MC1417A1 - TETRASUBSTITUTED BENZENE DERIVATIVES - Google Patents

Description

1

The present invention relates to new tetra-substituted benzene compounds, a process for their preparation and the antiviral agents which contain them.

More particularly, the invention relates to new tetra-substituted benzene compounds of formula where X represents an oxygen or sulfur atom or a hydroxyimino; Y represents a methylene or an imino;

1

R represents a hydroxy, a phosphonooxy, a glycosyloxy,

an acylated glycosyloxy, an acyloxy or an alkaxycarbonyloxy

2,

inferior; R represents a lower alkoxy, an alkenyloxy

3

inferior, or a lower alkyl-thio; R represented a

4 -

lower alkoxy; R represents a lower alkoxy, a p-lower alkoxybenzoyl, or a substituted or unsubstituted phenyl, benzyl, pyridylmethyl, furfuryl, tetrahydrofurfuryl, thenyl, tetrahydrothenyl, pyrrolylmethyl, pyrrolinylmethyl, or pyrrolidinylmethyl group; with the

- . . 4

Note that when R represents an alkyl, a phenyl,

a substituted phenyl, a benzyl, or a p-hydroxybenzyl,

Y does not represent a methylene radical; and with the

- . . , 4

Further clarification that when R represents a p-

2 3

methoxybenzyl and Y represent methylene, R and R are different,

and their pharmaceutically acceptable salts.

Preferred examples of glycosyloxy and acylated glycosyloxy are α-Q-glucopyranosyloxy and tetra-O-acetyl-α-D-glucopyranosyloxy. Acyloxy radicals are preferably derived from aliphatic acids containing 2

2

10

1 5

20

25

to 18 carbon atoms or aromatic di-acids, the preferred acyloxy radicals being acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, stearoyloxy, and benzoyloxy. Lower alkoxycarbonyl-oxy radicals preferably contain up to 7 carbon atoms, a preferred alkoxycarbonyloxy radical being ethoxycarbonyloxy. Lower alkoxy radicals preferably contain from 1 to 6 carbon atoms, particularly from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, or butoxy. Lower alkoxyl-thio radicals preferably contain from 1 to 6 carbon atoms, particularly from 1 to 4 carbon atoms, such as methylthio. Lower alkoxy radicals preferably contain 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and butyl. Lower alkenyloxy radicals preferably contain 2 to 7 carbon atoms, especially 2 to 4 carbon atoms, such as allyloxy and 3-methyl-2-propenyloxy. Preferred examples of substituted phenyl, benzyl, and pyridylmethyl radicals are lower alkoxy-phenyls such as p-methoxyphenyl; Benzyl, which is substituted by one or more substituents such as hydroxyl, halogen, lower alkyl, lower alkoxy, lower alkyl-thio, amino, dialcoylamino, allyloxy, benzyloxy, and alkoylenedioxy, in particular p-hydroxybenzyl, m-hydroxy-p-methoxybenzyl, p-chlorobenzyl, p-methylbenzyl, p-methoxybenzyl, m-methoxybenzyl, m,p-dimethoxybenzyl, p-butoxybenzyl, p-C-methylthiobenzyl, p-C-dimethylaminobenzyl, p-Callyloxybenzyl, p-C-benzyloxybenzyl, and m,p-Cmethylenedioxybenzyl. An exemplary pyridylmethyl radical is 4-pyridylmethyl. Preferred examples of substituted furfuryl, thenyl, and pyrrolylmethyl radicals and their saturated derivatives are furfuryl, 5-methyl-

3

Furfuryl, tetrahydro-5-methylfurfuryl, 2-thenyl,

tetrahydro-2-thenyl, and 2-pyrrolylmethyl.

A preferred group of compounds with formula I is 2

consists of those where R is a lower alkoxy or a

13 4

5 lower alkyl-thio and R, R, R, X and Y are as defined above.

Compounds with formula I are also preferred

1

where R is a hydroxy, a lower alkanoyloxy, a benzoyloxy, a phosphonooxy, a lower alkoxycarbonyloxy;

2„ ,

10R is a lower alkoxy or a lower alkenyloxy;

3 4

R is a lower alkoxy; R is a substituted phenyl;

and X is an oxygen or sulfur atom and Y is a methylene or an imino, especially those where Y is an imino'. Particularly interesting compounds are 1 5 4-ethoxy-2-hydroxy-S-methoxy-N-[p-methoxybenzyl]-benzamide, the diacid phosphate of 2-(Cp-anisylamino3carbony1]]-5-ethoxy-3-methoxyphenyl and its disodium salt.

According to the process provided by the invention, the new tetrasubstituted benzene compounds 20 of formula I and their pharmaceutically acceptable salts are prepared

Ca] by hydrogenating a compound of general formula

II

25

12 3 4

where X, R, R i R and R are such as defined in formula I,

in the presence of a catalyst in a solvent, or

[bj by reacting a reactive derivative of a carboxylic acid with the general formula

CCOH

R

1 i

2 3

where R and R are as defined in formula I and R represents a protected hydroxyl radical,

with a compound of general formula

R - NHp

IV

where R is such that defined in formula I,

then by removing the protective fraction of the protected hydroxyl radical, or

This] by reacting an acetophenone of general formula

V

1 H 3

or Fi, R and R are such as defined in formula I, with iodine in a tertiary amine and by reacting a resulting salt with an amine of formula IV above, or

Cd] by submitting an ester of general formula

2 3 4

where R, R and R are as defined in formula I, to a transposition in the presence of a base in a solvent, or

[e] by reacting a ketone with general formula

R"

.VII

2 3 4

where R, R and R are as defined in formula I, with a hydroxylamine salt in a solvent,

[Cf] by reacting a carbonyl compound of general formula

R2

VIII

2 3 4

10 where Y, R, R and R are as defined in formula I, with phosphorus pentasulfide in the presence of a base in a solvent, or

CgD by reacting a phenol of general formula

R'

IX

R'

OH X'

2 3 4

15 where Y, R, R and R are as defined in formula I and X' represents an oxygen or sulfur atom,

with an acylant agent in the presence of a base, or

'*N

6

10

[h] by reacting a phenol of Formula IX above with phosphorus oxychloride or dibenzyl phosphorochloridate in the presence of a base in a solvent, then proceeding with hydrolysis or hydrogenolysis as appropriate, and, if necessary, transforming the resulting compound into a se, or

Ci] by reacting a phenol of formula IX above with a glycosyl halide which can be acylated in the presence of a catalyst in a solvent and then, if necessary, by removing the acyl radicals.

L-'.,hydrogenation according to embodiment Ca] of the process can be carried out by treating a compound of formula II with hydrogen in the presence of a catalyst such as palladium black, palladium on carbon, etc., in a solvent such as chloroform.

The reaction according to embodiment Cb of the process can be carried out by reacting a reactive derivative of a carboxylic acid of formula III with an amine of formula CIV and then removing the protective fraction of the protected hydroxyl radical in the resulting compound. Preferred examples of such reactive derivatives of carboxylic acids of formula III are acyl halides such as acyl chlorides, acyl bromides, etc., and active esters such as N-hydroxysuccinimidester, p-nitrophenyl ester, etc. The removal of the protective fraction of the protected hydroxyl radical can be carried out by a conventional method.

The reaction according to embodiment Ce] of the process is a novel reaction. In carrying out this reaction, an acetophenone of formula V is reacted with iodine in a tertiary amine such as pyridine, lutidine, etc., at a high temperature, and then a salt obtained is reacted with an amine of formula IV.

Base-catalyzed transposition according to embodiment Cd] of the process can be carried out in

20

25

30

35

7

subjecting an ester of formula VI to a transposition in the presence of a base such as potassium carbonate, sodium hydride, sodium amide, etc., in a solvent such as benzene, toluene, tetrahydrofuran, 5-dioxane, etc.

Oxidation according to embodiment [e] of the process can be carried out by reacting a ketone of formula VII with a hydroxylamine salt in a solvent such as dimethyl sulfoxide.

10 The reaction according to embodiment CfO of the process can be carried out by reacting a carbonyl compound of formula VIII with phosphorus pentasulfide in the presence of a base such as triethylamine in a solvent such as carbon disulfide.

The acylation of the hydroxyl radical in a phenol of formula IX according to embodiment [g] of the process can be carried out conventionally by treatment with an acylizing agent such as acetic anhydride, ethoxycarbonyl chloride, stearic anhydride, 20-benzoyl chloride, etc., in the presence of a base such as sodium acetate, pyridine, triethylamine, 4-C-dimethylaminopyridine, etc.

The phosphorylation of the hydroxyl radical in a phenol of formula IX according to embodiment Ch} of the 25th process can be carried out conventionally by treatment with phosphorus oxychloride or dibenzylphosphorochloridate in the presence of a base such as triethylamine, N,N-diisopropylamine, etc., in a solvent such as benzene, toluene, triethylamine, etc. When phosphorus oxychloride is used, the resulting compound is hydrolyzed. When dibenzylphosphorochloridate is used, the compound obtained is subject to hydrogenolysis. The phosphate of a compound of formula IX thus obtained can be transformed into a salt by a conventional process.

