CA1160234A - Thiadiazole derivatives and process for preparing same - Google Patents
Thiadiazole derivatives and process for preparing sameInfo
- Publication number
- CA1160234A CA1160234A CA000363648A CA363648A CA1160234A CA 1160234 A CA1160234 A CA 1160234A CA 000363648 A CA000363648 A CA 000363648A CA 363648 A CA363648 A CA 363648A CA 1160234 A CA1160234 A CA 1160234A
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- thiadiazole
- lower alkyl
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Abstract
ABSTRACT OF THE DISCLOSURE
A compound represented by the formula,
A compound represented by the formula,
Description
- ~Z34 , BACKGROUND OF THE INVENTION
.
Field of the Invention This invention relates to novel thiadiazole derivatives or acid addition salts thereof, and a process for producing the same.
Description of the Prior Art There have heretofore been developed and used a number of anti-tumor agents for malignant tumors and leukemia. How-ever, these anti-tumor agents are highly toxic and hence require especial care, for their actual application, in avoid-ing any adverse side effects. Another disadvantage is that when being formulated, such agents encounter much inconveni--ence due primarily to their relatively poor solubility in water or other media. Accordingly, the conventional anti-tumor agents are not necessarily satisfactory.
In order to overcome the a~ove noted disadvantages of the prior art techniques, a variety of anti-tumor agents have been studied.
In the studies leading to the present invention, it has been discovered that thiadiazole derivatives and acid addition salts thereof of a specific class can achieve the desired and satisfac-tory results.
SUMMP~RY OF THE INVENTION
One object of the present invention is to provide novel thiadiazole derivatives or acid addition salts thereof which are substantiallydevoid of the defects of the existing anti-tumor agents and which possess strong healins effects on leukemia and malignant tumors.
It is another object of the invention to provide a process for producing these novel thiadiazole derivatives or acid addition salts thereof.
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These and other objects and advantages of the inven-tion as hereinafter will become readily apparent can be attained by the discovery of compounds represented by the formula (I), Rl N - N
R2-C-CONH ~ S Y (I) wherein Rl represents a hydrogen atom, and R2 represents a lower alkyl group, an aryl group, an aralkyl group, a lower alkylthio lower alkyl group, a lower alkyl group substituted by a carboxyl or hydroxyl group, or a 3-indolylmethyl group, or wherein Rl and R2 define in combina-tlon an alkylene group, and pharmaceutically acceptable acid addition salts thereof.
Such derivatives and acid addition salts have been fcund to have an extremely low degree of toxicity and exhibit excellent anti-tumor effects on leukemia and malignant tumors such as sarcoma, cancer and the like. Particularly, the acid addition salts are desirable because they are readily soluble in water.
These derivatives and acid addition salts can be administered by injection (intravenous, subuctaneous and intramuscular), an oral route and other routes.
DE~ILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compounds of the formula (I) according to the inven-tion can be prepared, for example, by reacting 2-amino-1,3,4-thiadiazole of the formula (III) or a reactive derivative thereof with an amino acid of the formula (II) or a reactive derivative thereof, as illustrated by the following reaction scheme:
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R2-C-COOH + J~ Jl , R2-C-COHN~ S JJ
l~H2 H2N NH2 (II) (III) (I) wherein Rl and R2 have the same meanings as defined herein-before.
One starting compound or 2-amino-1,3,4--thiadiazole of the formula (III) useful in the process of the invention can be readily prepared in high yields by the method described, for example, in Chem. Ber. 40, 642 (1907~.
The process of the invention is xeduced to practice us~g any of the reactions which have been widely utilized in the field of peptide syntheses.
The amino group of another starting compound or amino acid of the formula (II) is preferably protected prior to being sub-ected to a condensation reaction. Examples of the amino-protecting group include acyl groups such as an acetyl group, a propionyl group, a benzoyl group, a p-nitrobenzoyl group and the like;
alkyloxycarbonyl groups such as an ethyloxycarbonyl group, a ter-butyloxycarbonyl group, a ter-amyloxycarbonyl group and the like; cycloalkyloxycarbonyl groups such as a cyclohexyloxy-carbonyl group and the like; aralkyloxycarbonyl groups such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group and the like; aryloxycarbonyl groups such as an o-nitrophenoxy-carbonyl group and the like; and protecting groups of the Schiff base type such as a phthaloyl group and a salicylidene group.
The condensation reaction is conducted by any of the following methods:
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(1) A free N-protected amino acid of the formula (II) and 2-amino-1,3,4-thiadiazole of the formula (III) are interacted in the presence of a dehydrating agent or a condens-ing agent. The dehydrating agent is, for example, N,N'-dicvclohexylcarbodiimide or the like. The condensing agent is, for example, a chlorocarbonic ester or a phosphorous ester such as a dichlorphosphorous diester, a dichlorophosphorous acid monoester, tetraethyl pyrophosphate or the like.
.
Field of the Invention This invention relates to novel thiadiazole derivatives or acid addition salts thereof, and a process for producing the same.
Description of the Prior Art There have heretofore been developed and used a number of anti-tumor agents for malignant tumors and leukemia. How-ever, these anti-tumor agents are highly toxic and hence require especial care, for their actual application, in avoid-ing any adverse side effects. Another disadvantage is that when being formulated, such agents encounter much inconveni--ence due primarily to their relatively poor solubility in water or other media. Accordingly, the conventional anti-tumor agents are not necessarily satisfactory.
In order to overcome the a~ove noted disadvantages of the prior art techniques, a variety of anti-tumor agents have been studied.
In the studies leading to the present invention, it has been discovered that thiadiazole derivatives and acid addition salts thereof of a specific class can achieve the desired and satisfac-tory results.
SUMMP~RY OF THE INVENTION
One object of the present invention is to provide novel thiadiazole derivatives or acid addition salts thereof which are substantiallydevoid of the defects of the existing anti-tumor agents and which possess strong healins effects on leukemia and malignant tumors.
It is another object of the invention to provide a process for producing these novel thiadiazole derivatives or acid addition salts thereof.
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These and other objects and advantages of the inven-tion as hereinafter will become readily apparent can be attained by the discovery of compounds represented by the formula (I), Rl N - N
R2-C-CONH ~ S Y (I) wherein Rl represents a hydrogen atom, and R2 represents a lower alkyl group, an aryl group, an aralkyl group, a lower alkylthio lower alkyl group, a lower alkyl group substituted by a carboxyl or hydroxyl group, or a 3-indolylmethyl group, or wherein Rl and R2 define in combina-tlon an alkylene group, and pharmaceutically acceptable acid addition salts thereof.
Such derivatives and acid addition salts have been fcund to have an extremely low degree of toxicity and exhibit excellent anti-tumor effects on leukemia and malignant tumors such as sarcoma, cancer and the like. Particularly, the acid addition salts are desirable because they are readily soluble in water.
These derivatives and acid addition salts can be administered by injection (intravenous, subuctaneous and intramuscular), an oral route and other routes.
