HK1153657B - Pharmaceutical compositions comprising a basic or acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid or base - Google Patents

Description

Pharmaceutical composition comprising a basic or acidic pharmaceutical compound, a surfactant and a physiologically acceptable water-soluble acid or base

The present application is a divisional application of an invention patent application having an application date of 25/11/2003, application No. 200380104619.7, entitled "pharmaceutical composition containing basic or acidic pharmaceutical compound, surfactant, and physiologically acceptable water-soluble acid or base".

The present invention relates to novel pharmaceutical compositions, and in particular provides improved release and absorption of drugs, especially acid soluble drugs, for administration to the outer body cavity (e.g., gastrointestinal tract).

Many pharmaceutical compounds, having desirable therapeutic properties, cannot be effectively used due to their poor water solubility. Thus, for example, orally administered such compounds, only a small fraction of the drug is absorbed by the blood during gastrointestinal transit. Thus, to achieve adequate drug absorption, it may be desirable to administer high doses of the drug compound, to prolong the administration time, or to administer the drug compound multiple times. In fact, poor solubility and thus poor bioavailability of the drug may result in the poorly soluble drug being used in place of an alternative drug that may have undesirable side effects or require invasive administration (e.g., by injection or infusion).

One approach to poor solubility is to derivatize the drug molecule to introduce water-solubilizing groups, e.g., ionic groups such as carboxyl groups or non-ionic groups such as polyhydroxyalkyl groups, to obtain a soluble derivative. However, this approach is not always effective because of the potential failure to maintain a sufficiently high therapeutic efficacy and sufficiently low toxicity or other side effects. An example of a low solubility that is not replaced by a soluble derivative is the antibacterial agent itraconazole.

Attempts have therefore been made to enhance the uptake of e.g. itraconazole drugs by increasing the surface area of the drug compound exposed to saliva or gastric juice and to promote the dissolution of the drug compound by thin coating the drug compound onto the main inner carrier particles, e.g. sugar spheres. However, a disadvantage is that the volume of solid composition required for dosing the pharmaceutical compound is large, since the carrier significantly affects the overall dosing volume. The disadvantages of this approach are evident in the difficulties posed to the patient by the large number of capsules or tablets, or the large number of capsules or tablets of smaller volume.

Yet another approach is to use the drug compound in the form of a solution of the drug compound and a drug complexing agent such as cyclodextrin. This approach also has limitations in that the formulation must be such that it is capable of forming a complex with the cyclodextrin, the dosage is constrained by the solubilizing ability of the complexing agent, an easily incorporated solid dosage form cannot be used, and the drug compound is not gradually released for biological uptake.

The pharmaceutical compounds can also be formulated in the form of solid dispersions in cyclodextrins with physiologically tolerable water-soluble acids and physiologically tolerable water-soluble organic polymers. Reference is therefore made to WO 98/55148. This approach has limitations in that the formulations must be those capable of forming complexes with cyclodextrins and the dosage is constrained by the solubilizing ability of the complexing agent.

Another approach to increase the release of a drug from a dosage form and thereby increase the oral bioavailability of the drug is to use the drug with a suitable surfactant.

WO 97/35587 describes a liquid formulation comprising an HIV protease inhibitor together with a water-soluble tocopherol derivative, especially vitamin E-TPGS.

WO 98/08490 describes a dry solid co-precipitated composition comprising tocopherol polyethylene glycol succinate, a lipophilic active ingredient and a dispersing agent.

WO 99/26607 describes a solid dispersion of a drug and vitamin E TPGS.

WO 99/45918 describes compositions comprising a taxane, one or more surfactants and an acid. Acids are included in the formulation to improve the stability of the taxane.

WO 97/02017 describes solid dispersants containing a poorly soluble active ingredient in a hydrophilic polyhydroxylated hydrocarbon polymer. The solid dispersant may further contain an acid. The solid dispersion contains an acid to gradually provide the acid to facilitate dissolution of the active ingredient according to most release rate profiles.

The compositions of the present invention are significantly different from those provided in the prior art for rapid dissolution of the pharmaceutical compound and/or high solubility (resulting in a supersaturated state) of the pharmaceutical compound. This leads to an increase in the bioavailability of the pharmaceutical compound; the biological uptake of the drug compound is improved (the time parameter for improving the drug content in the plasma of the patient, e.g., the drug metabolism parameter as defined by AUC, Imax, Cmax, etc.). The pharmaceutical compounds incorporated in the compositions of the invention are also independent of the complex formulation, which makes the present compositions suitable for use in a wide range of pharmaceutical compound formulations.

We have now found that the above-mentioned features of the compositions of the present invention can be achieved by mixing a basic or acidic pharmaceutical compound with a surfactant and a significant amount of a water-soluble acid or base.

Thus, viewed from one aspect the invention provides a pharmaceutical composition comprising a basic pharmaceutical compound, a surfactant and a physiologically tolerable water soluble acid characterised in that the ratio of acid to pharmaceutical compound is at least 1: 1 by weight,

or

Comprising an acidic pharmaceutical compound, a surfactant and a physiologically tolerable water-soluble base, characterised in that the ratio of base to pharmaceutical compound is at least 1: 1 by weight.

In other words, the present invention provides a pharmaceutical composition comprising a basic or acidic pharmaceutical compound, a surfactant and a physiologically tolerable water soluble acid or base, characterised in that the ratio of acid or base to pharmaceutical compound is at least 1: 1 by weight.

Viewed from a further aspect the invention provides a method of use of a basic or acidic pharmaceutical compound, a surfactant and a physiologically tolerable water soluble acid or base in a ratio of acid or base to pharmaceutical compound of at least 1: 1 by weight for the manufacture of a pharmaceutical composition according to the invention for use in the prophylaxis, treatment or diagnosis of the human or non-human animal body (e.g. mammal, reptile or bird).

Still further, the present invention provides an improved method of prophylactic, therapeutic or diagnostic application to the human or non-human animal body (e.g. mammal, reptile or bird) comprising prophylactic, therapeutic or diagnostic application of a pharmaceutical composition to said body, an improved shuffled composition comprising the use of a composition according to the invention.

While not wishing to be bound by theory, potent drug compound dissolution parameters for the compositions of the present invention may be obtained as a result of a combination of the effects of exposing the components of the composition to water or aqueous fluids.

In compositions comprising a basic drug compound and a physiologically tolerable water soluble acid, the water and acid provide an acidic microenvironment that increases the solubility of the basic drug compound upon exposure to water or an aqueous liquid. The presence of the surfactant results in a further increase in the solubility of the drug compound to produce a supersaturated solution of the drug compound.

In a composition comprising an acidic drug compound and a physiologically tolerable water soluble base, upon administration, the water and base provide a basic microenvironment that increases the solubility of the acidic drug compound. The surfactant as described above results in the formation of a supersaturated state of the pharmaceutical compound.

The supersaturated solution produced by administration of the composition of the invention enhances the bioavailability of the pharmaceutical compound.

Since the compositions of the present invention may themselves provide an environment for increasing the solubility of the pharmaceutical compounds, they are administered orally at any time of day, independent of the food intake of the individual to whom they are administered.

Preferred compositions are those comprising a basic pharmaceutical compound, a surfactant and a physiologically tolerable water soluble acid, characterised in that the ratio of acid to pharmaceutical compound is at least 1: 1 by weight.

With respect to the surfactant in the present invention, any physiologically tolerable surfactant suitable for use in pharmaceutical compositions may be used.

The surfactant is an amphiphilic compound, which is well known in the art; it contains polar, hydrophilic groups and non-polar, hydrophobic groups.

The terms "hydrophilic" or "hydrophobic" are relative.

The relative hydrophilicity or hydrophobicity of a surfactant can be expressed in terms of its hydrophilic-lipophilic balance (HLB value). Surfactants with lower HLB values are classified as "hydrophobic" surfactants and surfactants with higher HLB values are classified as "hydrophilic" surfactants. Surfactants with HLB values greater than about 10 are conventionally considered to be hydrophilic surfactants; surfactants having HLB values less than about 10 are generally considered hydrophobic surfactants.

The composition of the present invention preferably contains a hydrophilic surfactant. It should be understood that the HLB value of a surfactant is only a rough indicator of the hydrophilicity/hydrophobicity of the surfactant. The HLB value of a particular surfactant may vary depending on the method used to determine the HLB value; may vary depending on its commercial source; depending on the batch to batch variation. Hydrophilic surfactants suitable for use in the pharmaceutical compositions of the present invention can be readily determined by one skilled in the art.

The surfactant of the present invention may be an anionic, cationic, zwitterionic or nonionic surfactant, the latter being preferred. The surfactant of the present invention may also be a mixture of two or more surfactants.

The choice of surfactant may be dictated by the particular compound used in the composition of the present invention. Thus, surfactants with greater solubility, having an increased ability to provide a supersaturated environment, are preferred for use with particular pharmaceutical compounds.

Suitable surfactants for use in the compositions of the present invention are listed below. It should be emphasized that this list of surfactants is illustrative, representative and not exhaustive in any way. Therefore, the present invention is not limited to the surfactants listed below. In the compositions of the invention, it is also possible to use mixtures of surfactants.

Suitable surfactants that may be used in the present invention include:

a) polyethylene glycol fatty acid monoesters include esters of lauric, oleic, stearic, ricinoleic acids such as PEG6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 32, 40, 45, 50, 55, 100, 200, 300, 400, 600, and the like. For example, PEG-6 laurate or stearate, PEG-7 oleate or laurate, PEG-8 laurate or oleate or stearate, PEG-9 oleate or stearate, PEG-10 laurate or oleate or stearate, PEG-12 laurate or oleate or stearate or ricinoleate, PEG-15 stearate or oleate, PEG-20 laurate or oleate or stearate, PEG-25 stearate, PEG-32 laurate or oleate or stearate, PEG-30 stearate, PEG-40 laurate or oleate or stearate, PEG-45 stearate, PEG-50 stearate, PEG-55 stearate, PEG-100 oleate or stearate, PEG-200 oleate, PEG-400 oleate, esters of stearic acid, and esters of stearic, PEG-600 oleate; (surfactants belonging to this group are known, for example, as Cithrol, Algon, Kessco, Lauridac, Mapeg, Cremophor, Emulgante, Nikkol, Myrj, Crodet, Albunol, Lactomul)

b) Polyethylene glycol fatty acid diesters including diesters of lauric acid, stearic acid, palmitic acid, oleic acid, and the like of PEG-8, 10, 12, 20, 32, 400, and the like, for example, PEG-8 dilaurate or distearate, PEG-10 dipalmitate, PEG-12 dilaurate or distearate or dioleate, PEG-20 dilaurate or distearate or dioleate, PEG-32 dilaurate or distearate or oleate, PEG-400 dioleate or distearate; (surfactants belonging to this group are known, for example, as Mapeg, Polyalso, Kessco, Cithrol)

c) Mixtures of mono-and diesters of polyethylene glycol fatty acids such as PEG4-150 mono-and dilaurate, PEG4-150 mono-and distearate, and the like; (surfactants belonging to this group are known, for example, as Kessco)

d) Polyethylene glycol glycerol fatty acid esters such as PEG-20 glyceryl laurate, glyceryl stearate, glyceryl oleate, PEG-glyceryl laurate, etc.; (surfactants belonging to this group are known, for example, as Tagat, Glyceroxl, Capmul),

e) the products of alcohol-oil transesterification comprise alcohols or polyalcohols such as glycerol, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, pentaerythritol, esters with natural and/or hydrogenated oils or oil-soluble vitamins, such as castor oil, hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitamin K, edible vegetable oils, such as corn oil, olive oil, peanut oil, palm kernel oil, almond oil, walnut kernel oil, etc., such as PEG-20 castor oil or hydrogenated castor oil or corn glycerides or walnut glycerides, PEG-23 castor oil, PEG-25 hydrogenated castor oil or trioleate, PEG-35 castor oil, PEG-30 castor oil or hydrogenated castor oil, PEG-38 castor oil, PEG-40 castor oil or hydrogenated castor oil or palm kernel oil, PEG-45 hydrogenated castor oil, PEG-50 castor oil or hydrogenated castor oil, PEG-56 castor oil, PEG-60 castor oil or hydrogenated castor oil corn glycerides or walnut glycerides, PEG-80 hydrogenated castor oil, PEG-100 castor oil or hydrogenated castor oil, PEG-200 castor oil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides, lauroyl polyethylene glycol-32 glycerol, stearoyl polyethylene glycol glycerides, tocopheryl PEG-1000 succinate (TPGS); (surfactants belonging to this group are known, for example, as Emalex, Cremophor, Emulgante, Eumulgin, Nikkol, Thornley, Simulsol, Cerex, Crovol, Labrasol, Softigen, Gelucire, vitamin E TPGS)

f) Polyglyceryl-modified fatty acids include polyglyceryl esters of fatty acids such as polyglyceryl-10 laurate, oleate, stearate, polyglyceryl-10 mono-and dioleate, and polyglyceryl polyricinoleate; (surfactants belonging to this group are known, for example, as Nikkol, Decaglyn, Caprol or Polymuls)

g) The stearyl alcohol derivatives include polyethylene glycol derivatives of stearyl alcohol such as PEG-24 cholesterol ether, PEG-30 cholesterol, PEG-25 plant stearyl alcohol, PEG-30 soybean stearyl alcohol, etc.; (surfactants belonging to this group are known, for example, as Solulan or Nikkol BPSH)

h) Polyethylene glycol sorbitan fatty acids such as PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate or sorbitan tristearate or sorbitan monooleate or sorbitan trioleate or sorbitan monoisostearate or sorbitan monopalmitate or sorbitan monostearate, PEG-4 sorbitan monolaurate, PEG-5 sorbitan monooleate, PEG-6 sorbitan monooleate or sorbitan monolaurate or sorbitan monostearate, PEG-8 sorbitan monostearate, PEG-30 sorbitan tetraoleate, PEG-40 sorbitan monooleate or sorbitan tetraoleate, PEG-60 sorbitan tetrastearate, PEG-80 sorbitan monolaurate, PEG sorbitan hexaoleate, etc.; (surfactants belonging to this group are known, for example, as Liposor, Tween, Dacol MSS, Nikkol, Emalex, Atlas)

i) Polyethylene glycol alkyl esters such as PEG-10 oleyl ether or cetyl ether or stearyl ether, PEG-20 oleyl ether or cetyl ether or stearyl ether, PEG-9 lauryl ether, PEG-23 lauryl ether (twelfth-23), PEG-100 stearoyl enzyme and the like; (surfactants belonging to this group are known, for example, as Volpo, Brij)

j) Sugar esters such as sucrose distearate/monostearate, sucrose monostearate or monolaurate and the like; (surfactants belonging to this group are known, for example, as Surcroester, Crodesta, sucrose monolaurate)

k) Polyethylene glycol alkylbenzenes such as PEG-10-100 nonylphenol (Triton X series), PEG-15-100 octylphenol ether (Triton N series), and the like;

l) polyoxyethylene-polyoxypropylene block copolymers (polyhydroxyalkylenes (poloxamers) such as polyhydroxyalkylene 108, polyhydroxyalkylene 188, polyhydroxyalkylene 237, polyhydroxyalkylene 288, and the like; (surfactants belonging to this group are known, for example, as Synperonic PE, Pluronic, Emkalyx, Lutrol^TM，Supronic，Monolan，Pluracare，Plurodac)

m) ionic surfactants include cationic, anionic and zwitterionic surfactants, for example fatty acid salts such as sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium tetradecanoate, sodium palmitate, sodium state, sodium ricinoleate, and the like; for example, bile salts such as sodium cholate, sodium taurocholate, sodium glycocholate, and the like; for example, phospholipids such as egg/soybean lecithin, hydroxylated lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, etc.; for example, esterification products of phosphoric acid esters such as diethanolammonium polyoxyethylene-10 oleyl ether phosphate, fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydrides; for example, carboxylic acid esters such as succinylated monoglycerides, sodium stearoylbutylene dicarboxylate, stearoylpropyleneglycol hydrogen succinate, mono/diacetylated mono-and diglycerides which are acid esters, citric acid esters of mono-and diglycerides, glyceryl-lactylates of fatty acids, lactic acid esters of fatty acids, calcium/sodium stearoyl-2-lactylate, calcium/sodium stearate, diatomates, propylene glycol silicates, ether carboxylates, etc.; for example, sulfates and sulfonates such as ethoxylated alkyl sulfates, alkyl benzene sulfates, alpha-olefin sulfonates, acyl 2-hydroxyethyl sulfonates, N-acyl taurates, alkyl glyceryl ether sulfonates, disodium octyl sulfosuccinate, disodium undecylenamide-MEA-sulfosuccinate, and the like; for example, cationic surfactants such as cetyltrimethylammonium bromide, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, dodecylammonium chloride, alkylbenzyldimethylammonium salts, diisobutylphenoxyethyldimethylbenzylammonium salts, alkylpyridines, betaines (laurylbetaine), ethoxylated amines (polyoxyethylenel-15-cocoamine) and the like.

Among the suitable surfactants listed above, different possibilities are listed such as PEG-20 oleyl ether or cetyl ether or stearyl ether, which means that PEG-20 oleyl ether and PEG-20 cetyl ether and PEG-20 stearyl ether are meant. Thus, for example, PEG-20 castor oil or hydrogenated castor oil or corn glycerides or hydrogenated walnut glycerides would be read as PEG-20 castor oil and PEG-20 hydrogenated castor oil and PEG-20 corn glycerides and PEG-20 hydrogenated walnut glycerides.

In the compositions of the present invention, the surfactant is preferably present in an amount of 1 to 70% by weight, more preferably 5 to 55%, most preferably 10 to 50% (relative to the total weight of surfactant, acid and drug). The amount of surfactant used will then generally depend on the amount of drug and the drug compound itself. The ratio by weight of surfactant to drug is preferably in the range 100: 1 to 1: 5, especially 50: 1 to 1: 2, more especially 10: 1 to 1: 1.

Preferred surfactants in the compositions of the present invention belong to the group of polyethylene glycol sorbitan fatty acid esters, the group of products of alcohol-oil transesterification, or the group of polyoxy vinyl-polyoxypropylene block copolymers. Preferably, the surfactant in the composition of the invention belongs to the group of fatty acid esters of polyethylene glycol sorbitan or to the group of products of alcohol-oil transesterification. The most preferred surfactants are those known as Tween, those known as Cremophor, and vitamin E TPGS (alpha-tocopheryl-polyethylene glycol succinate, also abbreviated as TGPS), especially Cremophor RH40 and vitamin ETPGS.

As another example of the composition of the present invention, the surfactant may be substituted with a suitable wax, such as polyethylene glycol and the like.

The acid used in the compositions of the present invention may be any water-soluble physiologically tolerable acid, especially any inorganic acid conventionally used in the preparation of acid salts of pharmaceutical compounds, or, more preferably, organic acids such as acetic, fumaric, tartaric, maleic, malic, succinic, oxalic, malonic, benzoic, mandelic and ascorbic acids.

Tartaric acid and more particularly citric acid are preferred because their salts with pharmaceutical compounds generally have a reduced tendency to precipitate from aqueous solutions. In general, however, any acid may be used as long as it is not so strong as to promote degradation of the surfactant and when added to water can create a low pH environment, preferably pH4 and ideally about pH 2. The acid may be in liquid (e.g., solution) or solid form; however, solid acids in the form of anhydrous or hydrates in the surrounding environment are preferred.

The base used in the compositions of the invention may be any water-soluble physiologically tolerable base, especially any inorganic or organic base conventionally used for the preparation of basic salts of pharmaceutical compounds, e.g. alkali and alkaline earth metals, e.g. lithium-, sodium-, potassium-, magnesium or calcium hydroxide, bicarbonates or carbonates, etc., NH₃N, N' -dibenzylethylenediamine, N-methyl-D-glucamine, hydrated amine, ethanolamine, diethanolamine, triethanolamine and the like, amino acids such as arginine, lysine and the like.

In the compositions of the present invention, the acid is present in a ratio of at least 1: 1 acid to drug by weight, preferably in a ratio of from 1: 1 to 100: 1 acid to drug by weight, more preferably from 1: 1 to 50: 1, even more preferably from 1: 1 to 10: 1 and most preferably from 3: 1 to 10: 1. The amount of acid used will depend on the acid and drug compound chosen, but generally an increase in the relative proportion of acid will result in accelerated dissolution of the drug upon contact with water. Generally, the amount of acid is at least that amount necessary to create an acidic microenvironment upon contact with water, particularly aqueous solutions, in which the solubility of the pharmaceutical compound is increased.

The acid is an important component of the composition of the present invention and it rapidly dissolves in the liquid. The invention therefore also relates to a pharmaceutical composition comprising a basic pharmaceutical compound, a surfactant and a physiologically tolerable water-soluble acid, characterized in that the weight percentage of acid by weight is in the range from 30% to 95%, preferably from 45% to 95%, more preferably from 50% to 90%, most preferably from 50% to 65%. The weight percentages by weight preferably correspond to the weight of the basic pharmaceutical compound, the surfactant and the physiologically tolerable water-soluble acid and the optional polymer.

Alternatively, the invention also relates to a pharmaceutical composition comprising a basic pharmaceutical compound, a surfactant and a physiologically tolerable water soluble acid, characterised in that the molar ratio of acid to pharmaceutical compound is at least 3: 1, preferably at least 5: 1, more preferably at least 10: 1.

The invention also relates to a pharmaceutical composition comprising a basic pharmaceutical compound, a surfactant and a physiologically tolerable water-soluble acid, characterized in that the weight percentage of acid is in the range from 30 to 95% by weight and in that the ratio of acid to pharmaceutical compound is at least 1: 1 by weight.