■s

B

The glyceosylation of the hydroxyl radical in a phenol of formula IX according to embodiment Ci] of the process can be carried out conventionally by treatment with a glycosyl halide in which the hydroxyl radicals are protected by radicals such as acetyl, benzyl, etc. Preferred glycosyls are glucosyl, mannosyl, glucosaminyl, etc.

The compounds of formula I provided by the invention exhibit antiviral activity and, in particular, inhibit the replication of human rhinoviruses in Heia cell cultures at 0.001 to 2.7 yg/ml.

The invention also relates to antiviral agents containing a compound of formula I or one of its pharmaceutically acceptable salts. Compounds of formula I are particularly effective against certain viruses of the Picorna group. However, the following compounds have particularly strong antiviral activity:

_ 9

1-(4-Ethoxy-2-hydroxy-6-rnetboxyphenyl)-3-(4-methoxy-phenyl)-1-propanone, ,

5-ethoxy-3-methoxy--2-[3-(p-methoxypheny1)-propionyl]phenyl-acetate, 5 • '4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxy-berizyl)benzamide,

2-hydroxy-4,6-dimethoxy-N-[p-(methylthio)benzyl]-benzamide,

2-{/ [p-(allyloxy)benzyl]amino_7carbony1}-3,5-10 -dimethoxyphenyl-benzoate,

1- (4-ethoxy-2-hydroxy-6-methoxypheny 1)'-3--(4-methoxyphenyl)-1-propanethione,

5-ethoxy-3-methoxy-2-[3-(4-methoxyphenyl)-propionyl]phenyl—ethyl-carbonate,

15 diacid phosphate of ci — C Cp-enisylaminol carbonylD—

5-ethoxy-3-methoxyphenyl

2- [(p-anisylamino) carbonyl] -5-e'thoxy--3-methoxyphenyl-phosphate disodium,

2-hydroxy-6-methoxy-4-propoxy-N-(p-methoxybenzyl) 20 benzamide,

4-(allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxybenzyl) benzamide,

2-hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-methoxybenzyl)benzamide 25 2-[(p-anisylamino)carbonyl ] -3-methoxy-

Disodium 5-propoxyphenyl phosphate.

10

Antiviral activity

We mix a suspension of HeLa cells

4 3

[6 x 10⁻¹⁰ D with HGP rhinovirus [3 x 10⁻¹⁰ plate-forming units, PFU] is loaded onto a microexperimental plate containing the serially diluted compounds to be tested. The cells are then cultured with Eagle's minimum essential medium containing 2% calf serum, 1% tryptose phosphate broth, 100 µg/ml streptomycin, and 20 units/ml penicillin G. The viral cytopathogenic effect (CPE) and cytotoxicity are observed under the microscope after 2 days of culture at 33°C. The antiviral activity (IC₁₀g³) of the experimental compounds is expressed as the concentration inhibiting viral cytopathogenic effect by 50% when compared with the control culture. Cytotoxicity is expressed as the minimum concentration at which toxic symptoms are observed (cytotoxic dose).

The results given in Table 1 show that the compounds provided by the invention exhibit anti-rhinovirus activity at concentrations that are 10 to 10,000 times lower than their cytotoxic dose.

In addition, Table 2 gives the antiviral spectra of 1-C4-ethoxy-2-hydroxy-6-methoxyphenyl3-3-[4-methoxyphenylD-1-propanone [compound A] and 4-ethoxy-2-hydroxy-S-methoxy-N-[p-methoxybenzyl3-benzamide [compound B] against various rhinovirus serotypes.

Table at 1

Compound .

CI

50

(Mg/nU)

i

Cytotoxicity (pg/mi)

1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-[3,4-(methylene-dioxy)phenyl]-1-propanone

0.03 - 0.1

>8

1- (2-Hydroxy-4, 6-dime't.hoxy-phdnyl)-3-[4-methylthio)-phenyl]-1-propanone

0.01 - 0.03

8

1- (2-Hydroxy-4,6-dimethylphenyl)-3-(4-methylphenyl)-1-propanone

0.01 - 0.03

>8

1-(4-Ethoxy-2-hydroxy-6--methoxypheny1)-3-(4--me'thoxyphenyl)-1-propanone

5-Ethoxy-3-methoxy-2-[3-(p-) diacid phosphate

-methoxyphenyl)propionyl]-

phenyl - .

0.002 0.3 - 0.8

>8 . >10

5-Ethoxy-3-methoxy-2-[3-(p--methoxyphenyl)propionyl]-phenyl-acetate

0.001

>8

1- (2-Hydroxy-4, 6-dime'thoxy-phenyl)-3-(4-methoxyphenyl)--1-propanone-oxime (iBDmer 2

n°>03

>10

1-(2-Hydroxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone-oxime (isomer)

0.3 - 0.9 E]

>10

2-Hydroxy-4,6-dimethoxy--N-(p-methoxybenzyl)-benzamide

0.002

• 8

3-(4-Chlorophenyl)-1-(2--hydroxy-4,6-dimethoxy-phenyl)-1-propanone

0.1

10

Table 1

Çsui te]

Compo s®

CI

50

( |jg/m£)

Cytotoxicity (pg/m³)

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(5-methyl-2-furyl) -1-propanone

0.9

>8

1-(2-Ethoxy-6-hydroxy-4--methoxyphenyl)-3-(4--methoxyphenyl)-1--propanone

0.01 - 0.03

0.9

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxyphenyl)--1z3-propanedione

0.01 - 0.03

8

1- (2-Hydroxy-6-methoxy-4--propoxyph^nyl)-3-(4--ip^thoxyphenyl) -1--propanone

0.004 - 0.01

2.7

1-(2-Hydroxy-4~isopropoxy--6-methoxyphenyl)-3-(4--meTth oxy phenyl) -1-propanone

0.03 - 0.1

8

4-Ethoxy-2-hydroxy-6--methoxy-N-(p-md'thoxy-benzyl)benzamide

0.002

>10

1- (2-Hydroxy-4,6-dimethoxy-phenyl)-3-(tetrahydro-5--me>thyl-2-furyl) -1--propanone

0.9

>8

2-Hydroxy-4,6-dimethoxy-N-- (4-methoxyphenyl)benzamide

0.03 - 0.1

>10

N-Benzyl-2-hydroxy-4,6--dimethoxy benzamide i

!

t

0.03 - 0.1

>8

_ 13 _

Table 1 [continued]

compound

CI

50

(ng/m2. )

Cytotoxicity (ng/ms)

2-Hydroxy-4,6-dimethoxy--N-[m,p-(methylenedioxy)benzyl]benzamide

0.003 - o,or

>8

2-Hydroxy-4,6-dimethoxy--N-(m-methoxybenzyl)-benzamide

0^002

>8

2-Hydroxy-4,6-dimethylbenzyl-N-(p-methylbenzyl)benzamide

0.01 - 0.03

8

N-(p-Chlorobenzyl)-2--hydroxy-4,6-dimethoxy-benzamide

0.01 - 0.03

(n / A

N-Furfuryl-2-hydroxy-4,6--dim^thoxybenzamide

0.03 - 0.1

>8

2-Hydroxy-4,6-dim^thoxy-N--methylbenzamide

0.9

>8

2-Hydroxy-N-(m-hydroxy-p--methoxybenzyl)-4,6--dirnethoxybenzamide

0.1 - 0.3

2/7

N-(m,p-Dimethoxybenzyl)-2--hydroxy-4,6-dimethoxy-behzamide

'

8

2-Hydroxy-4,6-dimethoxy-N--[(4-pyridyl)methyl] benzamide

0.9

8

-14 -

Table 1 [continued]

Compound

CI

50 -

(pg/m£)

Cytotoxicity

(ng/rru)

N-(p-Butoxybenzyl)-2--hydroxy-4,6-dimethoxy-benzamide

0.3

8

2-Hydroxy-N-(p-hydroxy-benzyl)-4,6-dimethoxy-benzamide

°?3

>8

N-[p-Dimethylamino)benzyl]--2-hydroxy-4,6-dimethoxy-benzamide

0.01

>8

2-Hydroxy-4,6-dimethoxy-N--[p-(methylthio)benzyl]-benzamide

0.002

>8

N"- [p- (Benzyloxy) benzyl] -2--hydroxy-4,6-dimethoxy- -benzamide

0.3 - 0.9

>8

2-Hydroxy-4,6-dimethoxy-N--(2-th^nyl)benzamide n O *•««.

O

8

N-[p-(Allyloxy)benzyl]-2--hyaroxy-4,6-dimethoxy-benzamide i—1

o o

8

2-Hydroxy-4,6-dim^thoxy-N--(t^trahydro-2-thenyl)-benzamide

0.004-0.01

8

2-Hydroxy-4,6-dimethoxy-N-. - [(2-pyrrolyl)methyl]-benzamide

2 7 *■) '

i

.. :

1L5

Table 1 [continued]

CompoSB

CI 50

(m g '/m£ )

Cytotoxicity ® (ng/m£)

2-[(p-Anisylamino)-carbonyl] -5-ethoxy-3--methoxypheny 1- acetate

•0.3

i

>8

2- [ [[p-(Allyloxy)benzyl]-amino]carbonyl]-3,5--dimethoxyphenyl—benzoate

0.002

2-{/ [p-(allyloxy)benzyl]-amino_/carbonyl}-3,5-■ -dimethoxyphenyl-octa-d^canoate

0.3

>8

1-(4-Ethoxy-2-hydroxy-6--methoxyphenyl)-3-(4-methoxy-phenyl)1-propanethione

0.002

2.7

4-Ethoxy- 2-hydroxy- 6-me'thoxy--N-(p-methoxybenzyl)thio-benzamide

0.01

>8

1- [ 2-Hydroxy-6-methoxy-4-'

- (methylthio)phenyl]-3-

- (4-methoxyphenyl)-1-propanone

0.1

1

5-Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-ph eny 1 - e thy 1 - c arb ona t e

0.002

s 1

1

5-Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-

phenyl-octadecanoate,

0.9

1

>8!

