AU735585B2 - Optically active 1-phenylpyrrolidone derivatives - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): TAIHO PHARMACEUTICAL CO., LTD.

Invention Title: ~~OPTICALLY- ACTIVE 1-PHENYLPYRROL-IDONE

DERIVATIVES

*The' following statement is afull d-esc:ri-pt-ion of-t-his invention, including the best method of perform -ing it known to me/us: 2 OPTICALLY ACTIVE 1-PHENYLPYRROLIDONE DERIVATIVES This application is divided from Patent Number 663233 and the entire disclosure in the specification of the said patent is by this cross-reference incorporated into the present specification.

The present invention relates to optically active derivatives of 1-phenylpyrrolidone useful for treating hyperlipidemia, having an activity to inhibit the synthesis of fatty acids and an activity to inhibit the synthesis of cholesterol.

Background Art 15 Example 9(5) of the specification of EP 393607 discloses a racemic form of the compound of formula (II) oCOOR oooo wherein R' is a hydrogen atom or a lower alkyl group, for example an alkyl group having 1 to 6 carbon atoms.

However, no report has been made on the synthesis of an optically active form of the compound of the formula (II).

Disclosure of the Invention The present inventors discovered that the racemic form of the compound of formula (II) could not be readily resolved by conventional techniques into its optical isomers. As a result, the present inventors conducted extensive research on processes for preparing Sthe optically active form of the compound of the formula 3 (II) and found that a 1-phenylpyrrolidone derivative having optical activity and represented by the formula (I) which is a novel compound undisclosed in literature is useful as an intermediate for preparing the optically active form of the compound of the formula (II), 0 0 (I CO R wherein R represents an optionally substituted 15 optically active a-phenylethylamino group.

The compound of formula and a process for producing optically active isomers of compounds of formula (II) are the subject of Patent No. 663233.

The present invention is based on the discovery that one of the optical isomers of the compound of formula (II) not only exhibits superior suppression of the biosynthesis of cholesterol and fatty acids than the racemic mixture, but also considerably lower toxicity than the racemic mixture.

25 Accordingly, the present invention provides (+)-4-[1-(4-t-butylphenyl)-2-pyrrolidone-4-yl] methoxybenzoic acid, or a lower alkyl ester thereof, represented by the formula (II) 0 N- O COOR' wherein R' is a hydrogen atom or a lower alkyl group.

4 The present invention also provides a pharmaceutical composition for treating hyperlipidemia which includes a compound of the present invention and a pharmaceutically acceptable carrier.

The following example illustrates a method of making the compound of the present invention.

EXAMPLE

Synthesis of (S)-(+)-4-[1-(4-t-butylphenyl)-2pyrrolidone-4-yl]methoxybenzoic acid.

A 5.7 ml quantity of an 8% aqueous solution of sodium hydroxide was added dropwise at 60 0 C to a suspension of 2.18g (5.72 mmol) of methyl t-butylphenyl)-2-pyrrolidone-4-yl]methoxybenzoate

(II)

15 obtained by the method of Reference Example 6 of Australian Patent No. 663233 to obtain the title compound (yield 98%, >99% e.e).

Melting point: 247 0 C-248 0

C

Specific rotation: [a]2 =+27.0(c MASS spectrum (FAB) 366 Elementary analysis (for C22H25N04) C H N Calculated 71.91 6.86 3.81 Found 71.76 6.93 3.60 The overall reaction scheme is depicted in the following chart:a a a a. a a. a a a a a a a. a a a a a a a. a a a *a a a. a aa Reaction,, -Scheme 0 +ON

OH

0 0o R Example 2: (S.S) Example 3: (R.R) 0 0 OH (Ia) Example1 0

OH

I-b) 1O N 1

,_OS

2

CH,

(III')

Reference Example I (S) Reference Example 2(R) Reference Example 3(R) Reference Example 4(S) 0 0 O-OC, 0-0/ l- Reference Example S(R) Reference Exampla 6(S) 00I Reference Example 7(R) Refer'ence Example 8(S) Examples and reference examples are drawn from Australian Patent No. 663233.

