Oxamic acid derivatives as hypocholesteremic agents.

Mixed acetic acid derivatives

Full description

Background of the invention:

This invention relates to derivatives of mixed acetic acid as defined herein which are particularly useful as effective agents in reducing the percentage of body fat, methods of preparing them from the same source, pharmaceutical compositions containing the forbidden compounds, and a method for treating the condition of hyperlipidemia, especially hypercholesterolemia, and similar conditions in mammals. By coadministration of the mentioned compounds or the mentioned pharmaceutical formulations that contain the compounds.

General description of the invention:

The compounds in this invention are selected thyromimetic lipid-lowering agents that increase the processes of cholesterol clearance in the form of low-density lipoproteins (LDL).

These agents upregulate (increase) the function of mammalian hepatic low-density lipoprotein (LDL) receptors within the mechanism.

Therefore, the compounds in this invention are initially limited to reducing all levels of cholesterol present in plasma in mammals, and in particular to reducing cholesterol levels in low-density lipoproteins (LDL). Therefore, the compounds of this invention are expected to be useful in preventing and/or treating applicable cardiovascular disease conditions in which excess lipids and excess lipoproteins are involved in their manifestation, such as: atherosclerosis and heart disease related to coronary obstruction (angina) in mammals. Detailed description of the invention:

The invention relates in particular to compounds with formula (I):

<img file="SA983B1_D0001.tif" />

In which:

R represents hydrogen, hydroxy, esterified or etherifiedhydroxy;

Rl represents hydrogen, halogen, trifluoromethyl or low alkyl;

R2 represents hydrogen, halogen, trifluoromethyl or low alkyl;

R3 forms a halogen, trifluoromethyl or aryl-lower alkyl, aryl - lower alkyl-aryl, cycloakyl or cycloakyl - low alkyl or R3 represents the moiety

<img file="SA983B1_D0002.tif" />

In which R8 represents hydrogen, low alkyl, aryl, cycloalkyl, or lower alkyl; And R9 represents hydroxy or acyloxy; R10 represents hydrogen or alkyl, lower alkyl; Or R9 and R10 together represent oxo;

R4 represents hydrogen, halogen, trifluoromethyl, or lower alkyl; W represents oxygen O or cuprene S; R7 represents hydrogen or low alkyl;

Z represents a carboxyl or a carboxyl derived as a pharmaceutically acceptable ester or as a pharmaceutically acceptable amide and its pharmaceutically acceptable salts. Particular embodiments of the invention relate to compounds of formula (I) in which: (a) R is located at position 4; Rl and R2 are located at positions 3 and 5; (b) W represents oxygen; (c) R4 represents hydrogen;

(d) R represents hydroxy, esterified hydroxy or esterified hydroxy; (e) Z represents a carboxyl or carboxylate esterified as a pharmaceutically acceptable ester;

<img file="SA983B1_D0003.tif" />

(f) R3 represents the slit

, or low alkyl or aryl-alkyl

Low or cycloalkyl - low alkyl. A preferred embodiment of the invention relates to compounds of Formula II

<img file="SA983B1_D0004.tif" />

where R represents hydroxy, esterified hydroxy, or etherified hydroxy; R1 and R2 individually represent hydrogen, halogen, trifluoromethyl, or alkyl C1-C3; And R3 represents lower alkanoyl or hydroxy - lower alkyl or carbocyclic aryhnetnyl carbocyclic aroyl or aryl carboxylic -hydroxymethyl; And R7 represents a reduced hydrogen or alkyl; And Z represents carboxylate Carboxyl or carboxyl derived in the form of an ester or amide that is pharmaceutically acceptable; Its salts are pharmaceutically acceptable.

Another embodiment of the invention relates to formula III compounds

<img file="SA983B1_D0005.tif" />

where R represents hydroxy, esterified hydroxy, or etherified hydroxy; And R1 represents hydrogen, halogen, trifluoromethyl, or C1-C3 alkyl; And R2 represents a halogen or trifluoromethyl, or in which R represents a hydroxy, hydroxy ester, or hydroxy ether; And R1 represents hydrogen, halogen, trifluoromethyl, or C1-C3 alkyl; It represents a halogen, trifluoromethyl, or alkyl containing 1-3 carbon atoms R3 represents the low alkyl, carbocyclic aroyl, carbocyclic arylmethyl or carbocyclic aryl-hydroxymethyl, R7 represents the low alkyl hydrogen or Z-d-carboxyl or carboxylic derivative.

Carboxyl in the form of an ester or amide is pharmaceutically acceptable and it is a pharmaceutically acceptable salt. Derived from the same source.

Distinctively, Z represents a carboxyl or a carboxyl mixed with an ester in the form of a pharmaceutically acceptable ester. Preferably, Z represents: an alkoxycarbonyl with 1-4 carbon atoms.

The aforementioned compounds with the formula (III) are preferred, in which R represents hydroxy, loweralkanoyloxy, low alkoxy or tetrahydropyranyloxy R2. Rl tetrahydropjranyloxy It is preferable that they be identical and represent a halogen or its alkyl with 1-3 C1-C3alkyl carbon atoms, R3 represents its alkyl with 1-3 C1-C3alkyl carbon atoms or a monocyclic arylmethyl carbocyclic arylmethyl, R7 represents a hydrogen or its alkyl with 1- 2 C1-2-alkyl carbon atom Z We form a carboxyl or a carboxylic derivative such as an ester or amide that is pharmaceutically acceptable and salts that are accepted pharmaceutically or derived from the same source. The most preferred meanings are those for compounds with formula (III) in which R is hydroxy, lower alkanoyloxy, lower alkoxy, or tetrahydropyranyloxy, R1. R2 preferably be identical, and represent a halogen or its alkyl 1-3 C1-C3alkyl carbon atoms, R3 represent a carbocyclic aroyl or carboxylic aryl-hydroxymethyl atom, R7, a carbocyclic aryl-hydroxymethyl form a hydrogen or its alkyl 1-2 C1-C2alkyl atoms. Carbon, Z is a carboxyl or a carboxyl derivative in the form of an ester or a pharmaceutically acceptable amide and pharmaceutically acceptable salts derived from the same source.

What is more preferred are the denatured compounds with the formula (III), in which R represents hydroxy R2, R1, hydroxy are identical and represent chloro or methyl R3, methyl is isopropyl, benzyl or benzyl, we replace it with halogen, lower alkyl, and alkyl.

Lower alkoxy or trifluoromethyl R7 trifluorometnyl forms hydrogen Z, hydrogen forms a carboxyl or lower alkoxycarbonyl, and pharmaceutically acceptable salts derived from the same source.

Compounds with formula (III) in which R is the hydroxy R2 are particularly preferred. R1 hydroxy are identical and represent an alkyl with 1-3 carbon atoms, such as methyl, or a halogen, ml of chlorine or bromo. R3, bromo represents (a) phenyl - hydroxymethyl or phenyl - hydroxymethyl - phenyl - hydroxymethyl replaced in phenyl with a halogen, alkyl Low, low alkoxy or trifluorometnyl, or, (b) benzoyl or benzoyl halogen-substituted alkyl Low alkoxy, or trifluorometnyl, or, (c) alkyl with 1-3 carbon atoms C1-3alkyl, Like isopropyl R7, isopropyl forms a hydrogen, and Z represents a carboxy or alkoxycarbonyl C1-C4alkoxycarbonyl carbon atoms, and are acceptable salts.

Pharmaceutical or derived from the same source.

Also, compounds with the formula (III) are particularly preferred, in which R is a hydroxy, R2, Rl, and hydroxy are identical and represent an alkyl containing 1-3 C1-3alkyl carbon atoms, such as methyl, or a halogen, such as chloro or bromo, R3, bromo provides (a): phenyl-hydroxylmethyl replaced in the vinyl with the halogen fluoro or chloro, or (b): Benzoyl is substituted with a halogen, fluoro or chlorine, or (c) the alkyl has 1-3 C1-3alkyl carbon atoms, such as isopropyl R7, isopropyl forms a hydrogen and Z represents a carboxy or alkoxy-carbonyl with C1-C4alkoxycarbonyl 4-1 atoms.

Carbon and pharmaceutically acceptable salts derived from the same source. Compounds with formula (III) are particularly preferred, in which R is a hydroxy, R2, Rl, and hydroxy are symmetrical and represent chloro or methyl, and R3 is a phenyl.

- Phenyl-hydroxylmethyl or phenyl - Hydroxymethyl phenyl-hydroxylmethyl is replaced in phenyl with a halogen such as, low alkyl, low alkoxy or trifluoromethyl R7, faloro methyl forms a hydrogen and Z forms a carboxyl or lower alkoxycarbonyl, and pharmaceutically acceptable salts are derived. From the same source.

Compounds with formula (III) are also particularly preferred, in which R is a hydroxy, R2, Rl, and hydroxy are identical and represent an alkyl containing 1-3 C1-C3alkyl carbon atoms, such as methyl, or a halogen, such as chloro or bromo, R3, bromo. Representing: (a) 4-halo-phenyl-hydroxylmethyl, especially in those in which the halo is represented by fluoro or chloro, or (b): An alkyl has 1-3 C1-C3alkyl carbon atoms, especially isopropyl R7. Isopropyl forms hydrogen and Z represents a carbocylic or alkoxy-carbonyl. It has 1-4 C1-C4alkoxycarbonyl atoms.

Carbon and pharmaceutically acceptable salts derived from the same source. A certain number of compounds of this invention which contain one or more asymmetric centers may appear as racemates, enantiomers and mixtures of the same source, all of which are provided in light of this invention. The definitions used here, unless they refer to other things, give rise to the following meanings in light of the invention. An aryl represents a cyclic carboxylic or mixed aryl. A carbocyclic aryl that represents either an optionally substituted phenyl or an optionally substituted naphthyl.

Optionally substituted phenyl preferably represents phenyl or phenyl substituted with 1 to 3 substituents, such as hydroxy alkyl, lower alkoxy, lower alknoyloxy, halogen.

Halogen, cyano, trifluoromethyl, lower alkanoylamino or alkoxycarbonyl.

The optionally substituted naphthyl represents 1- or 2-naphthyl or 1- or 2-naphthyl which is preferably substituted by a low alkyl, low alkoxy or halogen.

The mixed cyclic aryl preferably represents a monocyclic mixed aryl such as an optionally substituted thienyl, furanyl, pyridyl, pyrrolyl or N-lower alkylpyrolyl. The optionally substituted fiiranyl represents 2- or 3-furanyl or 2-3-firranyl, which is preferably substituted with a lower alkyl. The optionally substituted pyridyl represents 2-3- or 4-pyridyl, which is preferably substituted with a lower alkyl or halogen. The optionally substituted thienyl represents 2-3-thienyl, which is preferably substituted with a lower alkyl.

Optionally substituted pyrrolyl or lower pyrrolyl, respectively, represent 2- or 3- pyrrolyl or n-lower alkyl - 2- or 3-pyrrolyl or represent 2- or 3- pyrrolyl or n-lower alkyl. - N-lower alkyl - 2 or 3 - pyrrolyl, preferably replaced by a lower alkyl.

The aryl in the form of lower aryl and its equivalent preferably phenyl or phenyl substituted with one or two lower alkyls, lower alkanoyloxy, halogen, trifluoromethyl, cyano, lower alkanoyloxy. alkanoylamino or lower alkoxycarbonyl.

Low alkyl aryls, preferably benzyl or phenethyl, optionally substituted with one or two low alkyl, low alkyl, hydroxy, lower alknoyloxy, halogen, or trifluoromethyl.

The hydroxy mixed with an ester represents an acyloxy, such as an acyloxy derived from an organic carboxylic acid, preferably lower aklanoyloxy, aroyloxy or aryl - low aklanoyloxy, and also, 12, 7, 3 (3 alpha, 5 beta, 7 alpha). 12 alpha a) trihydroxy-cholan-24-oloxy (derived from cholic acid), and the like.

The hydroxy mixed with an etherified ether preferably represents the low alkoxy, the low alkoxy, the cycloxy with 5-7 C5-C7cycloalkyloxy carbon atoms, the carbocyclic (cyclic carboxy) aryl-lower alkoxy, the teahydropyranyloxy, the cyclic alkyl with 7 -5 C5-C7cyclokyloxy carbon atoms - low alkoxy, and the like.

Carboxyl derivatives in the form of a pharmaceutically acceptable ester represent a carboxyl mixed with an ester and are characterized as a pre-drug ester which can be converted by dissolution or under physiological conditions into a free carboxylic acid, preferably lower alkoxycarbonyl (amino, acylamino, mono). Or lower alkoxylcarbonyl, such as: alpha a-lower alkoxycarboxyl, lower alkoxycarbonyl, lower alkoxycarbonyl such as alpha, lower alkoxycarbonyl, low alkoxycarbonyl, and-(di-, low-alkyl-amino, amino-, mono-, alkyl-amino

low, morpholino, piperidino, pyrrolidino, 1-lower alkyl-piperazino)-carbonyl, lower alkoxycarbonyl, heterocyclic carboxycarbonyl (lower alkoxycarbonyl), It is preferable to choose (halo, low alkyl or low alkoxy) substituted benzyloxycarbonyl, or pyridylmethoxycarbonyl, 1-hydroxy, low alkyloxy or low alkoxy. 1-hydroxy, lower alkoanoyloxy or lower alkoxy) Low alkoxycarbonyl, 5-indanyloxycarbonyl, 3-phthalidoxycarbonyl

And (low alkyl, low alkyl or halo)-3-phthalidoxycarbonyl substituted, dihydroxypropyloxycarbonyl in which there are free or protected hydroxy groups in the form of an alkyl, such as: lower alkylidene, benzylidene or 5- Or 6-members of a cyclic alkylidene derivative, characterized by its being (2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl. The carboxyl derivative is a pharmaceutically acceptable diamide that provides a carbamoyl or substituted N-carbamoyl, and is characterized as lower alkylamino, arylamino, di-lower alkylamino, morpholino, and N-alkylamino. -lower alkylpiperazino, pyrrolidino, piperidino },

(Amino or acylamino) lower alkylamino or aryl-lower alkylamino } carbonyl. The term “subscript” refers here to the connection or relationship with organic moieties or compounds in order to be defined with a joining of 7, preferably more and including 4 and preferably one or two carbon atoms, that may be a straight or branched chain. The low alkyl group preferably contains 1-4 carbon atoms, C1-C4-alkyl, and represents, for example, ethyl, propyl, butyl, or distinctively, methyl.

methyl.