' ; 1

\ t <

he '

. ^

_ 1 6

TableaLJ 1 Csuite]

Compo

CI

50

(ng/m£)

Cytotoxicity (pg/m£)

5-Ethoxy-3-methoxy-2-[3--(4-methoxyphenyl)-propionyl]phenyl-benzoate

0.01

*

2- [(p-Anisylamino)carbonyl]--3,5-dimethoxypheriyl- ethyl carbonate

0.1

>8

2-[(p-Anisylamino)carbonyl]--3 / 5-dimethoxyphenyl-benzoat e 0.03

>8

2-[(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl-octadecanoate

0.3 - 0.9

>8

2- [(p-Anisylamino)carbonyl]--3,5-dimethoxyphenyl-tetra-0-acetyl-0-D-glucopyranos ide

2.7

>10

2- [(p-Anisylamino)carbonyl]--3,5-dimethoxyphehyl-/3-D--glucopyranoside

2.7

>10

5-Ethoxy-3-methoxy-2-[3-(4--methoxyphenyl)propionyl]-phenyl-3-D-glucopyranoside

2.7

>10

Disodium 5-ethoxy-3-methoxy--2-[3-(4-methoxyphenyl)-propionyl]phenyl-phosphate

0.03 - 0.1

>10

- 17 -

Table [continued]

Compound

CI50.

(ng/mi)

Cytotoxicity

(ng/m£)

Diacid phosphate of

2- [(p-Anisylamino)carbonyl]-

-3/5-dimethoxypheny le.

0.006-0.01

>8

•Diacidic phosphate of

2- [(p-Anisylamino)carbonyl]-.-5-ethoxy-3~rnethoxyphenyl-

0.01 -0.03

>8

Disodium 2-[(p-anisylamino)-carbonyl]-5-ethoxy-3--methoxyphenyl-phosphate

0.01 -0.03

>8

2-Hydroxy-6-methoxy-4-propoxy-N-(p-methoxy-benzylIbenzamide

0.001-0.003

•• >2 0

4-(Allyloxy)-2-hydroxy-6-methoxy-N-(p-methoxy-benzylJbenzamide

0? 002

■ >8

2-Hydroxy-6-methoxy-4-(3-methyl-2-butenyloxy)-N-(p-me'thoxybenzyl')-benzamide

0.001-0.002

>8

Disodium 2-[(p-anisylamino)-carbonyl]-3-m<^thoxy-5-propoxyphenyl-phosphate

0.01 -0.02

>200

S

18

Table at 2

Strain dB • Virus cl 5o(Mg/m£)

Compound A

Compound B

Rhinovirus 1A

0.03 - 0.09

0.009 - 0.027

1B

0.03 - 0.09

0.003 - 07009

2

0.001

0.001

'9

0.012 - 0.037

0.003

14.

0.1 - 0.3

0.009 - 0.027

16

-

0.003

21

<0.001

<0.001

23

0.004

-

24

0.01 - 0.03

-

25

0.01' - 0.09

-

30

-

0.001 - 0.003

31

0.03 - OjOS

0.081 - 0.24

32

- -

0.003 - 0.009

36

-

0.009 - 0.027

i 39

1

0.012 - 0.037

O, 003

i 44

' -

0.003

j 46

0.037 - 0.11

-

47

-

07003

50

0.004 - 0.012

0.01

55

■ -

0.009

The cytotoxic doses inhibiting HeLa cell growth by 50% are 60 ng/m£ (A) and 40 ng/m² (B), respectively.

19

As mentioned above, compounds of formula I and their pharmaceutically acceptable salts can be used as drugs against viral diseases, especially in the common cold, in the form of pharmaceutical preparations.

Pharmaceutical preparations contain at least one of the aforementioned antiviral compounds or their pharmaceutically acceptable salts in combination with a compatible pharmaceutical carrier, and may also contain other pharmaceutically active compounds such as a fever reducer, analgesic, anti-inflammatory, antihistamine, interferon inducer, etc. Pharmaceutical preparations include solid forms for oral administration such as tablets, capsules, pills, powders or granules; liquid forms for nasal or oral administration such as solutions, suspensions, syrups or elixirs; forms for parenteral administration such as sterile solutions, suspensions or emulsions; and forms for local administration such as solutions, nebulizers, micronized powders, ointments, gargles, lozenges or aerosols.

Pharmaceutical preparations can be administered in such a way that the concentration of active ingredient is higher than the minimum inhibitory concentration for the particular viral infection being treated.

The dosage for treatment depends on the method of administration, the patient's age, weight, and condition, as well as the specific disease being treated. In general,

For adults, a dose of approximately 100 to 2,000 mg 3 to 5 times a day can be suggested for the common cold.

2

In the case of oral treatment, the dose is approximately 0.1 to 100 yg/cm³ to S times per day in the case of local administration. The following examples further illustrate the invention.

25

30

20

Example 1,

A solution of 32B mg of 4'-ethoxy-2'-hydroxy-4,S'-dimethoxychalcone in 10 mL of chloroform is hydrogenated in the presence of 30 mg of 10% palladium on charcoal at room temperature and atmospheric pressure for 3 h. The catalyst is removed by filtration and the mixture is washed with 30 mL of chloroform. The filtrate and washing liquid are combined and evaporated under reduced pressure to give a crystalline residue. Recrystallization of the residue from methanol gives 302 mg of 1-C4-ethoxy-2-hydroxy-6-methoxyphenyl-3-3-C4-methoxyphenyl-3-1-propanone in the form of colorless needles at 100.5°–101°C.

Example 2

□In a manner analogous to that described in Example 1, the products listed in Table 3 are obtained from the corresponding chalcones listed in Table 3. c

V

21

Table at 3

Chalcones

Produ its

2'-Hydroxy-4,4',61--trimethoxychalcone

2'-Hydroxy-4'-6'--dimethoxy-4-(methylthio)-chalcone

2'-Hydroxy-41,6'-dimethoxy--3,4-(methylenedioxy)-chalcone

2'-Hydroxy-4 1, 6' --dimethoxy-4--methylchalcone

4-Chloro-21-hydroxy--4',6'-dimethoxychalcone

2'-Ethoxy-6'-hydroxy--4,4'-dimethoxychalcone -

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxyphenyl)-1-propanone; Melting point 110°C (crystallized from methanol)

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-[4-(methylthio)-phenyl]-1-propanone; Melting point 84° - 85°C (methanol)

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-[3,4-(methylenedioxy)-phenyl]-1-propanone; melting point 124j5°C (methanol)

1-(2-Hydroxy-4,6-dimethoxy-phenyl)-3-(4-methylphenyl)-1--propanone; melting point

128° - 129°C (methanol)

3-(4-Chlorophenyl)-1-(2-hydroxy--4,6-dimethoxyphenyl)-1-^-propanone; melting point

104.5°C (benzene/hexane)

1-(2-Ethoxy-6-hydroxy-4--methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone; melting point108° -•109°C (benzene/hexane)

22"

Example 3!

A solution of 400 mg of 2',-hydroxy-4',6'-dimethoxy-3-[5-methyl-2-furyl]acrylophenone in 25 mL of chloroform was hydrogenated in the presence of 40 mg of 10% palladium on 5% carbon at room temperature and atmospheric pressure for 4 h. After removal of the catalyst by filtration, the filtrate was evaporated to give an oily residue, which was dissolved in a small amount of benzene. The solution was introduced into a silica gel column and the column was eluted with hexane/ethyl acetate.

[5:1, v/v], which gives two fractions, A [R^0.29] and B [R^0.16], by control by silica gel thin-layer chromatography using cyclohexane-/ethyl acetate [4:1, v/v]. Solvent removal from fraction A and recrystallization from benzene/hexane gives 192 mg of 1-[2-hydroxy-4,6-dimethoxyphenyl]-3-[5-methyl-2-furyl]-1-propanone in the form of colorless crystals of

Pc 92-93 0 C.

r

A similar treatment of Fraction B gives

2>3 25 mg of 1-[2-hydroxy-4,6-dimethoxyphenyl]-3-[tetrahydro-5-methyl-2-Furylj-1-propanone in the form of colorless needles at P^_ 67.5°C [recrystallized from petroleum ether].

Example 4

25

On hydrogen 85 mg of 2'-hydroxy-4,6'-dimethoxy-4'-propoxychalcone in a manner analogous to that described in example 1. 69 mg of 1-[2-hydroxy-6-methoxy-4-propoxyphenyl]-3-[4-methoxyphenyl]-1-propanone is obtained in the form of colorless needles at P^_ Q5D-86°C.

