GB2208648A - Sulphonyl butene derivatives and processes for their preparati - Google Patents

Sulphonyl butene derivatives and processes for their preparati Download PDF

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Publication number
GB2208648A
GB2208648A GB8824140A GB8824140A GB2208648A GB 2208648 A GB2208648 A GB 2208648A GB 8824140 A GB8824140 A GB 8824140A GB 8824140 A GB8824140 A GB 8824140A GB 2208648 A GB2208648 A GB 2208648A
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compound
phenyl
formula
alkyl
heterocyclic radical
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GB8824140D0 (en
GB2208648B (en
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Toshihiro Takahashi
Koichiro Hagihara
Yoshikuni Suzuki
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Nisshin Seifun Group Inc
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Nisshin Seifun Group Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

9 n f-.
220864% SULPHONYL BUTENE DERIVATIVES AND PROCESSES FOR THEIR PREPARATION This invention relates to new sulphonyl butene derivatives useful as intermediates in the production of 1,4-dihydropyridine sulfone derivatives having such pharmacological activities as vasodilating, hypotensive and the like, and to processes for their preparation.
British Patent Application No. 8615240 provides compounds of the formula (1) @_ R 1 R200C so 2 R 3 H 3 c)'CH 3 H (1) in which R, is nitro or dimethylaminoethyloxy; R 2 is C l- c 6 alkyl or -(CH2)n-NR 4 RS; R 4 and R. which may be the same or different are independently hydrogen, Cl-C 6 alkyl or aralkyl; n is 1 to 6; 6 R 3 is c I- c 6 alkyl, C 2- c 6 alkenyl, phenyl or -(CH 2)n-R; 1.
0 11 R 6 is alkoxy, phenyl, aryloxy, -OC-R. or -NR,R,; R 7 is phenyl or Ncontaining heterocyclic radical; and R. and R. which may be the same or different are independently hydrogen, C,-C 6 alkyl, aralkyl or cycloalkyl, or R. and R. taken together with N-atom may form unsubstituted or substituted hereocyclic radical containing one or two N atoms, with the proviso that when R, is nitro and R 3 is CI-C 6 alkyl or phenyl, R 2 must be -(CH 2),,-NR 4 RS wherein R 4 and R. are not both alkyl and a pharmaceutically acceptable acid addition salt thereof.
That application also provides a process for preparing the compounds of formula (1) which comprises subjecting to a ring closure a compound of formula 0 so 2 R 3 H 3 d 1.11 R, (2) wherein R, and R 3 are as defined previously, and a compound of the formula H 2 NA,-,41 4 COOR (3) c i wherein R 4 is C l- c 6 alkyl and such processes wherein the compound of formula (2) is produced by reaction of a compound of formula (4) with a compound of formula (5) H 3 c 0 11 so R 2 3 (4) CHO 4_ R 1 (5) The present invention, in one aspect, provide compounds of formula (2) 0 h so 2 R 3 R 3 C^./ 0 "l (2) wherein R' is nitro or dime thylaminoe thyl oxy; R 3 is c 1_ c 6 alkyl, C 2_ c 6 alkenyl, phenyl or -(CH2)n-R 6 are intermediates useful for the synthesis of the compound of the formula (1). In the compounds of the invention, the substituent R, is in any position of ortho, meta or para relative to the phenyl nucleus, but preferably in the o- or m-position. Concrete examples of R 3 include methyl, ethyl, 1 1 n-propylr i-propyl, n-butyl, vinyl, phenyl, benzyl, phenylethyl, phenylpropyl, benzolyoxyethyl, -CH2 CH 2 -N (CH 3) -CH 2 -c - I-\ - -NI r X.. - CH -CO -CH CH -N N-CH2-C, -N(CH3)-CF-CH2 CH 2 Nxj 2 2 2 \--i and -NHCH2 CH2 The present invention further provides a process for producing the compounds of formula (2) by reacting a compound of the formula (4) with a compound of the formula (5) in accordance with the r -,-.ctictnscheme below.
0 CHO 11 S02 R E3 C 3 + 4- R, (4) (5) 0 0 2 R 3 a 3 c (2) The above reaction can be conducted in the presence or absence of a solvent, but preferably in the presence of a solvent inert to the reaction. The solvents used include hydrocarbons, e.g,. hexane, heptane, octane, ligroin, 1 benzene, toluene, xylene, halogenated hydrocarbons, e.g., dichlorethane, carbon tetrachloride.
The molar ratio of the compound of the formula (4) to the compound of the formula (5) can be varied over the broad range such as 1:10 to 10:1. The both compound are usually used in equimolecular amounts.
