Method for Treating Multiple Sclerosis

专利摘要:
Provided are methods of treating multiple sclerosis using certain aryl-substituted rhodanines.
公开号:KR19980701588A
申请号:KR1019970704980
申请日:1996-01-22
公开日:1998-05-15
发明作者:앤 이. 킹스톤；질 에이 파네타
申请人:피터 쥐. 스트링거；일라이 릴리 앤드 캄파니；
IPC主号:

专利说明:

How to treat multiple sclerosis
The present invention provides a method of treating multiple sclerosis in a mammal.
Multiple sclerosis was first described as a clinical problem in 1868. Clinically, multiple sclerosis is a very variable disease and usually begins in the 20s to 50s of life. The most common signs of multiple sclerosis are perceptual and visual motor dysfunction. In the chronic form, the patient undergoes several palliative stages but at each palliative stage there is a greater neuronal dysfunction.
Macroscopically, multiple sclerosis includes lesions of 1 to 4 cm called plaques dispersed through the white matter of the central nervous system. Microscopically, the disease is characterized by the destruction of myelin sheaths of the nervous system. There is also a loss of myelin basic protein in the lesion area.
The etiology and pathology of multiple sclerosis is still unclear. Both chronic infectious agents and autoimmunity are included, and both may actually be important. On the other hand, there is a need for safer and better tested drugs that will slow the progression of neurodegeneration associated with multiple sclerosis or entirely prevent such neurodegeneration.
It is an object of the present invention to provide a novel method for the treatment of multiple sclerosis, which method comprises administering a compound selected from certain aryl-substituted rhodanine derivatives of Formula I:
The method of the present invention provides a safe and effective treatment of multiple sclerosis by slowing (or possibly possibly preventing) the neurodegenerative process associated with multiple sclerosis.
The process of the present invention utilizes certain aryl-substituted rhodanine derivatives of Formula (I) above. Such compounds are known in the art to be useful for treating inflammation, arthritis, type I diabetes, inflammatory bowel disease, hyperglycemia, Alzheimer's disease and muscular atrophy and also for preventing ischemic induced cell damage (eg, Europe See patent applications 211,670, 587,377 and 391,644 and US patents 5,158,966 and 5,216,002.
The aryl-substituted rhodanine used in the methods of the present invention has never been used to treat multiple sclerosis in mammals. The known activity of such compounds does not present the methods of the present invention as described above. It is therefore an object of the present invention to provide novel pharmacological uses for certain known rhodanine derivatives.
Other objects, aspects and advantages of the invention will be apparent from the following detailed description and the appended claims.
The present invention provides a method of treating multiple sclerosis in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Formula I

