PH26186A - Substituted thiacycloalkeno (3,2-B) pyridine intermediates - Google Patents
Substituted thiacycloalkeno (3,2-B) pyridine intermediates Download PDFInfo
- Publication number
- PH26186A PH26186A PH37780A PH37780A PH26186A PH 26186 A PH26186 A PH 26186A PH 37780 A PH37780 A PH 37780A PH 37780 A PH37780 A PH 37780A PH 26186 A PH26186 A PH 26186A
- Authority
- PH
- Philippines
- Prior art keywords
- methyl
- alkyl
- substituted
- carboxylate
- benzyl
- Prior art date
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 3
- 239000000543 intermediate Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 42
- -1 p-tosyloxy, mesyloxy, pyridyl Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
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- 230000003287 optical effect Effects 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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- 230000005764 inhibitory process Effects 0.000 description 10
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- 229960005425 nitrendipine Drugs 0.000 description 9
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- 238000002360 preparation method Methods 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 4
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- 229940127291 Calcium channel antagonist Drugs 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- RSPISYXLHRIGJD-UHFFFAOYSA-N OOOO Chemical compound OOOO RSPISYXLHRIGJD-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 3
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
. ’ : : ’ . | 1 } : PHILIPPINE PATENT OFF - 1 = : : A AR 5 x
SUBSTITUTED THIACYCLOALKENO [3,2-b] PYRIDINES, METHO 0
PREPARATION, COMPOSITIONS AND METHOD OF USE
Raceive: By:
I
S ! ’
This invention relates to certain substituted thiacycloalkeno [3.2-b] pyridines. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic, antibronchospastic, gastric antisecretory, cytoprotective and platelet aggregation inhibitory activity. In addition. the compounds are useful in treating hypermotility of the G-I tract and in the treatment of diarrhea. This invention also relates to a process for preparing these compounds, compositions thereof, methods of use and novel intermediates.
Related Disclosure 2% U.S. Patent No. 4,285,955 and U.S. Patent No. 4,483,98S% (which is a divisional of the aforementioned patent) disclose acyclic sulfone substitution on simple dihydropyridines which possess calcium channel antagonist : activity. However, the compounds in question are chemically distinct from the compounds of the present invention. 10-Phenyl-2H-thiopyrano(3,2-bjquinolines are disclosed in
G.P.A. Pagani, J.Chem.Soc., Perkin Trans.2,1392-7(1974). : 35
ORTH 504 :
p 26186 -:- i However, these compounds are not calcium channel antagonists.
U.S. patent No. 4532248 discloses a broad genus of dihydropyridines including cyclic sulfones fused to a dihydropyridine nucleus. Cardiotonic activity is claimed a for the entire genus. The compounds of the present invention, on the other hand, are potent calcium . antagonists with pharmacologic activity opposite to that claimed in U.S. Patent No. 4,532,248.
The substituted thiacycloalkeno (3,2-b] pyridines which are the subject of this invention have the following general formula: 0 0 gr
J
Ss 11 coom, (
H I wherein n is an integer from 1 to 12; R, is hydrogen, amino, alkyl. haloalkyl or CH,OR,; R, is straight chained or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or alkylene-X having at least 2 carbon atoms, wherein X is alkoxy, hydroxy. halo, p-tosyloxy, mesyloxy. amino, pyridyl or -NR R_. wherein R, and Rg are the same or different and are selected from hydrogen, alkyl, cycloalkyl. phenyl, benzyl, phenylethyl, or Ry. Rg and the nitrogen atom to which they are attached form a 5, 6 or 7 membered heterocyclic ring which optionally contains 3s an oxygen or sulfur atom or an additional nitrogen atom or
ORTH 504
} | ' 9 - 3 = said heterocyclic ring may be fused to a benzene ring, as in indoline, isoindoline, tetrahydroquinoline or tetrahydroisoquinoline, and in the instance wherein said heterocyclic ring is piperazino, said piperazino may optionally be substituted in the 4- position with the . substituent R, which is selected from alkyl. cycloalkyl, benzyl, phenyl, or phenyl substituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; Ry is 2-pyridyl, 3- . pyridyl, 3-pyridyl substituted at positions 2, 4, 5 or 6 with one or more groups selected from halogen, nitro, alkoxy, alkylthio, cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl; 2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl or phenyl optionally substituted at positions 2 through 6 with one or more groups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy. alkyl-thio, difluoromethoxy, difluoromethylthio, alkylsulfonyl., halo, nitro or trifluoromethyl; or the pharmaceutically acceptable acid addition salts thereof. ‘The compounds of this invention are assymetric in the pyridine ring at the R, point of attachment and thus exist as optical antipodes and as such are part of this invention. The antipodes can be separated by methods 25° known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography in a Pirkle column.
