AU601739B2 - Para-substituted benzoic acid derivatives and methods of manufacture - Google Patents

Description

A,

601739 COMMONWEALTH OF AUSTRALIA FORM PATENTS ACT 1952 COMPLETE SPEC I FICAT ION

I

FOR OFFICE USE: Application Number: Lodged: C This docum!nt contains the amen8dmnt3s( alowed under Sctionl 83 by the Super vising Examlner on and is correct for printing c C Complete Specification Lodged: Accepted: Published: Pr ior ity: a a c 'Related Art: o a a a L r'.

;1 r ;lla rSctrL' for PIS 01A'l (-C P- cc Ga 0 0 a a 0 &o Name of Applicant: 0 Address of Applicant: on o oO 00 000 00 0 0 00 0 Actual Inventor: 00 0o 0 000 KLINGE PHARMA GmbH BERG-AM-LAIM STRABE 129, 8000 MUNCHEN FEDERAL REPUBLIC OF GERMANY HELMUT GRILL; PRIEDEMANN REITER; MICHAEL SCHLIACK; ROLAND LOSER; and KLAUS SEIBEL ,o0,Address for Service: SHELSTON WATERS, 55 Clarence Street, Sydney 0 0000 0 00 "Complete Specification for the Invention entitled: "PARA-SUBSTITUTED BENZOIC ACID DERIVATIVES AND METHODS OF MANUFACTURE" The following statement is a full description of this invertion, including the best method of performing it known to me/us:- 1- LODGED AT SUBOFFIC1 4 J UL 1987 Sydney Numerous agents have been introduced for the treatment of disturbances of lipid metabolism. CLIOFIBRAT was ox:e of the first representatives of the qoup of aryloxy-isoalkane acids. Because of its weak activity a series of derivatives, for example ETOFIBRAT OR ETOFYLLINCLOFIBRAT as well as structural analogs such as BEZAFIBRAT, FENOFIBRAT or GEMFIBROZIL were developed.

However, they resembled CLOFIBRAT with respect to undesirable activities, which led to the conclusion of a similar mechanism of action. Known side effects include gastrointestinal reactions, loss of appetite, nausea, allergic reactions, myositis, myalgia, and impotence as well as increases in serum creatinine, serum urea and the lithogenic index; a lowering of alkaline phosphatase, an increase in creatinine phosphokinase and stimulation of peroxisome formation.

Circumvention of these deficiencies appears to be possible only through the discovery of new agents, based on clearly modified structures which may be expected _o lead to changes in biological properties.

SUMMARY OF THE INVENTION Compounds comprising benzoic acid derivatives of cc C formula (1) CC,' CH CH -X-CH CH CO-R (1) and their physiologically compatible salts, where SR isopropyl, or t-butyl X= i j and R =-OH,or where R 1 may be a straight chain, branched, saturated or unsaturated C to C -alkylmoiety, or a -NHCH COOH- group.

I: i /2 Surprisingly, it has now been found that benzoic acid derivatives of Formula as indicated in claim 1. are clearly superior in hypolipemic activity to BEZAFIBRAT.

This involves para substituted phenylpentanol-or phenylpentanonebenzoic acids which belong to a not previously described series of structures.

Benzoic acid derivatives with ether substituents in the para position, with hypolipemic properties, are known. Among these compounds are ethers of glycerin (DE-PS No. 24 60 689), of 1,3-dihydroxyacetone (DE-OS Ho.

27 35 856) and other alcohols (DE-OS No. 33 26 164; U.,.3 Pat. No. 4,067,892; U.S. Pat. No. 4,154,850). Because of the ether function, alterations in biological properties S must be expected.

The preparation of these new hypolipidemically active compounds can be carried out by known procedures, using the process set forth below.

cc The starting materials needed for the synthesis of the compounds according to this invention can be prepared by the following procedures.