DE~ILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compounds of the formula (I) according to the inven-tion can be prepared, for example, by reacting 2-amino-1,3,4-thiadiazole of the formula (III) or a reactive derivative thereof with an amino acid of the formula (II) or a reactive derivative thereof, as illustrated by the following reaction scheme:
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R2-C-COOH + J~ Jl , R2-C-COHN~ S JJ
l~H2 H2N NH2 (II) (III) (I) wherein Rl and R2 have the same meanings as defined herein-before.
One starting compound or 2-amino-1,3,4--thiadiazole of the formula (III) useful in the process of the invention can be readily prepared in high yields by the method described, for example, in Chem. Ber. 40, 642 (1907~.
The process of the invention is xeduced to practice us~g any of the reactions which have been widely utilized in the field of peptide syntheses.
The amino group of another starting compound or amino acid of the formula (II) is preferably protected prior to being sub-ected to a condensation reaction. Examples of the amino-protecting group include acyl groups such as an acetyl group, a propionyl group, a benzoyl group, a p-nitrobenzoyl group and the like;
alkyloxycarbonyl groups such as an ethyloxycarbonyl group, a ter-butyloxycarbonyl group, a ter-amyloxycarbonyl group and the like; cycloalkyloxycarbonyl groups such as a cyclohexyloxy-carbonyl group and the like; aralkyloxycarbonyl groups such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group and the like; aryloxycarbonyl groups such as an o-nitrophenoxy-carbonyl group and the like; and protecting groups of the Schiff base type such as a phthaloyl group and a salicylidene group.
The condensation reaction is conducted by any of the following methods:
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(1) A free N-protected amino acid of the formula (II) and 2-amino-1,3,4-thiadiazole of the formula (III) are interacted in the presence of a dehydrating agent or a condens-ing agent. The dehydrating agent is, for example, N,N'-dicvclohexylcarbodiimide or the like. The condensing agent is, for example, a chlorocarbonic ester or a phosphorous ester such as a dichlorphosphorous diester, a dichlorophosphorous acid monoester, tetraethyl pyrophosphate or the like.
(2) A reactive derivative of an N-protected amino acid (II) is reacted with 2-amino-1,3,4-thiadiazole (III). Examples of the reactive derivative o~ the N-protected amlno acid include acid chlorides, azides, acid anhydrides, mixed acid anhydrides, and active esters such as a phenyl ester, a cyanomethyl ester, an N-hydroxysuccinimide ester, an N-hydroxyphthalimide ester and the like, and those generally useful in the syntheses of peptides.
(3) A free N-protected amino acid (II) is reacted with a reactive derivative of 2-amino-1,3,4-thiadiazole (III). The reactive derivative includes, for example, an isocyanate or a phosphazo compound.
In order to carry out the condensation reaction, approximately equimolar amounts of both starting compounds (II) and (III) are reacted at temperatures ranging from -70C -+250C for 1 - 30 hours in the presence or absence of a solvent under water-free conditions, which may vary depending upon the type of each of the starting materials to be actually used.
The reaction product can be isolated and purified in the usual manner known to the art.
The elimination of the amino-protecting group from the 3~
resulting condensation product is effected by conventional techniques. Favorably employed are a catalytic reduction me.hod in which as a catalyst, use is made of palladiwn, platin~m, Raney nickel or the like; a reduction method in which liquid ammonia is used together with either a metallic lithium or a metallic sodium; and a method in which hydrogen bromide, hydrogen chloride, hydrogen iodide or the like is reacted in a solvent such as glacial acetic acid, dioxane, nitromethane, carbon tetrachloride, diethyl phosphite, ethanol, trifluoro-acetic acid or the like.
The compounds having the formula (I) of the invention include the L-, D- and DL-isomers, and particularly desirable arethe L-lsomersin terms of their pharmaceutical effects.
The compounds of the formula (I) can be converted, in the known manner, to water-soluble acid addition salts which are pharmaceutically acceptable. Suitable acids useful in forming such addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid and the like; and organic acids such as acetic acid, propionic acid, dichloroacetic acid, benzilic acid, salycilic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid and the like.
Typical types of compoundsof the formula (I) accord-ing to the invention were tested to determine the degrees of their acute toxicity and anti-tumor efficacy with the results tabulated in Table 1.
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Table 1 ¦ Anti-tumor ~est ~ 3) Te st Acu te D Surviva l Compounds (1) [LD50 (mg/kg) ] 3i 1- ~t A >1,600 400 l454 B > 500 200 1464 _ C >500 200 116 __ E ~1,600 200 143 _ .
F ~500 200 183 _ G >S00 200 93 >1,600 200 121 I >1,600 200 125 K ¦>1,600 ¦ 460 116 L ¦1,200 420 ~0143 1,200 1 200 145 3~
(1) Test Compounds A: 2-DL-Leucylamino-1,3,4-thiadiazole.hydrochloride B: 2-L-Leucylamino-1,3,4-thiadiazole.hydrochloride C: 2-D-Leucylamino~1,3,4-thiadiazole.hydrochloride D: 2-DL-Isoleucylamino-1,3,4-thiadiazole.dihydrochloride E: 2-DL-Valylamino-1,3,4-thiadiazole.hydrochloride F: 2-L-Valylamino-1,3,4--thiadiazole.hydrochloride G: 2-D-Valylamino-1,3,4-thiadiazole.hydrochloride H: 2-DL-Methionylamino-1,3,4-thiadiazole.hydrochloride I: 2-DL-Phenylglycylamino-1,3,4-thiadiazole~hydrobromide J: 2-Cycloleucylamino-1,3,4-thiadiazole.hydrocnloride K: 2-L-~-Aspartylamino-1,3,4-thiadiazole.monohydrate ~: 2-L-Tryptophylamino-1,3,4-thiadiazole.hydrochloride M: 2-L-Phenylalanylamino-1,3,4-thiadiazole.hydrobromide (2) Acute Toxicity The median lethal dose (LD50) of each of the test compounds was determined by the Litchfield-Wilcoxon method after the intraperitoneal injection of the compound into ddy mice.
(3) Anti-tumor Test Each experimental group was composed of six CDF
mice. The mice were inoculated intraperitoneally with 106 P388 leukemia, and the test compounds dissolved in a physiological salt solution were administered intraperitoneally to the animals 24 hours and 5 days, respectively, a~ter the inoculation. The survival effect of each of the compounds was expressed by the ~L6(3~3~
percentage of the survival days of the treated animals in each group relative to those of the con~rol animals.
Further, the compounds of the invention possess remark-ably excellent survival effects on the mice inoculated with L1210 leukemia, Ehrlich carcinoma (solid type) and Crocker sarcoma.
This invention will now be described in further detail with reference to certain specific Examples, which are presented herein for purposes of illustration only and are not to be construed as limiting unless otherwise specified.
Example 1 (i) 9.6 g of N-benzyloxycarbonyl-DL-leucine and 3.7 g of triethylamine were dissolved in 150 mQ of chloroform, to which was added dropwise 3.9 g of ethyl chlorocarbonate under sodium chloride-ice cooling conditions. The solution was stirred for 2 hours, to which was then added 3.7 g of 2-amino-1,3,4-thiadiazole, followed by stirring for further 24 hours. The reaction solution was washed with water, and after drying, the solvent was removed by distillation to obtain 9.0 g (yield: 71~) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 118 - 120C.