Also included in this invention is a process for preparing the compounds of formula I, said process being disclosed in detail hereinafter,
Also part of the present invention are certain : 35 intermediates and the process for the preparation thereof.
ORTH 504
) 26186
Preferred compounds of the present invention are: 1. Ethyl 2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl) -1,1-dioxothieno{3,2-bjpyridine-6-carboxylate. 2. N,N-Dimethylaminoethyl 2,3,4,7-tetrahydro-5-methyl-7- (3-nitrophenyl)-1,1-dioxothieno(3,2-b]pyridine-6- carboxylate. 3. N-Benzyl-N-methylaminoethyl 2,3,4,7-tetrahydro-5- methyl-7-(3-nitrophenyl)-1,1-dioxothieno (3.2-b]lpyridine-6-carboxylate. 4. Ethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl) -1,1-dioxo-2H-thio-pyrano (3,2-b]lpyridine-7- ‘carboxylate.
S$. N,N-Dimethylaminoethyl 3,4,5,8- : tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1- dioxo-2H-thiopyrano[3,2-b])pyridine-7-carboxylate. 6. N-Benzyl-N-methylaminoethyl 3.4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl) : -1,1-dioxo-2H-thiopyrano(3,2-b)pyridine-7-carboxylate. 20 . 7. N-Benzyl-N-methylaminoethyl 3,4,5,8-tetrahydro -6-methyl-8-(2,3,4,5,6-pentaflucrophenyl)-1,1-dioxo0-2H- thiopyrano({3,2-b)pyridine-7-carboxylate. 8. Ethyl 9-(2,3,4.,5,6-pentafluorophenyl)-2,3,4,5.,6,9 -hexahydro-7-methyl-1,1-dioxothiacyclohepteno(3,2-b] pyridine-8-carboxylate. 9. N-Benzyl-N-methylaminoethyl 2,4,5,6,9-hexahydro-7- methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno (3.2-b]pyridine-8-carboxylate. 10. N,N-Dimethylaminoethyl 2,3,4,5,6,9-hexahydro-7-methyl -9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno(3,2-b] pyridine-8-carboxylate. 11. 2-Methoxyethyl 2.,3,4,5.6,.,9-hexahydro-7-methyl -9-(3-nitrophenyl)-1,1-dioxo-thiacyclohepteno(3,2-b] pyridine-8-carboxylate. 1s
ORTH 504 g ) 12. N-Benzyl-N-methylaminoethyl 9- (273,4.5,6-pentafluorophenyl)-2,3,4,5,6,9- hexahydro-7-methyl-1,1-dioxothiacyclohepteno(3,2-b]pyri dine-8-carboxylate. 5 13. Ethyl 10-(2,.3,4.,5.6-pentafluorophenyl) -3.4.5,6,7,10-hexahydro-8-methyl-1,1-dioxo-2H- thiacycloocteno(3,2-b]pyridine-9-carboxylate. 14. N-Benzyl-N-methylaminoethyl 10-(2,3.4,5, ’ 6-pentafluorophenyl)-3,4,5,6,7,10-hexahydro-8- } : 10 ’ methyl-1,1-dioxo-2H-thiacycloocteno[3,2-b}pyridine-9- carboxylate. : 15. N-Benzyl-N-methylaminoethyl 3.4,5,6,7,10-hexahydro-8 -methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno (3.2-b]pyridine-9-carboxylate. 16. N-Benzyl-N-methylaminoethyl 11-(3-nitrophenyl) 2.3.4, 6.7.8,11-octahydro-9-methyl-1,1-dioxothiacyclononeno[3, 2-b]pyridine-10-carboxylate. 17. N-Benzyl-N-methylaminoethyl 2.4,5,6,9-hexahydro-6- methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno (3,2-blpyridine-8-carboxylate. 18. N-Benzyl-N-methylaminoethyl 9-(2-chlorophenyl)- - 2,4.5.6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno (3.2-b)pyridine-8-carboxylate. 19. N-Benzyl-N-methylaminoethyl 9-(2,3- dichlorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1- dioxothiacyclohepteno(3,2-b]pyridine-8-carboxylate. 20. N-Benzyl-N-methylaminoethyl 9-(2-chloro-6- fluorophenyl)-2.4.5,6,9-hexahydro-7-methyl-1,1- dioxothiacyclohepteno(3.2-blpyridine-8-carboxylate. 21. N-Benzyl-N-methylaminoethyl 9-(2- cifluoromethoxyphenyl)-2,4,5,6,9-hexahydro-7-methyl- l,1-dioxothiacyclohepteno(3,2-b]pyridine-8- carboxylate.
