CA1101874A - Thiophene compounds - Google Patents

Abstract

ABSTRACT

The invention relates to compounds of the formula I

wherein R is aryl, aralkyl, -(CH2)n-R5, and , where R5 is hydroxy or with R6 being hydrogen, lower alkoxy, amino and R7 is lower alkyl, n is an integer from 1-6, R2 is hydrogen, hydroxy, lower alkoxy, or amino; R3 and R4, which may be the same or different, are lower alkyl, aryl, aralkyl, acyl and hydrogen;
and the pharmaceutically acceptable salts thereof, to intermediates for the preparation of these compounds and salts, as well as to a process for the preparation of said compounds, salts and inter-mediates. The compounds of formula I and the salts thereof have antiobesity and blood lipid lowering agents.

Description

~ iLQ~37~ ~
This invention is directed to novel thiophene compounds of the ~ormula COOR \ N~12 ~ S

wherein R is hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof. Compounds: within the scope of formula I are useful as antio~esity and blood lipid lowering agents.
As used throughout this application, the term "lower alkyl" de-notes straight and branched chainr saturated aliphatic alkyl groups having from 1 to 8 carbon atoms, such as methyl, ethyl, propylr isopropyl and the like. The thiophenes of formula I
are obtained by initially reacting a compound of the formula:

HS ~ COOR' III

with a compound of the formula:

~ ~ IV

\ / COOR
~ : :

to form a compound of the formula:
/\ COOP~

J

, ~L~0~37~ ~

wherein R' and Rl are lower alkyl, and R2 iS halogen, mesyloxy and tosyloxy.
The foregoing reaction is carried out in the present of a lower alkanol and an alkali metal alkoxide, preferably : :
methanol. and sod~um methoxide. ~lthough temperature and : .
pressure are not critical, this reaction is generally carried out at atmospheric pressure and temperatures of Erom about - .- :~
15C to about 60C, preferably 25C. :;`
Compound V is then treated with an alkali metal lQ alkoxide, preferably sodium methoxide in the presence of an ~ : ;
aromatic hydrocarbon, preferably benzene to form a compound .
of the formula: ~

~: ' COOR' ~

~ ~ VI

.

where~n R' i.s as defined above. Although temperatures and : :
pressures are not critical, this reaction is generally carried out at atmospheric pressure and a temperature of from about -~
15C to about 60C, preferably 25C.
Compound VI is then transformed to an oxime of the formula:
COOR' ,NOH

:

- 2 -. ~ ' .
. ~

... . . . .

. : .

~0~874 wherein R' is as clefined above.
Any conventional method of preparing an oxime from a keto compound can be used to convert the 4,5-dihydrothiophene of formula VI to the oxime of formula II. Preferably, the 4~5-dihydrotH~ophene is treated with a hydroxylamine hydro-halide, preferably hydroxylamine hydrochloride, in a nitrogen-containing base. In carrying out this reaction, any convention-al nitrogen-containing base can be utilized. The pref~rred nitrogen-containing bases are the amines. Among the amines which can be utilized are the primary amines, such as the loweralkylam~nesr particularly methylamine, ethylamine, and aniline; the secondary amines, such as the diloweralkylamines, particularly dimethylamine and diethylamine, and pyrrole; and the tertiary amines, such as the triloweralkylamines, partic-ularly trimethylamine and triethylamine, pyridine and picoline.
~lso, in carrying out this reaction with a hydroxylamine hydro-halide, temperature and pressure are not critical, and the reaction can be suita~ly carried out at from room temperature to reflux and at atmospheric pressure. Preferably, this reaction is carried out at room temperature (about 22C).
Furtherr thl~s reaction can be carried out in an inert organic solvent. In this reaction any conventional inert organic sol-vent can be utilized, such as the aliphatic or aromatic hydro-carbons, as for example n-hexane or benzene. Preferably, this reaction is carried out in an excess of the nitrogen-containing ~ase, which serves as tHe solvent mediumO
The oxime of formula II is converted to an amine of the formula Ii5 74 COOR' 2 I' .~ ~ ', ., wheréin R' is as above. Thls reaction i5 suitably carried out by treating the oxime with an acid, preferably a hydrohalide, in an inert solvent. This reaction can be carried out prefer-ably by treating the oxime with hydrogen chloride. In carrying out this reaction, any conventional inert solvent can be utilized. Preferably inert organic solvents are the ethers, particularly the dilower alkyl ethers, such as diethyl ether, and the cycl~c ethers, such as tetrahydrofuran and dioxane.
Other solvents that may be employed are lower alkanols and water. In carrying QUt th~is reaction, temperature and pressure are not critical, and th;s reaction can ~e suitably carried out at from 0C to a~out 70C and at atmospheric pressure.
Preferably, this reaction is carried out at room temperature. ~`
Compound I' may be transformed to the corresponding `~
acid. In carrying out this reaction, any conventional method o~ basic hydrolysis can be utiIized. This hydrolys~s can be suitabIy carried out in a conventional inert organic solvent.
The preferred solvents are~the lower alkanols, particularly ~-methanol and ethanolr and the aqueous ether solvents, prefer~
ably thé aqueous dilower alkyl ethers, particularly diethyl ether and the aqueous cyclic ethers, particularly tetrahydro~
furan and dioxane ~n this reaction, any conventional base can be utilized Among the preferred bases are the alkali metal hydroxides, such as sodium, potassium and lithium hydroxide, '. " I

