Patent Publication Number: US-4548753-A

Title: 2,3-Butanediol diester derivatives

Description:
This is a continuation of application Ser. No. 333,772, filed Dec. 23, 1981, now U.S. Pat. No. 4,469,704. 
    
    
     BACKGROUND OF THE INVENTION 
     (1) Field of the Invention 
     The present invention relates to 2,3-butanediol diester derivatives, process for producing the same, and an antiulcer drug containing the same. 
     (2) Description of the Prior Art 
     Heretofore, it has been known that coixenolide, a constituent of coix seed, has an antitumor effect (Japanese Patent Publication No. 36-13349) and some 2,3-butanediol diesters can be used as a durable perfume/flavor agent or modifier (Japanese Patent Laid-open No. 55-154940). 
     SUMMARY OF THE INVENTION 
     The present inventors have carried out a series of researches on the pharmacological actions of 2,3-butanediol diester derivatives (abbreviated as &#34;butanediol diester&#34; hereunder), and as the result of these researches, they have discovered that the butanediol diester represented by the formula (I) ##STR2## where R A  is a saturated or unsaturated alkyl group which may have a branched chain, or a group represented by ##STR3## (where R 1  is a hydrogen atom, cyano group, or lower alkyl group, and R 2  is a hydrogen atom, halogen atom, lower alkyl group, lower alkyloxy group, or lower acyloxy group); R B  is a saturated or unsaturated alkyl group which may have a branched chain, phenyl group which may be substituted with lower alkyl group, lower alkoxy group or halogen atom, phenyl alkyl group, phenyl propenyl group, phenyloxy alkyl group, or a group represented by ##STR4## (where R 3  is a hydrogen atom, halogen atom, cyano group, lower alkyl group, or phenyl group, and R 4  is a hydrogen atom, lower alkyl group, or phenyl group, and R 5  is a phenyl group which may be substituted with lower alkyl group, lower alkoxy group, acyloxy group or halogen atom) has an action to depress strongly the growth of peptic ulcer and has a very low toxicity and that among the compounds represented by the formula (I) the compound represented by the following formula (I) is a novel compound: ##STR5## where R A  is as defined above, R B  &#39; is a phenyl group which may be substituted with lower alkyl group, lower alkoxy group or halogen atom, phenyl alkyl group, phenyl propenyl group, phenyloxy alkyl group, or a group represented by ##STR6## (where R 3  is a hydrogen atom, halogen atom, cyano group, lower alkyl group, or phenyl group, and R 4  is a hydrogen atom, lower alkyl group, or phenyl group, and R 5  is a phenyl group which may be substituted with lower alkyl group, lower alkyloxy group, acyloxy group or halogen atom). 
     Therefore, it is an object of the present invention to provide an antiulcer drug containing a butanediol diester represented by the formula (I). 
     It is another object of the present invention to provide a novel butanediol diester represented by the formula (II). 
     It is a further object of the present invention to provide a process for producing the butanediol diester represented by the formula (II). 
     DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
     The butanediol diester (I) of this invention is a known compound or a novel compound produced by a process based on known reaction or any one of the following processes. 
     Process for Production 
     (1) According to this process, 2,3-butanediol (III) is converted to a 2,3-butanediol monoester derivative (V) by the reaction with a carboxylic acid (IV) or an active derivative thereof, and (V) is converted to the object compound (I) by the reaction with a carboxylic acid (VI) or an active derivative. ##STR7## where R A  and R B  are as defined above. 
     (2) According to this process, 2,3-butanediol (III) is converted to a 2,3-butanediol monoester derivative (VII) by the reaction with a carboxylic acid (VI) or an active derivative thereof, and (VII) is converted to the object compound (I) by the reaction with a carboxylic acid (IV). ##STR8## where R A  and R B  are as defined above. 
     (3) According to this process, 2,3-butanediol (III) is converted to a 2,3-butanediol diester derivative (I&#39;) by the reaction with a carboxylic acid (IV) or an active derivative thereof in twofold moles. ##STR9## where R A  is as defined above. 
     Examples of the active derivatives of the carboxylic acids (IV) and (VI) used in these processes include acid halogenide, acid anhydride, and mixed acid anhydrides. If these compounds are to be used, the reaction should preferably be carried out in the presence of a deacidifier such as pyridine, tertiary amine, alkali carbonate, alkali hydroxide, and hydrogenated alkali. 
     Typical butanediol diesters produced by the above processes are shown in Table 1, in which compounds No. 1 to 21 are known and compounds No. 22 to 81 are novel. 
     