ORTH 504 i ) 26186 °° 22. N-Benzyl-N-methylaminoethyl 2,4,5,6,9-hexahydro-7- methyl-9-(2-trifluoromethylphenyl)-1,1- dioxothiacyclohepteno(3,2-b]pyridine-8-carboxylate. 23. N-Benzyl-N-methylaminoethyl 10-(2-chlorophenyl)- 3,4,5.,6,7,10-hexahydro-8-methyl-1,1-dioxocycloocteno {3.2-b]lpyridine-9-carboxylate. 24. N-Benzyl-N-methylaminoethyl 10-(2,3-dichlorophenyl- 3,4,5,6,7,10-hexahydro-8-methyl-1,1- ’ dioxothiacycloocteno(3,2-b]lpyridine-9-carboxylate. ’ 10 25. N-Benzyl-N-methylaminoethyl 10-(2- ’ difluoromethoxyphenyl)-3,4,5,6,7,10-hexahydro-8-methyl- l.l1-dioxothiacycloocteno(3,2-b]lpyridine-9-carboxylate. 26. N-Benzyl-N-methylaminoethyl 10-(2-chloro-6- fluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1- dioxothiacycloocteno[3,2-blpyridine-9-carboxylate. 27. N-Benzyl-N-methylaminoethyl 10-(2-chloro-3- trifluoromethylphenyl)-3,4,5,6,7,10-hexahydro-8-methyl- 1,1-dioxothiacycloocteno(3,2-b]lpyridine-9-carboxylate. 28. N-Benzyl-N-methylaminoethyl 12-(2-chloro-3- trifluoromethylphenyl)-2,3,4,5,6.7,8,11-octahydro-9- methyl-1,1-dioxothiacyclononeno(3,2-b}pyridine-10- carboxylate. 29. N-Methyl-N-phenylaminoethyl 10-(2,3,4.5,6- pentafluorophenyl)-3.4.5,6,7,10-hexahydro-8-methyl-1,1- dioxothiacycloocteno(3,2-blpyridine-9-carboxylate.
The compounds of this invention are potent inhibitors of calcium ion uptake into smooth muscle tissue and act to relax or prevent contraction of tissue mediated by calcium mechanisms. The compounds of this invention have therapeutic utility in the treatment of cardiovascular disorders including hypertension, ischemia, angina, ’ : arrhythmias, congestive heart failure, peripheral vascular disorders such as intermittant claudication, migraines, myocardial infarction, platelet aggregation and stroke.
ORTH 504
)
Ca ) In addition, the compounds of the invention possess utility with respect to other disorders such as hypersensitivity, allergy. asthma, dysmenorrhea, bronchoconstriction, esophageal spasm, premature labor and
S urinary tract, gastric hypersecretory and membrane integrity disorders. The compounds, compositions and methods for making the various aspects of the present invention will become more readily apparent from the . following description. : Description and Preferred Embodiments
Various terms used herein should be understood to signify the following: : :
Unless specified otherwise, the term "alkyl" refers to a straight, branched or cyclic substituent consisting solely of carbon and hydrogen with no unsaturation and containing from 1 to 8 carbon atoms. The term "lower alkoxy" refers to a lower alkyl chain as described above having no more than 4 carbons. The term "halo" means fluoro, chloro, bromo and iodo.
The phrase “pharmaceutically acceptable salts" denotes salts of the free base which Possess the desired
Pharmacological activity of the free base and which are neither biologically nor otherwise undesirable, These salts may be derived from inorganic or organic acids.
Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acia, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3s mandelic acid, methanesulfonic acid, ethanesulfonic acid,
ORTH 504 ’
p-toluenesulfonic acid, salicylic acid and the like. . Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for ’ administration, e.g., aerosol, intravenous, sublingual, oral or topical. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case or oral solid preparations such as, for " example, powders, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case oo solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will : 25 usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
For aerosol use, suspensions or solutions may be + employed. The pharmaceutical compositions will generally contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 0.001 to about 100 mg/kg and preferably from about 0.001 to about 3s 20 mg/kg of the active ingredient.