The lower alkoxy group preferably contains 1-4 carbon atoms and includes, for example, methoxy, propoxy, isopropoxy, or, more specifically, ethoxy.

A cyclic alkyl represents a saturated cyclic hydrocarbon radical. The preferred cyclic alkyl has 5-7 C5-C7cycloalkoxy carbon atoms, and is characterized by a cyclopentyloxy pentagon, or a cyclohexyl (cyclohexa).

cyclohexyloxy).

cycloalkyl - subscript represents 1 or 2- (cyclopentyl or cyclohexyl) ethyl, 1-, 2- or 3- (cyclopentyl or cyclohexyl) propyl or 1-, 2- or 3- (cyclopentyl or cyclohexyl) propyl. Or 4-(cyclopentyl or cyclohexyl)-butyl. The cycloalkoxy represents a saturated cyclic hydrocarbon radical, preferably C5-C7-cycloalkyl, 5-7 carbon atoms, and is typically cyclopenyloxy or cyclohexyloxy.

The lower alkoxy represents the C5-C7-cycloalkyl, which has 5-7 carbon atoms. The C1-C4-alkoxy, which has 1-4 carbon atoms, is typically cyclopentylmethoxy or cyclohexylmethoxy.

lower alkenyloxy preferably represents allyloxy. Low alkyl amino preferably contains 1-4 carbon atoms in the low alkyl portion and represents, for example, N-methylamino, N-ethyl.

Amino N-ethylamino N-propylamino N-propylamino and N-butyl amino

N-butylamino is characterized by N-ethylamino N-cthylamino.

The low di-alkyl amino preferably contains 1-4 carbon atoms in each part. The low alkyl represents, for example, N,N-dimethylamino, N-methyl, N-ethylamino and N,N-diethyl. Amino N,N-diethylamino.

Lower alkoxycarbonyl preferably contains 1 to 4 carbon atoms in the alkoxy part and represents, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, or more specifically, ethoxycarbonyl. Hydroxy - Low alkyl preferably hydroxymethyl

hydroxymethyl.

A halogen (halo) preferably represents fluoro or chloro, but may also be bromo or iodo.

Lower alkanoyl is preferably acetyl, propionyl, butyryl or pivaloyl.

The new compounds in this invention have valuable pharmaceutical properties. They are powerful lipid-lowering pharmacological agents that reduce cholesterol levels in mammalian plasma.

Reduced alkanoyl is preferably represented by acetyl, propionyl, butionitrile or bivolyl. Low alkanoyloxy preferably represented as acetoxy, pivalyloxy, or pupionyloxy.

١٤

Acyl aminos preferably represent low alkanoyl aminos or aryl aminos, or low aryl-alkoxycarbonyl aminos such as benzoyloxycarbonyl aminos. Low amino alkanoyls preferably represent acetamide and propionamido. The pharmaceutically acceptable salts of any basic compounds that are the subject of the invention are acid addition salts, which are preferably of organic or inorganic acids that are therapeutically acceptable, such as strong mineral acids, such as hydrohalic acids, i.e. hydrochloric, hydrobromic, sulfuric, or phosphoric acid; Or aliphatic or aromatic carboxylic or sulfonic acids, such as acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, maleic, fumaric, pyruvate, phenylacetic, benzoic, pamoic, nicotinic, or methanesulfonic acids. or ethanesulfonic or hydroxyethanesulfonic or 1,2-ethane disulfonic or benzenesulfonic or para-toluene sulfonic: naphthalene sulfonic; Or ascorbic acid.

The compounds of this invention provide a strong combination with the nuclear receptor triiodothyronine (T3), which has a role in regulating the activity of low-density lipoprotein (DDL) receptors, increasing the purification of low-density lipoprotein cholesterol from the blood.

Compounds of this invention are particularly applicable in mammals as cholesterol-lowering agents for the treatment and prevention of cardiovascular diseases in which excess cholesterol is a factor in their occurrence, by reducing plasma contents of low-density lipoprotein cholesterol. The invention also relates to the use of compounds according to the invention to prepare medicines or treatments, especially medicines useful for treating and preventing cardiovascular diseases in which high cholesterol is involved, by reducing levels of low-density lipoprotein (LDL) cholesterol in the plasma.

There are also industrial preparations of materials in commercial closed form. The properties mentioned above were obtained in laboratory and mammalian tests, using mammals such as: mouse, rabbit, dog, monkey or separated organs, or separated tissues and preparations derived from the same source. The aforementioned compounds can be added in the laboratory in the form of solutions, such as: aqueous solutions In mammals, either internally, intestinally, preferably through the veins, for example: in the form of a suspension or solution.

water.

The dose used in the laboratory may range between about 10 M and 10 M concentration. The dosage used in mammals may range depending on the route of administration

Between about 0.1 and 300 micrograms/kg, preferably between about 0.5 and 100 micrograms/kg, and preferably around 1 and 100 micrograms/kg.

Nuclear T3 receptor conjugates in the laboratory are obtained as follows: mouse rat liver core and plasma membrane preparations are obtained from CD (Sprogue Dawley) rats (Charles River Laboratories or Riuer lais Choyles) by centrifugation. Differential (distinctive) as described in:

EMMELOT E AL (METHODS IN ENZYMOLOGY 31:75, PART A. 1974). g × with minor modifications, the nuclear fraction obtained from the 275

The pellet is purified again as described in: Spindler et al (J. Biol. Chem. 250:4118, 1975). The new test compounds were selected to combine into the nucleus in the manner described in

(Spindler et al (J. Biol. Chem. 250:4118, 1975).) -The nuclei were melted at 2°C with 0.3 nM of [125 I]L. (L-T3 L-T3 - Or) triiodothyronine (triiodothyronine). Parallel incubators were connected to tubes containing in addition to the radioactive nuclei and L-T3 - at different concentrations of the test compounds - or 3 -

Micromole of (L-T3 or T3-L) is unsaturated. The latter was used as a measure of indefinite union.

The radioactive union is obtained into nuclei, followed by the use of centrifugal force on the reaction mixture at 800 × g for 7 minutes, and the small pellets are washed. The amount of [125I]-L-T3 [T3-L-[125I]] combined (radiation contained in small nuclear globules followed by leaving in (3 micromol) of unsaturated L-T3 (L-T3) in excess). The concentration of the test compound that prevents the specific combination of [125I]-L-T3 (T3-L-[125I]) with 50% (IC50) is obtained representatively from a cross-reciprocal diagram of the combination [125I]-L-T3(T3). -L- ) [125I] versus different concentrations of the test compound. Cholesterol-lowering activity is obtained in the fraction as follows: Male Sprague-Dawley rats (230-250g) (tacrine farms) are

Get it as the worker desires and a meal rich in cholesterol (1.5% cholesterol and 0.5% cholesterol) for two weeks before and during the 7-day treatment period. A group of animals is treated orally through tube feeding (introducing food into the stomach with a tube), camels (a liquid in which the drugs are dissolved), either alone or with the test compound for 7 consecutive days without interruption.

After the last dose, the animals fast for 18 hours and then the blood is collected. The blood samples are subjected to centrifugal forces at a sample speed of 2500 dpm (250orpm) for 10 minutes to prepare plasma to obtain all concentrations of cholesterol, low-density lipoproteins (LDL) and high-density lipoproteins. (LDL). High-density lipoprotein (LDL) values are obtained after sedimentation of low-density lipoprotein (LDL) very low-density lipoproteins.

(Sigma chemical CO., St. Louis, MO)

The analysis was performed on the Bio-Mek automated workstation. The low-density lipoprotein (LDL)/very low-density lipoprotein (VLDL) fractions are precipitated in the following manner: 0.35 ml of plasma is divided into Eppendort tubes. To which are added 12 microliters of 2 M manganese chloride, 11.2 microliters of sodium heparin (extracted from pig intestines, 5000 units/ml) and 8.3 microliters of a neutral normal salt solution. The samples are stirred in a vortex-like manner, then left in ice for 15 minutes, then subjected to centrifugation at a temperature of 4°C for 1 minute at a speed of 1,300 rpm. Then the supernatant layer is analyzed with enzymes to obtain the cholesterol concentration. cholesterol.

The concentration of cholesterol present in high-density lipoproteins is adjusted for dilution by multiplying the cholesterol value of the supernatant layer by 1.09. Low-density lipoprotein (LDL)/very-low-density lipoprotein (VLDL) cholesterol values are obtained by subtracting the high-density lipoprotein (HDL) cholesterol value from the total cholesterol value.

Cholesterol-lowering activity can also be provided in dogs with normal cholesterol by feeding them regularly according to the method described above, and by giving the test compound orally for 5 days, and also in monkeys with normal lipids. Illustration of the combined invention

It shows an IC50 of about 0.2 nM in the T3 nuclear receptor binding test. Moreover, the aforementioned compound significantly reduces serum cholesterol at a daily dose equal to about 20 micrograms (μg)/kg.

Oral route in the mouse and about 30 μg/kg orally in the dog. For further clarification, the compound

IC50 = 0.1 nM) significantly reduces serum cholesterol at a daily dose About 5 (μg)/kg orally in the mouse, about 10 μg/kg orally in the dog and about 1 μg/kg orally in the monkey.

<img file="SA983B1_D0006.tif" />

In which R, R1-R4, W, and R7 are as previously defined, preferably with a reactive functional derivative of the compound with the formula.

<img file="SA983B1_D0007.tif" />

in which Z, as previously defined, is in a protected form at will; In the above described process, upon protective protection of any interfering reactive group(s); Said protecting group(s) are removed, followed by isolation of the resulting compound of the invention; As desired, converting any resulting compound of the invention into another compound of the invention and/or, as desired, converting the free carboxylic portion into a pharmaceutically acceptable ester or amide derivative, or converting the resulting ester or amide into the free acid or into another ester or amide derivative, and/ Or as desired. In the primary and intermediate compounds, which are converted into compounds of the invention by the method mentioned herein, the functional groups present therein,

Like carboxyl, amino and hydroxy groups, they may optionally be protected by conventional protected groups that are common in preparative organic chemistry. Protected carboxyl, amino and hydroxy groups are those that can be converted under mild conditions to carboxyl, amino and hydroxy groups. Hydroxy free without any unwanted side reactions. The purpose of providing protecting groups is to protect functional groups from undesirable interactions with reaction components and under the conditions used to obtain a desired chemical conversion, the need and choice of protecting groups for a particular reaction are known to those skilled in the invention and depend on the nature of the functional group to be protected ( hydroxy, carboxyl group, carboxyl group, amino group, etc.), and on the composition and degree of stability of the molecule of which the substituents are a part, and on the reaction conditions. Well-known protective groups that fit these conditions and the method of their introduction and removal are described, for example, in:

JF w. McOmie. “Protective Groups in Organic Chemistry” , Plenum Press, London, New York 1973, T.W. Greene, “Protective Groups in Organic Synthesis” , Wiley, New York 1984, and also in “The Peptides” Vol. I, Schroeder and Luebke,

Academic Press, London New York, 1965.

The active functional derivatives of compounds with formula (5) (oxalic acid derivatives) are preferably halides, mixed anhydrides such as: pivaloyl anhydride or alkoxycarbonyl anhydride, and ester esters such as: low alkyl esters.

The process of adaptation (acyl addition) according to the above-mentioned method for the compound with formula (5) with an active functional derivative of the compound with formula (5) is obtained.

According to a method well known in the invention, by reacting it without a solvent at high temperature or in a chemically inactive solvent such as: dimethylformamide or methylene chloride, preferably in the presence of a base such as: potassium carbonate, triethylamine, Isopropylethylamine pyridine diisoproplethylamine

and the like at room temperature or elevated temperature. For example, depending on the method of preparing compounds in which R6 and R5 together represent oxo, the compound with formula (6) in which XH represents, for example, NH2, is condensed with an ester or amide derivative of oxalic acid, such as: Diethyl oxalate (the active derivative of the compound with formula 5), using diethyl oxalate as a solvent and reagent at high temperature. Conversely, the half-ester half-halid of oxalic acid, such as: ethyl oxalyl chloride, can be used as a derivative of the compound with the formula (5), and the condensation takes place, for example, in a chemically inactive solvent such as: methylene chloride, and in The presence of a base such as potassium carbonate or triethylamine. If the ester half-amid half of oxalic acid is used, its corresponding amide is

Get it.

The starting materials with formula (5) are either known or can be prepared according to methods known to themselves in the invention.

Starting materials with the formula (4), in which XH represents NH2, can be prepared as follows:

A- Adapt 4-nitrophenol (or the corresponding thiophenol) appropriately by replacing it with R1, R2 from formula (6):

<img file="SA983B1_D0008.tif" />

Wherever it is:

R1, R2 and W have the same definitions as previously mentioned here, with bis-aryl iodonium tetrafluoroborate as

Conveniently, it can be replaced by R4, R3, and R from formula (7).