The reaction is usually conducted at temperatures ranging from an ordinary temperature to 1000C.
The reaction is preferably carried out in the presence of an organic base catalyst. Examples of the catalyst include pyrolidine, piperidine, morpholine and the like.
The compounds of the formula (2) as thus prepared are taken from the reaction mixtures by purification techniques such as concentration, recrystallization, chromatography and distillation.
The following examples will serve to further illustrate the nature of the present invention without being a limitation on the scope thereof, the scope being defined solely by the appended claims.
is solely by the appended claims.
EXAMPLE 1
1-(3-Nitrophenyl)-2-n-propylsulfonyl-lbuten-3-one A solution of l-n-propylsulfonyl-2-propanone(S.6 g) and m- nitrobenzaldehyde (6.85 g) in 100 ml of benzene was heated continuously under reflux for 6 hours in the presence of catalytic amount (3 drops) of piperidine, while removing azeotropically producing water with Molecular Sieve 3A. The reaction solution was concentrated and purified by silica gel chromatography to give 7.02 g (66% yield) of 1-(3-nitrophenyl)2-npropylsulfonyl-l-buten-3-one in the hexane effluent portion containing 5% ethyl acetate.
The title compound is identified below.
0 H cj--,so 2 nPr 3 -, NO 2 C'" M.P. 116.8 118.20C NMR (CDC1 3 6) 1.1 (3H, t, J=7 Ez) 1. 91 (2H, m) 2.22 (3H, s) 2.6-3.0 (2H, m) 7. 55 (1H, s) 1 k 7.61-8.32 (4H, m) The same procedure as mentioned in Example 1 was repeated by varying the starting materials to give the compounds which are listed below.
is 1) 2-Benzenesulfonyl-l-(3-nitrophenyl) buten-3-one 0 H 3 CA so 2 -c 0 0 2 Pale yellow crystal M.P. 124.6 126.51C NMR (CDC1 3 6) 2.36 (3H, s) 7.52-7.90 (8H, m) 8.20-8.32 (2H, m) IR (Nujol # cm-1) 1695, 1615, 1540 2) 2-(2-Benzoylo -ethyl IsulfofiY1-1.T XY (3-nitrophenyl)-1-buten-3-one 0 so 2,,.OC H 3 0- 2 0 Nujol is the registered Trade 4. 1 i 1 Pale yellow crystal M.P. 142.0 142.9C NMR (CDC1 3 6) 2.35 (3H, s) 3.82 (2H, t, J=6 Hz) 4.78 (2H, t, J=6 Hz) 7.26-8.30 UOH, m) IR (Nuiol, cm-1) 1720, 1685, 1625, 1540 3) 2-(2-Nicotinoyloxyethyl)sulfonyl-l- (3-nitrophenyl)-1-buten-3-one 0 H 3 c J.11, 0 vo 0 2 OCO ON NMR (CDC1 3 ' C- 2.37 (3H, s) 2.83 (2H, t, J=6 Hz) 4.83 (2H, t, J=6 HZ) 7.30-9.13 (9H, m) IR (neat, em-') 1720, 1690, 1615, 1590, 1530 MASS 404 (M), 387, 266, 106 (100%) 4) 1-(3-Nitrophenyl)-2-(3phenylpropyl)sulfonyl-l buten-3-one 1 -g- 0 H 3 c J, 0 2 NO 2 is Z1 NMR (CDC1 3' 6) 2.14 (2H, m) 2.36 (3H, S) 2.79 (2H, t, J=7 HZ) 3.27 (2H, m) 7.17-8.72 (10H, m) IR (neat, cm-1) 1700, 1615, 1530 MASS 0 374 (M++1), 309, 251, 183, 117, 91 (100%) 1-(2-Nitrophenyl)-2-n-propylsulfonyl-l- buten-3-one 0 SO nPr H C 3 0 0 2 0 1 NMR (CDC1 3' 6) 1.11 (3H, t, J=7 Hz) 1.86 (2H, m) 2.16 M, s) 3.29 (2H, m) 9 1 7.27-8.31 (4H, m) IR (neat, cm-1) 1700, 1610, 1575, 1530 6) 1-(3-Nitrophenyl)-2-(4-phenylbutyl)sulfonyl-l buten-3-one 0 E3 c 2 NO 2 0 0 NMR (CDC1 3 ' 6) 1.74-1.92 (4H, m) 2.35 (3H, S) 2.66 (2H, t, J=7 Hz) 3.29 (2H, t, J=7 HZ) 7.11-8.73 (9H, m) 10.13 (1H, S) IR (neat, cm-1) 3080, 3020, 2930, 2850, 1700, 1615 EXAMPLE 2 1-(3-Nitrophenyl)-2-n-butylsulfonyl-lbuten-3-one Following the same procedure as mentioned in Example 20 1, 0.85 9 (20.8%) of 1-(3nitrophenyl)-2-n-butylsulfonyl-lbuten-3-one was prepared as an oily substance from l-n-butyl- j! 1 1 sulfonyl-2-propanone (2.34 g) and m-nitrobenzaldehyde (2.98 g).
The title compound is identified below.
0 H 3 C.' so 2 n BU 0 _,,, N02 NMR (CDC1 3' 6) EXAMPLE 3
1-[2-(2-Dimethylaminoethyloxy)phenyll-2n-propylsulfonyl-l-buten-3-one Following the same procedure as mentioned in Example 1, 2.98 g (77.1%) of 1-[2-(2-dimethylaminoethyloxyphenyll- 2-n-propylsulfonyl-l-buten-3-one was prepared from l-n-propyl sulfonyl-2- propanone (1.87 g) and 2-(2-dimethylaminoethyloxy)benzaldehyde (2.20 g).
The title compound is identified below. 0 Al SO n Pr H 3 C., 2 0.97 (3H, t, J=7 Hz) 1.3-1.9 (4H, m) 2.26 (3H, S) 2.7-3.1 (2H, m) 7.6-8.3 (5H, m) U,t \--NMe2 0 1 NMR (CDC1 3' 6) -1.08 OH, t, J=7 HZ) 1.82 (2H, m) 2.25 OH, 5) 2.36 (6H, S) 2.78 (2H, t, J=6 HZ) 3.2-3.3 (2H, m) 4.15 (2H, t, J=6 EZ) 6.9-7.4 (4H, in) 8.04 (1H, S)