ORTH 504
The novel compounds of the present invention may be synthesized according to the following reaction scheme wherein R,. R,. R,. Rye R. are as defined above, MCPBA signifies m-chloroperoxybenzoic acid, and Y
S is p-methylphenyl or alkyl.
ORTH 504
2 6 1 8 6 -10-
Sylfgones Synthesis : NaBH S a M
Pe 22 ar Hom, ne III
II. HO 0, 4° 0, ,0 ——p
CH
(CH A a (CHa nt20 Noy 0 v v synthetic Roytes to Dioxothigcycloalkenaf3,2-Dlpyridines 0 OR R 0 SARE) 0, 2073 o_ # \ COOR > 2
Ns Rye oS \ 2 toluene, a a “ CaaR, —— Tog (CH) -CO0R, wd VR \="2 nTR, ne J i VIII H : Ia 0. ~0R 7 vi nel={d =f c= 2 + Ss Co0Ry (cry) . R a (CHy) N Ry Ib n=l Nas n \ 0 a H “pT, x o=4 a=/ : C00 ~0H v$S0.C1 7 3 c00~—0s0,Y =S R4CHA vil = | Ux g 2 ad w=" | ~~ 1 nt=2 I alCH Ty Fy al CH= 7, ? NR H Ic HV x v 2
Via a R
Ly 3 C00~NR,R
S 4's tls ) , ) a3 } a(CHz \ Ry 1d
) - 11 -
With reference to the above Reaction Scheme, the synthesis of the compounds of this invention is accomplished as follows:
The 3-keto cyclic sulfones of formula V (in the instance wherein n is 1-4) can be prepared in accordance with the procedure disclosed in B. Listert, P. Kiiffner, and T.J.
Arackel, Chem. Ber. 110, 1069-1085 (1977). ’
However, in the case of 3-oxo-tetrahydrothiophene-1, 1-dioxide, that is wherein n is 2, the reference procedure is quite laborious. It has been found. in accordance with the present invention, that the compounds of formula V, in which n is 2 or 3, can be obtained in high yield in a straightforward manner from the respective 3-cyclic sulfides of formula II. Said compound of formula II may be prepared in accordance with the procedure disclosed in
E.A. Fehnel, J. Amer. Chem. Soc. 74, 1569-74 (1952).
The 3-keto moiety of compound II is reduced to an alcohol (compound III) preferably with sodium borohydride although a number of other reducing agents such as diborane, lithium aluminum hydride or sodium cyanoborohydride may be used. Thereafter compound III is oxidized to compound Iv preferably with m-chloroperoxybenzoic acid. Other suitable oxidizing agents are hydrogen peroxide or sodium . periodate. Finally, the hydroxy moiety on compound IV is reoxidized to the corresponding keto moiety in compound V, preferably using Jones reagent (chromic anhydride in dilute sulfuric acid which is added to a solution of the alcohol in acetone). Other suitable oxidizing agents are: potassium dichromatic or Collins reagent (chromic anhydride in pyridine).
ORTH 504
: J - 12 -
The 7, 8 and 9 membered 3-keto cyclic sulfones may be : prepared in accordance with the method described in the
Listert et al reference, previously mentioned.
Compounds of the formula I, wherein n is 1-12 (designated compound Ia in the following Reaction Scheme) may be prepared by stirring equal molar amounts of for example : j_oxotetrahydrothiophene-1,1-dioxide, the appropriately - ~ substituted aldehyde of formula VII and the substituted 3-aminoester of formula VI in ethanol for two to twenty-four hours at room temperature (see example 4).
The resultant hydroxy intermediate of formula VIII is a novel compound. Said compound VIII is then heated in refluxing toluene for one to twenty-four hours to effect dehydration, thus proddcing compound Ia (see example 5).
The 6 to 15 membered cyclic sulfone products of formula I (wherein n is 3-12) may be obtained directly by refluxing a stirred ethanolic mixture of equimolar amounts of the ketosulfone of formula V, the aldehyde of formula VII and the substituted 3-aminoester of formula VI for about 16 - hours in accordance with the procedure of example 6. The resultant product wherein n is 3-12, is designated compound Ib and/or XII. Note that compound 1b is actually the same as compound la, but obtained by a different route. Where the novel compound XII is formed, it can be converted to Ib by heating with ethanolic hydrogen chloride aor toluene.
The preparation of compound I wherein R, is alkylene-
NR Rg can also be achieved when a compound of the formula V is reacted with an appropriate aldehyde of the formula VII and 2-hydroxyethyl-3-aminocrotonate of formula
Via in order to prepare the intermediate of formula Ic 15 (see example VIII). The latter intermediate of formula Ic
ORTH 504 .