         TABLE 1
  Compound    Melting  No. R.sub.A R.sub.B n.sub.D.sup.20 point °C.
  NMR(δppm: CCl.sub.4)
   1 (CH.sub.2).sub.6 CH.sub.3 (CH.sub.2).sub.6
  CH.sub.3 1.436  4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.26H)
 0.9(t.6H)  2 (CH.sub.2).sub.7 CH.sub.3 (CH.sub.2).sub.7 CH.sub.3 1.439
 4.7˜5.1(m.2H) 2.2(t.4H) 1.1˜1.9(m.30H)      0.9(t.6H) 3
 (CH.sub.2).sub.8 CH.sub.3 (CH.sub.2).sub.8
  CH.sub.3 1.444  4.7˜5.2(m.2H) 2.2(t.4H) 1.1˜1.9(m.34H)
 0.9(t.6H) 4 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.9 CH.sub.3 1.445
 4.6˜5.2(m.2H) 2.2(t.4H) 1.1˜1.9(m.38H)      0.9(t.6H) 5
 (CH.sub.2).sub.10 CH.sub.3 (CH.sub.2).sub.10 CH.sub.3  40˜42
 4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.42H)      0.9(t.6H) 6
 (CH.sub.2).sub.12 CH.sub.3 (CH.sub.2).sub.12 CH.sub.3  51˜53
 4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.50H)      0.9(t.6H) 7
 (CH.sub.2 ).sub.14 CH.sub.3 (CH.sub.2).sub.14 CH.sub.3  55˜57
 4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.8(m.58H)      0.9(t.6H)  8
  ##STR10##
  ##STR11##
  1.426  4.6˜5.2(m.2H) 2.0˜2.6(m.2H) 1.0˜2.0(m.16H)
 0.9(t.6H)
  9
 ##STR12##
  ##STR13##
  1.429  4.7˜5.2(m.2H) 2.1˜2.7(m.2H) 1.1(d.6H)0.7˜1.8(m.
 20H)
  10
 ##STR14##
  ##STR15##
  1.433  4.7˜5.2(m.2H) 2.1˜2.4(m.4H) 1.6˜2.1(m.2H)1.1.ab
 out.1.5(m.4H) 1.2(d.6H) 0.95(d.6H) 0.9(t.6H)
  11
 ##STR16##
  ##STR17##
  1.432  4.7˜5.2(m.2H) 2.4(t.4H) 1.5(m.6H)1.2(d.6H) 0.9(d.12H)  12
  ##STR18##
  ##STR19##
  1.437  4.6˜5.1(m.2H) 1.8˜2.1(m.6H) 0.8˜1.5(m.16H)
 0.9(s.18H)  13 CH.sub.2 CH.sub.2 CHCH.sub.2 CH.sub.2 CH.sub.2 CHCH.sub.2
 1.446  5.4˜6.1(m.2H) 4.6˜5.2(m.3H) 2.3(m.8H)      1.1(d.6H)
 14 CHCH(CH.sub.2).sub.6 CH.sub.3 CHCH(CH.sub.2).sub.6 CH.sub.3 1.464
 6.5˜7.1(m.2H) 5.7(d.2H) 4.7˜5.2(m.2H)      1.9˜2.5(m.4H
 ) 1.0˜1.9(m.26H) 0.9(t.6H) 15 (CH.sub.2).sub.7
  CHCHCH.sub.2CHCH(CH.sub.2).sub.4 CH.sub.3 (CH.sub.2).sub.7
  CHCHCH.sub.2CHCH(CH.sub.2).sub.4 CH.sub.3 1.471  5.1˜5.5(m.8H)
 4.6˜5.1(m.2H) 2.6˜3.0      (m.4H) 0.8˜2.5(m.56H) 16
 (CH.sub.2).sub.6 CH.sub.2(CHCHCH.sub.2).sub.3 CH.sub.3 (CH.sub.2).sub.6
 CH.sub.2(CHCHCH.sub.2).sub.3 CH.sub.3 1.481  5.0˜5.5(m.12H)
 4.5˜5.1(m.2H) 2.5˜3.0      (m.8H) 0.8˜2.5(m.44H) 17
 (CH.sub.2).sub.9 CH.sub.3 (CH.sub.2).sub.4
  CH.sub.3 1.440  4.7˜5.2(m.2H) 2.3(t.4H) 1.1˜1.9(m.28H)
 0.9(t.6H) 18 &#34;  (CH.sub.2).sub.6 CH.sub.3 1.443  4.7˜5.1(m.2H)
 2.2(t.4H) 1.1˜2.0(m.30H)      0.9(t.6H) 19 &#34; (CH.sub.2).sub.8
 CH.sub.3 1.445  4.7˜5.1(m.2H) 2.2(t.4H) 1.1˜2.0(m.32H)
 0.9(t.6H) 20 &#34; CHCHCH.sub.3 1.450  6.5-7.1(m.1H) 5.75(m.1H) 4.7˜5.1
 (m.2H) 2.2   trans   (t.2H) 1.9(dd.3H) 1.1˜1.8(m.22H) 0.9(t.3H) 21
 &#34; (CH.sub.2).sub.7