<img file="SA983B1_D0009.tif" />

Where R3, R and R4 represent R3, R and R4 as they were previously defined here, or R3, R and R4 are groups converted to R3, R and R4 in order in the presence of, for example, copper, or a base such as triethylamine and a non-solvent. Chemically active as methylene chloride or:

B- Condensate 4-chloronitrobenzene appropriately, where

Replace with R2, Rl from formula (8):

<img file="SA983B1_D0010.tif" />

With phenol (or u-phenol) conveniently replaced by R3, R and R4 of the formula:

<img file="SA983B1_D0011.tif" />

Where R4, R3, R and W have the same definitions mentioned here previously in the presence of a base such as potassium carbonate in a chemically inactive polar solvent such as: dimethylsulfoxide or N-methylpyrrolidone, and C - reduction of the compound resulting from the formula (10):

<img file="SA983B1_D0012.tif" />

Where R4, R3, R2, Rl, R and W have the same definitions mentioned here previously, and for example by catalytic hydrogenation in the presence of, for example, Raney nickel or palladium on charcoal as a catalyst, in a polar solvent such as glacial acetic acid or... Ethanol to obtain an amino intermediate with the formula (5) or an amino intermediate converted to an amino intermediate with the formula (4). Diaryls - aryliodornium tetrafluoro and borates with the formula (7), for example: where R represents 4-alkoxy or 4-benzyloxy (which may be substituted, for example, by a low alkyl) can be prepared, for example, by condensation of the corresponding and optionally substituted anisole. Benzyloxy benzene with di-trifluoroacetyl iodonium tetrafluoroborate (prepared from iodine, nitric acid

nitric acid, acetic anhydride, trifluoroacetic acid and sodium tetrafluoroborate according to methods known in the invention and described herein. 4- Chloronitrobenzene (4-chloronitrobenzene) with formula (8) can be prepared

From the corresponding 4-nitrophenol with formula (6), by first converting it to trifluoromethylsulfonyl ester, for example, and treating the latter with lithium chloride in a chemically inactive solvent such as: N-methylpyrrolidone or dimethylformamide. 4-nitrophenol can be prepared by nitration of phenol under conditions well known in the invention, for example, with nitric acid in acetic acid or with nitronium tetrafluoroborate. Suitably substituted phenols and thiophenols of formula (11) are known in the invention or are prepared as described herein. Example: A compound with formula (11) can be prepared by the Eries type method to reorganize the suitably substituted acetic acid ester of phenol with aluminum chloride, for example, to obtain suitably substituted hydroxyacetophenone, which is It is protected as an ether, and accordingly it is oxidized under Baeyer-Villiser Comdihim conditions with peracetic acid, for example, to an acetic acid ester with

Substituted phenol, which decomposes to phenol with formula (11). Intermediates with formula , by treating said intermediate of formula

For example, the acylation of a compound of formula X in which R represents 4-alkoxy

or 4-benyloxy R4 and R3, representing hydrogen, with an aryl chloride such as benzoyl chloride optionally substituted in the presence of titanium chloride in methylene chloride, yielding the corresponding compound of formula X in which R1 represents 4-alkoxy or 4-benzyloxy, and R3 represents 3 - Aroyl - and R4 represents hydrogen. The adhesive conversion of a compound of formula

Intermediate compounds with formula Intermediates with formula X in which R3 represents aryl-hydroxymethyl can be reduced using, for example, alkali metal borohydride, such

Hydroxymethylation using, for example, alkali metal borohydride, e.g

Sodium or lithium borohydrate in a polar solvent such as methanol or acetic acid, and the aforementioned ketone intermediates with formula And R3 represents a {yl-hydroxymethyl}.

Intermediates with formula IV, in which R7 represents hydrogen, can be converted into intermediates

In which R7 is different from hydrogen according to methods well known in the field of converting a monoamine to a diamine, for example by reductive alkylation, and in the case where R7 is methylated, the conversion can be achieved by treatment.

With ethyl chloroformate, this is followed by reduction with lithium aluminum hydride. Reducing compounds can be converted into each other according to traditional methods. Therefore, for example, the resulting amides or esters may be hydrolyzed with alkalis.

Aqueous substances, such as: hydrolyzed hydroxides or alkali metal carbonates. The resulting free acids may be ester mixed with, for example: the aforementioned substituted or unsubstituted alkanols, or derivatives mixed with an ester and active and derived from the same source, such as alkyl halides or diazoalkanes. It can also be converted Free acids are converted into (metal) metal, ammonium or acid mentioned in addition to salts in the traditional way. Therefore, any resulting free acid can be converted into the corresponding acid, ammonium, or metal (metal) plus a salt, respectively, by reacting it with an equal amount of the corresponding base or an ion exchange preparation, for example, free acids denatured with an alkali (base), ammonium hydroxides, or carbonates. Any resulting salt can also be converted into a free compound, by liberating the latter with strong acids, given the close relationship between the free compounds and the salts derived from them, wherever there is a reducing compound or an intermediate, here in the context of the conversation, it returns to the corresponding salt, which is also intended or intended. It is provided as probable or provisional under the circumstances.

Compounds according to reduction in which R3 represents group (a):

<img file="SA983B1_D0013.tif" />

In which R9 and R10 together represent oxo, they can be converted into compounds of the invention where R3 represents group (a) where R9 is hydrogen and R10 is hydroxy, for example by reduction, and for example by treatment, a suitable hydride and an optionally complex such as a hydride formed. From an element from group 1 and 3 of the periodic table of elements, such as: borohydride or sodium cyanoborohydride,

Compounds of the invention in which R3 represents a group (a) where R9 is a hydrogen and R10 is a hydroxy can also be reduced to compounds of the invention in which R3 represents a group (a) where R10 and R9 represent hydrogen, for example with hydrogen using catalytic hydrogenation.

Compounds, including their salts, can also be obtained in the form of hydrates or with other solvents used in the crystallization process. Moreover, functional derivatives of free acids with the formula (I), in which, for example, the carboxy is mixed with an ester, can be prepared by condensation of the free acid with the formula (I). ) with an esterifying agent of the formula.

(XI) R9-Y

Where Y represents an active hydroxy or hydroxy group mixed with an ester, and R9 represents an ester radical as defined here previously for esters (carboxy mixed with an ester).

The active hydroxy group mixed with an ester. The Y range in the compound with formula (11) is a hydroxy group mixed with an ester via a strong organic or inorganic acid. The corresponding Y groups are particularly halo, such as: chloride, bromo, or preferably iodo. iode and also sulfonyloxy groups, such as (methane, ethane, benzene, or toluene) sulfonyloxy groups, and also the trifluoromethylsulfonyloxy group.

The process of adding isto to a carboxyl group, optionally in the form of a salt, with the compound with the formula (11) where Y represents a hydroxyl group mixed with an active ester, takes place in a way known by itself, in the presence, for example, of an organic base such as an organic amine such as a tertiary amine such as:

Tri-lower alkylamine, such as: trimethylamine, triethylamine or ethyl-di-isopropylamine, N,N-di-alkyl-aniline -N,N-di- lower-alkyl-aniline, such as: n,n-di-methylaniline

, a cyclic tertiary amine such as N-morpholine, which is malcan

low, such as:

N-methyl-morpholine, a pyridine-type base, such as: pyridine, an inorganic base, such as: hydroxides, carbonates, or hydrogen carbonates of alkali metals or alkaline earth metals (metals). Such as hydrogen carbonates, carbonates, sodium hydroxides, potassium, calcium, or a quaternary ammonium base, such as: Tetrakyl ammonium hydroxide, carbonates or hydrogen carbonates such as those in which the alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl or the like, or an alkali metal salt of the di-trikylpenticillyl amide (e.g.: Trimethyl) and it is reported in the presence of Crown ether such as: 18-Crown - 6 - in a suitable chemically inactive solvent or solvent mixture, such as: acetonitrile and the like. The process of esterification (adding an ester) of a compound with a free carboxyl group using an excess amount of alcohol with the formula (11) (where Y represents a hydroxy) can be obtained in a method known by itself, for example: in the presence of a catalytic acid (acid catalyst), such as: sulfuric acid Or boron trifluoride etherate, preferably at a high temperature, preferably ranging from 40 degrees Celsius to 100 degrees Celsius. Conversely, the process of esterification of a compound with a free carboxyl group can take place with at least an equal amount of alcohol in the presence of a thickening agent such as dihexyl cyclohexyl.

Dicyclohexylcarbodiimide or N(3-dimethylaminopropyl) N-ethylcabodiimide in a polar solvent such as methylene chloride, in the presence of a base if desired, such as: 4- (Dimethylamino)pyridine 4-(dimethylamino)pyridine. Similarly, free carboxylic acids can also be converted into amides using methods well known in the invention, for example in the presence of a condensing agent such as: 2-ethoxy-carbonyl 1,2-dihydroquinoline (EEDCe). 1,2-dihydroquinoline). Conversely, carboxylic acids can be converted into compounds of the invention with a carboxyl group using methods and conditions generally known in the invention and described herein. Depending on the type of ester involved herein, the useful reagents include acids or bases, i.e. benzyl esters that can be selectively graded with, for example, hydrogen. In the presence of a catalyst such as palladium on charcoal. Compounds in which R represents a hydroxy mixed with an ester or a hydroxy mixed with an ether can be converted into compounds in which R represents a hydroxy using methods well known in the invention.

For example, compounds in which R represents methoxy can be treated by boron tribromide or boro trichloride in dichloromethane, for example, to obtain compounds in which R represents hydroxy. Also, if R represents benzylox, these can Extracting gasoline from it by decomposing it by adding hydrogen in the presence of palladium, for example, as a catalyst. In the case of hydroxy mixed with an ester, the ester can be separated from it with an aqueous acid, for example, or a base, such as lithium or sodium hydroxide.

In the case of mixtures of stereoisomers or optical isomers obtained, they can be separated into individual isomers by well-known methods; for example, on the basis of the physicochemical differences of the components, for example, by partial crystallization, the racemic products or intermediates can be Re-dissolving them into optical electrodes through known methods, mainly by separating the diasteromeric salts derived from them, through recrystallization processes [for example: For basic compounds by partial crystallization of the salts L-alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine or dehydroabietylamine, brucine or strychnine. ), from an optically active solvent, and condenser chromatography of gas molecules (distinctive), with the addition of suitable microorganisms by cleavage with immobilized enzymes, by forming implicit compounds, for example using ethers, A single enantiomer is one that is complexed or synthesized, or by conversion to diastereomeric slat salts, for example by reacting the last basic racemic substance with an optionally active acid, such as: carboxylic acid, such as: tartaric acid, malic acid, or sulfuric acid. sulfonic acid, such as: camphorsulfonic acid, and separating the mixture

Diastereomers are obtained in this way, for example: on the basis of their difference in degree of solubility, to diastereomers from which the enantiomer can be liberated if desired by appropriate reagents.

The conversions mentioned above can be carried out according to certain standard methods for the reactions involved in the presence or absence of diluents, preferably those that are chemically inactive towards the reagents and solvents derived from them, where the catalysts are 4 alkaline, acidic, condensing or other factors mentioned in order and/ Or atmosphere

Generally chemically inactive, at low temperature, room temperature or elevated temperatures preferably close to the boiling point of the solvent used under atmospheric pressure.

The present invention also relates to new starting materials that have been developed to specifically suit the process of manufacturing compounds belonging to the invention, and in particular the process of manufacturing compounds belonging to the invention, and in particular the selection of starting materials producing the final compounds, which go back to what was detailed in the beginning, where the variables had the same definitions and meanings mentioned, To manufacturing processes from the same source, to their use as intermediate materials.

Moreover, the invention includes any variables in the aforementioned processes, in which the intermediate product is obtained in any step of the process and is used as a starting material in any remaining steps that can be completed, or the process is not continuous at any of them or in those in which In which the starting materials were formed under the reaction conditions, or in those in which the reaction components are used in the form of their salts or pure optical electrodes, and in particular, these starting materials must be used in the mentioned reactions, which lead to the formation of those The compounds mentioned above were preferred.

The invention relates in particular to the processes described in the examples: In addition, the present invention relates to use in mammals to treat increased cholesterol concentrations in the blood using the compounds of the invention or drug compositions derived therefrom, such as:

Cholesterol-lowering agents, such as: reducing cholesterol found in low-density lipoproteins by giving them to mammals that need an effective therapeutic amount of the aforementioned compound.

Pharmaceutical compositions of the invention are those suitable for enteral, oral or rectal, transdermal and non-enteral administration to mammals, including humans, for the treatment of increased blood cholesterol concentrations, including a significant amount of the active medicinal compound of the invention alone or combined with one or More than pharmaceutically acceptable carriers.

The active pharmaceutical compounds of the invention are useful in the manufacture of pharmaceutical compositions containing a significant amount thereof in a mixture or combination with excipients or carriers suitable for either enteral or non-enteral administration. Gelatin tablets and capsules containing the active ingredient are preferred with, a) : diluents such as: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) : lubricants &amp;, Such as: silica, talcum, stearic acid, its salts of magnesium or calcium, and/or polyethyleneglycol, for tablets, and also, c): conjugates &amp; conjugates &amp;: ml: Aluminum magnesium silicate, nragnesium alunrinum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, and d): disinteyrants, such as: starches, agar, acid Alginic acid or its sodium salt, or foaming mixtures, and/or, e): absorbers, colorings, flavors and sweeteners. The compositions that are injected are preferably evaporated aqueous solutions or suspensions, or the satellites are preferably fat emulsions or suspensions. The aforementioned compositions can be sterilized and/or contain auxiliary materials such as preservative agents, stabilization, wetting or emulsification, solution controllers, salts for regulating osmotic pressure. And/or polish.

In addition, the compositions may also contain other valuable therapeutic substances. The decant compositions may be prepared according to conventional mixing methods, coating methods or filtration methods, respectively, and contain from 0.1 to 75% and preferably from 1 to 50% of the active ingredient.

Formulations suitable for transdermal administration comprise a significant amount of compounds of the invention with a carrier. The preferred carriers are those that include pharmaceutically acceptable and absorbable solvents to aid transport through the host's skin. Specifically, transdermal delivery devices are in the form of a bandage containing an organ. Or a portion that is gained to support it, a repository containing the compound, optionally with carriers, and optionally also a barrier or dam that controls the rate of transfer or delivery of the compound to the host's skin at a controlled and estimated rate over a long period of time, and means of securing the device to the skin.

The dosage unit for mammals is about 50 to 70 kg and may contain about 0.01 mg and 10 mg of the active ingredient. The dose of the active compound depends on the type of warm-blooded animal (mammal), body weight, age, internal conditions, and on the method and quality. Giving and on the compound involved in the subject. The following examples are intended to illustrate the invention but do not express a specific definition or restriction beyond that. Temperatures were given in degrees Celsius. If not stated elsewhere, all types of evaporation were carried out under reduced pressure, preferably between 15 and 100 C. mHg.

Reducing pressures were defined in mmHg or torr. Hydrogenation pressures are obtained as atmospheric pressures or as (pounds/quarter inch). Other abbreviations are those tinkerers (measurers) in invention.

Example (1):

37.5 g of dimethyl oxalate, 5-di-methyl-4-(3-isopropyl-4-methoxyphenoxy)-enlene 3,5-dimethyl-4-(3-isopropy!-4-methoxyphenoxy) are added. )-aniline, this thread is stirred at a temperature of 120 for 4 hours, the excess dimethyl oxalate is removed under a high vacuum in a hot water bath, and the precipitate is analyzed by chromatographic method on silica gel using 95:5 to 90:10 toluene: Ethyl acetate as a diluting agent to produce a crude product that is crystallized from toluene to give methyl N-[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl]oxamate.

N-[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl] oxamate NMR (CDCI3): &amp; 1.1 (6H, d), 2.1 (6H, s), 3.2 (1H, m), 3.7 (3H, s). 4.0 (3H.s), 6.3 (lH, dO d), 6.6 (1H, d). 6.7 (lH, d), 7.3 (2H, s) 8.7 (lH, s).