Alternatively, the invention also relates to a pharmaceutical composition comprising a basic compound, a surfactant, a physiologically tolerable water-soluble acid, characterized in that the weight percentage of acid by weight is between 30% and 95% and in that the molar ratio of acid to pharmaceutical compound is at least 3: 1.

The particular values of the acids set forth above also account for the bases in the compositions of the present invention which comprise the acidic drug compound, the surfactant, and the base.

The most specific advantage of the composition of the invention is that the pharmaceutical compound is only poorly soluble, but the drug dissolution parameters obtained by the combination of the drug, the surfactant and the acid (or base) are so significant that significantly improved drug uptake parameters can be obtained in which the pharmaceutical compound is more soluble.

Thus, the pharmaceutical compound in the composition of the invention may be any organic or inorganic substance. Pharmaceutical compounds can exert local physiological effects, as well as systemic effects, whether after passage through the mucosa or after transfer to the gastrointestinal tract with saliva upon oral administration.

Preferably, the pharmaceutical compound is not readily soluble, e.g., not readily soluble, slightly soluble, poorly soluble, or insoluble in purified water at 21 ℃ (i.e., it is desired to dissolve 1 part of the pharmaceutical compound in solution with 30, 100, 1000, 10000 parts by weight of water). In particular, the drug is a basic drug compound. The term basic drug compound refers to a drug compound having a pKa value above 7 or a drug compound that is soluble in an acid/acidic medium. The term acidic drug compound refers to a drug compound having a pKa value below 7 or a drug compound that is soluble in a base/alkaline (alkaline) medium.

Examples of compounds that may be used that are poorly water soluble in the compositions of the present invention include:

nifedipine (nifedipine),

itraconazole (itraconazole) (described in detail in EP-A-6711),

saperconazole (saperconazole) (see US-A-4916134),

(-)-[2S-[2α，4α(S^＊)]]-4- [4- [4- [4- [ [2- (4-chlorophenyl) -2- [ [ (4-methyl-4H-1, 2, 4-triazol-3-yl) thio ] thio]Methyl radical]-1, 3-dioxolan-4-yl radical]Methoxy radical]Phenyl radical]-1-hexahydropiperazinyl]Phenyl radical]2, 4-dihydro-2- (1-methylpropyl) -3H-1, 2, 4-triazol-3-one (compound 40 in WO 96/13499),

cisapride (described in detail in EP- ｃA-76530),

(B) -N- [4- [ 2-ethyl-1- (1H-1, 2, 4-triazol-1-yl) butyl ] phenyl ] -2-benzothiazolomine (detailed in WO-97/49704); 6, 11-dihydro-11- [1- [2- [4- (2-quinolinylmethoxy) phenyl ] ethyl ] -4-piperidinylidene ] -5H-imidazo [2, 1-b ] [3] benzazepine-3-carboxylic acid methyl ester (described in detail in WO-97/34897);

4- [ [ 4-amino-6- [ (2, 6-dichlorophenyl) methyl ] -1, 3, 5, -triazol-2-yl ] amino ] benzonitrile (described in detail in EP-0,834,507);

(B-cis) -1- [4- [4- [4- [ [4- (2, 4-difluorophenyl) -4- (1H-1, 2, 4-triazol-1-ylmethyl) -1, 3-dioxolan-2-yl ] methoxy ] phenyl ] 1-hexahydropiperazinyl ] phenyl ] -3- (1-methylethyl) -2-imidazolidinone;

(2S-cis) -1- [4- [4- [4- [ [4- (2, 4-difluorophenyl) -4- (1H-1, 2, 4-triazol-1-ylmethyl) -1, 3-dioxolan-2-yl ] methoxy ] phenyl ] 1-hexahydropiperazinyl ] phenyl ] -3- (1-methylethyl) -2-imidazolidinone;

3- [2- [3, 4-dihydrobenzofuro [3, 2-c ] pyridin-2 (1H) -yl ] ethyl ] -2-methyl-4H-pyrido- [1, 2-a ] pyrimidin-4-one;

n- [2- [4- (4-chlorophenyl) -1-hexahydropiperazinyl ] ethyl ] -2-benzothiazolomine;

(B1) -N- [4- [2- (dimethylamino) -1- (1H-imidazol-1-yl) propyl ] phenyl ] -2-benzothiazolomine (detailed in WO-97/49704 z)

(B) -6- [ amino (4-chlorophenyl) (1-methyl-1H-imidazol-5-yl) methyl ] -4- (3-chlorophenyl) -1-methyl-2 (1H) -quinolinone;

(B) -N- [4- [ 2-ethyl-1- (1H-1, 2, 4-triazol-1-yl) butyl ] phenyl ] -2-benzothiazolomine;

3- [6- (dimethylamino) -4-methyl-3-pyridinyl ] -2, 5-dimethyl-N, N-dipropylpyrazolo [2, 3-a ] pyrimidin-7-amine monohydrochloride;

(S) - [1- [2- [3- [ (2, 3-dichloro-1H-inden-2-yl) oxy ] -4-methoxyphenyl ] propyl ] -1H-imidazol-2-yl ] cyanamide;

(+) - (B-trans) -4- [1- (3, 5-bis (trifluoromethyl) benzoyl) -2- (phenylmethyl) -4-hexahydropyridi nyl ] -N- (2, 6-dimethylphenyl) -1-hexahydropiperazineacetamide (S) -hydroxybutanedioate (1: 1);

(-)-[2S-[2α，4α(S^＊)]]-4- [4- [4- [4- [ [2- (4-chlorophenyl) -2- [ [ (4-methyl-4H-1, 2, 4-triazol-3-yl) thio ] thio]Methyl radical]-1, 3-bisCyclopentadienyl-4-yl]Methoxy radical]Phenyl radical]-1-hexahydropiperazinyl]Phenyl radical]-2, 4-dihydro-2- (1-methylpropyl) -3H-1, 2, 4-triazol-3-one;

(+) - (trans) -4- [1- (3, 5-bis (trifluoromethyl) benzoyl) -2- (phenylmethyl) -4-hexahydropyridi nyl ] -N- (2, 6-dimethylphenyl) -1-hexahydropiperazineacetamide;

compounds described in WO99/50256, WO00/27828, WO01/85699, WO01/85700, WO01/64674 and EP0,834,507; said documents are incorporated herein by reference.

Compounds of formula (I) (see thus PCT/EP02/08953)

Its N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form,

wherein

-a¹＝a²-a³＝a⁴-represents a double bond group structure

-CH＝CH-CH＝CH- (a-1)；

-N＝CH-CH＝CH- (a-2)；

-N＝CH-N＝CH- (a-3)；

-N＝CH-CH＝N- (a-4)；

-N＝N-CH＝CH- (a-5)；

-b¹＝b²-b³＝b⁴-represents a double bond group structure

-CH＝CH-CH＝CH- (b-1)；

-N＝CH-CH＝CH- (b-2)；

-N＝CH-N＝CH- (b-3)；

-N＝CH-CH＝N- (b-4)；

-N＝N-CH＝CH- (b-5)；

n is 0, 1, 2, 3 or 4; and when-a¹＝a²-a³＝a⁴-is (a-1), then n may also be 5;

m is 1, 2, 3 and when-b¹＝b²-b³＝b⁴Is (b-1), then m may also be 4;

R¹is hydrogen; an aryl group; an aldehyde group; c_1-6An alkylcarbonyl group; c_1-6An alkyl group; c_1-6An alkyloxycarbonyl group; via formyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkyloxycarbonyl, C_1-6Alkylcarbonyloxy substituted C_1-6An alkyl group; warp C_1-6Alkyloxycarbonyl substituted C_1-6Alkyloxy C_1-6An alkylcarbonyl group;

R²each independently hydroxy, halogen, via cyano or-C (═ O) R⁶Optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups_2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups_2-6Alkynyl, C_1-6Alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or bis- (C)_1-6Alkyl) amino, polyhalomethyl, polyhalomethylthio, -S (═ O)_pR⁶，-NH-S(＝O)_pR⁶，-C(＝O)R⁶，-NHC(＝O)H，-C(＝O)NHNH₂，-NHC(＝O)R⁶-C (═ NH) R6, or a group of formula

Wherein A is₁Is each independently N, CH or CR⁶(ii) a And is

A₂Is NH, O, S or NR⁶

X₁is-NR⁵-，-NH-NH-，-N＝N-，-O-，-C(＝O)-，C_1-4Alkanediyl, -CHOH-, -S-, -S (═ O)_p-，-X₂-C_1-4alkanediyl-or-C_1-4alkanediyl-X₂-；

X₂is-NR⁵-，-NH-NH-，-N＝N-，-O-，-C(＝O)-，-CHOH-，-S-，-S(＝O)_p-；

R₃Is NHR¹³；NR¹³R¹⁴；-C(＝O)-NHR¹³；-C(＝O)-NR¹³R¹⁴；-C＝O)-R¹⁵；-CH＝N-NH-C(＝O)-R¹⁶(ii) a Through one or more groups selected from cyano, NR⁹R¹⁰、-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷C substituted by a substituent of (3)_1-6An alkyl group; through one or more groups selected from cyano, NR⁹R¹⁰、-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷And wherein two hydrogen atoms attached to the same carbon atom are replaced by C_1-4C substituted by alkanediyl-substituted substituents_1-6An alkyl group; via hydroxy and from cyano, NR⁹R¹⁰，-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷C substituted by a second substituent_1-6An alkyl group; through one or more groups selected from cyano, NR⁹R¹⁰、-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷C substituted by a substituent of (3)_1-6Alkyloxy C_1-6An alkyl group; through one or more substituents independently selected from halogen, cyano, NR⁹R¹⁰，-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷C substituted by a substituent of (3)_2-6An alkenyl group; through one or more groups selected from halogen, cyano, NR⁹R¹⁰、-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷C substituted by a substituent of (3)_2-6An alkynyl group; -C (═ N-O-R)⁸)-C_1-4An alkyl group; r⁷or-X₃-R⁷；

X₃is-NR⁵-，-NH-NH-，-N＝N-，-O-，-C(＝O)-，-S-，-S(＝O)_p-，-X₂-C_1-4Alkanediyl-, -C_1-4alkanediyl-X_2a-，-C_1-4alkanediyl-X_2b-C_1-4Alkanediyl, -C (═ N-OR)⁸)-C_1-4Alkanediyl-;

X_2ais-NH-, -N-, -O-, -C (═ O) -, -S-, S (═ O)_p-, and

X_2bis-NH-NH-, -N-, -C (═ O) -, -S-, S (═ O)_p-；

R⁴Is halogen, hydroxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_1-6Alkyloxy, cyano, nitro, polyhalo C_1-6Alkyl, polyhalo C_1-6Alkyloxy, aminocarbonyl, C_1-6Alkyloxycarbonyl radical, C_1-6Alkylcarbonyl, formyl, amino, mono-or di (C)_1-4Alkyl) amino or R⁷；

R⁵Is hydrogen; an aryl group; a formyl group; c_1-6An alkylcarbonyl group; c_1-6An alkyl group; c_1-6An alkyloxycarbonyl group; via formyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkyloxycarbonyl or C_1-6C substituted by alkylcarbonyloxy_1-6An alkyl group; warp C_1-6C substituted by alkyloxycarbonyl_1-6Alkyloxy C_1-6An alkylcarbonyl group;

R⁶is C_1-4Alkyl, amino, mono-or di- (C)_1-4Alkyl) amino or polyhalo C_1-4An alkyl group;

R⁷is a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein the carbocyclic or heterocyclic ring system may optionally be substituted by one, two, three, four or five substituents independently selected from halogen, hydroxy, acyl, C_1-6Alkyl, hydroxy C_1-6Alkoxy, amino C_1-6Alkyl, mono-or di (C)_1-6Alkyl) amino C_1-6Alkyl, formyl, C_1-6Alkylcarbonyl group, C_3-7Cycloalkyl radical, C_1-6Alkyloxy, C_1-6Alkyl oxygenCarbonyl radical, C_1-6Alkylthio, cyano, nitro, polyhalo C_1-6Alkyl, polyhalo C_1-6Alkyloxy, aminocarbonyl, -CH (═ N-O-R)⁸)，R^7a，-X₃-R^7aOr R^7a-C_1-4Alkyl substituents;

R^7ais a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocycle, wherein the ring system of the carbocycle or heterocycle may optionally be substituted by one, two, three, four or five groups independently selected from halogen, hydroxy, mercapto, C_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, mono-or di (C)_1-6Alkyl) amino C_1-6Alkyl, formyl, C_1-6Alkylcarbonyl group, C_3-7Cycloalkyl radical, C_1-6Alkyloxy, C_1-6Alkyloxycarbonyl, C_1-6Alkylthio, cyano, nitro, polyhalo C_1-6Alkyl, polyhalo C_1-6Alkyloxy, aminocarbonyl, -CH (═ N-O-R)⁸) Substituted by a substituent;

R⁸is hydrogen, C_1-4Alkyl, aryl or aryl C_1-4An alkyl group;

R⁹and R¹⁰Each is hydrogen; a hydroxyl group; c_1-6An alkyl group; c_1-6An alkoxy group; c_1-6An alkylcarbonyl group; c_1-6An alkyloxycarbonyl group; an amine group; mono-or bis (C)_1-6Alkyl) amino; mono-or bis (C)_1-6Alkyl) aminocarbonyl; -CH (═ NR)¹¹) Or R⁷Wherein each of C previously described_1-6The alkyl groups are optionally and individually substituted by one or two groups independently selected from hydroxy, C_1-6Alkoxy, hydroxy C_1-6Alkoxy, carbonyl, C_1-6Alkoxycarbonyl, cyano, amino, imino, mono-or bis (C)_1-4Alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S (═ O)_pR⁶、-NH-S(＝O)_pR⁶、-C(＝O)R⁶、-NHC(＝O)H、-C(＝O)NHNH₂、-NHC(＝O)R⁶、-C(＝NH)R⁶、R⁷Substituted by a substituent; or

R⁹And R¹⁰Can form the following double-bond or triple-bond groups

-CH₂-CH₂-CH₂-CH₂- (d-1)

-CH₂-CH₂-CH₂-CH₂-CH₂- (d-2)

-CH₂-CH₂-O-CH₂-CH₂- (d-3)

-CH₂-CH₂-S-CH₂-CH₂- (d-4)

-CH₂-CH₂-NR¹²-CH₂-CH₂- (d-5)

-CH₂-CH＝CH-CH₂- (d-6)

＝CH-CH＝CH-CH＝CH- (d-7)

R¹¹Is cyano; is selectively covered with C_1-4Alkoxy, cyano, amino, mono-or bis (C)_1-4Alkyl) amino or aminocarbonyl substituted C_1-4An alkyl group; c_1-4An alkylcarbonyl group; c_1-4An alkoxycarbonyl group; aminocarbonyl; mono-or bis (C)_1-4Alkyl) aminocarbonyl;

R¹²is hydrogen or C_1-4An alkyl group;

R¹³and R¹⁴Each independently being C optionally substituted by cyano or aminocarbonyl_1-6Alkyl, C optionally substituted by cyano or aminocarbonyl_2-6Alkenyl, C optionally substituted by cyano or aminocarbonyl_2-6An alkynyl group;

R¹⁵is by cyano or aminocarbonylSubstituted C_1-6An alkyl group;

R¹⁶is cyano or aminocarbonyl or R⁷Optionally substituted C_1-6An alkyl group;

p is 1 or 2;

aryl is phenyl or is respectively selected from halogen, hydroxyl, sulfhydryl and C by one, two, three, four or five_1-6Alkyl, hydroxy C_1-6Alkyl, amino C_1-6Alkyl, mono-or di (C)_1-6Alkyl) amino C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_3-7Cycloalkyl radical, C_1-6Alkyloxy, C_1-6Alkyloxycarbonyl, C_1-6Alkylthio, cyano, nitro, polyhalo C_1-6Alkyl, polyhalo C_1-6Alkyloxy, aminocarbonyl, R⁷or-X₃-R⁷Phenyl substituted by a substituent;

the compounds described in WO99/50250 are hereby incorporated by reference, i.e. the compounds of the formula (I-A)

Its N-oxide, pharmaceutically acceptable addition salt or stereochemically isomeric form, wherein

A is CH, CR⁴Or N;

n is 0, 1, 2, 3 or 4;

q is hydrogen or-NR¹R²；

R¹And R²Are respectively selected from hydrogen, hydroxyl and C_1-12Alkyl radical, C_1-12Alkoxy radical, C_1-12Alkylcarbonyl group, C_1-12Alkoxycarbonyl, aryl, amino, mono-or bis (C)_1-12Alkyl) amino, mono-or bis (C)_1-12Alkyl) aminocarbonyl, each of the previously mentioned C' s_1-12The alkyl groups are optionally and individually selected from hydroxy, C_1-6Alkyloxy, hydroxy C_1-6Alkoxy, carboxyl, C_1-6Alkyloxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono-or bis (C)_1-6Alkyl) amino, aryl, and Het substituents; or

R¹And R²Together may form a tetrahydropyrrolyl, hexahydropyridyl, morpholinyl, azido or mono-or bis (C)_1-12Alkyl) amino C_1-4A alkylidene group;

R³is hydrogen, aryl, C_1-6Alkylcarbonyl group, C_1-6Alkyl radical, C_1-6Alkyloxycarbonyl, quilt C_1-6C substituted by alkyloxycarbonyl_1-6An alkyl group; and is

R⁴Are each hydroxy, halogen, C_1-6Alkyl radical, C_1-6Alkyloxy, cyano, amino-carbonyl, nitro, amino, trihalomethyl, trihalomethyloxy or C substituted by cyano or aminocarbonyl_1-6An alkyl group;

R⁵is hydrogen or C_1-4An alkyl group;

l is C_1-10Alkyl radical, C_3-10Alkenyl radical, C_3-10Alkynyl, C_3-7Cycloalkyl, or substituted by one or two independently selected from C_3-7C substituted by cycloalkyl, hydroindenyl, indolyl and phenyl substituents_3-7Cycloalkyl, wherein the phenyl, hydroindenyl and indolyl may be substituted by one, two, three, four or possibly five radicals each independently selected from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, aminocarbonyl, C_1-6Alkyloxycarbonyl, formyl, nitro, amino, trihalomethyl, trihalomethyloxy and C_1-6Substituted with an alkylcarbonyl substituent; or

L is-X¹-R⁶or-X²-Alk-R⁷Wherein

R⁶And R⁷Each is phenyl or is substituted by one, two, three, four or five groups selected from halogen, hydroxy and C_1-6Alkyl radical, C_1-6Alkyloxy, C_1-6Alkylcarbonyl group, C_1-6Phenyl substituted with alkyloxycarbonyl, formyl, cyano, aminocarbonyl, nitro, amino, trihalomethyloxy and trihalomethyl substituents;

X¹or X²Each independently is-NR³-, -NH-, -N ═ N-, -O-, -S (═ O) -or-S (═ O)₂-；

Alk is C_1-4An alkanediyl group;

aryl is phenyl or is respectively selected from halogen and C by one, two, three, four or five_1-6Alkyl radical, C_1-6Phenyl substituted with alkyloxy, cyano, nitro and trihalomethyl substituents;

het is an aliphatic or aromatic heterocyclic group; the aliphatic heterocyclic group is selected from tetrahydropyrrolyl, hexahydropyridyl, homopiperidinyl, hexahydropiperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl, wherein the aliphatic heterocyclic group may be respectively optionally substituted with oxy; and the aromatic heterocyclic group is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, piperazinyl and pyridazinyl, wherein the aromatic heterocyclic group may be each optionally substituted with hydroxy;

the compounds described in WO 00/27825, i.e. compounds of the formula (I-B), are incorporated herein by reference

Its N-oxide, pharmaceutically acceptable addition salt, quaternary amines and stereochemically isomeric forms, wherein

-a¹＝a²-a³＝a⁴-represents a double bond group structure

-CH＝CH-CH＝CH- (a-1)；

-N＝CH-CH＝CH- (a-2)；

-N＝CH-N＝CH- (a-3)；

-N＝CH-CH＝N- (a-4)；

-N＝N-CH＝CH- (a-5)；

n is 0, 1, 2, 3 or 4; and when-a¹＝a²-a³＝a⁴-is (a-1), then n may also be 5;

R¹is hydrogen; an aryl group; a formyl group; c_1-6An alkylcarbonyl group; c_1-6An alkyl group; c_1-6An alkoxycarbonyl group; via formyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkoxycarbonyl group, C_1-6Alkylcarbonyloxy substituted C_1-6An alkyl group; warp C_1-6Alkoxycarbonyl substituted C_1-6Alkoxy radical C_1-6An alkylcarbonyl group;

R²each independently hydroxy, halogen, via cyano or-C (═ O) R⁶Optionally substituted C_1-6Alkyl radical, C_3-7Cycloalkyl, C optionally substituted by one or more halogen atoms or cyano groups_2-6Alkenyl, C optionally substituted by one or more halogen atoms or cyano groups_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or bis- (C)_1-6Alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S (═ O)_pR⁶，-NH-S(＝O)_pR⁶，-C(＝O)R⁶，-NHC(＝O)H，-C(＝O)NHNH₂，-NHC(＝O)R⁶，-C(＝NH)R⁶Or a group of the formula

Wherein A is each independently N, CH or CR⁶；

B is NH, O, S or NR⁶；

p is 1 or 2; and is

R⁶Is methyl, amino, mono-or di-methylamino or polyhalomethyl;

l is C_1-10Alkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_3-7Cycloalkyl, wherein the aliphatic groups may each be substituted with one or two substituents independently selected from:

^＊C_3-7a cycloalkyl group,

^＊indolyl or isoindolyl, each optionally substituted by one, two, three, or four, independently selected from halogen, C_1-6Alkyl, hydroxy, C_1-6Alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C_1-6Substituted by an alkylcarbonyl substituent group,