) - 13 - : is then converted to the sulfonyl ester preferably by refluxing with a compound of the formula IX, wherein Y is p-methylphenyl or alkyl. The sulfonyl ester of formula X is then displaced with an appropriate amine of formula XI in order to produce a compound of the - formula Id (see example 9).
In the following examples, both example 6 and example 10 illustrate the preparation of compound Ib, by the direct reaction of compound V, compound VII and compound VI, in the instance wherein n is 3-12.
Various Reaction Schemes discussed above are disclosed in the following additional references:
G.A. Pagani, J. Chem. Soc., Perkin Trans. 2. 1392-7 (1974).
K.G. Mason, M.A. Smith, and E.S. Stern, J. Chem. Soc. (QC) 2171-76 (1967).
Maruko Seiyaku, Japan No. 58201764 (1984).
The following specific examples are illustrative of the present invention and should not be considered as ; limitative thereof in any manner.
Example 1
Tetrahydrothiopyran-3-ol.
To a solution of tetrahydrothiopyran-3-one (ref 4) (10.0gq, 0.086 moles) in ethanol was added sodium borohydride (3.25 g, 0.086 moles) over a 5 minute period. After stirring for 30 minutes, a 1 N. solution of hydrochloric acid was added until a pH of 5 was reached. The reaction mixture was diluted with water and extracted with dichloromethane (6 x SO mL). The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and distilled
ORTH S504 oo oo ) - 14 - (approx. 100 torr, 158°C) to give 6.8 g product. H' NMR cpl, 3.9 (broad singlet, 1H) 2.2-2.9 (multiplet, SH) 1.4-2.2 (multiplet, 4H).
Example 2
Tetrahydrothiopyran-3-ol-1,1-dioxide.
A solution of tetrahydrothiopyran-3-ol (6.8 g, 0.58 moles) and chloroform (250 mL) was cooled to 0°C and treated with m-chloroperoxybenzoic acid (23.4 g, 0.135 moles) at a rate . 10 which did not cause the temperature to rise above 10°C.
After addition was complete, the thickened mixture was stirred at 0°C for 1 hour and then at room temperature for 30 minutes. The resulting solid was removed by filtration and the filtrate evaporated in vacuo. The resulting solid was diluted with ethanol and evaporated in vacuo to remove remaining chloroform. The resulting solid was diluted with water (150 mL) and filtered. The filtrate was evaporated in vacuo and residual water was removed by repeated evaporation with toluene. This afforded 7.5 g of product as a colorless oil. H' NMR Dg -DMSO 4.3 (broad : singlet, 1H) 3.4-4.0 (multiplet, 1H) 2.7-3.3 (multiplet, : 4H) 1.2-2.1 (multiplet, 4H).
Example 3
Tetrahydrothiopyran-3-one-1,1-dioxide.
To a solution of tetrahydrothiopyran-3-ol-1,1-dioxide (7.5 g, 0.05 moles) and acetone (150 mL) was slowly added enough Jones reagent to maintain a brown color for at least 10 minutes without need for additional reagent. The excess reagent was reduced by addition of isopropanol (S mL). The mixture was filtered through anhydrous magnesium sulfate and the chromium salts were washed 3x with acetone. The solvent was removed in vacuo to give a solid which was triturated with ethanol. The resulting crystals 3s were isolated by filtration and rinsed 3x with diethyl
ORTH 504 ether. After drying, 5.0 g of product was obtained. H'
NMR coCl, 4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet, 2H).
Example 4
Methyl 2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7- (2-nitrophenyl)-1,1-dioxo-thieno(3,2-blpycidine-6- carboxylate .
A solution of tetrahydrothiophene-3-o0xo-1,1-dioxide (1.3 g, 0.01 moles), 2-nitrobenzaldehyde (1.5 g, 0.01 moles) and methyl 3-aminocrotonate (1.1 g, 0.01 moles) in ethanol (20 mL) was stirred overnight. The resulting crystals were isolated by filtration and washed 2x with ethanol and 2x with diethyl ether. After drying under high vacuum for 24 hours 2.54 g of product was obtained, mp 175-179°C (dec).
Methyl 2,3,4,7,-tetrahydro-S-methyl-7-(2-nitrophenyl) -1,1-dioxothienof3,2-blpyridine-6-carboxylate.
