CA1078846A - Derivatives of 2-iminothiazolidines and thiazolines - Google Patents
Derivatives of 2-iminothiazolidines and thiazolinesInfo
- Publication number
- CA1078846A CA1078846A CA277,184A CA277184A CA1078846A CA 1078846 A CA1078846 A CA 1078846A CA 277184 A CA277184 A CA 277184A CA 1078846 A CA1078846 A CA 1078846A
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- lower alkyl
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- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
- C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
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- Engineering & Computer Science (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
A S T R A C T
The invention relates to a compound of the formula:
The invention relates to a compound of the formula:
Description
~078846 6 Background of the Invention .
7 This invention is concerned with derivatives of 8 2-iminothiazolidine and o~ 2-iminothiazoline which by 9 virtue of their ability to inhibit indoleamine-~-methyl transferase are useful in the treatment of certain mental 11 aberrations in man, such as schizophrenia.
}2 This invention also relates to processes for the 13 preparation of the imines of this invention; to pharmaceu-14 tical compositions comprising the novel iminesi and to a method of treating mental aberrations, such as schizophrenia, 16 comprising the administration of the novel imines and com-17 positions thereof. The novel imines may be depicted by tha 18 generic structure:
~2~S~ ' .
~N~N-R
R
19 N,N-dimethylindoleamines such as dimethyls~rotonin and dimethyltryptamine are psychotomimetic agents and are 21 be}ieved to be produced in excessive amounts by individuals 22 with certain mental aberrations, most co~monly classiied as 23 schizophrenia. Indoleamine-N-~.ethyl transferase is an 24 anzyme which catalyzes the methylation steps in the bio-synthesis of these compounas. ~ccordingly, it is believed 26 by those skilled in the art that inhibitors of this enzyme ~ ^ ~ 15743IA
71!~
1 will be o~ therapeutic value in management of the body
7 This invention is concerned with derivatives of 8 2-iminothiazolidine and o~ 2-iminothiazoline which by 9 virtue of their ability to inhibit indoleamine-~-methyl transferase are useful in the treatment of certain mental 11 aberrations in man, such as schizophrenia.
}2 This invention also relates to processes for the 13 preparation of the imines of this invention; to pharmaceu-14 tical compositions comprising the novel iminesi and to a method of treating mental aberrations, such as schizophrenia, 16 comprising the administration of the novel imines and com-17 positions thereof. The novel imines may be depicted by tha 18 generic structure:
~2~S~ ' .
~N~N-R
R
19 N,N-dimethylindoleamines such as dimethyls~rotonin and dimethyltryptamine are psychotomimetic agents and are 21 be}ieved to be produced in excessive amounts by individuals 22 with certain mental aberrations, most co~monly classiied as 23 schizophrenia. Indoleamine-N-~.ethyl transferase is an 24 anzyme which catalyzes the methylation steps in the bio-synthesis of these compounas. ~ccordingly, it is believed 26 by those skilled in the art that inhibitors of this enzyme ~ ^ ~ 15743IA
71!~
1 will be o~ therapeutic value in management of the body
2 chemistry of patients having mental aberrations such as
3 schizophrenia and thus result in alleviating some of the
4 symptoms of the disease. Thus it is an object of the present invention to provide the above-described imines and 6 their pharmaceutically acceptable salts; to provide 7 processes for the preparation o~ such compounds;
8 pharmaceutic~l compositions comprising such.compounds; and 9 to provide methods of treatment comprising administering such compounds and compositions~ when indicated for the 11 treatment/management of mental aberrations such as schizo-12 phrenia.
13 Detailed Description of the Invention 14 The novel compounds of this invention have structural formula I:
R2 7~5 ~N /~--R
R
16 or pharmaceutically acceptable salt thereo~, wherein 17 R represents 18 (1) lower alkyl, especially Cl 3 alkyl, either 19 straight or branched chain, such as methyl, ethyl, or propyl; ~
21 ~2) C3 5 alkenyl, such as allyl, 22 (3) lower alkynyl, especially C3 5 alkynyl, such as 23 propargyl;
24 R' represents O
~ C-R3, wherein R3 represents - 2 - :
- ~
... . .
~ 15743IA
7~!S146 1 (a) lower alkyl, especially Cl 5 alkyl sub-2 stituted with one or more groups selected from 3 (i) amino, 4 (ii~ lower alkanoylamino, especially C2 4-alkanoylamino, 6 (iii) phenyl, 7 (iv) carboxy, 8 (v) lower alkanoyl, especially C2_~ alkanoyl, g orO S ~ R
(vi) carboxamido, such as-C-~ ~
R
11 (b) pyridyl, 13 (2) -CH-N \ wherein R represents 16 (a) hydrogen, 17 (b) lower alkyl, especially Cl_5 alkyl, 18 (c~ phenyl, either unsubstituted or sub-19 stituted with one or more lower alkoxy groups, especially Cl_3 alkoxy groups, 21 (d) pyridyl;
22 R4 represents 23 (a) hydrogen, or 24 (b) lower alkyl, especially Cl_3 alkyl, and R represents 26 (a) lower alkyl, especially Cl 3 alkyl, 27 (b) -CoR7, wherein 28 R7 represents 29 (i) lower alkyl, especially Cl_3 alkylt (ii) phenyl, or ~a~7884~
1 R4 and R5 taken together, represent with 2 the nitrogen to which they are attached 3 (a) _ ~ (b) N ~ ~ R2 O
--C~--O
Ho~ ~
4 (3) ~J
C ~ N
8 pharmaceutic~l compositions comprising such.compounds; and 9 to provide methods of treatment comprising administering such compounds and compositions~ when indicated for the 11 treatment/management of mental aberrations such as schizo-12 phrenia.
13 Detailed Description of the Invention 14 The novel compounds of this invention have structural formula I:
R2 7~5 ~N /~--R
R
16 or pharmaceutically acceptable salt thereo~, wherein 17 R represents 18 (1) lower alkyl, especially Cl 3 alkyl, either 19 straight or branched chain, such as methyl, ethyl, or propyl; ~
21 ~2) C3 5 alkenyl, such as allyl, 22 (3) lower alkynyl, especially C3 5 alkynyl, such as 23 propargyl;
24 R' represents O
~ C-R3, wherein R3 represents - 2 - :
- ~
... . .
~ 15743IA
7~!S146 1 (a) lower alkyl, especially Cl 5 alkyl sub-2 stituted with one or more groups selected from 3 (i) amino, 4 (ii~ lower alkanoylamino, especially C2 4-alkanoylamino, 6 (iii) phenyl, 7 (iv) carboxy, 8 (v) lower alkanoyl, especially C2_~ alkanoyl, g orO S ~ R
(vi) carboxamido, such as-C-~ ~
R
11 (b) pyridyl, 13 (2) -CH-N \ wherein R represents 16 (a) hydrogen, 17 (b) lower alkyl, especially Cl_5 alkyl, 18 (c~ phenyl, either unsubstituted or sub-19 stituted with one or more lower alkoxy groups, especially Cl_3 alkoxy groups, 21 (d) pyridyl;
22 R4 represents 23 (a) hydrogen, or 24 (b) lower alkyl, especially Cl_3 alkyl, and R represents 26 (a) lower alkyl, especially Cl 3 alkyl, 27 (b) -CoR7, wherein 28 R7 represents 29 (i) lower alkyl, especially Cl_3 alkylt (ii) phenyl, or ~a~7884~
1 R4 and R5 taken together, represent with 2 the nitrogen to which they are attached 3 (a) _ ~ (b) N ~ ~ R2 O
--C~--O
Ho~ ~
4 (3) ~J
C ~ N
5 R represents ..
6 (1) hydrogen,
7 (2) lower alkyl, especially Cl 3 alkyl, or
8 (3) trifluoromethyl.
9 A preferred embodIment of the novel compounds is that wherein Rl i3 -CoR3-11 A still more preferred embodiment of the novel 12 compounds is that wherein Rl is -CoR3 and R3 is pyridyl, 13 lower alkanoylaminomethyl, lower alkanoylamino(benzyl)-14 methyl, or 2-(3-methylthiazolidin-2-ylidenaminocarbonyl)-ethyl.
16 The pharmaceutically acceptable salts contemplated 17 by this invention are generally acid addition salts formed 18 from a novel compound and an organic or inorganic acid 19 recognized by the art as providing a pharmaceutically acceptable acid addition salt, such as hydrochloride, hydro-21 bromide, dihydrogen phosphate, sulfate, citrate, pamoate, 22 pyruvate, napsylate, isethionate, maleate, fumarate, or ~:~
23 the likeO
24 Where the novel compound has a free caxboxylic 25 acid group the pharmaceutically acceptable salt can be -157~3IA
~07~3i 346 1 in the form of an ammonium, alkaline earth or alkali metal 2 salt of the carboxylate group such as the sodium, potassium, 3 calcium or the like salt.
4 A group of novel amide compounds is prepared in S accordance with the following equation:
R2~S ~OI R2 o ~ NH ~ Y-C-R3 - ~ ~7~N 1 1 3 R R
6 wherein Y is Cl-, P-NO2 ~ -, (C1 4 alkyl)OCO- or 7 N3 and Ra is aminolower alkyl, lower alkanoyl amino-lower 8 alkyl, lower alkanoylamino-phenyl lower alkyl, pyridyl, 9 lower alkanoyl-lower alkyl, or carboxamido-lower alkyl.
Where Ra is amino-lower alkyl, the reaction is conducted 11 with the amino group protected such as wi~h t-butoxycar-12 bonyl. Where Y is (Cl 4 alkyl)O~O- the acylating agent 13 can be formed _ situ by treating the corresponding free 14 carboxylic acid group with a Cl 4 lower alkyl chloroformate.
The reaction is conducted in an inert organic solvent such 16 as a chlorinated hydrocaxbon, for example, methylene chlor-17 ide, chloroform, or dimethyl ormamide at -5C. to 10C. or 18 1-72 hours.
19 Where R3 i5 carboxy-lower alkyl, the compounds are prepared by treating the 2-imino compound with a car-21 boxylic anhydride such as succinic anhydride in a chlori-22 nated hydrocarbon such as methylene chloride at 25C. to 23 reflux for 1-6 hours.
24 Where R3 is acetylmethyl, it can also be prepared by treating the 2-imino compound with diketene at 0-10C. in 26 a lower alkanol such as ethanol and allowing the mixture to 27 warm to room temperature.
- ~7~ 6 1 A second group o the novel compounds of this 2 invention are prepared in accordance with the following 3 equation:
R2 ~ ~ NH + Rl-X ~ R2 ~ N~I-Ra 4 wherein X is Cl or -N(C~3)2 ~ a and Rl is -CH2-N wherein \ R5 a 6 R4 is hydrogen or lower alkyl, 7 RS is lower alkyl, or 8 -CoR7 wherein R7 is lower alkyl or phenyl, g R4 and R5 taken together with the nitrogen to which they are attached is ~~ .
11 Where X is Cl the process is conducted by mixing 12 the two starting materials at 0-10C. in an inert organic 13 solvent, such as a chlorinated hydrocarbon, especially 14 methylene chloride and warming to room temperature to 50C.
for up to about 6 hours. Where X is (CH3)2N-, the process 16 is conducted by heating a mixture of the starting materials 17 in an inert organic solvent, such as benzene, at 50C.
18 to reflux temperature for 10-24 hours.
19 Another group of novel compounds, that is, where Rl is -CH- ~ and R4 and R5 taken together with 16 \ R5 ~ 15743IA
~ 1~7~38~6 1 the nitrogen to which they are attached represent )3~ R2 -N~` ~
2 is prepared in accordance with the following equation:
R2 ~ ~ ~2 ~ ~ ~ R2 3 In the above equation, the reagent is indicated as 4 an aldehyde for the sake of simplicity, but it is meant to include functional equivalents thereof, such as aldehyde 6 precursors for example para~ormaldehyde, aminal9 or the 7 like. The process is conducted by mixing the starting 8 material with the aldehyde or aldehyde precursor in an inert 9 organic solvent such as benzene, toluene, or the like, and heating between 50C. and reflux temperature with provision 11 for removing water produced by the condensation reaction 12 such as adding molecular sieves to the reaction mixture or 13 refluxing in a Dean-Stark apparatus.