^＊phenyl, pyridyl, pyrimidinyl, piperazinyl or pyridazinyl, wherein the aromatic ring may be optionally substituted with one, two, three, four or five independently of one another by R²Substituted by the defined substituents; or

L is-X¹-R³Wherein

R³Is phenyl, pyridyl, pyrimidinyl, piperazinyl or pyridazinyl, wherein the aromatic ring may be optionally substituted by one, two, three, four or five independently of one another by R²Substituted by the defined substituents; and is

X is-NR¹-, -NH-, -N ═ N-, -O-, -C (═ O) -, -CHOH-, -S (═ O) -or-S (═ O)₂-；

Q represents hydrogen, C_1-6Alkyl, halogen, polyhaloC_1-6Alkyl or-NR⁴R⁵(ii) a And is

R⁴And R⁵Are each independently selected from hydrogen, hydroxy, C_1-12Alkyl radical, C_1-12Alkoxy radical, C_1-12Alkylcarbonyl group, C_1-12Alkoxycarbonyl, aryl, amino, mono-or bis (C)_1-12Alkyl) amino, mono-or bis (C)_1-12Alkyl) aminocarbonyl, in which each of the previously mentioned C' s_1-12The alkyl groups are optionally and individually selected from hydroxy, C_1-6Alkoxy, hydroxy C_1-6Alkoxy, carboxyl, C_1-6Alkoxycarbonyl, cyano, amino, imino, mono-or bis (C)_1-16Alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S (═ O)_pR⁶、-NH-S(＝O)_pR⁶、-C(＝O)R⁶、-NHC(＝O)H、-C(＝O)NHNH₂、-NHC(＝O)R⁶、-C(＝NH)R⁶Aryl and Het substituents; or

R⁴And R⁵Together may form a tetrahydropyrrolyl, hexahydropyridyl, morpholinyl, azido or mono-or bis (C)_1-12Alkyl) amino C_1-4A alkylidene group;

y represents hydroxy, halogen, C_3-7Cycloalkyl, C optionally substituted by one or more halogen atoms_2-6Alkenyl, C optionally substituted by one or more halogen atoms_2-6Alkynyl, by cyano or-C (═ O) R⁶Substituted C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxycarbonyl, carboxyl, nitro, amino, mono-or bis (C)_1-6Alkyl) amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, -S (═ O)_pR⁶，-NH-S(＝O)_pR⁶，-C(＝O)R⁶，-NHC(＝O)H，-C(＝O)NHNH₂，-NHC(＝O)R⁶，-C(＝NH)R⁶Or an aryl group;

aryl is phenyl or is respectively selected from halogen and C by one, two, three, four or five_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_1-6Alkoxy, cyano, nitro, polyhalo C_1-6Alkane and polyhalogen C_1-6Phenyl substituted with an alkoxy substituent;

het is an aliphatic or aromatic heterocyclic group; the aliphatic heterocyclic group is selected from the group consisting of pyrrolidinyl, hexahydropyridyl, homopiperidinyl, hexahydropiperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothienyl, wherein the aliphatic heterocyclic group may be each optionally substituted with oxy; and the aromatic heterocyclic group is selected from the group consisting of pyrrolyl, pyranyl, thienyl, pyridyl, pyrimidinyl, piperazinyl and pyridazinyl, wherein the aromatic heterocyclic group may be each optionally substituted with hydroxy;

particular compounds of structural formula (I) are compounds 1, 25, 84, 133, 152, 179, 233, 239, 247, 248 (see tables 3, 4, and 5), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and their stereochemically isomeric forms.

The most preferred compounds of formula (I) are:

4- [ [4- [ [4- (cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

its N-oxide, addition salt, quaternary amine or stereochemically isomeric form.

Compounds of the specific formula (I-A) are:

4- [ [ 4-amino-6- [ (2, 6-dichlorophenyl) methyl ] -2-pyrimidinyl ] amino ] -benzonitrile;

6- [ (2, 6-dichlorophenyl) methyl ] -N2- (4-fluorophenyl) -2, 4-pyrimidinediamine;

4- [ [4- [ (2, 4-dichlorophenyl) methyl ] -6- [ (4-hydroxybutyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [ (3-hydroxybutyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

n- [2- [ (4-cyanophenyl) amino ] -6- [ (2, 6-dichlorophenyl) methyl ] -4-pyrimidinyl ] -acetamide;

n- [2- [ (4-cyanophenyl) amino ] -6- [ (2, 6-dichlorophenyl) methyl ] -4-pyrimidinyl ] -butyramide;

4- [ [ 2-amino-6- [ (2, 6-dichlorophenoxy) -4-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [ (2-hydroxy-2-phenylethyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [3- (2-oxo-1-tetrahydropyrrolyl) propyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [ [2- (2-hydroxyethoxy) ethyl ] amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [2, 3- (dihydroxypropyl) amino ] -2-pyrimidinyl ] -amino ] benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- (hydroxyamino) -2-pyrimidinyl ] amino-benzonitrile;

4- [ [4- [ (2-cyanoethyl) amino ] -6- [ (2, 6-dichlorophenyl) methyl ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) methyl ] -6- [ [2- (1-tetrahydropyrrolyl) ethyl ] amino ] -2-pyrimidinyl ] -amino ] -benzonitrile;

4- [ [ 4-amino-6- [ (2, 6-dichlorophenyl) methyl ] -5-methyl-2-pyrimidinyl ] amino ] -benzonitrile;

n2- (4-bromophenyl) -6- [ (2, 6-dichlorophenyl) methyl ] -5-methyl-2, 4-pyrimidinediamine;

4- [ [4- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [2- [ (2, 4, 6-trimethylphenyl) amino ] -4-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 4, 6-trimethylphenoxy) -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dichlorophenyl) thio ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dibromo-4- (1-methylethyl) phenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 6-dichloro-4- (trifluoromethyl) phenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 4-dichloro-6-methylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [2- [ (cyanophenyl) amino ] -4-pyrimidinyl ] amino ] -3, 5-dimethylbenzonitrile;

4- [ [4- [ (2, 4-dibromo-6-fluorophenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ 4-amino-6- [ (2, 6-dichlorophenyl) methyl ] -5-methyl-2-pyrimidinyl ] amino ] -benzeneacetonitrile;

4- [ [4- [ methyl (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 4, 6-trichlorophenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 4, 6, -trimethylphenyl) thio ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 4, 6, -trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [ 4-amino-6- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzeneacetonitrile;

4- [ [ 2-amino-6- [ (2, 4, 6-trimethylphenyl) amino ] -4-pyrimidinyl ] amino ] benzeneacetonitrile;

4- [ [4- (2-bromo-4-chloro-6-methylphenoxy) -2-pyrimidinyl ] amino ] benzeneacetonitrile;

4- [ [4- (4-chloro-2, 6-dimethylphenoxy) amino ] -2-pyrimidinyl ] amino ] benzeneacetonitrile;

3, 5-dichloro-4- [ [2- [ (4-cyanophenyl) amino ] -4-pyrimidinyl ] amino ] benzeneacetonitrile;

4- [ [4- [ [2, 6-dichloro-4- (trichloromethoxy) phenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 4-dibromo-3, 6-difluorophenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dibromo-4-propylphenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] aminobenzamide;

4- [ [4- [ (4- (1, 1-dimethylethyl) -2, 6-dimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [2- [ (4-cyanophenyl) amino ] -4-pyrimidinyl ] oxy ] -3, 5-dimethylbenzonitrile;

4- [ [4- [ (4-chloro-2, 6-dimethylphenyl) amino ] -5-methyl-2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [2- [ (4-cyanophenyl) amino ] -5-methyl-4-pyrimidinyl ] amino-3, 5-dimethylbenzonitrile;

4- [ [4- [ [4- (1, 1-dimethylethyl) -2, 6-dimethylphenyl ] amino ] -5-methyl-2-pyrimidinyl ] -amino ] benzonitrile;

4- [ [4- [ (4-bromo-2, 6-dimethylphenyl) amino ] -5-methyl-2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ 5-methyl-4- [ (2, 4, 6-trimethylphenylthio) -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [4- [ (2, 6-dibromo-4-propylphenyl) amino ] -5-methyl-2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ -4- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzamide, N3-oxide;

n2- (4-chlorophenyl) -N4- [ (2, 4, 6-trimethylphenyl) -2, 4-pyrimidinediamine;

4- [ [4- [ [2, 6-dibromo-4- (1-methylethyl) phenyl ] amino-5-methyl-2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [4- [ (4-cyanophenyl) amino ] -5-methyl-4-pyrimidinyl ] amino ] -3, 5-dimethyl-benzonitrile;

4- [ [4- [ (phenylmethyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

its N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form.

The most preferred compounds of formula (I-A) are:

4- [ [2- [ (cyanophenyl) amino ] -4-pyrimidinyl ] amino ] -3, 5-dimethylbenzonitrile; or

4- [ [4- [ (2, 4, 6, -trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

its N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form.

Compounds of the specific structural formula (I-B) are:

4- [ [ -amino-5-chloro-6- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ 5-chloro-4- [ (2, 4, 6-trimethylphenyl) amino ] -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [ 5-bromo-4- [ (4-cyano-2, 6-dimethylphenoxy) -2-pyrimidinyl ] amino ] benzonitrile;

4- [ [ 4-amino-5-chloro-6- [ (4-cyano-2, 6-dimethylphenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ 5-bromo-6- [ (4-cyano-2, 6-dimethylphenyl) amino ] -2-pyrimidinyl ] amino ] -benzonitrile;

4- [ [ 4-amino-5-chloro-6- [ (4-cyano-2, 6-dimethylphenyloxy) -2-pyrimidinyl ] -amino ] benzonitrile; or

4- [ [ 4-amino-5-bromo-6- [ (4-cyano-2, 6-dimethylphenyloxy) -2-pyrimidinyl ] -amino ] -benzonitrile;

its N-oxide, addition salt, quaternary amine or stereochemically isomeric form.

The most preferred compounds of formula (I-B) are:

4- [ [ 4-amino-5-bromo-6- [ (4-cyano-2, 6-dimethylphenyloxy) -2-pyrimidinyl ] -amino ] -benzonitrile;

its N-oxide, addition salt, quaternary amine or stereochemically isomeric form.

Other suitable pharmaceutical compounds in the compositions of the invention are:

analgesics and anti-inflammatory agents (NSAIDs, fentanyl, indomethacin, ibuprofen, ketoprofen, nabumetone, acetaminophen, piroxicam, tramadol, COX-2 inhibitors such as celecoxib and rofecoxib).

-antiarrhythmics (procainamide), quinidine (quinidine), verapamil (verapamil);

antibacterial and antiprotozoal drugs (amoxicillin, ampicillin (ampicilin), penicillin g (benzathine penillin), benzylpenicillin (benzathine), cefaclor (cefaclor), cefadroxil (cefadroxil), cefprozil (cefurozil), cefuroxime axetil (cefuroxime), cephalexin (cephalexin), chloramphenicol, chloroquinine (chloroquine), ciprofloxacin (ciprofloxacin), clarithromycin (clarithromycin), clavulanic acid (clavulanic acid), clindamycin, doxycycline, erythromycin, flucloxacillin sodium, halofantrine (halofantrine), isoniazid, kanamycin sulfate, lincomamomycin, mefloquine (fluquine), minocycline, floxacin sodium, nafcillin sodium, neomycin, fluxacin (fluxacin), penoxsulin, penoxpocetine, penoxsulin (penoxsulin), penoxsulosin, doxycycline (penoxsulin), cefaclin, doxycycline (penoxsulin, doxycycline (penciclovir, doxycycline);

-anticoagulants (warfarin);

antidepressants (amitriptyline, amoxapine (amoapine), butrityline (butritylin), clomipramine (clomipramine), desipramine (desipramine), dithiepin (dothiepin), doxepin (doxepin), fluoxetine (fluoxetine), rivastigmine (revoxetine), imipramine (amineptine), selegiline (selegiline), gepirone (gepirone), mipramine (imipramine), lithium carbonate, mienserin (miaciserin), milnacipran, nortriptypiline, paroxetine (oxepine), sertraline (setraline), 3- [2- [3, 4-dihydrobenzofluoro [3, 2-c ] pyridin-2 (1H) -yl ] ethyl ] -2-methyl-4H-pyrido [1, 2-a ] pyrimidine-4-one);

-antidiabetic agents (glibenclamide), metformin, RWJ-394718, RWJ-394720, RWJ-666589, RWJ-37082);

antiepileptics (carbamazepine, clorsnaxate (clonazepam), ethosuximide, carbasaladine (gabapentin), lamotrigine (lamotrigine), phenobarbital, bisphenopro-urea, primidone (primidone), tiagabine (tiagabine), terbinafine (topiramate), valpramine (valpromide), and vicatkins (vigabatrin).

Antifungal agents (amphotericin, chlorotritazozole, econazole, fluconazole, flucytosine, gresinoflumizone, itraconazole, ketoconazole, miconazole nitrate, noscapine, terbinafine, wortconazole, echinocandins);

antihistamines (astemizole), cinnarasin (cinnarizine), persimmonamide, descarboethoxyloratadine (decarboxyoratadine), fexofenadine (fexofenadine), flunarizine (flunaridine), levocabastine (levocabastine), latatidine (loratadine), noratimidazole (norastemizole), oxamide (oxyamide), promethazine (promethazine), terfenadine (terfenadine), terazosin (terazosin);

antihypertensives (angiotensin converting enzyme inhibitors, vasopressin converting enzyme antagonists, ketanserin (ketanserin), linopril (lisinopril), minoxidil (minoxidil), prazepine (prazosin), ruimipril (ramipril), reserpine, telapraxin (terazosin);

antimuscarinic drugs (atropine sulfate, scopolamine);

antineoplastic and antimetabolite (platinum compounds, such as cisplatin, carboplatin; taxanes, such as paclitaxel (paclitaxel), docetaxel (docetaxel), benzans (tecans), such as camptothecin, irinotecan (irinotecan), topotecan (topotecan), vinca alkaloids, such as vinblastine, vindesine (vindecenecine), vincristine, vannorubine (vinorelbine), nucleoside derivatives and PGA folate antagonists, such as 5-fluorouracil, capecitabine (capecitabine), gemcitabine (gemcitabine), thiopurine, thioguanine, cadribine (cladribine), aminomethylfolate; aminating agents, such as cyclophosphamide, chlorambucil, chloromethine (chlorotetracycline), chlorotetracycline (iphosphamide), levolysimachine, or urea, such as urea, for example, mechlorethamine, or other alkylating agents, buthioarene (busulphan), dabigatran (dacarbazine), procarbazine, thiotepa; antibiotics such as daunorubicin, doxorubicin (doxorubicin), idamycin (idarubicin), imazamycin (mitomycin), bleomycin, actinomycin, mitomycin; HER2 antibodies such as trastuzumab (trastuzumab); podophyllotoxin derivatives such as etoposide, teniposide; farnesyl convertase inhibitors, such as zanita (zarnestra); anthrax derivatives such as mitoxantrone (mitoxantrone); imatinib (imatinib); bordeaux (bortezomib);

-antimigraine drugs (aniditan), naratriptan (naratriptan), sumatriptan (sumatriptan), almatriptan (almotriptan);

-antiparkinsonian drugs (bromocriptine mesylate), levodopa, selegiline (selegiline), rasagiline (rasagiline);

antipsychotic, hypnotic and tranquilizer (alprazolam), amisulpride (amisulpride), buspirone (buspirone), chlordiazepoxide (chlorezapine), phenothiazine derivatives, clozapine (clozapine), diazepine, fluthiacet (fluphenazine), fluazepam (flurazepam), 9-hydroxyperidone (hydroxyvaliridone), lorazepam (lorazepam), mazapine (mazatine), olanzapine (olazine), oxazepam), pimozide (pimozide), piprazolone (piprazine), pimentamide (pioglitazone), sematel (selzetel), serezolidin (seratropine), sulpride (sulpride), flupridine (flupridine), flupridoliprazole (flupridine), flupridine (sulpride), thipridine (sulpride), thipride (piperadine (sulpride (flupride), flupridine (flupride), flupride (piperadine (sulpride), flupride (sulpride), flupride (sul;

-anti-stroke agents (lubeluzole), lubeluzole oxide (lubeluzole oxide), riluzole (riluzole), atigand (aptiganel), eliprodil (eliprodil), limamin (remacemide));

-antitussives (dextromethorphan morphinan, levodiprexazine (laevorepropizine));

anti-filtering virucidal agents (acyclovir), ganciclovir (ganciclovir), loviride (loviride), tevirapine (tivapine), zidovudine (zidovudine), lamivudine (lamivudine), zidovudine (zidovudine) + lamivudine (lamivudine), didanosine (didanosine), zalcitabine (zalcitabine), stavudine (stavudine), abacavir (abacavir), hydroxyurea, darunavir (darunavir));

- β -adrenergic receptor blockers (atenolol, carvedilol, metoprolol, nebivolol, propranolol);

-agents that influence myocardial contractility (amirone), digitoxin, digoxin, milrinone);

corticosteroids (beclomethasone dipropionate), betamethasone (betamethasone), budesonide (budesonide), dexamethasone (dexamethasone), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisone), prednisolone (prednisone), prednisone (prednisone), triamcinolone (triamcinolone));

-disinfectant (chlorhexidine)

Diuretics (acetazolamide), furosemide (frusemide), hydrochlorothiazide (hydrochlorothiazide), isosorbide);

-enzymes;

essential oils (anethole, anise oil (anise oil), carvacrol (caraway), cardamom oil (cardamom), cinnamon oil (cassia oil), eucalyptol (cineole), cinnamon oil (cinmamon oil), clove oil (clove oil), coriander seed oil (coriander oil), dementholized oil (dementholized min oil), dill oil (dill oil), eucalyptus oil (eucalyptol), eugenol (eugenol), ginger (gingger), lemon oil, mustard oil, bitter orange oil, nutmeg oil, orange oil, peppermint oil, sage, spearmint oil, terpineol, thyme;

-gastrointestinal agents (cimetidine), cisapride (cisapride), clobopride (clebopride), diphenoxylate (diphenoxylate), domperidone (domperidone), famotidine (famotidine), lansoprazole (lansoprazole), loperamide (loperamide), oxoperamide (loperamide oxide), mesalazine (mesalazine), metoclopramide (metoclopramide), mosapride (mosapride), nizatidine (nizatidine), norcisapride (norcisapride), oxalazine (sallazine), omeprazole (omeprazole), pantoprazole (pantoprazole), pirprazole (perprazole), pramiperide (uccaridine), rabeprazole (rizatriprazine), risperidonprazole (sulfaprazole), doxamide (sulfaprazine), sulfaprazine (sulfaprazine);

-hemostatic agents (aminocaproic acid);

lipid regulators (atorvastatin), lovastatin, pravastatin, probucol, simvastatin, rosuvastatin;

local anesthetics (benzocaine, lidocaine);

opiate analgesics (buprenorphine), codeine (codeine), dextromoramide (dexromoramide), dihydrocodeine (dihydrocodeine), dihydrocodeinone (hydrocodone), hydroxydihydrocodeinone (oxycodone), morphine);

parasympathetic mimetics and anti-dementias (leteprinim, etastine, galantamine, melphalan, melaminex, milameline, neostigmine, physostigmine, tacrine, donepezil, rivastigmine, sabcomeline, tasalidine, xanomeline, memantine, labetazoline, lazabemide, etc.);

polypeptides and proteins (antibodies, becaplamine (becaplmin), cyclosporine, erythropoietin, immunoglobulins, insulin growth factor, botulinum toxin, infliximab (infliximab);

sex hormones (estrogens, conjugated estrogens, ethinylestrol (ethinylestrol), mestranol (mestranol), estradiol (oesteradiol), estriol, estrone; progestins; chlormadinone acetate (chlormadinone acetate), cyproterone acetate (cyproterone acetate), 17-deacetyl norgestimate (17-deacetyl norgestimate), desogestrel (desogestrel), dienogest (dienogest), dydrogesterone (dygesterone), norethindrone diacetate (ethydiol diacetate), gestodene (gestodene), 3-ketodesogestrel (3-ketodesogestrel), levonorgestrel (levonorgestrel), lineestrol (lynestrenol), medroxyprogesterone acetate (medroxy-gesterone), medroxyprogesterone (medroxyprogesterone), medroxyprogesterone (medroxysterone), norethindrone acetate (norethindrone), norethindrone (norethindrone acetate (norethindrone), norgestrel (norgestrienone), progesterone (progasterone), acetylide (quinestanol acetate));

-stimulants (sildenafil), tadalafil (tadalafil), apomorphine (apomorphine), vardenafil (vardenafil));

vasodilators (amlodipine, buflomedil, amyl nitrite, azotemone, dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine, dimethylxanthine, pentaerythrityl nitrate);

their N-oxides, their pharmaceutically acceptable acid or base addition salts or their stereochemically isomeric forms.

Other embodiments include the following:

8-Oxytsoralen lithium salt vitamin K1

Pyrazole pyrimidineol magnesium salt propylthiouracil

Alpha-tocopherol artificial vitamin K3

Iron salt methylthiouracil

Pharmaceutical compounds suitable for the compositions of the present invention include all types of drugs conventionally used for topical administration (e.g., in gel patches) or into the outer discharge body cavity, e.g., oral, nasal, otic, rectal or vaginal administration. These include inter alia antifungals, calcium channel blockers, antibacterials, antihypertensives, anti-filtration viruses, analgesics, inhibitors of apolipoprotein B synthesis, and agents that alter the transfer of gastrointestinal contents (e.g., antidiarrheals or motility enhancers).