Where
R ¹ and R ² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or Wherein n is an integer from 0 to 3;
R ³ is hydrogen or C ₁ -C ₆ alkyl;
R ⁴ and R ⁵ are each hydrogen or together form a bond;
R ⁶ and R ⁷ are each hydrogen or together form = S, or if one of R ⁶ and R ⁷ is hydrogen the other is -SCH ₃ ;
X is Wherein m is 0, 1 or 2;
Q is -O- or NR ⁸ ;
R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, -SO ₂ CH ₃ or-(CH ₂ ) nY
[From here,
n is an integer from 0 to 3, Y is cyano, OR ⁹ , , Tetrazolyl, -NR ¹¹ R ¹² , -SH, -S (C ₁ -C ₄ alkyl) or :
(From here,
R ⁹ is hydrogen, C ₁ -C ₄ alkyl, tosyl or ego;
R ¹⁰ is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or —NH ₂ ;
R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl,-(CH ₂ ) qOH,-(CH ₂ ) qN (C ₁ -C ₄ alkyl) ₂ ,-(CH ₂ ) qS (C ₁ -C ₄ alkyl) or Wherein q is an integer from 1 to 6 and n is as defined above, or
R ¹¹ and R ¹² together form a morpholinyl, piperidinyl, piperazinyl or N-methylpiperazinyl ring.
As used herein, the term C ₁ -C ₆ alkyl refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert-butyl, n-pentane, isopentane, n-hexane, isohexane, and the like. It refers to straight and branched chain aliphatic radicals of the same 1 to 6 carbon atoms. The term C ₁ -C ₆ alkyl includes within its definition the term C ₁ -C ₄ alkyl.
The term C ₁ -C ₆ alkoxy refers to alkyl radicals of 1 to 6 carbon atoms bonded to the rest of the molecule by oxygen and include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, Secondary-butoxy, tert-butoxy, pentoxy, hexoxy and the like. The term C ₁ -C ₆ alkoxy includes within its definition the term C ₁ -C ₄ alkoxy.
The term C ₂ -C ₆ alkenyl refers to straight and branched chain radicals of 2 to 6 carbon atoms having a double bond. As such, the terms include ethylene, propylene, isopropylene, 1-butene, 2-butene, 2-methyl-1-propene, 1-pentene, 2-pentene, 2-methyl-2-butene and the like.
The term C ₂ -C ₆ alkynyl refers to straight and branched chain radicals of 2 to 6 carbon atoms with triple bonds. As such, the terms include acetylene, propine, 1-butyne, 2-butyne, 1-pentine, 2-pentine, 3-methyl-1-butyne, 1-hexyne, 2-hexyne, 3-hexin and the like. .
The term C ₃ -C ₈ cycloalkyl refers to saturated alicyclic rings of 3 to 8 carbon atoms, such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.
Q is -NR ⁸ , R ⁸ is not C ₂ -C ₆ alkenyl or -SO ₂ CH ₃ , and Y is not cyano, tetrazolyl, -SH or -S (C ₁ -C ₄ alkyl) Compounds of I are preferred for use in the method of treating multiple sclerosis of the present invention. Among these preferred groups of compounds:
R ¹ and R ² are each C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or Wherein n is 1, 2 or 3;
R ³ is hydrogen;
R ⁴ and R ⁵ are each hydrogen or together form a bond;
R ⁶ and R ⁷ are each hydrogen or together form = S;
X is Wherein m is 0;
Q is -NR ⁸ ,
R ⁸ is somewhat more preferred is a compound of formula I as defined for the preferred group of compounds. Among the more preferred groups of these compounds, particularly preferred compounds for use in the treatment of multiple sclerosis as described herein are R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Q, X and m are as described directly above, R ⁸ is hydrogen, C ₁ -C ₆ alkyl or-(CH ₂ ) n Y [where n is 0, 1 or 2 and Y is OR ⁹ (here , R ⁹ is hydrogen or C ₁ -C ₄ alkyl, or —NR ¹¹ R ¹² (R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl or — (CH ₂ ) qOH, wherein q Is 1, 2 or 3).
Among these particularly preferred compounds, particularly preferred compounds for use in the process of the invention are:
R ¹ and R ² are independently C ₁ -C ₆ alkyl (and in particular 1,1-dimethylethyl) or ego;
R ⁶ and R ⁷ together form hydrogen or together = S;
R ⁴ and R ⁵ together form a bond;
X is Wherein m is 0;
Q is -NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₄ alkyl or-(CH ₂ ) n Y [where n is 0, 1 or 2 and Y is —NR ¹¹ R ¹² (where R ¹¹ and R ¹² are each independently hydrogen, methyl or — (CH ₂ ) qOH where q is 2 or OR ⁹ where R ⁹ is hydrogen. Among these particularly preferred compounds, substantially preferred are compounds wherein R ⁸ is C ₁ -C ₄ alkyl, and especially methyl.
Most preferred compounds for use in the multiple sclerosis treatment methods provided herein are 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4- Thiazolidinones; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylamino) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-hydroxyethyl) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-amino-4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-hydroxyethyl) amino] -4-thiazolidinone and 4-[[ 3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -1,3-oxothiolan-5-one.
Further typical examples of compounds of Formula I useful for the treatment of multiple sclerosis according to the present invention include the following compounds:
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (3-methoxypropyl) -2-thioxo-4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-ethylthio) ethyl] -4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -3- (methylthiomethyl) -4-thiazolidinone,
3-acetyl-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -3- [N-methyl, N- (1-methylethyl) amino] -4-thiazolidinone ,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [N-methyl, N- (1-methylethyl) amino] -4-thiazolidinone ,
5- [4-hydroxybenzal] rhodanine,
5- (4-hydroxy-3-methoxybenzylidene) rhodanine,
5-[(4-hydroxy-3,5-dipropylphenyl) methylene] -3- [2- (dimethylamino) ethyl] -4-thiazolidinone,
5-[[3,5-bis (1-methylpropyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone,
5-[[3,5-dimethyl-4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylsulfonyl) -4-thiazolidinone,
5-[[4-hydroxy-3,5-bis (1,1-dimethylethyl) phenyl] methylene] -3- (propylamino) -4-thiazolidinone,
3-amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone,
5-[(4-hydroxy-3,5-dimethoxyphenyl) methylene] -3-methyl-2-thioxo-4-thiazolidinone,
5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -3- [2- (dimethylamino) ethyl] -4-thiazolidinone,
5-[(4-hydroxy-3,5-dimethoxyphenyl) methylene] -3-methyl-2-thioxo-4-thiazolidinone,
5-[[3,5-diethenyl-4-hydroxyphenyl] methylene] -3- (3-methoxypropyl) -2-thioxo-4-thiazolidinone,
5-[[3,5-bis (4-pentine) -4-hydroxyphenyl] methyl] -3-ethylamino-4-thiazolidinone,
5-[[3-ethylthiophenyl-4-hydroxy-5-methylphenyl] methylene] -2-thioxo-4-thiazolidinone,
5-[[3- (2-butene) -4-hydroxy-5-isopropoxyphenyl] methyl] -3- (3-diethylaminopropyl) -4-thiazolidinone,
5-[[3- (2-propenyl) -4-hydroxy-5- (1,1-dimethylethyl) phenyl] methylene] -3-cyclohexyl-4-thiazolidinone,
5-[[3,5- (methylthiophenyl) -4-hydroxyphenyl] methylene] -3-propyl-2-thioxo-4-thiazolidinone,
5-[[3- (3-methyl-1-butene) -4-hydroxy-5-propylphenyl] methylene] -3-ethylcyano-4-thiazolidinone,
5-[[3- (2-propenyl) -4-hydroxy-5-methoxyphenyl] methyl] -3-ethoxy-4-thiazolidinone,
5-[[3,5- (di-2-propenyl) -4-hydroxyphenyl] methylene] -3- (methylaminomethyl) -2-thioxo-4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone,
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -2-thioxo-4-thiazolidinone,
5-[[3,5-bis (1-methylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone.
The aryl-substituted rhodanine derivatives of formula (I) can be prepared in the art or by any of a number of well known procedures. For example, in Tuber et al. (Teuber et al., Leibigs Ann. Chem., 757 (1978)) 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2 -Tioxo-4-thiazolidinones (hereafter referred to as compound A) are disclosed, which compounds in 3,5-di-tert-butyl-4 in glacial acetic acid at reflux using molten sodium acetate as catalyst. Prepared by reacting hydroxybenzaldehyde with rhodanine 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone (Compound B), 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone (Compound C) and 5-[[3,5-bis (1,1 -Dimethylethyl) -4-hydroxyphenyl] methyl] -2-thioxo-4-thiazolidinone (Compound D) can be prepared from Compound A as follows.
Catalytic hydrogenation of compound A yields both compounds B and C. The relative ratios are obtained depending on the temperature, pressure and duration of hydrogenation, the solvent used and the specific catalyst used. For example, when Compound A is treated with 5% palladium on carbon in ethanol for about 18 hours at 100 ° C., the relative ratio of Compound B: C is about 60:40. Alternatively, this conversion can be done by heating Compound A in a mixture of hydrochloric acid and alcohol (eg ethanol) in the presence of zinc. Thion is heated with a reducing agent (tri-n-butyl tin hydride) in an unreactive solvent (eg toluene) and preferably in the presence of a free radical initiator (eg azobisisobutyronitrile) By doing so, thion can be reduced without harming the benzyl double bond. However, in order to effect such reduction, an N-substituted rhodanine substrate (ie R ⁸ cannot be hydrogen) must be used.
Compound A can be converted to Compound D by various methods known in the art. Preferred methods are taught by Nakamura et al., Tetrahedron Letters, 25, 3983 (1984). In this reaction, Compound A is treated with dihydropyridine such as diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate in the presence of silica gel. The reaction is preferably best carried out in an inert atmosphere, in the presence of a non-reactive solvent such as benzene or toluene. The reaction can be carried out at a temperature of about 25 ° C. to the reflux temperature of the mixture. At a preferred temperature of about 80 ° C., the reaction is terminated after substantially 12 to 18 hours.
Other thiazolidinones can be prepared in the same manner depending on the values chosen for the various substituents. For example, Q is NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or — (CH ₂ ) n Y where n is as defined for Formula I and Wherein Y is cyano or NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are each independently hydrogen or C ₁ -C ₆ alkyl, wherein the compound of formula I is It may be prepared using appropriate N-substituted rhodanine and R ¹ , R ² -substituted-4-hydroxy-benzaldehyde. Alternatively, rhodanine is used for condensation with aldehydes to form a species in which Q is NR ⁸ and R ⁸ is hydrogen and then alkylated with an appropriate R ⁸ containing halide (eg iodide or bromide) Whereby the corresponding N-substituted derivatives, ie, Q is NR ⁸ and R ⁸ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl or-(CH ₂ ) n Y ( Wherein Y is cyano, OR ⁹ , -SH, -S (C ₁ -C ₄ alkyl), NR ¹¹ R ¹² or And n, R ⁹ , R ¹¹ and R ¹² are as defined for Formula I). Alkylation is usually carried out in the presence of a strong base such as sodium hydride in an inert solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF). In a similar fashion, R ⁸ is used by condensation with aldehydes to form a species in which Q is NR ⁸ and R ⁸ is hydrogen, as is well known in the art, and then substituted with an appropriate R ⁸ containing halide to form R ^8. Is-(CH ₂ ) nY and Y is Where n and R ¹⁰ are as defined for Formula I, to yield N-substituted derivatives of Formula I.
Q is NR ⁸ and R ⁸ is — (CH ₂ ) n Y wherein Y is OR ⁹ or NR ¹¹ R ¹² [where R ⁹ is hydrogen, acetyl or tosyl, and R ¹¹ and R ¹² are represented by Formula I As defined for) can also be prepared according to Scheme 1:
Hydroxyalkyl rhodanine II is prepared by condensation of carbon disulfide, chloroacetic acid and appropriate hydroxyalkylamine by standard techniques. Condensation with the appropriate R ¹ , R ² -substituted-4-hydroxy-benzaldehyde as described above results in the condensed 2-thioxo-4-thiazolidinone III, which is converted to an acetyl derivative. The thioxo compound can optionally be converted to the methylene compound of formula IV as described above. Compound V (i.e., Q is NR ⁸ and R ⁸ is-(CH ₂ ) n Y (where Y is OR ⁹ and R is removed by treatment with aqueous ammonia in a solvent such as acetonitrile) is removed ⁹ is hydrogen). The hydroxy compound V is then converted to tosyl derivative VI by treatment with p-toluenesulfonyl chloride in pyridine, preferably at a temperature of about 0 ° C. The variable tosyl intermediate VI can then be converted to additional compounds of formula I by treatment with the appropriate HNR ¹¹ R ¹² amines, wherein R ¹¹ and R ¹² are as described in the paragraphs above. This latter conversion is best done by reacting VI in the presence of molar excess of amine. Once again, solvents such as acetonitrile are useful for performing this conversion.
Corresponding 1,3-oxothiolan-5-ones of formula (I) can be prepared from β- (3,5-di-t-butyl-4-hydroxyphenyl) -α-mercaptoacrylic acid (VII). The compounds of formula (VII) can be treated with carbon disulfide to produce thion homologues (Q is -O- and R ⁶ and R ⁷ = S), and the compounds of formula (VII) are reacted with formic acid to produce the corresponding destin ( Q is -O-, and R ⁶ and R ⁷ are each hydrogen. Compounds of formula (VIII) may be prepared by known methods (e.g., Campaign et al., J. Org. Chem., 26, 359 (1961); homology, 26, 1326 (1961); Chakrabarti et al. Et al., Tetrahedron, 25 (14), 2781 (1969)) or by heating Compound A with dilute aqueous base.
Formula I wherein Q is NR ⁸ , R ⁸ is — (CH ₂ ) nY (n = 0), and Y is NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined for Formula I Compounds of can be prepared according to Scheme 2:
Treatment of R ¹¹ -substituted hydrazine with benzaldehyde in an alcoholic (preferably methanol) solvent yields intermediate VII, which is then reacted with the appropriate R ¹² -halide in the presence of triethylamine and acetonitrile To obtain. The intermediate X is then treated with hydrazine to give R ¹¹ , R ¹² -hydrazine, XI. XI can alternatively be prepared by reducing the nitroso-R ¹¹ R ¹² amine using zinc powder and acetic acid or aluminum and a strong base. Nitroso-R ¹¹ R ¹² amines themselves are described in J. Am. Chem. Soc. 77, 790 (1955), is prepared by treating R ¹¹ , R ¹² amines with sodium nitrite in HCl. XII is condensed with the appropriate R ¹ , R ² -substituted-4-hydroxybenzaldehyde (ie ArCHO) to afford XIII. As mentioned above, the thiones can be reduced by treatment with a reducing agent such as tri-n-butyl tin hydride in a non-reactive solvent such as toluene, preferably in the presence of a free radical initiator such as azobisisobutyronitrile. Before or after the reduction of the thiones (as desired), the disubstituted compounds can be heated in a mixture of ethanol / water in the presence of a catalyst such as a rhodium catalyst to produce a species in which either R ¹¹ or R ¹² is hydrogen.
X is treated by treating sulfide (ie m = 0) with an oxidizing agent such as m-chloroperbenzoic acid in a suitable organic solvent such as chloroform for a time sufficient to effect the desired oxidation. Compounds of formula I, wherein m is 1 or 2, are readily prepared.
Compounds of formula I, wherein R ³ is C ₁ -C ₆ alkyl, are prepared by conventional Friedel-Crafts alkylation of the appropriate R ¹ , R ² -substituted phenols, followed by rhodanine or as described herein. It is prepared by condensation with a given N-substituted rhodanine or used as described in the other schemes described herein.
Those skilled in the art will readily understand that the aryl moiety of the compounds of formula (I) of the present invention may be prepared commercially or readily prepared by known techniques from commercially available starting materials. For example, p-hydroxybenzaldehyde can be alkylated under Friedel-Krafts conditions to yield alkylbenzaldehyde, which can then be alkylated on its own. Similarly, rhodanine or N-substituted rhodanine starting materials are either commercially available or can be prepared by well known methods from commercially available starting materials.
In the definition of R ⁸ , compounds of formula I, wherein Y is cyano, are prepared by treating an uncyanated homologue with a desired halo-substituted aliphatic nitrile. From cyano derivatives, tetrazolyl is prepared, for example, by treatment with tri-N-butyl tin azide in ethylene glycol dimethyl ether. Other compounds of formula (I) can be prepared from the compounds whose synthesis is generally described above, as described more fully below.
Depending on the definitions of R ³ , R ⁴ and R ⁵ , the compounds of formula I can exist in various isomeric forms. The present invention is not related to any particular isomer and includes all possible individual isomers and racemates. In general, such stereoisomers may be obtained according to procedures well known in the art. However, X is -S-; R ⁴ and R ⁵ are hydrogen; For compounds of Formula I wherein R ¹ , R ² , R ³ , R ⁶ , R ⁷ and Q are as defined above, the individual stereoisomers are in substantially pure isomeric form following the procedure described in US Pat. No. 5,216,002. Can be separated. The teachings of this application regarding stereoisomeric separation processes are incorporated herein by reference.
Pharmaceutically acceptable salts of compounds of formula (I) are also contemplated for inclusion in the methods of the present invention. Such salts well known in the art can be prepared by reacting a compound of formula I with a strong base such as sodium hydroxide or a strong acid such as hydrochloric acid.
The following examples further illustrate the preparation of compounds that can be used in the methods of treating multiple sclerosis provided by the present invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example 1
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone (Compound A)
Under a nitrogen atmosphere, 117.2 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 66.6 g of rhodanine and 143.5 g of molten sodium acetate were heated at reflux in 2500 ml of glacial acetic acid. After heating for 23 hours, the reaction mixture was cooled and poured into a mixture of 1 liter of ethanol and 1 liter of ice with stirring. 500 ml of water were added and after stirring for 30 minutes, the resulting precipitate was recovered by filtration. The solid was slurried with 500 mL ethyl acetate and filtered. The precipitate was then dissolved in 3 liters of ethanol, heated to boiling and water was added (ca. 450 ml) until the solution remained cloudy. Cool to room temperature and recover 99.6 g of the desired title product by filtration. Melting point of about 260 ° C.
Analysis of C ₁₈ H ₂₃ NO ₂ S ₂ :
Calc .: C, 61.86; H, 6.63; N, 4.01.
Found: C, 62.13; H, 6.55; N, 4.15.
Example 2-3
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone (Compound B) and 5-[[3,5-bis (1,1 -Dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone (Compound C)
A solution of 69.90 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone in 4 liters of ethanol at 100 ° C Hydrogenated at 500 psi (lbs / inch ² ) in the presence of 200 g of 5% palladium on carbon. The reaction mixture was filtered and evaporated to dryness. By decomposition, the material was dissolved in 1 volume of hot ethyl acetate, diluted with 2 volumes of hexane, filtered and loaded onto a silica gel chromatography column. Elution with 35% ethyl acetate in hexanes gave various fractions, which were combined according to the purity of each compound. Chromatography separated a total of 4.6 g of Compound B. Fractions, mainly compound B, were crystallized from ethyl acetate / hexanes to give compound B in a total yield of 13.79 g. Fractions containing impure Compound C were rechromatated on silica eluting with 25% ethyl acetate in hexanes to yield 9.82 g of Compound C.
2. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone. Melting point 209-213 ° C.
Analysis for C ₁₈ H ₂₅ NO ₂ S:
Calc .: C, 67.67; H, 7.89; N, 4.38.
Found: C, 67.44; H, 8.11; N, 4.65.
3. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone. Melting point 149-152 ° C.
Analysis for C ₁₈ H ₂₇ NO ₂ S:
Calc .: C, 67.25; H, 8. 47; N, 4.36.
Found: C, 67.43; H, 8. 44; N, 4.21.
Example 4
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-oxo-3-thiazolidinecarboxylic acid, methyl ester
Under a nitrogen atmosphere, 7.03 g of the compound of Example 2 was dissolved in 330 ml of THF, and 581 mg of sodium hydride was added thereto. After the mixture was stirred for 10 minutes, about 2 g of methyl chloroformate was added and the resulting mixture was stirred for an additional 50 minutes. Water (500 mL) and 7 mL 1N hydrochloric acid (solution pH: about 3) were added. The resulting mixture was extracted twice with 200 mL portions of ethyl acetate. The organic extracts were combined, stripped to dryness and crystallized from 15 mL ethyl acetate and 25 mL hexanes to afford the title compound. Melting point 165-167.5 ° C.
Analysis for C ₂₀ H ₂₇ NO ₄ S:
Calc .: C, 63.63; H, 7. 21; N, 3.71.
Found: C, 63.76; H, 7. 33; N, 3.68.
Example 5
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-oxo-3-thiazolidineacetamide
