Skip to content

Commit

Permalink
revision line 0-213 EP-0505058-B1
Browse files Browse the repository at this point in the history
  • Loading branch information
@ebenaissa
ebenaissa committed Sep 8, 2017
1 parent ebfab21 commit ba29657
Showing 1 changed file with 3 additions and 3 deletions.
6 changes: 3 additions & 3 deletions resources/dataset/quantities/corpus/xml/staging/EP-0505058-B1.tei.xml
View file
Original file line number Diff line number Diff line change
Expand Up @@ -288,7 +288,7 @@ wherein Ro represents hydrogen or methyl and Y represents hydrogen, ethoxycarbon
<p xml:id="_86caa">In compounds (A) and (B), their pharmacological activities are unknown. </p>
<p xml:id="_a109d">The present invention relates to thienopyridine derivatives [hereinafter referred to as Compound (I)] represented by formula (I):
wherein one of A and B represents -S-, and the other represents -CH=; R represents hydrogen or lower alkyl, and Z represents pyridyl; or a pharmaceutically acceptable salt thereof. </p>
<p xml:id="_7c3b0">In the definition of each group in formula (I), the lower alkyl means a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc. </p>
<p xml:id="_7c3b0">In the definition of each group in formula (I), the lower alkyl means a straight or branched alkyl having <measure type="interval"><num atLeast="1">1</num> to <num atMost="6">6</num></measure> carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc. </p>
<p xml:id="_b5202">The pharmaceutically acceptable salt of Compound (I) includes acid addition salts, metal salts, etc. The acid addition salt includes, for example, an inorganic acid salt such as hydrochloride, sulfate, phosphate, etc.; an organic acid salt such as acetate, maleate, fumarate, tartarate, citrate, etc. The metal salt includes for example, salts of alkali metal such as sodium, potassium, etc., salts of alkaline earth metal such as magnesium, calcium, etc.; aluminum salts, zinc salts and the like. </p>
<p xml:id="_eae01">Next, a process for preparing Compound (I) is described. </p>
<p xml:id="_fa5de">In the process shown below, in cases where the defined group(s) change under the conditions or are inappropriate for the practice of the process, the process can be easily operated by applying thereto means conventionally used in organic synthetic chemistry, for example, protection of functional groups, removal of protective groups, etc. </p>
Expand All @@ -308,7 +308,7 @@ wherein Z has the same significance as described above, preferably in the presen
<p xml:id="_6a299">Next, the immunoregulating activity, activity of inhibiting bone absorption and acute toxicity of Compound (I) are described by referring to test examples. </p>
<head xml:id="_69385">Test Example 1 Plaque Forming Cell Assay</head>
<p xml:id="_dad17">The methods developed by Jerne [Science, 140, 405 (1963)] and Yamamoto, et al[Drugs. Exptl. Clin. Res., 8, 5 (1982)] were modified for plaque forming cell assay. </p>
<p xml:id="_d6730">That is, Balb/c strain male mice (age of 7 weeks, Charles River Japan Inc.) were sensitized with <measure type="value"><num>1 x 108</num></measure> sheep red blood cells (Bio Test Research Institute) and the spleen was extirpated on the <measure type="list"><num>sixth</num> or <num>seventh</num> <measure type="TIME" unit="day">day</measure></measure>. The cells obtained from the spleen were treated with ACT solution (Tris-ammonium chloride isotonic buffer) to remove red blood cells. The cells were washed three times with RPMI1640 medium (Nissui Pharmaceutical Co.). The cells (<measure type="value"><num>1 x107</num></measure>) were incubated in RPMI-1640 medium containing <measure type="value"><num>10</num><measure type="FRACTION" unit="%">%</measure></measure> calf fetal serum (Gibco Co.), <measure type="value"><num>50</num> <measure type="DENSITY" unit="µg.ml⁻¹">µg/ml</measure></measure> streptomycin, <measure type="value"><num>50</num> <measure type="DENSITY" unit="IU.ml⁻¹">IU/ml</measure></measure> of penicillin, 2-mercaptoethanol (<measure type="value"><num>5 x 10-5</num> <measure type="DENSITY" unit="molarity">M</measure></measure>), sheep red blood cells (<measure type="value"><num>5 