A mixture of methyl 2,3,3a,4,7,7a-hexahydro- - Ja-hydroxy-S-methyl-7-(2-nitrophenyl)-1,1-dioxothieno {3.2-blpyridine-6-carboxylate (2.5 g, 0.0065 moles) and . toluene (60 mL) was refluxed for 24 hours. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol. The crystals were washed with diethyl ether 2x and dried at 65°C under high vacuum for 48 hours. This gave 1.78 g product; mp 215-217°C. kYe) 3s
ORTH 504
J
- 16 -
Example 6
Methyl 3,4,5,8,-tetrahydro-6-methyl-8- (3-nitrophenyl)-1,1-dioxo-2H-thiopyrano-f3,2-bjpyridine-7- carboxylate.
A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (0.830 g., 0.0056 moles), 3-nitrobenzaldehyde (0.846 g, 0.0056 moles) and methyl 3-aminocrotonate (0.644 g, 0.0056 moles) in methanol (20 mL) was refluxed for 16 hours. After ’ ~ cooling, the resulting solid was isolated by filtration and washed with diethyl ether. This solid was dried at 40°C for 4 hours under vacuum to give 0.620 g product; mp 236-238°C.
Example 7 2-Hydroxyethyl 3-Aminocrotonate
Anhydrous ammonia gas was bubbled through a solution of 2-hydroxyethyl 3-oxo-butyrate {25 g, 0.17 moles) (ref 9S) and ethanol (250 mL) for 20 minutes. This solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the resulting oil was chromatographed on silica gel (250 g) using ethyl acetate-hexane 60:40 as oC eluant. The enriched fractions were combined and the solvent removed in vacuo to give the product; H' NMR cpCl, 4.33 (t, 2H) 3.85 (t, 2H) 3.55 (s, lH) 2.85 (broad singlet, 1H) 2.31 (s, 3H).
Example 8 2-Hydroxyethyl 3,4,5,8-tetrahydro-6-methyl-8- (3-nitrophenyl)-1,1-dioxo-2H-thiopyrano {3,2-b]lpyridine-7-carboxylate.
A mixture of tetrahydrothiopyran-3-one-1,l1-dioxide (2.80 g, 0.0189 moles), 3-nitrobenzaldehyde (2.85 g., 0.0189 moles), 2-hydroxyethyl-3-aminocrotonate (3.28 g, 0.0226 moles), ammonium acetate (0.291 g, 0.0038 moles) and . is
ORTH 504
: " - - 17 - ethanol (35 mL) was refluxed for 16 hours. After cooling to room temperature the resulting solid was isolated by filtration, washed with ethanol and diethyl ether. The product was dried under vacuum for 16 hours at room 5 temperature affording the product; mp 233-235°C.
SE Example 9
N-Benzyl-N-methyl-2-aminoethyl 2,3,4,8-tetrahydro ’ =6-methyl-8-(3-nitrophenyl)-1,1-dioxo-5H-thiopyrano[3,2-b] pyridine-7-carboxylate Hemioxalate.
A mixture of 2-hydroxyethyl 3,4,5,8-tetrahydro-6-methyl-8- (3-nitrophenyl)- 1,1-dioxo-2H-thiopyrano(3,2-b]} pyridine-7-carboxylate (2.5 g, 0.0061 moles), p-toluenesulfonyl chloride (4.65 g. 0.0244 moles), triethylamine (2.46 g., 0.0244 moles) and dichloromethane (25 mL) was refluxed for 4.5 hours. The reaction mixture was cooled and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel (170 gq) using ethyl acetate - methanol 95:5 as eluant. The enriched fractions containing the tosylate (H' NMR CDCl, 7.3-8.2 (multiplet, 8H) 6.9 (singlet, 1H) 5.2 (singlet, 1H) ) were combined and N-benzyl-N-methylamine (4.69 g, - 0.0387 moles) was added to the solution. The solvent was removed in vacuo and the resulting residue was allowed to stand for 72 hours at room temperature. Chromatography of the mixture was accomplished on silica gel (170 g) using a mixture of ethyl acetate and methanol 97:3 as eluant. The isolated product was dissolved in ether and treated with a saturated solution of oxalic acid in diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether and dried at 60°C for 16 hours under vacuum affording the product (2.07 gq) mp 220-222°C. 3s
ORTH 504
: . - 18 =
Example 10
Ethyl 2,3,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1- dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.