The structural formula is:

<img file="SA983B1_D0014.tif" />

The starting material is prepared as follows:

2- Isopropylphenol (300 g), 262 mM dimethyl

Dimethyl sulfate, and 1500 grams of potassium carbonate in a liter of acetone are mechanically stirred to the point of vapor return for 6.5 hours, the mixture is filtered, the filter is washed with acetone, the combined filter is removed, and the precipitate is redissolved in ether, then gets rid of by

2N sodium hydroxide (twice) and salt water such as sea water (once). The ether is dried, filtered, and separated to leave an oil which is distilled under high vacuum to give 2-isopropylanisole,

Boiling point: 39 degrees Celsius.

Concentrated nitric acid (more than 90%, 12.4 ml) is added dropwise to 31.4 ml of acetic anhydride chilled in dry ice/carbon tetrachloride, iodine (11.26 g) is added in one part followed by With 20.5 ml of trifluoroacetic acid in drops. The mixture is stirred at room temperature until all the iodine and nitrogen oxides are dissolved. It is purged and cleaned with nitrogen gas. The solution is then stirred in a high vacuum at less than 40°C to give a solid, which is redissolved in 126 mM anhydride. anhydride, and re-cooled in dry ice/carbon tetrachloride. 2- Isopropylanisole (40 g), 151 mM anhydride

Acetic anhydride and 22.6 mM trifluoroacetic acid are added dropwise and the solution obtained is allowed to leave in the refrigerator overnight. The solution is left to separate under high vacuum at less than 40°C, taken in 150 mM methanol, and treated. With 150 ml of 10% (w/g) sodium, disulfide and a liter of 2 V sodium tetrafluoroborate. When the precipitate is collected, the supernatant is filtered and the precipitate is crushed with hexane to give crystals which are filtered, washed with hexane and dried at room temperature in vacuum to give: di-(3-isopropyl-4-methoxyphenyl)iodo.

Tetrafluoroborate 3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate.

Di(3-isopropyl-4-methoxyphenyl)uranium tetrafluorobutane

Borate 3-isopropyl-4-methoxohenyl) iodonium tetrafluoroborate (116.51 g) and

19.26 g of copper bronze are stirred in 300 mM dichloromethane and cooled in an ice water bath, a mixture of 25.36 g of 2, 6 - dichloromethane.

Methyl-4-nitrophenol 2.60dimethyl-4-nitrophenol and 6.88 1g of Tri

Ethylamine triethylamine is added in drops. The mixture is stirred in the dark for five days, then filtered through Celite to remove copper. The filtrate is separated and the precipitate is subjected to chromatography on silica gel with 98:2 hexan: ethyl acetate as a diluting agent, to give 3,5-dihydrate. Methyl-4-(3-isopropyl-4-methoxyphenoxy)-nitrobenzene 4.-chloro-3,5-dimethyl-nitrobenzene 6.3 ( NMR (CDCI3): &amp; 1.1 (6H, d), 2.2 (6H, s), 3 3 (lH, m), 3. 7 (3H, s).(lH, d OF d), 6.6 (lH, d). 6. 7 (lH, d), 8. 0(2H,s)

3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-nitrobenzene can also be prepared by the following method:

2,6-dimethyl-4-nitrophenol 2,6-dimethyl-4-nitrophenol (5.00 g) and 6.05 mM pyridine in 50 mM dichloromethane are cooled in an ice/salt bath and 6 04 ml of trifluoromethanesulfonic anhydride for 30 minutes. After cold stirring for an hour, the mixture is quenched with 25 ml of water, the layers are separated, and the organic phase is successfully washed with 2 N hydrochloric acid (twice). , water (twice), 2N NaOH sodium hydroxide and water (twice). The solvent is dried, filtered and separated to give l-4-nitrophenyl trifluoromethane sulfonate 2,6-dimeth. (NMR (CDCL3) S2. 5 (6H, s), 8. 0 (2H, s).

2,6-Dimethyl-4-nitrophenyltrifluoromethanesulfonate (8.54 g) and 3.63 g of lithium chloride are heated in 40 mM DMF at 150 C for four hours. The solvent is fined, the precipitate is stirred with water and ethyl acetate, filtered, and the filtrate is separated. Ethyl acetate is dried, filtered, separated, and the precipitate is subjected to chromatography on silica gel with 98:2 hexane: ethyl acetate, to give 4-chloro-3,5-dimethyl-nitro.

NMR benzene (CDCl) S 25 (6H,S), .9 (2H,S). . 4-chloro-3,5-dimethyl-nitrobenzene

4-chloro-3,5-dimethylnitrobenzine (2.12 g), 1.9 g of 3-isopropyl-4-methoxyphenol, and 1.47 g of potassium carbonate for 18 hours at 125°C in 25 mM dimethylsulfonoxide. The mixture is poured into ethyl acetate.

It is extracted once with water and five times with salt water such as sea water. The ethyl acetate is dried, filtered and separated to give an oil, which is subjected to chromatography on silica gel with 97:3 hexane: ethyl acetate.

To give 3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)

- Nitrobenzene 3,5-dimethyl-4-(3-is0pr0pyl-4-meth0xyphen0xy)-nitr0bezene. 6.3 (NMR (CDCI3): &amp; 1.1 (6H, d), 2.2 (6H, S), 3.3 (1H, m), 3.7 (3H, s).(lH, d OF d), 6 .6 (lH ,d 6 .7 (lH ,d) .

3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy) is hydrogenated -

Nitrobenzene 3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-nitrobenzene (6.0 g) and 600 mg of 10% platinum on carbon in * 2 L of ethanol in a shaker. The catalyst is removed by filtration through Celite and the filtrate is separated to give 3,5-dimethyl-4-(3-isopropyl-4-methoxy)

phenoxy)-ethylene 3,3-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-aniline-

Example (2):

A- 10 g of N-methyl [3,5-dimethyl-4(4-) is added

Methoxy-3-iso-propylphenoxy)-phenyl]-oxamate

N[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl]-oxamate in 150 mM of

Dichloromethane cooled in ice/acetone to 54 ml of 1 M boron tribromide in dichloromethane. The bath is removed and the mixture is poured after stirring it overnight in ice. The layers are separated and the aqueous phase is extracted with ethyl acetate twice. The combined organic phases are dried, filtered and separated to give crude acid. Re-esterification is effected by dissolving it in 100 mM dimethylformamide, cooled on an ice bath and treated with 9.15 g cesium carbonate and 2.66 mM dimethyl sulfate-3-N- [3,5-dimethyl-4-(4-hydroxy

isopropylphenoxy)-phenyl]-oxamate.

After stirring overnight, the mixture is filtered to ethyl acetate and washed 6 times with salt water such as sea water. The organic phase is dried, filtered and separated to give oil, which is subjected to chromatography on silica gel with 10:90 to 75:25 hexane:ethyl acetate. To give N-methyl [3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]

N-[3,5-dimethyl-4-(4-hydroxy-3-ispropylphenoxy)-phenyl]-oxamic oxamate

B- 1.0 N sodium hydroxide (51 ml) is added to 8.70 g of methyl

N-[3,5-dimethyl-4-(4-hydroxy-3-isopropyl)

Phenoxy)-phenyl]oxamate-3-N-[3,5-dimethyl-4-(4-hydroxy isopropylphenoxy)-phenyl]-oxamate in 12 mM methanol, the mixture is heated to the point of vapor return for 30 minutes, and cooled at At room temperature, the solvent is evaporated, the precipitate is dissolved in water, and extracted twice with ether. The aqueous layer is cooled in ice and hydrochloric acid is added to it.

Concentrated hydrochloric acid to make it acidic. The resulting steel is collected and dissolved in ethyl acetate and the solution is dried, filtered and separated. The precipitate is recrystallized from toluene to give N [3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl t-oxmic acid

N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenylJ-0xamate acid, degree

Melting = 183 - 185 degrees Celsius.

Example (3):

5,3-Dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-

N-[3,5-dimethyl-4-(3-isopropyl-4-methylphen0xy]-aniline (10.8 g) - melted at 120°C for 4 hours with 50 g of ethyl oxamate. The cold mixture is crushed twice with hot water, stirred with ethyl acetate, and filtered to remove insoluble substances. The ethyl acetate is dried, filtered, and separated to give an oily (fatty) solid. The degree of purification is affected by chromatography on silica gel with 95 : 5 to 80 : 20 toluene: ethyl acetate as a reducing agent to give N-{3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)phenyl}-oxamate-3-N-[3, 5-dimethyl-4-(4-hydroxy isopropylphenoxy)-phenyl]-oxamate.

NMR (D3 cod): d 1 . 1 (6H, d), 2. 1 (6H, s), 3. 2 (lH, m), 3. 8 (3H, s). (1H, d) 7.5 (2H, s, 6.4 (lH, d ofd). 6.7 (lH, d), 6.8 (lH) The building material is prepared as follows:

3, 5-Dimethyl-4-(3-isopropyl-4-methoxyphenoxy)nitrobenzene

3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-nitrobenzene and 50 mg of 10% platinum on carbon in 0.1 mM ethanol are reduced on a shaker. The catalyst is removed by filtration through Celile and the filtrate is separated. The precipitate is taken in ether and made acidic by adding hydrogen chloride.

Gaseous, the ether solution is crushed, filtered to remove insoluble materials, and separated to give 3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-aniline.

3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-aniline hydrochloride.

Melting point = 95-100 degrees Celsius.

Example (4):

N-[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-

Phenyl]oxamide 3,5-dimethyl-4-(4-methoxy-3- isopropylphenoxy)-oxamide (2.5 g) is suspended in 150 mM dichloromethane, 1 M

Boron tribromide in dichloromethane (30 ml) is added with dry ice/chilled acetone, then the solution is allowed to stir in the general atmosphere for 18 hours. The liquid is filtered into ice, followed by separating the layers and re-extracting with dichloromethane to give, Which is dried, filtered, and separated, to give a crude product. Crystallization of toluene gives N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl] -

N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-pheny1]-oxamide

Melting point = 112 - 42 degrees Celsius.

Example (5):

3, 5-Dichloro-4-(3-isopropyl-4-methoxyphenoxy)-nitro

3.5-dimethyl-4-(3-isopropyl-4- methoxyphenoxy)-nitrobenzene (2.0 g) and 2.0 mg of 10% platinum on carbon in 100 ml of ethanol are hydrogenated on a shaker. Then the catalyst is removed through the filter through Celile and the filtrate is separated to give 5,3-dichloro-4-(3-isopropyl)

-4-methoxyphenoxy) -aniline -4-3,5-dichloro-4-(3-isopropyl methoxyphenoxy)-aniline, 30 g of dimethyl oxalate is added automatically and stirred at 120°C for 4 hours, is removed. oxalate

The excess is subjected to high vacuum from a hot water bath, and the chromatographic precipitate is exposed to silica gel with 9:1 toluene: ethyl acetate to give methyl acetate.

N-[5,3-Hychloro-4-(4-methoxy-3-isopropylphenoxy)-

[3,5-dchloro-4-(4-methoxy-4- isopropylphenoxy)-phenyl]-oxamate [phenyl oxamate NMR (CDCl3): d 1. 2 (6H, d), 3. 3 (lH, m),3. 8 (3H, s), 4.0 (3H, s) 6. 5

(lH, d ofd). 6. 7 (lH, d), 6. 8 (lH, d) 7. 7(2H,s).

The starting material is prepared as follows:

Add to 31 g of 2,6-dichlorophenol 2,6-dichlorophenol in 120 ml of acetic acid chilled in an ice bath. Add for more than 5 minutes, 50 ml of 70% nitric acid, after stirring for an hour at temperature The mixture is shown in the room with nitrogen, then it is poured into water, filtered, then the product is washed with water, and dried in vacuum to give 2,6-dichloro-4-nitrophenol NMR (CD3OD): d 8.2(s). 2,6-dichloro-4-nitrophenol

Di(3-isopropyl-4-methoxyphenyl)iodonium tetrafluorocarbons are stirred

Borate 3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate (38.3 g) and

6.33 g of copper bronze in 150 mM dichloromethane and cooled in an ice water bath, a solution of 37.10 g of 2,6-dichloro-4-nitrophenol-4-2,6-dichloro is added. nitrophenol and 5.5 g of triethylamine dropwise. The mixture is stirred in the dark at room temperature for 3 days, then filtered through Celile to remove copper, the filtrate is separated and the chromatographic precipitate is exposed to silica gel with a ratio of 97:3 to 95:5. Hexane: Ethyl acetate as a diluting agent

To give 3,5-dichloro-4-(3-isopropyl-4-methoxyphenoxy)

- Nitrobenzene 3,5-dichloro-4-(3-isopropyl-4-methoxyphenoxy)-nitrobcnzene, melting point = 75 - 7 degrees Celsius.

Example (6):

to 16.21 g of N-methyl[5,3-dichloro-4-(4-methoxy-3-isopropyl-4-meoxyphenoxy)-phenyl]oxamate

N-[3,5-dichloro-4-(4-methoxy-3-isopropylphenoxy)-phenyl]-oxamate at 400 mM

Dichloromethane is cooled in dry ice/acetone

Add 79 ml of 1 M boron tribromide to dichloromethane. The bath is removed and the mixture is stirred overnight. Then the mixture is poured into ice. After the ice melts, the layers are separated and the aqueous phase is extracted twice using ethyl acetate. The mixture is dried. The combined organic phases are filtered and separated to give crude acid. The ester re-esterification process is affected by dissolving 150 mM dimethylformamide, cooled in an ice bath, and treated with 12.81 g of carbonate. Cesium carbonate and 3.8 mM dimethylsulfate. After stirring overnight, the mixture is filtered to ethyl acetate and extracted six times with salt water such as sea water. The organic phase is dried, filtered and separated and the precipitate is subjected to chromatography on a silica gel with... 90:10 to 50:50 toluene:ethyl acetate to give methane N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-oxamate

methyl N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-oxamate, is

It was taken in 100 ml of methanol, treated with 55 ml of 1 N sodium hydroxide solution, and heated to the point of vapor return for 30 minutes and cooled to room temperature. The mixture was separated, and the precipitate was taken in water and extracted, combined with ether. The aqueous phase was cooled. In an ice bath, concentrated hydrochloric acid is added to it to make it acidic, and it is extracted using ethyl acetate. The extract is dried, filtered, and separated to give the crude product. The crystallization process of toluene gives N- [3, 5 -

Dichloro-4(4-hydroxy-3-isopropylphenoxy)-phenyl]-acid

Oxamate acid[N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl.