SC a 00 o 0 00a o o 0 0 0 0 a a f c 9 C a I f C C C C C f f 2a J Condensation of acetone with aldehydes of the general formula (7) R -CHO where RI has the meaning indicated in Claim I yields benzalacetonides of general formula (8) R1- 3

>-CHCH--CH

3 nece CC C C CC C C C C C CC

.AQ

CC

C C C C C

CQ

ect C C

C

C C C C C C C CC C CC

(C

C,

(CCC

o C 00 a 00000C 0 a Reaction with 4-formylbenzoic acid alkylester of general formula (9) OHC- -COOR' where R' has the meaning indicated in Claim 1, leads to 1,4pentadienones of general formula (2)

R

1 >-CH=CH-q-CH=CH- >-COOR' 0 which can be selectively reduced with benzylalcohol in the presence of Tris(triphenylphophin) ruthenium-II-chloride to compounds of general formula according to the invention

R

1 -O -CH 2

CH

2

-C-CH

2

CH

2 c-COOR' (3) 0 By alkaline s-ponification followed by acidification with mineral acid one obtains the compounds of general formula to the invention.

R

1

-CH

2

CH

2 -q-CHCH -C00H 0 -3-

I'

Compounds of general formula can be reduced in the cold with sodium borohydride to compounds of the invention with general formula (4)

R

1 cCHCH- H-CH 2 CH -COOR' (4) S OH and converted, by alkaline saponification followed by acidification with mineral acid, to the acids of the invention with general formula (11).

CC1cC R

L

-CH

2

CH

2

H-CH

2

CH

2 -COOH (11) c ce C 2 2 9H 2 2 c C c c 0 -a Reaction with acetylchloride yields compounds with general C c formula (12) C C

R

l CH2-qH-CH CH2- F -COC1 (12)

OCOCH

3 C C which can be converted to acid chlorides with general formula (13) by reaction with thionylchloride R* -C H CH -H-CH CH- -COCl (13) a a 2 2 2cCH 2 -k- 3 Compounds according to this invention with general formula (14) are obtained by reaction with sodium glycinate followed by alkaline saponification, and acidification with mineral acid.

C C* trc c R -CH 2

CH

2 -9H-CIHCH 2 -CONHCH COOH (14)

OH

4

~I~

Compounds with general formulas and (14) are converted to compounds according to this invention with general formula (15) by selective oxidation with dimethylsulfoxide.

R

1

O

CH

2

CH

2 -8-CH 2

CH

2

-CO-R

2 where R 1 has the meaning indicated above and R 2 is -OH or -OR', o°01o The superiority of the claimed compounds over BEZAFIBRAT, which o was introduced to therapy a long time ago, can clearly be o 0 o demonstrated by the lipid lowering activity.

OO

0o %o Lipid lowering activity was evaluated in normolipemic, male a Wistar rats, 10 per group, weighing between 200 and 220 grams.

0 0 o 0 0 oo The tests were carried out after three weeks of retraining the ooo animals to new feeding habits. Controlled feeding took place daily from 10.00 to 12.00 o'clock. Administration of test materials took place at 11.00 o'clock.

The test compounds were taken up in an aqueous solution of 0.25% 0o2o, agar and 0.84% sodium chloride and administered orally. Blood samples were removed from the animals after administration of oo0o 3 x 100mg/kg over a three day time period.

0o Cholesterol and triglyceride determinations were carried out with a Hoffman-LaRoche "Cobas Bio" centrifugal analyzer.