87~L

and the alkaline earth metal hydroxides, such as barium,calcium and magnesium hydroxide r especially the alkali metal hydroxides. In this hydrolysis, temperature and pressure are not critical, and this reaction can be suitably carried out at from about 0C to a~out 100C and at atmospheric pressure.
Preferably, this reaction is carried out at reflux, especially at about 70C.

A solution of 104.95 g (.873 mole) of methyl-3-mercapto-propionate in 200 ml methanol was cooled to 0 and treated with 207.5 g o~ a 25% solut~on of sodium methoxide in methanol. To the resulting homogeneous solution was added dropwise under argon 200.0 g ~.873 mole) of methyl-~-bromo-phenyl acetate in 200 ml methanol. The reaction was stirred at 25 overnight.
The solvent was removed by evaporation, and the residue was partitioned ~etween water and methylene chloride to afford 234.0 g ~100%) o~ 2-phenyl-3-thia-adipic acid dimethyl ester as a colorless oil.
EXAMPLE _ A solution of 234.0 g (.873 mole) of 2-phenyl-3-thia-adipic acid dimethyl ester in 300 ml dry benzene was added dropwise at 25 to 54.05 g (.873 mole~ of sodium methoxide.
The reaction was stirred overnight and poured into water. The sol~d was filtered off and the filtrate was extracted two times with ether. The solid was then added to aqueous phase which ~ `
was then ac~dified to pH 1 ~ith 6N HCl. The mixture was ex-tracted three times with methylene chloride. The organic ex-tracts were dried over sodium sulfate and evaporated--to afford 145.24 g (.615 moler 71%) of 4-carbomethoxy-3-keto-2-phenyl-tetrahydrothiophene as a pale yellow oil.

~L~lJ3L874 :~
. .
, .

A solution of 82.24 g (.348 mole) of 4-carbomethoxy-

3-keto-2-phenyltetrahydrothiophene in 120 ml anhydrous pyridine was treated with 28.85 g (.418 mole) of hydroxylamine hydro-chloride. The solution was stirred at 25 for two days, and the sol~ent was evaporated ln vacuo. The residue was partitioned ~ ~
l~etween lN HCl and methylene chloride. The aqueous phase was ;
further extracted with methylene chloride. The organic ex~
tracts were pooled, dried over sodium sulfate, and evaporated to give 90.0 g ~.319 mole, 92%~ of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene oxime as a colorless oil.