The last step in the reaction scheme corresponds with the reaction described in this example, but-with reference only to reference examples 6 and 8.

6 Test Examples The following tests were performed using, as test compounds, (S)-(+)-4-[l-(4-t-butylphenyl)-2pyrrolidone-4-yl]methoxybenzoic acid (the compound of Reference Example 8 of Patent Number 663233: hereinafter referred to as compound"), butylphenyl)-2-pyrrolidone-4-yl]methoxybenzoic acid (hereinafter referred to as compound"), and t-butylphenyl)-2-pyrrolidone-4-yl]methoxybenzoic acid (the compound of Example 9(5) of EP 393607: hereinafter referred to as "racemic compound compound)).

*o*o 1. Efficacy Study Pharmacological test in Zucker fatty rats :i <Method> Zucker (fa/fa) rats (male, 7 months old, body weight: 700 g) after the acclimation were divided into four groups uniform in body weight and serum lipid level. Each of the test compounds was thoroughly

S.

milled and suspended in a 0.5% aqueous solution of hydroxy propyl methyl cellulose (HPMC). Every morning at 9:00, individual body weights were determined and the test drugs were respectively administered orally at a dose of 30 mg/kg/day for one week. The control group 7 similarly received a 0.5% aqueous solution of HPMC only.

During the treatment period, blood was drawn from the tail vein into a capillary blood micro-s.ampling tube and centrifuged to separate the plasma fraction, and using the COBAS FARA II automatic analyzer (manufactured by F. H. HOFFMANN-LA ROCHE lipid parameters were determined by the enzymatic method. The results on day 7 relative to the control group are shown in Table 1. In the table, TG stands for triglyceride, TC for total cholesterol, and PL for phospholipid.

<Results> Table 1 Percent Percent Percent TG TC PL depression depression depression Compound 81.3% 35.1% 38% Compound 52.8% 28.0% 12% Racemic compound compound) 46.5% 20.2% 13%

C

C

C

C

C. CC eq C

S.

In the efficacy evaluation of the data generated by this oral administration for one week to Zucker fatty rats, a model of hereditary obesity, compound showed a blood lipid lowering effect (depression of triglyceride, total cholesterol and phospholipid levels) surpassing the effects of compound and a a. a.

a a 8 racemic compound compound).

2. Safety Study (screening toxicity study) A oral administration test for two weeks in S.D.

rats <Method> After the acclimation for one week, Sprague- Dawley rats (male, 5 weeks old, body weight 150 g) were divided into groups uniform in body weight. Each of the test compounds was uniformly dispersed in a aqueous solution of HPMC. Every morning at 9:00, individual body weights and food consumptions were determined and the drug suspension was administered orally at a dose of 300 mg/kg/day for 2 consecutive weeks. The control group similarly received a aqueous solution of HPMC only.

After 2 weeks of the oral'administration, blood was drawn from the descending vena cava under ether anesthesia and, at the same time, a pathological examination of the organs was performed. Blood biochemical parameters y-GTP y-glutamyl transpeptidase) were determined using the COBAS FARA II automatic analyzer. Assay of lipid in the liver was carried out by the chemical method after extraction of the lipid by the Bligh Dyer method. The .results 9 o

S

Ott.

S

1 9

S

x.

*5 relative to the control group are shown in Table 2.

<Results> Table 2 Blood Intrahepatic biochemical lipid test accumulation (y-GTP) (TG) Compound 0% 0% Compound +251% +182% Racemic compound compound) +72% +99% In the blood biochemical tests performed after 2 weeks of the oral administration, 251% and 72% elevations of y-GTP, which is an indicator of liver disorder, were found in the compound treatment group and the racemic compound treatment group, respectively. In the group to which compound was administered, no change was found in y-GTP, suggesting that it is a highly safe compound. Regarding the intrahepatic TG concentration which is an indicator of fatty liver; 182% and 99% increases were found with compound and racemic compound, respectively, whereas no change was found with compound.