Methods: a) Cholesterol determination CHOD-PAP-method; colorimetric enzyme assay according to oe J.Siedel at al Clin. Chem. Clin, Biochem. 12,838 (1981)1 b) Triglyceride determination Enzymatic cleavage of triglycerides with special lipases followed by enzymatic determination of the liberated glycerin. [H.U.Bergmeyer, "Methods of enzymatic analysis", 3rd edition, Vol II, Verlag Chemie, Weinheim, 1974, page 1878] i 5 i TABLE Ib Percent change in total cholesterol(TC) and triglyceride(TG) levels in rat serum after oral administration of test materials Comnnound lamber %Change TO TG ox x x h S 0004 comparison compound BEZAFIBRAT -22.3 15.8 +6.1 9.9 0 a 0 aS 00 OU 2 -29.0 h 10.8 -42.6 12.8 0 3 -26.1 17.2 -21.9 11.5 0 4 -26.3 13.9 -42.0 S5 -17.6 15.0 -37.4 12.7 0 0 ~6 -9.1 ±5.6 -25.3 :k 20.4 7 -35.1 9,7 -31.3 13.0 t e 8 -23.1 13,1 -38,5 13.0 9 -35.6 20.9 -64.6 15.8 0 0o0c 10 -15.4 10.7 -31.3 25.6 2,11 -26,1 7.2 -35.4 14.7 13- 6.9 21.7 -15.7 14.8 14 -24.8 18.4 -45.4 12.4 -28.0 7,7 -20. 1 -6- For therapeutic use as hypolipemic agents the new compounds with general formula and their salts, are preferably administered orally. Generally the daily oral dose for adults is 0.1 to 1 gram.

For oral administration the agents can be compounded in the usual galenic fashion. Adjuvants such as lactose, sugars, mannitol, potato or cornstarch, cellulose derivatives or gelatin are suitable as pharmaceutical carriers, occasionally with addition of lu~ric( 5_ such as magnesium- or calcium stearate, as well as polyethylene glycols.

Preferred dosage forms are herd gelatin "steck"capsules as well as closed soft gelatin capsules. The liberation of the claimed compounds can be accilerated or slowed according to the pharmaceutical compounding.

a Cc9 The steck"capsules can contain pure agent, or possibly a so samll addition of a When compounded into soft gelatin capsules the pure agent can be dissolved or suspended in appropriate liquids, for example in liquid polyethylene *o glycols or vegetable oils. Agents with appropriate physical properties are preferably prepared as granules.

The synthetic steps are carried out by known procedures, w)ich are described below in several examples.

0 ccC 0c cc c CCc cc c 0c cc 414, JCaJ 000 c a ov* I 1 1 EXample 1 4-F 5-(4'-Tsopropvlphenv)-3-oxopentyllbenzoic acid methyl ester a) 4-r5-(4'-isopropylphenvi)-3-oxo-1.4-pentadienvllbenzoic acid methyly gategr 94.1 g (0.50 Mol) 4--isopropylbenzalacetone and 91.8 g (0.56 Mol) 4-formylbenzoic acid methyl ester were dissolved in 500 mL methanol under nitrogen and reacted, with stirring, with 45 mL 2N sodium hydroxide within 5 minutes, After one hour mL 2N sodium hydroxide is added, and stirring continued for an additional three hours. The separated product is removed by suction, washed to neutrality with cold methanol, and CC'C recrystallized from 675 mL methanol with addition of 70 mL 1) CaCC ethylacetate. Pale yellow crystals, melting point 113-115 C aC""C Yield 84.9 g 0 C 0 1 H-NMR- spectrum (CDC13)2): 1.27 d (CH3 2" 00 3.93 m (CH 3)2 3.93 s CH 0 6.80 to 8.2 m (12) a omatic,4 =C1- 00 0a S 1) Melting points were determined with a Kofler-Hotstage- Microscope and were not corrected 2) Determined at 60 MHz Ooi C The chemical shifts are given in ppm versus TMS the relative intensities are added in parentheses. a singlet, d doublet, t triplet, q quartet, m multiplet.