Example (7):

It was prepared by the same methods described in the previous examples and is: a-n-[5,3-dibromo-4-(3-isopropyl 4-hydroxy)

Phenoxy)-phenyl]-oxamic acid-4-3,5-dibromo-4-(3-isopropyl]N-hydroxyphenoxy)-phenyl]-oxamic acid. Melting point = 192 - 194 degrees Celsius.

B-N-[3,5-diiodo-4-(3-isopropyl-4-hydroxy)

Phenoxy)-phenyl]-oxamic acid-4-3,5-diiodo-4-(3-isopropyl]N-hydroxyphenoxy)-phenyl]-oxamic acid. Melting point = 201 - 204 degrees Celsius.

C-N-[4-(3-Isopropyl-4-hydroxyphenoxy)-phenyl]-acid

Oxamic N-[4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-oxamic acid. , melting point = 105 - 110 degrees Celsius.

D-N-[5,3-dibromo-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]

-Oxamic acid-3,5-dibromo-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-oxamide N]. ,

Melting point = 86 - 90 degrees Celsius.

H-N-[3,5-diisopropyl-4-(3-isopropyl-4-hydroxy)

phenoxy)-phenyl]-oxamic acid-4-3,5-diisopropyl-4-(3-isopropyl]N-hydroxyphenoxy)-phenyl]-oxamicacid. Melting point = 72 - 90 degrees Celsius. P-N-(3,5-dimethyl-4-(4-hydroxyphenoxy)-phenyl]-acid

Oxamic N-[3,5-dimethyl-4-( -4-hydroxyphenoxy)-phenyl]-cxamic acid. Melting point = 199 - 200 degrees Celsius.

Q-N-[3,5-dimethyl-4-(3-ethyl-4-hydroxyphenoxy)-

Phenyl]-oxamic acid -[3,5-dimethyl-4-(3-ethyl-4-hydroxyphenoxy)-phenyl] N- oxamic acid. Melting point = 177-178 degrees Celsius. S-N-[3-methyl-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-acid

N-[3-methyl-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-oxamic acid. , melting point = 33 1 - 37 1 degrees Celsius. Sh-N-[3,5-dimethyl-4-(3-isopropyl-4-hydroxyphenoxy) -

Phenyl]N-methyloxamic acid -(3,5-dimethyl-4-(3-isopropyl-4-hydroxyphenoxy]N-phenyl]-N-methyloxamic acid. Melting point = 140 - 156 degrees Celsius. The starting material is prepared As follows:

3, 5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy) -

Aniline 3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-aniline (2.57 g) and 1.73 mM diisopropylethylamine in 30 mM THF

Cool in an ice bath. They are treated with 0.95 ml of ethyl chloroformate. After stirring at room temperature for 8 1 hours, the mixture is separated, then dissolved in ethyl acetate and extracted with water. The aqueous phase is dried, filtered and separated to give crude oil, chromatography on silica gel with 9:1 hexane:ethyl acetate gives ethyl n-[3,5-

Dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl]carbamate

N-f3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-carbamate. 7. 3 (NMR (CDC13): d 1.0 (6H, d), 1.2 (3H, t), 2.0 (6H, s), 3.3 (lH, m.(6.7 (lH, d)) 7. 1 (2H, s), (3H, s), 4.2 (2H, q), 6.3 (lH, d ofd) 6.6 (lH, d)

To 650 mg of lithium aluminum hydride in 100 mM tetrahydrofuran.

Dry and cooled in an ice bath to which a solution of 3.06 g of ethyl N-[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl]carbamate imethyl-4-(4-mcthoxy-) is added. 3-isopropylphenoxy)-carhamateN-[3,5-d in 20 mM IV

Dry tetrahydrofiiran in drops. The mixture is heated to the point of vapor return for 3 hours, then cooled in an ice bath and heated with 0.65 ml of water, 0.65 ml of 15% sodium hydroxide, and 1.95 ml of water. The sediment is filtered and washed with tetrahydroxide. Hydrofuran tetrahydrofiiran, and the filtrate is concentrated, chromatographically on silica gel with toluene 95: toluene 5: ethyl acetate to give:

N-methyl-3,5-dimethyl-4-(3-isopropyl-4-methoxy)

Phenoxy)aniline N-methyl-3,5-dimethyl-4-(3-isopropyl-4-methoxyphenoxy)-aniline. 8. 3 (NMR (CDC13): d 1.2 (6H, d), 2.1 (6H, s), 2.8 (3H, s), 3.3 (lH, m).(3H, s), 6.4 (3H, m ), 6.7 (lH, d) 6.8 (lH, d)

Y-N-[3,5-diiodo-4-(4-hydroxyphenoxy)-phenyl]-acid

Oxamic N-[3,5-diiodo-4-(4-hydroxyphenoxy)-phenyl]-oxamic acid.

K-N-[3,5-dichloro-4-(4-hydroxyphenoxy)-phenyl]-acid

N-[3,5-dichloro-4-(4-hydroxyphenoxy)-phenyl]-oxamic acid.

L-N-[3,5-difluoro-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-oxamic acid melting point = 160-162°C.

N-[3,5-difluoro-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl]-oxamic acid.

M-N-[3-methyl-4-(3-isopropyl-4-hydroxyphenoxy)-phenyl] - oxamic acid melting point = 33 1 - 37 1 degrees Celsius.

N- [3-methyl-4-( 3-isopropyl- 4 -hydroxyphenoxy)phenyl]-oxamic acid.

The intermediate, 2-methyl-4-nitrophenol, is prepared as follows: 2-methylanisole (20 g) in 500 mM dichloromethane.

Dichloromethane cooled in an ice bath is treated with 27.2 g of nitronium tetrafluoroborate and stirred for two days. The mixture is poured into water, the layers are separated, and the aqueous phase is washed with dichloromethane. The combined organic layers are dried

It was filtered, separated, and exposed to chromatography on silica gel with 9:1 to 8:2 hexane: ethyl acetate to give: 2-methyl-4-nitroanisole.

NMR (CDC13): d 2.3 (3H, S), 6.8 (1H, d), 7.9 (lH, d ofd), 8.0 (lH, d).

Example (8):

N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)

-Phenyl]-oxamic acid (bromo-4-(4-hydroxy-3-isopropylphenoxydi-3,5]N-phenyl]-oxamic acid (500 mg) and 290 mg of 2-ethoxycarbonyl-1,2-di Hydroquinoline 2-ethoxyl-1-ethoxycarbonyl-1,2-dihydroquinoline is made

They were dissolved in 20 ml of diethylformamide. The solution was saturated by adding methylamine gas, covered and stirred under general atmosphere for 3 days. The solvent was removed under a vacuum of water and the precipitate was subjected to chromatography on a silica gel with a ratio of 95:5 toluene: ethyl acetate to 75: 25 Ethyl acetate: ethanol to give: N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-phenyl] N-methyl oximide, melting point: 140 - 5°C

N-[3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-N-methloxamide Example (9):

Methyl N-[3,5-dimethyl-4-(4-methoxy-3-isobutyl)

Phenoxy)-phenyl]oxamate-3-methyl N-[3,5-dimethyl-4-(4-methoxy isopropylphenoxy)-phenyl]-oxamate (2.02 g) in 50 mM methanol treated with 6.0 mM of 1.0 N sodium hydroxide, heated to the point of vapor return for 2.5 hours and cooled to the general atmosphere temperature, the solvent is fined, the precipitate is dissolved in water and extracted with ether, and the aqueous phase is neutralized using 6 ml of 1.0 N acid. Hydrochloric acid, the resulting precipitate is washed, taken in ethyl acetate and ethanol, and the solution is dried. It is filtered and separated to give the raw product, which is crystallized from toluene to give:

N-[3,5-dimethyl-4-(4-methoxy-3-isopropylphenoxy)-phenyl]-oxamic acid, melting point: 179-83°C

N-[3,5-dimethyl-4-(4-methoxy3-isopropylphenoxy)-phenyl]-N-oxamicacid.

Example (10):

(a) N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-oxamic acid

N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-oxamic acid (8.48 g), 8.04 g cesium carbonate, and 2.4 mM dimethyl sulfate dimethyl sulfate. They are stirred overnight in 50 ml of dimethylformamide. The mixture is poured into ethyl acetate and used once with water and five times with salt water like sea. The organic layer is dried, filtered and separated to give an oil, which is subjected to chromatography on silica gel with 90:10 to 50:50 toluene: ethyl acetate to give a pure substance, which is then crystallized from toluene to give: methyl N-(3, 5-Dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]oxamate-3-3,5-dimethyl-4-(4-hydroxy]methyl N-isopropylphenoxy)-phenyl]-oxamate, melting point : 93 1 - 3 degrees Celsius.

B-N-(3,5-dichloro-4-(4-hydroxy-3-isopropyl)

phenoxy)-phenyl]-oxamic acid-3-3,5-dichloro-4-(4-hydroxy]methyl N-isopropylphenoxy)-phenyl]-oxamic acid, (9.59 g), 8.13 g of cesium carbonate Cesium carbonate, and 2.4 mM dimethyl sulfate are stirred overnight in 50 mM dimethylformamide. The mixture is poured into ethyl acetate and extracted once with water and five times with salt water such as sea water. The layer is dried. The organic matter is filtered, separated, and the chromatographic precipitate is exposed to...

Silica gel with 10:90 to 50:50 toluene: ethyl acetate to give the desired product, which is crystallized from toluene to produce: methyl N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl ] - Oxamate acid. Melting point 181 -50 °C -(4-(4-hydroxy-3-isopropylphenoxy-3,5-dichloro]methyl N-phenyl]-oxamate

Example (11):

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl

phenoxy)-phenyl]-oxamic acid-3,5-dichloro-4-(4-hydroxy]N-3-isproppylphenoxy)-phenyl]-oxamic acid (3,0 g), 2,55 g carbonate

Cesium carbanate and 0.93 ml of benzyl bromide are stirred in 20 ml of dimethylformamide overnight. The mixture is poured into ethyl acetate and extracted once with water and five times with salt water such as sea water. The organic layer is dried, filtered, separated and extracted. Exposing the chromatographic precipitate on silica gel with 9:1 toluene: ethyl acetate eluent to give the product, the crystallization process of toluene gives benzyl-n-[3,

5-Dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]oxamate

benzyl N-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]-oxamate grade

Melting: 164:6 degrees Celsius.

Example (12):

to 100 mg of N-[3,5-dimethyl-4-(4-hydroxy-3-

Isopropylphenoxy)-phenyl]oxamic acid-3-3,5-dimethyl-4-(4-hydroxy]methyl N-ispropylphenoxy)-phenyl]-oxamic acid, in 20 mM ammonium hydroxide

ammonium hydroxide cooled in an ice bath, 6.06 ml of 0.06 is added

Molarity of ethanolic bromine. After stirring all night, the solution is gradually concentrated and made acidic by adding 2N hydrochloric acid. The steel is filtered out and the previous process is repeated.

Three additional times, the final raw steel is crystallized from toluene

To give: N-[3,5-dimethyl-4-(4-hydroxy-3-bromophenoxy)-phenyl] oxamic acid. Melting point: 161:5°C. N-[3,5-dim6thyl-4-(4-hydroxy-3-bromophenoxy)-phenyl]-oxamic acid.

Example (13):

to 250 mg of N-[3,5-dichloro-4-(4-hydroxyphenoxy)-phenyl]

- N-[3,5-dichloro-4-(4-hydroxyphenoxy)- phenyl]-oxamic acid: In 20 ml of ammonium hydroxide cooled in an ice bath, 2.2 ml of 0.394 M ethanolic iodine are added. When the addition is made, the solution is stirred in the general external atmosphere for two hours, then it is gradually concentrated and filtered. The filtrate is made acidic by adding 2N hydrochloric acid and extracted twice with ethyl acetate. The organic parts combine, are dried, filtered and separated to give the steel that is crystallized. from Toluene gives: N-[3,5-dichloro-4-(4-hydroxy-3-iodophenoxy)-phenyl]-oxamic acid. Melting point: 128: 20 degrees Celsius. N-[3,5-dichloro-4-(4-hydrox-3-iodophenoxy)-phenyl]-oxamic acid

Example (14):

Methyl-N-[3,5-dimethyl-4-(4-hydroxy-3-isopropyl)

Phenoxy)-phenyl]oxamate-(3,5-dimethyl-4-(4-hydr0xy-3-is0pr0pylphen0xy]methyl N-phenyl]-oxamate (74.1 g), 50 mM dihydropyran, 1 mM dihydropyran Dimethylformamide, and 3 drops of concentrated hydrochloric acid are stirred at room temperature overnight. The solvent is stirred and the precipitate is subjected to chromatography on silica gel with 9:1 acetate, 8:2 toluene: ethyl acetate as a diluting agent to give: methyl acetate. N-[3,5-dimethyl-4-(4-hydroxy-3-

Isopropyl-4-(2-tetrahydropyranyloxyphenoxy[-phenyl]oxamate)

-methyl N- [3S-dimethyl-4-(3-isopropyl-4-(2-tetrahydropyranyloxy)-phenoxy]-phenyl]-oxamate

NMR (CDCl3): d 1. 2 (6H, d ofd), 1 . 7 (6H, m), 2.1 (6H, s), 3. 3 (lH, m) 3. 5 (2H , m), 3.9 (3H , s), 5.3 (lH , t) 6.4 (lH , d lfd), 6.7 (lH , d), 7.0 (lH , d), 7.5

(2H,S).

Example (15)

N-methyl-[3,5-dimethyl-4-(-3-isopropyl-4-(2-tetra)

Hydropyranyloxy)phenoxy)-phenyl)oxamate-3,5-dimethyl-4-(3-isopropyl]methyl N-4-(2-tetrahydropyranyloxy)-phenoxy]-phenyl)-oxamate (1.23 g) and 3, 1 ml of 1.0 N sodium hydroxide in 40 ml of methanol is heated to the point of vapor return for 30 minutes, then stirred at normal or ambient temperature overnight, the solvent is fined, the precipitate is dissolved in water, extracted with ether, cooled in an ice bath and neutralized. With 1.3 mM 1.0 N HCl, the mixture was extracted twice with ethyl acetate and the organic fractions were dried. combined, filtered and separated to give: N-[3,5-dimethyl-4-(-3-isopropyl-4-(2-tetrahydropyranyloxy)phenoxy)-phenyl)oxamic

3,5-dimethyl-4-(3-isopropyl-4-(2-tetrahydropyranyloxy)-phenoxy]-phenyl]-oxamic

Methyl N-acid Melting point: 152°C - 6°C.