14 Under similar reaction conditions pyridoxal provides a compound of structure R ~ ~
~-C~-O
R H ~ ~ H2 H J~NJ
16 In the novel method of treatment of this inven-17 tion the route of administration can be oral, rectal, 18 intra~enous, intramuscular, or intraperitoneal. Doses of 19 0.10 to 100 mg./kg./day and preerably of 1 to 10 mg./kg./
day of active ing edient are generally adequate, and it is 21 preferred that it be administered in divided doses given two 22 to four times daily.
16 The pharmaceutically acceptable salts contemplated 17 by this invention are generally acid addition salts formed 18 from a novel compound and an organic or inorganic acid 19 recognized by the art as providing a pharmaceutically acceptable acid addition salt, such as hydrochloride, hydro-21 bromide, dihydrogen phosphate, sulfate, citrate, pamoate, 22 pyruvate, napsylate, isethionate, maleate, fumarate, or ~:~
23 the likeO
24 Where the novel compound has a free caxboxylic 25 acid group the pharmaceutically acceptable salt can be -157~3IA
~07~3i 346 1 in the form of an ammonium, alkaline earth or alkali metal 2 salt of the carboxylate group such as the sodium, potassium, 3 calcium or the like salt.
4 A group of novel amide compounds is prepared in S accordance with the following equation:
R2~S ~OI R2 o ~ NH ~ Y-C-R3 - ~ ~7~N 1 1 3 R R
6 wherein Y is Cl-, P-NO2 ~ -, (C1 4 alkyl)OCO- or 7 N3 and Ra is aminolower alkyl, lower alkanoyl amino-lower 8 alkyl, lower alkanoylamino-phenyl lower alkyl, pyridyl, 9 lower alkanoyl-lower alkyl, or carboxamido-lower alkyl.
Where Ra is amino-lower alkyl, the reaction is conducted 11 with the amino group protected such as wi~h t-butoxycar-12 bonyl. Where Y is (Cl 4 alkyl)O~O- the acylating agent 13 can be formed _ situ by treating the corresponding free 14 carboxylic acid group with a Cl 4 lower alkyl chloroformate.
The reaction is conducted in an inert organic solvent such 16 as a chlorinated hydrocaxbon, for example, methylene chlor-17 ide, chloroform, or dimethyl ormamide at -5C. to 10C. or 18 1-72 hours.
19 Where R3 i5 carboxy-lower alkyl, the compounds are prepared by treating the 2-imino compound with a car-21 boxylic anhydride such as succinic anhydride in a chlori-22 nated hydrocarbon such as methylene chloride at 25C. to 23 reflux for 1-6 hours.
24 Where R3 is acetylmethyl, it can also be prepared by treating the 2-imino compound with diketene at 0-10C. in 26 a lower alkanol such as ethanol and allowing the mixture to 27 warm to room temperature.
- ~7~ 6 1 A second group o the novel compounds of this 2 invention are prepared in accordance with the following 3 equation:
R2 ~ ~ NH + Rl-X ~ R2 ~ N~I-Ra 4 wherein X is Cl or -N(C~3)2 ~ a and Rl is -CH2-N wherein \ R5 a 6 R4 is hydrogen or lower alkyl, 7 RS is lower alkyl, or 8 -CoR7 wherein R7 is lower alkyl or phenyl, g R4 and R5 taken together with the nitrogen to which they are attached is ~~ .
11 Where X is Cl the process is conducted by mixing 12 the two starting materials at 0-10C. in an inert organic 13 solvent, such as a chlorinated hydrocarbon, especially 14 methylene chloride and warming to room temperature to 50C.
for up to about 6 hours. Where X is (CH3)2N-, the process 16 is conducted by heating a mixture of the starting materials 17 in an inert organic solvent, such as benzene, at 50C.
18 to reflux temperature for 10-24 hours.
19 Another group of novel compounds, that is, where Rl is -CH- ~ and R4 and R5 taken together with 16 \ R5 ~ 15743IA
~ 1~7~38~6 1 the nitrogen to which they are attached represent )3~ R2 -N~` ~
2 is prepared in accordance with the following equation:
R2 ~ ~ ~2 ~ ~ ~ R2 3 In the above equation, the reagent is indicated as 4 an aldehyde for the sake of simplicity, but it is meant to include functional equivalents thereof, such as aldehyde 6 precursors for example para~ormaldehyde, aminal9 or the 7 like. The process is conducted by mixing the starting 8 material with the aldehyde or aldehyde precursor in an inert 9 organic solvent such as benzene, toluene, or the like, and heating between 50C. and reflux temperature with provision 11 for removing water produced by the condensation reaction 12 such as adding molecular sieves to the reaction mixture or 13 refluxing in a Dean-Stark apparatus.
14 Under similar reaction conditions pyridoxal provides a compound of structure R ~ ~
~-C~-O
R H ~ ~ H2 H J~NJ
16 In the novel method of treatment of this inven-17 tion the route of administration can be oral, rectal, 18 intra~enous, intramuscular, or intraperitoneal. Doses of 19 0.10 to 100 mg./kg./day and preerably of 1 to 10 mg./kg./
day of active ing edient are generally adequate, and it is 21 preferred that it be administered in divided doses given two 22 to four times daily.
10 78846 15743 IA
1 It is to be noted that the p~ecise unit dosage 2 form and dosage level depend upon the case history of the 3 individual being treated and, consequently, are left to the 4 discretion of a skilled therapist.
Pharmaceutical compositions comprising a com-6 pound useful in the novel method o~ treatments as active 7 ingredient may be in any art recognized form suita~le for 8 oral use, such as tablets, troches, lozenges, aqueous or 9 oil suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, syrups, or elixirs. For intravenous
1 It is to be noted that the p~ecise unit dosage 2 form and dosage level depend upon the case history of the 3 individual being treated and, consequently, are left to the 4 discretion of a skilled therapist.
Pharmaceutical compositions comprising a com-6 pound useful in the novel method o~ treatments as active 7 ingredient may be in any art recognized form suita~le for 8 oral use, such as tablets, troches, lozenges, aqueous or 9 oil suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, syrups, or elixirs. For intravenous
11 and intramuscular and intraperitoneal use the pharmaceutical
12 compositions may be in any art recognized form of a sterile
13 injectahle preparation such as a sterile aqueous or ole-
14 aginous solution or suspension. The amount of active ingredient incorporated in a unit dosage of the above 16 described pharmaceutical compositions may be from 1 mg.
17 to 500 mg.
18 . Example 1 19 3,5-Dimethyl-2-iminothiazolidine_Fumarate Step A: Preparation of methyl N-(2-hydroxypropyl) 21 dlthiocarbamate -22 40 G (0.242 mmole) of 1-amino-2-propanol oxalate 23 was suspended in 180 ml. of pyridine and 101 g. of triethyl-24 amine was added. The mixture was stirred mechanically for 1 hour, there cooled to 0 and 38 g. of carbon disulfide 26 (0.5 mole) was added dropwise. Ater 2 hours at 0C., 36 g.
27 of methyl iodide (0.254 mole) was added dropwise and almost 28 all solids dissolved. The mixture was stored in a refriger-29 ator overnight (0-5C~). The mixture was poured into 2.4 1.
of 3N H2SO4 and extrac.ed with ether 3 times. The ether ., . : :.
- ` 1078134~
1 extracts were washed with water, 3N H2SO4, water, aqueous 2 NaHCO3 solution and water, dried over Na2SO4 and stripped 3 down to 18.79 g. (47%) of oily methyl N-(2-hydroxypropyl) 4 dithiocarbamate.
S Step B: Preparation of S-methyl-2-methylthio-2-thiazoline 6 17.37 G. of the dithiocarbamate from Step A in 7 30 ml. dry ether was added to 73 ml. thionyl chloride at 8 0-5C. The mixture was stirred at 0 for 2 hours, then 9 stored in a refrigerator overnight. The thionyl chloride was evaporated at 30C. and the residual oil (containing 11 elemental sulfur) was poured into saturated NaHCO3 solution 12 and extracted with ether. The etherial fraction was ex-13 tracted with dilute HCl. The aqueous fraction was basified 14 with NaOH solution and extracted with ether. Evaporation of the ether afforded 6.65 g. liquid residue. This was 16 chromatographed on a column of silica gel using benzene 17 as eluant to give 2.5 g. (16.2~) o~ oily 5-methyl-2-methyl-18 thio-2-thiazoline.
19 Step C: Preparation of 3,5-Dimethyl-2-methylthio-2-thiazoline fluoborate -21 588 Mg. of the S-methyl thiazoline from Step B
22 and 592 mg. trimethyl oxonium fluoborate were stirred 23 together in 40 ml. CH2Cl~ overnight at room temperature.
24 The fluoborate dissolves slowly as it reacts. The reaction mixture was stripped to dryness to give a colorless oil 26 which was used directly in the next step.
27 Step D: Preparation of 3,5-dimethyl-2 iminothiazolidine 28 fumarate 29 The cxude fluoborate salt from Step C was dis-solved in 40 ml. of alcohol and the solution was saturated 31 with gaseous NH3. The solution was stirred at room tem-_g_ ~ 1 5 7 4 3 IA
`` 1~7~
1 perature for 3 hours. The solution was evaporated to dry-2 ness. The resulting oily residue was taken up in 10 ml.
3 of water, then 40 ml. C~C13 was added with stirring and 4 40~ NaOH solution was added to make the aqueous fraction strongly basic. The ~wo layers were separated, and the 6 aqueous fraction was extracted once more with C~C13. ~he 7 combined CHC13 fraction was dried and concentrated to dry-8 ness to give 630 mg. o oil. The compound was converted to 9 the umarate, and crystallized from isopropanol-ether to give 720 mg. cream-colored crystals, m.p. 130-138C. (73%) 11 overall. Recrystallization of the fumarate from isopro-12 panol-ether gave 470 mg. 3,5-dimethyl-2-iminothiazolidine 13 fumarate, m.p. 133-6C.
14 ~xample 2 2-Imino-3-methy1-4-trifluoromethyl-4-thiazoline fluoro-16 sulfonate ~~ ~ ~~-~~
17 336 mg. of 2-amino-4-trifluoromethylthiazole was 18 dissolved in 15 mg. CH2C12. The flask was placed in an 19 ice bath and 240 mg. of CH3SO3F in 5 ml. CH2C12 was added.
The mixture was then placed in a refrigerator over the 21 weekend. The colorless crystals were collected on a 22 filter to give 450 mg. (80%) of 2-imino-3-methyl-4-tri-23 fluoromethyl-~-thiazoline 1uorosulfonate, m.p. 177-78C.
24 Example 3 2-Imino-3-methyl-4-thiazoline 26 A mixture of 1.0 g. of 2-aminothiazole and 2 ml.
27 of methyliodide in 10 ml. of isopropanol was heated at reflux 28 for 2 hours. The hot solution was treated with decolor-29 izing carbon, filtered, and the filtrate was cooled in the refrigerator. The precipitate was collected on a filter, ~ '~ 15743IA
3L~788~6 1 washed with isopropanol, and dried to give 1.377 g. (57~) 2 of 2-imino-3-methyl-4-thiazoline.
3 Example 4 4 2-Imino-3-methylthiazolidine.HCl.l/2 H2O
A solution of 44.5 g. o~ the corresponding hydro-6 iodide in 300 ml. of water was added to a suspension of 7 52.5 g. of silver chloride (0.366 mole) in 300 ml. of water.