(ii) 9.0 g of the thus obtained amino-protected product was added to a 25% hydrogen bromide-acetic acid, and the solution was reacted for 2 hours. Thereafter, ether was added to the reaction solution, and the resulting cry-stals were collected by filtration to obtain 7.6 g (quanti~
tative, total yield: 71%) of 2-~L-leucylamino-1,3,4-thiadiazole~ -~ ,s ~6~3~
hydrobr~mide in the form of white crystals having a meltingpoint of 232C (dec.).
(iii) 7.6 g of the hydrobromide was desalted by the usual method using an ion exchange resin (Amberlite IRA-400), thereby obtaining 5.0 g of a free base (yield: 9096, total yiela: 64%) as white crystals having a melting point of 186C
(dec.). 5.0 g of the thus obtained free base was converted to the corresponding hydrochloride using a 2096 hydrogen chloride-ethanol solution and then recrystallized from ethanol to obtain 5.5 g (yield: 85%, total yield: 61%) of 2-DL-leucylamino-1,3,4-thiadiazole.hydrochloride as colorless prisms having a melting point of 203C (de.).
Elementary analysis:
C H N
Calculated for CgHlsN4CQOS (%) 38.32 6.03 22.34 Found (%) 38.09 5.8122.38 (iv) N-Benzyloxycarbonyl-L-leucine and N-benzyloxy-carbonyl-D-leucine were treated in the same manner as in items ~i), (ii) and (iii) above to obtain 2-L-leucylamino-1,3,4-thiadiazole and 2-D-leucylamino-1,3,4-thiadiazole, and acid addition salts thereof.
2-L-Leucylamino-1,3,4-thiadiazole:
Hydrobromide mp: 213 - 219C (dec.) [~]D0: +6.79 (C=2.1, EtOH) - Hydrochloride mp: 196 - 199C (dec.) [~]D: +18.0 (C=l.l, MeOH) _ 9 _ * Trademarlc.
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2-D-Leucylamino-1,3,4-thiadiazole:
Hydrobromide mp: 215 - 219C (dec.) [~]D -6.25 (C-l.9, EtOH) Free base mp: 170 - 176C (dec.) [~]D : -1.77 (C=0.28, EtOH) Hydrochloride mp: 193 - 199C (dec.) [ ]20 -18.5 (C=l.l, MeOH) Example 2 (i) 9.6 g of N-benzyloxycarbonyl-DL-isoleuclne, 3.7 g of triethylamine, 150 mQ of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example l(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145 - 149C.
(ii) 10.3 g of the thus obtained amino-protected product was reacted with a 25% hydrogen bromide-acetic acid solution in a manner similar -to that in Example l(ii) to obtain 8.7 g of 2-DL-isoleucylamino-1,3,4-thiadiazole.
hydrobromide (quantitative, total yield: 81%) as white crystals having a melting point of 236C (dec.).
(iii) The product was desalted in a manner similar to that in Example l(iii) to obtain 5.3 g (yield: 84%, total yield: 68%) of a free base as white crystals having a melting point of 99 - 100C (dec.) Further, the corresponding hydrochloride was prepared in the same manner as in Example 1 (iii) and recrystallized from ethanol to obtain 6.4 g (yield:
75%, total yield: 62%) of 2-DL-isoleucylamino-1,3,4-thiadiazole.dihydrochloride as colorless prisms having a melting point of 198C (dec~).
Elementary analysis:
C H N CQ
Calculated for CgH16N4CQ2OS ~%) 33.45 5.61 19.51 24.69 Found (%) 33.76 5.41 19.79 24.41 Example 3 (i) 26.5 g of N-benzyloxycarbonyl-DL-leucine and 10 g of 2-amino-1,3,4-thiadiazole were dissolved in 80 mQ of lioxane, to which was added dropwise 2Q mQ of a dioxane solu-tion of 20.6 g of N,N'-dicyclohexylcarbodiimide, followed by _~irring at room temperature for 24 hours. The solvent was removed from the reaction solution by distillation under reduced pressure, and the residue was recrystallized from diluted ethanol to obtain 20.9 g (yield: 56%) of 2-(N-~enzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as color-less crystals having a melting point oE 1~1C (dec.).
(ii) 20.9 g of the condensate obtained in item (i) above was catalytically reduced in 200 mQ of ethanol in the presence of palladium chloride, and separated and purified in the usual manner to obtain 13 g (quantitative, total yield:
56%) of 2-DL-leucylamino-1,3,4-thiadiazole as colorless crystals having a meltins point of 186~C (dec.~.
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Example _ (i) 26.5 g of N-benzyloxycarbonyl-DI,-isoleucine and 10 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 3(i) to obtain 19.5 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-isoleuCylamino)-1,3,4-thiadiazole as white crystals having a melting point of 149C.
(ii) 19.5 g of the thus obtained N-protected product was reacted in the same manner as in Example l~ii) to obtain 12.0 g (quantitative, total yield: 56%) of 2-DL-isoleucy-lamino-1,3,4-thiadiazole as colorless crystals having a melting point of 99 - 100C (dec.).
Example 5 (i) 10 g of N-benzyloxycarbonyl-DL-phenylglycine, 3.6 g of triethylamine, 150 m~ of chloroform, 3.8 g of ethyl chlorocarbonate and 3.6 g of 2-amino~1,3,4-thiadiazole were reacted in the same manner as in Example l(i) to obtain 8.2 g (yield: 63~) of 2-(N-benzyloxycarbonyl-DL-phenylglycylamino)-1,3,4-thiaaiazole as white crystals having a melting point of 172 - 174C.
(ii) 8.2 g of the thus obtained amino-protected product was treated with a 25~ hydrogen bromide-acetlc acid `
solution and recrystallized from water to obtain 7.0 g (quanti-tative, total yield: 63~) of 2-~L-phenylglycylamino-1,3,4-thiadiazole.hydrobromide as colorless prisms having a meltlng point of 239C (dec.).
J,' i -323~
Elementary analysis:
C H N
Calculated for ClOHllN4OSBr (%) 38.11 3.52 17.7~
Found (%) 38.40 3.48 17.97 (iii~ The hydrobromide was desalted to obtain a free base as white crystals having a melting point of 160C (dec.).
Example 6 (i) 9.5 g of N-benzyloxycarbonyl-DL-methionine, 3.4 g of triethylamine, 150 mQ of chloroform, 3.7 g of ethyl chlorocarbonate and 3.4 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example l(i) to obtain 10.3 g (yield: 84%) of 2-(N-benzyloxycarbonyl-DL-methionylamino)-1,3,4-thiadiazole as white crystals having a melting point of 155 - 159C.
~ ii) 10.3 g of the thus obtained amino-protected product was suspended in anisole, to which were added 7 mQ
of methyl ethyl sulfide and a 25~ hydrogen bromide-acetic acid solution, followed by reaction at room temperature for 1 hour. The reaction solution was treated in the usual manner to obtain 8.8 g (quantitative, total yieId: 84%) of 2-DL-methionylamino-1,3,4-thiadiazole.hydrobromide as white crystals having a melting point of 207C (dec~).