30 The 2'-hydroxy-4,6'-dimethoxy-4'-propoxychalcone used as a starting material is prepared as follows:

A mixture of 182 mg of 2',4'-dihydroxy-6'-methoxyacetophenone, 187 mg of propyl iodide, and 276 mg of potassium carbonate is heated under reflux for 16 hours.

V,

23

anhydrous in 5 ml of acetone. After cooling, the mixture is diluted with 30 ml of water and extracted 3 times with 30 ml of dichloromethane each time. The combined dichloromethane extracts are washed with water, dried over sodium sulfate, and evaporated to give 2'-hydroxy-S'-methoxy-4'-propoxyacetophenone as a pale yellow oil.

The previous oil B is dissolved in 5 mL of ethanol containing 120 mg of p-methoxybenzaldehyde, to which 4 mL of 15% aqueous sodium hydroxide is added. After stirring at room temperature for 2 days, the mixture is adjusted to pH 5-6 with hydrochloric acid and extracted with 3 fractions of 30 mL of ethyl acetate. The combined ethyl acetate extracts are washed with water, dried over sodium sulfate, and evaporated to give an oily residue. Recrystallization of the residue from methanol gives 110 mg of 2'-hydroxy-4,6'-dimethoxy-4'-propoxychalcone in the form of yellow needles of 95-9 60 G.

r

20 Example 5

In a manner analogous to what is described in example 1, from 2'-hydroxy-4'-isopropoxy-4,6'-dimethoxychalcone we obtain 1-C2-hydroxy-4-isopropoxy-6-methoxyphenyl D-3-[4-methoxyphenyl D-1-propanone of P^_ 25 96.5°C [recrystallized from methanol].

The starting product is prepared in a manner similar to that described in example 4, except that isopropyl iodide is used instead of propyl iodide.

24

Example B

120 mg of 2'-hydroxy-4,6'-dimethoxy-4'-[methylthio3-chalcone] is dissolved in 10 mL of chloroform. The solution is hydrogenated in the presence of 180 mg of 10% palladium on activated carbon at room temperature and atmospheric pressure for 33 h. After removal of the catalyst by filtration, the filtrate is evaporated to give a pale yellow residue, which is recrystallized from methanol. 103 mg of 1-[2-hydroxy-B-1-methoxy-4-C-methylthio]phenylD-3-C4-methoxy-phenyl3-1-propanone is obtained as cream-colored needles of P₁₂₇-127.5°C.

The starting product is prepared as follows:

To a solution of 120 mg of 2'-hydroxy-S'-methoxy-15-4'-[methylthio]acetophenone and 92 mg of p-methoxybenzal dehyde in B mL of ethanol, 4 mL of 15% aqueous sodium hydroxide is added. After stirring at room temperature for 24 h, the mixture is diluted with 10 mL of water and acidified with 1 N hydrochloric acid. The resulting crystalline precipitate is collected by filtration and washed with a small amount of 50% methanol.

and it is recrystallized from methanol to give 144 mg of 2'-hydroxy-4,6'-dimethoxy-4'-[methylthio3-chalcone in the form of yellow needles at P^_ 145-147°C.

25 Example 7

One g of 2-[benzyloxy]-4,B-dimethoxybenzoic acid is dissolved in 5 mg of thionyl chloride and the solution is stirred at room temperature for 1 h. Removal of excess thionyl chloride by repeated evaporation with benzene yields an oil that dissolves in 5 mL of benzene. This solution is added dropwise to an ice-cooled solution of 1.8 mL of p-methoxybenzylamine in 5 mL of

benzene. After stirring at room temperature for 17 h, the mixture is diluted with 50 ml of ethyl acetate, washed successively with dilute hydrochloric acid and with water, dried on sodium sulfate and evaporated under reduced pressure to give 1.66 g of an oil.

The previous oil was dissolved in 2 mL of benzene, and the solution was introduced into a silica gel column [60 g in hexane]. The column was eluted with 600 mL of hexane/ethyl acetate [1:1, v/v]. Removal of the solvent from the eluate followed by recrystallization from the ethyl acetate gave 700 mg of 2-[benzyloxy]-

4.5-dimethoxy-N-[p-methoxybenzylJbenzamide in the form of colorless needles at P^_ 123-124°C.

A solution of 700 mg of the preceding benzamide in 20 mL of chloroform in the presence of 140 mg of 10% palladium on activated charcoal at room temperature and atmospheric pressure was heated for 4 h with hydrogen. Removal of the catalyst by filtration followed by evaporation of the filtrate yielded a crystalline residue. Recrystallization of the residue from methanol gave 475 mg of 2-hydroxy-

4.6-dimethoxy-N-[p-methoxybenzyl3-benzamide in the form of colorless needles of P^_ 108-109°.

The 2-[benzoyloxyD-4,6-dimethoxy-benzoic acid used as a starting material is prepared in the following manner:

In a stirred suspension of 39.75 g of methyl 2-hydroxy-4,S-dimethoxybenzoate and 207 g of anhydrous potassium carbonate in 2 mL of acetone, a solution of 22.3 mL of benzyl bromide in 300 mL of acetone is added dropwise. After stirring at room temperature for 78 h, the mixture is filtered. The filtrate is evaporated under reduced pressure to give an oil, which is dissolved in 500 mL of chloroform. The solution is washed with 400 mL of water and dried over sulfate.

SB

of sodium and evaporated to give 78.7 g of crude methyl 2-[benzyloxy]-4,6-dimethoxybenzoate in the form of a colorless oil.

78.7 g of the previous crude ester is dissolved in 5220 mL of dioxane/methanol [4:1, v/v]. To this solution, 900 mL of 2.4 N sodium hydroxide is added, the mixture is heated under reflux for 16 h, cooled, and then acidified with hydrochloric acid. The resulting crystalline precipitate is collected by filtration and washed with ethyl acetate to give 48 g of acid.

2-[benzyloxy3-4,6-dimethoxybenzoic acid in the form of colorless needles of P 167-168SC.

Example 8

□In a manner analogous to what is said in example 7, we obtain the products listed in the Table

4 from 2-[benzyloxy3-4,5-dimethoxybenzoic acid[ prepared as starting material in Example 73 and the respective amines listed in Table 4.

27

Table 4

Amino acids

p-Methoxyaniline products

2-Hydroxy-4,6-dimethoxy-N-(4-methoxypheriy 1)benzamide; Melting point 131° - 132°C [recrystallized from methanol]

Benzylamine

N-Benzy1-2-hydroxy-4,6-dimethoxybenzamide; Melting point 96°C (methanol)

m,p-(Methylenedioxy)-benzylamine

2-Hydroxy-4, 6-dimethoxy-N-(m,p--methylenedioxybenzy1)benzamide; Melting point 116° - 117°C (methanol)

m-Methoxybenzylamine

2-Hydroxy-4,6-dimethoxy-N-(m--methoxybenzyl)benzamide; Melting point 95° - 96°C (methanol) p-Methylbenzylamine

• 1

2-Hydroxy-4,6-dimethoxy-N-(p--methylbenzyl)benzamide; -Melting point 100° - 100.5°C (methanol):

p-Chlorobenzylamine

• N-(p-Chlorobenzy1)-2-hydroxy-

-4,6-dimethoxybenzamide; Melting point 131° - 132°C (methanol)

2- (Aminomethyl)furannc

N-Furfuryl-2-hydroxy-4,6--dimethoxybenzamide; Melting point 74° - 75°C (methanol)

y

Methylamine

2-Hydroxy-4,6-dirn^thpxy-N-a., , -methylbenzamide point; K

Melting point 144° - 145.5°C (methanol)

28

Table 9" 4 [continued]

Amino acids

m-(Benzyloxy)-p-methoxybenzylamine products

2-Hydroxy-N-(m-hydroxy-p-methoxybenzyl)-4,6-dimethoxybenzamide; Melting point 144° _ I45°c (methanol)

m, p-Dimethoxybenzyl 1-amino

2-Hydroxy-4,6-dimethoxy-N--(m,p-dimethoxybenzyl)benzamide; Melting point 115° - 116°C (methanol)

p-Butoxybenzylamine

N-(p-Butoxybenzyl)-2-hydroxy--4,6-dimethoxybenzamide; Melting point 88° - 89°C (methanol)

p-Hydroxybenzylamine

2-Hydroxy-N-(p-hydroxybenzyl)--4,6-dimethoxybenzamide; Melting point 170° - 171°C (methanol)

p-(Dimethylamino)-benzylamine j...'.'

i

N-[p-(Dimethylamino)benzyl]-2--hydroxy-4,6-dimethoxybenzamide Melting point 79° - 82°C (methanol)

p-(Methylthio)-benzylamine

2-Hydroxy-4,6-dimethoxy-N-[p-(methylthio)benzyl]benzamide; Melting point: 110°C

(methanol)

p-(Benzyloxy)-benzylamine

N-[p-(Benzyloxy)benzyl]-2--hydroxy-4,6-dimethoxybenzamide Melting point 109° - 110°C (methanol)

2-Thenylamine

2-Hydroxy-4,6-dirnethoxy-N-(2--thenyl)benzamide; melting point -60°C (methanol)

N

Tetrahydro-2-thenylamine

2-Hydroxy-4,6-dimethoxy-N--(tetrahydro-2-thenyl)benzamide; Melting Point 81°–82°C

(methanol)

29

Example 9 t

To a cooled suspension of 2-[benzyl-oxy]-4,6-dimethoxybenzoic acid [1 g 3s] prepared as the starting material in Example 7, and 400 mg of N-hydroxysuccinimide in 20 mL of dioxane, 858 mg of dicyclohexylcarbodiimide is added. The mixture is stirred at room temperature for 19 h and then filtered. Removal of the solvent from the filtrate yields an oil, which is chromatographed on 50 g of silica gel by eluating with ethyl hexane acetate [4:1, v/v]. The eluate is evaporated to give a syrup which, when left to stand in a cool place, solidifies into a crystalline mass.