  CHCH(CH.sub.2).sub.7CH.sub.3 1.456  5.0˜5.5(m.2H) 4.6˜5.0(m.
 2H) 1.1˜2.4   cis   (m.52H) 0.9(t.6H)  22 (CH.sub.2).sub.4
 CH.sub.3
  ##STR20##
  1.514  7.6(d.1H) 7.2˜7.6(m.5H) 6.3(d.1H), 4.7˜5.3(m,2H)2.25(
 t.2H) 1.0˜1.9(m.12H), 0.9(t.3H)  23 (CH.sub.2).sub.6 CH.sub.3 &#34;
 1.509  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.3(m.2H)
 2.25(t.2H) 1.0˜1.9(m.16H) 0.9(t.3H) 24 (CH.sub.2).sub.7 CH.sub.3 &#34;
 1.505  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.3(m.2H)
 2.25(t.2H) 1.0˜1.9(m.18H), 0.9(t.3H) 25 (CH.sub.2).sub.8 CH.sub.3
 &#34; 1.501  7.7(d.1H) 7.3˜7.7(m.5H), 6.4(d.1H) 4.8˜5.7(m.2H)
   2.0˜2.5(t.2H), 1.0˜1.8(m.20H) 0.9(t.3H) 26 (CH.sub.2).sub.9
  CH.sub.3 &#34; 1.503  7.6(d.1H) 7.2˜7.5(m.5H) 6.3(d.1H) 4.7˜5.2(m
 .2H)      2.2(t.2H) 1.0˜1.8(m.22H) 0.9(t.3H) 27 (CH.sub.2).sub.10
 CH.sub.3 &#34; 1.500  7.6(d.1H), 7.1˜7.5(m.5H), 6.3(d.1H) 4.7˜5.2
 (m.2H)      2.2(t.2H) 1.0˜1.8(m.24H) 0.9(t.3H) 28 (CH.sub.2).sub.8
 CHCH.sub.2 &#34; 1.509  7.6(d.1H) 7.3(m.5H) 6.35(d.1H) 5.4˜6.1(m.1H)
    4.7˜5.3(m.4H) 2.2(t.2H) 1.0˜2.1(m.20H) 29 (CH.sub.2).sub.7
  CHCH(CH.sub.2).sub.7 CH.sub.3 &#34; 1.503  7.6(d.1H) 7.1˜7.5(m.5H)
 6.8(d.1H) 5.1˜5.4(m.2H)  (cis)    4.8˜5.1(m.2H) 1.0˜2.4
 (m.34H) 0.9(t.3H) 30 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7 CH.sub.3 &#34;
 1.505  7.65(d.1H) 7.2˜7.5(m.5H) 6.35(d.1H), 5.2˜5.5(m.2H)
 (trans)    4.9˜5.2(m.2H) 1.1˜2.5(m.34H) 0.9(t.3H)  31
 (CH.sub.2).sub.4
  CH.sub.3
 ##STR21##
  1.504  7.55(d.1H) 7.3(d.1H) 7.05(d.1H) 6.3(d.1H) 4.7˜5.2(m.1H)2.3(
 s.3H) 2.0˜2.4(t.2H) 1.0˜2.0(m.12H) 0.9(t.3H)
   32 (CH.sub.2).sub.9 CH.sub.3 &#34; 1.499  7.5(d.1H) 7.37(d.2H) 7.05(d.2H)
 6.25(d.1H) 4.7˜5.3(m.2H)      2.35(s.3H) 2.2(t.2H) 1.1˜1.9(m.
 22H) 0.9(t.3H)
  33
 ##STR22##
  &#34;  72˜74 7.5(d.2H) 7.35(d.4H) 7.15(d.4H) 6.35(d.2H)4.7˜5.1(m
 .2H) 2.3(s.6H) 1.4(d.6H)  34 (CH.sub.2).sub.4
  CH.sub.3
 ##STR23##
  1.528  7.5(d.1H) 7.4(d.2H) 6.8(d.2H) 6.15(d.1H)4.7˜5.3(m.2H)
 3.8(s.3H) 2.2(t.2H)1.0˜1.9(m.12H) 0.9(t.3H)  35 (CH.sub.2).sub.9
 CH.sub.3 &#34; 1.519  7.5(d.1H) 7.4(d.2H) 6.8(d.2H) 6.15(d.1H)      4.7.about
 .5.2(m.2H) 3.8(s.3H) 2.2(t.2H)      1.0˜1.9(m.22H) 0.9(t.3H)  36
  ##STR24##
  &#34;  115˜117 7.6(d.2H) 7.4(d.2H) 7.3(d.2H) 6.3(d.2H)4.9˜5.4(m.
 2H) 3.8(s.6H) 1.4(d.6H)  37 (CH.sub.2).sub.4
  CH.sub.3
 ##STR25##
  1.524  7.6(d.1H)7.4(d.d.4H) 6.35(d.1H) 4.8˜5.4(m.2H)2.3(t.3H)
 1.1˜1.9(m.12H) 0.9(t.3H)  38 (CH.sub.2).sub.9 CH.sub.3 &#34; 1.514
 7.6(d.1H) 7.4(d.d.4H) 6.35(d.1H) 4.8˜5.4(m.2H)      2.3(t.3H)
 1.1˜1.9(m.22H) 0.9(t.3H)
  39
 ##STR26##
  &#34;  133˜136 7.6(d.2H) 7.3(m.8H) 6.3(d.2H) 4.9˜5.4(m.2H)1.3(d.
 6H)  40 (CH.sub.2).sub.9