A solution of thiacycloheptane -3-one-1l,1-dioxide (1.3 gq, 0.0080 moles), 3-nitrobenzaldehyde (1.2 g, 0.0080 moles), ethyl 3-aminocrotonate (1.04 g, 0.0080 moles) and ethanol (20 mL) was refluxed 16 hours. After removal of the solvent in vacuo the residue was chromatographed on silica gel (170 g) using a mixture of ethyl acetate and hexane (4:1) as eluant. The enriched fractions were combined and the solvent removed in vacuo. The solid was triturated with diethyl ether, filtered and dried under vacuum overnight to give 1.52 g of product; mp 211-213°C. : 15 Example 11
Ethyl 3,4,5,7,10,10a-hexahydro-8-methyl-10-(3-nitrophenyl) . -1, 1-dioxo-2H-thiacycloocteno{3,2-b] pyridine-9- carboxylate. ’
A solution of thiacyclooctane -3-one-1,1-dioxide (0.354, 0.002 moles), 3-nitrobenzaldehyde (0.30g, 0.002 moles), ethyl 3-aminocrotonate (0.26g, 0.002 moles) and ethanol {(30mL) was refluxed 16 hours. After cooling to room temperature a yellow precipitate formed which was isolated by filtration, washed with diethyl ether and dried in vacuo to afford the product (0.56g) mp 211-214.
Example 12
Ethyl 3,4,5,6,7,10-hexahydro-8-methyl-10-(3-nitrophenyl -1, 1-dioxo-2H-thiacyclooctenof{3,2-b] pyridine-9 ~carboxylate.
A mixture of ethyl 3,4,5,7,10,10a-hexahydro-8-methyl- 10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno{3,2-b] pyridine-9-carboxylate (0.459,0.0011 moles) and toluene (30mL) was refluxed for 24 hours. The resulting solid was
ORTH 504 s . - 19 - isolated by filtration, washed with diethyl ether and dried in vacuo to afford the product mp 234-235°C.
The compounds of the present invention were evaluated for their biological properties. The present compounds have : shown the ability to influence calcium mediated events including inhibition of smooth muscle contraction of trachea and vascular tissues. The model screening regimen used to evaluate these compounds has shown: 1) Inhibition of nitrendipine binding to calcium channels. 2) Ability to modulate the activity of tissues which are dependent on calcium utilization as in trachea and vascular tissue, . 3) Their use as antihypertensives and/or bronchodilating agents in mammals.
Based on the above results, it is believed that these - compounds will be useful in hypertension, myocardial, ischemia. angina, congestive heart failure, migraine, myocardial infarction, platelet aggregation, stroke, hypersensitivity, allergy. asthma, gastric secretory dysmenorrhea, esophageal spasm, premature labor and urinary tract disorders.
The following Table 1 sets forth inhibition of nitrendipine binding as well as inhibition of calcium dependent smooth muscle contraction in terms of percent inhibition, for a number of representative compounds of the present invention.
ORTH 504
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QQ
— = - - = x = =" = = ~| TFFTETIET
LEIS SEES
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Ss dgssSss ’ =» NNN NNN AA mon
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Pd SEE LEERY : = 5 a = = =, =, )° sae SAA CK of fossfy : ~ O° PEA A z * . = =
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-
The assay for inhibition of nitrendipine binding follows the following procedure:
Female, New Zealand white rabbits (1-2 kg) are sacrificed by cervical dislocation, and the heart is immediately removed, cleaned, and chopped into small oo pieces. The tissue is homogenized in 5X volume of ’ 0.05M Hepes buffer, pH 7.4. The homogenate is . centrifuged at 4000 xg for 10 minutes: the supernatant is recentrifuged 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 until used. Each tube of the binding assay contains Iu- nitrendipine (0.05-0.50nM), buffer. membranes (0.10 ml), and test compound in a total volume of 1.0 ml. After 90 minutes at 4%c, the bound nitrendipine is separated from the unbound by filtration on Whatman GF/C fibers. After rinsing, the filters are dried and ’ 20 counted in a liquid scintillation counter.
Non-specific binding of 34_nitrendipine (that amount bound in the presence of excess unlabelled nitrendipine) is subtracted from the total bound to 2% obtain specifically bound radiolabeled nitrendipine.