The foregoing results of this screening toxicity study revealed that (.+).compound is a very safe 10 compound.

A oral administration test for two weeks in beagle dogs <Method> Beagle dogs (male, 6 months old, body weight kg) after the acclimation were divided into four groups uniform in blood chemistry parameters. Each of the test compounds was thoroughly milled and filled in gelatin capsule shells. Every morning at 9:00, individual body weights and food consumptions were determined and the capsule was administered orally at a dose of 300 mg/kg/day. The control group similarly received the capsule shell only.

*.During the treatment period, blood was drawn from the forearm vein. After this 2-week repeated 0. administration period, necropsy was performed. Blood

S

biochemical parameters were determined using the COBAS FARA II automatic analyzer. Intrahepatic lipid was determined by the chemical method after extraction of lipid by the Bligh Dyer'method. The results relative to the control group are shown in Tables 3 and 4. It should be noted that the change in body weight is the :change from the initial value the value prior to repeated administration).

-A; >i/

J

S? I- 11 <Results> Change in body weight Table 3 Change in Intrahepatic food lipid consumption accumulation 0010 a* S0..

S

0 0

S

S

a a a a.

S

Compound 0% 0% +149% Compound -19% -63% +2891% Racemic compound compound) -12% -48% +813% Table 4 Percent Percent Percent TG TC PL depression depression depression Compound 39% 72% 72% Compound 31% 48% 41% Racemic compound compound) 16% 63% 57%.

As the result of two-week repeated administration, decreases .in body weight and food consumption were noted in the compound and racemic compound treatment groups but no change was found at all in the compound treatment group.

As to the intrahepatic TG concentration which is an indicator of fatty liver, 2891% and 813% increases 12 compared with the control group were found in the compound treatment group and the racemic compound treatment group, respectively, indicating that both compounds have a very serious side effect. In the compound treatment group, however, only a very slight elevation was found.

In Blood biochemistry, compound showed more remarkable lipid-lowering effects than compound and racemic compound, indicating that (+).compound is superior in efficacy.

It was clear from the above results that compound is a very favorable compound in-efficacy (blood lipid-lowering effect) as well as in safety.

3. Conclusion The above experimental results indicate that compound is more efficacious than compound and racemic compound and, also, is a very safe compound and that it is quite advantageous for drug development to resolve the racemic compound and use compound.

Claims (4)

1. (S)-(+)-4-C1-(4-t-ButylpLenyl)-2-pyrrolidone-4. y1]methoxcybenzoic acid, or a lower alkyl. ester thereof, represented by the formula (11) 00 11 -0 COR wherein R' is a hydrogen atom or a lower alkyl group- (II)

2. Methyl (S)-(+)-4-(l-(4-t-butylpheny1)-2- pyrrolidone-4 -yl] methoxybenzoate.

3. (S)-(.i)-4-(-(4-t-Butylphenyl)-2-pyrrolidone-4- yl Jmethoxybenzoic acid.

4. A pharmaceutical composition for treating hyperlipidemia comprising as an active ingredient (4-t-butylphenyl) -2-pyrrolidone-4- yllmethoxybenzoic acid, or a lower alkyl ester thereof as defined in any one of claims I to 3 in combination with a pharmaceutically acceptable carrier. I4:~tm.O4%[email protected]~da 1/04/97 '4 14 (4-t-butylphenyl) -2-pyrrolidone-4- yl]methoxybenzoic acid, or a lower alkyl ester thereof, represented by the formula (II) 0 1 N K- i_ 0o /COOR' (11) o* o *o o o *"o wherein R' is a hydrogen atom or a lower alkyl group when used for treating hyperlipidemia. Dated this 23rd day of April 2001 TAIHO PHARMACEUTICAL CO., LTD. By their Patent Attorneys GRIFFITH HACK Fellows Institute of Patent and Trade Mark Attorneys of Australia