(iii) The thus obtained hydrobromide was desalted using Amberlite IRA-400 to obtain 6.1 g (yield: 94~, total yield: 78%) of a free base as white crystals having a melting point of 150 - 153C (dec.).
* Trademark.
~.
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(iv) The f~ee base was treated with a 20% hydrochloric acid-ethanol solution and recrystallized from ethanol to obtain 5.4 g ~yield: 76%, total yield: 60%) of a hydrochloride as colorless flakes having a melting point of 193 - 194C
(dec.).
Elementary analysis:
C ~ N
Calculated for C7H13N4OS2CQ (%) 31.28 4.87 20.84 Found (%) 31.68 4.82 20.96 Example 7 (i) 10 g of N-benzyloxycarbonylcycloleucine, 3.9 g of triethylamine, 150 mQ of chloroform, 4.1 g of ethyl chlorocarbonate and 3.9 g of 2-amino-1,3,4-thiadiaæole were reacted in the same manner as in Example l(i) to obtain 8.4 g (yield: 64%) of 2-(N-benzyloxycarbonyl-cycloleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 229 -233C.
(ii) 8.4 g of the thus obtained amino-protected product was reacted with a 25% hydrobromic acid-acetic acid solution at room temperature for 2 hours and treated in the usual manner to obtain 7.1 g (quantitative, total yield: 64%) of 2-cycloleucylamino-1,3,4-thiadiazole.hydrobromlde as white crystals having a melting point of 230C (dec.).
(iii) To the aqueous solution of the hydrobromide was added sodium hydroxide to render it alkaline, followed by treatment in the usual manner to obtain 4.5 g (yield: 88%r total yield: 56%) of a free base as white crystals having a melting point of 125 - 127C (dec.).
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(iv) The free base was treated with an equimolar amount of concentrated hydrochloric acid and recrystallized from ethanol to obtain 4.9 g (yield: 91%, total yield: 51~) of a hydrochloride as colorless prisms having a melting point of 199C (dec.).
Elementary analysis: C H N
Calculated for C8H13N4OSC~ (%) 38-63 5.27 22-53 Found (%) 38.48 5.31 22.14 Example 8 (i) 10 g of N-benzyloxycarbonyl-DL-valine, 4.1 g of triethylamine, 150 mQ of chloroform, 4.4 g of ethyl chlorocarbonate and 4.1 g of 2-amino-1,3,4-thiadiaæole were reacted in the same manner as in Example l(i) to obtain 10.5 g (yield: 79%) of 2-(N-benzyloxycarbonyl-DL-valylamino)-1,3,4-thiadiazole as white crystals having amelting point of 162 - 164C~
(ii) 10.5 g of the thus obtained amino-protected product was treated with a 25% hydrobromic acid-acetic acid solution to obtain 8.8 g (quantitative, total yield: 79%) of 2-DL-valylamino-1,3,4-thiadiazole.hydrobromide as white crystals having a melting point of 236C (dec.).
(iii) The hydrobromide was desalted using Amberlite IRA-400 to obtain 5.4 g (yield: 86%, total yield: 68%) of a free base as white crystals having a melting point of 104 -106C (dec.).
(iv) The free acid obtained in item (iii) above was treated with an equimolar amount of concentra~ed hydrochloric %:3~
acid and recrystallized from ethanol to obtain 5.9 g (yield:
93%, total yield: 63%) of a hydrochloride as colorless prisms having a melting point of 218C (dec.).
Elementary analysis:
C H N
Calculated for C7H13N4OSCQ (%) 35.52 5.54 23.67 Found (%) 35.79 5.46 23.53 ~ v~ N-Benzyloxycarbonyl-L-valine and N-benzyloxycarbonyl-D-valine were treated in the same manner as in items (i) to (iv) above to obtain 2-L-valylamino-1,3,4-thiadiazole and 2-D-valylamino-1,3,4-thiadiazole,and acid addition salts thereof.
2-L-Valylamino-1,3,4-thiadiazole:
Hydrobromide mp: 229 - 230C (dec.) [~]D : +21.6 (C=1.3, MeOH) Free base mp: 125 - 126C (dec.) [a]D +16.5 (C=1.3, MeOH) Hydrochloride mp: 203 - 204C (dec.) [~]D0 +35 0O (C=1.0, MeOH~
2-D-Valylamino-1,3,4-thiadiazole:
Hydrobromide mp: 222 - 227C (dec.) [~]D : -19.7 (C=1.4, MPOH) ~ 23~
Free base mp: 126 - 1~8C (dec.) [a]20 -4.55 (C=l.l, MeOH) Hydrochloride mp: 199 - 200C ~dec.) [~]D ~35 5 (C=l.l, MeOH) Example 9 ~ i) Using the same procedure as in Example l(i), 10 g of a ~-~enzyl ester of N-t-butoxycarbonyl-L-asparatic acid, 3.1 g of triethylamine, 3.4 g of ethyl chlorocarbonate and 3~1 g of 2-amino-1,3,4-thiadiazole were reacted ïn 100 m~ of chloroform to obtain 8.1 g (yield: 64~) of a ~-benzyl ester of 2-tN--t-butoxycarbonyl-L-~-aspartylamino)-1,3,4-thiadiazole as white crystals of mp: 112 - 1]4C and [~]20: -30.0 (C=1.0, MeOH).
(ii) 8.1 g of the resul-ting condensation product was treated with an alkali at room temperature for 1 hour to obtain 5.9 g (yield: 93%) of 2~(N-t-butoxycarbonyl-L-~-aspartylamino)-1,3,4-thiadiazole as white powder of mp: 120 -128C ~dec.) and [~]D : -40.8 (C=l.l, MeOH).
(iii) 5.9 g of the thus obtained amino-protected product was treated with a dioxane solution of hydrogen chloride at room temperature for 2 hours to remove the amino-protect-ing group. A crude hydrochloride of mp: 150 - 154C (dec.) and [~]D0: +7.4 (C=1.0, MeOH) was obtained (quantitative yield: 4.7 g). The resulting hydrochloride in the amount of
In order to carry out the condensation reaction, approximately equimolar amounts of both starting compounds (II) and (III) are reacted at temperatures ranging from -70C -+250C for 1 - 30 hours in the presence or absence of a solvent under water-free conditions, which may vary depending upon the type of each of the starting materials to be actually used.
The reaction product can be isolated and purified in the usual manner known to the art.
The elimination of the amino-protecting group from the 3~
resulting condensation product is effected by conventional techniques. Favorably employed are a catalytic reduction me.hod in which as a catalyst, use is made of palladiwn, platin~m, Raney nickel or the like; a reduction method in which liquid ammonia is used together with either a metallic lithium or a metallic sodium; and a method in which hydrogen bromide, hydrogen chloride, hydrogen iodide or the like is reacted in a solvent such as glacial acetic acid, dioxane, nitromethane, carbon tetrachloride, diethyl phosphite, ethanol, trifluoro-acetic acid or the like.
The compounds having the formula (I) of the invention include the L-, D- and DL-isomers, and particularly desirable arethe L-lsomersin terms of their pharmaceutical effects.