8 The mixture was stirred at 80C. for 3 1/~ hours, cooled 9 and filtered. The filtrate was evaporated to dryness and the solid was crystallized from isopropanol and a little 11 ether to give 23.73 g. (85%) of 2-imino-3-methyl~hiazoli~
12 dine.HCl.l/2 H2O, m.p. 73-76C.
13 Concentration of the mother liquors afforded a 14 second crop of 4.17 g. of the product.
Employing the procedure substantially as described 16 in Example 3, but substituting for the methyl iodide and 17 the 2-aminothiazole used therein, an equimolecular amount of 18 an organic halide of formula R Hal and compound of formula:
R ~ ~ NH2 19 there are produced according to Equation I the 3-R-2 iminothiazolidines amd thiazolines identi~ied in Table I.
21 Equation I
~ i NH ~ R~al ~
_~ ~ 15743IA
~L0t7~384G~
1 Table I
2 R R' R2 Hal m.p. ( C.) 3 Thiazolidines 4CH3CH2C~I2- H H Br 121-123 5CH CH - H H I 8û-83 63 2 ~as maleate salt) 7CH2=CHCH2 H H Br 112-116 8CH-C-C~2- H H Br 143-145 9 Thiazolines 10 CH3CH2CH2- H H Br CH3 2 H ~ I _ 12 CH2=CEICH2 H H Br 13 CH~C-CH2- H H Br 14 Example 5 2-Dimethylaminomethylimlno-3-methylthiazolidine 16 A mixture of 600 mg. o 2-imino-3-methylthia-17 zolidine, 10 mg. of its hydrogen iodide salt, and 550 mg. of 18 bis(dimethylamino)methane in 10 ml. o~ benzene were re~luxed 19 overnight. The mixture was concentrated to dryness, and the residue was twice taken up in chloroform and evaporated 21 to dryness to give 200 mg. of 2-dimethylaminomethylimino-22 3-methylthiazolidine, b.p. 98-102C. at 2.5 mm of Hg.
23 pressure.
24 Following the procedure of Example 5, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 26 an equivalent amount of the 2-imino-3-R-thiazolidines and 27 thiazolines depicted in Table II, there are produced the 28 2-dimethylaminomethylimino-3-R-thiazolidines and thiazolines 29 also depicted in Table II, in accordance with E~uation II:
~ILC17~346 1 Equation TI
+ C~2[N(CH3)2]2 ~ R ~ ~
NH I NCH2N(C~3)2 R R
2 Table II
3 R R~
. ~ ..
4 Thiazolines 7 Thiazolidines _, .
13 Exam~le 6 14 3-Methyl-2-SuccinLmidomethyliminothiazolidine Bromomethylsuccinimide (53.9 g.) was add~d 16 portion-wise to a mixture of 32.7 g. of 2-imino-3-methyl-17 thiazolidine and 42 ml. of triathylamine and lSO ml. of 18 methylene chloride. A reaction occurred spontaneously.
19 The mixture was evaporated to dryness, and the residue was taken up in chloroform and sodium hydroxide solution. ~he 21 aqueous phase was separated and extracted three times with 22 chloroform. The combined chloroform extracts were dried 23 and concentrated to dryness. The residue was crystallized 24 twice from benzene to give 13.5 g. of 3-methyl-2-succinimido-25 methyliminothiazolidine, m.p. 142-144C.
~ ~ 15743IA
.
~07889~6 1 Following the procedure of Exa~ple 6, but sub-2 stituting for the 2-imino-3-methylthiazolidine used therein, 3 an equimolar amount of the 2-imino-3-R-thiazolidines and ~.--4 thiazolines depicted in Table III, there are produced the 2-succinimidomethylimino-3-R-thiazolidines and thiazolines 6 also depicted in Table III, in accordance with Equation III.
7 Equation III
O . ' R2 ~ ~ BrCH2N ~ ~ R2 ~ S ~
NH ~ O N>-NCH2N
8 Table III
Thiazolines 13 Thiazolidines
17 to 500 mg.
18 . Example 1 19 3,5-Dimethyl-2-iminothiazolidine_Fumarate Step A: Preparation of methyl N-(2-hydroxypropyl) 21 dlthiocarbamate -22 40 G (0.242 mmole) of 1-amino-2-propanol oxalate 23 was suspended in 180 ml. of pyridine and 101 g. of triethyl-24 amine was added. The mixture was stirred mechanically for 1 hour, there cooled to 0 and 38 g. of carbon disulfide 26 (0.5 mole) was added dropwise. Ater 2 hours at 0C., 36 g.
27 of methyl iodide (0.254 mole) was added dropwise and almost 28 all solids dissolved. The mixture was stored in a refriger-29 ator overnight (0-5C~). The mixture was poured into 2.4 1.
of 3N H2SO4 and extrac.ed with ether 3 times. The ether ., . : :.
- ` 1078134~
1 extracts were washed with water, 3N H2SO4, water, aqueous 2 NaHCO3 solution and water, dried over Na2SO4 and stripped 3 down to 18.79 g. (47%) of oily methyl N-(2-hydroxypropyl) 4 dithiocarbamate.
S Step B: Preparation of S-methyl-2-methylthio-2-thiazoline 6 17.37 G. of the dithiocarbamate from Step A in 7 30 ml. dry ether was added to 73 ml. thionyl chloride at 8 0-5C. The mixture was stirred at 0 for 2 hours, then 9 stored in a refrigerator overnight. The thionyl chloride was evaporated at 30C. and the residual oil (containing 11 elemental sulfur) was poured into saturated NaHCO3 solution 12 and extracted with ether. The etherial fraction was ex-13 tracted with dilute HCl. The aqueous fraction was basified 14 with NaOH solution and extracted with ether. Evaporation of the ether afforded 6.65 g. liquid residue. This was 16 chromatographed on a column of silica gel using benzene 17 as eluant to give 2.5 g. (16.2~) o~ oily 5-methyl-2-methyl-18 thio-2-thiazoline.
19 Step C: Preparation of 3,5-Dimethyl-2-methylthio-2-thiazoline fluoborate -21 588 Mg. of the S-methyl thiazoline from Step B
22 and 592 mg. trimethyl oxonium fluoborate were stirred 23 together in 40 ml. CH2Cl~ overnight at room temperature.
24 The fluoborate dissolves slowly as it reacts. The reaction mixture was stripped to dryness to give a colorless oil 26 which was used directly in the next step.
27 Step D: Preparation of 3,5-dimethyl-2 iminothiazolidine 28 fumarate 29 The cxude fluoborate salt from Step C was dis-solved in 40 ml. of alcohol and the solution was saturated 31 with gaseous NH3. The solution was stirred at room tem-_g_ ~ 1 5 7 4 3 IA
`` 1~7~
1 perature for 3 hours. The solution was evaporated to dry-2 ness. The resulting oily residue was taken up in 10 ml.
3 of water, then 40 ml. C~C13 was added with stirring and 4 40~ NaOH solution was added to make the aqueous fraction strongly basic. The ~wo layers were separated, and the 6 aqueous fraction was extracted once more with C~C13. ~he 7 combined CHC13 fraction was dried and concentrated to dry-8 ness to give 630 mg. o oil. The compound was converted to 9 the umarate, and crystallized from isopropanol-ether to give 720 mg. cream-colored crystals, m.p. 130-138C. (73%) 11 overall. Recrystallization of the fumarate from isopro-12 panol-ether gave 470 mg. 3,5-dimethyl-2-iminothiazolidine 13 fumarate, m.p. 133-6C.
14 ~xample 2 2-Imino-3-methy1-4-trifluoromethyl-4-thiazoline fluoro-16 sulfonate ~~ ~ ~~-~~
17 336 mg. of 2-amino-4-trifluoromethylthiazole was 18 dissolved in 15 mg. CH2C12. The flask was placed in an 19 ice bath and 240 mg. of CH3SO3F in 5 ml. CH2C12 was added.
The mixture was then placed in a refrigerator over the 21 weekend. The colorless crystals were collected on a 22 filter to give 450 mg. (80%) of 2-imino-3-methyl-4-tri-23 fluoromethyl-~-thiazoline 1uorosulfonate, m.p. 177-78C.
24 Example 3 2-Imino-3-methyl-4-thiazoline 26 A mixture of 1.0 g. of 2-aminothiazole and 2 ml.
27 of methyliodide in 10 ml. of isopropanol was heated at reflux 28 for 2 hours. The hot solution was treated with decolor-29 izing carbon, filtered, and the filtrate was cooled in the refrigerator. The precipitate was collected on a filter, ~ '~ 15743IA
3L~788~6 1 washed with isopropanol, and dried to give 1.377 g. (57~) 2 of 2-imino-3-methyl-4-thiazoline.
3 Example 4 4 2-Imino-3-methylthiazolidine.HCl.l/2 H2O
A solution of 44.5 g. o~ the corresponding hydro-6 iodide in 300 ml. of water was added to a suspension of 7 52.5 g. of silver chloride (0.366 mole) in 300 ml. of water.
8 The mixture was stirred at 80C. for 3 1/~ hours, cooled 9 and filtered. The filtrate was evaporated to dryness and the solid was crystallized from isopropanol and a little 11 ether to give 23.73 g. (85%) of 2-imino-3-methyl~hiazoli~
12 dine.HCl.l/2 H2O, m.p. 73-76C.
13 Concentration of the mother liquors afforded a 14 second crop of 4.17 g. of the product.
Employing the procedure substantially as described 16 in Example 3, but substituting for the methyl iodide and 17 the 2-aminothiazole used therein, an equimolecular amount of 18 an organic halide of formula R Hal and compound of formula:
R ~ ~ NH2 19 there are produced according to Equation I the 3-R-2 iminothiazolidines amd thiazolines identi~ied in Table I.
21 Equation I
~ i NH ~ R~al ~
_~ ~ 15743IA
~L0t7~384G~
1 Table I
2 R R' R2 Hal m.p. ( C.) 3 Thiazolidines 4CH3CH2C~I2- H H Br 121-123 5CH CH - H H I 8û-83 63 2 ~as maleate salt) 7CH2=CHCH2 H H Br 112-116 8CH-C-C~2- H H Br 143-145 9 Thiazolines 10 CH3CH2CH2- H H Br CH3 2 H ~ I _ 12 CH2=CEICH2 H H Br 13 CH~C-CH2- H H Br 14 Example 5 2-Dimethylaminomethylimlno-3-methylthiazolidine 16 A mixture of 600 mg. o 2-imino-3-methylthia-17 zolidine, 10 mg. of its hydrogen iodide salt, and 550 mg. of 18 bis(dimethylamino)methane in 10 ml. o~ benzene were re~luxed 19 overnight. The mixture was concentrated to dryness, and the residue was twice taken up in chloroform and evaporated 21 to dryness to give 200 mg. of 2-dimethylaminomethylimino-22 3-methylthiazolidine, b.p. 98-102C. at 2.5 mm of Hg.
23 pressure.
24 Following the procedure of Example 5, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 26 an equivalent amount of the 2-imino-3-R-thiazolidines and 27 thiazolines depicted in Table II, there are produced the 28 2-dimethylaminomethylimino-3-R-thiazolidines and thiazolines 29 also depicted in Table II, in accordance with E~uation II:
~ILC17~346 1 Equation TI
+ C~2[N(CH3)2]2 ~ R ~ ~
NH I NCH2N(C~3)2 R R
2 Table II
3 R R~
. ~ ..
4 Thiazolines 7 Thiazolidines _, .
13 Exam~le 6 14 3-Methyl-2-SuccinLmidomethyliminothiazolidine Bromomethylsuccinimide (53.9 g.) was add~d 16 portion-wise to a mixture of 32.7 g. of 2-imino-3-methyl-17 thiazolidine and 42 ml. of triathylamine and lSO ml. of 18 methylene chloride. A reaction occurred spontaneously.