Claims (7)

1. A compound of formula (2) 0 H 3 c 0 2 R 3 1, R 1 (2) wherein Rl is nitro or dimethylaminoethyloxy; R 3 is C 1- C 6 alkyl, C 2- C 6 alkenyl, phenyl, substituted amino or -(CH 2), -R 6; 0 11 R. is alkoxy, phenyl, aryloxy, -OC-R 7 or NR, R9; R 7 is phenyl or N-containing heterocyclic radical; and R. and R 9' which may be the same or different are independently hydrogen, C1-C. alkyl, aralkyl or cycloalkyl, or R. and R 9 taken together with N-atom may form unsubstituted or substituted heterocyclic radical containing one or more two N atoms.
2. A compound of claim I wherein R, is o-nitro or m-nitro.
3. A compound of claim 1 wherein R, is dimethylaminoethyloxy.
1 n.
T I 1
4. A compound of any one of the preceding claims wherein R 3 is CI-C 6 alkyl, C -C, alkenyl, phenyl or 0 11 -(CH2)n-R6i R6 is alkoxy, phenyl, aryloxy, -OC-R7 or _NR&Rg, R7 is phenyl or N-containing heterocyclic radical, R. and R. are C,-C, alkyl, aralkyl or cycloalkyl, and R. and R. taken together with N-atom may form unsubstituted or substituted heterocyclic radical containing one or two N atoms.
5. A process for preparing a compound of the formula (2) wherein R. and R 3 are as defined in any one of claims 1 to 4 which comprises reacting a compound of the formula 0 11 so 2 R ]a 3 C,,," (4) wherein R 3 is as defined previously, with a compound of the formula CEO 0 R, 6- wherein R, is as defined previously.
6. A compound of claim 1 (5) hereinbefor e k -is- 1 1 specifically mentioned.
7. A process according to claim 5 substantially as hereinbefore described with reference to any one of the Examples.
Published 1988 at The Patent Wice. State House. 6671 High Holborn. London WC1R 4TP. Further copies may be obtained from The Patent Office.
GB8824140A 1985-06-24 1988-10-14 Suphonyl butene derivatives and processes for their preparation Expired - Fee Related GB2208648B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP60135990A JPS61293972A (en) 1985-06-24 1985-06-24 1,4-dihydroxypyridinesulfone derivative and production thereof