The amount of specifically bound nitrendipine in the presence of a test compound is compared to that amount bound in the absence of a compound. A percent displacement (or inhibition) can then be obtained. :
The test for inhibition of calcium dependent smooth muscle contraction is determined according to the following : procedure: 1s
ORTH 504
) - 25 -
Trachea from dogs sacrificed by excess KCl injection are stored overnight at 4°C in oxygenated
Krebs-Henseleit buffer. Tracheal rings, one cartilage segment wide (5-10 mm), are cut starting
S from the bronchial end. After cutting the cartilage, the trachealis muscle tissue is suspended in oxygenated Krebs-Henseleit buffer at 37°C in a 25 ml tissue bath. After a 60 minutes equilibration period, the tissues are challenged with 10 uM carbachol. After 5 minutes the tissues are rinsed and allowed to rest 50 minutes. The tissues are then challenged with 50 mM KCl and, after 30 minutes, the contractions are quantitated. The tissues are then rinsed and reequilibrated for 50 minutes. Test compounds are then added for 10 minutes, and the tissue is rechallenged with 50 mMKcl. After 30 minutes, the contraction is recorded and used to determine the % inhibition of control. ' The percent inhibition of smooth muscle contraction is calculated from response data before and after drug treatment. % inhibition = 100-100 (peak response after drug treatment) peak response before drug treatment
A rating is assigned to the compound depending upon the percent inhibition obtained. ™"
Claims (2)
1. A compound bf the formula (formula VIII) ; TTT 1 oT oo eo | oo 3 Ce n(Cf,) A 2: = i Cy : Ci y Ry oo ’ wherein n=1-12: Rj is hydrogen, amino, alkyl, haloalkyl "or 1 CH0-Ry; Rp is straight chained or branched alkyl having 1 tc 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, Or : alkylene-X having at least 2 carbon atoms, wherein X is alkoxy, hydroxy, halo, p-tosyloxy, mesyloxy, pyridyl, amino or -NR4Rg, wherein Ry and Rs are the same or different and. are selected from hydrogen, alkyl, cycloalkyl, phenyl, 0 benzyl, phenylethyl, or Ry: Rj and the nitrogen atom to i which they are attached form a 5, 6 or 7 membered hetero- cyclic ring which optionally contains an oxygen or sulfur atom or an additional nitrogen atom, or said heterocyclic “ring may be fused to a benzene ring to form an indoline, 85 isoindoline, tetrahydcoquinoline or tetrahydroisoquinoline ; group, and in the instance wherein said heterocyclic ring is piperazino, said oiperazino may optionally be substituted in the 4-position with the substituted Rg which is selected - from the group consisting of alkyl, cycloalkyl, benzyl, i» 0 phenyl or phenyl substituted by alkoxy, halo, alkyl, nitro " or trifluoromethyl; R3 is 2-pyridyl, 3-pyridyl, 3-pyridyl] i : ! - Co
— To oo oe | ~ ; substituted at positions 2, 4, 5 or 6 with one or more groups selected from halogen, nitro, lower alkoxy, lower - alkylthio, cyano, lower carbalkoxy, difluoromethoxy, difluoromethylthio or lower alkylsulfonyl; 2-thienyl, 3- thienyl, 2, 1, 3-benzoxadiazolyl, 2, 1, 3-benzthiadiazolyl or phenyl optionally substituted at positions 2 through 6 with one or more groups selected from hydrogen, lower alkyl, - lower alkoxy, cyano, lower carbalkoxy, -alkylthio, difluoro- methoxy, difluoromethylthio, alkylsulfonyl, halo, nitro or oo trifluoromethyl; their optical antipodes or the pharma- ceutieally acceptable acid and base addition salts thereof.
2. Methyl 2,3,3a,4,7,7a~hexahydro-3a~hydroxy-5-methyl- 7-(2-nitrophenyl)-1,1-dioxo~thienc[3,2~b]pyridine~6~-carboxy- : { late. CHARLES F. SCHWENDER JOHN H. DODD Co + Inventors ‘ j , " v
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/849,647 US4705785A (en) | 1986-04-09 | 1986-04-09 | Substituted thiacycloalkeno (3,2-b) pyridines and pharmaceutical compositions and method of use |
US07/010,858 US4777167A (en) | 1986-04-09 | 1987-02-04 | Pharmaceutically useful substituted thiacycloalkeno [3,2-b]pyridines, compositions and method of use |
PH35117A PH26673A (en) | 1986-04-09 | 1987-04-09 | Substituted thiacycloalkeno Ú3, 2-B¾ pyridines compositions and method of use |
Publications (1)
Publication Number | Publication Date |
---|---|
PH26186A true PH26186A (en) | 1992-03-18 |
Family
ID=27353988
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PH37780A PH26186A (en) | 1986-04-09 | 1988-11-08 | Substituted thiacycloalkeno (3,2-B) pyridine intermediates |
Country Status (1)
Country | Link |
---|---|
PH (1) | PH26186A (en) |
-
1988
- 1988-11-08 PH PH37780A patent/PH26186A/en unknown
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