19 The mixture was evaporated to dryness, and the residue was taken up in chloroform and sodium hydroxide solution. ~he 21 aqueous phase was separated and extracted three times with 22 chloroform. The combined chloroform extracts were dried 23 and concentrated to dryness. The residue was crystallized 24 twice from benzene to give 13.5 g. of 3-methyl-2-succinimido-25 methyliminothiazolidine, m.p. 142-144C.
~ ~ 15743IA
.
~07889~6 1 Following the procedure of Exa~ple 6, but sub-2 stituting for the 2-imino-3-methylthiazolidine used therein, 3 an equimolar amount of the 2-imino-3-R-thiazolidines and ~.--4 thiazolines depicted in Table III, there are produced the 2-succinimidomethylimino-3-R-thiazolidines and thiazolines 6 also depicted in Table III, in accordance with Equation III.
7 Equation III
O . ' R2 ~ ~ BrCH2N ~ ~ R2 ~ S ~
NH ~ O N>-NCH2N
8 Table III
Thiazolines 13 Thiazolidines
15 C2H5- H ~ .
16 C3H7- H
17 CH2=CH-CH2- H
18 CH_C-CH2- H
19 Example 7 2-Benzamidomethylimino-3-met~ylthiazolidine, maleate 21 A solution of 676 mg. of N-chloromethyI benzamide 22 in 15 ml. of methylene chloride was slowly added to an ice . -14-~788~6 1 cold mixture of 2.0 ml. of triethylamine, 488 mg. of 2-2 imino-3-methylthiazolidine, and 25 ml. of methylene 3 chloride. After stirring 2 hours at room temperature, tha 4 mixture was evaporated to dryness. The residue was dissolved in methylene chloride, washed with water, and 6 dilute hydrochloric acid~ The combined aqueous phases 7 were basified with sodium bicarbonate and extracted with 8 methylene chloride. The methylene chloride was washed with 9 water, dried, and evaporated to dryness. The residue was triturated with ether and the product free base 11 (250 mg.) was collected on a filter.
12 The maleate salt was prepared from 11.0 g. of 13 free base and 5.12 g. of maleic acid in 100 m. methanol 14 and isolated by adding ether to incipient cloudiness, seeding and cooling to give 10.42 g. of 2-benzamidomethyl-16 imino-3-methylthiazolidine, maleate, m.p. 120-121C.
17 A second crop of 4.28 g. was isolated from the 18 mother liquors, m.p. 119-120C.
19 Employing the procedure substantially as described in Example 8, but substituting ~or the N-chloromethylbenz-21 amide used therein, an equimolar amount of N-chloromethyl-22 propionamide there is produced 2-propionamidomethylimino-23 3-methylthiazolidine and maleate salt thereof.
24 Following the procedure of Example 8, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 26 an equivalent amount of the 2-imino-3-R-thiazolidines and 27 thiazolines depicted in Table IV, there are produced the 28 2-benzamidomethylimino-3-R-thiazolidines and thiazolines 29 also depicted in Table IV, in accordance with Equation IV:
~ ~ 15743 IA
18;~78846 1 E~uation IV
~ ~ ~NH I ClCH NHC ~ > R2 ~ ~ 0 ~ I CH2NH-C-~
2 Table IV
4 Thiazolines 7 Thiazolidines 12 Example 8 13 Bis~3~ thiazolidin-2-~lideneamino]methane 14 A mixture of 25 g. of 2-imino-3-methylthia201i-15 dine, 6.5 g. of paraformaldehyde, 75 g. of molecular seives, 16 and 250 ml. of benzene was refluxed for 5 hours. Molecular 17 seives (30 g.) and 6.5 g. of para~ormaldehyde were added and 18 refluxing was continued overnight. The molecular seives 19 were collected on a filter and washed well with benzene.
12 The maleate salt was prepared from 11.0 g. of 13 free base and 5.12 g. of maleic acid in 100 m. methanol 14 and isolated by adding ether to incipient cloudiness, seeding and cooling to give 10.42 g. of 2-benzamidomethyl-16 imino-3-methylthiazolidine, maleate, m.p. 120-121C.
17 A second crop of 4.28 g. was isolated from the 18 mother liquors, m.p. 119-120C.
19 Employing the procedure substantially as described in Example 8, but substituting ~or the N-chloromethylbenz-21 amide used therein, an equimolar amount of N-chloromethyl-22 propionamide there is produced 2-propionamidomethylimino-23 3-methylthiazolidine and maleate salt thereof.
24 Following the procedure of Example 8, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 26 an equivalent amount of the 2-imino-3-R-thiazolidines and 27 thiazolines depicted in Table IV, there are produced the 28 2-benzamidomethylimino-3-R-thiazolidines and thiazolines 29 also depicted in Table IV, in accordance with Equation IV:
~ ~ 15743 IA
18;~78846 1 E~uation IV
~ ~ ~NH I ClCH NHC ~ > R2 ~ ~ 0 ~ I CH2NH-C-~
2 Table IV
4 Thiazolines 7 Thiazolidines 12 Example 8 13 Bis~3~ thiazolidin-2-~lideneamino]methane 14 A mixture of 25 g. of 2-imino-3-methylthia201i-15 dine, 6.5 g. of paraformaldehyde, 75 g. of molecular seives, 16 and 250 ml. of benzene was refluxed for 5 hours. Molecular 17 seives (30 g.) and 6.5 g. of para~ormaldehyde were added and 18 refluxing was continued overnight. The molecular seives 19 were collected on a filter and washed well with benzene.
20 The combined ~iltrate and washings were evaporated to
21 dryness to give 21 g. of crystalline bis ~-methylthia201i-
22 din-2-ylideneamino~methane, m.p. 57-59C.
23 A hydrochloride salt was prepared by dissolving
24 350 mg. in 2 ml. of water and 2 ml. of 6N hydrochloric acid ~ ` 15743IA
~6~78846 1 and evaporating to an oily residue. Evaporation of acetone, 2 isopropanol and benzene from the residue followed by 3 trituration gave crystalline hydrochloride salt.
4 Employing the procedure substantially as described in Example 8 but substituting for the paraformaldehyde used 6 therein an equimolar amount of acetaldehyde, benzaldehyde 7 (or aminal), 3,4-dimethoxybenzaldehyde, 4-pyridinecarbox-8 aldehyde and pyridoxal, there are produced respectively:
9 1,l~bis(3-methylthiazolidin-2-ylidenamino)ethane dihydro-chloride, m.p. 292~C.
11 a, a-bis (3-methylthiazolidin-2-ylideneamino)toluene, 12 m~p. 167-169C.;
13 a, a-bis (3-methylthiazolidin-2-ylideneamino)-3,4-dimethoxy-14 toluene, m.p. 144-145C.
15 a, a-bis (3-methylthiazolidin-2-ylideneamino)-~-picoline;
16 m.p. 110-113C.
17 and r ~
~N J~N
~3 H ~ , m.p. 172-175C.
~ N
18 Following the procedure o~ ~xample 8, but sub-19 stituting for the 2-imino-3-methylthiazolidine and para-formaldehyde used therein, an equivalent amount of the 21 2-imino-3-R-thiazolidines and thiazolines and aldehydes 22 depicted in Table V, there are produced the bis[3-R-23 thiazolidin-2-ylideneamino]-R3-methanes and bis[3-R-24 thiazolin-2-ylidineamino]-R3-methanes also depicted in Table V, in accordance with Equation V
~ . . . : .
. . .
:~7 !3841~
1 Equation V
S
R2 ~ NH + CHO ~ ~ R
R R6 R l6 R
2 Tabie V
3 _ _ R ___ ___ R R6 4 Thiazolines ~
5 CH3- 4-CF3 H ~ i -6 CH3- ~ H
7 Thiazolidines , C3H7 H ~ ~- -11 CH2=CH-CH2- H ~ OCH3 OCH
12 CH~C-CH2- H ~
13 reagent is the aminal, N,N,N',M'-tetramethyltoluenediamine.
14 Example 9 !~ -15 N~Nl-bls-(3-methylthiazolidin-2-ylidene)succinamide i~
16 Step A: Preparation of bis-(4-nitrophenyl) succinate 17 A mixture of 2.36 g. (20 mmoles) of succinic 18 acia, 6.516 g. (44 mmoles) of 4-nitrophenol and 8.24 g.
19 (40 mmoles) of N,N'-dicyclohexylcarbodiimide was stirred 20 at room temperature in 225 ml. of ethylacetate for 2 days.
' ` ~ -18-8~ 6 1 The mixture was filtered and the filtrate was concentrated 2 to dryness. The residue was triturated with 40 ml. of 3 chloroform and the solids were collected on a filter and air 4 dried to give 1.38 g. of bis-(4-nitrophenyl) succinate, 5 m.p. 176-178C.
6 ~@_~: Preparation of N,N'-bis-(3-methylthiazolidin-2-7 ylidene)succinamide 8 A mixture of 80 mg. of ~-imino-3-methylthiazoli-9 dine, 118 mg. of bis-(4-nitrophenyl) succinate and 8 ml.
10 of chloroform was refluxed for 5.5 hours. The mixture 11 was diluted with chloroform, washed twice with sodium 12 carbonate solution, dried over sodium sulfate and concen-13 trated to dryness. The residue was recrystallized from 14 2 ml. of methanol to give 68 mg. of N,N'-bis-(3-methyl-thiazolidin-2-ylidene)succinamide, m.p. 181-183C.
16 Exam~e 10 17 N-(3-methylthiazolidin-2-ylidene) aminoacetamide dihydro-18 chloride 19 Step A: Preparation of N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide _ 21 Ethyl chloroformate (0.25 ml.) at -5C. was added 22 to a solution of 350 mg. of t-butoxycarbonylaminoacetic 23 acid and 0.4 ml. of triethylamine in 10 ml. of methylene 24 chloride at -5C. After stirring S minutes at -5C. there was added a solution o 610 mg. of 2-imino-3-methylthiazo-26 lidine hydrogen iodide and 1.0 ml. of triethylamine in 10 27 ml. of methylene chloride also at -5C. Stirring was 28 continued at -5C. for 15 minutes and one hour at room 29 temperature. The reaction mixture was washed with 40 ml.
of 20~ (w/v) citric acid solution, sodium bicarbonate 31 solution, and water, dried and concentrated to dryness.
--19-- .
~ 15743 IA
07~6 1 The residue was triturated with ether, petroleum ether and 2 ether and finally collected to give pure N-(3-methylthia-3 zolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.
4 Step B: Preparation of N-~3-methylthiazolidin-2-ylidene) aminoacetamide dihydrochloride 6 The product from Step A, (2.0 g.) was dissolved 7 in 100 ml. of chloroform and the solution was saturated 8 with hydrogen chloride gas by bubbling it through the 9 solution for 20 minutes. After 2 hours at room temperature the excess hydrogen chloride was expelled by bubbling in 11 nitrogen. The precipitated product was collected and air 12 dried under nitrogen to give 1.66 g. of N-t3-methylthia-13 zolidin-2-ylidene) aminoacetamide dihydrochloride, m. p.
14 190-194C.
Employing the procedure substantially as de-16 scribed in Example 10, Step A, but substituting for the 17 t-butoxycarbonylaminoacetic acid used therein an equimolar 18 amount of 2-acetylamino-2-benzylacetic acid, nicotinic 19 acid, acetoace~ic acid and 3-methyl-2-succinyliminothiazoli-dine (See Example 11), there are produced respectively:
21 N-(3-methylthiazolidin-2-ylidene) 2-acetylamino-2-benzyl-22 acetamide, m.p. 142-149C.
23 N-(3-methylthiazolidin-2-ylidene) nicotinamide, m.p.
24 108-lOgC.
N-(3-methylthiazolidin-2-ylidene) acetoacetamide, m.p.