Under a nitrogen atmosphere, 7.03 g of the compound of Example 2 was dissolved in 330 mL of THF. To this, 0.581 g of sodium hydride was added and the mixture was stirred for 10 minutes. Iodoacetamide (4.07 g) was added and the resulting mixture was heated at reflux for 1 h and then cooled. The solution was then poured into 500 ml rapidly stirred ice / water mixture. 10 mL of 1N hydrochloric acid was added to lower the pH of the mixture to about pH 3. The resulting mixture was extracted three times with 200 mL portions of ethyl acetate. The extracts were combined, stripped and crystallized from a mixture of 120 ml ethyl acetate and 100 ml hexanes to afford 2.79 g of the title compound. Melting point 232-235 ° C.
Analysis for C ₂₀ H ₂₈ N ₂ O ₃ S:
Calc .: C, 63.80; H, 7. 50; N, 7.44.
Found: C, 63.53; H, 7.67; N, 7.14.
Example 6
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (methylthio) ethyl] -4-thiazolidinone
26.7 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene-4-thiazolidinone (i.e. compound of Example 2) are dissolved in 418 ml of DMF To this, 3.34 g of 60% sodium hydride dispersion was added. The resulting mixture was stirred at 100 ° C. under argon atmosphere. To this, 8.33 mL of methylthioethyl chloride was added and the resulting black solution was stirred at 100 ° C. for 6 days. The material was cooled to 30 ° C. and then the insoluble material was taken by filtration. The solid was washed with DMF until its color disappeared and a white solid remained, which was discarded. 1N hydrochloric acid was added with stirring to adjust the pH of the filtrate and wash to 1.5. The mixture was then diluted with a mixture of 1000 mL diethyl ether and 500 mL 1N hydrochloric acid, which was then shaken and separated. The organic layer was washed with 2 parts of water and 1 part of water, then dried over sodium sulfate, filtered, evaporated and chase with chloroform to give a black foam / oil. This material was triturated with about 75 mL of chloroform, then filtered and the insoluble solid was washed with additional chloroform until its brown color disappeared. The filtrate was then loaded onto a silica gel column and eluted with a 8000 mL gradient of 10-30% ethyl acetate in hexanes. The various fractions containing the desired product were combined and again loaded onto a silica gel column and eluted with a 8000 mL 10-35% acetone gradient in hexanes. Fractions containing the desired product were recrystallized from hexane / ethyl acetate to yield 1.2 g of the title compound as a tan / orange solid. Melting point 165.5-168 ° C .;
Analysis of C ₂₁ H ₃₁ NO ₂ S ₂ :
Calc .: C, 64.08; H, 7.94; N, 3.56.
Found: C, 63.99; H, 8.13; N, 3.45.
Example 7
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-methoxyethyl) -4-thiazolidinone
Under argon atmosphere, 9.58 g of the compound of Example 2 was dissolved in THF with stirring. To this was added 1.2 g of 60% sodium hydride dispersion and then the reaction mixture was heated to reflux. Then 2.82 mL of methoxyethylbromide was added and the resulting mixture was stirred at reflux for 5 days. After 5 days, 0.2 equivalents of potassium iodide was added and the reaction was held at reflux for an additional 2 days. The mixture was then cooled and diluted with diethyl ether and water. The pH of the mixture was adjusted to pH 2 by addition of 1N hydrochloric acid with stirring. An organic layer and an aqueous layer are formed, which are separated and the organic layer is washed with saturated sodium bicarbonate, followed by brine, and subsequently dried over sodium sulfate, filtered, evaporated and chased with chloroform. The resulting material is then dissolved in 50 ml of chloroform to form a precipitate. An additional 25 ml of chloroform was added and the mixture was heated. The resulting solution was filtered, chromatographed on silica gel and subsequently eluted with a 8000 mL of 10-30% gradient of ethyl acetate in hexanes, then eluted with 4000 mL of 30-40% gradient of ethyl acetate in hexanes. Various fractions containing the desired product were combined, evaporated to dryness and chased with chloroform to give an orange viscous solid. This material was then dissolved in 15 ml of ethyl acetate while heated in a steam bath and subsequently diluted with 250 ml of hexane. Cooling the mixture to room temperature gave a precipitate which was left for 3 days. The material was filtered off and washed with hexane to give 5.16 g of the title compound. Melting point 147-149 ° C.
Analysis for C ₂₁ H ₃₁ NO ₃ S:
Calc .: C, 66.80; H, 8. 28; N, 3.71.
Found: C, 67.04; H, 8. 30; N, 3.74.
Example 8
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -2-thioxo-4-thiazolidinone (Compound D)
Under nitrogen atmosphere, 13.98 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone, 13.17 g of diethyl Dissolution was carried out by stirring 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and 600 ml of toluene. 40 g of silica gel 60 (finer than 230 mesh), previously dried at 50 ° C. under vacuum for 7 hours, was added to the reaction. The reaction was heated at reflux for 18 h and heat filtered. The filtrate was evaporated to dryness. The residue was dissolved in 500 mL of ethyl acetate and washed five times with 400 mL of 1N hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuo to afford a yellow solid. Chromatography on silica gel eluting with 2.5% ethyl acetate in toluene gave 8.0 g of the desired title product. Melting point 178-179 ° C.
Analysis of C ₁₈ H ₂₅ NO ₂ S ₂ :
Calc .: C, 61.50; H, 7. 17; N, 3.98.
Found: C, 61.28; H, 7. 19; N, 3.94.
Example 9
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-2-thioxo-4-thiazolidinone
The title compound was prepared in 76% yield from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-methylrodanine following the procedure of Example 1. Melting point 230 ° C.
Analysis of C ₁₉ H ₂₅ NO ₂ S ₂ :
Calc .: C, 62.77; H, 6.93; N, 3.85; S, 17.64.
Found: C, 62.54; H, 7.05; N, 3.66; S, 17.82.
Example 10
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone
10.31 g of Example 9 was heated at reflux with 38.15 mL of tri-n-butyl tin hydride and 1.16 g of azobisisobutyronitrile (AIBN) in 142 mL of toluene for 1 hour to heat the title compound. Prepared in 71% yield. Water was added to the cooled reaction mixture, the layers were separated and the organic layer was washed with 1N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate, concentrated in vacuo, and the residue was gradientd from 10-50% hexane in ethyl acetate. Purification by chromatography on silica gel eluting with. The melting point of the purified product was 142-144 ° C.
Analysis of C ₁₉ H ₂₇ NO ₂ S:
Calc .: C, 68.43; H, 8. 16; N, 4.20.
Found: C, 68.68; H, 8.00; N, 3.97.
Example 11
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -3-methyl-4-thiazolidinone
To 100 mL of THF, 6.43 g of the compound of Example 3 was added. When sodium hydride (0.9 g) was added, the gas was released. 1.25 mL (1.0 equiv) of iodomethane was added and the resulting mixture was stirred at rt for 23 h before the mixture was diluted with a volume of diethyl ether and 1N HCl. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. The resulting solid was chased with chloroform to give an orange foam. A 5.93 g sample of this material was dissolved in 14 ml of a thermal mixture of ethyl acetate diluted with 225 ml of hexane and then cooled to room temperature overnight. The solvent was evaporated and the resulting solid was dissolved in 40 ml of a thermal mixture of diethyl ether diluted with about 400 ml of hexane. The mixture was cooled to rt overnight, and the formed precipitate was collected by filtration, washed with hexanes and dried in vacuo to afford 3.98 g of the title compound. Melting point 102-105 ° C.
Analysis for C ₁₉ H ₂₉ NO ₂ S:
Calc .: C, 68.02; H, 8.71; N, 4.17.
Found: C, 68.22; H, 8. 80; N, 4.21.
Example 12
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone, 1-oxide
Under a nitrogen atmosphere, 6.67 g of the compound of Example 10 was dissolved in 100 mL of chloroform with stirring and the resulting mixture was cooled to 4 ° C. After dropwise addition of meta-chloroperbenzoic acid (with additional chloroform), the reaction mixture was poured into a separatory funnel and washed with saturated sodium bicarbonate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and evaporated to give a white foam. The foam was dissolved while heating in 70 ml of ethyl acetate in a steam bath and diluted with boiling with 125 ml of hexane. A precipitate formed and the reaction mixture was cooled to room temperature overnight. The precipitate was filtered off, subsequently washed with hexanes and dried in vacuo for 2 hours to afford 6.10 g of the title compound. Melting point 183-184 ° C.
Analysis of C ₁₉ H ₂₇ NO ₃ S:
Calc .: C, 65.30; H, 7.79; N, 4.01.
Found: C, 65.46; H, 7.68; N, 4.01.
Example 13
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone, 1,1-dioxide
Under a nitrogen atmosphere, 1 g of the compound of Example 10 was dissolved in 15 mL of chloroform while stirring with cooling in an ice bath. To this was added dropwise 1.29 g of m-chloroperbenzoic acid and an additional 18 ml of chloroform, ending the addition within 15 minutes. The mixture was removed from the ice bath, stirred at rt for 22 h, transferred to a separatory funnel and washed with saturated sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, separated and dried over sodium sulfate, filtered and evaporated. The resulting residue was dissolved in 12 mL of ethyl acetate and diluted with 50 mL of hexane while boiling on a steam bath. The mixture was cooled to rt overnight, the resulting precipitate was filtered, washed with hexanes and dried in vacuo to yield 0.75 g of the title compound. Melting point 217-221 ° C.
Analysis of C ₁₉ H ₂₇ NO ₄ S:
Calc .: C, 62.44; H, 7. 45; N, 3.83.
Found: C, 62.17; H, 7. 26; N, 3.95.
Example 14
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-ethyl-4-thiazolidinone
Sodium hydride in mineral oil in a solution of 9.58 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone in 150 ml of tetrahydrofuran, 1.20 g of% dispersion was added. After gas evolution ceased, 2.4 mL of ethyl iodide was added and the reaction mixture was stirred for 2 days under an argon atmosphere. The mixture was heated at reflux for 6 h, cooled, diluted with diethyl ether and water and adjusted to pH 3 with 1N hydrochloric acid. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution followed by saturated sodium chloride solution. The dried organic solution was concentrated and the resulting residue was chromatographed on silica gel eluting with a 10-30% ethyl acetate gradient in hexanes to afford 3.65 g of the desired title product. Melting point 169-172.5 ° C.
Analysis for C ₂₀ H ₂₉ NO ₂ S:
Calc .: C, 69.12; H, 8.41; N, 4.03.
Found: C, 69.39; H, 8.52; N, 4.30.
Example 15-16
The following compounds were prepared from the appropriate alkyl iodide following the procedure of Example 14.
15. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-propyl-4-thiazolidinone. 60% yield. Melting point 145-146.5 ° C.
Analysis of C ₂₁ H ₃₁ NO ₂ S:
Calc .: C, 69.76; H, 8. 64; N, 3.87.
Found: C, 70.05; H, 8. 76; N, 4.01.
16. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-butyl-4-thiazolidinone. 60% yield. Melting point 168.5-169.5 ° C.
Analysis of C ₂₂ H ₃₃ NO ₂ S:
Calc .: C, 70.36; H, 8.86; N, 3.73.
Found: C, 70.60; H, 8.81; N, 3.97.
Example 17-19
The following compounds were prepared using the appropriate N-substituted rhodanine and benzaldehyde following the procedure of Example 1 (or according to the procedure described elsewhere herein).
17. 5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -2-thioxo-3-methyl-4-thiazolidinone. Melting point 137 ° C.
Analysis of C ₂₀ H ₁₉ NO ₃ S ₃ :
Calc .: C, 57.53; H, 4.59; N, 3.35.
Found: C, 58.80; H, 4.38; N, 3.43.
18. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-cyclopropyl-2-thioxo-4-thiazolidinone. 93% yield. Melting point 158-168 ° C.
19. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-dimethylamino-2-thioxo-4-thiazolidinone. 65% yield.
Example 20-21
The thiones of Examples 18 and 19 were reduced using the procedure of Example 10 to prepare the following compounds of the present invention.
20. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-cyclopropyl-4-thiazolidinone. 46% yield. Melting point 162-164 ° C.
Analysis for C ₂₁ H ₂₉ NO ₂ S:
Calc .: C, 70.16; H, 8.13; N, 3.90.
Found: C, 69.91; H, 8.23; N, 3.75.
21. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -4-thiazolidinone. 41% yield. Melting point 138-141 ° C.
Analysis for C ₂₀ H ₃₀ N ₂ O ₂ S:
Calc .: C, 66.26; H, 8.34; N, 7.73.
Found: C, 66.55; H, 8.59; N, 7.47.
Example 22
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -4-thiazolidinone, 1-oxide
Under a nitrogen atmosphere, 9.06 g of the compound of Example 21 was dissolved in 125 ml of chloroform while stirring with cooling in an ice bath. To this, 5.39 g of meta-chloroperbenzoic acid in 75 ml of chloroform was added (drop) at 0 ° C. over 25 minutes. After an additional 10 minutes, the reaction mixture was transferred to a separatory funnel, washed with saturated sodium bicarbonate and the layers separated. The aqueous layer was washed with chloroform. This wash was added to the original chloroform extract to produce an emulsion that slowly degraded. The organic layer was dried over sodium sulfate, filtered and washed to evaporate off the solvent. The resulting residue was subsequently dissolved in about 225 ml of ethyl acetate while heating on a steam bath and then diluted with about 100 ml of hexane. A precipitate formed and the resulting mixture was cooled to room temperature overnight. The precipitate was filtered off, washed with hexane, air dried for 1 hour and subsequently dissolved in 100 ml of isopropyl alcohol on a steam bath. The resulting solution was cooled to room temperature overnight to form a precipitate, which was then washed again with hexane and dried under vacuum at 80 ° C. for about 4 hours to afford 5.41 g of the title compound. Melting point 198-201 ° C.
Analysis for C ₂₀ H ₃₀ N ₂ O ₃ S:
Calc .: C, 63.46; H, 7.97; N, 7.40.
Found: C, 63.68; H, 7.78; N, 7.56.
Example 23
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone, 1-oxide
Using the procedure described in Example 22, 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-dimethylamino-4-thiazolidinone (ie , Compound of Example 21) was prepared to yield 5.12 g of the title compound. Melting point 103-110 ° C.
Analysis for C ₁₈ H ₂₅ NO ₃ S:
Calc .: C, 63.77; H, 8.41; N, 3.54.
Found: C, 64.11; H, 8. 26; N, 3.55.
The following additional compounds were prepared using the procedure described herein.
Example 24
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-propenyl) -4-thiazolidinone. Melting point 154.5-156.5 ° C.
Analysis for C ₂₁ H ₂₉ NO ₂ S:
Calc .: C, 70.16; H, 8.13; N, 3.90; S, 8.92.
Found: C, 70.27; H, 8.21; N, 4.01; S, 9.09.
Example 25
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylmethylene] -3-methyl-4-thiazolidinone. Melting point 152.5-153.5 ° C.
Analysis for C ₂₀ H ₂₉ NO ₂ S:
Calc .: C, 69.12; H, 8.41; N, 4.03.
Found: C, 69.18; H, 8. 25; N, 4.26.
Example 26
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (acetyloxy) ethyl] -4-thiazolidinone
A. Preparation of N- (2-hydroxyethyl) rodanine.
60 ml of carbon disulfide was added to 200 ml of diethyl ether. The solution was cooled to -5 ° C and slowly added to a solution of 138 mL ethanolamine in 250 mL ethanol. The mixture was kept at ambient temperature for 16 hours, then the resulting top layer was decanted and the residual oil was washed twice with 50 ml of diethyl ether. To the oil was added a solution of 71 g of chloroacetic acid in 150 mL of 5N sodium hydroxide at 0 ° C. The cold bath was removed and the reaction left for 75 minutes. The mixture was poured into 400 mL of 6N hydrochloric acid and the resulting mixture was heated to 91 ° C. for 20 minutes. The heating was removed and the solution was left at ambient temperature for 5 hours. The oily organic layer was separated from the aqueous layer and the aqueous layer was extracted twice with 250 ml of ethyl acetate. The organic layers were combined, washed twice with saturated sodium chloride solution, dried and concentrated in vacuo to afford 113.4 g of the desired subtitle intermediate, which was used without further purification.
B. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (acetyloxy) ethyl] -2-thioxo-4-thiazoli Manufacture of dinon
7.5 hours of a mixture of 124 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 103.1 g of the lower title intermediate of Example 26A, 346.9 g of sodium acetate, and 2.65 L of glacial acetic acid under nitrogen atmosphere Heated at reflux temperature. The heating was removed and the mixture was cooled overnight with stirring. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. 2 liters of ethyl acetate were added to the residue followed by 1.5 liters of water. The layers were separated and the aqueous layer was extracted with 500 ml of ethyl acetate. The organic layers were combined, washed with water and sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 7% ethyl acetate gradient in toluene to toluene. Appropriate fractions were combined and concentrated in vacuo. The residue was crystallized from 75 mL of ethanol to yield 10.28 g of the desired subtitle intermediate. Melting point 140-143 ° C.
C. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (acetyloxy) ethyl] -4-thiazolidinone
Under nitrogen atmosphere, 82.2 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (acetyloxy) ethyl] in 950 ml of toluene 2-Tioxo-4-thiazolidinone was heated to 65 ° C. Tri-n-butyl tin hydride (219.7 g) and AIBN (4.65 g) were added and the solution was heated at reflux for an additional 10 minutes. After cooling, the mixture was washed with 1.25 L 1N hydrochloric acid and then with 500 mL saturated sodium chloride solution. Stripping the organic layer and leaving overnight left the precipitate separated during this period. The liquid portion was decanted off and the resulting residue was purified by chromatography on silica gel, eluting with a 25-50% ethyl acetate gradient in hexanes. Appropriate fractions were combined and concentrated in vacuo to afford 45.7 g of the title compound. Melting point 152-155 ° C.
Analysis of C ₂₂ H ₃₁ NO ₄ S:
Calc .: C, 60.66; H, 6.71; N, 3.22.
Found: C, 60.71; H, 6. 90; N, 3.21.
Example 27
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-aminoethyl) -4-thiazolidinone
A. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-hydroxyethyl) -4-thiazolidinone.
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (acetyloxy) from 85.2 g of Example 26 in 1.5 L of acetonitrile The solution of ethyl] -4-thiazolidinone was treated with 1 L of concentrated ammonium hydroxide. The reaction mixture was left at room temperature for about 90 hours. The solution was concentrated in vacuo, 500 ml of ethyl acetate was added and the pH was adjusted to 3.0 with concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted with 250 ml of ethyl acetate. The combined organic layers were washed with 250 ml saturated sodium chloride solution and concentrated in vacuo. The residue was crystallized from 95 mL hexane and 70 mL ethyl acetate to yield 35.68 g of the desired subtitle intermediate. Melting point 131-135 ° C.
Analysis for C ₂₀ H ₂₉ NO ₃ S:
Calc .: C, 66.08; H, 8.04; N, 3.85.
Found: C, 65.91; H, 8.21; N, 3.96.
B. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (tosyloxy) ethyl] -4-thiazolidinone
A solution of 27A hydroxyethyl intermediate of 27A in 415 ml pyridine was cooled to −3 ° C. and 39.6 g of p-toluenesulfonyl chloride was added with stirring. After the mixture was stirred at 0 ° C. for 4 hours, the solution was stored overnight at −10 ° C. in the refrigerator. About 1 L of ice water was added and the mixture was extracted twice with 700 mL of diethyl ether. The combined organic layers were washed twice with 1 L 1N hydrochloric acid and ice, dried over sodium sulfate and concentrated in vacuo to yield 41.7 g of the desired tosyl intermediate, which was used without further purification.
C. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-aminoethyl) -4-thiazolidinone
A mixture of 13 g of the tosyl intermediate of Example 27B, 250 ml of concentrated ammonium hydroxide and 250 ml of acetonitrile was stirred at room temperature for 2 days. The mixture was concentrated in vacuo and diluted with 500 mL of ethyl acetate. The pH was adjusted to 9.0 and the layers separated. The organic layer was washed twice with water, dried and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a gradient of methylene chloride / ethanol / ammonium hydroxide, individually from methylene chloride to 90: 10: 1. The desired fractions were combined and concentrated in vacuo. The residue was triturated with hexanes to afford 1.47 g of the desired title product. Melting point 176-178 ° C.