The previous paragraph was prepared in 5 mL of dimethylformamide. To the resulting solution, 88 mg of p-methoxybenzylamine was added, and the mixture was stirred at room temperature. After 18 h, the mixture was diluted with 20 mL of 1 N hydrochloric acid, and the extract was performed twice, each time with 50 mL of ethyl acetate. The combined ethyl acetate extracts were washed with water, dried over sodium sulfate, and evaporated to give a crystalline residue. Recrystallization of the residue from ethyl acetate/hexane yielded 228 mg of 2-[benzyloxy]-4,6-dimethoxy N-[p-methoxybenzyl]benzamide in the form of colorless needles.

dent by hydrogenolysis following the process described in example 7 gives the 2-hydroxy-4,6-dimethoxy-N-[p-methoxybenzyl]benzamide of F 108—109°C.

Example 10

To a solution of 980 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone in 20 ml of pyridine, add

225 mg of the solid obtained is dissolved according to the recipe at P^_ 123-124°C.

The removal of the benzyl group from the aforementioned benzamide

30

1.27 g of iodine. The mixture is heated to 100°C for 1 h to give a solid mass. After cooling, the solid is washed successively with 50 ml of ether and a small amount of cold water, then dried under reduced pressure to give 2 g of crude 1-[[2-hydroxy-4,6-dimethoxybenzoyl]-methylpyridinium iodide in the form of a brown powder.

One g of the previous pyridinium salt is added to 514 mg of p-methoxybenzylamine, and the mixture is heated at 80°C for 72 h. After cooling, the mixture is poured into 20 mL of 1 N hydrochloric acid. The resulting suspension is extracted twice, each time with 100 mL of dichloromethane. The combined dichloromethane extracts are washed with water, dried over sodium sulfate, and evaporated to give 945 mg of an oily residue, which is purified by silica gel chromatography using hexane/ethyl acetate [3:1, v/v].

for elution. Removal of 1 l/eluate of solvent followed by recrystallization of the residue from methanol gives 316 mg of 2-hydroxy-4,6-dimethoxy-N-[p-methoxybenzyl ]-benzamide at P 108-109°C.

Example 11

Similar to what is described in Example 10, the products listed in Table 5 are obtained from the pyridinium salt prepared in Example 10 and the respective amines listed in Table 5.

31

Table 5

1

Amino acids

Produ its

4-(Aminomethyl)pyridine p-(Allyloxy)benzylamine ■ 2-(Aminomethyl)pyrrole

2-Hydroxy-4,6-dimethoxy-N-[(4--pyridyl)methyl]benzamide; melting point _114° - 115°C [re-processed from the -e-

'ther]

N-[p-(Allyloxy)benzyl]-2--hydroxy-4,6-dimethoxybenzamide; melting point 93° - 94°C (methanol)

2-Hydroxy-4,6-dimethoxy-N- (2--pyrrolylmethyl)benzamide melting point 116° - 117°C (ether)

Example 12

A solution of 9.8 g of 4'-ethoxy-2'-hydroxy-6T-methoxyacetophenone and 12 g of iodine in 22 mL of pyridine is heated at 100°C for 1 h. The resulting slurry is cooled, triturated, and heated again at 100°C for 1 h. After cooling, the mixture is filtered, and the solid residue is washed successively with 100 mL of ether and 100 mL of water, then dried at 60°C for 3 h under reduced pressure. 18.2 g of 1-[C4-ethoxy-2-hydroxy-6-methoxybenzoyl]methyl]pyridinium iodide is obtained as a pale brown solid.

15.4 g of the previous pyridinium salt is added to 100 ml of p-methoxybenzylamine, and the stirred mixture is heated to 80°C for 18 h under nitrogen. After cooling-

32

The mixture is treated with 200 ml of ethyl acetate and 150 ml of water. The ethyl acetate phase is separated, and the aqueous phase is extracted with 150 ml of ethyl acetate. The combined ethyl acetate solutions are washed successively with two 150 ml fractions of dilute hydrochloric acid, 150 ml of aqueous sodium bicarbonate, and brine. The mixture is dried over sodium sulfate and then evaporated to give 15 g of oil, which is purified by silica gel chromatography using hexane/ethyl acetate for elution. The removal of the solvent from the eluate followed by the recrystallization of the residue from methanol gives 6.3 g of 4-ethoxy-2-hydroxy-6-methoxy-N-Cp-methoxybenzy1]-benzamide in the form of colorless needles at P^_ 87—88°C.

Example 13

A mixture of 336 mg of 2-acetyl-3,5-dimethoxyphenyl-4-methoxybenzoate and 735 mg of anhydrous potassium carbonate in 5 mL of toluene is heated to 100°C for 17 h, cooled, and then filtered. After washing with benzene, the filtered cake is treated with 50 mL of dichloromethane and 50 mL of water. The dichloromethane phase is separated, dried over sodium sulfate, and evaporated to give a crystalline residue. Recrystallization of the residue from methanol yields 77 mg of 1-[2-hydroxy-4,6-dimethoxyphenyl-3-3-[4-methoxyphenyl-3-1,3-propanedione in the form of yellow prisms with a polarity of 136-136.5°.

Example 14

A stirred suspension of 580 mg of 1-C2-hydroxy-4,6-dimethoxyphenyl 3-3-[4-methoxyphenyl]-1-propanone, obtained as described in Example 2, and 482 mg of sodium acetate in 9 ml of dimethyl-

33

204 mg of hydroxylamine hydrochloride is added to the sulfoxide. □ The mixture is heated to 80°C for 15 h, cooled, diluted with 30 ml of ethyl acetate, washed successively with dilute hydrochloric acid and with 5 ml of water, dried on sodium sulfate, then evaporated to give 710 mg of a yellow oil which is dissolved in 1 ml of benzene.

The solution obtained according to the previous paragraph is introduced into a 25 g gel column.

10 silica and the column is elute with hexane/ethyl acetate: 1, v/v] with fractionation [each fraction representing 15 ml]. Fractions 5 to 8 are combined and evaporated to give 435 mg of a pale yellow oily residue. Recrystallization of the residue from

15 ethyl acetate/hexane gives 301 mg of the E isomer of

1-[2-hydroxy-4,6-dimethoxyphenyl]-3-C4-methoxyphenyl]-

1-Propanone oxime in the form of colorless crystals of

F_ 82-83.5°C.

f '

The corresponding Z isomer 2'J of the oxime is also obtained in the form of colorless crystals [102-104°C]

from fractions 10 to 30 after solvent removal then recrystallization from ethyl acetate/hexane [yield 95 mg].

Example 15

25. A mixture of 500 mg of 4-ethoxy-2-hydroxy-6-methoxy-N-[p-methoxybenzyl]benzamide, obtained as described in Example 12, 873 mg of phosphorus pentasulfide, and 259 mg of triethylamine in 10 mL of carbon disulfide is stirred at room temperature for 3 days. 30. Then, 100 mL of ethyl acetate and 100 mL of water are added, and the mixture is stirred. The ethyl acetate phase is separated, and the aqueous phase is extracted with 100 mL of ethyl acetate. The acetate solutions are washed.

V,

34

Ethyl compounds are combined with brine and evaporated. The residue is chromatographed on Bn silica gel using benzene/ethyl acetate [10:1, v/v] for elution. Removal of the solvent from the eluate and recrystallization from methanol yield 4-ethoxy-2-hydroxy methoxy-N-Cp-methoxybenzylthiobenzamide as pale yellow needles at 98-99°C.

Example 16

In a manner analogous to what is described in Example 15 but using 1-[4-ethoxy-2-hydroxy-5-methoxyphenyl]-3-[4-methoxyphenyl]-1-propanone [obtained as stated in Example 1] instead of 4-ethoxy 2—hydroxy—5-methoxy-N-[p—methoxybenzyl]benzami, 1-[4-ethoxy-2-hydroxy-S-methoxyphenyl]-3-[4-methoxyphenyl]-1-propanethione is obtained in the form of orange needles of P^_ 69-7QDC [recrystallized from methanol].

Example 17

A mixture of 165 mg of 1-[4-ethoxy-2-hydroxy-6-methoxyphenyl]-3-[4-methoxyphenyl]-1-propanone, 0.2 ml of acetic anhydride and 5 mg of sodium acetate is heated at 140°C for 3 h in a sealed tube.