26 43-45C.; and 27 N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide, m.p.
28 183-184C.
29 Following the procedure of Example 10, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 31 an equivalent amount of the 2-imino-3-R-thiazolidines and 32 thiazolines depicted in Table VIII, there are produced the ~C~715 8~6 1 N-(3-R-thiazolidin-2-ylidene)aminoacetamides and N-(3-R-2 thiazolin-2-ylidene)aminoacetamides also depicted in Table 3 Vl in accordance with Equation VI:
4 Equatlon Vl NH ~ HOOCCH2N~COOC(C~3)3 ~ ~N-C-CH2NH2 R O
Table VI
7 Thiazolines 10 Thiazolidines 14 CH2=CH-CH2- H
CH_C-C~2- H
17 Example 11 18 N-(3-methylthiazolidin-2-ylidene) acet~laminoacetamide 19 4-Nitrophenyl acetylaminoacetate (1.19 g.) was added portionwise to a solution o 580 mg. of 2-imino-3-21 methylthiazolidine in 60 ml. of chloroform. A~ter stirring 22 2 hours at room temperature, the solu~ion was concentrated 23 to dryness. The residue was triturated with ether and 24 collected on a filter. The crude product was dissolved in
~6~78846 1 and evaporating to an oily residue. Evaporation of acetone, 2 isopropanol and benzene from the residue followed by 3 trituration gave crystalline hydrochloride salt.
4 Employing the procedure substantially as described in Example 8 but substituting for the paraformaldehyde used 6 therein an equimolar amount of acetaldehyde, benzaldehyde 7 (or aminal), 3,4-dimethoxybenzaldehyde, 4-pyridinecarbox-8 aldehyde and pyridoxal, there are produced respectively:
9 1,l~bis(3-methylthiazolidin-2-ylidenamino)ethane dihydro-chloride, m.p. 292~C.
11 a, a-bis (3-methylthiazolidin-2-ylideneamino)toluene, 12 m~p. 167-169C.;
13 a, a-bis (3-methylthiazolidin-2-ylideneamino)-3,4-dimethoxy-14 toluene, m.p. 144-145C.
15 a, a-bis (3-methylthiazolidin-2-ylideneamino)-~-picoline;
16 m.p. 110-113C.
17 and r ~
~N J~N
~3 H ~ , m.p. 172-175C.
~ N
18 Following the procedure o~ ~xample 8, but sub-19 stituting for the 2-imino-3-methylthiazolidine and para-formaldehyde used therein, an equivalent amount of the 21 2-imino-3-R-thiazolidines and thiazolines and aldehydes 22 depicted in Table V, there are produced the bis[3-R-23 thiazolidin-2-ylideneamino]-R3-methanes and bis[3-R-24 thiazolin-2-ylidineamino]-R3-methanes also depicted in Table V, in accordance with Equation V
~ . . . : .
. . .
:~7 !3841~
1 Equation V
S
R2 ~ NH + CHO ~ ~ R
R R6 R l6 R
2 Tabie V
3 _ _ R ___ ___ R R6 4 Thiazolines ~
5 CH3- 4-CF3 H ~ i -6 CH3- ~ H
7 Thiazolidines , C3H7 H ~ ~- -11 CH2=CH-CH2- H ~ OCH3 OCH
12 CH~C-CH2- H ~
13 reagent is the aminal, N,N,N',M'-tetramethyltoluenediamine.
14 Example 9 !~ -15 N~Nl-bls-(3-methylthiazolidin-2-ylidene)succinamide i~
16 Step A: Preparation of bis-(4-nitrophenyl) succinate 17 A mixture of 2.36 g. (20 mmoles) of succinic 18 acia, 6.516 g. (44 mmoles) of 4-nitrophenol and 8.24 g.
19 (40 mmoles) of N,N'-dicyclohexylcarbodiimide was stirred 20 at room temperature in 225 ml. of ethylacetate for 2 days.
' ` ~ -18-8~ 6 1 The mixture was filtered and the filtrate was concentrated 2 to dryness. The residue was triturated with 40 ml. of 3 chloroform and the solids were collected on a filter and air 4 dried to give 1.38 g. of bis-(4-nitrophenyl) succinate, 5 m.p. 176-178C.
6 ~@_~: Preparation of N,N'-bis-(3-methylthiazolidin-2-7 ylidene)succinamide 8 A mixture of 80 mg. of ~-imino-3-methylthiazoli-9 dine, 118 mg. of bis-(4-nitrophenyl) succinate and 8 ml.
10 of chloroform was refluxed for 5.5 hours. The mixture 11 was diluted with chloroform, washed twice with sodium 12 carbonate solution, dried over sodium sulfate and concen-13 trated to dryness. The residue was recrystallized from 14 2 ml. of methanol to give 68 mg. of N,N'-bis-(3-methyl-thiazolidin-2-ylidene)succinamide, m.p. 181-183C.
16 Exam~e 10 17 N-(3-methylthiazolidin-2-ylidene) aminoacetamide dihydro-18 chloride 19 Step A: Preparation of N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide _ 21 Ethyl chloroformate (0.25 ml.) at -5C. was added 22 to a solution of 350 mg. of t-butoxycarbonylaminoacetic 23 acid and 0.4 ml. of triethylamine in 10 ml. of methylene 24 chloride at -5C. After stirring S minutes at -5C. there was added a solution o 610 mg. of 2-imino-3-methylthiazo-26 lidine hydrogen iodide and 1.0 ml. of triethylamine in 10 27 ml. of methylene chloride also at -5C. Stirring was 28 continued at -5C. for 15 minutes and one hour at room 29 temperature. The reaction mixture was washed with 40 ml.
of 20~ (w/v) citric acid solution, sodium bicarbonate 31 solution, and water, dried and concentrated to dryness.
--19-- .
~ 15743 IA
07~6 1 The residue was triturated with ether, petroleum ether and 2 ether and finally collected to give pure N-(3-methylthia-3 zolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.
4 Step B: Preparation of N-~3-methylthiazolidin-2-ylidene) aminoacetamide dihydrochloride 6 The product from Step A, (2.0 g.) was dissolved 7 in 100 ml. of chloroform and the solution was saturated 8 with hydrogen chloride gas by bubbling it through the 9 solution for 20 minutes. After 2 hours at room temperature the excess hydrogen chloride was expelled by bubbling in 11 nitrogen. The precipitated product was collected and air 12 dried under nitrogen to give 1.66 g. of N-t3-methylthia-13 zolidin-2-ylidene) aminoacetamide dihydrochloride, m. p.
14 190-194C.
Employing the procedure substantially as de-16 scribed in Example 10, Step A, but substituting for the 17 t-butoxycarbonylaminoacetic acid used therein an equimolar 18 amount of 2-acetylamino-2-benzylacetic acid, nicotinic 19 acid, acetoace~ic acid and 3-methyl-2-succinyliminothiazoli-dine (See Example 11), there are produced respectively:
21 N-(3-methylthiazolidin-2-ylidene) 2-acetylamino-2-benzyl-22 acetamide, m.p. 142-149C.
23 N-(3-methylthiazolidin-2-ylidene) nicotinamide, m.p.
24 108-lOgC.
N-(3-methylthiazolidin-2-ylidene) acetoacetamide, m.p.
26 43-45C.; and 27 N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide, m.p.
28 183-184C.
29 Following the procedure of Example 10, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 31 an equivalent amount of the 2-imino-3-R-thiazolidines and 32 thiazolines depicted in Table VIII, there are produced the ~C~715 8~6 1 N-(3-R-thiazolidin-2-ylidene)aminoacetamides and N-(3-R-2 thiazolin-2-ylidene)aminoacetamides also depicted in Table 3 Vl in accordance with Equation VI:
4 Equatlon Vl NH ~ HOOCCH2N~COOC(C~3)3 ~ ~N-C-CH2NH2 R O
Table VI
7 Thiazolines 10 Thiazolidines 14 CH2=CH-CH2- H
CH_C-C~2- H
17 Example 11 18 N-(3-methylthiazolidin-2-ylidene) acet~laminoacetamide 19 4-Nitrophenyl acetylaminoacetate (1.19 g.) was added portionwise to a solution o 580 mg. of 2-imino-3-21 methylthiazolidine in 60 ml. of chloroform. A~ter stirring 22 2 hours at room temperature, the solu~ion was concentrated 23 to dryness. The residue was triturated with ether and 24 collected on a filter. The crude product was dissolved in
25 chloroform, washed with sodium bicarbonate solu~ion, dried ~
26 and concentrated to dryness. Trituration with ether gave ~ -~ 15743 IA
8~
1 600 mg. of N-(3-methylthiazolidin-2-ylidene) acetylamino-2 acetamide, m.p. 138-139C.
3 Following the procedure of Example 11, but sub-4 stituting for the 2-imino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3--R-thiazolidines and 6 thiazolines depicted in Table VII, there are produced the 7 N-(3-R-thiazolidin-2-ylidene) acetylaminoacetamides and 8 N-(3-R-thiazolin-2-ylidene) acetylaminoacetamiaes also 9 depicted in Table IX, in accorda~ce with Equation VII:
Equation VII
~NH ~ NO 43-OOCCH2NHCOCH3 ,~ ~
NR 2 N ~N-CcH2~HcOc~I3 12 Table VII
14 Thiazolines 17 Thiazolidines 21 CH2=CH-CH2- H
23 Example 12 24 3-Methyl-2-succinyliminothiazolidine Succinic anhydride ~2.0 g.) was added to a solu-26 tion o~ 2-Lmino-3-me~hylthiazolidine in 70 ml. of methylene r~ ~ 15743IA
-071~346 1 chloride. After refluxing 3 hours, the mixture was filtered 2 and the filtrate was evaporated to dryness. The residue 3 was ~riturated with ether and collected on a filter to 4 give 3.63 g. of 3-methyl-2-succinylLminothiazolidine, m.p. 90-105C.
6 The product ~rom Example 12 was converted to the 7 sodium salt by dissolving 864 mg. of it in 25 ml. o~ water 8 and adding 336 mg. o~ sodium ~icarbonate. The mixture 9 was concentrated to dryness and the residue was triturated with isopropanol. The solids were collected on a filter 11 to give 730 mg. of 3-me~hyl-2-succinylIminothiazolidine 12 sodium salt, m.p. 205-210C.
13 Following the procedure of Example 12, but sub-14 sti~uting for the 2-Lmino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and 16 thiazolines depicted in Table VIII, there are produced the 17 3-R-2-succinyliminothiazolidines and 3-R-2-succinylimino-18 thiazolines also depicted in ~able VIII, in accordance with 19 Equation VIII:
E~uation VIII
~'. ..
W ~ H + ~ ~N-C-CH2CH2COOH
R O R
21 Table VIII
23 Thiazolines - . - -~ ~ 15743~
34~`
1 Table_VIII (con't) _ _ . . .
3 Thiazolidines .
~ C3H7 7 CH2=CH-CH2- H
8 CH_C-CH2 g Example 13 2-Acetoacetylimino-3-methylthiazolidine ll A solution of 13 g. of diketene in lO0 ml. of 12 ethanol was added dropwise to an ice-cold solution of 13 18 g. of 2-imino-3-methylthiazolidine in 100 ml. o~ ethanol.