The invention is particularly applicable to anti-HIV agents, particularly non-nucleoside reverse transcriptase inhibitors, more particularly non-nucleoside reverse transcriptase inhibiting pyrimidine derivatives.

The compositions of the invention suitably contain from 0.001 to 50% by weight of the pharmaceutical compound, preferably from 0.1% to 35%, more preferably from 0.5% to 30%, especially from 8% to 25% and most preferably from 10% to 15% by weight (relative to the total weight of acid (base), surfactant and pharmaceutical compound). The amount of drug will, of course, depend upon the desired dissolution parameters, the intrinsic solubility of the drug compound, and the amount of drug that is to be considered as being in accordance with the desired dosage of drug in a dosage unit (e.g., capsule, coated tablet, etc.).

In the compounds of the formula (I), (I-A) or (I-B), C_1-4Alkyl as a group or as part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; c_1-6Alkyl as a group or as part of a group defines straight or branched chain having 1 to 6 carbon atoms, e.g. C_1-4The group defined by alkyl, pentyl, hexyl, 2-methylbutyl, and the likeA saturated hydrocarbon group of (a); c_2-6Alkyl as a group or moiety defines a straight or branched chain saturated hydrocarbon group having 2 to 6 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl, and the like; c_1-4Alkanediyl defines straight-chain or branched saturated divalent hydrocarbon radicals having from 1 to 4 carbon atoms, such as methylene, 1, 2-ethanediyl or 1, 2-ethylene, 1, 3-propanediyl or 1, 3-propylene, 1, 4-butanediyl or 1, 4-butylene, and the like; c_3-7Cycloalkyl is the generic name for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; c_2-6Alkenyl defines straight or branched chain hydrocarbon radicals containing one double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like having 2 to 6 carbon atoms; c_2-6Alkynyl defines straight or branched chain hydrocarbyl groups containing triple bonds such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like having 2 to 6 carbon atoms; monocyclic, bicyclic or tricyclic saturated carbocycle represents a ring system containing 1, 2 or 3 rings and consisting of only carbon atoms, and which contains only single bonds; monocyclic, bicyclic or tricyclic partially saturated carbocycle represents a ring system containing 1, 2 or 3 rings, consisting of only carbon atoms and providing at least one double bond if the ring system is not an aromatic ring; monocyclic, bicyclic or tricyclic aromatic carbocycle represents an aromatic carbocycle containing 1, 2 or 3 rings, which ring system consists only of carbon atoms; the term "aromatic" is a cyclic conjugated system known to the person skilled in the art and designated 4n +2 electrons, i.e. having 6, 10, 14 etc. pi electrons (hooke's law); monocyclic, bicyclic or tricyclic saturated heterocyclic ring represents a ring system containing 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S, which ring system contains only single bonds; monocyclic, bicyclic or tricyclic partially saturated heterocyclic ring represents a ring system containing 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S, and if the ring system is not aromatic, at least one double bond; monocyclic, bicyclic or tricyclic aromatic heterocycle represents an aromatic ring system containing 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S.

For therapeutic use, salts of the pharmaceutical compounds are those in which the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

The aforementioned pharmaceutically acceptable addition salts refer to the non-toxic acid addition salt forms which the pharmaceutical compounds may form, comprising therapeutic activity. The latter are suitably obtained by treating the base with a suitable acid, for example, hydrohalic acids, e.g., hydrochloric acid, hydrobromic acid, and the like; sulfuric acid; nitric acid; phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxy-propionic acid, 2-ketopropionic acid, oxalic acid, malonic acid, succinic acid, cis-butenedioic acid, trans-butenedioic acid, malic acid, tartaric acid, 2-hydroxy-1, 2, 3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. Conversely, the salt form may be converted to the free base form by base treatment.

Pharmaceutical compounds containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salts by treatment with appropriate organic and inorganic bases. Suitable base forms include, for example, lithium, sodium, potassium, magnesium and calcium salts and the like, salts with organic bases, for example, primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-N-butylamine, tetrahydropyrrole, hexahydropyridine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, phenothiazine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol, hydrated amine salts and salts with amino acids, for example, arginine, lysine and the like. The salt form, in turn, can be converted to the free acid form by acid treatment.

The term addition salt also encompasses hydrates and solvates which the pharmaceutical compounds may form. Examples of these forms are hydrates, alcoholates and the like.

The term "quaternary ammonium" is used herein to define quaternary ammonium salts which may be formed from a pharmaceutical compound by reaction of a basic nitrogen atom with a suitable quaternizing agent, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g., methyl iodide or benzyl iodide. Other reactants having good leaving groups may be used, such as alkyltrifluoromethane sulfonates, alkyl methane sulfonates, and alkyl p-toluene sulfonates. The quaternary ammonium salt has a positively charged nitrogen atom. Pharmaceutically acceptable counterions include chloride, bromide, iodide, trifluoroacetate and acetate. The selection of the counterions can be performed using ion exchange resins.

By N-oxide form is meant that one or several of the trivalent nitrogens comprising the pharmaceutical compound is oxidized to the so-called N-oxide.

It will be appreciated that some of the pharmaceutical compounds and their N-oxides, addition salts, quaternary ammonium salts and stereochemically isomeric forms may contain one or more chiral centers and exist as stereochemically isomeric forms.

The term "stereochemically isomeric forms" in all the preceding paragraphs defines all possible stereoisomers of the pharmaceutical compounds, their N-oxides, addition salts, quaternary ammonium salts or physiologically functional derivatives. Unless otherwise mentioned or indicated, the chemical designation of a compound refers to a mixture of all possible stereochemically isomeric forms, which comprises all diastereomers and enantiomers of the basic molecular structure as well as each isomer and its N-oxide, salt, solvate or essentially free quaternary ammonium, i.e. admixed with less than 10%, preferably less than 5%, especially less than 2% and most preferably less than 1% of the other isomers. Thus, when the compound of formula (I) is specifically (E), this means that the compound is substantially free of the (Z) isomer.

In particular, the chiral centers may have an R-or S-conformation; the substitution of the saturated groups of the divalent ring (moiety) can be in either the cis-or trans-conformation. Compounds containing a double bond may have the stereochemistry of e (entgegen) or z (zusammen) at the double bond. The terms cis, trans, R, S, E and Z are well known to those skilled in the art.

Stereochemical isomers of the pharmaceutical compounds are clearly within the scope of the present invention.

Some pharmaceutical compounds may also exist in their tautomeric forms. These forms, although indicated in the above structural formulae, are also included in the scope of the present invention.

Compounds of formula (I) may be prepared by reacting an intermediate of formula (II) wherein W is₁Is a suitable leaving group such as halogen, trifluoroacetate, tosylate, methylsulfonyl and the like, with an intermediate of formula (III). This reaction can be carried out at elevated temperatures.

Alternatively, the above reaction may be carried out in the presence of an appropriate solvent. Suitable solvents are, for example, acetonitrile, alcohols, such as ethanol, 2-propanol-HCl; n, N-dimethylformamide, N-dimethylacetamide, 1-methyl-2-pyrrolidone; 1, 4-dioxane, propylene glycol monomethyl ether. Preferred solvents are 2-propanol, 2-propanol containing 6N HCl or acetonitrile, especially acetonitrile. Optionally, sodium hydride may also be present.

In this and the following preparation processes, the reaction product may be isolated from the reaction intermediates and, if desired, further purified according to methods generally known in the art, for example, extraction, crystallization, distillation, trituration and chromatography.

A compound of formula (I) wherein R³Is R⁷Represents a monocyclic, bicyclic or tricyclic aromatic ring system, R³From R⁷Represented by formula (I-a), by reacting an intermediate of formula (IV) wherein W is₂Represents a suitable leaving group, e.g., halogen, hydroxy, trifluoroacetate, tosylate, thiomethyl, methylsulfonyl, trifluoromethylsulfonyl, and the like, with an intermediate of formula (V) wherein R is^aRepresents borate or tri (C)_1-4Alkyl) stannates, e.g., trimethylstannate, in the presence of a suitable catalyst, e.g., tetrakis (triphenylphosphine) palladium, suitable salts, e.g., disodium carbonate, dipotassium carbonate, and Cs₂CO₃And suitable solvents, e.g. bisAlkyl, dimethyl ether, toluene or alcohol/water mixtures. R^aIt may also represent halogen, for example bromine, obtained by reaction in the presence of 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -di-1, 3, 2-dioxaborate.

A compound of formula (I) wherein R³Is R⁷Represents a monocyclic, bicyclic or tricyclic saturated ring system, R³With R⁷"and the compound is represented by structural formula (I-b), can be obtained by reacting an intermediate of structural formula (IV) with an intermediate of structural formula (VI).

A compound of formula (I) wherein R³Represents cyanogenRadical substituted C_1-6Alkyl radical, the R³With C_1-6alkyl-C N and the compound is represented by structural formula (I-c), can be prepared by reacting an intermediate of structural formula (V II) wherein W is₃Represents a suitable leaving group, for example halogen, such as bromine, and a suitable cyanide salt, for example sodium cyanide or potassium cyanide, in the presence of a suitable solvent, for example N, N-dimethylformamide or dimethylsulfoxide.

A compound of formula (I) wherein R³Is represented by R⁷Substituted C_1-6An alkyl group; NR (nitrogen to noise ratio)⁹R¹⁰Or optionally by CN, R⁷Or NR⁹R¹⁰Substituted C_1-6Alkoxy radical, the R³With C_1-6alkyl-Q represents, wherein Q represents R⁷；NR⁹R¹⁰Or C_1-6Alkoxy is optionally substituted by CN, R⁷Or NR⁹R¹⁰Substituted and represented by the formula (I-d), can be obtained by reacting an intermediate of formula (VII) with an intermediate of formula (VIII), optionally in the presence of a suitable salt, such as dimethyl carbonate, potassium cyanide, iodine cyanide, and in a suitable solvent, such as acetonitrile.

A compound of formula (I) wherein R³represents-C (═ N-O-R)⁸)-C_1-4Alkyl, which is represented by structural formula (I-e), can be prepared by reacting an intermediate of structural formula (IX) with an intermediate of structural formula (X) in the presence of a suitable solvent, for example an alcohol, such as ethanol.

A compound of formula (I) wherein R³Represents CR^C’＝CR^c-CN, wherein R^cRepresents hydrogen or C_1-4Alkyl and R^c' represents hydrogen, C_1-4Alkyl or R⁷So that CR is^c’＝CR^cMust be C_2-6Alkyl, which is represented by structural formula (I-f), can be prepared by reacting an intermediate of structural formula (XI) with Witting or Horner-Emmons reagent of structural formula (XII), wherein R is^bRepresents for example (phenyl)₃P⁺-Cl^-Or (CH)₃CH₂-O)₂P (═ O) -, which can be considered to be a suitable precursor for the phosphorus salt, is prepared by reaction in a suitable salt, such as potassium t-butoxide, and a suitable solvent, such as tetrahydrofuran.

Compounds of formula (I-f-1) and (I-f-2) can be prepared by reacting an intermediate of formula (XXXIX), wherein W is as shown below, or a suitable addition salt thereof₅Represents a suitable leaving group, and acrylonitrile or acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent.

Suitable leaving groups in the above reaction are, for example, halogen, trifluoroacetate, tosylate, mesylate and the like. Preferably, W₅Is halogen, more preferably iodine or bromine.

The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as Pd (OAc)₂，PdCl₂，Pd(PPh₃)₄，Pd(PPh₃)₂Cl₂Bis (dibenzylideneacetone) palladium, palladium thiomethylphenyl glutamine metal substituted ring, or the like, or heterogeneous Pd catalysts such as palladium on charcoal, palladium on metal oxides, palladium on zeolites.

Preferably, the palladium catalyst is a heterogeneous palladium catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, fixed and relatively inexpensive. It can be easily separated (filtered) from the reaction mixture and thus can reduce the palladium residue in the final product. The use of Pd/C also avoids the need for ligands, such as phosphine ligands, which are expensive, toxic and synthesis product contaminants.

Suitable bases for the above reaction are, for example, sodium acetate, potassium acetate, N, N-diethylethylamine, sodium bicarbonate, sodium hydroxide and the like.

Suitable solvents in the above-mentioned reactions are, for example, acetonitrile, N, N-dimethylacetamide, ionic liquids such as [ bmim [ ]]PF₆N, N-dimethylformamide, water, tetrahydrofuran, dimethyl sulfoxide, 1-methyl-2-pyrrolysine and the like.

A compound of formula (I) wherein R³Represents CR^c＝CR^c"-CN, wherein R^cAs previously defined and R^c"represents NR⁹R¹⁰，-C(＝O)-NR⁹R¹⁰，-C(＝O)-C_1-6Alkyl or R⁷The compounds represented by formula (I-g) can be prepared by reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII) in the presence of a suitable solvent such as alcohol and alcoholates, e.g., methanol and sodium ethoxide.

A compound of formula (I) wherein R³Represents CH ═ C (CN) -CH₂CN, represented by formula (I-h), which can be prepared by reacting an intermediate of formula (XI-b) with 2-butenedionitrile in the presence of tributylphosphine and a suitable solvent such as tetrahydrofuran.

A compound of formula (I) wherein R³Represents CH ═ C (CN)₂The compound represented by the formula (I-h') can be prepared by reacting an intermediate of the formula (XI-b) with propanedinitrile in the presence of a suitable base such as piperidine and a suitable solvent such as ethanol and the like.

A compound of formula (I) wherein R³represents-CHOH-CH₂-CN, represented by formula (I-I), obtainable by reacting an intermediate of formula (XI-b) with CH₃-CN is prepared by reaction in the presence of a suitable proton abstracting agent, such as butyllithium, in the presence of a suitable proton abstracting agent substrate, such as N- (1-methylethyl) -2-propanolamine, and in the presence of a suitable solvent, such as tetrahydrofuran.

A compound of formula (I) wherein R³Represents CR^c’＝CR^c-halogen, wherein R^cRepresents hydrogen or C_1-4Alkyl and R^c' represents hydrogen, C_1-4Alkyl or R⁷So that CR is^c’＝CR^cMust be C_2-6Alkyl, represented by structural formula (I-j), obtainable by reacting an intermediate of structural formula (XI) with a compound of structural formula (XII') The Witting or Horner-Emmons reagent of (1), wherein R is^bRepresents what can be considered as suitable precursors of phosphonium salts, e.g. (phenyl)₃P⁺-Cl^-Or (CH)₃CH₂-O)₂P (═ O) -, prepared by reaction in the presence of nBuLi and a suitable solvent such as tetrahydrofuran.

A compound of formula (I) wherein R³Represents CR^c＝CR^c"-halogen, wherein R is^cAs previously defined and R^c' represents CN, NR⁹R¹⁰、-C(＝O)-NR⁹R¹⁰、-C(＝O)-C_1-6Alkyl or R⁷The compounds represented by formula (I-k) can be prepared by reacting an intermediate of formula (XI-a) with an intermediate of formula (XIII-a) in a Horner-Emmons reagent such as (CH)₃CH₂-O)₂P (═ O) -Cl, nBuLi, 1, 1, 1-trimethyl-N- (trimethylsilyl) -silylamine, and a suitable solvent such as tetrahydrofuran.

A compound of formula (I) wherein R³Represents CH ═ C (Br)₂The compound is represented by the formula (I-l) by reacting an intermediate of the formula (XVIII) with CBr₄In the presence of a suitable catalyst salt such as (CuCl)₂In the presence of a suitable base such as NH₃In the presence of a suitable solvent, such as dimethyl sulfoxide.

Compounds of formula (I-m) can be prepared by reacting an intermediate of formula (XIV) with Cl₂In a suitable solvent such as diIn the presence of an alkane.

Compounds of formula (I-n) may be prepared by reacting an intermediate of formula (XV) with an intermediate of formula (XVI) in the presence of a suitable solvent such as ethanol or an alcoholate, such as ethanol or sodium methylate.

A compound of formula (I) wherein R³Is represented by C (═ O) NR⁹R¹⁰C substituted and optionally further substituted by cyano_2-6Alkenyl, which is represented by the formula (I-o), wherein C_2-6Alkenyl' represents C optionally substituted by cyano_2-6Alkenyl groups can be prepared by reacting an intermediate of formula (XXIX) with an intermediate of formula (XXX) in hydroxybenzotriazole with ethyldimethylaminopropyl carbodiamide and in a suitable solvent such as dichloromethane or tetrahydrofuran, and optionally in a suitable base such as N, N-diethylethanamine, NH₄OH, etc. in the presence of the catalyst.

A compound of formula (I) wherein R³represents-C (═ O) NR¹³R¹⁴or-C (═ O) NHR¹³The compound has the structureThe compounds of formulae (I-p-1) and (I-p-2) can be prepared by reacting an intermediate of formula (XXXI) with an intermediate of formula (XXXII-1) or (XXXII-2) in the presence of hydroxybenzotriazole and ethyldimethylaminopropylcarbodiamide and a suitable solvent such as dichloromethane or tetrahydrofuran, optionally in the presence of a suitable base such as N, N-diethylethylamine.

A compound of formula (I) wherein R³Represents CH-N-NH-C (═ O) -R¹⁶The compound represented by the formula (I-q) can be prepared by reacting an intermediate of the formula (XI-b) with an intermediate of the formula (XXXIII) in the presence of an appropriate solvent such as methylene chloride and an alcohol such as methanol, ethanol and the like.

A compound of formula (I) wherein R³Represents N (CH)₃)₂The compounds represented by formula (I-r) can be prepared by reacting an intermediate of formula (XXXIV) with formaldehyde in the presence of a suitable catalyst such as an appropriate acid, acetic acid or the like, palladium on carbon, Raney nickel, and in the presence of a suitable reducing agent such as sodium cyanoborohydride or H₂And a suitable solvent such as acetonitrile.

A compound of formula (I) wherein R³Represents a pyrrolyl group, represented by the formula (I-s), obtainable by reacting an intermediate of formula (XXXIV) with 2, 5-dimethoxytetrahydrofuran in the presence of a suitable acid such as acetic acidIn the presence of a catalyst.

A compound of formula (I) wherein R³Represents CH ═ CH-R⁷The compounds are represented by the formula (I-t) and can be prepared by reacting an intermediate of the formula (XXXV) (Ph means phenyl) with an intermediate of the formula (XXXVI) in the presence of nBuLi and a suitable solvent such as tetrahydrofuran.

The compounds of formula (I) may be further prepared by interconversion of compounds of formula (I) according to group transfer reactions known in the art.

The compounds of formula (I) may be converted to the corresponding N-oxide forms according to methods known in the art for converting trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting the starting materials of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides include peroxy acids, for example, benzene carbonic peroxy acid or halogen-substituted benzene carbonic peroxy acids, for example 3-chlorobenzoic peroxy acid, peroxy alkanol acids, for example peroxy acetic acid, alkyl hydroperoxides, for example tert-butyl peroxide. Suitable solvents are, for example, water, lower alcohols, e.g.ethanol and the like, hydrocarbons, e.g.toluene, ketones, e.g.2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and also mixtures of these solvents.

For example, a compound of formula (I) wherein R³Containing cyano groups, can be converted into compounds of the formula (I) by reaction with HCOOH in the presence of a suitable acid, such as hydrochloric acidA compound of formula (I) wherein R³Comprising an aminocarbonyl group. A compound of formula (I) wherein R³Containing a cyano group, can be further converted to a compound of formula (I) by reaction with sodium azide in the presence of amine chloride and N, N-dimethylacetamide³Comprising a tetrazolyl group.

A compound of formula (I) wherein R³Comprising an aminocarbonyl group, which can be converted in the presence of a suitable dehydrating agent into a compound of formula (I) wherein R³Containing a cyano group. The dehydration reaction can be carried out according to methods well known to those skilled in the art, for example, as described in Richard C.Larock, John Wiley&The "organic transformation" published by Sons corporation in 1999 is largely complete. The guidelines for functional group preparation ", published on pages 1983 and 1985, are incorporated herein by reference. Various suitable reactants are listed in this reference, such as SOCl₂，HOSO₂NH₂，ClSO₂NCO，MeO₂CNSO₂NEt₃，PhSO₂Cl，TsCl，P₂O₅，(Ph₃PO₃SCF₃)O₃SCF₃Polyphosphate ester, (EtO)₂POP(OEt)₂，(EtO)₃PI₂2-chloro-1, 3, 2-dioxophosphane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxophosphane, POCl₃，PPh₃，P(NCl₂)₃，P(NEt₂)₃，COCl₂，NaCl.AlCl₃，ClCOCOCl，ClCO₂Me，Cl₃CCOCl，(CF₃CO)₂O，Cl₃CN＝CCl₂2, 4, 6-trichloro-1, 3, 5-triazine, NaCl. AlCl₃，HN(SiMe₂)₃，N(SiMe₂)₄，LiAIH₄And the like. All reactants listed in this publication are incorporated herein by reference.

A compound of formula (I) wherein R³Comprises C_2-6The alkenyl radical may be in the presence of a suitable reducing agent such as H₂Palladium on a suitable catalyst, e.g. carbon, and in a suitable solvent, e.g. an alcohol such asIs converted by reduction in the presence of methanol to a compound of formula (I) wherein R³Comprises C_1-6An alkyl group.