  CH.sub.3
 ##STR27##
  1.520  7.45(d.1H) 6.65(s.2H) 6.2(d.1H)4.8˜5.3(m.2H) 3.78(d.9H)
 2.2(t.2H)1.0˜1.9(m.22H) 0.9(t.3H)  41 (CH.sub.2).sub.9 CH.sub.3
  ##STR28##
  1.507  7.55(d.1H) 7.5(d.2H) 7.05(d.2H) 6.3(d.1H)4.7˜5.2(m.2H)152
 2.25(s.3H) 2.2(t.2H)1.1˜2.0(m.22H) 0.9(t.3H)
  42
 ##STR29##
  &#34;  112˜116 7.6(d.2H) 7.45(d.4H) 7.05(d.4H) 6.3(d.2H)5.0˜5.4(
 m.2H) 2.3(s.6H) 1.35(d.6H)
  43
 ##STR30##
  ##STR31##
   177˜180 8.25(s.2H) 7.8˜8.1(m.4H) 7.3˜7.7(m.6H)5.1.abo
 ut.5.5(m.2H) 1.4(d.6H)  44  (CH.sub.2).sub.4
  CH.sub.3 &#34; 1.523  8.15(s.1H) 7.7˜8.1(m.2H) 7.2˜7.7(m.3H)
   4.7˜5.4(m.2H) 2.25(t.2H) 1.0˜1.9(m.12H) 0.9(t.3H) 45
 (CH.sub.2).sub.6 CH.sub.3 &#34; 1.509 30-35 8.15(s.1H) 7.7˜8.1(m.2H)
 7.3˜7.7(m.3H)      4.8˜5.3(m.2H) 2.25(t.2H) 1.0˜2.0(m.1
 6H) 0.9(t.3H) 46 (CH.sub.2).sub.7
  CH.sub.3 &#34; 1.516  8.2(s.1H) 7.8-8.1(m.2H) 7.3˜7.7(m.3H)
 4.7˜5.3(m.2H) 2.3(t.2H) 1.0˜1.8(m.18H) 0.9(t.3H)  47
 (CH.sub.2).sub.8
  CH.sub.3
 ##STR32##
  1.514  8.15(s.1H) 7.7˜8.1(m.2H) 7.2˜7.7(m.3H)4.7˜5.4(m
 .2H) 2.25(t.2H) 1.0˜1.9(m.20H)0.9(t.3H)  48 (CH.sub.2).sub.9
 CH.sub.3 &#34; 1.514  8.13(s.1H) 7.7˜8.1(m.2H) 7.3˜7.7(m.3H)
  4.8˜5.3(m.2H) 2.0˜2.5(t.2H) 1.0˜1.9(m.22H)
 0.9(t.3H) 49 (CH.sub.2).sub.10
  CH.sub.3 &#34; 1.512  8.1(s.1H) 7.8˜8.1(m.2H) 7.3˜7.6(m.3H)
  4.8˜5.4(m.2H) 2.3(t.2H) 1.1˜1.7(m.24H) 0.9(t.3H) 50
 CHCHCH.sub.3 &#34;  78˜81 8.1(s.1H) 7.7˜8.1(m.2H) 7.3˜7.6(m
 .3H)      6.6˜7.1(m.1H) 5.6˜6.0(m.1H) 4.7˜5.3(m.2H)
   1.85(d.d.3H) 1.30(d.3H) 1.25(d.3H)
  51
 ##STR33##
  &#34; 1.550  8.1(s.1H) 7.7˜8.1(m.2H) 7.3-7.6(m.3H)6.5˜7.0(m.1H)
 4.8˜5.4(m.2H) 1.8(s.3H)1.75(d.3H) 1.35(d.3H) 1.3(d.3H)  52
 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7 CH.sub.3 &#34; 1.509  8.1(s.1H)
 7.7˜8.0(m.2H) 7.2˜7.6(m.3H)  (cis)    4.7˜5.4(m.4H)
 1.0˜2.4(m.34H) 0.9(t.3H) 53 (CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7
 CH.sub.3 &#34;   8.1(s.1H) 7.7˜8.0(m.2H) 7.2˜7.6(m.3H)  (Trans)
   4.7˜5.4(m.4H) 1.0˜2.4(m.34H) 0.9(t.3H)
  54 (CH.sub.2).sub.4
  CH.sub.3
 ##STR34##
  1.506  7.6(m.1H) 7.3(b.s.5H) 4.8˜5.3(m.2H)2.25(t.2H) 2.1(d.3H)
 1.0˜2.0(m.12H)0.9(t.3H)  55 (CH.sub.2).sub.9 CH.sub.3 &#34; 1.501
 7.6(m.1H) 7.34(b.s.5H) 4.8˜5.3(m.2H)      2.25(t.2H) 2.1(d.3H)
 1.1˜2.0(m.22H)      0.9(t.3H) 56 (CH.sub.2).sub.10 CH.sub.3 &#34;
 1.500  7.6(m.1H) 7.3(b.s.5H) 4.8˜5.3(m.2H)      2.25(t.2H)
 2.1(d.3H) 1.0˜2.0(m.24H)      0.9(t.3H)
  57
 ##STR35##
  &#34; 1.559  7.6(m.1H) 7.3(b.s.5H) 4.9˜5.4(m.2H)2.1(m.6H) 1.4(d.6H)
 58 (CH.sub.2).sub.4
  CH.sub.3
 ##STR36##
  1.480  7.8˜8.2(m.2H) 7.2˜7.7(m.3H) 4.7˜5.3(m.2H)
 2.2(t.2H)1.0˜1.9(m.12H) 0.9(t.3H)
  59 &#34;
 ##STR37##