Analysis for C ₂₀ H ₃₀ N ₂ O ₂ S:
Calc .: C, 66.26; H, 8.32; N, 7.73.
Found: C, 66.25; H, 8. 24; N, 7.59.
Example 28-30
The following compounds were prepared by reacting the intermediate of Example 27B with an appropriate amine according to the procedures described herein.
28. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (methylamino) ethyl] -4-thiazolidinone. 28% yield. Melting point 137-140 ° C.
Analysis for C ₂₁ H ₃₂ N ₂ O ₂ S:
Calc .: C, 66.98; H, 8.57; N, 7.44.
Found: C, 66.76; H, 8.33; N, 7.24.
29. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (dimethylamino) ethyl] -4-thiazolidinone. 64% yield. Melting point 148-153 ° C.
Analysis for C ₂₂ H ₃₄ N ₂ O ₂ S:
Calc .: C, 67.65; H, 8. 77; N, 7.17.
Found: C, 67.43; H, 8.55; N, 6.98.
30. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (2-hydroxyethylamino) ethyl] -4-thiazolidinone . 59% yield. Melting point 174-176 ° C.
The following additional compounds were prepared using the procedure described herein.
Example 31
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (methyl-2-propynylamino) ethyl] -4-thiazolidinone. Melting point 116-118 ° C.
Analysis for C ₂₄ H ₃₄ N ₂ O ₂ S:
Calc .: C, 69.53; H, 8. 27; N, 6.76.
Found: C, 69.27; H, 8. 46; N, 6.65.
Example 32
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2-[[2- (dimethylamino) ethyl] amino] ethyl] -4-thia Zolidinones. Melting point 245-249 ° C. (decomposition).
Analysis for C ₂₄ H ₃₉ N ₃ O ₂ S:
Calc .: C, 56.90; H, 8. 16; N, 8.30.
Found: C, 57.12; H, 7.98; N, 8.09.
Example 33
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2-[(phenylmethyl) amino] ethyl] -4-thiazolidinone hydrochloride. Melting point 254-259 ° C. (decomposition).
Analysis for C ₂₇ H ₃₆ N ₂ O ₂ S:
Calc .: C, 66.30; H, 7.63; N, 5.73.
Found: C, 66.46; H, 7.53; N, 5.80.
Example 34
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [3- (methylamino) propyl] -4-thiazolidinone. Melting point 177-180 ° C.
Analysis for C ₂₂ H ₃₄ N ₂ O ₂ S:
Calc .: C, 67.65; H, 8. 77; N, 7.17.
Found: C, 67.72; H, 8.94; N, 7.00.
Example 35
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-hydroxyethyl) -4-thiazolidinone. Melting point 131-135 ° C.
Analysis for C ₂₀ H ₂₉ NO ₃ S:
Calc .: C, 66.08; H, 8.04; N, 3.85.
Found: C, 66.36; H, 8.13; N, 3.87.
Example 36
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(4-methoxyphenyl) methyl] -4-thiazolidinone. Melting point 129-130 ° C.
Analysis of C ₂₆ H ₃₃ NO ₃ S:
Calc .: C, 71.04; H, 7.57; N, 3.19.
Found: C, 70.75; H, 7.69; N, 3.18.
Example 37
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- [2- (propylamino) ethyl] -4-thiazolidinone. Melting point 155-158 ° C.
Analysis for C ₂₃ H ₃₆ N ₂ O ₂ S:
Calc .: C, 68.28; H, 8.97; N, 6.92.
Found: C, 68.38; H, 9. 17; N, 7.13.
Example 38
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-oxo-3-thiazolidineacetonitrile
7.03 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone and 2.64 g of bromoacetonitrile are added to 60 in 0.97 g of mineral oil. The reaction was carried out in the presence of% sodium hydride and 330 ml of tetrahydrofuran. The reaction mixture was worked up to afford 3.21 g of the desired title product. Melting point 186-188 ° C.
Analysis for C ₂₀ H ₂₆ N ₂ O ₂ S:
Calc .: C, 67.01; H, 7. 31; N, 7.81.
Found: C, 66.80; H, 7. 36; N, 7.67.
Example 39
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (1H-tetrazol-5-ylmethyl) -4-thiazolidinone
The title compound was prepared by treating the nitrile of Example 38 with tri-N-butyl azide in ethylene glycol dimethyl ether. Melting point 260-263 ° C. (decomposition).
Analysis for C ₂₀ H ₂₇ N ₅ O ₂ S:
Calc .: C, 59.83; H, 6. 78; N, 17.44.
Found: C, 59.93; H, 6. 82; N, 17.32.
Example 40
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (ethylmethylamino) -4-thiazolidinone
A. Preparation of Nitrosomethylethylamine.
70.15 g of methylethylamine was maintained at 10 ° C. on an ice bath. To this, 104 ml of concentrated hydrochloric acid was added (added dropwise with stirring). Hydrochloric acid addition was continued at a constant rate while maintaining the reaction temperature at about 15 ° C. At the end of the acid addition, 90 g of sodium nitrite was added in small portions to the reaction. When sodium nitrite dissolved, a gas formed and the temperature of the reaction mixture dropped to about 0 ° C. The mixture was placed in an oil bath and heated to about 70 ° C. during the termination of the sodium nitrite addition. After about 90 minutes, gas evolution ceased, and additional 10 mL of concentrated hydrochloric acid was added, resulting in additional gas evolution. While further stirring, an additional 5 ml of concentrated hydrochloric acid was added. After stirring the reaction mixture overnight with cooling, the resulting layer was separated. The top layer was extracted with 100 mL of diethyl ether, followed by a second extraction with an additional 50 mL of diethyl ether. The extracts were combined and evaporated in a steam bath to yield 26.8 g of the desired subtitle intermediate.
B. Preparation of N, N-methylethylhydrazine
To a stirred mixture of 46.75 g nitrosomethylethylamine, 588 mL water and 133.9 g zinc powder was added 159 mL acetic acid (dropwise). The addition was terminated over about 2 hours and the reaction mixture was kept at 25-30 ° C. The reaction mixture was then heated to about 90 ° C., after about 30 minutes cooled to 60 ° C., cooled to room temperature and filtered. The aqueous filtrate was then cooled in an ice bath and adjusted to pH 11 with 50% sodium hydroxide. A white precipitate forms, which makes it difficult to add agitation. The white suspension was filtered and washed with 2 parts of water. The original filtrate and the first wash were combined and distilled off. The mixture was heated and several fractions collected over a temperature range of about 67 ° C. to 99 ° C., each of which contained the desired subtitle intermediate.
C. Preparation of S-carboxymethyl-N'-dithiocarboxy-N-methyl-N-ethylhydrazine
N, N-methylethylhydrazine (13.3 g) and 20 mL of ethanol were cooled in an ice / water bath. To this was added a dropwise mixture of 4.69 ml of carbon disulfide and 15.6 ml of diethyl ether with stirring over about 13 minutes. The resulting yellow solution was stirred at 0 ° C. for an additional 15 minutes and then removed in an ice bath. Additional diethyl ether was added to form a precipitate. When the total volume reached 125 ml (by addition of diethyl ether), two layers formed. Within about 10 minutes, the oily bottom layer began to crystallize and the reaction mixture was left at room temperature overnight. The reaction mixture was then kept at 5 ° C. for 2 hours and then filtered. The mixture was filtered, washed with diethyl ether, dried under vacuum at room temperature for 3 hours and then added to a stirred cooled (4 ° C.) mixture of 5.66 g chloroacetic acid in 12 mL 5N sodium hydroxide. The reaction mixture was then removed from the ice bath, warmed to room temperature with stirring for 45 minutes and then added over 3 minutes to 31.2 mL of 6N hydrochloric acid heated to 85 ° C. The mixture was warmed to 90 ° C. over about 10 minutes and cooled to room temperature overnight with stirring. A precipitate formed, which was filtered off, washed lightly with cold water and air dried for about 15 minutes. The precipitate was then dried under vacuum at 80 ° C. for 3 days to yield 4.64 g of the desired subtitle intermediate. The filtrate is stirred at room temperature for 3 days to form additional precipitate which is subsequently filtered off, washed lightly with water and dried at 80 ° C. for 24 hours under vacuum to add 1.76 g of the desired subtitle intermediate. Obtained.
D. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (ethylmethylamino) -2-thioxo-4-thiazolidinone
Under a nitrogen atmosphere, 6.40 g of intermediate prepared in Example 40C, 154 ml of acetic acid and 8.82 g of sodium acetate were stirred for 10 minutes. 7.2 g of 3,5-bis (1,1-dimethylethyl) -4-hydroxybenzaldehyde was added and the resulting mixture was heated at reflux for 23 hours, followed by stirring in 400 ml of a mixture of ice / water Poured. The resulting mixture was stirred for an additional 20 minutes, filtered and washed with a volume of water to afford the desired subtitle intermediate. This intermediate was dried under vacuum at 100 ° C. for 3 days, then it was dissolved in 45 ml of ethanol in a steam bath and diluted by dropwise addition of water with stirring until turbidity persisted. The mixture was then stirred for an additional 5 minutes, cooled to room temperature overnight and dried at 80 ° C. for 4 hours in vacuo to yield 6.99 g of the desired subtitle intermediate.
E. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (ethylmethylamino) -4-thiazolidinone
7.02 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (ethylmethylamino) -2-thioxo-4-thiazolidinone (implemented Example 40D) and 86.3 mL of toluene were stirred and heated to 60 ° C. under a nitrogen atmosphere. To this was added 18.6 mL of tri-n-butyl tin hydride and 0.43 g of AIBN. The resulting mixture was heated to reflux for 30 minutes. At this point, additional 0.43 g of AIBN was added. The resulting mixture was heated at reflux for an additional 30 minutes, cooled and transferred to a separatory funnel. To this, 100 ml of 1N hydrochloric acid and 100 ml of ethyl acetate were added. The resulting mixture was shaken and separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated and subsequently chased with chloroform to give an orange / red oil, which was dissolved in 50 ml of chloroform and filtered. The filtrate was chromatographed on a silica gel column using a 8000 mL 10-40% ethyl acetate gradient in hexanes. Fractions identified to contain product were evaporated and chased with chloroform. 15 mL of hexane was added to these fractions and the resulting solution was slightly heated. A precipitate formed which was diluted with about 25 ml of additional hexanes. The resulting mixture was triturated for about 2 hours, filtered and washed with hexane to yield 1.94 g of the desired product. Melting point 133.5-135 ° C.
Analysis for C ₂₁ H ₃₂ N ₂ O ₂ S:
Calc .: C, 66.98; H, 8.57; N, 7.44.
Found: C, 66.97; H, 8. 80; N, 7.24.
The following additional compounds were prepared using the procedure substantially described in Example 40 and described elsewhere herein.
Example 41
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (butylmethylamino) -4-thiazolidinone. Melting point 128.5-131 ° C.
Analysis for C ₂₃ H ₃₆ N ₂ O ₂ S:
Calc .: C, 68.28; H, 8.97; N, 6.92.
Found: C, 68.45; H, 9.00; N, 6.70.
Example 42
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-phenylethyl) methylamino] -4-thiazolidinone. Melting point 93-97 ° C.
Analysis for C ₂₇ H ₃₆ N ₂ O ₂ S:
Calc .: C, 71.64; H, 8.02; N, 6.19.
Found: C, 71.48; H, 8. 30; N, 5.81.
Example 43
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (4-methyl-1-piperazinyl) -4-thiazolidinone. Melting point 221-225 ° C.
Analysis for C ₂₃ H ₃₄ N ₂ O ₂ S:
Calc .: C, 66.15; H, 8. 45; N, 10.06.
Found: C, 66.10; H, 8. 36; N, 9.81.
Example 44
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (1-piperidinyl) -4-thiazolidinone. Melting point 213-215 ° C.
Analysis for C ₂₃ H ₃₄ N ₂ O ₂ S:
Calc .: C, 68.62; H, 8.51; N, 6.96.
Found: C, 68.41; H, 8.49; N, 7.26.
Example 45
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (4-morpholinyl) -4-thiazolidinone. Melting point 226-228 ° C.
Analysis for C ₂₂ H ₃₂ N ₂ O ₃ S:
Calc .: C, 65.31; H, 7.97; N, 6.92.
Found: C, 65.59; H, 7.94; N, 7.20.
Example 46
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylmethylene] -3- (dimethylamino) -4-thiazolidinone
A. Preparation of 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] ethanone.
Under a nitrogen atmosphere, 6.89 mL of acetylchloride and 14.75 mL of ditin chloride were dissolved in 200 mL of methylene chloride and cooled to -4 ° C. To this was added 20 g of 2,6-di-t-butylphenol (in 100 mL methylene chloride) over 10 minutes. The resulting mixture was stirred at 0 ° C. for 30 minutes, then poured into a mixture of 400 ml of ice and 1N hydrochloric acid and stirred. The mixture was separated into subsequently separated layers. The organic layer was washed with 100 mL of saturated sodium bicarbonate and 100 mL of brine. The organic layer was dried and the solvent was evaporated to yield 23.39 g of the desired subtitle intermediate.
B. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylmethylene] -3- (dimethylamino) -2-thioxo-4-thiazolidinone
In 675 ml of toluene, 20.9 g of 1- [3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] ethanone, 13.3 g of N-dimethylaminorhodanine, 6.5 g of ammonium acetate And about 20 ml of acetic acid. The mixture was heated at reflux and any resulting aqueous layer was collected in a Dean-Stark trap. Over 52 hours, additional 39 g of ammonium acetate and about 100 mL of acetic acid were then added in bulk and a total of 89.2 mL of aqueous phase was obtained. Further operation was carried out by conventional techniques to recover 17.1 g of the desired subtitle intermediate.
C. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylmethylene] -3- (dimethylamino) -4-thiazolidinone
Using the procedure described in Example 40E, thion was reduced using tri-n-butyl tin hydride and AIBN in toluene to afford the title compound. Melting point 181-186 ° C.
Analysis for C ₂₁ H ₃₂ N ₂ O ₂ S:
Calc .: C, 66.98; H, 8.57; N, 7.44.
Found: C, 66.84; H, 8. 48; N, 7.39.
Example 47
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylamino) -4-thiazolidinone
A. Preparation of Benzaldehyde Methyl Hydrazone
50.8 mL of benzaldehyde (500 mmol) and 26.5 mL (500 mmol) of methylhydrazine were dissolved in 1 L of methanol. The mixture was stirred together at room temperature for 75 minutes and then the solvent was stripped to yield 67.8 g of the desired subtitle intermediate.
B. Preparation of Benzaldehyde N-methyl, N-2-propenyl-hydrazone
67.8 g of benzaldehydemethylhydrazone (prepared in 47A above), 60.5 g of allyl bromide and 50.5 g of triethylamine were dissolved in 1 L of acetonitrile and the mixture was heated at reflux for 16 h and then cooled . An additional 45 g of allyl bromide and 38 g of triethylamine were added and the mixture was again heated at reflux for an additional 7 hours, cooled and stripped of solvent to give 268 g of residue. 500 mL of THF was added to this residue and the resulting mixture was shaken, filtered and washed with an additional 125 mL of THF. The filtrate was stripped of solvent to yield 67 g of the desired subtitle intermediate.
C. Preparation of N-Methyl, N-2-propenylhydrazine
59.9 g of benzaldehyde N-methyl, N-2-propenylhydrazone (prepared as described above in Example 47B), 44 g of hydrazine and 137 mL of ethanol were heated and cooled at reflux for 21.5 hours. . The reflux condenser was replaced with a distillation head and the mixture was distilled at atmospheric pressure. The first 3 distillates were collected and combined and 100 ml of 1N HCl was added. An additional 100 ml of concentrated HCl was added with ice and the resulting mixture was separated and washed with a little ethyl acetate. The resulting layer was separated and the water was distilled off until the solid stuck to the stir bar. The solid was filtered off and the filtrate was stripped and added to 125 ml of cooled 50% NaOH. The resulting solid was filtered off and discarded. The filtrate comprises two layers, which are separated. The upper layer contained the desired subtitle intermediate, and the lower layer, the aqueous layer, was extracted with diethyl ether and stripped to obtain additional product.
D. Preparation of N-Methyl, N-3-propenyl-5-carboxymethyl-dithiocarbamate
A solution of 11.18 g of carbon disulfide in 26 ml of diethyl ether in 12.67 g of N-methyl, N-2-propenylhydrazine (prepared as described in Example 47C) in 23 ml of ethanol cooled to 0 ° C. Was added. The resulting mixture was removed in an ice bath and left at room temperature for about 15.5 hours before the solvent was stripped to yield about 36.5 g of residue. To this residue was added 13.9 g of chloroacetic acid dissolved in 29.5 mL 5N NaOH (cooled in ice bath). The resulting solution was left at room temperature for 3 hours. 8 mL of concentrated hydrochloric acid was added to lower the pH of the solution to about 3. To this was added 50 ml of diethyl ether to separate the three phases. The aqueous phases were combined, extracted with an additional 50 mL of chloroform and the solvent stripped to yield about 40.4 g of the desired subtitle intermediate.
E. 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-3- (methyl-2-propenylamino) -4-thiazoli Preparation of dinones.
29.3 g of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 38.8 g of the intermediate prepared as described in Example 47D and 40.34 g of sodium acetate were mixed in 810 ml of acetic acid and The resulting solution was heated at reflux for 24 h. The solution was then cooled and stirred for an additional 60 hours at room temperature. The solution was then poured into 2 liters of ice water, separated and washed with additional volume of water to yield about 44 g of the desired subtitle intermediate.
F. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methyl-2-propenylamino) -4-thiazolidinone
Using the procedure described in Example 40E and described elsewhere herein, 42.8 g of the thion of Example 47E was reduced to afford the desired subtitle intermediate (8.34 g).
G. Preparation of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylamino) -4-thiazolidinone
6.11 g of the subtitle intermediate of Example 47F was dissolved in a mixture of 135 ml ethanol and 15.3 ml water and the mixture was heated to 70 ° C. 50 mg of tris (triphenylphosphine) rhodium (I) chloride is added and the mixture is heated at reflux for 50 minutes, after which an additional 550 mg of catalyst is added and then at reflux for an additional 2.5 hours Heated. The mixture was cooled, stirred at rt overnight, and the solvent stripped to yield 2.05 g of the desired product after further operation. Melting point 151-153.5 ° C.
Analysis for C ₁₉ H ₂₈ N ₂ O ₂ S:
Calc .: C, 65.86; H, 7.56; N, 8.09.
Found: C, 65.67; H, 7.81; N, 8.34.
Using the procedure described herein, the following additional compounds were prepared.
Example 48
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylmethylene] -4-thiazolidinone. Melting point 230 ° C.
Analysis of C ₁₉ H ₂₇ NO ₂ S:
Calc .: C, 68.43; H, 8. 16; N, 4.20.
Found: C, 68.60; H, 8. 28; N, 4.17.
Example 49
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2- (4-morpholinyl) ethyl)]-4-thiazolidinone. Melting point 218-222 ° C. (decomposition).
Analysis for C ₂₄ H ₃₆ N ₂ O ₃ S:
Calc .: C, 66.83; H, 8.39; N, 6.48.
Found: C, 66.58; H, 8. 15; N, 6.67.
Example 50
3-amino-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone. Melting point 162-164 ° C.
Analysis for C ₁₈ H ₂₆ N ₂ O ₂ S:
Calc .: C, 64.64; H, 7. 84; N, 8.38.
Found: C, 64.85; H, 7.92; N, 8.19.
Example 51
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (propylamino) -4-thiazolidinone. Melting point 131-136 ° C.
Analysis for C ₂₁ H ₃₂ N ₂ O ₂ S:
Calc .: C, 66.98; H, 8.57; N, 7.44.
Found: C, 67.22; H, 8. 70; N, 7.37.
Example 52
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (ethylamino) -4-thiazolidinone. Melting point 125-127 ° C.
Analysis for C ₂₀ H ₃₀ N ₂ O ₂ S:
Calc .: C, 66.26; H, 8.34; N, 7.73.
Found: C, 66.46; H, 8. 35; N, 7.95.
Example 53
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -2-thioxo-4-thiazolidinone. Melting point 158-160 ° C.
Analysis for C ₂₀ H ₂₈ N ₂ O ₂ S:
Calc .: C, 61.19; H, 7. 19; N, 7.14.
Found: C, 61.33; H, 7. 23; N, 7.43.
Example 54
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-hydroxyethyl) amino] -4-thiazolidinone. Melting point 128-132 ° C.
Analysis for C ₂₀ H ₃₀ N ₂ O ₃ S:
Calc .: C, 63.46; H, 7.99; N, 7.40.
Found: C, 63.57; H, 7.92; N, 7.45.
Examples 55-56
5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4-thiazolidinone and 5-[(3,5-di-2-propenyl-4-hydroxyphenyl ) Methyl] -4-thiazolidinone
A. Preparation of 3,5-di- (2-propenyl) -4-hydroxybenzaldehyde.
Using a mechanical stirrer under a nitrogen atmosphere, 250 g of parahydroxybenzaldehyde, 247.6 g of allyl bromide, 311.7 g of potassium bicarbonate and 650 ml of acetone were heated to reflux for about 18 hours. After cooling the mixture, about 1 L of water was added and then extracted twice with 800 mL portions of diethyl ether. The organic phase was then distilled to yield about 299 g of 4- (2-propenyl) oxybenzaldehyde, which was then heated with about 300 ml of diethylaniline at 195-205 ° C. for 5.5 hours. The mixture was cooled and 750 mL of ethyl acetate was added. The mixture was washed three times with 500 ml of 1N HCl and subsequently operated to yield about 138 g of 3- (2-propenyl) -4-hydroxybenzaldehyde. Monosubstituted aldehyde (159 g) was heated to reflux again for 3 hours with 152 g of potassium carbonate and 465 mL of acetone and then cooled. The mixture was poured into 900 ml of ice water and then extracted twice with 430 ml of diethyl ether to yield about 170 g of 3- (2-propenyl) -4- (2-propenyloxy) benzaldehyde. The disubstituted aldehyde was then heated to 195-205 ° C. for about 6.5 hours in about 500 ml of diethylaniline under a nitrogen atmosphere. The mixture was cooled and dissolved in about 800 mL of ethyl acetate, washed three times with 1 L of 1N HCl and further manipulated to yield about 121.9 g of the desired subtitle intermediate.