Example (16):

Cholic acid (1.71 g) and 1.50 g of N-methyl[3,5-di

Methyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]oxamate,

N-ethylcarbodiimide hydrochloride -3-methyl N-[3,5-dimethyl-4-(4-hydroxy isopropylphenoxy)-phenyl]oxamate, 1.61 g of N-(dimethylamino-propyl)-N - N-(dimethylaminopropy)-N ethylcarbodiimide hydrochloride, and 260 mg of N,N-dimethylaminopjridine, stirred in 150 ml.

Tetrahydrofuran for 48 hours, the solvent is evaporated and the precipitate is re-dissolved in acetate before being washed with water and then salt water such as sea water. The solvent is dried, filtered and separated, and the chromatographic precipitate is exposed to silica gel with pre-acetate/ethyl acdtate/ethanol to give: 4-{2,6-dimethyl-4-{(2-methoxy-2,1-dioxoethyl)amino} phenoxy}-2-isopropylphenyl-7,3,12-(3&amp;,O,7p&amp;' 12&amp; trihydroxycholan

-12,7,3 4-[2,6-dimethyl-4-[2-methoxy-l,2-dioxoethyl)amino]phenoxy]-2-isopropylphenyl 3a,5B7a,12a)-trihydroxycholan)-24- Watt.

Example (17):

Cholic acid (1.79 g) and 2.08 g of benzene-n-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]

methyl N-{3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]oxamate, 1.68 g of N-(dimethylaminopropyl) stirred in 150 ml IV Tetrahydrofuran for 18 hours, the solvent is mixed and the precipitate is re-dissolved in ethyl acetate. It is extracted with water. The ethyl acetate is dried, filtered and separated, and the precipitate is subjected to chromatography on silica gel with 20:80 acetate and 10:90 toluene: ethyl acetate to give: 4 -

{2-benzyloxy-2,1-dioxoenylamino}-2,6-dichloro

Phenoxy} -2-isopropylphenyl 12,7,3-(3&amp;B5,7&amp;12&amp;trihydroxycholan 4-[4-[2-benzyloxy-1,2-dioxoethyl)amino]-2,6- dichlorophenoxy]-2-

isopropylphenyl 3, 7, 12-(3a,5c7a,12a)-trihydroxycholan-24-W, as an amorphous solid, melting point = 119-128°C.

Example (18):

4- {4- {(4- {(2-benzyloxy-1,2-dioxoethyl)amino}-2,6-dichlorophenoxy}-2-isopropylphenyl-12,7,3(3&amp;,B) 5, 7 &amp; 12 &amp;) Trihydroxyco-Lan-24-W (260 mg) and 26 mg of

10% palladium on carbon in 50 ml of ethanol is treated with hydrogen on a shaking device, the catalyst is removed by filtration through Celile and the mixture is separated to give: 4-{2,6-dichloro-4-{(2-hydroxy- 1,2-Phi-oxoethyl)amino)phenoxy}-2-isopropylphenyl 12,7,3-

(3 &amp; 12-(3a,5fi7a,12a(dioxoethyl trihydroxycholan, 24-watt) in the form of an amorphous monohydrate, melting point: 180 - 92 degrees Celsius.

Example (19):

A solution of 480 mg (137 mmol) of [5-(4-amino-2,6-diphenoxy)-2-hydroxyphenyl](4-fluorophenyl)methanone [5-(4-amino-2,6-

Dimeftylphenoxy)-2-hydroxyphenyl](4-fluorophenyl)methanone in 5 ml of dithyl oxalate is heated at 100 C for 2.5 hours. The excess dithyl oxalate is evaporated with nitrogen vapor and the precipitate is crushed with petroleum ether and then filtered. The steel is dissolved in methylene chloride, the solution is filtered and the filtrate is evaporated to give: ethyl N-[4-[3- (4). -Fluorobenzyl)-4-hydroxyphenoxy-3,5-dimethylphenyl]

EthylN-[4-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl] oxamate. The starting material is prepared as follows:

To a solution of 26.0 g (61.0 mmol) of 4,4-dimehoxydiphenyliodonium tetrafluoroborate

And 10.7 g (64.0 mmol) of 2,6-dimethyl-4-nitro-phenol 2,6-dimethyl-4-nitrophenol in 250 ml of methylene chloride, 0.5 g of copper powder and 10 One millimeter (72.0 mmol) of triethylamine. The reaction mixture is stirred at room temperature for 6 days, then filtered, the filtrate is washed with 1001 ml of 1 N hydrochloric acid,

100 One milliliter of water, and dry calcium sulphate (CaSO4), then it is filtered by evaporation, the precipitate is washed with ethanol to give 3,5-dimethyl-4-(4-methoxyphenoxy)-nitrobenzene 3,5-dimethyl-4-(4-methoxyphenoxy) )-nitrobenzene, melting point = 117-20°C. to a solution of 4.5 g (16.5 mmol) of 3,5-dimethyl-4-(4-

Methoxyphenoxy)-nitrobenzene 3,5-dmethyl-4-(4-methoxyphenoxy)-nitrobenzene and 6.63 g (41.8 mmol) of p-fluorobenzoyl chloride in 1.0 mM methylene chloride methylene chloride Add 15.8 g (83.3 mmol) of titanium tetrachloride. The reaction mixture is stirred for 8 days at room temperature, poured into an ice bath (300 ml) and stirred for two hours. The organic layer is separated, washed using 5% aqueous sodium carbonate, water, and calcium sulfate (aSO4), dried and finely ground. The precipitate was crushed with ether - petroleum ether and recrystallized from methanol to give: (4-fluorophenyl) [2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)-phenyl]methanone (4-fluorophenyl)[2 -methoxy-5-(2,6

dimethyl-4-nitrophenoxy)phenyl]methanone Melting point = 167 - 168 degrees Celsius.

A solution of 5.12 g (13.0 mM) of (4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-petrophenoxy)phenyl]methanone-5-4-fluorophenyl) [2-methoxy) 2,6-dimethyl-4-nitrophenoxy)phenyl]methanone) in 100 mM methylene chloride cooled in an ice bath and 40 mM (40 mmol) of 1.0 M boron trichloride in chloride Methylene nrethylene chloride is added gradually, the solution is stirred at room temperature overnight, then poured into 300 ml of ice water and stirred for two hours, The organic layer is separated, washed with 5% aqueous sodium carbonate, water, and dry calcium sulphate (CaSO4) and evaporated. The precipitate is recrystallized from

Ethanol gives: (4-fluorophenyl) (2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone. (4-fluorophenyl)[2-hydroxy-5-(2,6)

dimethyl-4-nitrophenoxy)phenyl]methanone Melting point = 148 - 150 degrees Celsius

A solution of 2.77 g (7.3 mmol) of (4-fluorophenyl)[2-hydroxy-5-

[2,6-Dimethyl-4-nitrophenoxy)phenyl]methanone (4-fluorophenyl)[2-

hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone in 200 mM acetate

Ethyl with 1.0 g of 10% palladium on carbon is hydrogenated on a bar (shaking device) for 2.5 hours at 50 Psi and at room temperature, and it is metallized and evaporated to give: [5- (4-Amino-2,6-dimethylphenoxy)-2-hydroxyphenyl]-(4-fluorophenyl)methanone [5-(4-amino-(2,6-dimethylphenoxy)-2-

hydroxyphenyl]-(4-fluorophenyl)methanone.

Example (20):

A slurry of Raney nickel (10 ml) is washed with water (3 x 25 ml), ethanol (2 x 25 ml) and added to a solution of 1.4 g (3.1 mmol) of Ethyl-[4-[3-Fluorobenzoyl)-4-Hydroxyphenoxy]

- 3,5-dimethylphenyl]oxamate-4-(ethyl N-[4-[3-fluorobenzoyl hydroxyphenoxy]-3,5-dimethylphenyl]oxamate in 20 mM ethyl acetate

Diluted with 80 ml ethanol. The reaction mixture is hydrogenated on a shaker for two hours at room temperature, then filtered and evaporated. The precipitate is recrystallized from ether - petroleum ether to give: ethyl-N- [4-[3- [4-Fluorophenyl)hydroxymethyl] - 4

- Hydroxyphenoxy]-3,5-dimethylphenyl]oxamate

[4-[3-[(4-fluorobenzoyl)hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]-ethyl N

oxamate, melting point = 6 4 1 - 8 4 1 °C.

<img file="SA983B1_D0015.tif" />

Example (21)_:

A solution of 900 mg (200 mmol) of ethyl n[4-[3-fluorobenzoyl)-4-

Hydroxyphenoxy]-3,5-dimethylphenyl]oxamate-3]-4]-ethyl N-fluorobenzoyl)-4-hydroxyhenoxy]-3,5-dimethylphenyl]oxamate in 20 ml of

Ethanol and 2.5 ml (2.5 mmol) of 1.0 N aqueous sodium hydroxide are heated to the point of vapor return for two hours, then steamed, the precipitate is dissolved in water and the aqueous solution is washed with ethyl acetate, making Acid using 6N aqueous hydrochloric acid and extracted with ether, the ether layer is washed with water, and dry calcium sulphate (CaSO4) is evaporated. Recrystallization of methylene chloride - petroleum ether to give n-[4-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-3,5-di

Methylphenyl]oxamic acid-3,5-[N-[4-[3-fluorobenzoyl)-4-liydroxyphcnoxy oxamate acid [dimethylphenyl, melting point = 160 - 162 °C.

Example (22):

The following compounds are prepared using the same method as described in the previous examples for the compound N-(4-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamic acid -[N-[4- [3-fluorobenzoyl)-4-hydroxyphenoxy 3,5-dimethylphenyl] oxamate acid as the corresponding ethyl ester:

(a) N-[3,5-dichloro-4-[3-(4-fluorobenzoyl)]-4-

Hydroxyphenoxy]phenyl]oxamic acid-4]-3]-4-N-[3,5-dichlorofluorobszoyl]-4-hydroxyphenoxy]phenyl]oxamic acid, melting point = 196 degrees Celsius.

(b) N-[3,5-dichloro-4-[3-(4-chlorobenzoyl)-4-hydroxy

Phenoxy]phenyl]oxamic acid-4-(N-[3,5-dichloro-4-[3-[4-chlorobenzoyl hydroxyphenoxy]phenyl]oxamic acid, melting point = 199°C.

(c) N-[4-[3-(4-chlorobutyl)-4-hydroxyphenoxy]-3,5-di

Methylphenyl oxamic acid -3,5-[N-[ -4-[3-(4-chlorobenzoyl]-4-hydroxyphenoxy oxamic acid [dimethylphenyl), melting point = 188°C.

(d)N-[3,5-dichloro-4-[4-hydroxy-3-(1-oxobutyl)

phenoxy]phenyl]-oxamic acid-3-N-[3,5-dichloro-4-[4-hydroxy]

l-oxobutyl)phenoxy[phenyl] oxamic acid), melting point = 183°C.

(e)N-[4-[3-(benzoyl)-4-hydroxyphenoxy]-3,

5- Dimethyl-phenyl]oxamic acid -4- (N-[ -4-[3-(benzoyl hydroxyphenoxy]-3,5-dimethyl-phenyl] oxamic acid.

Example (23):

to a solution of 300 mg (0.71 mmol) of N-[4-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-3,5-di

Methylphenyl oxamic acid -4-[N-[ -4-[3-(4-fluorobenzoyl hydroxyphenoxy]-3,5-dimethylphenyl] oxamic acid, in 10 ml of methanol add 130 mg (3.5 mmol) of borosilicate Sodium hydride, sodiumborohydride. The reaction mixture is stirred at room temperature for 15 minutes, then diluted with water, made acidic by adding 6 N aqueous hydrochloric acid and extracted with ether. The ether layer is washed with water and dry calcium sulfate (CaSO4) is added and evaporated.

The precipitate is taken into methylene chloride, filtered and evaporated. Recrystallization of methylene chloride, a petroleum ether, gives, n-[4-[3-(4-fluorophenyl)hydroxymethyl]-4-hydroxyphenoxy]-

3,5-dimethylphenyl]oxamic acid [N-[ -4-[3-[(4-fluorophenyl hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamic acid, grade

Melting = 142 - 147 degrees Celsius.

Example (24):

The following compounds are prepared using the same conditions described here above

For the boat. N-[4-[3-(4-fluorophenyl)hydroxymethyl]-4-hydroxy

Phenoxy]-3,5-dimethylphenyl]oxamic acid-4)]-3]-4-[-N-fluorophenyl]hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamic acid:

(a) N-31,5-dichloro-4-[3-[(4-chlorophenyl)hydroxymethyl]

- 4-Hydroxyphenoxy]oxamic acid (N-[4-[3-(4-fluorophenyl hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimetbylphenyl] oxamic acid, degree

Melting = 155°C.

(b) N-[4-[3-(4-chlorophenyl)hydroxymethyl]-4-hydroxy

Phenoxy]-3,5-dimethylphenyl]oxamic acid [N-[ -4-[3-[(4-chlorophenyl hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl] oxamic acid, melting point = 123 degrees percentage.

Example (25):

A 600 mg (1.96 mmol) solution of 4-(4-amino-2,6-dimethylphenoxy)-2-[(4-fluorophenyl)myl]phenol-2,6-4-(4- amino dimethylphenoxy)-2-[(4-fluorophenyl)methyl)phenol in 5 mM diethyl oxalate is heated at 100 °C for 1.25 hours, the excess of diethyl oxalate is evaporated with nitrogen vapor

The precipitate is filtered with petroleum ether and metallized. Optical chromatography gives: N-[4-[3-[(4-fluorophenyl)methyl]-4-hydroxyphenoxy]-5,3

- Dimethylphenyl]oxamate-4-[4-fluorophenyl)methyl)]-3]-4]-ethyl N hydroxyphenoxy]-3,5-dimethylphenyl]oxamate, melting point = 153 - 156

Celsius.

The starting material is prepared as follows:

To a solution of 2.2 g (5.55 mmol) of (4-fluorophenyl)[2-oxy

-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone

In 4-fluorophenyl)[2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone)

1 mM methylene chloride and 3 mM trifluoroacetic acid. Add 2.1 g (18.0 mmol) of triethylsilane. The solution is stirred overnight at room temperature, then diluted with ether (100 ml) and washed with 5% sodium carbonate, water, dry calcium sulphate (CaSO4) and evaporated.

The oily precipitate was subjected to photochromatography to give: 1-[(4-Fluorophenyl)

Methyl]-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene-4-l-[(4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl nitrophenoxy) )benzene melting point = 105 - 110 degrees Celsius.

to a solution of 1.7 g (4.5 mmol) of 1-{4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene

4-fluorophenyl)methyl)-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene)]-

100 Add 13.5 ml (13.5 mmol) of N boron tribromide 1.0 to methylene chloride. The solution is stirred overnight at room temperature.