  1.481  7.8(d.2H) 7.1(d.2H) 4.7˜5.3(m.2H) 2.3(s 3H) 2.0˜2.4(t
 .2H) 1.1˜2.0(m.12H) 0.9(t.3H)
  60 &#34;
 ##STR38##
  1.492  7.9(d.2H) 6.9(d.2H) 4.8˜5.4(m.2H) 3.8(s.3H) 2.0˜2.4(t
 .2H) 1.1˜2.0(m.12H) 0.9(t.3H)
  61 &#34;
 ##STR39##
  1.492  7.7(d.2H) 7.2(d.2H) 4.7-5.3(m.2H) 2.0˜2.4(t.2H)1.1˜2.
 0(m.12H) 0.9(t.3H)
  62 &#34;
 ##STR40##
  1.493  7.2(s.2H) 4.8˜5.4(m.2H) 3.8(d.9H) 2.2(t.2H)1.0˜2.0(m.
 12H) 0.9(t.3H)
  63 &#34;
 ##STR41##
  1.498  7.0˜7.5(m.5H) 6.0˜6.6(m.2H) 4.6˜5.2(m.2H)
 3.2(d.2H)2.0˜2.4(t.2H) 1.1˜2.0(m.12H) 0.9(t.3H)
  64 (CH.sub.2).sub.9
  CH.sub.3
 ##STR42##
  1.477  7.8˜8.2(m.2H) 7.2˜7.7(m.3H) 4.7˜5.4(m.2H)
 2.2(t.2H)1.0˜1.9(m.22H) 0.9(t.3H)
  65 &#34;
 ##STR43##
  1.481  7.75(d.2H) 7.05(d.2H) 4.7˜5.3(m.2H) 2.4(s.3H)2.2(t.2H)
 1.1˜2.0(m.22H) 0.9(t.3H)
  66 &#34;
 ##STR44##
  1.488  7.9(d.2H) 6.8(d.2H) 4.8˜5.4(m.2H) 3.8(s.3H) 2.2(t.2H)
 1.1˜2.0(m.22H) 0.9(t.3H)
  67 &#34;
 ##STR45##
  1.488  7.85(d.2H) 7.3(d.2H) 4.7˜5.3(m.2H) 2.2(t.2H)1.1˜2.0(m
 .22H) 0.9(t.3H)
  68 &#34;
 ##STR46##
  1.491  7.15(s.2H) 4.8˜5.4(m.2H) 3.8(d.9H) 2.2(t.2H)1.1˜2.0(m
 .22H) 0.9(t.3H)
  69 &#34;
 ##STR47##
  1.475  7.2(m.5H) 4.6˜5.1(m.2H) 3.5(s.2H) 2.1(t.2H)1.0˜1.9(m.
 22H) 0.9(t.3H)
  70 &#34;
 ##STR48##
  1.475  7.15(s.5H) 4.7˜5.2(m.2H) 2.8(t.2H) 2.7(t.2H)2.2(t.2H)
 1.0˜1.9(m.22H) 0.9(t.3H)
  71 &#34;
 ##STR49##
  1.478  6.7˜7.4(m.5H) 4.7˜5.2(m.2H) 4.5(s.2H) 2.2(t.2H)1.0.ab
 out.1.9(m.22H) 0.9(t.3H)
  72 &#34;
 ##STR50##
  1.474  7.2(s.5H) 4.6˜5.1(m.2H) 3.3(t.1H) (0.6˜2.3(m.28H)
 73 (CH.sub.2).sub.4
  CH.sub.3
 ##STR51##
  1.536  7.65(s.1H) 6.8˜7.4(m.10H) 4.7˜5.3(m.2H) 2.0˜2.5
 (t.2H)1.1˜2.0(m.12H) 0.9(t.3H)  74 (CH.sub.2).sub.9 CH.sub.3 &#34;
 1.525  7.6(s.1H) 6.7˜7.4(m.10H) 4.7˜5.1(m.2H) 2.0˜2.4(t
 .2H)      1.1˜2.0(m.22H) 0.9(t.3H)  75 (CH.sub.2).sub.4 CH.sub.4
  ##STR52##
  1.496  7.1˜7.8(m.5H) 6.8(d.1H) 4.7˜5.3(m.2H) 2.3(t.2H)1.1.ab
 out.2.0(m.12H) 0.9(t.3H)
  76 &#34;
 ##STR53##
  1.506  7.30(m.5H) 6.15(m.1H) 4.8˜5.3(m.2H) 2.56(m.3H)2.30(t.2H)
 1.1˜1.9(m.12H) 0.86(t.3H)  77 (CH.sub.2).sub.9
  CH.sub.3
 ##STR54##
  1.495  7.32(m.5H) 6.10(m.1H) 4.8˜5.3(m.2H) 2.58(m.3H)2.30(t.2H)
 1.0˜1.9(m.22H) 0.89(t.3H)  78 (CH.sub.2).sub.4
  CH.sub.3
 ##STR55##
  1.539  7.21(s.10H) 6.30(s.1H) 4.5˜5.2(m.2H) 2.28(t.2H)1.2˜1.
 9(m.6H) 1.08(d.6H) 0.89(t.3H)  79 (CH.sub.2).sub.9
  CH.sub.3
 ##STR56##
  1.520  7.22(s.10H) 6.30(s.1H) 4.6˜5.2(m.2H) 2.30(t.2H)1.2˜1.
 9(m.16H) 1.10(d.6H) 0.9(t.3H)  80 (CH.sub.2).sub.6
  CH.sub.3
 ##STR57##
  1.525  7.7(s.1H) 6.8˜7.5(m.10H) 4.7˜5.3(m.2H) 2.25(t.2H)1.0.
 about.2.0(m.18H) 0.9(t.3H)
  81 &#34;
 ##STR58##
  1.498  7.0˜7.5(m.5H) 6.0(m.1H) 4.6˜5.2(m.2H) 2.5(m.3H)2.2(t.
 2H) 1.0˜2.0(m.18H) 0.9(t.3H)
 