The compounds of the formula (I) can be converted, in the known manner, to water-soluble acid addition salts which are pharmaceutically acceptable. Suitable acids useful in forming such addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid and the like; and organic acids such as acetic acid, propionic acid, dichloroacetic acid, benzilic acid, salycilic acid, oxalic acid, malonic acid, adipic acid, maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid and the like.
Typical types of compoundsof the formula (I) accord-ing to the invention were tested to determine the degrees of their acute toxicity and anti-tumor efficacy with the results tabulated in Table 1.
~6~3Z3~
Table 1 ¦ Anti-tumor ~est ~ 3) Te st Acu te D Surviva l Compounds (1) [LD50 (mg/kg) ] 3i 1- ~t A >1,600 400 l454 B > 500 200 1464 _ C >500 200 116 __ E ~1,600 200 143 _ .
F ~500 200 183 _ G >S00 200 93 >1,600 200 121 I >1,600 200 125 K ¦>1,600 ¦ 460 116 L ¦1,200 420 ~0143 1,200 1 200 145 3~
(1) Test Compounds A: 2-DL-Leucylamino-1,3,4-thiadiazole.hydrochloride B: 2-L-Leucylamino-1,3,4-thiadiazole.hydrochloride C: 2-D-Leucylamino~1,3,4-thiadiazole.hydrochloride D: 2-DL-Isoleucylamino-1,3,4-thiadiazole.dihydrochloride E: 2-DL-Valylamino-1,3,4-thiadiazole.hydrochloride F: 2-L-Valylamino-1,3,4--thiadiazole.hydrochloride G: 2-D-Valylamino-1,3,4-thiadiazole.hydrochloride H: 2-DL-Methionylamino-1,3,4-thiadiazole.hydrochloride I: 2-DL-Phenylglycylamino-1,3,4-thiadiazole~hydrobromide J: 2-Cycloleucylamino-1,3,4-thiadiazole.hydrocnloride K: 2-L-~-Aspartylamino-1,3,4-thiadiazole.monohydrate ~: 2-L-Tryptophylamino-1,3,4-thiadiazole.hydrochloride M: 2-L-Phenylalanylamino-1,3,4-thiadiazole.hydrobromide (2) Acute Toxicity The median lethal dose (LD50) of each of the test compounds was determined by the Litchfield-Wilcoxon method after the intraperitoneal injection of the compound into ddy mice.
(3) Anti-tumor Test Each experimental group was composed of six CDF
mice. The mice were inoculated intraperitoneally with 106 P388 leukemia, and the test compounds dissolved in a physiological salt solution were administered intraperitoneally to the animals 24 hours and 5 days, respectively, a~ter the inoculation. The survival effect of each of the compounds was expressed by the ~L6(3~3~
percentage of the survival days of the treated animals in each group relative to those of the con~rol animals.
Further, the compounds of the invention possess remark-ably excellent survival effects on the mice inoculated with L1210 leukemia, Ehrlich carcinoma (solid type) and Crocker sarcoma.
This invention will now be described in further detail with reference to certain specific Examples, which are presented herein for purposes of illustration only and are not to be construed as limiting unless otherwise specified.
Example 1 (i) 9.6 g of N-benzyloxycarbonyl-DL-leucine and 3.7 g of triethylamine were dissolved in 150 mQ of chloroform, to which was added dropwise 3.9 g of ethyl chlorocarbonate under sodium chloride-ice cooling conditions. The solution was stirred for 2 hours, to which was then added 3.7 g of 2-amino-1,3,4-thiadiazole, followed by stirring for further 24 hours. The reaction solution was washed with water, and after drying, the solvent was removed by distillation to obtain 9.0 g (yield: 71~) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 118 - 120C.
(ii) 9.0 g of the thus obtained amino-protected product was added to a 25% hydrogen bromide-acetic acid, and the solution was reacted for 2 hours. Thereafter, ether was added to the reaction solution, and the resulting cry-stals were collected by filtration to obtain 7.6 g (quanti~
tative, total yield: 71%) of 2-~L-leucylamino-1,3,4-thiadiazole~ -~ ,s ~6~3~
hydrobr~mide in the form of white crystals having a meltingpoint of 232C (dec.).
(iii) 7.6 g of the hydrobromide was desalted by the usual method using an ion exchange resin (Amberlite IRA-400), thereby obtaining 5.0 g of a free base (yield: 9096, total yiela: 64%) as white crystals having a melting point of 186C
(dec.). 5.0 g of the thus obtained free base was converted to the corresponding hydrochloride using a 2096 hydrogen chloride-ethanol solution and then recrystallized from ethanol to obtain 5.5 g (yield: 85%, total yield: 61%) of 2-DL-leucylamino-1,3,4-thiadiazole.hydrochloride as colorless prisms having a melting point of 203C (de.).
Elementary analysis:
C H N
Calculated for CgHlsN4CQOS (%) 38.32 6.03 22.34 Found (%) 38.09 5.8122.38 (iv) N-Benzyloxycarbonyl-L-leucine and N-benzyloxy-carbonyl-D-leucine were treated in the same manner as in items ~i), (ii) and (iii) above to obtain 2-L-leucylamino-1,3,4-thiadiazole and 2-D-leucylamino-1,3,4-thiadiazole, and acid addition salts thereof.
2-L-Leucylamino-1,3,4-thiadiazole:
Hydrobromide mp: 213 - 219C (dec.) [~]D0: +6.79 (C=2.1, EtOH) - Hydrochloride mp: 196 - 199C (dec.) [~]D: +18.0 (C=l.l, MeOH) _ 9 _ * Trademarlc.
3~
2-D-Leucylamino-1,3,4-thiadiazole:
Hydrobromide mp: 215 - 219C (dec.) [~]D -6.25 (C-l.9, EtOH) Free base mp: 170 - 176C (dec.) [~]D : -1.77 (C=0.28, EtOH) Hydrochloride mp: 193 - 199C (dec.) [ ]20 -18.5 (C=l.l, MeOH) Example 2 (i) 9.6 g of N-benzyloxycarbonyl-DL-isoleuclne, 3.7 g of triethylamine, 150 mQ of chloroform, 3.9 of ethyl chlorocarbonate and 3.7 g of 2-amino-1,3,4-thiadiazole were subjected to a reaction similar to that in Example l(i) to obtain 10.3 g (yield: 82%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 145 - 149C.
(ii) 10.3 g of the thus obtained amino-protected product was reacted with a 25% hydrogen bromide-acetic acid solution in a manner similar -to that in Example l(ii) to obtain 8.7 g of 2-DL-isoleucylamino-1,3,4-thiadiazole.
hydrobromide (quantitative, total yield: 81%) as white crystals having a melting point of 236C (dec.).
(iii) The product was desalted in a manner similar to that in Example l(iii) to obtain 5.3 g (yield: 84%, total yield: 68%) of a free base as white crystals having a melting point of 99 - 100C (dec.) Further, the corresponding hydrochloride was prepared in the same manner as in Example 1 (iii) and recrystallized from ethanol to obtain 6.4 g (yield:
75%, total yield: 62%) of 2-DL-isoleucylamino-1,3,4-thiadiazole.dihydrochloride as colorless prisms having a melting point of 198C (dec~).