It is poured into ice water (300 ml) and stirred for an hour, the organic layer is separated

It is washed with water, and calcium sulphate (CaSO4) is dried and evaporated. Chromatography

Photosynthesis of the precipitate gives: 2-[(4-fluorophenyl)methyl]-4-(2,6-dimethyl-4-nitrophenoxy)phenol-4-2-[(4-fluorophenyl)methyl]-4-(2). ,6-dimethyl nitrophenoxy)phenol. Melting point = 127-132 degrees Celsius. A slurry (clay or thin slurry) of Raney nickel (10 ml) is washed with water (2 x 25 ml), ethanol (2 x 25 ml) and added to a solution of 2- [(4-

Fluorophenyl)methyl]4-(2,6-dimethyl-4-nitrophenoxy)phenol

2-[(4-flu0r0phenyl)methyl]-4-(2,6-dimethyl-4-nitr0phen0xy)phen0l in 100 mM ethanol, the reaction mixture is hydrogenated on a shaker for 1.5 hours at 45°C (45 Psi) and room temperature, and is filtered

Evaporated, recrystallization from ether - petroleum ether gives 4-(4-amino-2,6-dimethylphenoxy)-2[(4-fluorophenyl)methyl]phenol

4-(4-amino-2,6-dimethylphenoxy)-2-[(4-fluorophenyl)methyl]phenol, grade

Melting = 79 1 - 82 1 degrees Celsius.

Example (26):

A solution of 440 mg (1.0 mmol) of ethyl-n[4-[3-[(4-fluorophenyl)

Methyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate ethyl N-[4-[3-[(4-fluorophenyl)methyl]4-hydroxyphenoxy]-3,5-dimethylphenyl] oxamate in

20 1 ml of ethanol and 1.2 ml (1.2 mmol) of 1.0 N sodium hydroxide and 1.0 N of aqueous sodium hydroxide. They are heated to the point of vapor return for an hour, then evaporated. The precipitate is dissolved in water, the solution is washed with ether, and it is acidic. By adding 6 N hydrochloric acid 6 aqueous and extracting it with ether, the ether layer is washed with water, and dry calcium sulphate (CaSO4) is added and boiled. The precipitate is recrystallized from methylene chloride to give: N-[3-(4-Fluorophenyl)methyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamic acid -4-[N-f4-[3-(4-fluorophenyl)methyl hydroxyphenoxy]- 3,5-dimetliylphenyl]oxamic acid, melting point = 182 - 184 degrees Celsius.

Example (27):

The following examples were prepared using the same method as described above for the compound, n-[4-[3-(4-fluorophenyl)methyl]-4-hydroxyphenoxy]-3,5-

Dimethylphenyl]oxamic acid-4)-3]-4]-N

Fluorophenyl)methyl)-4-hydroxyhenoxy]-3,5-dimethylphenyl]oxamic acid:

(a) N-[3,5-dichloro-4-[3-[(4-chlorophenyl)methyl]hydroxy

Methyl]-4-hydroxyphenoxy]-phenyl]oxamic acid-4-N-[3,5-dichloro]

3-[(4-fluorophenyl)methyl)-4-hydroxyhenoxy]phenyl]oxamic acid], degree

Melting = 180°C.

(b) N-[3,5-dichloro-4-[3-[(4-chlorophenyl)methyl]-4-

Hydroxyphenoxy]phenyl]oxamic acid-4)-3]-4-N-[3,5-dichloro chlorophenyl)methyl]-4-hydroxyphenoxy]phenyl]oxamic acid, melting point =

185°C.

(c) N-[4-[4-hydroxy-3-(phenylmethyl)phenoxy]-3,5-di

Methylphenyl]oxamic acid (N-[4-[4-hydroxy-3-(phenylmethyl phenoxy]-3,5-dimethylphenyl]oxamic acid, melting point = 154 °C.

(d) N-[4-[3-[(4-chlorophenyl)methyl]-4-hydroxyphenoxy]-3,

5- Dimethylphenyl oxamic acid -4-N-[4-[3-[(4-chloropheny)methyl[ hydroxyphenoxy]phenyl]-3S-dimethylphenyl] oxamic acid, melting point = 155 degrees Celsius.

Example (28)

3, 5-Dimethyl-4-(3-isopropylphenoxy)-nitrobenzene

3,5-dimediyl-4-(3-isopropylphenoxy)-nitrobenzene (5.21 g) and 521 mg of 10% platinum on carb. n in 150 ml of ethanol. They are reduced under hydrogen on a shaking device (Barr device). The solution is filtered through Celile to remove the agent

The catalyst separates the filtrate to give 3,5-dimethyl-4-(3-isopropylphenoxy)-aniline, which is combined with 50 g of dimethyl oxalate at 0. 2 1°C for four hours. The resulting mixture is concentrated under high vacuum and the precipitate is subjected to chromatography on silica gel with 9:1 toluene:ethyl acetate as a diluting agent to give: methyl N-[3,5-dimethyl-4-(3-isopropylphenoxy)-phenyl]oxamate.

methyl N-[3,5-dimethyl-4-(3-isopropylphenoxy)-phenyl]oxamate NMR (CDCI3): &amp; 1.2 (6H, d), 2.1 (6H, s), 2.8 (lH, m), 4.0 (3H, s), 6. 5 (lH, d of d), 6.7 (lH, t). 6.9 (lH, d ofd), 7.2 (1H, t), 7.4 (2H, s), 8.8 (lb, br s).

The starting material is prepared by reacting 3-isopropylphenol with 4-chloro-3-5-dimethylnitrobenzene using methods described in Example (1).

:(29) Example

3, 5-Dimethyl-4-(3-isopropyl-4-hydroxyphenoxy) -

Aniline 3,5-dimethyl-4-(3-isopropyl-4-hydroxyhenyl)-aniline (1.65 kg, 6.08 mol) is suspended in dithyl oxalate (8.5 L) and heated to a temperature Internally, about 100 degrees Celsius, a complete solution is obtained at a temperature of 85 degrees Celsius after 3 hours at a temperature of 0 01 C, so that the reaction has been completed. When cooling to a temperature of 50 degrees Celsius, the solution is diluted with heptane (8 liters) and the mixture is cooled to a temperature of 5 degrees Celsius. The steel is collected by filtration, then the filter base is washed with heptane (3 x 200 ml), after dilution overnight (50 degrees Celsius, 1 torr) The substance is dissolved in hot ethyl acetate (12 litres), this solution is diluted with heptane (12 litres) and the mixture is cooled to 10°C for an hour. It is filtered, the filter base is washed using heptane (2 x 1 litres) and then dried. for 72 hours (60°C, 0.5 torr) to obtain ethyl n-[3,5-dimethyl-4-(4-hydroxy-3-

Isopropylphenoxy)-phenyl]oxamate-3-ethyl N[3,5-dimethyl-4-(4-hydroxy isopropylphenoxy)phenyl]oxamate, melting point = 170 - 171 degrees Celsius. The starting material is prepared as follows:

2- Isopropylphenyl (5.0 kg, 36.7 mol) is dissolved in Yale acetate (20.8 liters) and triethylamine (4.48 kg, 44.1 mol) is added to it. This is cooled The solution is brought to -12 degrees Celsius and acetyl chloride (3.15 kg, 40.2 mol) is added to it for a period of time of about 2.5 hours to keep the temperature below -10 degrees Celsius.

Triethylamine hydrochloride precipitates quickly. After the addition is done, stirring continues for an hour at a temperature of 15 degrees Celsius until a solid mass is formed. This is dissolved by adding water (12 liters). After separating the layers, the organic layer is washed with water (2 x 12 liters) and evaporated in a vacuum (50 degrees Celsius, 2 Torr) and then at 70 °C, 2 Torr to give 2-isopropyl-phenyl acetate as an oily precipitate.

amber.

2- Isopropyl-phenyl acetate (3.24 kg, 18.2 liters) is dissolved in nitrobenzene (12.5 litres). After cooling this solution to 10°C, aluminum chloride (6.0 kg/45.0 mol) is added in parts, and the temperature is kept at about 20°C. After the addition is complete, the reaction mixture is heated to 35°C. Celsius for 8 1 hours. After cooling to room temperature, this mixture is poured into hydrochloric acid (1.0, 16.5 liters), and the temperature is kept between 20 - 25 degrees Celsius with ice cooling. Stirring continues for 15 minutes after The addition is complete, after this time the steel is collected by filtration and washed Using water (20 litres), this substance is combined with those in the same series that have the same volume and dissolved in methanol (16 litres). Add charcoal (100 gm)

To this solution, after stirring for 30 minutes, this mixture is filtered. To this colorless solution, water (18 liters) is slowly added to precipitate the product. This mixture is cooled to a temperature of 4 degrees Celsius for an hour, then the steel is collected by filtration, and washed with hexane (4 x 2 liters) to remove excess nitrobenzene and temper it in vacuum (50 °C, 1 torr) for 18 hours to obtain 4-acetyl-2-isopropyl phenol 2-isopropyl-phenyl acetate, melting point = 142 - 144 °C.

4- Acetyl-4-isopropylphenol 4-acet (3.69 kg, 20.7 yl-2-isopropylphenol

mole) dissolved in dimethylformamide (14 liters). Added to this solution is potassium carbonate anhydrate in powder form (3.16 kg, 22.8 moles), and anhydrous potassium iodide (369 g, 2.22 moles). mol) and benzyl chloride (2.88 kg, 22.8 mol). This mixture is heated to 80 degrees Celsius for two hours, cooled to 50 degrees Celsius and diluted with water (46 litres) after cooling to 5 degrees Celsius. The mixture is stirred for an hour. The steel is collected by filtration and washed with water (20 L), after drying it by atmospheric air overnight, the steel is dissolved in methanol (16 L) at 50°C and filtered in a 20-gallon vessel. The filtrate is diluted with water (10 L) for a period of time of about 20 minutes at 40°C, after the addition is complete. The mixture is stirred for an hour at 5°C, and the steel is filtered and dried in vacuum (80°C, 15 Torr) for 5 days to obtain 4-benzyloxy-3-isopropylacetophenone, melting point = 55-56. Celsius.

4-Benzyloxy-3-isopropylacetophenone 4-benzyloxy-3-isopropylacetophenone (5.50 kg) (20.5 mol) is dissolved in acetic acid (25 liters) added to this

The solution is anydrous sodium acetate (502 g, 6.10 mol) with stirring, which continues until the complete solution is obtained at 0.2

0°C At this time, add per acdtic acid (35%, 0.8.9 kg, 40.1 mol) and dissolve it once. In the beginning, the temperature drops to 4 1°C, then it is accompanied by a heat that appears as the temperature rises from 4 1 - 32 °C for five hours. The accompanying temperature is controlled. Bath with cold water. After stirring overnight at room temperature, the solution is cooled. To 15 degrees Celsius, a solution of sodium sulfite (4.5 kg, 35.7 mol) in water (20 liters) is slowly added to it, and the temperature is kept below 20 degrees Celsius. After adding all the solution, a starch reaction is obtained. / Iodor minus starch/iodide. The toluene mixture (3 x 10 liters) is extracted and washed

Extracts combined with water (4 x 12 litres) Toluene is distilled in vacuum (50

°C, 3 Torr) to give 4-benzyloxy-3-isopropylphenyl

4-benzyloxy3-isopropylphenyl acetate as an amber oil. 4-benzyloxy-3-isopropylphenyl acetate 4-benzyloxy-3-isopropylphenyl acetate (5.59 kg, 19.7 mol) is added to a solution of sodium hydroxide (1.20 kg, 30.0 mol) in a mixture of Water (30 litres) and methanol (30 litres). This solution is stirred at 24°C for an hour. A black solution appears. It is concentrated in vacuum (40 °C, 3 Torr) to remove the methanol. This precipitate is extracted with ethyl acetate (2 x 1 liter The combined organic layers are washed with aqueous sodium hydroxide (1 N, 2 x 10 L) and water (3 x 12 L). The solvent is separated in vacuum (50°C, 3 Torr) to give an amber oil. This oil is filtered with heptane (10 litres) for 4 hours and then left like that overnight at room temperature, during which time the steel is collected by filtration and washed with cold heptane (2 × 1 litre) After drying in atmospheric air, the product is further dried in vacuum (25 °C, 120 Torr) for 72 hours to give 4-venzyloxy-3-isopropyiphenyl acetate as a melting point solid. Low, melting point: 39 - 40 degrees Celsius.

A suspension of 4-nitro-2,6-dimethylphenol is cooled.

(2.68 kg, 16.1 mol) in dichloromethane (30 liters) to - 15 ° C. To this mixture, pyridine (3017 kg, 19.5 mol) is added both at once to obtain a black solution. Triflic anhydride (5.50 kg, 19.5 mol) is added over a period of two hours, maintaining the temperature between -10°C and -5°C. After the addition is complete, stirring continues for 2.5 hours at -3°C. Celsius, at this time cold water (3°C, 24 litres) is added to dissolve the black suspension, after separating Layers: The organic layer is washed with hydrochloric acid (1 N, 12 L), water (2 x 12 L), sodium hydroxide (2 (3 degrees Celsius) and the prepared temperature at that time is about 5 degrees Celsius. After drying through magnesium sulfur (5.0 kg). The organic layer is filtered and evaporated in vacuum at 40°C, the precipitate is dissolved in heptane (4 ml), the dark solution is stirred, distributed and organized to begin the crystallization process. After waiting overnight at 4°C, the steel is collected by filtration and washed with heptane (2 x 500 ml ). After drying in vacuum (24 °C, 120 Torr) for 24 hours, 4-nitro-2,6-dimethylphenyltrifluoromethanesulfonate 4-nitro-2,6-dimethylphenyl trifluoromethanesulfonate is obtained as a brown solid, melting point : 64-66 degrees Celsius. 4-nitro-2,6-dimethylphenyltrifluoromethanesulfonate 4-nitro-2,6-dimethylphenyl trifluoromethanesulfonate (40.6 kg, 13.6 mol) is dissolved in N-methylpyrrolidinone anhydride

(42 liters) and add to this solution anhydrous lithium chloride (900 g) all at once. The internal temperature is raised to 120 degrees Celsius, where the color changes to dark golden brown. After 10 hours have passed at this temperature, the color of the solution becomes dark brown. The reaction is then cooled to 5°C

It is dried with cold water (5°C, 21 litres) at this rate to keep the temperature below 15°C, so that until the addition process is complete, the mixture is stirred for an hour at 5°C. The product is collected by filtration and washed with water (4 x 1 litre). The dark brown steel is dissolved in n-butyl methyl ether (42 litres) and stirred first with vegetable charcoal, then anhydrous magnesium sulfate (10 pounds). After filtration, the solvents are removed in vacuum (40°C, 3 Torr) to obtain a brown solid, which is dried in vacuum (25°C, 3 Torr) for two days to obtain: 4-chloro-3,5-dimethylnitrobenzene.