B. 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4-thiazolidinone and 5-[(3,5-di-2-propenyl-4-hydrate Preparation of oxyphenyl) methyl] -4-thiazolidinone
3,5-di- (2-propenyl) -4-hydroxybenzaldehyde (50.5 g), 36.6 g of rhodanine, and 164 g of sodium acetate were heated together in 1.25 L of acetic acid at reflux for 14.5 hours. The resulting solution was cooled and poured into 2 liters of ice water and after separation about 75 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -2-thioxo-4 -Thiazolidinone was obtained. Melting point 157-160 ° C.
The produced thion (74.8 g) was reduced by treatment with zinc powder (62 g) and concentrated hydrochloric acid (950 mL) in 2.1 L of heat (about 82 ° C.) ethanol. Once the reactions were combined, the solution was cooled to room temperature, stirred for 1 hour and then added to 3.75 L of ice water. The resulting solution was left overnight to give a gum. The liquid layer was decanted and extracted with 750 ml of chloroform, the gum was dissolved in 560 ml of chloroform and the resulting solution was washed sequentially with 75 ml of saturated sodium carbonate solution, 75 ml of water and 75 ml of saturated hydrous solution. The chloroform solutions were combined and then ground with 100 ml of methylene chloride. Silicagel chromatography gave the title product. Elution with a 25-60% ethyl acetate gradient in hexanes gave various fractions, which were treated as follows.
Fractions 13-15 were concentrated and then washed with ethyl acetate to afford 2.91 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methyl] -4-thiazolidinone. Fractions 16-18 were concentrated and the residue was triturated with 30 mL methylene chloride. Fractions 19-23 were concentrated and the residue was triturated with 35 ml methylene chloride. After grinding, the remaining insolubles were separated by filtration and ground with 40 ml of ethyl acetate to give 3.85 g of 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4 -Thiazolidinone was obtained.
Ethyl acetate washes from fractions 13-15, methylene chloride solution containing fractions 16-18 and methylene chloride and ethyl acetate solutions obtained from fractions 19-23 were combined and loaded onto a silica gel chromatography column. Elution with 1: 1 ethyl acetate / hexane solution gave various fractions, which were combined according to the purity of each compound. A fraction, predominantly 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methyl] -4-thiazolidinone, was crystallized from thermal ethyl acetate to yield 1.24 g of this compound (5-[(3 Total yield of, 5-di-2-propenyl-4-hydroxyphenyl) methyl] -4-thiazolidinone: 4.14 g). A fraction, predominantly 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4-thiazolidinone, was ground with 30 ml of hot ethyl acetate to yield 1.73 g of this compound (5- [Total yield of [(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4-thiazolidinone: 5.58 g) was obtained.
55. 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -4-thiazolidinone. Melting point 184-188 ° C.
Analysis for C ₁₆ H ₁₇ NO ₂ S:
Calc .: C, 66.87; H, 5.96; N, 4.87.
Found: C, 66.62; H, 5.92; N, 4.89.
56. 5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methyl] -4-thiazolidinone. Melting point 142-144 ° C.
Analysis for C ₁₆ H ₁₉ NO ₂ S:
Calc .: C, 66.41; H, 6. 62; N, 4.84.
Found: C, 66.18; H, 6.69; N, 4.60.
Using the procedures described in Examples 55 and 56 and elsewhere herein, the following additional compounds were prepared.
Example 57
5-[(3,5-di-2-propenyl-4-hydroxyphenyl) methylene] -3-methyl-4-thiazolidinone. Melting point 155-159 ° C.
Analysis of C ₁₇ H ₁₉ NO ₂ S:
Calc .: C, 67.74; H, 6. 35; N, 4.65.
Found: C, 67.53; H, 6.09; N, 4.45.
Example 58
5-[(3,5-dipropyl-4-hydroxyphenyl) methylene] -3-methyl-4-thiazolidinone. Melting point 162-165 ° C.
Analysis of C ₁₇ H ₂₃ NO ₂ S:
Calc .: C, 66.85; H, 7.59; N, 4.59.
Found: C, 67.12; H, 7. 37; N, 4.52.
Example 59
5-[(3,5-dipropyl-4-hydroxyphenyl) methylene] -4-thiazolidinone. Melting point 202-205 ° C.
Analysis for C ₁₆ H ₂₃ NO ₂ S:
Calc .: C, 65.95; H, 7. 26; N, 4.81.
Found: C, 66.16; H, 7. 49; N, 4.79.
Example 60
5-[(3,5-dipropyl-4-hydroxyphenyl) methyl] -4-thiazolidinone. Melting point 155-157 ° C.
Analysis for C ₁₆ H ₂₃ NO ₂ S:
Calc .: C, 65.49; H, 7.90; N, 4.77.
Found: C, 65.71; H, 7.73; N, 4.99.
Example 61
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -4-thiazolidinone
A. Preparation of 3- (1,1-dimethylethyl) -4-hydroxy-5-methylbenzaldehyde.
Under a nitrogen atmosphere, 76.65 g of 2- (1,1-dimethylethyl) -6-methylphenol (Aldrich), 65.42 g of hexamethylenetetramine and 700 ml of trifluoroacetic acid are stirred at reflux for about 24 hours. Then cooled and evaporated. The residue from evaporation was dissolved in 1500 ml of water and 1000 ml of chloroform and neutralized to pH 7 with solid sodium carbonate. The resulting layer was separated and the aqueous layer was washed with chloroform. The organic layer was dried over sodium sulfate overnight, then washed with a volume of chloroform and evaporated. The resulting residue was then dissolved in 375 ml of toluene, heated in a steam bath and then cooled to room temperature overnight. Subsequent manipulations yielded 28.3 g of the desired subtitle intermediate.
B. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -2-thioxo-4-thiazolidinone
28.3 g of the intermediate prepared in Example 61A, 24 g of N-aminorodanine and 48.3 g of sodium acetate in 735 ml of acetic acid were heated to reflux for about 7 hours and then cooled to room temperature with stirring overnight I was. The resulting mixture was poured into 1500 ml of ice water with stirring and filtered. The wet filter cake was transferred to a beaker, dissolved in a mixture of ethyl acetate and water and then separated. The organic layer was dried over sodium sulphate, filtered and washed with ethyl acetate. Polishing in hot chloroform and subsequent vacuum drying followed by further operation yielded about 18 g of the desired subtitle intermediate. Melting point 210-216 ° C.
C. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -4-thiazolidinone
The thion of Example 61B was reduced as described herein and then subsequently operated to yield 1.56 g of the title product. Melting point 162-165 ° C.
Analysis for C ₂₅ H ₁₉ NO ₂ S:
Calc .: C, 64.95; H, 6. 90; N, 5.05.
Found: C, 65.12; H, 7.05; N, 4.99.
Using the procedure described in Example 61 and elsewhere herein, the following additional compounds were prepared.
Example 62
3-amino-5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -4-thiazolidinone. Melting point 110 ° C. (decomposition).
Analysis for C ₁₅ H ₂₀ N ₂ O ₂ S:
Calc .: C, 61.81; H, 7. 29; N, 9.01.
Found: C, 61.90; H, 7.47; N, 8.78.
Example 63
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -3-dimethylamino-2-thioxo-4-thiazolidinone. Melting point 189-190 ° C.
Analysis for C ₁₇ H ₂₂ N ₂ O ₂ S:
Calc .: C, 58.26; H, 6. 33; N, 7.99.
Found: C, 58.55; H, 6.08; N, 8.28.
Example 64
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -3-methyl-4-thiazolidinone. Melting point 192-195 ° C.
Analysis for C ₁₆ H ₂₁ NO ₂ S:
Calc .: C, 65.95; H, 7. 26; N, 4.81.
Found: C, 66.24; H, 7. 17; N, 5.02.
Example 65
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methylene] -3-dimethylamino-4-thiazolidinone. Melting point 182-192 ° C.
Analysis for C ₁₇ H ₂₄ N ₂ O ₂ S:
Calc .: C, 63.72; H, 7.55; N, 8.74.
Found: C, 63.45; H, 7. 58; N, 8.93.
Example 66
5-[[3,5-bis (1-methylethyl) -4-hydroxyphenyl] methyl] -2-thioxo-4-thiazolidinone.
Example 67
5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -2-thioxo-3- (dimethylamino) -4-thiazolidinone. Melting point 137-141 ° C.
Analysis of C ₂₁ H ₂₂ N ₂ O ₃ S ₃ :
Calc .: C, 56.48; H, 4.97; N, 6.27.
Found: C, 56.77; H, 5.07; N, 5.99.
Example 68
5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -4-thiazolidinone. Melting point 190-192 ° C.
Analysis of C ₁₉ H ₁₇ NO ₃ S ₃ :
Calc .: C, 56.55; H, 4. 25; N, 3.47.
Found: C, 56.76; H, 4. 42; N, 3.44.
Example 69
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-propylphenyl] methylene] -3-methyl-4-thiazolidinone. Melting point 189.5-191.5 ° C .;
Analysis for C ₁₈ H ₂₅ NO ₂ S:
Calc .: C, 67.68; H, 7.89; N, 4.38.
Found: C, 67.97; H, 8. 16; N, 4.40.
Example 70
5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone
A. Preparation of 3- (1,1-dimethylethyl) -4-hydroxybenzaldehyde.
To 101.5 g of N-methylformanilide, 107 g of phosphoryl chloride was added dropwise with cooling over 15 minutes. The mixture was warmed to room temperature and stirred for 70 minutes. 67.5 g of ortho-t-butylphenol were added and stirred for about 45 minutes, then the mixture was heated to about 50-60 ° C. and stirred for 4.5 hours. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 mL of 5% potassium hydroxide solution. The aqueous potassium hydroxide layer was separated and added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to 3 with stirring with concentrated hydrochloric acid. The resulting layer was separated and the aqueous layer was again extracted with chloroform and dried over sodium sulfate overnight to yield 18.1 g of the desired subtitle intermediate.
B. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-2-thioxo-4-thiazolidinone
The benzaldehyde intermediate (17.5 g) prepared in Example 70A was dissolved in 490 mL of acetic acid. The resulting solution was added to a mixture of 14.45 g N-methylrodanine and 28.18 g sodium acetate. The resulting suspension was heated, stirred at reflux for 24 hours (at which time a yellow precipitate formed), filtered and washed with acetic acid and diethyl ether. The precipitate was triturated with 300 mL of diethyl ether, filtered off and washed again with diethyl ether and again triturated twice with 600 mL of water. The resulting solid was dried in vacuo to afford the desired subtitle intermediate. Melting point 230 ° C.
C. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone
The thion prepared in Example 70B was reduced using tri-n-butyl tin hydride and AIBN as described above to afford the title product. Melting point 230 ° C.
Analysis for C ₁₅ H ₁₉ NO ₂ S:
Calc .: C, 64.95; H, 6. 90; N, 5.05.
Found: C, 65.07; H, 7.02; N, 5.28.
Using the procedure described herein, the following additional compounds were prepared.
Example 71
5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid. Melting point 202-206 ° C.
Analysis of C ₂₁ H ₁₉ NO ₅ S ₃ :
Calc .: C, 54.65; H, 4. 15; N, 3.04.
Found: C, 54.91; H, 4. 23; N, 3.11.
Example 72
5-[(4-hydroxy-3,5-dimethylphenyl) methylene] -3-methyl-4-thiazolidinone. Melting point 207-212 ° C. (decomposition).
Analysis for C ₁₃ H ₁₅ NO ₂ S:
Calc .: C, 62.62; H, 6.06; N, 5.62.
Found: C, 62.58; H, 6.05; N, 5.65.
Example 73
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] methyl] -4-thiazolidinone
A solution of 0.28 g of Example 61 compound in 30 ml tetrahydrofuran was hydrogenated at 60 psi overnight at 60 ° C. in the presence of 1.12 g of 5% palladium on carbon. The reaction mixture was filtered and evaporated to dryness. The resulting residue was dissolved in 3.5 ml of 1: 1.5 ethyl acetate / hexane solution and loaded onto a silica gel chromatography column. Elution with 40% ethyl acetate in hexanes gave a fraction, which was evaporated to dryness to give 0.05 g of the title compound. Melting point 64-68 ° C.
Analysis for C ₁₅ H ₂₁ NO ₂ S:
Calc .: C, 64.48; H, 7. 58; N, 5.01.
Found: C, 64.32; H, 7. 66; N, 4.79.
Example 74
5-[[3,5-bis (1-methylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone
Using the method described in Example 73, 4.73 g of 5-[[3,5-bis (1-methylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone was converted to 1.88 g of The title compound was obtained. Melting point 136-139 ° C.
Analysis for C ₁₆ H ₂₃ NO ₂ S:
Calc .: C, 65.49; H, 7.90; N, 4.77.
Found: C, 65.79; H, 7.90; N, 4.81.
Example 75
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-propylphenyl] methyl] -4-thiazolidinone
A. Preparation of 3- [2- (1,1-dimethylethyl)] phenoxypropene.
Allyl bromide (69.2 mL), 2-t-butylphenol (122.9 mL) and potassium carbonate (121.6 g) were stirred for 50 hours at reflux in 265 mL of acetone and then cooled to 35 ° C. Water (600 mL) was added and the resulting layer was separated. The aqueous layer was extracted with 600 ml of diethyl ether. The organic layer was combined with the ether extract of the aqueous layer and the resulting solution was dried over sodium sulfate overnight. After removal of sodium sulfate, the solvent was evaporated to yield 147 g of subtitle intermediate after further operation.
B. Preparation of 2- (1,1-dimethylethyl) -6- (2-propenyl) phenol
147 g of this compound were all inverted as described in Examples 55A and 56A to yield 100.8 g of subtitle intermediate.
C. Preparation of 2- (1,1-dimethylethyl) -6-propylphenol
A solution of 54.9 g of the compound in 575 mL toluene was hydrogenated at 60 psi for 3 hours at room temperature in the presence of 55 g of Raney nickel. The reaction mixture was filtered and evaporated to dryness to yield 59.2 g of subtitle intermediate.
D. Preparation of 3- (1,1-dimethylethyl) -4-hydroxy-5-propylbenzaldehyde
The compound (55.48 g) was converted using the method described in Example 61A to yield 23.33 g of subtitle intermediate.
E. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-propylphenyl] methylene] -2-thioxo-4-thiazolidinone
Using the method described in Example 61B, 5.51 g of this compound were converted to yield 6.26 g of subtitle intermediate. Melting point 190.5-192 ° C.
F. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-propylphenyl] methyl] -2-thioxo-4-thiazolidinone
Using the method described in Example 8, 4.73 g of this compound were converted to yield 2.1 g of subtitle intermediate.
G. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxy-5-propylphenyl] methyl] -4-thiazolidinone
A solution of 2.1 g of the compound in 185 ml of ethanol was hydrogenated at 500 psi for 20 hours at 100 ° C. in the presence of 8.4 g of 5% palladium on carbon. The reaction mixture was filtered and evaporated to dryness. The resulting residue was dissolved in 25 mL methylene chloride and loaded on a silica gel chromatography column. Elution with 2000 mL 10-50% ethyl acetate gradient in hexanes followed by 2000 mL 1: 1 solution of ethyl acetate / hexanes gave a fraction, which was evaporated to dryness to yield 0.75 g of the title product. Melting point 50-55 ° C.
Analysis for C ₁₇ H ₂₅ NO ₂ S:
Calc .: C, 66.41; H, 8. 20; N, 4.56.
Found: C, 66.61; H, 8.22; N, 4.55.
Example 76
5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -3-dimethylamino-4-thiazolidinone
A. Preparation of 5-[[3-ethoxy-4-hydroxyphenyl] methylene] -3-dimethylamino-2-thioxo-4-thiazolidinone
3-ethoxy-4-hydroxybenzaldehyde (45.7 g), N-dimethylaminorhodanine (53.35 g) and molten sodium acetate (92.4 g) were reacted in the manner described in Example 1, yielding a lower 52.92 g The title intermediate was obtained. Melting point 194-198 ° C.
B. Preparation of 5-[[3-ethoxy-4-hydroxyphenyl] methylene] -3-dimethylamino-4-thiazolidinone
Using the method described in Example 10, 47.66 g of the compound were converted to yield 14.02 g of subtitle intermediate.
C. Preparation of 5-[[3- (methylthiophenyl) -4-hydroxy-3-ethoxyphenyl] methylene] -3-dimethylamino-4-thiazolidinone
A 40 wt% solution of sodium hydroxide (0.95 g) and 17.3 mL of formaldehyde was dissolved in 50 mL of 2-ethoxyethanol. Phenylthiol (2.62 g) and 7.0 g of the compound were added and the resulting solution was refluxed for 4 hours and then cooled. Ethyl acetate (50 mL) and water (25 mL) were added to the cooled reaction mixture and the pH of the resulting two-phase solution was lowered to about 5 with concentrated hydrochloric acid. The organic phase was separated from the aqueous phase, washed with saturated hydrous solution and then loaded onto a silica gel chromatography column. Elution with 4 liters of methylene chloride followed by 4 liters of 3% methanol / 97% methylene chloride solution gave a fraction containing the title product. These fractions were combined and loaded once more on silica gel chromatography columns. Elution with 4 liters of methylene chloride followed by 22.5% acetonitrile solution in 1 liter of methylene chloride yields a fraction and the solvent is evaporated to give the title product. The product was further purified by grinding with a thermal solution of 50 mL of hexane and 30 mL of ethyl acetate to give 6.20 g of 5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] Methylene] -3-dimethylamino-4-thiazolidinone was obtained. Melting point 118-120 ° C.
Analysis for C ₂₁ H ₂₄ N ₂ O ₃ S:
Calc .: C, 60.55; H, 5.81; N, 6.73; S, 15.39.
Found: C, 60.75; H, 5. 76; N, 6.76; S, 15.58.
Example 77
5-[[3- (1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone
A. Preparation of 3- (1,1-dimethylethyl) -4-hydroxybenzaldehyde
To 184.4 mL (1.494 mole) of N-methylformanilide, 130.9 mL (1.404 mole) of phosphoryl chloride was added dropwise while cooling over 20 minutes. The mixture was warmed to rt and stirred for 1 h. Ortho-tert-butylphenol (138.2 mL; 0.9 mol) was then added dropwise to the reaction solution over 25 minutes. After the phenol addition was completed, the resulting reaction mixture was stirred for an additional 30 minutes at room temperature and then heated to about 60 ° C. and stirred at this temperature for 5 hours. The reaction mixture was poured into a volume of crushed ice and extracted with chloroform. The aqueous layer was separated and washed again with chloroform. The chloroform layers were combined and extracted with 2000 mL of 5% potassium hydroxide solution. An aqueous potassium hydroxide extract was then added to 1000 ml of chloroform. The pH of the resulting two-phase mixture was adjusted to about pH 2.0 with concentrated hydrochloric acid. The layers of the mixture were separated and the aqueous layer was extracted again with chloroform. The organic layer and chloroform extract from the two-phase mixture were combined, washed with water and then dried over sodium sulfate. The volatile components of the solution were removed under reduced pressure to give a residue. The residue was dissolved in 100 ml of hot toluene and the resulting solution was diluted with 100 ml of hexane. When the solution was cooled slowly to room temperature, a precipitate formed. This precipitate was recovered by filtration, washed with hexane and dried in vacuo to yield 20.0 g of the desired subtitle intermediate.
B. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-amino-2-thioxo-4-thiazolidinone
Benzaldehyde intermediate (20.0 g; 112.2 mmol), N-aminorodanine (18.29 g; 123.4 mmol) and sodium acetate (36.8 g; 448.8 mmol) from Example 77A were suspended in 560 mL of acetic acid. The suspension was heated to reflux and stirred at this temperature for 7 hours (at which time a precipitate formed) and then cooled to room temperature with stirring. The precipitate was recovered by filtration and then washed sequentially with a 1: 1 ethyl acetate / diethyl ether solution followed by a diethyl ether wash. The recovered precipitate was dried under vacuum at 60 ° C. for 2 hours to afford 14.5 g of the desired subtitle intermediate. Melting point 225 ° C.
C. Preparation of 5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-thiazolidinone
Intermediate from Example 77B (14.3 g; 46.4 mmol) was suspended in 230 ml of heat (60 ° C.) toluene. To this suspension, tri-n-butyl tin hydride (62.4 mL; 232 mmol) and AIBN (1.14 g; 6.96 mmol) were added. When the resulting suspension was heated to reflux, the suspended solids slowly dissolved. Additional AIBN was added 30 and 55 minutes (twice in 1.14 g portions) after the start of heating. After 80 minutes of starting heating, the thermal reaction solution was transferred to a separatory funnel and 1N hydrochloric acid was added. The resulting two-phase mixture was diluted with ethyl acetate and the layers separated. The aqueous phase was washed with ethyl acetate and then this wash was combined with the organic layer from the two-phase mixture. The combined solution was washed with saturated sodium chloride solution and then dried over sodium sulfate. The volatile components of the solution were removed under reduced pressure to yield 87.7 g of a yellow solid. This solid was suspended in 1000 mL of hexanes and the resulting suspension was stirred for 15 minutes. After 15 minutes, the suspension was filtered and the recovered solid was dissolved in 500 ml of diethyl ether. The diethyl ether solution was used with 8000 mL of 5-20% isopropyl alcohol gradient in hexane, followed by 2000 mL of 20-30% isopropyl alcohol gradient in hexane followed by 2000 mL of 30-35% isopropyl alcohol gradient in hexane. Chromatography on silica gel column. Fractions identified to contain product were evaporated and chased with methylene chloride. The resulting residue was dissolved in ethyl acetate, reduced to dryness under reduced pressure and then chased with ethanol to yield 4.31 g of the title compound. Melting point 110 ° C. (decomposition).