    
     The butanediol diester (I) is described below with respect to its antiulcer action and acute toxicity. 
     (i) Antiulcer Action 
     Wister male rates each weighing about 200 g were given, after fasting for 24 hours, orally 25 mg/kg of indomethacin suspended in 1% aq. solution of sodium carboxymethylcellulose. Five hours later, 1 ml of physiological saline containing 2% brilliant blue was injected intravenously on their tails, and 10 minutes later, they were slaughtered and their stomachs were removed. After fixation by injecting 12 ml of 1% formalin aq. solution, the stomachs were extended on a flat plate and the injured parts on the stomach was measured with slide calipers. The sum of the lengths in mm was regarded as the ulcer index. 
     The test compound was emulsified or suspended in physiological saline containing one drop of polysolvate 80, and this was given orally or subcutaneously on the back one hour before administration of indomethacin. 
     The ulcer inhibition ratio was obtained from the following formula. 
     
         Inhibition ratio (%)=A/B×100 
    
     A: (ulcer index of control group)-(ulcer index of test group given the test compound) 
     B: (ulcer index of control group) 
     The results are shown in Table 2, in which the compound numbers correpond to those in Table 1. 
     
                       TABLE 2                                                     
______________________________________                                    
Compd. No. of  Dosage               Inhibition                            
No.    rats    (mg/kg)    Route     ratio (%)                             
______________________________________                                    
1      5       200        Subcutaneously                                  
                                    92                                    
2      &#34;       &#34;          &#34;         90                                    
3      &#34;       &#34;          &#34;         50                                    
4      &#34;       &#34;          &#34;         74                                    
6      &#34;       &#34;          &#34;         57                                    
7      &#34;       &#34;          &#34;         30                                    
15     &#34;       &#34;          &#34;         47                                    
16     &#34;       &#34;          &#34;         86                                    
17     &#34;       &#34;          &#34;         37                                    
22     &#34;       &#34;          &#34;         91                                    
24     &#34;       &#34;          &#34;         90                                    
25     &#34;       &#34;          &#34;         95                                    
28     &#34;       &#34;          &#34;         62                                    
31     &#34;       &#34;          &#34;         91                                    
34     &#34;       &#34;          &#34;         75                                    
35     &#34;       &#34;          &#34;         77                                    
37     &#34;       &#34;          &#34;         85                                    
40     &#34;       &#34;          &#34;         99                                    
45     &#34;       &#34;          &#34;         84                                    
46     &#34;       &#34;          &#34;         56                                    
48     4       &#34;          Orally    84                                    
48     5       300        Subcutaneously                                  
                                    96                                    
54     &#34;       200        &#34;         87                                    
57     &#34;       &#34;          &#34;         80                                    
60     &#34;       &#34;          &#34;         41.4                                  
62     &#34;       &#34;          &#34;         50.0                                  
64     &#34;       &#34;          &#34;         41.3                                  
68     &#34;       &#34;          &#34;         89.3                                  
70     &#34;       &#34;          &#34;         45.9                                  
71     &#34;       &#34;          &#34;         59.2                                  
______________________________________                                    
 
    
     As Table 2 indicates, all of the test compounds are apparently effective in antiulcer action. 
     (ii) Acute Toxicity 
     ddy male mice, arranged in groups each consisting of five mice, were given intraperitoneally 1000 mg/kg of the test compounds Nos. 1-4, 8-10, 14-18, 21, 22, 24, 25, 28, 31, 34, 35, 37, 45, 46, 48, 54, 57, 60, 62, 64, 68, 70, and 71 (as shown in Table 1) dissolved in cotton seed oil. After observation for seven days, all the mice lived without any anomaly. The test compounds were found to have an LD 50  higher than 1000 mg/kg and a very low toxicity. 
     The antiulcer drug of this invention can be administered either orally or non-orally in the form of powder, tablets, capsules, granules, solutions, injections (subcutaneous, intramuscular, intravenous), transfusion, and suppositories. 
     The above-mentioned preparations can be manufactured by the known methods. Powder, tablets, capsules, and granules can be prepared combining butanediol diester with a diluting agent such as starch, lactose, and mannitol; a binder such as sodium carboxymethylcellulose and hydroxypropylcellulose; a disintegrator such as crystalline cellulose and calcium carboxymethylcellulose; a lubricant such as talc and magnesium stearate; and a fluidity improving agent such as light silicic anhydride. Solutions and injections can be prepared by dissolving butanediol diester in olive oil or peanut oil, or by dissolving or suspending butanediol diester in water or physiological saline using an anionic surface active agent such as polysolvate 60 and polysolvate 80. Suppositories can be prepared by dispersing butanediol diester in cacao butter or synthetic fats in the conventional manner. 
     The antiulcer drug thus prepared is administered at the dosage of 0.1 to 1000 mg/kg (orally) and 0.05 to 500 mg/kg (non-orally) once to several times a day for adults. 
    