Elementary analysis:
C H N CQ
Calculated for CgH16N4CQ2OS ~%) 33.45 5.61 19.51 24.69 Found (%) 33.76 5.41 19.79 24.41 Example 3 (i) 26.5 g of N-benzyloxycarbonyl-DL-leucine and 10 g of 2-amino-1,3,4-thiadiazole were dissolved in 80 mQ of lioxane, to which was added dropwise 2Q mQ of a dioxane solu-tion of 20.6 g of N,N'-dicyclohexylcarbodiimide, followed by _~irring at room temperature for 24 hours. The solvent was removed from the reaction solution by distillation under reduced pressure, and the residue was recrystallized from diluted ethanol to obtain 20.9 g (yield: 56%) of 2-(N-~enzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as color-less crystals having a melting point oE 1~1C (dec.).
(ii) 20.9 g of the condensate obtained in item (i) above was catalytically reduced in 200 mQ of ethanol in the presence of palladium chloride, and separated and purified in the usual manner to obtain 13 g (quantitative, total yield:
56%) of 2-DL-leucylamino-1,3,4-thiadiazole as colorless crystals having a meltins point of 186~C (dec.~.
~3~
Example _ (i) 26.5 g of N-benzyloxycarbonyl-DI,-isoleucine and 10 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 3(i) to obtain 19.5 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-isoleuCylamino)-1,3,4-thiadiazole as white crystals having a melting point of 149C.
(ii) 19.5 g of the thus obtained N-protected product was reacted in the same manner as in Example l~ii) to obtain 12.0 g (quantitative, total yield: 56%) of 2-DL-isoleucy-lamino-1,3,4-thiadiazole as colorless crystals having a melting point of 99 - 100C (dec.).
Example 5 (i) 10 g of N-benzyloxycarbonyl-DL-phenylglycine, 3.6 g of triethylamine, 150 m~ of chloroform, 3.8 g of ethyl chlorocarbonate and 3.6 g of 2-amino~1,3,4-thiadiazole were reacted in the same manner as in Example l(i) to obtain 8.2 g (yield: 63~) of 2-(N-benzyloxycarbonyl-DL-phenylglycylamino)-1,3,4-thiaaiazole as white crystals having a melting point of 172 - 174C.
(ii) 8.2 g of the thus obtained amino-protected product was treated with a 25~ hydrogen bromide-acetlc acid `
solution and recrystallized from water to obtain 7.0 g (quanti-tative, total yield: 63~) of 2-~L-phenylglycylamino-1,3,4-thiadiazole.hydrobromide as colorless prisms having a meltlng point of 239C (dec.).
J,' i -323~
Elementary analysis:
C H N
Calculated for ClOHllN4OSBr (%) 38.11 3.52 17.7~
Found (%) 38.40 3.48 17.97 (iii~ The hydrobromide was desalted to obtain a free base as white crystals having a melting point of 160C (dec.).
Example 6 (i) 9.5 g of N-benzyloxycarbonyl-DL-methionine, 3.4 g of triethylamine, 150 mQ of chloroform, 3.7 g of ethyl chlorocarbonate and 3.4 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example l(i) to obtain 10.3 g (yield: 84%) of 2-(N-benzyloxycarbonyl-DL-methionylamino)-1,3,4-thiadiazole as white crystals having a melting point of 155 - 159C.
~ ii) 10.3 g of the thus obtained amino-protected product was suspended in anisole, to which were added 7 mQ
of methyl ethyl sulfide and a 25~ hydrogen bromide-acetic acid solution, followed by reaction at room temperature for 1 hour. The reaction solution was treated in the usual manner to obtain 8.8 g (quantitative, total yieId: 84%) of 2-DL-methionylamino-1,3,4-thiadiazole.hydrobromide as white crystals having a melting point of 207C (dec~).
(iii) The thus obtained hydrobromide was desalted using Amberlite IRA-400 to obtain 6.1 g (yield: 94~, total yield: 78%) of a free base as white crystals having a melting point of 150 - 153C (dec.).
* Trademark.
~.
Z3~L
(iv) The f~ee base was treated with a 20% hydrochloric acid-ethanol solution and recrystallized from ethanol to obtain 5.4 g ~yield: 76%, total yield: 60%) of a hydrochloride as colorless flakes having a melting point of 193 - 194C
(dec.).
Elementary analysis:
C ~ N
Calculated for C7H13N4OS2CQ (%) 31.28 4.87 20.84 Found (%) 31.68 4.82 20.96 Example 7 (i) 10 g of N-benzyloxycarbonylcycloleucine, 3.9 g of triethylamine, 150 mQ of chloroform, 4.1 g of ethyl chlorocarbonate and 3.9 g of 2-amino-1,3,4-thiadiaæole were reacted in the same manner as in Example l(i) to obtain 8.4 g (yield: 64%) of 2-(N-benzyloxycarbonyl-cycloleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 229 -233C.
(ii) 8.4 g of the thus obtained amino-protected product was reacted with a 25% hydrobromic acid-acetic acid solution at room temperature for 2 hours and treated in the usual manner to obtain 7.1 g (quantitative, total yield: 64%) of 2-cycloleucylamino-1,3,4-thiadiazole.hydrobromlde as white crystals having a melting point of 230C (dec.).
(iii) To the aqueous solution of the hydrobromide was added sodium hydroxide to render it alkaline, followed by treatment in the usual manner to obtain 4.5 g (yield: 88%r total yield: 56%) of a free base as white crystals having a melting point of 125 - 127C (dec.).
Z3~
(iv) The free base was treated with an equimolar amount of concentrated hydrochloric acid and recrystallized from ethanol to obtain 4.9 g (yield: 91%, total yield: 51~) of a hydrochloride as colorless prisms having a melting point of 199C (dec.).
Elementary analysis: C H N
Calculated for C8H13N4OSC~ (%) 38-63 5.27 22-53 Found (%) 38.48 5.31 22.14 Example 8 (i) 10 g of N-benzyloxycarbonyl-DL-valine, 4.1 g of triethylamine, 150 mQ of chloroform, 4.4 g of ethyl chlorocarbonate and 4.1 g of 2-amino-1,3,4-thiadiaæole were reacted in the same manner as in Example l(i) to obtain 10.5 g (yield: 79%) of 2-(N-benzyloxycarbonyl-DL-valylamino)-1,3,4-thiadiazole as white crystals having amelting point of 162 - 164C~
(ii) 10.5 g of the thus obtained amino-protected product was treated with a 25% hydrobromic acid-acetic acid solution to obtain 8.8 g (quantitative, total yield: 79%) of 2-DL-valylamino-1,3,4-thiadiazole.hydrobromide as white crystals having a melting point of 236C (dec.).
(iii) The hydrobromide was desalted using Amberlite IRA-400 to obtain 5.4 g (yield: 86%, total yield: 68%) of a free base as white crystals having a melting point of 104 -106C (dec.).