14 The mixture was allowed to warm spontaneously to room tem-perature and then evaporated to dryness. The residue was 16 triturated with ether, collected on a fiiter and dried in 17 a dessicator to give 2-acetoacetylimino-3-methylthiazoli 18 dine, m.p. 43-45C.
l9 Following the procedure of Example 13, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 21 an equivalent amount of the 2-imino-3-R-thiazolidines and 22 thiazolines depicted in Table IX, there are produced the 23 ~-acetoacetylimino-3-R-thiazolidines and 2-acetoacetyl-24 imino-3-R-thiazolines also depicted in Table IX, in accord-ance with Equation IX:
26 Equation IX
N~ N~ ~ N N-CCR2cOcR3 ~ 15743 IA
1~7i5384~6 1 Table IX
2 R R _ _ 3 Thiazolines 4 C~3- 4-CF3 6 Thiazolidines CH2=CH-C~2- H
ll CH-C-CH2- H
12 Example 14 13 Pharmaceutical compositions 14 A typical tablet containing 5 mg. of N-(3-methyl-thiazolidin-]-ylidene) acetylaminoacetamide per tablet is }6 prepared by mixing together with the active ingredient 17 ca}cium phosphate, lactose and starch in the amounts shown 18 in the tables below. After these ingredients are thoroughly 19 mixed, the dry mixture blended for an additional three minutes. ~his mixture is then compressed into tablets 21 weighing approximately 129 mg. each. Similarly prepared 22 are tablets containing N-(3-methylthiazolidin-2-ylidene) 23 2-acetylamino-2-benzylacetamide; N-(3-methylthiazolidin-2-24 ylidene)nicotinamide; and N,~'-bis-(3-methylthiazolidin-2-ylidene)succinamide.
,~ ~ 15743 IA
~ .
~C~78~4~;
1 Tablet Formula 2 In~redient Mg. per tablet 3 N-(3-methylthiazolidin-2-4 ylidene) acetylaminoacetamide 5 mg.
5 Calcium phosphate 52 mg.
6 Lactose 60 mg.
7 Starch 10 mg.
8 Magnesium stearate 1 mg.
9 ~ablet Formula 10 Ingredient Mg. Per Tablet 11 N-(3-methylthiazolidin-2-12 ylidene) 2-acetylamino-2-13 benzylacetamide 5 mg.
14 Calcium phosphate 52 mg.
15 Lactose 60 mg.
16 Starch 10 mg.
17 Magnesium stearate 1 mg.
18 Tablet Formula 19 Ingredient Mg. per Tablet 20 N-(3-methylthiazolidin-2-21 ylidene)nicotinamide 5 mg.
22 Calcium phosphate 52 mg.
23 Lactose 60 mg.
24 Starch 10 mg.
25 Magnesium stearate 1 mg.
~ ~ 15743IA
.
~788~6 l ablet Formula 2 Ingredient Mg. Per Tablet 3 N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide 5 mg Calcium phosphate 52 mg.
6 Lactose 60 mg.
7 Starch 10 mg.
8 Magnesium stearate 1 mg.
9 In the process description of the ~oregoing specification, there is disclosed the following 11 condensation to provide N,N'-bis-(3-methyl-thia~olidin-12 2-ylidene)succinamide:
~ ~H + Y-C-R~ > ~ r N
13 wherein R3 is carboxamido-lower alkyl, such as -C~2CH2C-N= ~ ~ and Y is Cl, NO2- ~ -~
14 (Cl 4 alkyl)OCO- or N3. In this reaction Y, may also 15 be -OCH2CN, F~ H OH
O ~ F -O-IP-F O Ph , -O-~ ~ -O-C~ 2 (Cl_4 alkY1)2 ~O(Cl 4alkyl), 16 or -O~Cl 4 alkyl).
:' ' ' ' , ':~, .' '' ' ''' ' ' ''' ~- ' ' -.~ . ~ ~ 15743IA
~71!384~
1 SLmilarly, the product, N,N'-bis-(3-methyl-2 thiazolidin-2-ylidene)succinamide can be prepared as 3 ~ollows:
NE + Y~C-CH2C~2-C-Y > ~N ~ W-C-CEI 1 4 wherein Y is as defined above. These condensation reactions are conducted in an anhydrous inert organic 6 solvent such as chloroform,tetrahydrofuran, toluene or 7 the like from -10C. to reflux temperature for l to 8 about 72 hours.
9 Another procedure for the synthesis of ~10 N,N'-bis-(3-methyl-thiazolidin-2-ylidene~SUCCinamide ll is depicted as follows:
C ~yC ~ ~-C-C32C~-C N ~u~
12 wherein Z is -OH, -Br, -Cl, or other leaving groups such 13 as tosyloxy, mesyloxy or the like. ~rhe cyclization 14 proceeds under aqueous acidic conditions, the strensth of the acid, and time of reaction being dependent on the ~7~
1 nature of Z. Where Z is -OH, fortified hydrochloric 2 acid, or mineral acids of similar strength are 3 required for periods of 10-48 hours, where 2 is halo 4 or tosyloxy for example, a trace of the acid produced by the cyclization is su~ficient to catalyze the 6 ring closure, so that much shorter times such as a 7 few minutes, and less vigorous acid conditions are 8 required.
9 Examples 15-18 show the synthesis o~ N,N'-bis-(3-methyl-thiazolidin-2-ylidene)succinamide by the 11 a~ove described procedures.
12 Example 15 13 To a mixture of 21.6 g. of 3-methyl-2-14 succinyliminothiazolidine from Example 12 and 10.2 g.
of triethylamine in 80 ml. of anhydrous chloroform 16 is added dropwise 13.7 g. of isobutylchloroformate at 17 -5 to 0C. After 30 minutes stirring 10.2 g. of 2-18 imino-3-methylthiazolidine in 50 ml. chloroform is added, 19 maintaining the temperature at 0C. by external cooling.
After one hour aging at ambient temperature the precip-21 itated triethylamine hydrochloride is filtered off.
22 The chloroform filtrate is washed with sodium bicarbonate 23 solution, dried (Na2S04) and the solvent is removed ln 24 vacuo. The residue is recrystallized from me~hanol to give N,N'-bis-t3-methyl-thiazolidin-2-ylidene)-succinamide.
26 Example 16
8~
1 600 mg. of N-(3-methylthiazolidin-2-ylidene) acetylamino-2 acetamide, m.p. 138-139C.
3 Following the procedure of Example 11, but sub-4 stituting for the 2-imino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3--R-thiazolidines and 6 thiazolines depicted in Table VII, there are produced the 7 N-(3-R-thiazolidin-2-ylidene) acetylaminoacetamides and 8 N-(3-R-thiazolin-2-ylidene) acetylaminoacetamiaes also 9 depicted in Table IX, in accorda~ce with Equation VII:
Equation VII
~NH ~ NO 43-OOCCH2NHCOCH3 ,~ ~
NR 2 N ~N-CcH2~HcOc~I3 12 Table VII
14 Thiazolines 17 Thiazolidines 21 CH2=CH-CH2- H
23 Example 12 24 3-Methyl-2-succinyliminothiazolidine Succinic anhydride ~2.0 g.) was added to a solu-26 tion o~ 2-Lmino-3-me~hylthiazolidine in 70 ml. of methylene r~ ~ 15743IA
-071~346 1 chloride. After refluxing 3 hours, the mixture was filtered 2 and the filtrate was evaporated to dryness. The residue 3 was ~riturated with ether and collected on a filter to 4 give 3.63 g. of 3-methyl-2-succinylLminothiazolidine, m.p. 90-105C.
6 The product ~rom Example 12 was converted to the 7 sodium salt by dissolving 864 mg. of it in 25 ml. o~ water 8 and adding 336 mg. o~ sodium ~icarbonate. The mixture 9 was concentrated to dryness and the residue was triturated with isopropanol. The solids were collected on a filter 11 to give 730 mg. of 3-me~hyl-2-succinylIminothiazolidine 12 sodium salt, m.p. 205-210C.
13 Following the procedure of Example 12, but sub-14 sti~uting for the 2-Lmino-3-methylthiazolidine used therein, an equivalent amount of the 2-imino-3-R-thiazolidines and 16 thiazolines depicted in Table VIII, there are produced the 17 3-R-2-succinyliminothiazolidines and 3-R-2-succinylimino-18 thiazolines also depicted in ~able VIII, in accordance with 19 Equation VIII:
E~uation VIII
~'. ..
W ~ H + ~ ~N-C-CH2CH2COOH
R O R
21 Table VIII
23 Thiazolines - . - -~ ~ 15743~
34~`
1 Table_VIII (con't) _ _ . . .
3 Thiazolidines .
~ C3H7 7 CH2=CH-CH2- H
8 CH_C-CH2 g Example 13 2-Acetoacetylimino-3-methylthiazolidine ll A solution of 13 g. of diketene in lO0 ml. of 12 ethanol was added dropwise to an ice-cold solution of 13 18 g. of 2-imino-3-methylthiazolidine in 100 ml. o~ ethanol.
14 The mixture was allowed to warm spontaneously to room tem-perature and then evaporated to dryness. The residue was 16 triturated with ether, collected on a fiiter and dried in 17 a dessicator to give 2-acetoacetylimino-3-methylthiazoli 18 dine, m.p. 43-45C.
l9 Following the procedure of Example 13, but sub-stituting for the 2-imino-3-methylthiazolidine used therein, 21 an equivalent amount of the 2-imino-3-R-thiazolidines and 22 thiazolines depicted in Table IX, there are produced the 23 ~-acetoacetylimino-3-R-thiazolidines and 2-acetoacetyl-24 imino-3-R-thiazolines also depicted in Table IX, in accord-ance with Equation IX:
26 Equation IX
N~ N~ ~ N N-CCR2cOcR3 ~ 15743 IA
1~7i5384~6 1 Table IX
2 R R _ _ 3 Thiazolines 4 C~3- 4-CF3 6 Thiazolidines CH2=CH-C~2- H
ll CH-C-CH2- H
12 Example 14 13 Pharmaceutical compositions 14 A typical tablet containing 5 mg. of N-(3-methyl-thiazolidin-]-ylidene) acetylaminoacetamide per tablet is }6 prepared by mixing together with the active ingredient 17 ca}cium phosphate, lactose and starch in the amounts shown 18 in the tables below. After these ingredients are thoroughly 19 mixed, the dry mixture blended for an additional three minutes. ~his mixture is then compressed into tablets 21 weighing approximately 129 mg. each. Similarly prepared 22 are tablets containing N-(3-methylthiazolidin-2-ylidene) 23 2-acetylamino-2-benzylacetamide; N-(3-methylthiazolidin-2-24 ylidene)nicotinamide; and N,~'-bis-(3-methylthiazolidin-2-ylidene)succinamide.
,~ ~ 15743 IA
~ .
~C~78~4~;
1 Tablet Formula 2 In~redient Mg. per tablet 3 N-(3-methylthiazolidin-2-4 ylidene) acetylaminoacetamide 5 mg.
5 Calcium phosphate 52 mg.
6 Lactose 60 mg.
7 Starch 10 mg.
8 Magnesium stearate 1 mg.
9 ~ablet Formula 10 Ingredient Mg. Per Tablet 11 N-(3-methylthiazolidin-2-12 ylidene) 2-acetylamino-2-13 benzylacetamide 5 mg.
14 Calcium phosphate 52 mg.
15 Lactose 60 mg.
16 Starch 10 mg.
17 Magnesium stearate 1 mg.
18 Tablet Formula 19 Ingredient Mg. per Tablet 20 N-(3-methylthiazolidin-2-21 ylidene)nicotinamide 5 mg.
22 Calcium phosphate 52 mg.
23 Lactose 60 mg.
24 Starch 10 mg.
25 Magnesium stearate 1 mg.
~ ~ 15743IA
.
~788~6 l ablet Formula 2 Ingredient Mg. Per Tablet 3 N,N'-bis-(3-methylthiazolidin-2-ylidene)succinamide 5 mg Calcium phosphate 52 mg.
6 Lactose 60 mg.
7 Starch 10 mg.
8 Magnesium stearate 1 mg.
9 In the process description of the ~oregoing specification, there is disclosed the following 11 condensation to provide N,N'-bis-(3-methyl-thia~olidin-12 2-ylidene)succinamide:
~ ~H + Y-C-R~ > ~ r N
13 wherein R3 is carboxamido-lower alkyl, such as -C~2CH2C-N= ~ ~ and Y is Cl, NO2- ~ -~
14 (Cl 4 alkyl)OCO- or N3. In this reaction Y, may also 15 be -OCH2CN, F~ H OH
O ~ F -O-IP-F O Ph , -O-~ ~ -O-C~ 2 (Cl_4 alkY1)2 ~O(Cl 4alkyl), 16 or -O~Cl 4 alkyl).