After cooling, the mixture is poured into 20 ml of water. The mixture is extracted with 50 ml of chloroform and the extract is washed with water, dried over sodium sulfate, and evaporated to give 178 mg of an oily residue. Recrystallization of the residue from methanol gives 138 mg of 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]propionyl]phenylacetate in the form of colorless needles at 58-59°C.

35

10

Example 18,

To a solution of 200 mg of 4-ethoxy-2-hydroxy-6-methoxy-N-[p-methoxybenzyl]benzamide, obtained as described in Example 12, in 2 mL of pyridine, 0.07 mL of acetic anhydride is added. The mixture is stirred at room temperature for 18 h and then evaporated under reduced pressure to give an oily residue. Recrystallization of the residue from methanol gives 60 mg of 2-[[p-anisylamino]carbonyl]-5-ethoxy-3-methoxyphenylacetate in the form of colorless needles at 121–122 °C.

Example 19

To a solution of 317 mg of 2-hydroxy-4,6-dimethoxy-N-[p-methoxyberzyl]benzamine, obtained as described in the example, 0.14 mL of triethylamine and 24 mg of 4-C-dimethylaminopyridine in 0 mL of dichloromethane, 0.1 mL of ethoxycarbonyl chloride is added. The mixture is stirred at room temperature for 1 h, washed successively with dilute hydrochloric acid and water, dried over sodium sulfate, and then evaporated to give 480 mg of a yellow oil. The oil is chromatographed on silica gel using hexane/ethyl acetate [3:1, v/v] for elution. Solvent removal from the eluate and recrystallization from ether/petroleum ether yields 110 mg of 2-[[p-anisylamino]carbonyl]-3,5-dimethoxyphenyl-ethyl-

carbonate in the form of colorless crystals of P_ 123-

f

124.5°C

36

Example 20 i

Similar to what is described in example 19 but using 1-[4-ethoxy-2-hydroxy-6-

methoxyphenyl]-3-[4-methoxyphenyl]-1-propanone instead

5 of 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzyl]-benzamide,

we obtain 5-ethocy-3-methoxy-2-[3-[4-methoxyphenyl]-

1

propionylphenyl-ethyl-carbonate; H NMR spectrum [in CDC1]: S 1.38 [3H], 1.40 [3H], 3.00 [4H]f 3.75 [6H],

J

4.02 C2H], 4.34 [2H], 6.32 [2H], 6.80 C^H] and 7.13 ppm [2H] 1□ Example 21

To a solution of 200 mg of 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzylbenzamide, obtained as described in Example 7, in 5 mL of pyridine, 347 mg of stearic anhydrous is added. The mixture is heated at 60°C for 22 hours and then evaporated under reduced pressure to give an oily residue, which is dissolved in 30 mL of ethyl acetate. The solution is washed successively with dilute hydrochloric acid and brine, dried over sodium sulfate, and evaporated. Recrystallization of the residue from ethyl acetate gives 92 mg of 2-[[p-anisylamino]carbonyl]-3,5-dimethoxyphenyl-octadecanoate in the form of colorless needles at P_ 88-89°C.

r

25

Example 22

Similar to what is described in Example 21, but using N-Cp-[allyloxy]benzyl]-2-hydroxy-4,6-dimethoxybenzamide instead of 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzyl]benzamide, we obtain 2-[/Cp-Cp-allyloxy]benzyl]amino/carbonyl-3,5-dimethoxy-30 phenyl-octadecanoate in the form of colorless Pj_ 88°-89DC crystals [recrystallized from ethanol/hexane].

37

Example 23 1

Similar to what is described in Example 21, but using 1-C4-ethoxy-2-hydroxy-6-methoxyphenyl-3-C4-methoxyphenyl-3-1-propanone instead of 2-hydroxy-4,6-dimethoxy-N-[p-methoxybenyl-3-benzamide, we obtain 5-ethoxy-3-methoxy-2-[3-[4-methoxy-phenyl 3propionyl 3-phenyl-o-ctadecanoate at 40-41 °C [recrystallized from methanol3-

Example 24

In a manner analogous to what is described in Example 19, but using benzoyl chloride instead of ethoxycarbonyl chloride, 2-Cp-ani sylami no]carbonyl3-3 , 5 Cdimethoxyphenyl-benzoate is obtained in the form of colorless P^_ 124.5-125.5DC crystals recrystallized from ethyl acetate/hexane3.

Example 25

In a manner analogous to that described in Example 19, but using N-[p-allyloxy3benzyl3-2-hydroxy-4,6-dimethoxybenzamide ([obtained as stated in Example 113 and benzoyl chloride instead of 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzyl3benzamide and ethoxycarbonyl chloride, respectively, 2-I/Cp-[allyloxy3benzyl3-amino/carbonyl1-3,5[dimethoxy-phenyl-benzoate is obtained in the form of colorless crystals of P^_ 105-106°G [recrystallized from methanol.3.

Example 26

In a manner analogous to what is described in example 19, but using 1-[4-ethoxy-2-hydroxy-6-methoxyphenyl3-3-C4-methoxyphenyl3-1-propanone and benzoyl chloride instead of 2-hydroxy-4,5-dimethoxy-

38

N-[p-methoxybenzyl3benzamide and ethoxy-carbonyl chloride, respectively, yield 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl3propionyl3phenylbenzoate; ¹H NMR spectrum: S 1.42 [3H3, 2.85 - 3.35 [4H3, 3.75 [3H3» 3.80 [3H3, 4.06 [2H3, 5.40 [2H], 6.75 [2H3, 7.11 [2H3 and 7.42-7.70 ppm [3H].

Example 27

To a 9SD mg solution of 1-[4-ethoxy-2-hydroxy-6-methoxyphenyl-3-3-[4-methoxyphenyl-3-1-propanone], obtained as described in Example 1, and 2 mL of N,N-diisopropylethylamine in 20 mL of toluene, 10 mL of phosphorus oxychloride is added all at once. The mixture is stirred at room temperature for 1 h and then evaporated under reduced pressure at a bath temperature below 40°C to give an oily residue, which is dissolved in 10 mL of toluene. After removing the solvent by evaporation under reduced pressure, the resulting oily residue is dissolved in 4 mL of tetrahydrofuran/water [1:3, - v/v3]. The solution is vigorously stirred at room temperature for 50 minutes and concentrated under reduced pressure at a bath temperature of 30-40°C to an aqueous solution, which is then extracted three times with 50 mL of chloroform each time. The combined chloroform extracts are washed with a small amount of water, dried over sodium sulfate, and...

Evaporate to give an oily residue which is dissolved in 100 ml of 0.1 N potassium carbonate. Wash the solution twice, each time with 30 ml of ethyl acetate, acidify with hydrochloric acid, and extract three times with 50 ml of ether each time. Wash the extracts

of ether combined with a small amount of water, it is dried over sodium sulfate and evaporated to give an oily residue. The residue is then recrystallized from

1

39

Ether gives 93Q mg of diacid phosphate of 5-ethoxy-3-methoxy-2-[3~[4-methoxyphenyl]propionyl]phenyl in the form of colorless needles at P^ 122-125°C [decomposition].

Example 28

410 mg of 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]propionyl]phenyl diacid phosphate, obtained as described in Example 27, is dissolved in 15 mL of 0.1 N sodium hydroxide. After carefully adjusting the pH to 8.0 with 0.1 N sodium hydroxide, the solution is lyophilized to give a white solid. Recrystallization of the solid from acetonitrile water gives 380 mg of disodium 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]propionyl]phenyl phosphate in the form of colorless needles at 138–139°C.

Example 29

To a stirred solution of 380 mg of dibenzyl phosphorochloridate in 10 mL of benzene, a solution containing 350 mg of 4-ethoxy-2-hydroxy-6-methoxy-N-[p-methoxybenzyl]benzamide, obtained as described in Example 12, and 51 mg of 60% sodium hydride in 10 mL of dimethylformanide is added. After stirring at room temperature for 14 h 24, the mixture is diluted with 50 mL of ethyl acetate, washed three times with 50 mL of water each time, dried over sodium sulfate, and evaporated to give 1.25 g of a yellow oil. The oil is chromatographed on 37.5 g of silica gel using ethyl acetate/hexane [1:1, v/v] for elution. Removing the solvent from 1 îjéluate gives 237 mg of dibenzyl-2-[[p-anisyl-amino]carbonyl]-5-ethoxy-3-methoxyphenyl-phosphate in the form of a colorless syrup which is dissolved in 20 ml of chloroform.

The hydrogen solution obtained according to the paragra-

The previous solution was heated for 34 h in the presence of 47 mg of 10% palladium on carbon at room temperature and atmospheric pressure. Removal of the catalyst by filtration followed by evaporation of the filtrate yielded 34 mg of a white residue. Recrystallization of the residue from methanol gave 79 mg of 2-Cp-anisylamino-carbonyl-5-ethoxy-3-methoxyphenyl diacid phosphate in the form of colorless crystals at 162-163.5°C.

The compound thus obtained is transformed into 2-Cp-anisylamina]carbonyl]-5-ethoxy-3-methoxyphenyl-phosphate disodium of P^. 125-127°C in a manner analogous to that described in example 28.