(iv) The free acid obtained in item (iii) above was treated with an equimolar amount of concentra~ed hydrochloric %:3~
acid and recrystallized from ethanol to obtain 5.9 g (yield:
93%, total yield: 63%) of a hydrochloride as colorless prisms having a melting point of 218C (dec.).
Elementary analysis:
C H N
Calculated for C7H13N4OSCQ (%) 35.52 5.54 23.67 Found (%) 35.79 5.46 23.53 ~ v~ N-Benzyloxycarbonyl-L-valine and N-benzyloxycarbonyl-D-valine were treated in the same manner as in items (i) to (iv) above to obtain 2-L-valylamino-1,3,4-thiadiazole and 2-D-valylamino-1,3,4-thiadiazole,and acid addition salts thereof.
2-L-Valylamino-1,3,4-thiadiazole:
Hydrobromide mp: 229 - 230C (dec.) [~]D : +21.6 (C=1.3, MeOH) Free base mp: 125 - 126C (dec.) [a]D +16.5 (C=1.3, MeOH) Hydrochloride mp: 203 - 204C (dec.) [~]D0 +35 0O (C=1.0, MeOH~
2-D-Valylamino-1,3,4-thiadiazole:
Hydrobromide mp: 222 - 227C (dec.) [~]D : -19.7 (C=1.4, MPOH) ~ 23~
Free base mp: 126 - 1~8C (dec.) [a]20 -4.55 (C=l.l, MeOH) Hydrochloride mp: 199 - 200C ~dec.) [~]D ~35 5 (C=l.l, MeOH) Example 9 ~ i) Using the same procedure as in Example l(i), 10 g of a ~-~enzyl ester of N-t-butoxycarbonyl-L-asparatic acid, 3.1 g of triethylamine, 3.4 g of ethyl chlorocarbonate and 3~1 g of 2-amino-1,3,4-thiadiazole were reacted ïn 100 m~ of chloroform to obtain 8.1 g (yield: 64~) of a ~-benzyl ester of 2-tN--t-butoxycarbonyl-L-~-aspartylamino)-1,3,4-thiadiazole as white crystals of mp: 112 - 1]4C and [~]20: -30.0 (C=1.0, MeOH).
(ii) 8.1 g of the resul-ting condensation product was treated with an alkali at room temperature for 1 hour to obtain 5.9 g (yield: 93%) of 2~(N-t-butoxycarbonyl-L-~-aspartylamino)-1,3,4-thiadiazole as white powder of mp: 120 -128C ~dec.) and [~]D : -40.8 (C=l.l, MeOH).
(iii) 5.9 g of the thus obtained amino-protected product was treated with a dioxane solution of hydrogen chloride at room temperature for 2 hours to remove the amino-protect-ing group. A crude hydrochloride of mp: 150 - 154C (dec.) and [~]D0: +7.4 (C=1.0, MeOH) was obtained (quantitative yield: 4.7 g). The resulting hydrochloride in the amount of
4.7 g was dissolved in water and neutralized with an alkali, 3~
and the free base was recrystallized from water to obtain 2.9 g (yield: 66%) of 2-L-a-aspartylamino-1,3,4-thiadiazole.mono-hydrate as colorless prisms of mp: 151C (dec.) and [~}DO
+31.1 (C=l.0, H2O).
Elementary analysis:
C H N
Calculated for C6HloN4O4S (%) 30.77 4.30 23-92 Found (%) 30.38 4.14 23.66 Example 10 (i) Using the same procedure as in Example l(i), 10 g of N-t-butoxycarbonyl-DL-threonine, 4.6 g of triethylamine,
and the free base was recrystallized from water to obtain 2.9 g (yield: 66%) of 2-L-a-aspartylamino-1,3,4-thiadiazole.mono-hydrate as colorless prisms of mp: 151C (dec.) and [~}DO
+31.1 (C=l.0, H2O).
Elementary analysis:
C H N
Calculated for C6HloN4O4S (%) 30.77 4.30 23-92 Found (%) 30.38 4.14 23.66 Example 10 (i) Using the same procedure as in Example l(i), 10 g of N-t-butoxycarbonyl-DL-threonine, 4.6 g of triethylamine,
5.0 g of ethyl chlorocarbonate and 4.6 g of 2-amino-1,3,4, thiadiazole were reacted in 150 mQ of tetrahydrofuxan to obtain 10.9 g (yield: 79%) of 2-(N-t-butoxycarbonyl-DL-threonylamino)-1,3,4-thiadiazole as white powder having a melting point of 165 - 170C (dec.).
(ii) 10.9 g of the thus obtained amino-protected product was treated with a dioxane solution of hydrogen chloride at room temperature for 2 hours to remove the amino-protecting gro~p. The resulting hydrochloride was recrystal-lized from methanol to obtain 7.5 g (yield: 87%) of 2-DL-threonylamino-1,3,4-thiadiazole.hydrochloride as colorless prisms having a melting point of 218C (dec.).
Elementary analysis:
C H N
Calculated for C6HllN4O2SCQ ~%) 30.19 4.64 23.47 Found (%) 30.05 4.67 23.63 %3~
Example 11 (i) Using the same procedure as in Example l(i), 10 g of N-t-~utoxycarbonyl-L-tryptophan, 3.3 g of triethylamine, 3.5 g of ethyl chlorocarbonate and 3.3 g of 2-amino-1,3,4-thiadiazole were reacted in 150 mQ of chloroform to obtain 10.7 g (yield: 84~) of 2-(N-t-butoxycarbonyl-L-tryptophanylamino)-1,3,4-thiadiazole as light yellow powder of mp: 98 - 101~C
(dec.) and [~]D : +41.0 (C=1.0, MeOH).
(ii) 10.7 g of the thus obtained amino-protectèd pro-duct was treated with a hydrogen chloride-dioxane solution and then wit~ 2-mercaptoethanol at room temperature for 2 hours to remove the amino-protecting group. The resulting hydrochloride was recrystallized from methanol to obtain 7.3 g (yield: 82%) of 2-L-tryptophanylamino-1,3,4-thiadiazole.
hydrochloride as pinky prisms of mp: 210C (dec.) and [~]DO
+93.0 (C=1.0, MeOH).
Elementary analysis:
C H N
Calcula ed o C13H14N5O C (%)48. 4.36 1.63 Eound (%) 48.34 4.28 21.70 Example 12 (i~ Using the same procedure as in Example l(i), 10 g of N-benzyloxycarbonyl-L-phenylalanine, 3.3 g of triethylamine, 3.7 g of ethyl chlorocarbonate and 3.5 g of 2-amino-1,3,4-thiadiazole were reacted in chloroform to obtain 9.1 g (yield:
71%) of 2-(N-benzyloxycarbonyl-L-phenylalanylamino)-1,3,4-thiadiazole as white crystals of mp: 78 - 83C and [~]DO
-- .
;23~
+28.0 (C=1.2, MeOH).
(ii) 9.1 g of the thus obtained amino-protected pro-duct was treated with a 25% hydrogen bromide-acetic acid solu-tion and reerystallized from methanol to obtain 6.2 g (yield:
79%) of 2~L-phenylalanylamino-1,3,4-thiadiazole.hydrobromide as colorless prisms of mp: 231C ~dee.) and [a]D : +55.1 (C=1.4, MeOH).