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GB8824140D0 GB8824140D0 (en) 1988-11-23
GB2208648A true GB2208648A (en) 1989-04-12
GB2208648B GB2208648B (en) 1990-03-07

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GB8615240A Expired - Fee Related GB2178738B (en) 1985-06-24 1986-06-23 1,4-dihydropyridine sulfone derivatives, processes for their preparation and pharmaceutical compositions comprising the same
GB8824140A Expired - Fee Related GB2208648B (en) 1985-06-24 1988-10-14 Suphonyl butene derivatives and processes for their preparation

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DE (1) DE3620632A1 (en)
FR (1) FR2588003B1 (en)
GB (2) GB2178738B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210401992A1 (en) * 2018-06-26 2021-12-30 Tsrl, Inc. Metabolically stable prodrugs

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ES2207523T3 (en) 1999-06-14 2004-06-01 Ortho-Mcneil Pharmaceutical, Inc. DITIEPINO (6,5-b) PIRIDINE AND ASSOCIATED COMPOSITIONS AND PROCEDURES.

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2616995A1 (en) * 1976-04-17 1977-10-27 Bayer Ag Sulphur substd. (1,4)-dihydro-pyridine derivs. - with circulatory activity, e.g. vasodilating and hypotensive effects
DE2639498A1 (en) * 1976-09-02 1978-03-09 Bayer Ag NEW SULFUR-CONTAINING AMINO-DIHYDROPYRIDINES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT
DE2747513A1 (en) * 1977-10-22 1979-05-03 Bayer Ag DIHYDROPYRIDINE WITH SULFUR-CONTAINING ESTER GROUPS
EP0111453A1 (en) * 1982-12-10 1984-06-20 Ciba-Geigy Ag Amide derivatives

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Publication number Priority date Publication date Assignee Title
CH607848A5 (en) * 1974-06-04 1978-11-30 Bayer Ag
DE2616991A1 (en) * 1976-04-17 1977-10-27 Bayer Ag Thio-substd. dihydro-pyridine derivs. - coronary vasodilators and antihypertensives prepd. e.g. by reacting dicarbonyl cpds. with amines and thio-substd. ketones
US4523847A (en) * 1983-07-07 1985-06-18 International Business Machines Corporation Frequency modulation-polarization spectroscopy method and device for detecting spectral features
DE3501695A1 (en) * 1985-01-19 1986-07-24 Bayer Ag, 5090 Leverkusen USE OF SULFONYL DIHYDROPYRIDINE AS A MEDICINAL PRODUCT FOR TREATING ASTHMA
ZA863578B (en) * 1985-06-21 1987-02-25 Hoffmann La Roche Dihydropyridine derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2616995A1 (en) * 1976-04-17 1977-10-27 Bayer Ag Sulphur substd. (1,4)-dihydro-pyridine derivs. - with circulatory activity, e.g. vasodilating and hypotensive effects
DE2639498A1 (en) * 1976-09-02 1978-03-09 Bayer Ag NEW SULFUR-CONTAINING AMINO-DIHYDROPYRIDINES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT
DE2747513A1 (en) * 1977-10-22 1979-05-03 Bayer Ag DIHYDROPYRIDINE WITH SULFUR-CONTAINING ESTER GROUPS
EP0001769A1 (en) * 1977-10-22 1979-05-16 Bayer Ag Sulfur-containing esters of 1,4-dihydropyridine carboxylic acids, their preparation and pharmaceutical use
EP0111453A1 (en) * 1982-12-10 1984-06-20 Ciba-Geigy Ag Amide derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210401992A1 (en) * 2018-06-26 2021-12-30 Tsrl, Inc. Metabolically stable prodrugs

Also Published As

Publication number Publication date
GB8824140D0 (en) 1988-11-23
GB2208648B (en) 1990-03-07
FR2588003A1 (en) 1987-04-03
DE3620632A1 (en) 1987-01-02
JPS61293972A (en) 1986-12-24
GB2178738B (en) 1990-02-28
GB8615240D0 (en) 1986-07-30
FR2588003B1 (en) 1989-09-15
GB2178738A (en) 1987-02-18

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