Example 30

In a manner analogous to what is described in example 29, but using 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzyl]benzamide instead of 4-ethoxy-2-hydroxy-6-methoxy-N-[p-methoxybenzyl]-benzamide, the diacid phosphate of 2-C[p-anisylamino]-carbonyl]-3,5-dimethoxyphenyl is obtained in the form of colorless crystals at P^_ 160.5—162.5°C.

Example 31

To a stirred solution of 300 mg of 2-hydroxy-4,6-dimethoxy-N-Cp-methoxybenzylbenzamide, obtained as described in Example 7, and 50 mg of 60% sodium hydride in 3 mL of dimethylformamide, 600 mg of 2,3,4,6-tetra-O-acetyl-O-D-glucopyranosyl bromide is added. The mixture is stirred at room temperature for 18 h and then treated with 50 mL of ethyl acetate and 30 mL of water. The ethyl acetate phase is separated, washed with water, dried over sodium sulfate, and evaporated to give an oily residue. The residue is chromatographed on 10 g of silica gel using ethyl acetate.

41

for elution. Removal of solvent from the eluate followed by recrystallization from methanol gives 135 mg of 2-[[p-anisylamino]carbonyl]-3,5-dimethoxyphenyl-tetra-O-acetyl-P-jD-glucopyranoside in the form of colorless crystals at F 73 76°C.

Example 32

A 100 mg suspension of 2-[[p-anisylamino]-

carbonyl ] -3, 5-dimethoxypheny l-tetra-O-acetyl - -D-gluco-

pyranoside, obtained as described in example 31,

in 30 ml of methanol we add 0.09 ml of water and 0.09 ml.

of triethylamine. After shaking at room temperature for 3 days, the mixture is evaporated to give a solid residue. The residue is chromatographed on

10 g of silica gel using ethyl acetate/

methanol [10:1, v/v] for elution. Removal of the solvent from the eluate followed by recrystallization from ethanol/hexane gives 40 mg of 2-[[p-anisylamino]-

carbonyl]-3,5-dimethoxyphenyl-^-D-glucopyranoside under

Colorless needle shape at P_ 132-133°C.

r

Example 33

To a stirred solution of 330 mg of 1-[4-ethoxy-2-hydroxy-β-methoxyphenyl]-3-[4-methoxyphenyl]-1-propanone, obtained as described in Example 1, and 44 mg of sodium hydride in 5 mL of dimethylformamide, tetra-0-acetyl-1-CX-0-glucopyranosyl bromide is added. The mixture is stirred at room temperature for 18 h, diluted with 30 mL of cold water, and extracted with 3 fractions of 30 mL of ethyl acetate. The combined extracts are washed with water, dried over sodium sulfate, and evaporated to give 700 mg of crude 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]propionyl]phenyl-tetra-0-acetyl-1-D-glucopyranosyl.

42

□ n purifies the previous crude material by silica gel chromatography using hexane/ethyl acetate [3:1, v/v] for elution and then saponifies using the process described in Example 32 to give 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]-propio--nyl ]phenyl - -□-glucopyranoside ; NMR ^ H : S 1.35 C3H], 2.6-3.2 [4H], 3.2-4.6 [6H], 3.72 [3H], 3.78 [3H], 4.025 [2H], 4.87 [1H], 6.26 [1H], 6.45 [1H], 6.78 [2H] and 7.15 ppm [2H].

Example 34

In a manner analogous to what is described in example 12, but using 2'-hydroxy-6'-methoxy-4'-propoxyacetophenone instead of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone, 2-bydroxy-6-methoxy-4-propoxy-N-[p-methoxybenzyl]benzami is obtained in the form of colorless crystals at P^_ 9G,5-97,5°C [recrystallized from methanol].

Example 35

In a manner analogous to what is described in example 12 but using 2'-hydroxy-6'-methoxy-4'-[2-propenyloxy]acetophenone instead of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone, 4-[allyl-oxy]-2-hydroxy-6-methoxy-N-[p-methoxybenzyl]-benzami is obtained in the form of colorless crystals of P^_ 69.5-7Q°C [recrystallized from methanol].

Example 36

Similar to what is described in Example 12, but using 2'-hydroxy-6'-methoxy-4'-[3-methyl-2-butenyloxy]acetophenone instead of 4'-ethoxy-2'-hydroxy-6'-methoxyacetophenone, we obtain

V"

)

43

2-hydroxy-S-methoxy-4-C3-methyl-2-butenyloxy]-N-[p-methoxybenzyl]benzamide in the form of colorless crystals at 48.0-48.5°C [recrystallized from petroleum ether],

5 Example 37

Similar to what is described in example 29 but using 2-hydroxy-S-methoxy-4-

propoxy-N-Cp-methoxybenzyl]benzamide, obtained as stated in example 37, in place of 4-ethoxy-2-hydroxy-.

10 G-methoxy-N-Cp-methoxybenzyl]-benzamidel we obtain the

H—[p-anisylamino]carbonyl]—3-methoxy-5-propoxyphenyl-

disodium phosphate in the form of colorless crystals

P_ 116-119°C [recrystallized from ethyl acetate]. r

Example A

A j- ^ ^ ^

Tablets containing the following ingredients are prepared using conventional methods:

Active ingredient, i.e., composed of

Formula I] 300 mg

Dried lactose 200 mg

20 Cellulose Cmicrocrystalline] 30 mg

Polyvinylpyrrolidone 5 mg

Magnesium stearate 4 mg

44

Example B 1

Intranasal drops containing the following ingredients per 1 ml can be prepared using conventional methods:

Active ingredient [i.e., compound of formula 1] . 0.1 mg

Surfactant 0.05 mg Propylene glycol/water [1:1, v/v] q.s.p. 1 ml

An acceptable concentration range for the active ingredient is 0.001 to 1 mg/ml.

Example C

Lozenges containing the following ingredients are prepared using conventional methods:

Active ingredient [i.e. compound]

of formula I] 0.1 g

'Powdered sucrose 1.5 g Acacia g

Dextrin 0.1 g

Flavoring agent 0.001 g.

45

Claims (1)