(iii) 2-L-Phenylalanylamino-1,3,4-thiadiazole.hydro-ehloride:
eolorless prisms mp: 205 - 206C (dee.) [ ]20: +86 io (C=1.0, MeOH) (iv) 2-L-Phenylalanylamino-1,3,4-thiadiazole:
white powder mp: 133C (dee.) [a]D : +3S.2 (C=1.2, MeOH) Having fully deseribed the invention, it will be apparent to one skilled in this art that many ehanges and modifications can be made without departing from the spirit or scope of the appended claims.
(ii) 10.9 g of the thus obtained amino-protected product was treated with a dioxane solution of hydrogen chloride at room temperature for 2 hours to remove the amino-protecting gro~p. The resulting hydrochloride was recrystal-lized from methanol to obtain 7.5 g (yield: 87%) of 2-DL-threonylamino-1,3,4-thiadiazole.hydrochloride as colorless prisms having a melting point of 218C (dec.).
Elementary analysis:
C H N
Calculated for C6HllN4O2SCQ ~%) 30.19 4.64 23.47 Found (%) 30.05 4.67 23.63 %3~
Example 11 (i) Using the same procedure as in Example l(i), 10 g of N-t-~utoxycarbonyl-L-tryptophan, 3.3 g of triethylamine, 3.5 g of ethyl chlorocarbonate and 3.3 g of 2-amino-1,3,4-thiadiazole were reacted in 150 mQ of chloroform to obtain 10.7 g (yield: 84~) of 2-(N-t-butoxycarbonyl-L-tryptophanylamino)-1,3,4-thiadiazole as light yellow powder of mp: 98 - 101~C
(dec.) and [~]D : +41.0 (C=1.0, MeOH).
(ii) 10.7 g of the thus obtained amino-protectèd pro-duct was treated with a hydrogen chloride-dioxane solution and then wit~ 2-mercaptoethanol at room temperature for 2 hours to remove the amino-protecting group. The resulting hydrochloride was recrystallized from methanol to obtain 7.3 g (yield: 82%) of 2-L-tryptophanylamino-1,3,4-thiadiazole.
hydrochloride as pinky prisms of mp: 210C (dec.) and [~]DO
+93.0 (C=1.0, MeOH).
Elementary analysis:
C H N
Calcula ed o C13H14N5O C (%)48. 4.36 1.63 Eound (%) 48.34 4.28 21.70 Example 12 (i~ Using the same procedure as in Example l(i), 10 g of N-benzyloxycarbonyl-L-phenylalanine, 3.3 g of triethylamine, 3.7 g of ethyl chlorocarbonate and 3.5 g of 2-amino-1,3,4-thiadiazole were reacted in chloroform to obtain 9.1 g (yield:
71%) of 2-(N-benzyloxycarbonyl-L-phenylalanylamino)-1,3,4-thiadiazole as white crystals of mp: 78 - 83C and [~]DO
-- .
;23~
+28.0 (C=1.2, MeOH).
(ii) 9.1 g of the thus obtained amino-protected pro-duct was treated with a 25% hydrogen bromide-acetic acid solu-tion and reerystallized from methanol to obtain 6.2 g (yield:
79%) of 2~L-phenylalanylamino-1,3,4-thiadiazole.hydrobromide as colorless prisms of mp: 231C ~dee.) and [a]D : +55.1 (C=1.4, MeOH).
(iii) 2-L-Phenylalanylamino-1,3,4-thiadiazole.hydro-ehloride:
eolorless prisms mp: 205 - 206C (dee.) [ ]20: +86 io (C=1.0, MeOH) (iv) 2-L-Phenylalanylamino-1,3,4-thiadiazole:
white powder mp: 133C (dee.) [a]D : +3S.2 (C=1.2, MeOH) Having fully deseribed the invention, it will be apparent to one skilled in this art that many ehanges and modifications can be made without departing from the spirit or scope of the appended claims.
Claims (12)
1. A process for producing a compound represented by the formula, wherein R1 represents a hydrogen atom, and R2 represents a lower alkyl group, an aryl group, an aralkyl group, a lower alkylthio lower alkyl group, a lower alkyl group substituted by a carboxyl or hydroxyl group, or a 3-indolylmethyl group, or wherein R1 and R2 define in combination an alkylene group, which comprises reacting 2-amino-1,3,4-thiadiazole or a reactive derivative thereof selected from the group consisting of an isocyanate and a phosphazo compound thereof, represented by the formula, with an amino acid or a reactive derivative thereof selected from the group consisting of an acid halide, an azide, an acid anhydride, a mixed acid anhydride and an active ester thereof, represented by the formula, wherein R1 and R2 have the same meanings as defined above, and when desired recovering the product as a pharmaceutically acceptable acid addition salt thereof.
-21a-
-21a-
2. A process as in claim 1 wherein said compound is recovered as a pharmaceutically acceptable acid addition salt, by treatment with a pharmaceutically acceptable acid.
3. A process as in claim 1 wherein the product is recovered in the form of a hydrochloride or a hydrobromide salt.
4. A process as in claim 2 wherein the product is recovered in the form of a hydrochloride or a hydrobromide salt.
5. A process as in claim 1, wherein the materials are in the form of an L-isomer.
6. A process as in claim 2, wherein the materials are in the form of an L-isomer.
7. A compound represented by the formula, wherein R1 represents a hydrogen atom, and R2 represents a lower alkyl group, an aryl group, an aralkyl group, a lower alkylthio lower alkyl group, a lower alkyl group substituted by a carboxyl or hydroxyl group, or a 3-indolylmethyl group, or wherein R1 and R2 define in combination an alkylene group or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
8. A pharmaceutically acceptable acid addition salt of a compound of claim 7, whenever prepared or produced by the process of claim 2, or by an obvious chemical equivalent thereof.
9. A hydrochloride or hydrobromide salt of a compound of claim 7, whenever prepared or produced by the process of claim 3, or by an obvious chemical equivalent thereof.
10. An L-isomer of a compound of claim 7, whenever prepared or produced by the process of claim 5, or by an obvious chemical equivalent thereof.
11. A process as in claim 1, wherein the materials are in the form of a D-isomer.
12. A D-isomer of a compound of claim 7, whenever prepared or produced by the process of claim 11, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000363648A CA1160234A (en) | 1980-10-30 | 1980-10-30 | Thiadiazole derivatives and process for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000363648A CA1160234A (en) | 1980-10-30 | 1980-10-30 | Thiadiazole derivatives and process for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1160234A true CA1160234A (en) | 1984-01-10 |
Family
ID=4118304
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000363648A Expired CA1160234A (en) | 1980-10-30 | 1980-10-30 | Thiadiazole derivatives and process for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1160234A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011528016A (en) * | 2008-07-15 | 2011-11-10 | ノバルティス アーゲー | Heteroaryl derivatives as DGAT1 inhibitors |
-
1980
- 1980-10-30 CA CA000363648A patent/CA1160234A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011528016A (en) * | 2008-07-15 | 2011-11-10 | ノバルティス アーゲー | Heteroaryl derivatives as DGAT1 inhibitors |
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