Into a solut;on of 80.0 g (.319 mGle) of 4-carbomethoxy-3-keto-2-phenyltetrahydrothiophene oxime in 600 ml of anhydrous ether was buhbled gaseous hydrogen chloride at 0 for one hour.
The suspension was treated with 300 ml of methanol and stirred at 25 overnignt. The product was collected by filtration and was-hed with ether to yield 70.0 g of 4-amino-5-phenyithio-phene-3-carboxyl~c acid methyl ester hydrochloride as a pale yellow solid, m.p. 181-182. The compound may be recrystallized from methanol.
EX~MPLE 5 A solution of 10.0 g (.0371 mole) of 4-amino-5-phenyl-thiophene-3-carboxylic acid methyl ester hydrochloride in 80 ml methanol was treated with 82 ml of lN sodium hydrochloride (.0816 mole). The reactants were heated under reflux for 30.0 minutes, and cooled to room temperature. The pH was ad]usted to 5 and the product wh~ch separated was fi~tered off and dried to afford 8.2 ~ (100%) of pure 4-amino-5-phenylthiophene-3-carboxylic acid, m.p. 201-202 after recrystallization from ethylacetate/pentane.

~ -- 6 --~ . , ' ~:

8t7~

Example A
Tablet Formulation ~ let Ingredients 250 500

4-Amino-5-phenylthiophen-3-carboxylic methyl ester hydrochloride 250 500 Pregelatinized starch 12.5 25 Modified starch 12.5 25 Magnesium stearate _1.5 3 Ta~let weight 276.5 mg 553 mg PROCESS~
1. Mix compound and both starches, mill and remix well.
2. Granulate with water.
3. Dry overnight.
4. Mill with magnesium stearate and remix.

5. Compress on a suitable punch.
Example B
Capsule Formulation mg/capsule Ingredients 250 500 4~Amino-5-phenylthiophen-3-carboxylic methyl ester hydrochloride 250 500 Cornstarch 25 50 Talc 4 8 Magnesium stearate 1 2 Capsule weight 280 mg 560 mg ~ ;
PROCESS:
1. Mix compound and both starches, mill and remix well.
2. Add talc and magnesium stearate and mix for 5 minutes.
3. Encapsulate in hard-shell capsules.
:

~' ' 87~

Example C
I'ablet Formulation mg/tab:Let Ingredients 250 S00 4-Amino-5-phenylt}liophen-3-carboxylic acid 250 500 Pregelatinized starch 12.5 25 Modified starch 12.5 25 Magnesium stearate 1.5 3 Tablet weight276.5 mg553 mg PROCESS:
1. Mix compound and bo~h starches, mill and remix well.
2. Granulate with water.
3. Dry overnight.
4, Mill with magnesium stearate and remix.
5. Compress on a suitable punch.
Example D
Capsule Formulation ~ mg!capsule Ingredients 250 500 ~-Amino-5-phenyl~hiophen-3-carboxylic acid 250 500 Cornstarch 25 5Q
Talc 4 8 Magnesium stearate 1 2 Capsule weight 280 mg 560 mg PROCESS: ,--1. ~lix the compound with the cornstarch, mill and remix well.
2. Add talc and magnesium stearate and mix for 5 minutes.
3. Encapsulate in hard-shell capsules.

. ~ .
,, . ~ .

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I
wherein R is hydrogen or lower alkyl, and of pharmaceutically acceptable salts thereof, comprising reacting a compound of the formula II
wherein R' is lower alkyl, with an acid and, if desired, hydrolyzing an ob-tained compound of formula I wherein R is lower alkyl with a base.

2. A process according to claim 1, for the preparation of 4-amino-5-phenylthiophene-3-carboxylic acid methyl ester hydrochloride, wherein 4-car-bomethoxy-3-keto-2-phenyl-tetrahydrothiophene oxime is utilized as starting material of formula XI.

3. A process according to claim 1, for the preparation of 4-amino-5-phenylthiophene-3-carboxylic acid, wherein 4-amino-5-phenyl-thiophene-3-carboxylic acid methyl ester hydrochloride is hydrolized with a base.

4. A compound of the formula I

wherein R is hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof, whenever prepared by the process as claimed in claim 1 or by an obvious chemical equivalent thereof.

5. 4-Amino-5-phenylthiophene-3-carboxylic acid methyl ester hydro-chloride, whenever prepared by the process as claimed in claim 2 or by an obvious chemical equivalent thereof.

6. 4-Amino-5-phenylthiophene-3-carboxylic acid, whenever prepared by the process as claimed in claim 3 or by an obvious chemical equivalent thereof.