cc C C c CCCCC0 8 r~-p----ollYlra~- -u b)Preparation, according t. thg invention, of 4-15-(4 -isopropylphenyl-3-oxopentyl1benzoic acid methyl e 33.4 g (0.10 Mol) 4-[5-(4'-isopropylphenyl)-3-oxo-l,4pentadienyllbenzoic acid methyl ester are dissolved in 40 mL (0.385 Mol) benzylalcohol, reacted with 0.20 g (0.2 mMol) Tris(triphenylphosphin)ruthenium(II)-chloride under nitrogenr and heated for two houre in an aircooler under a slow stream of nitrogen at 190-200 'C (bath temperature). Subsequently the benzaldehyde formed, together with the remaining benzylalcohol, is removed under vacuum and, to complete the reducti 8 n, the residue is heated for an additional two hours at 190-200 C (bath temperature) under nitrogen with 30 mL fresh benzylalcohol and 0.15 g cataXst. The volatile components are then removed at 0.1 mbar and 100 C (bath temperature) and the reddish brown oily residue taken up in dichloromethane. After column chromatographic purification on silica gel with dichloromethane, the solvent is remoged in a vacuum and the residue distilled at 0.03 mbar and 225C in a qherical tube heater. Colorless oil with refractive index of n 1.5445. Yield 11.2 g C22 2603 (338.4) Molwt. 338 (determined via mass spectrometry)x IR-spectrum (film) 9(C=O) 1720, 1710 cml H-NMR-spectrum (CDC1 3 1.20 s (Cf 3 2 ca 2.47 to 3.13 m 2 ArCJ C1i 2 3.9 s OC3 6.93 to 8.10 m aromatic with electron pulse ionization (70 eV) -9- 110 Example 2 4- 5-(4'-isoprpylphenyl)-3-hydroxvyentyl benzoic acid 34.0 g (0.10 mol) crude 4-[5-(4'-isopropylphenyl)-3-oxopentyl]benzoic acid methyl ester, prepared according to Example 1, are dissolved in 100 mL ethanol and slowly reacted at 0-10 C with an ice cold solution of 2.0 g (0.053 Mol) sodium borohydride in 10 mL water. After tje addition is complete the coolant is removed and the reaction mixture stirred for 2.5 hours at room temperature. 13 g Potassium hydroxide are then added, stirring is continued for an additional 3 hours at room temperature and the mix allowed to stand overnight. After dilution of the reaction mixture with water, it is extracted twice with ether, the aqueous phase is acidified with concentrated hydrochloric acid, and the separated product taken Scc up in ethyl acetate. The product is washed with water until feo Q neutral, dried over sodium sulfate, and the solvent removed in oo o vacuo. The residue is purified chromatographically, using silica o'oo gel and CH Cl /CH OH After removal of the solvent it is Soo, crystallizeo from acetonitrile. Colorless crystals, 0° 20 m.p.104-106 C. Yield 12.7 g. 00 o00 0 0 0 o°

C

21

H

26 0 3 (326.4) 0 0 0 000 mol. wt. 326 via mass spectrometry) -1 IR-spectrum (KBr) 3500 to 2400 cm 00 °o 1685 cm 0 00 0 00 00 0 0 00 0 00 000 1.23 d C3) 2CH 1.57 to 2.07 m 2 ArCH 2

CH

2 i. 2.50 to 3.03 n 2 ArCH2CH 2 and o (CH3 )2CH ooooe 3.67 m CH(OH) 0 C 6.67 wide s OL, COOKi 7.03 to 8.13 m aromatic u ILbl Example 4-15-(4'-tert.butylphenyl-3-hydroxypentvy11benzo acid isoro 34.0 g (0.10 Mol) 4-[5-(4'-tert.butyl )-3-hydroxypentyl benzoic acid, prepared analogously to examples 1 and 2 is refluxed for 20 hours in 300 mL isopropanal and 5 mL concentrated sulfuric acid. After cooling, the reaction mixture is poured into ice water and shaken with dichloromethane. The organic phase is washed with water, then with an aqueous sodium bicarbonate solution, and finally washed to neutrality with water. After drying over sodium sulfate, the solvent is removed in vacuo and the colorless residue purified chromatographically on silica gel with CH C1 /CH OH After removal of the solvent in vasuo, the pr dut is crystallized from petr 8 leum ether (40-60 C fraction). Colorless crystals, m.p. 47-48 C, yield 18.4 g. C25H3403 (382.5) Mol. wt.: 382 via mass spectrometry) -1 IR-spectrum (KBr) P(OH) 3600 to 2800 cm 1720 cm 1 H-NMR-spectrum (CDC13): 1.30 s (C 3 3