A compound of formula (I) wherein R³Represents CH (OH) -R¹⁶Can be converted to compounds of formula (I) wherein R is³Represents C (═ O) -R¹⁶。

A compound of formula (I) wherein R³Represents C (═ O) -CH₂-R^16aWherein R is^16aRepresents cyano or aminocarbonyl, which may be reacted with POCl₃The reaction is converted to a compound of formula (I) wherein R³Represents C (Cl) ═ CH-R^16a。

A compound of formula (I) wherein R³Represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring substituted by an aldehyde group, which may be prepared by reaction with NH in the presence of a suitable base such as sodium hydroxide and a suitable solvent such as an alcohol, e.g. ethanol and the like²OR⁸The reaction is converted to a compound of formula (I) wherein R³Is represented by CH (═ N-O-R⁸) A substituted monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring. A compound of formula (I) wherein R³Is represented by CH (═ N-O-R⁸) Substituted mono-, bi-or tricyclic saturated, partially saturated or aromatic carbocyclic rings or mono-, bi-or tricyclic saturated, partially saturated or aromatic heterocyclic rings may be converted to compounds of formula (I) by reaction with a carbodiamide in the presence of a suitable solvent such as tetrahydrofuran³Represents a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic carbocyclic ring or a monocyclic, bicyclic or tricyclic saturated, partially saturated or aromatic heterocyclic ring substituted by CN.

A compound of formula (I) wherein R⁴Represents nitrogen, may beWhen reducing agents such as H₂In the presence of a suitable catalyst, e.g. raney nickel, and in the presence of a suitable solvent, e.g. an alcohol such as methanol, to a compound of formula (I) wherein R is⁴Is an amino group.

A compound of formula (I) wherein R¹Is hydrogen, may be reacted with a suitable alkylating agent, e.g. iodo-C, in the presence of a suitable base, e.g. sodium hydride, and in the presence of a suitable solvent, e.g. tetrahydrofuran_1-6Alkyl is reacted to be converted into a compound of formula (I) wherein R¹Is C_1-6An alkyl group.

Some of the compounds of formula (I) of the present invention, as well as some of the intermediates, may contain asymmetric carbon atoms. Pure stereochemical isomers of the compounds and of the intermediates can be obtained by using methods known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques such as countercurrent distribution, liquid chromatography, and the like. Enantiomers can be obtained by racemic mixtures first converted into diastereomeric salts or mixtures of compounds with a suitable solvent, e.g., a chiral acid; the diastereomeric salt or mixture of compounds is then physically separated by methods such as selective crystallization or chromatographic techniques such as liquid chromatography; finally, the separated diastereomeric salt or compound is converted into the corresponding enantiomer. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reactions are stereochemically specific.

Another method for separating the optical isomers of the compounds of formula (I) and intermediates includes liquid chromatography, particularly using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds and are commercially available or can be prepared according to methods known in the art or some of the compounds of formula (I) or said intermediates can be prepared according to the methods described in WO99/50250 and WO 00/27825.

Intermediates of formula (II) can be prepared by reacting an intermediate of formula (XVII) with a leaving group directing agent of formula (XIX), wherein W is₁Representing a leaving group and R represents the remainder of the leaving group directing agent, e.g. POCl₃And then carrying out a reaction.

Intermediates of formula (III) wherein X₁Represents NH, represented by formula (III-a), which may be represented by an intermediate of formula (XX) in ZnCl₂And in the presence of a suitable solvent such as an alcohol, e.g. ethanol.

Intermediates of the following structural formula (III' -a) can be prepared from intermediates of structural formula (XX), wherein R³Represents C substituted by CN_2-6Alkenyl, the intermediate being represented by the formula (XX-a), in ZnCl₂And suitably C_1-4alkyl-OH such as ethanol.

Intermediates obtained by reacting compounds of the following structural formulae (III-b-1) and (III-b-2) by reacting compounds of the structural formula (XLI) or a suitable acid addition salt thereof, wherein W is₆Represents a suitable leaving group, with acrylonitrile or acrylamide in the presence of a suitable palladium catalyst, a suitable base and a suitable solvent.

Suitable leaving groups in the above reaction are, for example, halogen, trifluoroacetate, tosylate, mesylate and the like. Preferably, W₆Is halogen, more preferably iodine or bromine.

The palladium (Pd) catalyst may be a homogeneous Pd catalyst, such as Pd (OAc)₂，PdCl₂，Pd(PPh₃)₄，Pd(PPh₃)₂Cl₂Bis (dibenzylideneacetone) palladium, palladium thiomethylphenyl glutamine metal substituted ring, or the like, or heterogeneous Pd catalysts such as palladium on charcoal, palladium on metal oxides, palladium on zeolites.

Preferably, the palladium catalyst is a heterogeneous palladium catalyst, more preferably palladium on charcoal (Pd/C). Pd/C is a recoverable catalyst, fixed and relatively inexpensive. It can be easily separated (filtered) from the reaction mixture and thus can reduce the palladium residue in the final product. The use of Pd/C also avoids the need for ligands, such as phosphine ligands, which are expensive, toxic and synthesis product contaminants.

Suitable bases for the above reaction are, for example, sodium acetate, potassium acetate, N, N-diethylethylamine, sodium bicarbonate, sodium hydroxide and the like.

Suitable solvents in the above-mentioned reactions are, for example, acetonitrile, N, N-dimethylacetamide, ionic liquids such as [ bmim [ ]]PF₆N, N-dimethylformamide, water, tetrahydrofuran, dimethyl sulfoxide, 1-methyl-2-pyrrolysine and the like.

The intermediate of formula (III-b-2) is converted to an intermediate of formula (III-b-1) in the presence of a suitable dehydrating agent. The dehydration reaction can be carried out according to methods well known to those skilled in the art, for example, as described in Richard C.Larock, John Wiley&Sons corporation 1999The organic transformation of (1) is complete. The guidelines for functional group preparation ", published on pages 1983 and 1985, are incorporated herein by reference. Various suitable reactants are listed in this reference, such as SOCl₂，HOSO₂NH₂，ClSO₂NCO，MeO₂CNSO₂NEt₃，PhSO₂Cl，TsCl，P₂O₅，(Ph₃PO₃SCF₃)O₃SCF₃Polyphosphate ester, (EtO)₂POP(OEt)₂，(EtO)₃PI₂2-chloro-1, 3, 2-dioxophosphane, 2, 2, 2-trichloro-2, 2-dihydro-1, 3, 2-dioxophosphane, POCl₃，PPh₃，P(NCl₂)₃，P(NEt₂)₃，COCl₂，NaCl.AlCl₃，ClCOCOCl，ClCO₂Me，Cl₃CCOCl，(CF₃CO)₂O， Cl₃CN＝CCl₂2, 4, 6-trichloro-1, 3, 5-triazine, NaCl. AlCl₃，HN(SiMe₂)₃，N(SiMe₂)₄，LiAIH₄And the like. All reactants listed in this publication are incorporated herein by reference.

An intermediate of formula (XX) wherein R³Represents a compound having R as previously described^cAnd R^c' CR of^c’＝CR^c-CN, represented by formula (XX-b), which can be prepared from the intermediate of formula (XXI) by reacting the above-mentioned process for preparing the compound of formula (I-f).

Intermediates of formula (XXI) can be prepared by reacting an intermediate of formula (XXII) in a suitable oxidizing agent such as KMnO₄In the presence of a suitable solvent such as methylene chloride and tris [2- (2-methoxyethoxy) ethyl]In the presence of an amine.

Intermediates of formula (XXI), wherein R^c' is H, the intermediate is represented by formula (XXI-a), and also by reacting an intermediate of formula (XXIII), wherein W is₄Represents a suitable leaving group, for example a halogen such as bromine, with N, N-dimethylformamide in the presence of nBuLi and in the presence of a suitable solvent such as tetrahydrofuran.

Intermediates of formula (XXII) wherein R^c' represents C_1-4Alkyl, which is represented by formula (XXII-a), can be prepared by reacting an intermediate of formula (XXIII) with an intermediate of formula (XXII-a) in the presence of nBuLi and a suitable solvent such as tetrahydrofuran.

Intermediates of formula (XI) can be prepared by reacting an intermediate of formula (XXV) with an intermediate of formula (II), optionally in the presence of a suitable base, such as 1-methyl-tetrahydropyrrole-2-one, or a suitable acid, such as hydrochloric acid.

Intermediates of formula (XV) can be prepared by reacting an intermediate of formula (XXVI) with an intermediate of formula (II) in the presence of a suitable base, such as 1-methyl-tetrahydropyrrole-2-one and sodium hydride and a suitable acid,for example twoIn the presence of an alkane.

Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (XXVII) with a leaving group directing agent of formula (XIX'), e.g., SOCl₂In the presence of a suitable solvent such as dichloromethane.

An intermediate of formula (XXVII), wherein C_1-6Alkyl represents CH₂The intermediate is represented by formula (XXVII-a) and can be prepared by reacting an intermediate of formula (XV) or (XXXI) with a suitable reducing agent, such as LiAlH₄And is prepared by carrying out a reduction reaction in the presence of a suitable solvent such as tetrahydrofuran.

Intermediates of formula (XXVII-a) may be converted to intermediates of formula (XXXI) by reaction with Jones reagent in the presence of a suitable solvent such as acetone.

Intermediates of formula (XI-b) can be prepared by reacting an intermediate of formula (XXVII-a) in a suitable oxidizing agent, e.g., MnO₂And in place ofIn the presence of a solvent such as methylene chloride or N, N-dimethylformamide.

Intermediates of formula (XIV) can be prepared by reacting an intermediate of formula (XV) with H₂N-NH₂In the presence of a suitable solvent, for example an alcohol such as ethanol and the like.

The structures (IX) and (XI-a) can be carried out in the presence of a suitable reducing agent, for example NaBH₄，LiAlH₄Or BuLi and a suitable solvent, e.g., tetrahydrofuran or an alcohol such as methanol, ethanol, etc., to form intermediates of structural formulae (XXVII '-a) and (XXVII' -b).

Intermediates of formula (XI-b) can be reacted with C in the presence of Mg and a suitable solvent such as diethyl ether and tetrahydrofuran_1-4Alkyl-iodides are converted to intermediates of formula (XXVII' -a).

Intermediates of formula (XVIII) can be prepared by reacting formula (XI-b) with H₂N-NH₂In the presence of a suitable solvent, e.g., an alcohol such as ethanol and the like.

Intermediates of formula (XXIX) or (XXXI) can be prepared by reacting an intermediate of formula (XXXVII), wherein C_2-6Alkenyl' represents C optionally substituted by cyano_2-6Alkenyl groups, or intermediates of formula (XV), are prepared by hydrolysis in the presence of an appropriate aqueous acid, such as 2N hydrochloride and the like, and in the presence of an appropriate solvent, such as an alcohol, e.g., isopropanol and the like.

Intermediates of formula (XXXVII) wherein C_2-6The alkenyl group is CH ═ CH, the intermediate is represented by formula (XXXVII-a), and can be prepared by reacting an intermediate of formula (XI-b) with Witting or Horner-Emmons reagent of formula (XII ″), wherein R is^bRepresents a precursor which may be a suitable phosphonium ylide, e.g. (phenyl)₃P⁺-Cl^-Or (CH)₃CH₂-O)₂P (═ O) -, by reaction in the presence of a suitable solvent such as tetrahydrofuran.

Intermediates of formula (XXXVII) wherein C_2-6Alkenyl' is-CH ═ c (cn) -, which is represented by formula (XXXVII-b), and can be prepared by reacting an intermediate of formula (XI-b) with NC-CH₂-C(＝O)-C_1-6Alkyl, in the presence of a suitable base, such as piperidine, and a suitable solvent, such as an alcohol, e.g. ethanol.

Intermediates of formula (XXXIV) can be prepared by reacting an intermediate of formula (XXXVIII) at H₂And a suitable catalyst, such as palladium on carbon or raney nickel, and reduced in the presence of a suitable solvent, such as an alcohol, e.g. methanol or the like.

Intermediates of formula (XXXV) can be prepared by reacting formula (VII-a) in the presence of triphenylphosphine and a suitable solvent such as acetonitrile.

Formula (XXXIX) can be prepared by reacting an intermediate of formula (XL) with an intermediate of formula (II-a), wherein W is₅And W₁As previously defined.

The compounds of formula (I) prepared according to the methods described hereinbefore may exist as a mixture of stereoisomers after synthesis, especially as a mixture of racemic enantiomers, which may be separated by established separation procedures. Racemic compounds of formula (I) can be converted to the corresponding diastereomeric salts by reaction with an appropriate chiral acid. The diastereomeric salts are then separated, for example, by selective or multiple crystallization, and the enantiomers separated by a base. Another method for separating enantiomers of compound (I) is liquid chromatography using a chiral column as the stationary phase. Pure stereochemically isomeric forms may be derived from the pure stereochemically isomeric forms of the starting materials, provided that the reaction is stereoselective. If a particular stereoisomer is desired, the compounds may be synthesized by stereoselective methods of preparation. These methods are applicable to starting materials that are relatively pure enantiomers.

It is known to the person skilled in this respect that the functional groups of the intermediate compounds to be retained should be blocked by protective groups.

Groups to be protected include hydroxy, amino and carboxylic acid. Suitable hydroxyl-protecting groups which may be employed include trihydrocarbylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable amino-protecting groups which may be employed include t-butyloxycarbonyl or benzyloxycarbonyl. Suitable carboxylic acid protecting groups include C_1-6Hydrocarbyl or benzyl esters.

The protection or deprotection of the groups may occur before the reaction or after a one-step reaction.

The use of protecting groups is described in detail in "organic synthetic protecting groups" second edition, edited by J W F McOmie, published by Plenum (1973) and by TWGreene and P G M Wutz, Wiley Interscience, published by Wiley Interscience (1991).

Compounds of formula (I) or its subfamily exhibit antiretroviral (reverse transcriptase inhibiting) properties, particularly the Human Immunodeficiency Virus (HIV), which is the cause of Acquired Immune Deficiency Syndrome (AIDS).

Compounds of formula (I) or subfamily thereof also exhibit activity against (multi) drug resistant HIV bacteria, particularly multi-drug resistant HIV-1 bacteria, and particularly the compounds herein are active against HIV bacteria, particularly HIV-1 bacteria, the production of such activity requiring the inhibition of the action of one or more known non-nucleoside reverse transcriptase inhibitors. These compounds have no or very weak affinity for human alpha-1 acid glycoprotein, and human alpha-1 acid glycoprotein does not affect or very weakly affects anti-HIV activity of the compounds.

The effective daily dosage can be determined by a physician skilled in the treatment of HIV infection from the results of the tests herein. In general, the effective daily dosage is considered to be in the range of 0.01mg/kg to 50mg/kg body weight, preferably 0.1mg/kg to 10mg/kg body weight. It is preferred that the dose is administered in two, three or four or more sub-doses at appropriate intervals throughout the day. The sub-doses are unit doses to be administered, e.g. 1 to 1000mg, and the unit preparations contain 5 to 200mg of the active ingredient.

The specific dose and interval of administration will depend upon the compound of formula (I), the particular circumstances of treatment, the severity of the condition, the age, weight and physiological condition of the patient and other medications the patient may be taking at the same time, for the skilled practitioner. In addition, the effective daily dose may be reduced or increased depending on the patient's post-dose response and/or the physician prescribing the instant invention's evaluation of the drug. Thus, the effective daily dosage mentioned above is intended only as a guide and is not intended to limit the extent and scope of use of the invention.

The following examples describe compounds of formula (I).

Hereinafter, "DMF" is N, N-dimethylformamide, "DIPE" is diisopropyl ether, "THF" is tetrahydrofuran, "DMA" is N, N-dimethylacetamide, "DMSO" is dimethyl sulfoxide, "DME" is dimethyl ether, "EtOAc" is ethyl acetate, "EDCT" is N' - (ethyliminocarbonate) -N, N-dimethyl-1, 3-propanediamine.

A. Preparation of intermediate compounds

Example A1

a) Preparation of intermediate 1

In N₂nBuLi (0.012mol) was added dropwise to a mixture of N' - (4-bromo-2, 6-dimethylphenyl) -N, N-dimethylmethane imidamide (0.0078mol) to THF (20ml) at-70 ℃ under a stream of air. The mixture was stirred at-30 ℃ for 30 minutes and then cooled to-70 ℃. A mixture of DMF (0.078mol) in THF (30ml) was added dropwise. The mixture was stirred at-70 ℃ for 2 hours and then moved to 0 ℃ and poured into H₂O and extracted with ethyl acetate. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The yield is as follows: 1.8g of intermediate 1.

b) Preparation of intermediate 2

A mixture of diethyl (cyanomethyl) phosphate (0.0037mol) in THF (10ml) was stirred in N₂Cooled to 5 ℃ under air flow. Potassium tert-butoxide (0.0037mol) was added in portions. The mixture was stirred at 5 ℃ for 30 minutes and then at room temperature for 30 minutes. A mixture of intermediate 1(0.0024mol) in THF (10ml) was added. The mixture was stirred at room temperature for 1 hour and then H was poured in₂In O with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The yield is as follows: 0.82g (100%) of intermediate 2.

c) Preparation of intermediate 3 and intermediate 22

Intermediate 3 intermediate 22

Intermediate 2(0.059 mol)) And ZnCl₂(0.299mol) in ethanol (150ml) with stirring and refluxing for 24 hours, then K is poured in₂CO₃In solution (10% in water) with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (9g) was crystallized from DIPE. The precipitate was filtered off and dried. The yield is as follows: 0.8g (6%) of intermediate 22. The filtrate was concentrated and recrystallized from DIPE to yield 6g of intermediate 3.

Alternatively, the intermediates may be prepared as follows:

63.8g of sodium acetate are added to a solution of 159g of 4-iodo-2, 6-dimethyl-aniline. The reaction mixture was kept under nitrogen atmosphere. 7g of moist palladium on charcoal (Pd/C10%) and 64.4ml of acrylonitrile are added. The reaction mixture was heated to 130 ℃ and stirred overnight. After cooling to room temperature, 0.5 l of toluene and 0.5 l of N, N-dimethylacetamide were added. The reaction mixture was filtered over celite and the filter was washed with 0.5 l of toluene. Water (6 liters) was added to the mixture which was stirred for 30 minutes. The layers were separated. 1l of toluene was added to the aqueous layer and the mixture was stirred for 30 minutes. The layers were then separated. The separated organic layer was collected and the solvent was evaporated, yielding 123g of intermediate 3.

The conversion of intermediate 3 to its hydrochloride salt was carried out as follows:

1.25 litres of diisopropyl ether are added to a mixture of 123g of intermediate 3 and 630ml of ethanol. The reaction mixture was stored under nitrogen atmosphere. The mixture was heated to 60 ℃ and stirred for 30 minutes. 120ml of 6N hydrochloric acid were added to 2-propanol and the mixture was stirred for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and the residue was washed with 100ml of 2-propanol. The resulting residue was dried at 50 ℃ under reduced pressure. The yield is as follows: 103g (77%) of the hydrochloride salt of intermediate 3 (1: 1).

Intermediate 3(E) was prepared as follows:

x) preparation of intermediate 3a (E)

Intermediate 3a (E)

2g (10.0mol) of 4-bromo-2, 6-dimethylaniline, 1.07g (1.5 eq) of acrylamide, 224mg (0.1 eq) of Pd (OAc)₂609mg (0.2 eq) of tris (2-methylphenyl) phosphine and 1.52g N, N-diethylethylamine were dissolved in 10ml of dry acetonitrile. Mixing the mixture with N₂Rinsed for 20 minutes and stirred at 70 ℃ overnight. The mixture was diluted with 150ml dichloromethane and saturated Na₂HCO₃Washing with water solution, and drying (saturated NaCl, Na)₂SO₄) And filtered. The solvent was evaporated and the residue was stirred in diisopropyl ether, followed by filtration. The yield is as follows: 1.51g (79.5%) of intermediate 3a (E).

y) preparation of intermediate 3(E)

Intermediate 3(E)

Adding POCl₃(3ml) cooled to 0 ℃ and 500mg (2.63mmol) of intermediate 3a (E) added. After 30 minutes, the cold bath was removed and the mixture was stirred at 20 ℃ overnight. 150ml of diisopropyl ether are stirred vigorously and added dropwise to the mixture. The precipitate was filtered off and washed with diisopropyl ether. 100ml ethyl acetate/100 ml NaHCO₃Is added to the residue and stirred. Separating ethyl acetate layer, and drying (saturated NaCl, Na)₂SO₄) And filtered. The solvent was evaporated off. The yield is as follows: 380mg (84%) of intermediate 3 (E).

d) Preparation of intermediate 4

4-bromo-2, 6-dimethylaniline (0.024mol) and H₂SO₄(30ml) the mixture was stirred at-5 ℃. Slowly adding KNO₃(0.024 mol). The mixture was stirred at-5 ℃ for 30 minutes and H was poured in₂O and extracted with ethyl acetate. H for organic layer₂O washing, separating and drying (MgSO)₄) Filtered and the solvent evaporated. The residue (0.058g, 95%) was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate; 70/30; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The yield is as follows: 4.1g of intermediate 4.

Example A1A

Preparation of intermediate 28

1-chloro-tetrahydropyrrole-2, 5-dione (0.032mol) was added to ethyl 4-amino-3-methyl-benzoate [ CAS 40800-65-5 ] at 60 ℃](0.029mol) and CH₃CN (50 ml). The mixture was stirred and slowly refluxed. Adding 10% of K₂CO₃. CH for the mixture₂Cl₂And (4) extracting. The organic layer was evaporated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate; 85/15; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The yield is as follows: 5.2g of intermediate 28 (84%).

Example A2

Reacting 4- [ (1, 4-dihydro-4-oxy-2-pyrimidinyl) amino]Benzonitrile (0.12mol) was added to POCl₃(90ml) the mixture in (90ml) was stirred under hydrogen chloride gasStirred and refluxed for 20 minutes. The reaction mixture was poured slowly onto 750ml of ice/water and the solid was isolated using filtration. The solid was suspended in 500ml of water and the pH of the suspension was adjusted to neutral by addition of 20% NaOH solution. The solid is isolated by filtration, suspended in 200ml of 2-propanone and charged with 1000ml of CH₂Cl₂. The mixture was heated until all the solids were dissolved. After cooling to room temperature, the aqueous layer was separated and the organic layer was dried. The drying agent was removed using filtration to form a white solid in the filtrate. The filtrate was further cooled in a refrigerator, followed by filtration to give 21.38g (77.2%) of [4- (4-chloro-2-pyrimidinyl) amino group]Benzonitrile (intermediate 5).