x 106</num></measure> cells) and a test compound dissolved in dimethyl sulfoxide supplied on a microculture plate (NUNC Co., 24 wells) in a carbon dioxide gas incubator (TABAI ESPEC CORP) at <measure type="value"><num>37</num><measure type="TEMPERATURE" unit="°C">°C</measure></measure> for <measure type="value"><num>5</num> <measure type="TIME" unit="day">days</measure></measure>. </p><p xml:id="_a8041">After completion of the incubation, the cells were transferred to a plastic test tube and centrifuged at 2000 rpm. After the supernatant was removed, the cells were resuspended in <measure type="value"><num>1</num> <measure type="MASS" unit="ml">ml</measure></measure> of RPMI-1640 medium. The cell suspension was sealed in a Cunnigham chamber (Takahashi Giken Co.) together with sheep red blood cells and guinea pig complement (Cedarlane Research Institute) according to the method of Cunnigham [Immunology, 14, 599 (1968)] and incubated at <measure type="value"><num>37</num><measure type="TEMPERATURE" unit="°C">°C</measure></measure> for <measure type="interval"><num atLeast="1">1</num> to <num atMost="2">2</num> <measure type="TIME" unit="h">hours</measure></measure>. Direct plaque forming cell (PFC) count was counted. </p>
<p xml:id="_d6730">That is, Balb/c strain male mice (age of 7 weeks, Charles River Japan Inc.) were sensitized with <measure type="value"><num>1 x 108</num></measure> sheep red blood cells (Bio Test Research Institute) and the spleen was extirpated on the <measure type="list"><num>sixth</num> or <num>seventh</num> <measure type="TIME" unit="day">day</measure></measure>. The cells obtained from the spleen were treated with ACT solution (Tris-ammonium chloride isotonic buffer) to remove red blood cells. The cells were washed <measure type="value"><num>three</num></measure> times with RPMI1640 medium (Nissui Pharmaceutical Co.). The cells (<measure type="value"><num>1 x107</num></measure>) were incubated in RPMI-1640 medium containing <measure type="value"><num>10</num><measure type="FRACTION" unit="%">%</measure></measure> calf fetal serum (Gibco Co.), <measure type="value"><num>50</num> <measure type="DENSITY" unit="µg.ml⁻¹">µg/ml</measure></measure> streptomycin, <measure type="value"><num>50</num> <measure type="DENSITY" unit="IU.ml⁻¹">IU/ml</measure></measure> of penicillin, 2-mercaptoethanol (<measure type="value"><num>5 x 10-5</num> <measure type="DENSITY" unit="molarity">M</measure></measure>), sheep red blood cells (<measure type="value"><num>5 x 106</num></measure> cells) and a test compound dissolved in dimethyl sulfoxide supplied on a microculture plate (NUNC Co., 24 wells) in a carbon dioxide gas incubator (TABAI ESPEC CORP) at <measure type="value"><num>37</num><measure type="TEMPERATURE" unit="°C">°C</measure></measure> for <measure type="value"><num>5</num> <measure type="TIME" unit="day">days</measure></measure>. </p><p xml:id="_a8041">After completion of the incubation, the cells were transferred to a plastic test tube and centrifuged at <measure type="value"><num>2000<num> <measure type="FREQUENCY" unit="rpm">rpm</measure></measure>. After the supernatant was removed, the cells were resuspended in <measure type="value"><num>1</num> <measure type="MASS" unit="ml">ml</measure></measure> of RPMI-1640 medium. The cell suspension was sealed in a Cunnigham chamber (Takahashi Giken Co.) together with sheep red blood cells and guinea pig complement (Cedarlane Research Institute) according to the method of Cunnigham [Immunology, 14, 599 (1968)] and incubated at <measure type="value"><num>37</num><measure type="TEMPERATURE" unit="°C">°C</measure></measure> for <measure type="interval"><num atLeast="1">1</num> to <num atMost="2">2</num> <measure type="TIME" unit="h">hours</measure></measure>. Direct plaque forming cell (PFC) count was counted. </p>
<p xml:id="_d1901">A rate of inhibiting antibody production by the test compound was determined by the following equation. Inhibition rate (%) = A - BA x 100 A :PFC count in the absence of test compound (dimethylsulfoxide alone) B :PFC count in the presence of test compound </p>
<p xml:id="_daaa2">The results are shown in Table 3.