    
     The invention is illustrated by the following examples. 
     EXAMPLE 1 
     (Synthesis of Compound No. 22) 
     (1) Dissolve 9 g (0.1 mole) of 2,3-butanediol in 50 ml of ether. 
     (2) Add 10 ml of pyridine. 
     (3) With stirring and ice cooling, add dropwise 30 ml of ether solution containing 16.65 g (0.1 mole) of cinnamoyl chloride. 
     (4) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 4 hours. 
     (5) Add water and separate the ether layer. 
     (6) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (7) Dry the solution with anhydrous sodium sulfate. 
     (8) Remove ether by distillation under reduced pressure. 
     (9) Purify the residue by column chromatography (SiO 2 ) to give 9.4 g of colorless liquid monoester (yield 42.7%). 
     (10) Dissolve 9.4 g (0.043 mole) of this monoester in 120 ml of ether. 
     (11) Add 6.8 ml of pyridine. 
     (12) With stirring and ice cooling, add dropwise 120 ml of ether solution containing 5.75 g (0.043 mole) of caproyl chloride. 
     (13) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 4 hours. 
     (14) Add water and separate the ether layer. 
     (15) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (16) Dry the solution with anhydrous sodium sulfate. 
     (17) Remove ether by distillation under reduced pressure. 
     (18) Purify the residue by column chromatography (SiO 2 ) to give 9.3 g of colorless liquid which is identified as compound No. 22 in Table 1 (yield 71%). 
     n D   20  1.514, 
     IR ν max   neat  cm -1  1720 (C=O). 
     EXAMPLE 2 
     (Synthesis of compound No. 35) 
     (1) With stirring and ice cooling, add dropwise 40 ml of ether solution containing 9 g (0.1 mole) of 2,3-butanediol to 40 ml of ether in which 4 g (0.1 mole) of sodium hydride, is suspended. 
     (2) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 30 minutes. 
     (3) With ice cooling again, add dropwise 40 ml of ether solution containing 20.45 g (0.1 mole) of undecanoyl chloride. 
     (4) Stir at room temperature for 3 hours. 
     (5) Add water and separate the ether layer. 
     (6) Carry out the same steps as in Example 1 to give 10.5 g of colorless liquid monoester (yield 40.7%). 
     (7) Dissolve 10.32 g (0.04 mole) of this monoester in 80 ml of tetrahydrofuran. 
     (8) Add 6.4 ml of pyridine. 
     (9) With stirring and ice cooling, add dropwise 80 ml of tetrahydrofuran solution containing 7.86 g (0.04 mole) of p-methoxycinnamoyl chloride. 
     (10) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 4 hours. 
     (11) Remove the solvent by distillation under reduced pressure. 
     (12) Dissolve the residue in chloroform. 
     (13) Wash the chloroform solution with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (14) Dry the solution with anhydrous sodium sulfate. 
     (15) Remove chloroform by distillation under reduced pressure. 
     (16) Purify the residue by column chromatography (SiO 2 ) to give 6 g of colorless liquid which is identified as compound No. 35 in Table 1 (yield 35.8%). 
     n D   20  1.519, 
     IR ν max   neat  cm -1  1720 (C=O) 
     EXAMPLE 3 
     (Synthesis of compound No. 43) 
     (1) Dissolve 4.5 g (0.05 mole) of 2,3-butanediol in 60 ml of tetrahydrofuran. 
     (2) Add 10 ml of pyridine. 
     (3) With stirring and ice cooling, add dropwise 60 ml of tetrahydrofuran solution containing 19.15 g (0.1 mole) of α-cyanocinnamoyl chloride. 
     (4) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 4 hours. 
     (5) Remove the solvent by distillation under reduced pressure. 
     (6) Dissolve the residue in chloroform. 
     (7) Wash the chloroform solution with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (8) Dry the solution with anhydrous sodium sulfate. 
     (9) Remove chloroform by distillation under reduced pressure. 
     (10) Recrystallize the residue from benzene to give 12.4 g of light yellow needle crystal, which is identified as compound No. 43 in Table 1 (yield 62%). 
     Melting point: 177° to 180° C. 
     IR ν max   KBr  cm -1  1720 (C=O). 
     EXAMPLE 4 
     (Synthesis of compound 60) 
     (1) With stirring and ice cooling, add 40 ml of ether solution containing 6.3 g (0.07 mole) of 2,3-butanediol to 40 ml of ether in which 3.0 g (0.075 mole) of sodium hydride is suspended. 
     (2) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 30 minutes. 
     (3) With ice cooling again, add dropwise 40 ml of ether solution containing 11.9 g (0.07 mole) of p-anisoyl chloride. 
     (4) Stir at room temperature for 3 hours. 
     (5) Add water and separate the ether layer. 
     (6) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogencarbonate solution, and water in the order listed. 
     (7) Dry the ether layer with anhydrous sodium sulfate. 
     (8) Remove ether by distillation under reduced pressure. 
     (9) Purify the residue by column chromatography (SiO 2 ) to give 6.8 g of colorless liquid monoester (yield 43.4%). 
     (10) Dissolve 2.02 g (0.009 mole) of this monoester in 20 ml of ether. 
     (11) Add 2 ml of pyridine. 
     (12) With stirring and ice cooling, add dropwise 20 ml of ether solution containing 1.22 g (0.009 mole) of n-caproyl chloride. 
     (13) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 3 hours. 
     (14) Add water and separate the ether layer. 
     (15) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (16) Dry the solution with anhydrous sodium sulfate. 
     (17) Remove ether by distillation under reduced pressure. 
     (18) Purify the residue by column chromatography (SiO 2 ) to give 2.7 g of colorless liquid which is identified as compound No. 60 in Table 1 (yield 93.2%). 
     n D   20  1.492, 
     IR ν max   neat  cm -1  1720 C=O). 
     EXAMPLE 5 
     (Synthesis of compound 68) 
     (1) With stirring add ice cooling, and 20 ml of ether solution containing 2.7 g (0.03 mole) of 2,3-butanediol to 40 ml of tetrahydrofuran in which 1.2 g (0.03 mole) of sodium hydride is suspended. 
     (2) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 30 minutes. 
     (3) With ice cooling again, add dropwise 40 ml of tetrahydrofuran solution containing 6.92 g (0.03 mole) of 3,4,5-trimethoxybenzoyl chloride. 
     (4) Stir at room temperature for 5 hours. 
     (5) Remove the solvent by distillation under reduced pressure. 
     (6) Dissolve the residue in chloroform. 
     (7) Wash the chloroform layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (8) Dry the chloroform layer with anhydrous sodium sulfate. 
     (9) Remove chloroform by distillation under reduced pressure. 
     (10) Purify the residue by column chromatography (SiO 2 ) to give 3.66 g of colorless liquid monoester (yield 43%). 
     (11) Dissolve 2.84 g (0.01 mole) of this monoester in 20 ml of ether. 
     (12) Add 2 ml of pyridine. 
     (13) With ice cooling, add dropwise 20 ml of ether solution containing 2.05 g (0.01 mole) of undecanoyl chloride. 
     (14) Continue stirring at the cooled temperature for 30  minutes and further continue stirring at room temperature for 3 hours. 
     (15) Add water and separate the ether layer. 
     (16) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (17) Dry the ether layer with anhydrous sodium sulfate. 
     (18) Remove ether by distillation under reduced pressure. 
     (19) Purify the residue by column chromatography (SiO 2 ) to give 2.04 g of colorless liquid which is identified as compound No. 68 in Table 1 (yield 50%). 
     n D   20  1.491, 
     IR ν max   neat  cm -1  1720 (C=O). 
     EXAMPLE 6 
     (Synthesis of Compound No. 70) 
     (1) Dissolve 9 g (0.1 mole) of 2,3-butanediol in 50 ml of ether. 
     (2) Add 10 ml of pyridine. 
     (3) With stirring and ice cooling, add dropwise 75 ml of ether solution containing 20.5 g (0.1 mole) of undecanoyl chloride. 
     (4) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 4 hours. 
     (5) Add water and separate the ether layer. 
     (6) Carry out the treatment as in Example 4 to give 13.2 g of colorless liquid monoester (yield 51%). 
     (7) Dissolve 12.9 g (0.05 mole) of this monoester in 100 ml of ether. 
     (8) Add 10 ml of pyridine. 
     (9) With stirring and ice cooling, add dropwise 100 ml of ether solution containing 8.43 g (0.05 mole) of phenylpropionyl chloride. 
     (10) Continue stirring at the cooled temperature for 30 minutes and further continue stirring at room temperature for 3 hours. 
     (11) Add water and separate the ether layer. 
     (12) Wash the ether layer with water, 10% hydrochloric acid, water, saturated sodium hydrogenbicarbonate solution, and water in the order listed. 
     (13) Dry the solution with anhydrous sodium sulfate. 
     (14) Remove ether by distillation under reduced pressure. 
     (15) Purify the residue by column chromatography (SiO 2 ) to give 16.2 g of colorless liquid which is identified as compound No. 70 in Table 1 (yield 85.3%). 
     n D   20  1.475, 
     IR ν max   neat  cm -1  1720 (C=O). 
     EXAMPLE 7 
     (Preparation of tablet) 
     A tablet of the following composition was prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester   100       mg                                         
(Compound No. 1 in Table 1)                                               
Light silicic anhydride                                                   
                     100       mg                                         
Crystalline cellulose                                                     
                     50        mg                                         
Hydroxypropyl cellulose                                                   
                     10        mg                                         
Calcium carboxymethylcellulose                                            
                     25        mg                                         
Talc                 4         mg                                         
Magnesium stearate   2         mg                                         
Lactose              An amount sufficient                                 
to bring the final                                                        
                     weight to 350 mg                                     
______________________________________                                    
 