C

cc 1,33 d (CJ'3)2CHO 1,53 to 2.07 m 2ArCH2CH, and O (exchangeable with D 2 0) 2.50 to 3.00 m 2ArCI 2

CH

2 3.60 m Cl(OH) cc.c 5.23 m (OCH 3 6.53 to 8.10 m aromatic 11 n. ,i r\ nln 2 S :p~ 0) S 0* 'IEe 0 .5 .0m~le IA o O, v 0 0 0 0 00 0 0 N-Carboxyrnthyl-4- 5- (4 '-ter t. bu tyliphenyl y r6Xyp 4 6 l nz aVid a) 4-5-(4tert butyhenv)--3-acetoxYPto llbzfl.e x 34.0 g (0.10 Mol) (4 1 te t.bu ylphe nyl) oxyge3t2" benzoic acid and 0,30 g (2.2 mMol) anhydrous zina aholoxide apa suspended in 50 mb glacial acetic acid and reacted ,wjth 14 4?t t (0.20 Mol) acetyichloride, resulting in a clear solutv.,, KZ'teg stirring at room temperature for two hours the reaction Vj%,tare is poured into ice water. The separated product, Is itgken i up i chloroform and washed with water. After c.Iryinq i over =,dim sulfate the solvent is removed in vacuo and th eclexlss crystallizable crude product used for further ieotn wihu purification. Crude yield 38.3 g (100% 0000 9 9 0 ;D 0000 09 0 0 004 0 00 0n o020 00 00 0 090 1 H-NMR-spectrum (CDC1 3 1.30 S (9) 1.63 to 2.1 3 (7 2.0s S 2,37 to 2.90 M (4) 4.97 m (I) 6.83 to 8.XG :M 2 ArCH 2 an Cai 3 co 2 ArClkcB1 2 0

C

0 '9 9 99g 11 a3 wide S M2' 9 0 C Ce

I.

0 9 9 g a i

PZ

.JU

O

i

I

4 4 9 .4 jr b ggqdnt ptmiveto,2 N-pr oymehy -4-f 5- (4 -tert .butv1ihg J-3-hydroxypentyl.

38.3 g (0.10 Mol) crude (4-tert.butylphenyl)-3-acetoxypentyllbenzoic acid and 12 ML (0.165 Mol) thionyichioride i~n 200 ML toluene are heated unler reflux for 3.5 hours.

Solvent and excess thionyichioride are distilled off under vacuum and the oily residue taken up in 250 ML dry dioxane. This 0 solution is added dropwise with vigorous stirring at 5 to 7 C to a solution of 29.6 g (0,30 Mol) glycine and 15.6 g (0.39 Mol) I sodium hydroxide in 350 mL water, stirred three hours at room temperature and left to stand overnight. 20 g sodium hydroxide are then added and stirred an additional 3.5 hours at room temperature. Finally the reaction mixture is diluted with water and, after acidification with concentrated hydrochloric acid, the precipitated end product is taken up in ethyl acetate, After two washings the organic phase is dried over sodium sulfate, the solvent removed in vacuo and the residue 0 crystallized from acetonitrile. Colorless crystals, m.p.133-13 1 0 yield 32.2 g (81W.).