<figure><table cols="4"><row><cell>Compound No. </cell><cell>Concentration (M) </cell><cell>Direct PFC Count (mean ± S.E.M.) </cell><cell>Inhibition Rate (%) </cell></row><row><cell>Control</cell><cell/><cell>5023 ± 38 </cell></row><row><cell>3</cell><cell>10-4</cell><cell>101 ± 76</cell><cell>98.0 </cell></row><row><cell/><cell>10-5</cell><cell>59 ± 38</cell><cell>98.8 </cell></row><row><cell>4</cell><cell>10-4</cell><cell>336 ± 124</cell><cell>93.3 </cell></row><row><cell/><cell>10-5</cell><cell>395 ± 52</cell><cell>92.1 </cell></row><row><cell>5</cell><cell>10-4</cell><cell>109 ± 77</cell><cell>97.8 </cell></row><row><cell/><cell>10-5</cell><cell>227 ± 131</cell><cell>95.5 </cell></row><row><cell>6</cell><cell>10-4</cell><cell>42 ± 29</cell><cell>99.2 </cell></row><row><cell/><cell>10-5</cell><cell>59 ± 29</cell><cell>98.8 </cell></row></table></figure>
Expand All @@ -319,7 +319,7 @@ wherein Z has the same significance as described above, preferably in the presen
<figure><table cols="3"><row><cell>Compound No. </cell><cell>Concentration (µM) </cell><cell>Inhibition Rate (%) </cell></row><row><cell>1</cell><cell>100</cell><cell>-1 </cell></row><row><cell>2</cell><cell>100</cell><cell>51 </cell></row><row><cell>3</cell><cell>10</cell><cell>141 </cell></row><row><cell>4</cell><cell>10</cell><cell>58 </cell></row><row><cell>5</cell><cell>10</cell><cell>53 </cell></row><row><cell>6</cell><cell>10</cell><cell>38 </cell></row><row><cell>7</cell><cell>10</cell><cell>32 </cell></row><row><cell>8</cell><cell>10</cell><cell>18 </cell></row></table></figure>
</p>
<head xml:id="_b1c62">Test Example 3 Acute toxicity test</head>
<p xml:id="_b7e8b">A test compound was orally administered to <measure type="value"><num>three</num> dd-strain male mice weighing <measure type="interval"><num type="base">20</num> ± <num type="range">1</num> <measure type="MASS" unit="g">g</measure></measure>. The minimum lethal dose (MLD) was determined by observing the mortality for <measure type="value"><num>7</num> <measure type="TIME" unit="day">days</measure></measure> after the administration. </p><p xml:id="_d10b5">The results are shown in Table 5.
<p xml:id="_b7e8b">A test compound was orally administered to three dd-strain male mice weighing <measure type="interval"><num type="base">20</num> ± <num type="range">1</num> <measure type="MASS" unit="g">g</measure></measure>. The minimum lethal dose (MLD) was determined by observing the mortality for <measure type="value"><num>7</num> <measure type="TIME" unit="day">days</measure></measure> after the administration. </p><p xml:id="_d10b5">The results are shown in Table 5.
<figure><table cols="2"><row><cell>Compound No. </cell><cell>MLD (mg/kg) </cell></row><row><cell>4</cell><cell>&gt; 300 </cell></row><row><cell>7</cell><cell>&gt; 300 </cell></row></table></figure>
</p>
<p xml:id="_37c9c">Compound (I) or a pharmaceutically acceptable salt thereof may be used as it is, or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be prepared by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof as the active ingredient with pharmaceutically acceptable carriers. The pharmaceutical compositions are desirably in a single dose unit suited for oral or parenteral administration. </p>
Expand Down

0 comments on commit ba29657

Please sign in to comment.