:' ' ' ' , ':~, .' '' ' ''' ' ' ''' ~- ' ' -.~ . ~ ~ 15743IA
~71!384~
1 SLmilarly, the product, N,N'-bis-(3-methyl-2 thiazolidin-2-ylidene)succinamide can be prepared as 3 ~ollows:
NE + Y~C-CH2C~2-C-Y > ~N ~ W-C-CEI 1 4 wherein Y is as defined above. These condensation reactions are conducted in an anhydrous inert organic 6 solvent such as chloroform,tetrahydrofuran, toluene or 7 the like from -10C. to reflux temperature for l to 8 about 72 hours.
9 Another procedure for the synthesis of ~10 N,N'-bis-(3-methyl-thiazolidin-2-ylidene~SUCCinamide ll is depicted as follows:
C ~yC ~ ~-C-C32C~-C N ~u~
12 wherein Z is -OH, -Br, -Cl, or other leaving groups such 13 as tosyloxy, mesyloxy or the like. ~rhe cyclization 14 proceeds under aqueous acidic conditions, the strensth of the acid, and time of reaction being dependent on the ~7~
1 nature of Z. Where Z is -OH, fortified hydrochloric 2 acid, or mineral acids of similar strength are 3 required for periods of 10-48 hours, where 2 is halo 4 or tosyloxy for example, a trace of the acid produced by the cyclization is su~ficient to catalyze the 6 ring closure, so that much shorter times such as a 7 few minutes, and less vigorous acid conditions are 8 required.
9 Examples 15-18 show the synthesis o~ N,N'-bis-(3-methyl-thiazolidin-2-ylidene)succinamide by the 11 a~ove described procedures.
12 Example 15 13 To a mixture of 21.6 g. of 3-methyl-2-14 succinyliminothiazolidine from Example 12 and 10.2 g.
of triethylamine in 80 ml. of anhydrous chloroform 16 is added dropwise 13.7 g. of isobutylchloroformate at 17 -5 to 0C. After 30 minutes stirring 10.2 g. of 2-18 imino-3-methylthiazolidine in 50 ml. chloroform is added, 19 maintaining the temperature at 0C. by external cooling.
After one hour aging at ambient temperature the precip-21 itated triethylamine hydrochloride is filtered off.
22 The chloroform filtrate is washed with sodium bicarbonate 23 solution, dried (Na2S04) and the solvent is removed ln 24 vacuo. The residue is recrystallized from me~hanol to give N,N'-bis-t3-methyl-thiazolidin-2-ylidene)-succinamide.
26 Example 16
27 A mixture of 3.1 g. of succinic acid, 7.4 g.
28 of triethylamine and 10.1 g. of chloroacetonitrile in
- 29 -~ r~ 15743IA
7~6 1 50 ml. ethyl acetate is refluxed for three hours. The 2 precipitated triethylamine hydrochloride is filtered 3 and the filtrate is washed with saturated NaCl solution, 4 dried (Na2SO4) and concentrated ln vacuo.
The crude di-cyanomethylsuccinate (3.9 g.) 6 is dissolved in 80 ml. of tetrahydrofuran. 2-Imino 3-7 methylthiazolidine (3.88 g.) and 0.8 ml. of acetic acid 8 are added and the reaction mixture is allowed to stand 9 at ambient temperature for 48 hours.
The mixture is quenched onto 300-350 g. ice-11 water and extracted with ethyl acetate. The combined 12 extracts are washed with sodium bicarbonate solution, 13 then with water. The ethylacetate phase is dried over 14 Na2SO4, filtered and concentrated in vacuo. The residue is recrystallized from methanol to give N~N'-bis-(3-16 methyl-thiazolidine-2-ylidene)-succinamide.
17 Example 17 18 A mixture of 15.5 g. of succinylchloride and 19 20.5 g. of 2-imino-3-methylthiazolidine in 150 ml. dry toluene is refluxed until two equivalents of hydrogen 21 chloride are formed. The solution is cooled to room 22 temperature and washed with saturated sodium bicarbonate 23 solution. After removing the solvent in vacuo, the 24 residue is recrystallized from methanol to give N,N'-bis-(3-methyl-thiazo}idine-2-ylidene)-succinamide.
26 The above described reaction can also be 27 conducted in the presence of equivalent amounts of tert.
28 base such as triethylamine or dimethyl aniline or the 29 like at ambient temperature.
7~6 1 50 ml. ethyl acetate is refluxed for three hours. The 2 precipitated triethylamine hydrochloride is filtered 3 and the filtrate is washed with saturated NaCl solution, 4 dried (Na2SO4) and concentrated ln vacuo.
The crude di-cyanomethylsuccinate (3.9 g.) 6 is dissolved in 80 ml. of tetrahydrofuran. 2-Imino 3-7 methylthiazolidine (3.88 g.) and 0.8 ml. of acetic acid 8 are added and the reaction mixture is allowed to stand 9 at ambient temperature for 48 hours.
The mixture is quenched onto 300-350 g. ice-11 water and extracted with ethyl acetate. The combined 12 extracts are washed with sodium bicarbonate solution, 13 then with water. The ethylacetate phase is dried over 14 Na2SO4, filtered and concentrated in vacuo. The residue is recrystallized from methanol to give N~N'-bis-(3-16 methyl-thiazolidine-2-ylidene)-succinamide.
17 Example 17 18 A mixture of 15.5 g. of succinylchloride and 19 20.5 g. of 2-imino-3-methylthiazolidine in 150 ml. dry toluene is refluxed until two equivalents of hydrogen 21 chloride are formed. The solution is cooled to room 22 temperature and washed with saturated sodium bicarbonate 23 solution. After removing the solvent in vacuo, the 24 residue is recrystallized from methanol to give N,N'-bis-(3-methyl-thiazo}idine-2-ylidene)-succinamide.
26 The above described reaction can also be 27 conducted in the presence of equivalent amounts of tert.
28 base such as triethylamine or dimethyl aniline or the 29 like at ambient temperature.
- 30 -~ ~ 15743IA
, 1 Example 18 2 To a solution of 20 g. of succinyl-di-isothio-3 cyanate (J. Chem. Soc. 67 565O) in 50 ml. acetone is 4 added 7.51 g. of ~-methylaminoethanol in 20 ml. acetone.
The reaction mixture is heated under reflux for 30 minutes, 6 then quenched, after cooling to room temperature r onto 7 350-400 ml. of ice-cold water. The precipitated 8 N-succinyl-N'-methyl-N'-2-hydroxyethyl-thiourea is 9 iltered and purified by crystallization from ethanol.
The substituted urea is dissolved in 100 ml.
11 of 75% sulfuric acid and aLlowed to stand at ambient 12 temperature for 24 hours. Upon pouring the mixture 13 into 5-6 times its volume of ice-water, N,N'-bis-(3-14 methylthiazolidine-2-ylidene)-succinamide is precipitated.
Recrystallization from methanol ~ives pure ~,N'-bis-(3-16 methyl-thiazolidin-2-ylidene)suCCinamide.
, 1 Example 18 2 To a solution of 20 g. of succinyl-di-isothio-3 cyanate (J. Chem. Soc. 67 565O) in 50 ml. acetone is 4 added 7.51 g. of ~-methylaminoethanol in 20 ml. acetone.
The reaction mixture is heated under reflux for 30 minutes, 6 then quenched, after cooling to room temperature r onto 7 350-400 ml. of ice-cold water. The precipitated 8 N-succinyl-N'-methyl-N'-2-hydroxyethyl-thiourea is 9 iltered and purified by crystallization from ethanol.
The substituted urea is dissolved in 100 ml.
11 of 75% sulfuric acid and aLlowed to stand at ambient 12 temperature for 24 hours. Upon pouring the mixture 13 into 5-6 times its volume of ice-water, N,N'-bis-(3-14 methylthiazolidine-2-ylidene)-succinamide is precipitated.
Recrystallization from methanol ~ives pure ~,N'-bis-(3-16 methyl-thiazolidin-2-ylidene)suCCinamide.
- 31 -
Claims (14)
1. The process for preparing a compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R1 is (1) , wherein R3 is (a) lower alkyl of 1 to 3 carbon atoms and is substituted with (i) amino, (ii) lower alkanoylamino of 2 to 4 carbon atoms, (iii) carboxy, (iv) lower alkanoyl of 2 to 4 carbon atoms; or (v) phenyl and lower alkanoylamino (b) pyridyl, (c) (2) , wherein R6 is (a) hydrogen, (b) lower alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) phenyl substituted with one or more lower alkoxy groups of 1 to 3 carbon atoms, (e) pyridyl, or (f) benzyl;
R4 is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
and R5 is (a) lower alkyl of 1 to 3 carbon atoms, (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R4 and R5 taken together with the nitrogen to which they are attached is (a) or (b) ;
(3) which comprises:
I: when R1 is : reacting a compound of the formula:
with a compound of the structure wherein Y is chloro, , -N3, or ; and R3 is as defined above; or II: when R1 is : xeacting a compound of the structural formula:
with a compound of the formula:
wherein X is chloro or -N(CH3)2; or III: when R1 is : reactiny a compound of the formula:
with pyridoxal; or IV: when R1 is and R4 and R5 taken together with the nitrogen to which they are attached represent reacting a compound of the formula:
with an aldehyde of the formula:
V: when R3 is : reacting a compound of the formula:
with a compound of the formula:
where Y is chloro, , -N3, or , and isolating the desired products.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R1 is (1) , wherein R3 is (a) lower alkyl of 1 to 3 carbon atoms and is substituted with (i) amino, (ii) lower alkanoylamino of 2 to 4 carbon atoms, (iii) carboxy, (iv) lower alkanoyl of 2 to 4 carbon atoms; or (v) phenyl and lower alkanoylamino (b) pyridyl, (c) (2) , wherein R6 is (a) hydrogen, (b) lower alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) phenyl substituted with one or more lower alkoxy groups of 1 to 3 carbon atoms, (e) pyridyl, or (f) benzyl;
R4 is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
and R5 is (a) lower alkyl of 1 to 3 carbon atoms, (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R4 and R5 taken together with the nitrogen to which they are attached is (a) or (b) ;
(3) which comprises:
I: when R1 is : reacting a compound of the formula:
with a compound of the structure wherein Y is chloro, , -N3, or ; and R3 is as defined above; or II: when R1 is : xeacting a compound of the structural formula:
with a compound of the formula:
wherein X is chloro or -N(CH3)2; or III: when R1 is : reactiny a compound of the formula:
with pyridoxal; or IV: when R1 is and R4 and R5 taken together with the nitrogen to which they are attached represent reacting a compound of the formula:
with an aldehyde of the formula:
V: when R3 is : reacting a compound of the formula:
with a compound of the formula:
where Y is chloro, , -N3, or , and isolating the desired products.
2. A process for the preparation of a compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is , wherein R? is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
R? is (a) lower alkyl, or (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R? and R? taken together with the nitrogen to which they are attached is which comprises reacting a compound of structural formula:
with a compound of formula:
R?-X
wherein X is chloro or -N(CH3)2, and isolated the desired compound.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is , wherein R? is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
R? is (a) lower alkyl, or (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R? and R? taken together with the nitrogen to which they are attached is which comprises reacting a compound of structural formula:
with a compound of formula:
R?-X
wherein X is chloro or -N(CH3)2, and isolated the desired compound.