Analysis for C ₁₄ H ₁₇ NO ₂ S:
Calc .: C, 63.85; H, 6.51; N, 5.32.
Found: C, 64.15; H, 6.73; N, 5.60.
Example 78
5-[[3- (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone
A portion (395.1 mg; 1.5 mmol) of the title compound from Example 77 was dissolved in 9 ml methanol. Magnesium (72.9 mg; 3.0 mmol) was then added to the solution and the resulting reaction mixture was stirred at rt for 3 h. After 3 hours, most of the magnesium originally added appeared to disappear, and therefore an additional 182.3 mg (7.5 mmol) of magnesium was added. The reaction solution was stirred overnight at room temperature. The next morning, a yellow precipitate formed. A methanolic reaction solution was added to the ethyl acetate / 1N hydrochloric acid mixture to dissolve this precipitate. The organic layer from the resulting two-phase mixture was separated and then dried over sodium sulfate. The volatile components of the organic layer were removed and the resulting residue was chased with methylene chloride, the residue was then dissolved in 25 ml of methylene chloride and the resulting solution using a 5-20% isopropyl alcohol gradient in hexanes. Chromatography on silica gel chromatography column. Fractions found to contain substantially pure product were evaporated to yield 0.29 g of the title compound. Melting point 65-70 ° C.
Analysis for C ₁₄ H ₁₉ NO ₂ S:
Calc .: C, 63.37; H, 7.22; N, 5.28.
Found: C, 63.08; H, 7. 30; N, 4.99.
Example 79
(-)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone
In a 50 ml three necked round bottom flask containing 25 ml of methylene chloride, 1.31 g of 4mm molecular sieve, 0.56 ml (1.88 mmol) of titanium isopropoxide, 0.79 ml (3.75 mmol) of (+)-diiso Propyl tartrate and 34 L (1.88 mmol) of deionized water were added. The resulting solution was stirred for 20 minutes and then 0.8 g (2.5 mmol) of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidi Discussion The racemic mixture was added. The resulting solution was cooled to −20 ° C. and a 2.57 M solution of t-butylhydroperoxide in 0.73 mL (1.88 mmol) of isooctane was added. The reaction solution was then stirred at -20 ° C for 6 hours.
After 6 hours, the reaction solution was poured into 50 ml of a solution prepared from 9.9 g of iron (II) sulfate heptahydrate, 3.3 g of citric acid monohydrate and water to quench. The resulting solution was stirred for 30 minutes and then the stirring was stopped to separate the organic layer and the aqueous layer. The aqueous layer was decanted and washed with methylene chloride. Methylene chloride washes were combined with the organic layer and the resulting solution was washed with saturated hydrous solution and then dried over sodium sulfate. Sodium sulfate was filtered off and the remaining liquid was evaporated to yield 1.81 g of residue.
The residue was dissolved in 25 mL methylene chloride and the resulting solution was chromatographed on a silica gel chromatography column. Elution with a 6000 mL 10-50% ethyl acetate gradient in hexanes afforded various fractions containing the title compound. These fractions were combined and the liquid was evaporated to yield 0.19 g of the title compound. [a] ²⁵ = -73.6 ° (c = 1.0, MeOH).
Analysis for C ₁₈ H ₂₇ NO ₂ S:
Calc .: C, 67.25; H, 8. 47; N, 4.36.
Found: C, 67.50; H, 8.53; N, 4.48.
Examples 80, 81 and 82
(+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone, (-)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide and (+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide
In a manner similar to that described in Example 79, 0.89 mL (3.0 mmol) titanium isopropoxide, 1.27 mL (6.0 mmol) of (-)-diisopropyl tartrate, 54 L (3.0 mmol) deionized water, 1.61 g (5.0 mmol) of racemic mixture of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone and 2.4 mL (6.5 mmol) A 2.57M solution of t-butylhydroperoxide in isooctane at was reacted to give a residue. The residue was dissolved in 75 mL methylene chloride and the resulting solution was chromatographed on a silica gel chromatography column. Eluted with a 6000 mL 10-50% ethyl acetate gradient in hexane to afford (+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazoli Various fractions containing dinon were obtained. These fractions were combined and the liquid was evaporated to yield 0.43 g of the title compound. Further elution with 4000 ml of a 50% isopropanol solution in hexanes afforded various fractions. Combining fractions believed to contain (-)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide and The liquid was evaporated to yield 0.87 g of product. Combine the fractions believed to contain (+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide and The liquid was evaporated to yield 0.27 g of product.
80. (+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone
[a] ²⁵ = + 70.41 ° (c = 1.0, MeOH).
Analysis for C ₁₈ H ₂₇ NO ₂ S:
Calc .: C, 67.25; H, 8. 47; N, 4.36.
Found: C, 66.95; H, 8.22; N, 4.26.
81. (-)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide. Melting point 182-184 ° C.
[a] ²⁵ = -21.84 ° (c = 1.0, MeOH).
Analysis for C ₁₈ H ₂₇ NO ₃ S:
Calc .: C, 64.06; H, 8.06; N, 4.15.
Found: C, 63.84; H, 8.09; N, 4.12.
82. (+)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -4-thiazolidinone-1-oxide. Melting point 177-181 ° C.
[a] ²⁵ = + 163.05 ° (c = 1.0, MeOH).
Analysis for C ₁₈ H ₂₇ NO ₃ S:
Calc .: C, 64.06; H, 8.06; N, 4.15.
Found: C, 63.88; H, 8.12; N, 4.29.
Example 83
(-)-5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -3-methyl-4-thiazolidinone
In a manner similar to that described in Example 79, 0.45 mL (1.5 mmol) titanium isopropoxide, 0.63 mL (3.0 mmol) of (+)-diisopropyl tartrate, 27 L (1.5 mmol) water, 0.84 g (2.5 mmol) of a racemic mixture of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methyl] -3-methyl-4-thiazolidinone and 0.58 ml ( 1.5 mmol) was reacted with a 2.57 M solution of t-butylhydroperoxide in isooctane to give a residue. The residue was dissolved in 25 mL methylene chloride and the resulting solution was chromatographed on a silica gel chromatography column. 1000 ml of methylene chloride, followed by 6000 ml of 0-10% ethyl acetate gradient in methylene chloride, followed by 4000 ml of 20-50% isopropyl alcohol gradient in hexane followed by 2000 ml of 50% isopropyl alcohol / hexane solution , Various fractions containing the title compound were obtained. These fractions were combined and the liquid was evaporated to yield 0.35 g of the title compound.
Analysis for C ₁₉ H ₂₉ NO ₂ S:
Calc .: C, 68.02; H, 8.71; N, 4.17.
Found: C, 67.95; H, 8.55; N, 4.18.
NMR (300 MHz; CDCl) δ = 1.4 (s, 18H), 2.9 (s, 3H), 3.0 (dd, 1H), 3.3 (dd, 1H), 3.8 (dd, 1H), 4.0 (d, 1H) , 4.2 (d, 1H), 5.1 (s, 1H), 7.1 (s, 2H).
Using the procedure described herein, the following additional compounds were prepared.
Example 84
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(4-morpholinyl) methyl] -4-thiazolidinone. Melting point 204-206 ° C. (decomposition).
Example 85
5-[[3,5-dimethoxy-4-hydroxyphenyl] methylene] -2-thioxo-3-methyl-4-thiazolidinone. Melting point 211-213 ° C.
Example 86
5-[[3,5-dimethoxy-4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone. Melting point 207-212 ° C.
Example 87
5-[[3,5- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -4-thiazolidinone. Melting point 182-184 ° C.
Analysis of C ₁₉ H ₁₉ NO ₃ S ₂ :
Calc .: C, 61.10; H, 5.13; N, 3.75; S, 17.17.
Found: C, 61.31; H, 5.07; N, 3.80; S, 17.44.
Example 88
5-[[3- (methylthiophenyl) -4-hydroxy-5-ethoxyphenyl] methylene] -3-methyl-4-thiazolidinone. Melting point 142-145 ° C.
Analysis of C ₂₀ H ₂₁ NO ₃ S ₂ :
Calc .: C, 61.99; H, 5. 46; N, 3.61.
Found: C, 62.15; H, 5.68; N, 3.49.
Example 89
5-[(4-hydroxyphenyl) methylene] -2-thioxo-4-thiazolidinone. Melting point 287-290 ° C.
Example 90
5-[(3-methoxy-4-hydroxyphenyl) methylene] -2-thioxo-4-thiazolidinone. Melting point 229-231 ° C.
Example 91
5-[(3-methoxy-4-hydroxyphenyl) methylene] -2-thioxo-3- (2-propenyl) -4-thiazolidinone.
Example 92
5-[(3-ethoxy-4-hydroxyphenyl) methylene] -2-thioxo-4-thiazolidinone. Melting point 217-217.5 ° C.
Example 93
5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid. Melting point -265 degreeC.
Example 94
5-[(3,5-dimethyl-4-hydroxyphenyl) methylene] -2-thioxo-4-thiazolidinone. Melting point 260 deg.
Example 95
5-[(3,5-dimethoxy-4-hydroxyphenyl) methylene] -2-thioxo-4-thiazolidinone. Melting point 230 ° C.
Example 96
5-[[3- (1,1-dimethylethyl) -4-hydroxy-5- (methylthiophenyl) phenyl] methylene] -2-thioxo-4-thiazolidinone. Melting point 181-184 ° C.
Example 97
5-[(3-ethoxy-4-hydroxyphenyl) methylene] -2-thioxo-3-cyclohexyl-4-thiazolidinone. Melting point 122-123 ° C.
Example 98
5-[(3-ethoxy-4-hydroxyphenyl) methylene] -2-thioxo-3-methyl-4-thiazolidinone. Melting point 157 ° C.
Example 99
5-[[3,5-bis (1-methylpropyl) -4-hydroxyphenyl] methylene] -4-oxo-2-thioxo-3-thiazolidine acetic acid. Melting point 191-193 ° C.
Example 100
5-[[3,5-bis (1-methylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone. Melting point 200-210 ° C.
Analysis of C ₁₇ H ₂₃ NO ₂ S:
Calc .: C, 66.85; H, 7.59; N, 4.59.
Found: C, 67.03; H, 7.55; N, 4.37.
Example 101
4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -1,3-oxothiolane-5-one
A. Preparation of β- (3,5-di-t-butyl-4-hydroxyphenyl) -α-mercaptoacrylic acid
Of 174.5 g of 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -2-thioxo-4-thiazolidinone in 1250 ml of 10% sodium hydroxide solution The solution was heated on a steam bath for 4 hours. Decolorized carbon was added and the mixture was filtered through a high flow diatomaceous earth layer. Ice was added to cool the filtrate and treated with 6N hydrochloric acid. The precipitated product was recovered by filtration, washed with water and dried to afford 150 g of the desired subtitle intermediate.
B. Preparation of 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -1,3-oxothiolan-5-one.
See Agr. Biol. Chem., 29 (8), 728 (1965)], 6 g of mercaptoacrylic acid from above were heated with 36 ml of acetic acid and 6 ml of formaldehyde (37% solution) for 1 hour in a steam bath. . The mixture was evaporated and the residue was chromatographed on silica gel to give 1.7 g of the desired product. Melting point 127-129 ° C.
Analysis for C ₁₈ H ₂₄ O ₃ S:
Calc .: C, 67.47; H, 7.55.
Found: C, 67.71; H, 7.62.
As mentioned above, the compounds of formula (I) are useful for treating multiple sclerosis. Such activity was demonstrated in the following test system.
Experimental autoimmune encephalomyelitis (EAE) model
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune demyelination disease that can be induced in laboratory animals by injecting myelin basic protein. This disease has become the standard laboratory model for studying clinical and experimental autoimmune diseases. Indeed, many papers (eg, Abramsky et al. (J. Neuroimmunol., 2, 1 (1982)) and Bolton et al. (Bolton et al., J. Neurol. Sci., 56, 147 (1982))) Noted that the similarity between multiple sclerosis in humans and chronic relapsing EAE in animals represents the value of EAE in the study of autoimmune myeloid destructive disorders, particularly multiple sclerosis. As such, an EAE test model was used to establish the activity of the compound of formula I against multiple sclerosis. Such tests were performed according to the following procedure.
Female Lewis rats (Olac Ltd., U.K.) received 12.5 μg of myelin basic protein (MBP) (produced from guinea pig vertebrae) in complete Freunds supplements through the soles of the feet. Test compounds in carboxymethylcellulose were administered orally to test animals daily at day 0 (MBP infusion date) at a dose of 33 mg / kg. A control solution (carboxymethylcellulose alone) was administered to certain other test animals. Animals are then weighed and daily for symptoms of EAE according to grades 0-3 (0 = no change; 1 = tail relaxation; 2 = hind limb disorders; 3 = paralysis / death after 1/4). Scored. Animals were sacrificed when a score of 3 was reached.
The results of the experiments described above are reported in Table I below. In Table I, column 1 shows the example number of the test compound used or, if appropriate, the test compound was not used (control). Columns 2-16 record EAE disease scores at various times after MBP infusion day (day 0).
Inhibition of EAE Compound Example Number / ControlEAE Disease Score on Days After MBP Administration ^* One23456789101112131415 Control00000000000.51.52.22.72.8 Example 2100000000000.51.82.32.52.5 Example 200000000000.31.52.83.03.0 Example 10000000000000.12.02.73.0 * EAE disease score based on average of 6 test animals
The results reported in Table I above confirmed that compounds of Formula I inhibit EAE progression when given an appropriate dosage paradigm. In particular, the compound of Example 10 delayed the onset of the disease for at least 1 day compared to the control. As such, the compounds of Formula I will be expected to be effective in treating multiple sclerosis.
As mentioned above, the compounds of formula (I) can slow the progression of neurodegeneration associated with multiple sclerosis, thereby providing a valuable method of treatment claimed herein. The method comprises administering to a mammal in need of treatment of multiple sclerosis an amount of at least one compound of formula (I) sufficient to achieve the desired therapeutic effect. The composition can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or nasal routes. Oral and transdermal routes of administration are preferred. Whatever route of administration is chosen, such administration is carried out by pharmaceutical compositions prepared by techniques well known in the pharmaceutical sciences.
When preparing a pharmaceutical composition, one or more active ingredients will generally be mixed with the carrier, diluted with the carrier, or incorporated into the carrier, which may be in capsule, sachet, paper or other container form. If the carrier serves as a diluent, it may be a solid, semisolid or liquid substance which serves as a vehicle, excipient or medium for the active ingredient. Thus, the compositions may be used in tablets, pills, powders, lozenges, sachets, cassettes, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example For example, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders containing less than 10% by weight of active compound.
Some examples of suitable carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanta gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl Pyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl- and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The formulation may additionally include lubricants, wetting agents, emulsifiers and suspending agents, preservatives, sweeteners or flavoring agents. The composition may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient using procedures well known in the art.
The composition is preferably formulated in unit dosage forms such that each dosage form comprises about 5 to about 500 mg, more preferably about 25 to about 300 mg of the active ingredient. The term unit dosage form refers to physically discrete units suited as unit use dosages for human patients and other mammals, each unit comprising one or more predetermined doses of the active substance calculated to provide the desired therapeutic effect. Together with suitable pharmaceutical diluents, excipients or carriers.
The compounds used in the methods of the invention are effective over a wide range of dosages for the treatment of multiple sclerosis. Thus, as used herein, the term therapeutically effective amount refers to a dosage range of about 0.5 to about 500 mg / kg body weight / day. In the treatment of adults, single or divided doses in the range of about 1 to about 100 mg / kg are preferred. However, the actual amount of compound to be administered will be determined by the physician in view of the relevant environment, including the selected compound to be administered, the route of administration chosen, the age, weight and response of the individual patient, and the severity of the patient's symptoms and, therefore, the administration It will be understood that the amount ranges are not intended to limit the scope of the invention in any way.
The following formulation examples can use any compound of formula (I) as the active ingredient. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
Example 102
Hard gelatin capsules were prepared using the following ingredients:
Dose (mg / capsule) Compound of Example 10250 Dry starch200 magnesium10
The ingredients were mixed and filled into hard gelatin capsules at a 460 mg dose.
Example 103
Tablet formulations were prepared using the following ingredients:
Dose (mg / tablet) Compound of Example 21250 Cellulose, Microcrystalline400 Silicon dioxide, fume10 Stearic acid5
The ingredients were mixed and compressed to form tablets weighing 665 mg each.
Example 104
An aerosol solution was prepared comprising the following ingredients:
weight % Compound of Example 1010.25 ethanol29.75 Propellant 22 (chlorodifluoromethane)70.00
The active compound was mixed with ethanol and the mixture was added to a portion of propellant 22 and cooled to -30 ° C and delivered to the filling device. The required amount was then supplied to the stainless steel vessel and diluted with the remaining propellant. The valve unit was then mounted to the vessel.
Example 105
Tablets containing 60 mg of active ingredient each were prepared as follows:
Compound of Example 4760mg Starch45mg Microcrystalline cellulose35mg Polyvinylpyrrolidone (10% solution in water)4mg Sodium carboxymethyl starch4.5mg Magnesium stearate0.5mg Talc1mg Total amount150mg
The active ingredient, starch and cellulose were extracted from the 45th mesh U.S. Pass through the sieve and mix thoroughly. A solution of polyvinylpyrrolidone was mixed with the resulting powder, which was then subjected to 14th mesh U.S. Passed through the sieve. The granules so produced are dried at 50-60 ° C. and the 18th mesh U.S. Passed through the sieve. Sodium Carboxymethyl Starch, Magnesium Stearate and Talc were prepared in advance on 60th Mesh U.S. Passed through the sieve and then added to the granules, which were mixed and compressed on a tableting machine to give 150 mg weight tablets each.
Example 106
Capsules containing 80 mg of medicament each were prepared as follows:
Compound of Example 3580mg Starch59mg Microcrystalline cellulose59mg Magnesium stearate2mg Total amount200mg
The active ingredient, cellulose, starch and magnesium stearate are mixed and the 45th mesh U.S. Pass through the sieves and fill the hard gelatin capsules at a 200 mg dose.
Example 107
Suppositories containing 225 mg of active ingredient each were prepared as follows:
Compound of Example 50225 mg Saturated Fatty Acid GlycerideAmount to 2,000 mg total
The active ingredient is 60th mesh U.S. Pass through the sieve and suspend in saturated fatty acid glycerides pre-melted by applying the minimum heat required. The mixture was then poured into a regular 2 g volume of suppository and cooled.
Example 108
Suspensions each containing 50 mg of medicament per 5 ml dose were prepared as follows:
Compound of Example 5450 mg Sodium carboxymethyl cellulose50 mg syrup1.25 ml Benzoic acid solution0.10 ml SpiceEnough flashEnough Purified waterThe total amount of 5 ml
Medications 45 mesh U.S. Pass through the sieve and mix with sodium carboxymethyl cellulose and syrup to form a soft paste. The benzoic acid solution, flavor and coloring were diluted with a portion of water and added with stirring. Subsequently, a sufficient amount of water was added to fill the required volume.
Example 109
Capsules containing 150 mg of medicament each were prepared as follows:
Compound of Example 10150mg Starch164mg Microcrystalline cellulose164mg Magnesium stearate22mg Total amount500mg
The active ingredient, cellulose, starch and magnesium stearate are mixed and the 45th mesh U.S. Pass through the sieves and fill hard gelatine capsules at a 500 mg dose.