    
     EXAMPLE 8 
     (Preparation of granules) 
     Granules of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 1 in Table 1)                                               
Light silicic anhydride 100     mg                                        
Mannitol                650     mg                                        
Starch                  135     mg                                        
Polyvinyl pyrrolidone   15      mg                                        
Total                   1000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 9 
     (Preparation of injection) 
     An oil injection of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 2 in Table 1)                                               
Peanut oil              1900    mg                                        
Total                   2000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 10 
     (Preparation of suppository) 
     A suppository of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 2 in Table 1)                                               
Cacao butter            1000    mg                                        
Total                   1100    mg                                        
______________________________________                                    
 
    
     EXAMPLE 11 
     (Preparation of tablet) 
     A tablet of the following composition was prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester   100       mg                                         
(Compound No. 31 in Table 1)                                              
Light silicic anhydride                                                   
                     100       mg                                         
Crystalline cellulose                                                     
                     50        mg                                         
Hydroxypropyl cellulose                                                   
                     10        mg                                         
Calcium carboxymethylcellulose                                            
                     25        mg                                         
Talc                 4         mg                                         
Magnesium stearate   2         mg                                         
Lactose              An amount sufficient                                 
                     to bring the final                                   
                     weight to 350 mg                                     
______________________________________                                    
 
    
     EXAMPLE 12 
     (Preparation of granules) 
     Granules of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 25 in Table 1)                                              
Light silicic anhydride 100     mg                                        
Mannitol                650     mg                                        
Starch                  135     mg                                        
Polyvinyl pyrrolidone   15      mg                                        
Total                   1000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 13 
     (Preparation of injection) 
     An oil injection of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 31 in Table 1)                                              
Peanut oil              1900    mg                                        
Total                   2000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 14 
     (Preparation of suppository) 
     A suppository of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 40 in Table 1)                                              
Cacao butter            1000    mg                                        
Total                   1100    mg                                        
______________________________________                                    
 
    
     EXAMPLE 15 
     (Preparation of tablet) 
     A tablet of the following composition was prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester   100       mg                                         
(Compound No. 68 in Table 1)                                              
Light silicic anhydride                                                   
                     100       mg                                         
Crystalline cellulose                                                     
                     50        mg                                         
Hydroxypropyl cellulose                                                   
                     10        mg                                         
Calcium carboxymethylcellulose                                            
                     25        mg                                         
Talc                 4         mg                                         
Magnesium stearate   2         mg                                         
Lactose              An amount sufficient                                 
                     to bring the final                                   
                     weight to 350 mg                                     
______________________________________                                    
 
    
     EXAMPLE 16 
     (Preparation of granules) 
     Granules of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 62 in Table 1)                                              
Light silicic anhydride 100     mg                                        
Mannitol                650     mg                                        
Starch                  135     mg                                        
Polyvinyl pyrrolidone   15      mg                                        
Total                   1000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 17 
     (Preparation of injection) 
     An oil injection of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 71 in Table 1)                                              
Peanut oil              1900    mg                                        
Total                   2000    mg                                        
______________________________________                                    
 
    
     EXAMPLE 18 
     (Preparation of suppository) 
     A suppository of the following composition were prepared according to the conventional manner. 
     
         ______________________________________                                    
Butanediol diester      100     mg                                        
(Compound No. 68 in Table 1)                                              
Cacao butter            1000    mg                                        
Total                   1100    mg                                        
______________________________________