated from response data before and after drug treatment.

5% inhibition = 100-100 (maximum reaction after drug treatment) (maximum reaction before drug treatment)

The compound is classified according to the percentage inhibition obtained.

The following Table I shows inhibition of nitrendipine binding as well as inhibition of calcium-dependent contraction in the smooth muscle expressed as percent inhibition for a number of representative compounds of the invention.

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C> 1 O 1

-f- r- I

CM 4-> · <0 -v; i O «1 4- - * -> tu i <0 C C7> ·

O (Λ C I

σ »^ 3 i- 1 10

C ε ί- I CM

σι <u I

5- I- + j J3 1 α> σ> <ø - i · - W σ> c - £ = _ £ I 1

C l (- I

· —1 Λ <0 &? 1

<4- I

(0 I I

c D) r 1

C Ω. .-. 1 O

i · r Σι s- -o σ> a. 1 00 · -> Φ C C - i

-Q Φ r- I

<- ί- -σ o <s «

O) £ +) C U) 1 10

-Ω C r- - O 1 1Λ (0 · —1 C Λ 1—1 1 H- 1 t I o> 1 -Ό o 1 σι O I t '*

• I I

o. 1 in e * t '»LO 1 * -1 i

1 O

1 CM CM CO

I AND X

1 * G O

|| «% R« e: 0 O 1

Li- I

1 I 1

Claims (4)

1. Dioxothiacycloalkenohydroxypyridine compound of the general formula (VIII) 5 h VJC> coor2 n {(iT | [Γ HO H 1 VIII is n is an integer from 2-6, R 1 is alkyl, R 9 is straight or branched alkyl of 1-8 carbon atoms, benzyl, cycloalkyl of 3-7 carbon atoms or alkylene-X of at least 2 carbon atoms wherein X is alkoxy, hydroxy, pyridyl or -NR 1 R 6 wherein R 1 and R 2 are the same or different and are selected from hydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenylethyl, or R 2, R 9 and the nitrogen atom to which they are bound, forms a 5- or 6-membered heterocyclic ring optionally containing an oxygen or sulfur atom or an additional nitrogen atom, or the heterocyclic ring may be fused with a benzene ring, R 1 is 3-pyridyl, 3-pyridyl substituted at the 2-, 4-, 5- or 6-position with one or more groups or atoms selected from halogen, mtro, alkoxy, alkylthio, cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or all alkyl sulfonyl; or phenyl optionally substituted in 2- to 6-membered by one or more groups or atoms selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy, alkylthio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halogen, nitro or trifluoromethyl , the optical antipodes or pharmaceutically acceptable acid or base addition salts thereof. 2. A compound according to claim 1, characterized in that it is methyl - 2,3,3a, 4,7,7a-hexahydro-3a-hydroxy-5-methyl-7- (2-methrophenyl) -1,1-dioxo thieno [3,2-b] pyridine-6-carboxylate. Process for the preparation of a compound of formula 35 (VIII) according to claims 1-2, characterized in that DK 174189 B1, a) a compound of formula (II) n 5 n , is reduced by NaBH 2, to produce a compound of formula (III) 10, ___ n 'nj (CH 2 + Ul HO 15 where nj is 2 or 3, followed by oxidation of compound (III) with m-chlorobenzoic acid of a compound of formula (IV) • V, ° ~ 20 Π where nj is 2 or 3, then compound (IV) is reoxidized with Jones reagent to produce compound (Va) 25 0. /., ¾ - 30 where nj is 2 or 3, or that b) a compound of formula (Vb) Π vb 35! CH 2> A to where ng is 3-6 is prepared in a manner known per se, followed by DK 174189 B1 c) the compound of formula (Va) or (Vb) is reacted with a compound of formula (VI) 2 coor2 5 η2ιγ VI and a compound of formula RjCHO (VII), to prepare a compound of formula (VIII) ci2Tf if 110 H 1 VIII 15 where n is 2-6 and then, if desired, a obtained compound of formula (VIII) is digested into optical antipodes thereof or converted to a pharmaceutically acceptable acid or base addition salt thereof Pharmaceutical composition, characterized in that it contains as active ingredient a compound of formula (VIII) according to claim 1 in addition to a conventional pharmaceutical carrier.