权利要求:
Claims (34)
[1" claim-type="Currently amended] A method of treating multiple sclerosis in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Formula I

Where
R ¹ and R ² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or Wherein n is an integer from 0 to 3;
R ³ is hydrogen or C ₁ -C ₆ alkyl;
R ⁴ and R ⁵ are each hydrogen or together form a bond;
R ⁶ and R ⁷ are each hydrogen or together form = S, or if one of R ⁶ and R ⁷ is hydrogen the other is -SCH ₃ ;
X is Wherein m is 0, 1 or 2;
Q is -O- or NR ⁸ ;
R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, -SO ₂ CH ₃ or-(CH ₂ ) nY
[From here,
n is an integer from 0 to 3,
Y is cyano, OR ⁹ , , Tetrazolyl, -NR ¹¹ R ¹² , -SH, -S (C ₁ -C ₄ alkyl) or
(From here,
R ⁹ is hydrogen, C ₁ -C ₄ alkyl, tosyl or ego;
R ¹⁰ is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or —NH ₂ ;
R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl,-(CH ₂ ) qOH,-(CH ₂ ) qN (C ₁ -C ₄ alkyl) ₂ ,-(CH ₂ ) qS (C ₁ -C ₄ alkyl) or Wherein q is an integer from 1 to 6 and n is as defined above, or
R ¹¹ and R ¹² together form a morpholinyl, piperidinyl, piperazinyl or N-methylpiperazinyl ring.
[2" claim-type="Currently amended] The compound of claim 1, wherein Q is —NR ⁸ and R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, or — (CH ₂ ) n Y, wherein n is an integer from 0 to 3 And Y is OR ⁹ , , -NR ¹¹ R ¹² or Wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined in claim 1.
[3" claim-type="Currently amended] The process according to claim 2, wherein R ³ is hydrogen.
[4" claim-type="Currently amended] 4. The compound of claim 3 wherein X is Wherein m is 0.
[5" claim-type="Currently amended] 5. The process of claim 4, wherein R ⁶ and R ⁷ are each hydrogen or together form = S.
[6" claim-type="Currently amended] 6. A compound according to claim 5, wherein R ¹ and R ² are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or Wherein n is 1, 2 or 3, wherein the compound of formula I is used.
[7" claim-type="Currently amended] The compound of claim 6, wherein Q is —NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₆ alkyl, or — (CH ₂ ) n Y [where n is 0, 1 or 2, and Y is OR ⁹ (here R ⁹ is hydrogen or C ₁ -C ₄ alkyl, or —NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl, or — (CH ₂ ) qOH ( Wherein q is 1, 2 or 3), wherein the compound of formula I is used.
[8" claim-type="Currently amended] 8. A process according to claim 7, wherein R ⁴ and R ⁵ together form a bond.
[9" claim-type="Currently amended] 9. A process according to claim 8 wherein R ⁶ and R ⁷ are both hydrogen.
[10" claim-type="Currently amended] 10. The compound of claim 9, wherein Q is NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₄ alkyl or — (CH ₂ ) n Y wherein n is 0, 1 or 2 and Y is hydroxy or NR ^11. R ¹² wherein R ¹¹ and R ¹² are each independently hydrogen, methyl or — (CH ₂ ) ₂ OH].
[11" claim-type="Currently amended] The compound of claim 10, wherein R ¹ and R ² are each independently C ₁ -C ₆ alkyl or Using a compound of formula (I).
[12" claim-type="Currently amended] 12. The process according to claim 11, wherein R ¹ and R ² are both 1,1-dimethylethyl.
[13" claim-type="Currently amended] 12. The method of claim 11, wherein Q is NR ⁸ and R ⁸ is C ₁ -C ₄ alkyl.
[14" claim-type="Currently amended] The process according to claim 13, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone is used.
[15" claim-type="Currently amended] 13. The process according to claim 12, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -4-thiazolidinone is used.
[16" claim-type="Currently amended] 13. The process according to claim 12, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylamino) -4-thiazolidinone is used.
[17" claim-type="Currently amended] 13. The process according to claim 12, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-hydroxyethyl) -4-thiazolidinone is used. How to.
[18" claim-type="Currently amended] 13. The process according to claim 12, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-amino-4-thiazolidinone is used.
[19" claim-type="Currently amended] 13. A compound according to claim 12, wherein 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-hydroxyethyl) amino] -4-thiazoli How to use dinons.
[20" claim-type="Currently amended] The method of claim 1 wherein 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -1,3-oxothiolan-5-one is used.
[21" claim-type="Currently amended] Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of multiple sclerosis.
Formula I