4-chloro-3,5-dimethylnitrobenzene. Melting point: 101 - 105 degrees Celsius.

Powdered anhydrous potassium carbonate (1.95 kg, 14.1 mol) is dissolved in anhdrouse dimethyl sulfoxide (20 litres) and 4-benzyloxy-3-isopropyl-vinyl acetate is added to this suspension. 3-isopropyl-phenylacetate (2.36 kg, 9.74 mol) and 4-chloro-3,5-dimethylnitrobenzene (1.81 kg, 9.74 mol), this mixture is heated to the internal temperature which is 125°C for 23 hours after post to 40°C, the reaction mixture is dried with ice water (40 litres) the precipitate is filtered and washed with water (5 x 4 litres) They are dried in air for 48 hours to obtain partially moist brown solids. The resulting product is dissolved in hot isopropanol (4 litres) and added to this heated solution to the vapor return temperature. Vegetable charcoal (kb, 200 g) is added after stirring at the vapor return temperature for 0.5 hours. The hot mixture is filtered and the filtrate is cooled to 10 degrees Celsius for an hour. . The solids are collected by filtration and washed with isopropanol cold (4°C) (3 x 500 ml). After drying overnight (25°C, 3 torr), put the resulting product in the crystallization process of isopropanol (3 litres) to obtain 3.5-

Dimethyl-4-(3-isopropyl-4-benzyloxyphenoxy-nitro

Benzene 3,5-dimethyl-4-(3-isopropyl-4-benzyloxyphenoxy)-nitrobenzene, melting point: 99 - 100 degrees Celsius.

3, 5-Dimethyl-4-(3-isopropyl-4-benzyloxyphenoxy)-nitrobenzene

3,5-dimethyl-4-(3-is0pr0pyl-4-benzyl0xyphen0xy)-nitr0benzene, (2.86 kg, 7.31 mol) is dissolved in a mixture of ethanol/tetrahydrofuran (10: Hydrogenation continues for 18 hours, the mixture is then filtered through Celite, then the Celite is washed using tetrahydrofuran (30 litres), then the filtrate is evaporated in a vacuum to the point of dryness (50 m3, 3 torr). The precipitate is filtered with heptane (3 liters) and filtered. The filter base is washed with heptane (2 x 500 ml) to obtain a crude product, which is dissolved in ethyl acetate (14 liters) and diluted with heptane (30 liters). The product is gradually sedimented and the mixture is cooled. To 10°C for an hour, collection is done by filtration, then washed with ethyl acetate/hexane 1:2 (2 x 500 ml). The filter base is then dried (60°C, 3 Torr) for 24 hours to give: 3,5-dimethyl-4-(3-isopropyl-4-hydroxyphenoxy)-aniline 3,5-dimethyl-4-(3). -isopropyl-4-hydroxy-phenoxy)-aniline, melting point: 180 - 181 degrees Celsius. Example (30):

Ethyl N-[3,5-dimethyl-4-(4-hydroxy-3-isopropyl)

Phenoxy)-phenyl]oxamate-3-ethyl N-[3,5-dimethyl-4-(4-hydroxy isopropylphenoxy)-phenyl]oxamate (1.59 kg, 4.2 mol) is suspended in sodium hydroxide solution Aqueous (1.0 N, 12 litres) at room temperature (24°C). After stirring at this temperature for 4 hours, a blue solution is obtained. This is filtered to remove some sediments and added

Gradually filtrate into a solution of hydrochloric acid (1.2, 1.4 litres) in methanol (8 litres) to precipitate a solid. This is dissolved in ethyl acetate (6.5 L) at room temperature and charcoal (KB, 100 g) is added to this solution. After stirring for 0.5 hours, the mixture is filtered and diluted with heptane (16.3 L). After stirring at room temperature for 2 hours, the solids were collected using filtration, washed with ethyl acetate/heptane (500×2.25:1 mM) and dried overnight (65°C, 0.5 Torr) to give the product. Melting point: 87 1 degrees Celsius 0 This substance is dissolved in hot acetonitrile (4 litres) and to this, PHL and water (12 litres) are added slowly, keeping the temperature at about 60 degrees Celsius until the addition process is complete. The solution is left for the crystallization process slowly at 50 After starting the crystallization process, cooling is added, then the mixture is kept at 10 degrees Celsius for an hour. The product is collected by filtration and washed with acetonitril/water (1:1). 4, 2

N-[3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenyl]

N-[3,5-dimethyl-4-(4-hydroxy-3-is0pr0pylphen0xy)-phenyl]0xamic acid. Melting point: = 487 C - 188 C.

Example (31):

[5-(4-Amino-2,6-dimethylphenoxy-2-hydroxyphenyl]5-[4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl] (4-fluorophenyl)methanone 4-fluorophenyl)methanone ) (48 g, 0.13 mol) and diethyl oxalate (99.7 g, 0.6 mol) are combined and heated with stirring under a nitrogen atmosphere at 100 °C for 10 hours, the reaction is brought to room temperature Overnight, the resulting suspension is filtered using heptane (300 ml), the product is filtered, washed with heptane (3 x 100 ml), and dried in Vacuum at 60°C/3 mmHg to give: ethyl

N-[4-[3-(4-Fluorobenzoyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl]

- Oxamate -[ethyl N-t4-[3-(4-fluorohenzoyl)-4-hydroxyphenoxyl3,5-dimethylphenyl oxamate. Melting point: 150°C - 152°C. The primary material is prepared as follows:

A mixture of dimethylsulfoxide (875 ml), p-methoxyphenol (43.3 g, 0.348 mol), potassium carbonate powder (6.9 g, 0.5 mol) and 4-chloro-3 , 5-dimethylnitro-benzene 4-chloro-3,5-dimethylnitrobenzene (Natr

Example (30), 64.6 g, 0.348 mol) is heated at 125°C for 18 hours. The suspension is cooled to 25°C and pumped into ice water (2620 ml) with stirring. The mixture was stirred for two hours. The product was filtered, washed with water (4 x 300 ml) and dried in atmospheric air. A solution of the resulting compound in tert-butylmethyl ether (3 litres) was dried over magnesium sulfate and heated with vegetable charcoal ( 6.4 g) for 2.5 hours. The dried agent is filtered out and the filtrate is concentrated in a vacuum at 50°C/30 mmHg to give the resulting process, which is recrystallized from toluene (212 ml) and petroleum air (600 ml) to give 3,5-dimethyl-4-(4). -Methoxyphenoxy)nitro

Benzene 3,5-dimethyl-4-(4-methoxyphenoxy)nitrobenzene, melting point: 120-123 degrees Celsius.

The above-mentioned nitrobenzene derivative is converted to (4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)

Phenoxy)phenylmethanone-4-4-fluorophenyl)[2-hydroxy-5-(2,6-dimethyl)nitrophenoxy)phenoxy)phenyl]methanone in a manner similar to that mentioned in Example (20).

(4-Fluorophenyl)[2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone-4-[5-(2,6-dimethy-4-f]uorophenyl)[2 -hydrox)

nitrophenoxy)phenyl]methanone (62.8 g, 0.16 mol) is dissolved in ethyl acetate (4 L) and hydrogenated at an atmospheric pressure exceeding 5% platinum on carbon (13.2 g) when the theoretical amount of hydrogen is consumed Hydrogenation stops, the catalyst is filtered out, and the ethyl acetate solution is concentrated to dryness at 50°C/3 mmHg. The hot precipitate is crushed with isopropanol (1 liter) and collected to give: [5- (4-

Amino-2,6-dimethylphenoxy)-2-hydroxyphenyl](4-

Fluorophenyl)methanone-4)[5-(4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl]

Fluorophenyl)methanone, melting point: 198°C - 202°C.

Example (32):

To a stirred suspension of sodium borohydride (5.42 g, 0.14 mol) in tetrahydrofuran (310 mM) at a temperature of 0 C under nitrogenous atmospheric pressure, acetic acid (17.3 g) (0, 29 mol) for an hour. The cooling bath is removed and the suspension is stirred at 24°C. Ethyl-N-[4-(4-Fluorobenzyl)-4-Hydroxy

Phenoxy]-3,5-dimethylphenyl]-oxamate-(4-[3-(4-tluorobenzoyl)-ethyl N 4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate (60.3 g, 0.13 mol ) They are added in parts to the suspension for 5 minutes, the solution is stirred for 3 hours at 4 2°C. The reaction is cooled to 10 °C and water (6.4 ml) is added. The pH is adjusted at 5-7 using a solution Saturated sodium bicarbonate (180 ml). The product is extracted with needles (3 A solution of the crude product in ethyl acetate (50 mM) is passed through a Kessel gel column.

(kiesebgel) 60 (23-400 mesh eyes) using a mixture of ethyl acetate (7.5 liters) and heptane (2.5 liters) as a diluting agent. The resulting compound is dissolved in ethyl acetate (1.1 litres), treated with charcoal (12 gm), filtered and concentrated in a vacuum to give a foam.

Foam in 470 ml of ethyl acetate and crystallize out with the addition of heptane (660 ml). The mixture is stirred for 48 hours and the resulting compound is filtered and washed using a mixture of heptane (20 ml) and ethyl acetate (10 ml).

It is dried in vacuum at 60/3 mmHg to give: N-[4-[3-[(4-fluorophenyl)hydroxymethyl]4-hydroxyphenoxy]-3,5-di

Methylphenyloxamate-4-[ethyl N[4-[3-[(4-fluorophenyl) hydroxymethyl hydroxyphenoxy]3,5-dimethylphenyl]oxamate, melting point: 148 - 150 degrees Celsius.

Example (33):

The following compounds were prepared using methods similar to those described here:

(a) Ethyl N-[3,5-dichloro-4-[3-[(4-chlorophenyl)hydroxymethyl]-

4- Hydroxyphenoxy]phenyl]oxamate-4)]-3]-4-3,5-dichloro[-ethylN chlorophenyl]hydroxymethyl]-4-hydroxyphenoxy]phenyl]oxamate.

(b) Ethyl N-[4-[3-[(4-chlorophenyl)hydroxymethyl]-4-hydroxy

Phenoxy]3,5-dimethylphenyl]oxamate-4-[ethyl N-[4-[3-](4-chlorophenyl hydroxyphenoxy]-3,5-dimethylphenyl]oxamate

(c) Ethyl N-4-[3-(phenyl-hydroxymethyl)-4-hydroxyphenoxy]3,5-

Dildedg phenyl]oxamate-(ethyl N-4-[3-(phenyl-hydroxymethyl)-4-hydroxyphenoxy 3,5dimethylphenyl]oxamate

(d) Ethyl N-[4-[3-[(4-tolyl)hydroxymethyl]-4-hydroxyphenoxy]3,5-dimethylphenyl]oxamate-4-[ethyl N-[4-[3-[ (4-tolyl]hydroxymethyl

hydroxyphenoxy]-3,5-dimethylphenyl]oxamate

(d) Ethyl N-[4-[3-[(4-fluorophenyl)hydroxymethyl]-4-

Methoxyphenoxy]-3,5-dimethylphenyl]oxamate-4)]-3]-4]-ethyl N fluorophenyl]hydroxymethyl]-4-methoxyphenoxy]-3,5-dimethylphenyl]oxamate. degree

Melting: 155 AD - 156 AD.

Ethyl N-[4-[3-[(4-fluorophenyl)hydroxymethyl]-4-

Hydroxyphenoxy]-3,5-dimethylphenyl]oxamate-4)]-3]-4]-ethyl N fluorophenyl]hydroxymaethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate according to e.g.

(20) It is redissolved under high pressure liquid chromatography (HPLC) on a Chiralo Daicel column (cellulose para-methylbenzoate coated on silca gel) and diluted with 80:20 hexana/ethanol. To give isomer A (retention period 115 minutes), D&amp; =

+ 23.1 °C (°C = 0.64 in acetonitrile) Melting point: 150 - 152 °C, isomer B (retention time 150 minutes), D&amp; = - 7.21 degrees Celsius (0.47 degrees Celsius in acetonitrile), melting point: 147 - 150 degrees Celsius.

Example (35):

Prepare 10,000 tablets, each containing 0.2 mg of the active ingredient.

For example: N-{3,5-dimethyl-4-(4-hydroxy-3-isopropyl)

phenoxy)-phenyl} oxamic acid-3-N-[3,5-dimethyl-4-(4-hydroxy isopropylphenoxy)-phenyl]oxamic acid.

<img file="SA983B1_D0016.tif" />

Method:

All powders are passed through a screen with holes of about 0.6 mm, and the anesthetic agents lactose, magnesium stearate and half the amount of starch are all mixed using a suitable mixer. The other half of the starch is dissolved in 65 ml of water. This suspension is added to a boiling solution consisting of polyethylene glycol in 250 ml of water. The resulting paste is added to the powders, which are pulverized when necessary by adding another amount of water. The granules are dried overnight at 35 degrees Celsius, so that it is crushed on a screen with 1.2 milliliter holes and is pumped into the tablets using concave holes with two halves (upper halves). Homogenous tablets are prepared, containing approximately 0.01 - 10 mg of one of the other closely related compounds represented here.

:(36) Example

Prepare 1,000 capsules, each containing 0.05 mg of the active ingredient.

For example: ethylene-N-(4-{3- {(4-fluorophenyl) hydroxymethyl} -4-

Hydroxyphenoxy}-3,5-dimethylphenyl}oxamate-4]-3]-4]-ethyl N fluorophenyl)hydroxymethyl]-4-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate.

<img file="SA983B1_D0017.tif" />

Method:

All powders are passed through a screen with openings of approximately 0.6 mm. The narcotic substance is placed in a suitable blender and mixed first with magnesium stearate and then with lactose and starch until homogeneity is achieved. No. 20 hard gelatin capsules are filtered with 300 mg of the aforementioned mixture separately, using a machine for filling the capsules.

Homogeneous capsules are prepared, containing approximately 0.01-10 mg of other homogeneous compounds represented here.