Example A3

a) Preparation of intermediate 6

In N₂nBuLi (0.024mol) was added dropwise to a mixture of N' - (4-bromo-2, 6-dimethylphenyl) -N, N-dimethylmethanesulphenamide (0.0157mol) and THF (50ml) at 70 ℃ under a stream of air. The compound was stirred at-30 ℃ for 30 minutes and then cooled to-70 ℃. A solution of 2-methylpropionaldehyde (0.055mol) in THF was added. The mixture was stirred at-70 ℃ for 2 hours, then brought to 0 ℃ and poured into H₂In O with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (6.7g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 95/5/0.5; 15-40 μm). The two fractions were collected and the solvent was evaporated. Fraction 1: the yield is as follows: 1.5g of intermediate 6 (38%).

b) Preparation of intermediate 7

Reacting tris [2- (2-methoxyethoxy) ethyl]Amine (0.0193mol) intermediate 6(0.0048mol) and CH were added at room temperature₂Cl₂(20ml) in water. Adding a portion of KMnO₄(0.0193 mol). The mixture was stirred at room temperature overnight, then filtered through celite and filtered over CH₂Cl₂And (5) cleaning. The organic layer was treated with 10% K₂CO₃And (5) cleaning. By drying (MgSO)₄) Filtered and the solvent evaporated. The yield is as follows: 1.2g (100%) of intermediate 7.

c) Preparation of intermediate 8

Intermediate 7(0.0043mol) and ZnCl₂(0.017mol) and ethanol (20mol) were stirred and refluxed overnight, H was poured in₂In O with CH₂Cl₂/CH₃And (5) OH extraction. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The yield is as follows: 0.94g (82%) of intermediate 8.

d-1) preparation of intermediate 9

A mixture of intermediate 8(0.0049mol) and intermediate 5(0.0025mol) was stirred at 150 ℃ for 2 hours and at K₂CO₃10％/CH₂Cl₂/CH₃Extracting in OH. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.3g) was crystallized from DIPE. The precipitate was filtered off and dried. The mother liquor is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 98.5/1.5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The yield is as follows: 0.21g of intermediate 9.

d-2) preparation of intermediate 29

The mixture of intermediate 28(0.023mol) and intermediate 5 (prepared according to A2) (0.025mol) added to HCL 3N (10ml) was stirred at 105 ℃ then allowed to warm to room temperature and filtered. The precipitate was washed with DIPE and dried. The yield is as follows: 8.4g of intermediate 29 (96%).

d-3) preparation of intermediate 30

Ethyl 4-amino-3-chlorobenzoate [ CAS 82765-44-4 ]]A mixture of (0.02mol) and intermediate 5 (prepared according to A2) (0.0243mol) with 1-methyl-pyrrolidin-2-one (40ml) was stirred at 180 ℃ for 2H and then H was poured in₂In O and extracted with EtOac (80 ml). The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (10g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂(ii) a 100, respectively; 15-30 μm). The two fractions were collected and the solvent was evaporated. The yield is as follows: 1.7g F1 and 1g F2. F2 was extracted in diethyl ether. The precipitate was filtered off and dried. The yield is as follows: 0.95g of intermediate 30 (12%).

e-1) preparation of intermediate 17

Reacting NaBH₄(0.0001mol) in N₂To a mixture of intermediate 9(0.0001mol) and ethanol (7ml) was added portionwise under a stream of gas at 5 ℃. The mixture was stirred at 5 ℃ for 1 hour, poured onto ice and washed with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.1g) was crystallized from DIPE. The precipitate was filtered off and dried. The yield is as follows: 0.044g of intermediate 17.

e-2) preparation of intermediate 32

In N₂BuLi 1.6M (0.009mol) was added to the gas stream at-78 deg.C

(intermediate 31) (prepared according to A4 a) (0.0029mol) and THF (25 ml). The compound was stirred at-78 ℃ for 10 minutes, then brought to room temperature and stirred for 3 hours. Addition of H₂And O. CH for the mixture₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.28g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 98/2/0.1; 15-40 μm). The three fractions were collected and the solvent was evaporated. The yield is as follows: 0.189g of fraction 1, 0.14g of fraction 2 and 0.5g of fraction 3 (48%). Fraction 3 was purified by column chromatography on kromasil gel (eluent: CH)₂Cl₂/EtOAc; 80/20, respectively; 10 μm). The two fractions (F1, F2) were collected and the solvent was evaporated. The yield is as follows: 0.25g of F1 and 0.1g of F2. F1 was crystallized from diethyl ether. The precipitate was filtered off and driedAnd (5) drying. The yield is as follows: 0.21g of intermediate 32 (20%).

e-3) preparation of intermediate 34

A solution of methylmagnesium iodide (1.0M solution in diethyl ether) (0.6ml) was added to

Intermediate 33 (prepared according to A5. a) (0.0006mol) and THF (3 ml). The compound was stirred for 2 hours. Addition of H₂And O. The mixture was filtered over celite. Addition of H₂And O. The mixture was extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.05g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 96/4, respectively; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The yield is as follows: 0.015g of intermediate 34 (7.2%).

Example A4

a) Preparation of intermediate 10

Adding 3, 5-dimethyl-4-hydroxybenzoic acid ethyl ester (0.0025mol) into 1, 4-diMixture of alkanes (2.5ml) in N₂Under air flow at room temperatureStirring. Sodium hydride (0.0033mol) was added. The mixture was stirred for 2 minutes. Intermediate 5(0.0028mol) was added. The mixture was stirred for 10 minutes. 1-methyl-2-pyrrolidone (2.5ml) was added. The mixture was stirred at 150 ℃ for 12 hours and H was poured in₂In O with CH₂Cl₂/CH₃And (5) OH extraction. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.7g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 92/8, respectively; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The yield is as follows: 0.7g of intermediate 10 (70%).

b-1) preparation of intermediate 11

A solution of intermediate 10(0.0005mol) in THF (5ml) was dissolved in N₂Dropwise adding into LiAlH at 0 deg.C under gas flow₄(0.001mol) in a suspension of THF (5 ml). The mixture was stirred at 0 ℃ for 1 hour and then H was poured in₂O (0.5 ml). Adding CH₂Cl₂. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on kromasil gel (eluent: CH)₂Cl₂100 to CH₂Cl₂/CH₃OH 99/1; 99/1, respectively; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.1g) was crystallized from diethyl ether. The precipitate was filtered off and dried. The yield is as follows: 0.043g of intermediate 11 (24%).

b-2) preparation of intermediate 37

Mixing LiAlH₄(0.0196mol, 0.75g) in N₂To a mixture of intermediate 29 (prepared according to A3 d-2) (0.0098mol) and THF (100ml) was added portionwise under a stream of gas and at 5 ℃. The mixture was stirred at room temperature overnight, poured into EtOAc and then poured into H₂In O and filtered over celite. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 3.4 g. This fraction was purified by column chromatography on kromasil gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 97/3/0.1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 1g (27%). The fraction was composed of DIPE/CH₃CN is crystallized out. The precipitate was filtered off and dried. The yield is as follows: 0.03g of intermediate 37.

c) Preparation of intermediate 12

Intermediate 11(0.0043mol) was added to CH₂Cl₂The mixture in (50ml) was stirred at 0 ℃. Adding SOCl portion by portion₂(0.0206 mol). Pouring the mixture into ice water/K₂CO₃In (1). The mixture was stirred at room temperature for 5 minutes. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The yield is as follows: 1.5g of intermediate 12 (98%).

d) Preparation of intermediate 55

Jones' reagent (0.0084mol) was added to a mixture of intermediate 19 (see Table 1) (prepared according to A4 b-1) (0.0028mol) and acetone (50 ml). The mixture was stirred at room temperature for 2 hours and then poured into H₂O and then NaHCO₃Alkalization is carried out. The precipitate was filtered off and dried. The yield is as follows: 1.39 g. The residue (0.1g) was purified by column chromatography on silica gelPurification (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 85/15/1, respectively; then CH₃OH 100). The fractions were crystallized from isopropanol/DIPE. The yield is as follows: 0.071g of intermediate 55.

Example A5

a) Preparation of intermediate 13

Intermediate 19 (see Table 1) (prepared according to A4. b-1) (0.0037mol) and MnO₂(0.0185mol) CH is added₂Cl₂The mixture in (100ml) was stirred overnight at room temperature and then filtered over celite. The filtrate was evaporated. The yield is as follows: 1.3g of intermediate 13.

b) Preparation of intermediate 21

Intermediate 13 (prepared according to A5. a) (0.0029mol) and H₂N-N H₂，H₂A mixture of O (0.0058mol) and EtOH (10ml) was stirred at room temperature overnight. The solvent was evaporated to dryness. The yield is as follows: 0.53g of intermediate 21.

Example A6

Preparation of intermediate 14

Hydrazine (0.0077mol) is added

(prepared according to A3. d-1) (0.0005mol) in EtOH (10ml) to give a mixture. The mixture was stirred and refluxed overnight. Hydrazine (0.028mol) was added. The mixture was stirred and refluxed overnight. The yield is as follows: 0.28g of intermediate 14.

Example A7

a) Preparation of intermediate 23

The intermediate 35 is reacted with

Prepared according to A3.d-1 (0.0056mol) was added to a mixture of HCl 3N (60ml) and iPrOH (15ml) with stirring and refluxing overnight. Filtering the precipitate with H₂O washed, extracted in DIPE and dried. The yield is as follows: 2.3g of intermediate 23 (100%).

b) Preparation of intermediate 56

Intermediate 10 (prepared according to A4. a) (0.0012mol) was added to a mixture of HCl 3N (26ml) and iPrOH (4ml) with stirring and refluxing 12And (4) hours. The solvent was evaporated to dryness. Separating the residues from (CH)₃)₂Extracting in CO. The solvent was evaporated off. The residue was extracted in diethyl ether. The precipitate was filtered off and dried. The yield is as follows: 0.4g (78.5%). The fraction was stirred at 60 ℃ for 20 minutes. Generating: 0.19 g. The fraction is separated from H₂Crystallizing out from O/2-acetone. The precipitate was filtered off and dried. Yield: 0.12g of intermediate 56 (26%).

Example A8

a) Preparation of intermediate 24

Intermediate 31 (prepared according to A4. a) (0.0005mol) and ethyl (triphenylphosphino) acetate [ CAS 1099-45-2](0.0006mol) the mixture added to THF (5ml) was stirred at 80 ℃ for 48 hours and then H was poured in₂In O with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.4g) was crystallized from DIPE. The precipitate was filtered off and dried. Yield: intermediate 24 (33%).

b) Preparation of intermediate 25

Hexahydropyridine (0.0011mol) was added at room temperature for 30 minutes. Intermediate 31 (prepared according to a4. a) (0.0005mol) was added. The mixture was stirred at room temperature for 1 hour, poured into H₂In O with CH₂Cl₂And (4) extracting. The precipitate was filtered and dried. The residue (0.2g) was separated from CH₃Crystallized from OH/DIPE. The precipitate was filtered off and dried. Yield: 0.048g of intermediate 25 (19%) (m.p. 222 ℃ C.).

Example A9

Preparation of intermediate 26

Will be provided with

(prepared according to A3. d-1) (0.0011mol) and a mixture of Pd/C (0.2g) in methanol (30ml) were hydrogenated at room temperature under a pressure of one bar for 2 hours and then filtered over celite. The residue (0.3g) was washed with 2-propanol/CH₃OH/diethyl ether. The precipitate was filtered off and dried. Yield: 0.07g of fraction 1. Fraction 1 was purified by column chromatography on kromasil gel (eluent: CH)₂Cl₂/CH₃OH; 99.5/0.5; 5 μm). The three fractions (F1, F2, F3) were collected and the solvent was evaporated. Yield: 0.0516g F1, 0.1g F2, and 0.15g F3. F1 was extracted in diethyl ether. The precipitate was filtered off and dried. Yield: 0.028g of intermediate 26 (8%) (m.p. 272 ℃ C.).

Example A10

Preparation of intermediate 27

Will be provided with

Prepared according to A4. c) (0.0005mol) and triphenylphosphine (0.0005mol) are added to CH₃The resulting mixture in CN (10ml) was stirred and refluxed over the weekend. The solvent was evaporated to dryness. The residue was extracted in diethyl ether. The precipitate was filtered off and dried. Yield: 0.34g of intermediate 27 (94%).

Example A11

Preparation of intermediate 58

A mixture of 4-bromo-2, 6-dimethylaniline (0.013mol) and intermediate 5(0.013mol) was stirred at 150 ℃ for 1 hour. The mixture was poured into 10% K₂CO₃Using CH in combination with aqueous solutions₂Cl₂MeOH (95/5) extraction. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. The yield is as follows: 2.3g (45%). The mother liquor is purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH-NH₄OH; 98.5/1.5; 15-40 μm). The net distillate was collected and the solvent was evaporated. Yield: 0.90g (17%). The overall yield of intermediate 5 was: 3.2g (62%).

Intermediate 59 was prepared analogously.

Intermediate 59

The intermediates in the preparation of the compounds of formula (I) are listed in tables 1 and 2.

TABLE 1

TABLE 2

B. Preparation of the Final Compounds

Example B1

Preparation of Compound 1

A mixture of intermediate compounds 3(0.034mol) and 5(0.0174mol) was stirred at 150 ℃ for 1 hour, 10% of K was poured in₂CO₃Solution of CH₂Cl₂/CH₃OH extraction, precipitation by filtration and drying. Disabled personThe retentate (10g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂Ethyl acetate; 80/20, respectively; 15-40 μm). Fraction 1 was crystallized from iPrOH. The precipitate was filtered and dried. Yield: 1.3g 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1) (20%).

Example B1A

Compound 1 can also be synthesized using the following method:

in N₂Under a stream of gas, a mixture of 93.9g (0.45mol) of intermediate 3 hydrochloride (prepared according to A1. c) and 109g (0.4725mol) of intermediate 5 in 1.8l of acetonitrile. The mixture was stirred at reflux for 69 hours, after which time it was cooled to 55 ℃. The mixture was filtered and the residue was washed with 200ml acetonitrile and then dried under reduced pressure at 50 ℃ overnight. 144.6g (0.3666mol) of the solid obtained were taken and added to 1 liter of 10% K₂CO₃An aqueous solution. The mixture was stirred at room temperature and filtered. The residue obtained was washed twice with water and dried under reduced pressure at 50 ℃. The residue was added to 6.55 l of ethyl propanol and the mixture was refluxed, stirred overnight and filtered at room temperature. The residue was dried under reduced pressure at 50 ℃. Yield: 113.2g (68.6%) 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] ethyl ester]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1).

Example B1B

Alternatively, compound 1 can also be synthesized according to the following method:

a) intermediate 58(0.00021mol) (prepared according to A11) was reacted with acrylonitrile (CH)₂CH-CN) (0.00213mol), pd (oac)2(0.000043mol), N-diethylethanamine (0.000043mol) and tris (2-methylphenyl) phosphine (0.00021mol) and CH₃CN (7ml) was stirred overnight at 150 ℃ in a closed vessel. Adding water. CH for the mixture₂Cl₂And (4) extracting. Separating the organic phase and dryingDried (MgSO)₄) Filtering and volatilizing the solvent. The residue (0.15g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂Ethyl acetate; 80/20, respectively; 15-40 μm). Fraction 1 was collected and the solvent was evaporated to give 0.045g of 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] benzene]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E/Z ═ 80/20). The resulting solid was crystallized from diethyl ether. Yield: 0.035g4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] -2]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E) (compound 1) (55%).

b) In N₂4.41g (10mmol) of intermediate 59 and 15ml of N, N-dimethylacetamide were charged under a gas flow into a 100ml flask. To the mixture was added 0.98g of sodium acetate (12mmol), 107mg (0.1mmol Pd) Pd/C10% (wet) and 1ml (15mmol) acrylonitrile. The mixture was heated to 140 ℃ and subjected to liquid chromatography after the reaction. Reaction to produce 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E/Z ═ 80/20), which can be converted into 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl]Amino group]-2-pyrimidinyl]Amino group]Benzonitrile (E), as described in example B1 Ba).

Example B2

a) Preparation of Compound 2

Will be provided with

(0.0002mol) (prepared according to A3. d-1), 2-benzofuranboronic acid (0.0005mol), Pd (PPh3)4(0.00002mol) and Na₂CO₃(0.0007mol) was mixed in DME (3ml) and stirredReflux in scell tube for 3 hours. Adding water. The mixture was extracted with ethyl acetate. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.126g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 98/2, respectively; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.011g Compound 2 (10%).

b) Preparation of Compound 3

Will be provided with

(0.0002mol) (prepared according to A3. d-1), tert-butyl-2-furanstannoic acid (0.0005mol) and (PPh)₃)₄A mixture of (0.00001mol) dioxane (5ml) was stirred at 80 ℃. The solvent was evaporated and the residue was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 98/2, respectively; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.021g Compound 3 (22%).

c) Preparation of Compound 104

Will be provided with

(0.005mol) (prepared according to the method of A3. d),

[CAS73183-34-3](0.0055mol)、(PPh₃)₄(0.29g)、K₂CO₃A mixture of (2.8g, 0.02mol), toluene (100ml) and ethanol/water (5 to 10ml) was stirred under reflux over the weekend. 5-bromo-furan-2-carbaldehyde (0.0055mol) and K were added₂CO₃(1.4g, 0.01 mol). The mixture was stirred at reflux overnight. The mixture (2.25g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 100/0-99/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.135g of Compound 104 (6%).

Example B3

Preparation of Compound 4

A mixture of intermediate 15 (see Table 1) (prepared according to A4. c) (0.0005mol), NaCN (0.0011mol) in DMF (5ml) was stirred at 80 ℃ overnight before being poured into water and extracted with ethyl acetate. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.15g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH; 99/1, respectively; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.024g) was purified by column chromatography on silica gel (eluent: acetonitrile/H)₂O; 52/48, respectively; 8 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.02g Compound 4 (10%).

Example B4

a) Preparation of Compound 5

Will be provided with

Prepared according to A3. d) (0.0006mol) and thiomorpholine (0.5g) were stirred at 120 ℃ for 48 hours with CH₂Cl₂Extraction and evaporation of the solvent. The residue (0.44g) was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH; 99/1, respectively; 10 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.06g (20%). The fractions can be crystallized from diethyl ether/2-propanone. The precipitate was filtered and dried. Yield: 0.035g of Compound 5.

b) Preparation of Compound 6

Intermediate 15 (see Table 1) (preparation of 0(0.000137mol), N, N, N' -trimethyl-1, 2-ethanediamine (2 eq., 0.000275mol), K according to A4. c)₂CO₃(2 equiv., 0.000275mol) and acetonitrile (q.s.) were stirred at 80 ℃ for 12 hours. Adding water. By CH₂Cl₂Extracting, and volatilizing the extraction solvent. The residue was purified by chromatography. The product fractions were collected and the solvent was evaporated. Yield: 0.006g Compound 6 (10.16%).

c) Preparation of Compound 7

A mixture of intermediate 15 (see Table 1) (prepared according to A4. c) (0.0005mol) and 3-hydroxy-propionitrile (2ml) was stirred overnight, poured into water and treated with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH; 99/1/0.1; 15-40 μm). Fractions 1 and 2(F1, F2) were collected and the solvent was evaporated. Yields 0.034g F1 and 0.514g F2. F2 washed with 3N HCl and CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.039g Compound 7 (18%).

a) Preparation of Compound 105

A mixture of intermediate 50 (prepared according to A4. c) (0.001mol), KCN (0.0011mol), KI (0.00005mol) in EtOH (15ml) was stirred at reflux for 4 h. And volatilizing the solvent to dry. Residual CH₂Cl₂/H₂And (4) extracting. The mixture is reused with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.31g) was purified by chromatography on a kromasyl packed chromatography column (eluent: cyclohexane/EtOAc; 70/30; 10 μm). Three fractions were collected and the solvent was evaporated. Yield: 0.044g of fraction 1, 0.11g of fraction 2 and 0.055g of fraction 3. Fraction 3 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.046g of compound 105 (12%) (mp.140 ℃ C.).

Example B5

a) Preparation of Compound 8

A mixture of intermediate 9(0.0001mol) and hydroxylamine (0.0002mol) in ethanol (7ml) was stirred at room temperature for 3 hours, poured in 10% K₂CO₃In (C) with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.1g) was treated with DIPE/CH₃And (4) crystallizing CN. The precipitate was filtered and dried. Yield: 0.026g Compound 8.

b) Preparation of compound 9

A mixture of intermediate 9(0.0002mol) and O-methylhydroxylamine (0.0003mol) in ethanol (10ml) was stirred at room temperature overnight, poured into water and CH-added₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.13g) was purified by chromatography on a kromasyl packed chromatography column (eluent: cyclohexane/iPrOH/NH)₄OH; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.06g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.036g Compound 9 (34%).