Where
R ¹ and R ² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or Wherein n is an integer from 0 to 3;
R ³ is hydrogen or C ₁ -C ₆ alkyl;
R ⁴ and R ⁵ are each hydrogen or together form a bond;
R ⁶ and R ⁷ are each hydrogen or together form = S, or if one of R ⁶ and R ⁷ is hydrogen the other is -SCH ₃ ;
X is Wherein m is 0, 1 or 2;
Q is -O- or NR ⁸ ;
R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, -SO ₂ CH ₃ or-(CH ₂ ) nY
[From here,
n is an integer from 0 to 3,
Y is cyano, OR ⁹ , , Tetrazolyl, -NR ¹¹ R ¹² , -SH, -S (C ₁ -C ₄ alkyl) or
(From here,
R ⁹ is hydrogen, C ₁ -C ₄ alkyl, tosyl or ego;
R ¹⁰ is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or —NH ₂ ;
R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl,-(CH ₂ ) qOH,-(CH ₂ ) qN (C ₁ -C ₄ alkyl) ₂ ,-(CH ₂ ) qS (C ₁ -C ₄ alkyl) or Wherein q is an integer from 1 to 6 and n is as defined above, or
R ¹¹ and R ¹² together form a morpholinyl, piperidinyl, piperazinyl or N-methylpiperazinyl ring.
[22" claim-type="Currently amended] The compound of claim 21, wherein Q is —NR ⁸ and R ⁸ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, or — (CH ₂ ) n Y where n is an integer from 0 to 23. And Y is OR ⁹ , , -NR ¹¹ R ¹² or (Wherein R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are as defined in claim 21) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of multiple sclerosis.
[23" claim-type="Currently amended] Use according to claim 22 for the preparation of a medicament for the treatment of multiple sclerosis, of a compound or a pharmaceutically acceptable salt thereof wherein R ³ is hydrogen.
[24" claim-type="Currently amended] The compound of claim 23, wherein X is (Wherein m is 0) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of multiple sclerosis.
[25" claim-type="Currently amended] 25. The use according to claim 24, for the preparation of a medicament for the treatment of multiple sclerosis, of a compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ and R ⁷ are each hydrogen or together form = S.
[26" claim-type="Currently amended] The compound of claim 25, wherein R ¹ and R ² are each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or Use of the compound of which n is 1, 2 or 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of multiple sclerosis.
[27" claim-type="Currently amended] 27. The compound of claim 26, wherein Q is -NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₆ alkyl or-(CH ₂ ) n Y [where n is 0, 1 or 2 and Y is OR ⁹ (here R ⁹ is hydrogen or C ₁ -C ₄ alkyl, or —NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are each independently hydrogen, C ₁ -C ₆ alkyl, or — (CH ₂ ) qOH ( Wherein q is 1, 2 or 3), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of multiple sclerosis.
[28" claim-type="Currently amended] 28. The use according to claim 27, wherein the compound or pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁵ together form a bond, for the manufacture of a medicament for the treatment of multiple sclerosis.
[29" claim-type="Currently amended] 29. The use according to claim 28, wherein the compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ and R ⁷ are both hydrogen, for the manufacture of a medicament for the treatment of multiple sclerosis.
[30" claim-type="Currently amended] The compound of claim 29, wherein Q is NR ⁸ , R ⁸ is hydrogen, C ₁ -C ₄ alkyl or — (CH ₂ ) n Y [where n is 0, 1 or 2 and Y is hydroxy or NR ^11. For the manufacture of a medicament for the treatment of multiple sclerosis of a compound or a pharmaceutically acceptable salt thereof, wherein R ¹² (wherein R ¹¹ and R ¹² are each independently hydrogen, methyl or — (CH ₂ ) ₂ OH) Usage.
[31" claim-type="Currently amended] The compound of claim 30, wherein R ¹ and R ² are each independently C ₁ -C ₆ alkyl or Use of a phosphorus compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of multiple sclerosis.
[32" claim-type="Currently amended] 32. The use according to claim 31, wherein the compound or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are both 1,1-dimethylethyl, for the manufacture of a medicament for the treatment of multiple sclerosis.
[33" claim-type="Currently amended] 32. Use of the compound of claim 31 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of multiple sclerosis according to claim 31, wherein Q is NR ⁸ and R ⁸ is C ₁ -C ₄ alkyl.
[34" claim-type="Currently amended] 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-methyl-4-thiazolidinone for the manufacture of a medicament for the treatment of multiple sclerosis; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (dimethylamino) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (methylamino) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3- (2-hydroxyethyl) -4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-amino-4-thiazolidinone; 5-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -3-[(2-hydroxyethyl) amino] -4-thiazolidinone or 4-[[ Use of 3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] methylene] -1,3-oxothiolan-5-one.

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JPH10512883A|1998-12-08|

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EP0722729A2|1996-07-24|

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MX9705557A|1997-10-31|

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EP0722729A3|1997-11-26|

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HU9702293A2|1998-04-28|

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CA2210566A1|1996-08-01|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1995-01-23|Priority to US37660695A

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1995-01-23|Priority to US8/376,606

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1996-01-22|Application filed by 피터 쥐. 스트링거, 일라이 릴리 앤드 캄파니

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1998-05-15|Publication of KR19980701588A

优先权:

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申请号 | 申请日 | 专利标题

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US37660695A| true| 1995-01-23|1995-01-23|

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US8/376,606|1995-01-23|