C 24

H

31 NO 4 (397,5) oMol. wt. 397 (via mass spectrometry) XR-spectrum VOWH 3600 to 2400 cm-1 'I 172 5 cm 1 (NH) $360 cm- 1 H-NMR-spectrum 6 acetone): 1.23 s (CkII 3 3

C

1.57 to 2.03 m 2 ArCH 2

R

2 2.50 to 3.03 m 2 ArCli CH 2 3.60 m Cli (OH) 4,10 4.20 2 s(2) NCH 2 6.47 to 8.17 m (11) aromatic, Nli, 0OH, COOkI -13- _II~ I_ Further compounds of general formula 1 were prepared by methods analogous to those described in the examples and are listed, together with their melting points, in the following table.

Table 2 R -CH CH 2 X-CH CH 2

_CO

Sle XX Nr. R X Rm..(oc) solvent X 1 H 2 3 4 o C44 6 00 8 a oP o a C 9 00Q 00 o 1' 11 12 000, 12 13 14 15 (icis anc 0 C (CH 2

CH

(CH3)3 C

H

H

(CH3)4,

CH

(CH3), CH

(CH

3 3

C

(:CH3 3 CB (Onj C

H

H

(0113)2z CH ;clFI,

C

CO

CO

CO

CHO

CHOH

CHO$

CHOH

011011

CHOH

CHOH

CO

011011

CHO

01OH OCH3

OH

OCH)

OH

00H. CHL.CH,

OH

OCE(,CH=CHZ

OH

OCH CH3 OCH(C 1)2

NHCHCOO

NHCH

2

COOH

NHCH02COH

NHCHCOOH

obtained with 140-141 (a) 2.5 XXX n D 1.544 5(oil) 139-140 (fI 47-48 (d) 99-100 (a) 48-49 (b) 104-106 (a) 55-56 (d) 122-123 (a) 46-47 (d) 47-48 (d) 126-128 (a) 97-99 (C) 116-119 (e) 133-135 (a) a Kofler-Hotstage-M4croscope 4elting points were I are not corrected xx) crystallized from: a, acetonitrile b, l-chlorobtane/petroleum ether (40-60) c, ethylacetate/diisopropylether d, petrolewn ether (40-60) e, acetortitri /chloroform f, l-chlorobutane xxx) boiling point 22500/0.03 mbar 14 i~-hYI -PC I ibYhi ~-ii~C~ 4[5-(4 -isoropvliphenyl-3-oxopentyl1bezoi acid methlester fontaining pharmaceutical Premation 400 g 4-[5-(4'-isopropylphenyl)-3-oxopentyl]benzo ic ester are mixed with 200 g polyethylene glycol and, the procedure of Scherer, filled into one thousand capsules, each containing 400 mg active.

acid methyl according to soft gelatin crc 10 6 ce cc c o cI Bc c* aI 0 C 00

C

a ocic ccc 00 0 Ofi o 0.

J i U ~f 0) 0 0 c' QCiC 5--(4'-tert.butyliPhenv l-3-hydroxvpentvllbenzoic AgO containins pharmaceutical Preparation 500 g 4-[5-(4-tert.butylphenyl)-3-hydroxypentyl)benzoic are finely pulverized and then mixed with talc and stearate; after thorough mixing they are filled into two hard gelatin oapsules, so that each capsule contains 250 active.

acid calcium thousand mg

CC

C C C j 15

Claims (3)

1. Benzoic acid derivatives of general formula (1) Rl-- CH2CH -X-CH2CH,-- VCO-R2 (1) 2 and their physiologically compatible salts, where R' H, isopropyl, or t-butyl X and OH R

2 -OH, or OR', where R' may be straight chain, o0 branched, saturated or unsaturated C to C an~ 1

3 Salkylmoiety, or a -NHCH COOH group. 0 2 0 a o c 2. A pharmaceutical composition comprising a compound 00 o0 o cc according to Claim 1, in a pharmaceutically acceptable solvent or carrier. DATED this 4th day of June, 1990 S°KLINGE PHARMA GmbH Attorney: IAN T. ERNST j Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS 0 -16-