Example B6

a) Preparation of Compounds 1 and 10

Compound 1 ═ E; compound 10 ═ (Z)

In N₂A mixture of (cyanomethyl) triphenylphosphine chloride (0.0022mol) and potassium tert-butoxide (0.0022mol) in THF (7ml) was stirred at 5 ℃ for 30 minutes under a stream of air, followed by stirring at 5 ℃ for 30 minutes. A mixture of intermediate 13(0.0015mol) in THF (7ml) was added. The mixture was stirred in the dark for 8 hours, poured into water and washed with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.4g) was purified by column chromatography on silica gel (eluent: toluene/iPrOH/NH)₄OH; 96/4/0.1; 15-40 μm). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.165g F1 (E/Z32/68) (30%), 0.225g F2 (E/Z90/10) (41%). F2 was crystallized from CH3 CN/diethyl ether. Yield: 0.036g Compound 1 (7%). F1 was purified by chromatography on a kromasyl packed chromatography column (eluent: toluene/iPrOH 98/2; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.029g Compound 10 (5%).

b) Preparation of Compound 11(Z) and Compound 103(E)

In N₂Potassium tert-butoxide (0.0196mol) was added dropwise to a mixture of (1-cyanovinyl) -diethyl phosphate (0.0196mol) in THF (25ml) under a stream at 5 ℃ the mixture was stirred at 5 ℃ for 30 minutes, then at room temperature for 30 minutes. A solution of intermediate 13(0.0130mol) in THF (25ml) was added. The mixture was stirred at room temperature overnight, poured into water and washed with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (5.8g) was purified by column chromatography on silica gel (eluent: toluene/iPrOH/NH)₄OH; 92/8/0.5; 15-40 μm). Four fractions (F1, F2, F3, F4) were collected and the solvent was evaporated. Yield: 0.21g F1 (blend Z/E90/10), 0.836g F2 (blend Z/E57/43), 0.9g F3 and 0.87gF 4. FCrystallization of 3 from DIPE/iPrOH gave 0.7g of Compound 11 (14%). Crystallization of F4 from DIPE/iPrOH gave 0.67g of Compound 103 (13%).

c) Preparation of Compounds 12 and 13

Compound 12 ═ (E)

Compound 13 ═ (Z)

In N₂Potassium tert-butoxide (0.0008mol) was added dropwise to a mixture of (cyanovinyl) -diethyl phosphate (0.0005mol) in THF (20ml) at 5 ℃ under a stream of air. The mixture was stirred at room temperature for 30 minutes. Dropwise addition

(prepared according to A3. d-1) (0.0005mol) in THF (4 ml). The mixture was stirred at room temperature for 4 hours, poured into water and washed with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield 0.3 g. The product was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH 99/1; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield 0.21 g. The product was purified by chromatography on a kromasyl packed chromatography column (eluent: cyclohexane/ethyl acetate 50/50; 10 μm). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.04g F1 and 0.047g F2. F1 was dried at 70 ℃ for 2 hours. Yield: 0.038g Compound 13 (18%). F2 was dried at 70 ℃ for 2 hours. Yield: 0.041g Compound 12 (20%).

d) Preparation of Compound 14

In N₂Potassium tert-butoxide (0.0013mol) was added dropwise to a mixture of (cyanovinyl) -diethyl phosphate (0.0013mol) in THF (10ml) at 5 ℃ under a stream of air. The mixture was stirred at room temperature for 30 minutes. Adding into

(prepared according to A3. d-1) (0.0009mol) in THF (10 ml). The mixture was stirred at room temperature for 4 hours, poured into water and washed with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.17g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂100 to CH₂Cl₂/CH₃OH 99/1; 5 μm). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.054g F1 and 0.05g F2. F1 was crystallized from DIPE/iPrOH. The precipitate was filtered and dried. Yield: 0.046g Compound 14 (12%).

e) Preparation of Compound 15

4-Fluorophenylacetonitrile (1.2 eq, 0.000175ml) was added to intermediate 13(0.000146mol) in CH₃OH (1 ml). NaOCH (NaOCH)₃/CH₃OH (1.2 eq, 0.000175mol) was added at room temperature. The mixture was stirred at 60 ℃ for 2 hours, then poured into ice water with CH₂Cl₂And (4) extracting. The solvent was evaporated. The residue was purified by chromatography. The product fractions were collected and the solvent was evaporated. Yield: 0.009g Compound 15 (13.42%).

f) Preparation of Compound 106

A mixture of intermediate 13 (preparation 0(0.0005mol) according to A5.a and piperidine (0.0005mol) in ethanol (5ml) was stirred at room temperature for 30 minutes 4, 4-dimethyl-3-keto-propionitrile (0.0011mol) was added and the mixture was stirred at room temperature overnight, poured into water and treated with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.3g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.2g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.141g of Compound 106 (54%) (mp.193 ℃ C.).

Example B7

Preparation of Compound 16

Intermediate 14(0.00005mol) and dichlorothiocarbohydrazide (0.001mol) in bisThe mixture in alkane (10ml) was stirred at room temperature. Adding water. CH for the mixture₂Cl₂And (4) extracting. The fractions were purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 90/10/0.1; 15-40 μm). The product fractions were collected and the solvent was evaporated. Yield: 0.027g Compound 16 (95.6%).

Example B8

Preparation of Compound 17

NaOCH₃A mixture of (0.001mol) and 2- (dimethylamino) -N-hydroxy-glyoxylimidazole (0.001mol) in ethanol (10ml) was stirred at room temperature for 30 minutes. Adding into

(prepared according to A3. d-1) (0.0005 mol). CH for the mixture₂Cl₂And (4) extracting. The fractions were purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-40 μm). The product fractions were collected and the solvent was evaporated. Yield: 0.07g of Compound 17 (31%).

Example B9

Preparation of Compound 18

In N₂nBuLi (0.0038mol) was added dropwise to-70 ℃ iPr under a gas stream₂NH (0.0038mol) in a mixture of THF (5 ml). The mixture was warmed to-20 ℃ and stirred for 30 minutes and then cooled to-70 ℃. A mixture of intermediate 13(0.0009mol) in THF (1ml) was added. The mixture was stirred for 2 hours, poured onto ice at-30 ℃ and extracted with ethyl acetate. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Residue (0.433g) Purification by column chromatography on silica gel (eluent: CH (CH)₂Cl₂/CH₃OH 98/2; 35-70 μm). Two fractions were collected and the solvent was evaporated. Yield; 0.056g F1 and 0.23g F2 (78%). F1 was crystallized from DIPE/iPrOH. The precipitate was filtered and dried. Yield: 0.036g of Compound 18.

Example B9A

a) Preparation of Compound 107

In N₂Under the air flow, nBuLi 1.6](0.0026mol) was added dropwise to a mixture of intermediate compound 13 (prepared according to A5. a) (0.0008mol) in THF (10ml) at-70 ℃. The mixture was stirred at-70 ℃ for 30 minutes. A solution of (chloromethyl) triphenylphosphine chloride (0.0026mol) in THF (5ml) was added dropwise to the mixture. The mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.7g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.155g) was purified by chromatography on a C18 column (eluent: CH)₃CN/NH₄Ac 0.5% 60/40). The pure fractions were collected and the solvent was evaporated. The residue (0.051g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.029g of compound 107 (9%). (mp.250 ℃ C.).

b) Preparation of Compounds 108 and 109

Compound 108 Compound 109

In N₂Under the air flow, nBuLi 1.6](0.00261mol) was added dropwise to a mixture of-70 deg.C (chloromethyl) triphenylphosphine chloride (0.00261mol) in THF (10 ml). The mixture was stirred for 30 minutes. A solution of intermediate 31 (prepared according to A4. a) (0.00087mol) in THF (5ml) was added dropwise to the mixture. The mixture was stirred at room temperature overnight, then poured into water and extracted with EtOAc. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.1g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15-40 μm). The product fractions were collected and the solvent was evaporated. The residue (0.3g) was purified by chromatography on a C18 column (eluent: CH)₃CN/NH₄Ac 0.5％70/30)。

Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.097g F1 and 0.085gF 2. F1 was crystallized from DIPE/iPrOH. The precipitate was filtered and dried. Yield: 0.045g of compound 108 (14%) (mp.165 ℃ C.). F2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.049g of compound 109 (15%) (mp.200 ℃ C.).

c) Preparation of Compound 110

Mixing nBuLi [1.6 ]](1.1ml, 0.0017mol) was added dropwise to-70 ℃ 1, 1, 1, 3, 3, 3-hexamethyldisilylamine (HN (TMS)₂) (0.0017mol) in a mixture of THF (6 ml). The mixture was stirred at-70 ℃ for 30 minutes. Cyanofluoromethyl group (0.0017mol) was added. The mixture was stirred for 30 minutes. Diethyl phosphorochloridate (0.0017mol) was added. The mixture was stirred at-70 ℃ for 15 minutes. Dropwise adding nBuLi [1.6 ]](1.1ml, 0.0017 mol). The mixture was stirred for 30 minutes. A solution of intermediate 31 (prepared according to A4. a) (0.0008mol) in THF (4ml) was added dropwise to the mixture. The mixture was stirred at room temperature overnight, after which it was pouredIn water with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.1g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂EtOAc 95/5; 15-40 μm). Four fractions (F1, F2, F3, F4) were collected and the solvent was evaporated. Yield: 0.026g of Compound 110 (8%) (mp.254 ℃ C.).

d) Preparation of Compound 111

Will (CuCl)₂(0.00015mol) in NH₃A solution in the aqueous phase (500. mu.l) was added to a solution of intermediate 21 (prepared according to A5. b) (0.0014mol) in DMSO (1 ml). Adding CBr at 0 deg.C₄(0.0044mol) in DMSO (1.5ml) was added to the aforementioned mixture. The mixture was stirred at room temperature overnight, poured onto ice and filtered. CH for organic layer₂Cl₂Washed and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (2.73g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH100/0 to 99/1; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.007g of fraction 1 and 0.11g of fraction 2. Fraction 2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.075g of compound 111(mp.223 ℃ C.).

Example B9B

a) Preparation of Compound 112

Intermediate 23(0.0005mol), 1-hydroxybenzotriazole (0.0007mol) and EDCI (0.0007mol) were stirred in CH₂Cl₂(10ml) and THF (2 ml). Adding NH (CH)₃)₂HCl (0.0006mol) and Et₃N (0.0005 mol). The mixture was stirred at room temperature for 12 hours. Adding water. By CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH100/0 to 90/10; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.124g (58%). Product) was purified by chromatography on a kromasyl packed column (eluent: CH (CH)₂Cl₂/CH₃OH 99/1; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.045g of compound 112 (21%) (mp. > 264 ℃ C.).

b) Preparation of Compound 113

Intermediate compound 57 (prepared according to A7.b 0(0.0002mol), 1-hydroxybenzotriazole (0.0003mol) and EDCI (0.0003mol) in CH was stirred₂Cl₂(10 ml). Adding N-methyl-butylamine [ CAS110-68-9 ]](0.0002 mol). The mixture was stirred at room temperature for 12 hours. Adding water. By CH₂Cl₂The mixture is extracted. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 0.149 g. The product was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH100/0 to 90/10; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.065 g. The collected product was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.035g of Compound 113 (30%) (mp.212 ℃ C.).

c) Preparation of Compound 114

Intermediate 23(0.0005mol), 1-hydroxybenzotriazole (0.0007mol) and EDCI (0.0007mol) were stirred in CH₂Cl₂(10ml) and THF (2 ml). 3- (methylamino) propionitrile (0.0006mol) was added. The mixture was stirred at room temperature for 12 hours. Adding water. By CH₂Cl₂The mixture is extracted. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH100/0 to 90/10; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.068 g. The collected product was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.032g of Compound 114 (14%) (mp.168 ℃ C.).

d) Preparation of Compound 115

(0.000195mol) and methylamine (2 eq, 0.000390mol) in THF (5ml) and Et₃A mixture of EDCI (2 equiv., 0.000390mol) and 1-hydroxybenzotriazole (2 equiv., 0.000390mol) was added to N (0.054 ml). The reaction mixture was stirred at room temperature for 12 hours, after which it was poured into water. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The product was isolated and purified by column chromatography. Yield: 0.026g Compound 115 (17.92%).

Example B9C

Preparation of Compound 116

Intermediate 13 (prepared according to a5. a) (0.000291mol) and isoniazid (2.5 eq., 0.000728mol) in ethanol (1ml) and CH₂Cl₂The resulting mixture (2ml) was stirred and refluxed for 12 hours. The solution was evaporated to dryness. The residue was purified by chromatography. Yield: 0.033g compound 116 (24.50%).

Example B9D

a) Preparation of Compound 117

In N₂Cyanoborocyanide (0.0024mol) was added to intermediate 26 (prepared according to A9) (0.0008mol) in formaldehyde (0.5ml) and CH under gas flow at room temperature₃CN (20 ml). Acetic acid (0.5ml) was added. The mixture was stirred at room temperature for 2 hours and H was poured in₂O/K₂CO₃Solutions (10% in water) with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.3g) was purified by chromatography on a column packed with hypersol (eluent: CH)₂Cl₂/CH₃OH 97/3; 5 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.08g (28%). The collected product was crystallized from 2-propanone/ether and the precipitate was filtered and dried. Yield: 0.012g of Compound 117 (5%) (mp.132 ℃ C.).

b) Preparation of Compound 118

Will be provided with

(preparation of a mixture of 0(0.0015mol) and tetrahydro-2, 5-dimethoxyfuran (0.0077mol) according to A9 in acetic acid (10ml) was stirred and refluxed for 1 hour, after which ice water and K were poured in₂CO₃In and use CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1g) was purified by column chromatography on silica gel (eluent: cyclohexane/EtOAc 95/5; 15-40 μm). The pure fractions were collected and the solvent was evaporated off. Yield: 0.23 g. The product was crystallized from DIPE/diethyl ether. The precipitate was filtered and dried. Yield: 0.075 g. The product was recrystallized from DIPE/diethyl ether. The precipitate was filtered and dried. Yield: 0.027g Compound 118 (5%).

Example B9E

a) Preparation of Compound 119

tert-Butylphosphoric acid (0.0015mol) was added to a solution of butyl-2-enedinitrile (0.0015mol) in THF (8 ml). The mixture was stirred at reflux for 2 hours. Adding into

(0.0005mol) (prepared according to A5. a). The mixture was stirred at reflux overnight. Adding water. By CH₂Cl₂The mixture is extracted. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.618g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂100, respectively; 10 μm). The two fractions were collected and the solvent was evaporated. Yield:0.03g of Compound 119 (13%).

b) Preparation of Compound 120

Intermediate 13 (prepared according to A5. a) (0.002mol) was added to a mixture of propionitrile (0.004mol) and piperidine (0.004mol) in ethanol (10 ml). The mixture was stirred at room temperature for 5 minutes. The solvent was evaporated to dryness. Residual CH₂Cl₂Extraction and purification by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was evaporated to dryness. Yield: 0.6g of Compound 120.

Example B9F

Preparation of Compound 122

In N₂Under the air flow, nBuLi [1.6M ]](0.0016mol) was added dropwise to a mixture of intermediate 27 (prepared according to A10) (0.0004mol) in THF (10ml) at-78 deg.C the mixture was stirred for 1h at-78 deg.C. Then, the mixture was left at room temperature, stirred for 30 minutes, and cooled to-78 ℃. A solution of 2-pyridinecarboxaldehyde (0.0004mol) in THF (10ml) was added. The mixture was stirred at room temperature for 2 hours, poured onto ice and extracted with EtOAc. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.32g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 10 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.021g of compound 122 (10.4%) (mp.120 ℃ C.).

Example B10

Preparation of Compound 20

In N₂NaBH is reacted under a gas stream₄(0.0015mol) Compound 19 (see Table 3) (prepared according to B1) (0.0014mol) was added in portions to CH at 5 ℃₃OH (15 ml). The mixture was stirred at 5 ℃ for 1 hour, then poured into water and washed with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.15g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated to dryness. The residue (0.068g, 12%) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.032g of Compound 20.

Example B11

Preparation of Compound 21

Stirring Compound 2 (see Table 3) (0.0002mol), 3-Thienylboronic acid (0.0005mol), Pd (PPh)₃)₄(0.00002mol) and Na₂CO₃(0.0007mol) of a mixture formed in DME (3ml) and refluxed in a closed tube for 3 hours. Adding water. The mixture was extracted with ethyl acetate. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH 98/2; 15-40 μm), the pure fractions were collected and the solvent was evaporated off. Yield: 0.04g Compound 21 (40%).

Example B12

Preparation of Compound 23

H at a pressure of 2bar₂Stirring of Compound 22 (see Table 3) (prepared according to B4. a) (0.0002mol) and Raney nickel (0.1g) in CH with a stream of gas at room temperature₃The resulting mixture in OH (10ml) was filtered through Celite for 15 minutes. By CH₃OH washes the diatomaceous earth. The eluate was evaporated to dryness. Yield: 0.48 g. The product was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH 99/1; 15-40 μm). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.13g F1 and 0.13g F2. F2 was crystallized in diethyl ether. The precipitate was filtered and dried. Yield: 0.09g of Compound 23 (20%).

Example B13

Preparation of Compound 24

H at a pressure of 3bar₂Gas flow, room temperature Compound 1(0.0004mol) and Pd/C (0.07g) in CH₃The mixture formed in OH (10ml) was hydrogenated for 5 hours, then filtered through celite, and washed with CH₂Cl₂The celite was washed and the eluate was evaporated to dryness. The residue was crystallized from DIPE. Filtering the precipitate andand (5) drying. The residue (0.7g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂/CH₃OH100/0 to 99/1; 5 μm). The pure fractions were collected and the solvent was evaporated to dryness. The residue (0.06g) was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.04g of Compound 24 (27%).

Example B14

Preparation of Compound 26

NaH 60% (0.0004mol) was added at room temperature to a mixture of compound 25 (see Table 4) (prepared according to B6. c) (0.0004mol) in THF (30 ml). The mixture was stirred at room temperature for 1 hour. Adding ICH to the mixture₃(0.0004mol) in THF (30 ml). The mixture was stirred at 60 ℃ for 2 hours, cooled and poured into water with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.12g) was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated to dryness. Yield: 0.049g Compound 26 (32%).

Example B15

a) Preparation of Compound 123

In N₂Jones's reagent (0.0056mol) was added to compound 18 (manufactured according to B9) at 5 ℃ under air flowPrepared) (0.0029mol) in 2-propanone (20 ml). The mixture was stirred at 5 ℃ for 2 hours, then poured into water and washed with NaHCO₃Alkalizing with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (1.5g) was purified by column chromatography on silica gel (eluent: CH)₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 15-40 μm). Two fractions (F1, F2) were collected and the solvent was evaporated. Yield: 0.122g F1 (11%) and 0.19gF2 (17%). F2 was crystallized from DIPE. The precipitate was filtered and dried. Yield: 0.034g of compound 123(mp.150 ℃ C.).

b) Preparation of Compound 124

Compound 123(0.0005mol) in POCl₃(1.5ml) the resulting mixture was stirred at 80 ℃ for 24 hours, poured as ice and K₂CO₃In a mixture of 10% solutions, with CH₂Cl₂/CH₃And (5) OH extraction. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.14g) was purified by chromatography on a kromasyl packed column (eluent: CH)₂Cl₂/CH₃OH 99/1; 10 μm). The pure fractions were collected and the solvent was evaporated to dryness. Yield: 0.026g Compound 124.

Example B16

a) Preparation of Compound 125

NaOH 5N (2ml) was added dropwise to compound 104 (see Table 3) (prepared according to B2. c) ((R) NaOH 5N) at 50 ℃0.0003mol) and NH₂OH HCl (0.0004mol) in a mixture of ethanol (10 ml). The mixture was stirred at 50 ℃ for 2 hours. The mixture was evaporated to dryness at 2/3. The remaining mixture was poured into water and CH was used₂Cl₂And (4) extracting. 10% of K for the organic layer₂CO₃The solution was washed and dried (MgSO)₄) Filtered and the solvent evaporated. Yield: 0.21g of Compound 125.

b) Preparation of Compound 126

To a mixture of compound 125(0.0003mol) in THF (20ml) was added 1, 1' -carboxydiimidazole (0.0012 mol). The mixture was stirred at reflux overnight, then poured into water with CH₂Cl₂And (4) extracting. The organic phase was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue (0.17g) was purified by chromatography on a kromasyl packed chromatography column (eluent: CH)₂Cl₂/CH₃OH 98/2; 10 μm). The two fractions were collected and the solvent was evaporated. Yield: 0.035g of fraction 1 and 0.05g of fraction 2. The two fractions were combined and crystallized from diethyl ether. The precipitate was filtered and dried. Yield: 0.05g of Compound 126 (38%) (mp. > 260 ℃ C.).

Example B17

Preparation of Compound 253

a) In N₂Under a stream of air, 2.53ml of acetonitrile, 0.056g (0.253mol) of Pd (OAc)₂And 0.154g (0.506mol) of tris- (2-tolyl) phosphoric acid were added to the 100ml flask and the mixture was stirred for 10 minutes. 1g (2.5) was added to the mixture3mol) intermediate 58, 0.51ml (3.8mmol) N, N-diethylethanamine and 0.36g (5.06mmol) acrylamide the mixture is heated at 80 ℃ under reflux for 5 days to give 28% of compound 253.

b) In N₂0.8g (4.33 mmol; 1 eq) of intermediate 3a (E), 1g (4.33 mmol; 1 eq) of intermediate 5 and 16ml of 2-propanol were introduced under a stream of gas into a 100ml flask. To this mixture was added 0.72ml of 6N HCl (solvent 2-propanol). The mixture was stirred under reflux for 72 hours and then cooled to form the hydrochloride salt of compound 253, compound 254.

Compound 254 can be converted into the isolated state according to methods of the art known to date (see example B1A).

Compound 253 can be converted to compound 1 according to the methods described previously in example A1c) y).

The compounds of formula (I) listed in tables 3, 4, and 5 below may be prepared according to one of the preceding examples (example number).