3. A process for the preparation of a compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, and R6 is (1) hydrogen, (2) lower alkyl of 1 to 3 carbon atoms, (3) phenyl, (4) phenyl substituted with 1 or more lower alkoxy groups of 1 to 3 carbon atoms, or (5) pyridyl, which comprises reacting a compound of structural formula:
with a compound of formula R6-CHO or functional equivalent thereof, wherein R6 is as defined above, and isolating the desired compound.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, and R6 is (1) hydrogen, (2) lower alkyl of 1 to 3 carbon atoms, (3) phenyl, (4) phenyl substituted with 1 or more lower alkoxy groups of 1 to 3 carbon atoms, or (5) pyridyl, which comprises reacting a compound of structural formula:
with a compound of formula R6-CHO or functional equivalent thereof, wherein R6 is as defined above, and isolating the desired compound.
4. A process for the preparation of a compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, which comprises reacting a compound of structural formula:
with pyridoxal, and isolating the desired compound.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, which comprises reacting a compound of structural formula:
with pyridoxal, and isolating the desired compound.
5. A process for the preparation of a compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (1) amino, (2) lower alkanoylamino of 2 to 4 carbon atoms, (3) lower alkanoyl of 2 to 4 carbon atoms, or (4) carboxy;
(5) phenyl and lower alkanoylamino; or (b) pyridyl, which comprises reacting a compound of structural formula:
with a compound of structural formula:
wherein Y is chloro, , -N3, or , and isolating the desired compound.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (1) amino, (2) lower alkanoylamino of 2 to 4 carbon atoms, (3) lower alkanoyl of 2 to 4 carbon atoms, or (4) carboxy;
(5) phenyl and lower alkanoylamino; or (b) pyridyl, which comprises reacting a compound of structural formula:
with a compound of structural formula:
wherein Y is chloro, , -N3, or , and isolating the desired compound.
6. The process for preparing the compound of formula:
which comprises treating a compound of formula:
with a compound of formula:
in the presence of ethyl chloroformate, or with a compound of formula:
wherein Y is chloro, , -N3, or , and isolating the desired compound.
which comprises treating a compound of formula:
with a compound of formula:
in the presence of ethyl chloroformate, or with a compound of formula:
wherein Y is chloro, , -N3, or , and isolating the desired compound.
7. A process for the preparation of a compound of formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R8 is lower alkylene of 1 to 3 carbon atoms which comprises reacting a compound of formula:
with a compound of formula:
wherein R8 is lower alkylene of 1 to 3 carbon atoms, and isolating the desired compound.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R8 is lower alkylene of 1 to 3 carbon atoms which comprises reacting a compound of formula:
with a compound of formula:
wherein R8 is lower alkylene of 1 to 3 carbon atoms, and isolating the desired compound.
8. A compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R1 is (1) , wherein R3 is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (i) amino, (ii) lower alkanoylamino of 2 to 4 carbon atoms, (iii) carboxy, (iv) lower alkanoyl of 2 to 4 carbon atoms; or (v) phenyl and lower alkanoylamino (b) pyridyl, (c) (2) wherein R6 is (a) hydrogen, (b) lower alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) phenyl substituted with one or more lower alkoxy groups of 1 to 3 carbon atoms, (e) pyridyl, or (f) benzyl;
R4 is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
and R5 is (a) lower alkyl of 1 to 3 carbon atoms, (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R4 and R5 taken together with the nitrogen to which they are attached is (a) or (b) ;
(3 when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R1 is (1) , wherein R3 is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (i) amino, (ii) lower alkanoylamino of 2 to 4 carbon atoms, (iii) carboxy, (iv) lower alkanoyl of 2 to 4 carbon atoms; or (v) phenyl and lower alkanoylamino (b) pyridyl, (c) (2) wherein R6 is (a) hydrogen, (b) lower alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) phenyl substituted with one or more lower alkoxy groups of 1 to 3 carbon atoms, (e) pyridyl, or (f) benzyl;
R4 is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
and R5 is (a) lower alkyl of 1 to 3 carbon atoms, (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R4 and R5 taken together with the nitrogen to which they are attached is (a) or (b) ;
(3 when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
9. A compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is , wherein R? is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
R? is (a) lower alkyl, or (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R? and R? taken together with the nitrogen to which they are attached is when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is , wherein R? is (a) hydrogen, or (b) lower alkyl of 1 to 3 carbon atoms;
R? is (a) lower alkyl, or (b) -COR7, wherein R7 is (i) lower alkyl of 1 to 3 carbon atoms, or (ii) phenyl; or R? and R? taken together with the nitrogen to which they are attached is when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
10. A compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl or 1 to 3 carbon atoms; and R6 is (1) hydrogen, (2) lower alkyl of 1 to 3 carbon atoms, (3) phenyl, (4) phenyl substituted with 1 or more lower alkoxy groups of 1 to 3 carbon atoms, or (5) pyridyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl or 1 to 3 carbon atoms; and R6 is (1) hydrogen, (2) lower alkyl of 1 to 3 carbon atoms, (3) phenyl, (4) phenyl substituted with 1 or more lower alkoxy groups of 1 to 3 carbon atoms, or (5) pyridyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
11. A compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
12. A compound of structural formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (1) amino, (2) lower alkanoylamino of 2 to 4 carbon atoms, (3) lower alkanoyl of 2 to 4 carbon atoms, or (4) carboxy;
(5) phenyl and lower alkanoylamino; or (b) pyridyl, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R? is (a) lower alkyl of 1 to 3 carbon atoms, substituted with (1) amino, (2) lower alkanoylamino of 2 to 4 carbon atoms, (3) lower alkanoyl of 2 to 4 carbon atoms, or (4) carboxy;
(5) phenyl and lower alkanoylamino; or (b) pyridyl, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
13. The compound of formula:
when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
14. A compound of formula:
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R8 is lower alkylene of 1 to 3 carbon atoms, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
or pharmaceutically acceptable salt thereof, wherein R is lower alkyl of 1 to 3 carbon atoms; and R8 is lower alkylene of 1 to 3 carbon atoms, when prepared by the process defined in Claim 7 or by an obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68287676A | 1976-05-03 | 1976-05-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1078846A true CA1078846A (en) | 1980-06-03 |
Family
ID=24741558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA277,184A Expired CA1078846A (en) | 1976-05-03 | 1977-04-27 | Derivatives of 2-iminothiazolidines and thiazolines |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS52133981A (en) |
| AU (1) | AU508889B2 (en) |
| BE (1) | BE854172A (en) |
| CA (1) | CA1078846A (en) |
| CH (1) | CH629490A5 (en) |
| DE (1) | DE2719577A1 (en) |
| DK (1) | DK173777A (en) |
| ES (2) | ES458237A1 (en) |
| FI (1) | FI771285A (en) |
| FR (1) | FR2350351A1 (en) |
| GB (1) | GB1534242A (en) |
| HU (1) | HU180504B (en) |
| IE (1) | IE46011B1 (en) |
| IL (1) | IL51935A (en) |
| IT (1) | IT1082657B (en) |
| LU (1) | LU77243A1 (en) |
| NL (1) | NL7704322A (en) |
| NO (1) | NO146061C (en) |
| NZ (1) | NZ183941A (en) |
| PH (1) | PH14030A (en) |
| PL (1) | PL123449B1 (en) |
| SE (1) | SE7704594L (en) |
| YU (1) | YU111677A (en) |
| ZA (1) | ZA772614B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU188852B (en) * | 1983-03-16 | 1986-05-28 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for producing thiazolidine derivatives active against gastric ulcer and intestinal ulcer |
| US5555162A (en) * | 1994-04-26 | 1996-09-10 | Sylvan R. Shemitz Designs, Inc. | Compact fluorescent luminaire |
| USRE37310E1 (en) | 1994-12-06 | 2001-08-07 | Sylvan R. Shemitz Designs, Inc. | Compact fluorescent luminaire |
| FR2748023B1 (en) * | 1996-04-30 | 1998-07-24 | Rhone Poulenc Chimie | HYDROGENOFLUOROSULFONATES OF ORGANIC BASIS, THEIR USE TO RELEASE ORGANIC BASES FROM THEIR FLUORHYDRATE, THEIR PREPARATION PROCESS, COMPOSITIONS CONTAINING THEM |
-
1977
- 1977-04-20 DK DK173777A patent/DK173777A/en active IP Right Grant
- 1977-04-20 NL NL7704322A patent/NL7704322A/en not_active Application Discontinuation
- 1977-04-21 NO NO77771375A patent/NO146061C/en unknown
- 1977-04-21 SE SE7704594A patent/SE7704594L/en not_active Application Discontinuation
- 1977-04-22 FI FI771285A patent/FI771285A/fi not_active Application Discontinuation
- 1977-04-25 IL IL51935A patent/IL51935A/en unknown
- 1977-04-26 CH CH518177A patent/CH629490A5/en not_active IP Right Cessation
- 1977-04-26 NZ NZ183941A patent/NZ183941A/en unknown
- 1977-04-27 ES ES458237A patent/ES458237A1/en not_active Expired
- 1977-04-27 AU AU24630/77A patent/AU508889B2/en not_active Expired
- 1977-04-27 CA CA277,184A patent/CA1078846A/en not_active Expired
- 1977-04-28 IT IT49173/77A patent/IT1082657B/en active
- 1977-04-29 PH PH19725A patent/PH14030A/en unknown
- 1977-04-29 HU HU77ME2062A patent/HU180504B/en unknown
- 1977-04-29 IE IE867/77A patent/IE46011B1/en unknown
- 1977-04-29 FR FR7713017A patent/FR2350351A1/en active Granted
- 1977-04-30 PL PL1977223798A patent/PL123449B1/en unknown
- 1977-05-02 ZA ZA00772614A patent/ZA772614B/en unknown
- 1977-05-02 DE DE19772719577 patent/DE2719577A1/en not_active Withdrawn
- 1977-05-02 JP JP5003977A patent/JPS52133981A/en active Pending
- 1977-05-02 BE BE177189A patent/BE854172A/en not_active IP Right Cessation
- 1977-05-02 GB GB18273/77A patent/GB1534242A/en not_active Expired
- 1977-05-03 LU LU77243A patent/LU77243A1/xx unknown
- 1977-12-28 YU YU01116/77A patent/YU111677A/en unknown
-
1978
- 1978-03-30 ES ES468377A patent/ES468377A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT1082657B (en) | 1985-05-21 |
| NL7704322A (en) | 1977-11-07 |
| FR2350351B1 (en) | 1979-03-02 |
| YU111677A (en) | 1983-01-21 |
| ES468377A1 (en) | 1978-12-16 |
| JPS52133981A (en) | 1977-11-09 |
| DK173777A (en) | 1977-11-04 |
| IE46011B1 (en) | 1983-01-26 |
| IL51935A0 (en) | 1977-06-30 |
| SE7704594L (en) | 1977-11-04 |
| FR2350351A1 (en) | 1977-12-02 |
| AU2463077A (en) | 1978-11-02 |
| DE2719577A1 (en) | 1977-11-24 |
| PH14030A (en) | 1980-12-12 |
| AU508889B2 (en) | 1980-04-03 |
| IE46011L (en) | 1977-11-03 |
| FI771285A (en) | 1977-11-04 |
| GB1534242A (en) | 1978-11-29 |
| HU180504B (en) | 1983-03-28 |
| NO771375L (en) | 1977-11-04 |
| NZ183941A (en) | 1980-12-19 |
| ES458237A1 (en) | 1978-07-01 |
| ZA772614B (en) | 1978-12-27 |
| NO146061C (en) | 1982-07-28 |
| PL123449B1 (en) | 1982-10-30 |
| CH629490A5 (en) | 1982-04-30 |
| LU77243A1 (en) | 1977-12-13 |
| NO146061B (en) | 1982-04-13 |
| IL51935A (en) | 1981-07-31 |
| BE854172A (en) | 1977-11-03 |
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