DEMANDS 1. Process for preparing compounds of General Formula where X represents an oxygen or sulfur atom or a hydroxyimino; Y represents a methylene or an imino; 1 R represents a hydroxy, a phosphonooxy, a glycosyloxy, an acylated glycosyloXy, an acyloxy, or an inferior alkoxycarbonyloxy; RC represents an inferior alkoxy, an alkeny- ^ 3 lower loxy or lower alkyl-thio; R represents 4 - an inferior alkoxy; R represents an inferior alkoxy, a p-inferior alkoxy-benzoyl or a substituted or unsubstituted phenyl, a benzyl, a pyridylmethyl, a furfuryl, a tetrahydrofuryl, a thenyl, a tetrahydrotenyl a pyrrolylmethyl, a pyrrolinylmethyl, or a pyrroli- 4 dinylmethyl, with the clarification that where R represents an alkyl, phenyl, substituted phenyl, benzyl, or p-hydroxybenzyl, Y does not represent a methylene radical; and with the further clarification that when 4 " " R represents a p-methoxybenzyl and Y represents a S 3 methylene, R and R are different, and their pharmaceutically acceptable salts, process which involves Ca] to hydrogenate a compound of general formula II 46 12 3 4 where X, R, R, R and R sqnt are such as defined in formula I, in the presence of a catalyst in a solvent, Or C b] to react a reactive derivative of a carboxylic acid of general formula COOiï III 2 3 where R and R• are such that defined in formula I and 1' - or R represents a protected hydroxyl radical, with a compound of general formula R - N 12 IV where R is such that defined in formula I, then to remove the protective fraction of the protected hydroxyl radical, or [c] to react an acetophenone of general formula V CH3 12 3 or R, R and R are as defined in formula I, with iodine in a tertiary amine and reacting a salt obtained with an amine of formula IV given above in the present claim, or V) 47 [d] to submit an ester of General Formula i VI 2 3 4 where B, R, and R are such that, as defined in Formula I, a transposition occurs in the presence of a base in a solvent, or [e] of Reacting a ketone of General Formula VII OH O 2 3 4 where R, R and R are such as defined in Formula I, with a hydroxylamine salt in a solvent, or CF] of Reacting a carbonyl compound of General Formula VIII 2-34 where V, R, and R are such as defined in Formula I with phosphorus pentasulfide in the presence of a base in a solvent, or Cg] of Reacting a phenol of General Formula IX 'OH X' 48 2 3 4 where V, R, R and R are such as defined in formula I i and X' represent an oxygen or sulfur atom, with an acylant agent in the presence of a base, or C h 3 to react a phenol of formula IX given above in the present claim with phosphorus oxychloride or dibenzylphosphorochloridate in the presence of a base in a solvent and then to proceed to hydrolysis or hydrogenolysis as appropriate and, if necessary, to transform a compound obtained into a salt, or C i D to react a phenol of formula IX given above in the present claim with a glycosyl halide which can be acylated in the presence of a catalyst in a solvent and then, if necessary, by removing the acyl radicals. 2. A process according to claim 1 for preparing compounds of Formula I where X represents an oxygen or sulfur atom or a hydroxyimino; Y represents a methylene 1 or an imino; R represents an hydroxy, a phosphonooxy, a glycosyloxy, an acylated glycosyloxy, an acyloxy, or a 2 lower alkoxycarbonyloxy; R represents an alkoxy - . - 3 lower, or a lower alkyl-thio; R represents a 4 lower alkoxy; R represents a lower alkoxy, a lower p-alkoxy-benzoyl or a phenyl, benzyl group, Pyridylmethyl, Furfuryl, Tetrahydrofurfuryl, Thényl, tetrahydrothenyl, pyrrolylmethyl, pyrrolinylmethyl or 4 pyrrolidinylmethyl, with the precision that when R Represents an alkyl group, a phenyl group, a substituted phenyl group, a benzyl or a p-hydroxybenzyl, Y does not represent a methylene radical; and with the additional precision 4 that when R represents a p-methoxybenzyl and Y represents- 2 3 if a methylene is present, R and R are different. 3. A method according to claim 1 for preparing 1 compounds of formula I where R is a hydroxy, an alkanoyloxy 49 inferior, a benzoyloxy, a phosphonooxy or an alkoxy- lower carbonyloxy; is a lower alkoxy or a 3 - 4 lower alkenyloxy; R is a lower alkoxy; R is a substituted p'-phenyl; and X is an oxygen or sulfur atom and Y is a methylene or an imino. 4. A method according to claim 1 for the preparation 1 4 of compounds of formula I where Y is an imino and R -R and X are such as in claim 3. 5. A method according to claim 1, for the preparation of 4-ethoxy-2-hydroxy-S-methoxy-N — Cp-methoxybenzyl]benzamide. B. Process according to claim 1 for the preparation of the diacid phosphate of 2-[[p-anisylamino]carbonyl]-5-ethoxy-3-methoxyphenyl and its disodium salt. 7. Process according to claim 1 for the preparation of 1-C4-ethoxy-2-hydroxy-6-methoxyphenyl]-3-C4-methoxyphenyl ]-1-propanone. 8. A method according to claim 1 for the preparation of 5-ethoxy-3-methoxy-2-C3-CP-methoxyphenyl]-propionylDphenyl-acetate. 9. Process according to claim 1 for the preparation of 2-hydroxy-4,S-dimethoxy—N — Cp-Cmethylthi o]benzyl]benzami de. 10. Process according to claim 1 for the preparation of 2- £/[p-[allyloxy]benzyl]amino/carbonylJ -3,5-dimethoxy-phenyl-benzoate. 11. Process according to claim 1 for the preparation of 1-[4-ethoxy-2-hydroxy-S-methoxyphenyl]-3-[4-methoxy-phenyl}-1-propanethi one. SD 5 10 12. Method according to claim 1 for preparing the 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenyl]propionyl]phenyl-ethyl-carbonHte. 13. A process according to claim 1 for the preparation of 2-hydroxy-S-methoxy-4*-propoxy-N-Cp-methoxybenzyl]-benzamide; 14. A process according to claim 1 for the preparation of 4-[allyloxy-2-hydroxy-S-methoxy-N-Cp-methoxybenzyl]-benzamide; 15. A process according to claim 1 for the preparation of 2-hydroxy-6-methoxy-4-[3-methyl-2-butenyloxy-3-N-Cp-methoxybenzyl]-benzamide; 16. A process according to claim 1 for the preparation of 2-Cp-anisylamino-carbonyl-3-3-methoxy-5-propoxyphenyl-phosphate disodium.;51;17) A process according to claim 1 for the preparation of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-[3,4-(methylenedioxy)-phenyl]-1-propanone, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-[4-(methylthio)phenyl]-1-propanone, 1-(2-hydroxy-4,6-5-dimethoxyphenyl)-3-(4-methylphenyl)-1-propanone, 1-(4-ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl)-1-propanone, diacid phosphate of 5-ethoxy-3-methoxy-2-[3-Cp-methoxyphenyl]-propionylDphenyl ^ 1-(2-hydroxy-4,6-;dimethoxyphenyl) -3 - (4-methoxyphenyl) - 1-propanone-oxime -- Cisomer Z3# 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(4-;methoxyphenyl)-l-propanone-oxime[isomer E3, 2-hydroxy-4, 6-dimethoxy-N-(p-methoxyben zyl)benzamide, 3-(4-chloro-phenyl) -1 - (2-hydroxy-4 ,6-dimethoxyphenyl)-1-propanone,;1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(5-methyl-2-furyl)-15 1-propanone, 1-( 2-ethoxy-6-hydroxy-4-me'thoxyphenyl)-3-;(4-methoxyphenyl)-1-propanone, 1-(2-hydroxy-4,6-dimethoxy-phenyl)-3-(4-methoxyphenyl)-1,3-propanedione, 1-(2-hydroxy-6-methoxy-4-propoxyphenyl)-3-(4-methoxyphenyl)-l-propanone, 1-(2-hydroxy-4-isopropoxy-6-methoxyphenyl)-3-2o(4-methoxyphenyl)-1-propanone, 1-(2-hydroxy-4,6-dimethoxy-phenyl)-3-( té"tr ahydro- 5-methy 1-2 -furyl) -1-propanone",;2-hydr oxy-4,6-dimethoxy-N-(4-methoxyphenyl)ben z amide, N-benzyl-2-hydroxy-4, 6-dimethoxybenzamide, 2-hydroxy-4, 6-dimethoxy-N-[m,p-(methylenedioxy)benzyl]benzamide,;25 2-hydroxy-4,6-dimethoxy-N-(m-methoxybenzyl)-;benzamide, 2-hydroxy-4, 6-diraethoxy-N-(p-methyl-benzyl)benzamide, N-(p-chlorobenzy1)-2-hydroxy-;52;/;-4,6-dimethoxybenzamide, N-furfury1-2-hydroxy-4,6--dimethoxybenzamide, 2-hyçlroxy-4,6-dimethoxy-N--methylbenzamide, 2-hydroxy-N-(m-hydroxy-p-methoxy-benzyl)-4, 6-dimethoxybenzamide, N- (m,p-dimethoxy-5' benzyl)-2-hydroxy-4,6-dimethoxybenzamide, 2-hydroxy--4, 6-dimethoxy-N- [(4-pyridy1) methy1] benzamide, N-(p-butoxybenzyl)-2-hydroxy-4,6-dimethoxybenzamide, ■ 2-hydroxy-N-(p-hydroxybenzyl)-4,6-dimethoxybenzamide, N-[(p-dimethylamino)benzyl]-2-hydroxy-4,6-dimethoxy-10 benzamide, N-[p-(benzyloxy)benzyl]-2-hydroxy-4,6-;dimethoxybenzamide, 2-hydroxy-4, 6-dimethoxy-N- (2-the'nyl)-benzamide, N-[p-(al lyloxy)benzyl]-2-hydroxy-4, 6-dime'thoxybenzamide, 2-hydroxy-4,6-dimethoxy-N-(tetrahydro-2-thenyl)benzamide, 2-hydroxy-4,6-dime'thoxy-N-[(2-pyrrolyl)-3' methyllbenzamide, 2-Cp-anis'ylamino)carbonyl]-5-ethoxy--3-me'thoxyphenyl-acetate , 2--[/T [p- (allyloxy)benzyl] amino__7 carbonylJ"-3, 5-dimethoxyphenyl-octadecanoate, 4-ethoxy-2-hydroxy-6-methoxy-N-(p-methoxyben zyl)thiobenzamide,;1-[2-hydroxy-6-me'thoxy-4-(methylthio)phenyl]-3-( 4-methoxy-2ophenyl)-1-propanone, 5-ethoxy-3-methoxy-2-[ 3-(4-methoxy-;phenyl)propionyl]-phenyl-octadecanoate, 5-ethoxy-3-methoxy-; , 5-dimethoxypheny 1-ethyl—carbonate, 2-[(p-anisylamino)carbonyl]-3,5-;25-dimethoxyphenyl-benzoate, 2-[(p-anisylamino)-carbonyl]-3, 5-dime'thoxypheny 1-octadecanoate, 2-[(p-anisylamino)carbonyl]-3, 5-dimethoxyphenyl—;tetra-0~^cetyl-;3-D-glucoDvranoside, 2-[(p-anisylamino)-;* 53 carbonylJ-3,5-dimethoxyphertyl-|3-D-glucopyranoside, 5-ethoxy-3-methoxy-2-[3-[4-methoxyphenylDpropionyl]-phenyl ^.-Dtrglucopyranoside, 5-ethoxy-3-methoxy-2-C3-[4-methoxyphenyl DpropionylDphenyl-phosphate disodium, 2-[[p-anisylaminoDcarbonylD-3,5-dimethoxy-phenyl diacid phosphate. 54 1B. A process for preparing compounds of formula I given in claim 1 or of one of its pharmaceutically acceptable salts, which involves mixing a compound of formula I or one of its pharmaceutically acceptable salts with an inert, non-toxic, pharmaceutically acceptable support, and processing the mixture to give a pharmaceutical dosage formulation. . ORIGINAL in d5L pages containing References —»— me «joui© ffioî scratched null CURAU Industrial Property Consultancy 26 bu, Bou( Princess Charlotte) MONTE CARLO nroct i r»! !om f -4lo . juatu jPoeifl. J G. ■