TABLE 3

^＊(MH⁺) Defined as the mass of the protonated compound; it was measured by a micro-mass spectrometer equipped with an electron-jet probe and a quaternary analyzer.

TABLE 4

^＊(MH⁺) Defined as the mass of the protonated compound; it was measured by a micro-mass spectrometer equipped with an electron-jet probe and a quaternary analyzer.

TABLE 5

C. Pharmacological examples

The pharmacological activity of the compounds of the invention is determined by the following assay.

The evaluation of anti-HIV agents in vitro uses a rapid, sensitive and automated analytical procedure. The HIV-1 modified T4-cell line, MT-4 which previously has shown high susceptibility and permissivity to HIV infection (Koyanagi et al, int. J. cancer, 36, 445-Asonic 451, 1985), serves as the target cell line. The end point is the inhibition of HIV-induced cytopathic effects. The viability of HIV-and mock-infected cells was analyzed spectrophotometrically as a reduction in the remote 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenylthiazolidine bromide (MTT). 50% Cytotoxic Concentration (CC)₅₀In M) is defined as the concentration of compound that reduces the absorbance of the infected mock-controlled sample by 50%. The percent protection achieved by the compounds in HIV-infected cells was calculated according to the following formula:

expressed in% by weight, the total amount of the active ingredient,

wherein (OD)_T)_HIVOptical density as measured at a given concentration of test compound in HIV-infected cells; (OD)_C)_HIVIs to control the optical density measured on HIV-infected cells that have not been treated; (OD)_C)_MOCKIs to control the optical density measured on mock-infected cells that have not been treated; all optical density values were measured at 540 nm. The protective dose to 50% according to the above formula is defined as the 50% Inhibitory Concentration (IC)₅₀In M). CC (challenge collapsar)₅₀And IC₅₀The ratio of (a) to (b) is defined as the Selectivity Index (SI).

The pIC's in the compounds of formula (I) are listed in Table 6₅₀(-logIC₅₀)，pCC₅₀(-logCC₅₀) And pSI (pCC)₅₀-pIC₅₀) The value of (c). For example the compound pIC₅₀Has a value of 10^-9M; i.e. pIC₅₀9 and CC₅₀Has a value of 10^-5M, i.e. pCC₅₀SI of 10 at 5^-5M/10^-9M10000, i.e. pSI of 5-9-4.

TABLE 6

Co.No.	pIC50(M)	pCC50(M)	pSI
				21	8.4	4.9	-3.5
3	8.4	5.5	-2.9
				1	9.4	5.0	-4.4
34	8.0	4.8	-3.2
				19	8.4	4.8	-3.6
45	8.7	5.0	-3.8
				49	8.0	4.8	-3.2
70	8.1	4.8	-3.3
				75	9.0	5.0	-4.0
78	8.4	4.9	-3.5
				79	8.0	5.3	-2.7
84	9.0	4.5	-4.5
				18	8.8	4.9	-4.0
25	9	4	-5
				24	9.1	5.7	-3.4
81	9.1	5.6	-3.5
				11	9.2	5.7	-3.5
10	9.2	6.3	-2.9
				174	8.8	5.3	-3.5
227	9.5	＜4.0	＜-5.5
				144	8.6	6.4	-2.2
229	8.8	＜4.0	＜-4.8
				118	8.4	4.1	＜-4.1
177	8.3	＜4.0	＜-4.3
				106	7.7	5.2	-2.5
145	8.7	5.3	-3.4
				147	9.4	5.7	-3.7
148	8.8	4.9	-3.9
				230	9.2	＜4.0	＜-5.2
231	9.2	＜4.0	＜-5.2
				232	8.4	＜4.0	＜-4.4
105	7.2	＜4.0	＜-3.2

Co.No.	pIC50(M)	pCC50(M)	pSI
				110	8.6	4.3	-4.3
233	9.3	5.7	-3.6
				234	8.7	＜4.0	＜-4.7
235	9.3	＜4.0	＜-5.3
				236	8.8	＜4.0	＜-4.8
149	9.1	5.3	-3.8
				150	8.8	4.8	-4.0
237	8.9	＜4.0	＜-4.9
				151	9.1	5.5	-3.6
152	9.1	4.8	-4.3
				178	8.8	5.7	-3.1
179	8.9	＜4.0	＜-4.9
				153	9.2	6.3	-2.9
124	8.5	4.7	-3.8
				238	9.5	5.6	-3.9
112	9.1	4.9	-4.2
				244	9.2	4	-5.2
209	8.6	4.9	-3.7
				210	8.3	4.8	-3.5
155	8.8	6.3	-2.5
				156	7.7	5.1	-2.6
158	8	5.5	-2.5
				212	9.1	5	-4.1
114	8.6	5.1	-3.5
				213	9	4.8	-4.2
214	8.6	5.1	-3.5
				215	9.1	5.5	-3.6
216	8.2	5	-3.6
				219	9.1	5	-4.1
245	8.8	4	-4.8
				146	8.4	5.4	-3
247	9.2	6.2	-3
				248	9.3	5.7	-3.5
249	8.5	4	-4.5

Co.No.	pIC50(M)	pCC50(M)	pSI
				42	9	6.3	-2.7
251	8.9	5	-3.9
				133	9.2	4	-5.2
9	8.8	4.8	-4
				239	8.9	5	-3.9
241	9.4	5.3	-4.1
				126	8.4	4.9	-3.5

The compound in the present invention may further comprise an organic polymer.

As previously mentioned, supersaturated solutions of pharmaceutical compounds produced by the components of the compounds when exposed to water can be stabilized by virtue of the viscosity enhancing effect of the organic polymer. The organic polymer may hinder the precipitation of the drug compound as more water enters so that the microenvironment becomes more dilute.

The organic polymer used in the compounds of the present invention may be any pharmacologically acceptable water-soluble synthetic, semi-synthetic or non-synthetic organic polymer.

Thus, for example, the polymer may be a natural polymer, such as a polysaccharide or polypeptide or derivative thereof, or may be a synthetic polymer, such as a polyalkylene oxide (e.g., PEG), polyacrylate, polyvinylpyrrolidone, or the like. It is also possible to use mixed polymers, such as block copolymers and glycopeptides.

It is believed that the effect of the organic polymer, which is dissolved in the compound of the invention for stabilizing supersaturated solutions of the pharmaceutical compound, is caused by an increase in viscosity, the polymer typically having a molecular weight in the range of from 500D to 2MD and typically having an apparent viscosity of from 1 to 100mpa.s in a 2% aqueous solution at 20 ℃. For example, the water-soluble polymer may be selected from the group comprising:

alkylcelluloses, such as methylcellulose,

hydroxyalkyl celluloses, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose,

hydroxyalkyl alkylcelluloses, such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,

carboxyalkylcelluloses, e.g. carboxymethyl cellulose

Alkali metal salts of carboxyalkylcelluloses, such as sodium carboxymethylcellulose,

carboxyalkylalkylcelluloses, such as carboxymethylethylcellulose,

-carboxyalkylcellulose esters of cellulose,

-a group of starches,

pectins, such as carboxymethyl amyl pectin,

chitin derivatives, such as chitosan,

-a source of heparin and heparinoids,

polysaccharides, such as alginic acid, its alkali metal and ammonium salts, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum,

-polyacrylic acids and salts thereof,

polymethacrylic acids and salts thereof, copolymers of methyl acrylate,

-a polyvinyl alcohol (PVA),

-polyvinylpyrrolidone) copolymers of polyvinylpyrrolidone with vinyl acetate,

polyoxyalkylenes, such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, such as polyhydroxyalkylenes (poloxamers) and polyhydroxyimines (poloxamines).

Polymers not listed which are pharmaceutically acceptable and which have the appropriate physicochemical properties as defined hereinbefore are also suitable for preparing the compositions of the invention.

Preferred organic polymers are cellulose ethers, such as methylcellulose, hydroxyethylmethaneCellulose based, or hydroxypropyl methylcellulose (HPMC), e.g. Methocel^TM(from Colorcon, UK.) such as Methocel^TM A、Methocel^TM E、Methocel^TM F、Methocel^TM K、Methocel^TMJ and Methocel^TMHB, or e.g. Metholose^TME.g. Metolose^TM SM、Metolose^TMSH or Metholose^TMAnd (SE). The most preferred organic polymer is hydroxypropyl methylcellulose, for example from 5cps Methocel^TME to 15000cpsMethocel^TMK15M.

The effective action of the compositions of the invention can be achieved even with very small masses of organic polymers. Thus, the organic polymer in the composition of the present invention may be present in an amount of 0.05 to 35% by weight, preferably 0.1 to 20%, more preferably 0.5 to 15%, most preferably 2 to 11% by weight (relative to the total mass of the pharmaceutical compound, acid or base, surfactant and organic polymer). Both the content of organic polymer and the viscosity grade affect the dissolution of the pharmaceutical compound in the composition of the invention, increasing the content of organic polymer and/or increasing the viscosity grade (e.g. 15000mpa.s instead of 5mpa.s (mpa.s in a 2% aqueous solution at 20 c)) both have a tendency to slow the dissolution of the pharmaceutical compound. The identity and amount of organic polymer is therefore generally selected according to the desired state of dissolution. For example, a water-soluble polymer having an apparent viscosity of greater than 1000mPa.s, dissolved in a 2% aqueous solution at 20 ℃, provides a sustained release of the drug.

Thus, the composition according to the invention may in this way be designed to provide a particularly advantageous drug dissolution release. For example, dissolution may be fast enough to determine that the pharmaceutical compound is actually fully bioavailable (e.g., by mouth, nose, stomach, or vagina), but slow enough to provide a longer-term plasma intake state, e.g., to avoid re-precipitation of the pharmaceutical composition before it reaches the stomach.

A preferred embodiment is a pharmaceutical compound comprising a basic pharmaceutical compound, a surfactant, a physiologically acceptable water-soluble acid and optionally an organic polymer, characterized in that the pharmaceutical compound is in the form of a solution in said hydrochloric acid after addition of said composition containing 100mg of said pharmaceutical compound in amounts of 7 to 25 (preferably 10 to 20, especially 12 to 18)%, 45 to 70 (preferably 50 to 65, especially 54 to 63)% and at least 96 (preferably at least 97, especially at least 98)% for 5, 15 and 45 minutes, respectively, to 600ml of 0.1N hydrochloric acid at 37 ℃. These data are consistent with the study of USP23, <711> dissolution, page 1791-.

For example, the dissolution state proposed hereinbefore is determined by placing the composition in 0.1N HCl (or other suitable medium) either uncoated or in a rapidly dissolving coating (e.g. gelatin capsule shell) and slurrying using the USP-method, apparatus 2, stirring at 50 or 100 rpm.

The compositions of the invention may if desired be aqueous, but are generally preferably substantially anhydrous, e.g. containing up to 3% by weight, preferably less than 1% by weight, and most preferably less than 0.5% water, but may be mixed with water immediately prior to administration or may be coated and dispersed in an aqueous medium, the coating being broken only after administration. Such water-soluble compositions are considered to be within the scope of the present invention.

Depending on the choice of the components, the compositions of the invention may be in liquid, solid or semi-solid form-for example, in the form of a gel. The composition is preferably non-free flowing rather than free flowing particles at ambient temperature (e.g., 21 ℃). Thus the composition is preferably a solid or semi-solid state, or less preferably a highly viscous fluid, at ambient temperature.

The pharmaceutical compound, surfactant, acid or base and the selected organic polymer in the composition of the present invention are intimately mixed together.

Thus, where the composition is a particulate, the acid (base), the pharmaceutical compound, the surfactant and the selected organic polymer are mixed together within the particle (e.g., on a molecular scale; this can be used to separate the solvent from a solution of these components so that a solid or semi-solid dispersion is formed). Individual particles in the granular mixture do not contain all three or selected four of the constituent components, or it may be desirable to encapsulate a core of one or more of the constituent components with other constituent components. Such intimate admixture is important because the components of the present invention, as previously described, assist at the microscopic level when dissolved.

Preferably, all the constituent components are dispersed so as to form a system of balanced chemical and physical properties or homogeneous overall, or consist of one phase as defined in thermodynamics; such a dispersion will be referred to hereinafter as a thermoplastic phase or thermoplastic system. The components of the thermoplastic system are rapidly bioavailable to the organism to which it is administered. This advantage can be explained by the fact that thermoplastic systems readily form liquid solutions when in contact with body fluids such as gastric juices. The fact that it is readily soluble can be attributed, at least in part, to the fact that the energy required to dissolve the constituent from the thermoplastic system is less than the energy required to dissolve the constituent from the crystalline or microcrystalline solid phase.

The term "solid dispersion" as used hereinbefore and hereinafter refers to a system comprising the components of the composition of the invention in the solid state (as opposed to the liquid or gaseous state), wherein one of the components is more or less evenly dispersed throughout the other component (which may include additional pharmaceutically acceptable formulation agents, such as plasticizers, preservatives and the like, generally known in the art). When the dispersion of constituents is such a chemically and physically balanced or entirely homogeneous system, or a phase as defined in thermodynamics; such a solid dispersion will be referred to as a "solid solution". Solid solutions are the preferred physical system because the components therein are generally rapidly bioavailable to the organism to which it is administered. This advantage can be explained by the ease with which the solid solution can form a liquid solution upon contact with a liquid medium, such as gastrointestinal fluid. The fact that it is readily soluble can be attributed, at least in part, to the fact that the energy required to dissolve from a solid solution is less than the energy required to dissolve the constituent from a crystalline or microcrystalline solid phase.

The term "solid dispersion" also encompasses dispersions that are less homogeneous overall than solid solutions. These dispersions are not chemically or physically homogeneous throughout or contain more than one phase. For example, the term "solid dispersion" also relates to a system having a specific structural part or small region of a macromolecule, wherein an amorphous, microcrystalline or crystalline drug compound, and/or an amorphous, microcrystalline or crystalline surfactant, and/or an amorphous, microcrystalline or crystalline acid or a selected amorphous, microcrystalline or crystalline polymer is dispersed more or less homogeneously in another phase comprising a solid solution, which comprises the drug compound, the surfactant, the acid (base) and the selected polymer. The particular structural moiety of the macromolecule is a region within the solid dispersion that is marked by some distinct physical characteristic and by small size that is uniformly and randomly distributed throughout the solid dispersion.

The compositions of the present invention may be obtained by preparing an intimate mixture of the pharmaceutical compound, the surfactant, the acid (base) and the selected organic polymer. This may be directly affected by the process of removing the solvent after dissolving these ingredients in the liquid solvent. Thus, in the long term, the present invention provides a process for preparing a pharmaceutical composition, namely: dissolving a pharmaceutical compound, a surfactant, a physiologically tolerable water soluble acid (base), and a selected physiologically tolerable organic polymer in a solvent; removing the solvent from the solution obtained above; optionally shaping the resulting product into a desired shape; the product is coated with a coating material that is acceptable in physiological conditions.

Alternatively, if the components of the composition are stable to heat, the components may be co-melted to produce a physical mixture thereof. Accordingly, the present invention also provides a process for preparing a formulation composition, namely: co-melting a pharmaceutical compound, a surfactant, a physiologically tolerable water soluble acid (base), and a selected physiologically tolerable water soluble organic polymer; forming the obtained product into a desired shape; the product is coated with a physiologically tolerable coating material.

In particular, the above process can be accomplished by using one of the following techniques:

a) spray drying:

the components of the present composition may be dissolved in a suitable solvent, and the resulting solution may be spray-dried to obtain a powder. These powders may be further processed into exemplary tablets or filled into capsules.

b) And (3) freeze drying:

the ingredients of the present composition may be dissolved in a suitable solvent and the resulting solution may be freeze-dried to provide a powder which may be tableted or encapsulated. Alternatively, the solution can be freeze dried directly in a mold suitable for blister packs to give a shape suitable for blister packs.

c) Supercritical fluid technology:

the ingredients of the present composition may be dissolved in a compressible fluid, especially a supercritical fluid (i.e. any substance above the critical temperature and critical pressure, the supercritical fluid having gas and liquid properties) (in this case, supercritical fluid refers to a solvent; and thus can be referred to as a standard such as RESS (rapid expansion of supercritical solution) or PGSS (particles in gas saturated solution)), followed by removal of the supercritical fluid using supercritical techniques (e.g. pressure reduction) and thus obtaining a powder which can be further tableted or encapsulated. The supercritical fluid technique can also be applied to supercritical fluid as an antisolvent (reference such as GAS antisolvent), SEDS (supercritical fluid adds dispersed solvent), ASES (aerosol solvent extraction system), SAS (supercritical antisolvent) or PCA (compressed antisolvent precipitation)). In this case, the ingredients of the composition are dissolved in a suitable solvent and a supercritical fluid is used to increase the solvent evaporation, thus obtaining powders which can be further used for the above-mentioned purposes.

d) Coating a carrier:

the ingredients of the present composition may be dissolved in a suitable solvent, and the resulting solution may be coated, sprayed, or granulated by volatilizing the solvent on a suitable carrier. Suitable carriers which can be used depend on the technique used, e.g. the use of microcrystalline cellulose as carrier for the preparation of micropellets using a fluidized bed apparatus, or the use of gas phase SiO for granulation₂The carrier is prepared by using a high shear granulator or by spraying a solution of the ingredients of the composition onto an inert core, such as sugar beads. The solvent is removed by techniques such as high temperature vacuum drying, vacuum drying or microwave.

e) Co-melting:

when the ingredients in the composition are stable to heat, they may be physically mixed, melted and then mixed. The molten mixture can be directly formed into the desired shape (milled, pressed; injection molded), for example the melt can be directly poured or injected, e.g. into the final blister pack, or directly into a mould, or directly into a capsule, followed by coating. The molten mixture may also be cooled prior to processing, such as grinding to a powder and tableting or encapsulating. The ingredients of the present composition may be made as a eutectic by simply heating the physical mixture or melt extruding the same. In the latter case, the components are physically mixed and then fed into an extruder at an elevated temperature, where the mixture is heated to melt and form a mixture, after which the resulting molten extrudate is shaped by the methods described above, e.g., injected into a mold or the molten extrudate can be cooled and then ground into a powder for tableting or encapsulation.

Alternatively, the melt may be granulated (melt granulation; high shear granulation), sprayed or coated on a suitable carrier (see item d). Melt granulation may be carried out in a melt extruder, with the carrier being added during extrusion, and the extrudate obtained being shaped by the methods described above. When the carrier employed is an excipient suitable for spheronization, the resulting extrudate may be spheronized using a pellet mill.

f) Extruding:

the ingredients of the present composition may be mixed and fed into an extruder, such as through a dry powder feeder, and a solvent containing a suitable surfactant may be added to the extruder, such as through an air inlet. While the mixture was still in the extruder, the solvent was evaporated off. After extrusion, the extrudate is shaped (milling, crushing).

Alternatively, the solution containing the ingredients of the composition of the invention is fed into an extruder, the solvent is evaporated while the product is still in the extruder, and the extrudate is finally shaped.

Alternatively, a solution containing the ingredients of the present composition is granulated on a suitable carrier, such as microcrystalline cellulose, extruded as a wet powder. The extrudate was spheronized by a pellet mill, after which the resulting pellets were dried to remove the solvent. The pellets can be directly filled into capsules or prepared into tablets.

Preferably, the present composition is prepared by the extrusion process described in f. The skilled worker is able to carry out the appropriate steps and process parameters in order to extrude a solution containing the constituents of the composition and to evaporate the solvent in the extruder. See patent WO 98/10752.

The solvents used in the above process are finally physiologically tolerable materials, suitable organic solvents such as alkanols having from 1 to 6 carbon atoms (e.g. ethanol), acetone, N, N-dimethylformamide, linear or cyclic ethers (e.g. diethyl ether, dimethyl ether or tetrahydrofuran), cyclohexane, dimethyl sulfoxide, etc., or solvent mixtures are employed which may contain water. For acids with higher melting points, solvents or solvent mixtures with high boiling points can be conveniently used; however, in general, the boiling point of the solvent or solvent mixture does not exceed 100 ℃. Such solvents can be effectively used in the preparation of the compositions of the present invention with little solvent residue. The solvent may be conveniently removed by evaporation, for example under reduced pressure, and since this may result in some solvent remaining (e.g. more than 3%), it is recommended to use pharmaceutical excipients such as ethanol (or alcohol-water mixed solvents) which are acceptable for use.

As described above, a supercritical fluid may be used. Suitable supercritical fluids such as CO₂，N₂O，N₂Short-chain alkanes, such as methane, ethane and the like.

If the pharmaceutical compound is insoluble or poorly soluble in the selected solvent, the process of the present invention may include a particulate dispersion (e.g., nanoparticles having a particle size of 1-100 nm) of the pharmaceutical compound in the solvent, rather than completely dissolving the pharmaceutical compound. If this step is carried out, the smaller the particle size of the pharmaceutical compound, the better. Nanoparticles of insoluble compounds can be prepared, for example, by various precipitation techniques or by co-milling with physiologically tolerable inorganic substances, such as zirconium oxide (EP-0,499,299).

Removal of the solvent may or may not be complete, the former producing a solid or gelatinous solid or semi-solid, the latter possibly resulting in a viscous liquid that can be encapsulated.

Generally, complete removal of the solvent is preferred, since the resulting product is readily settable. It has been mentioned above that spray drying of the solution (to obtain a granular product), volatilization of the solvent in a mold, shaping (e.g. injection molding), extrusion, etc. are effective shaping methods. As described above, the product may be prepared while heating and solidified upon cooling. The shaped product can be formed into a film or tablet form by evaporating the solvent or pouring the hot mass onto a disk to evaporate the solvent.

In a preferred embodiment, the product is filled (e.g., poured or extruded or injected) into a capsule shell, such as a gelatin capsule.

Another procedure for preparing the compositions of the present invention is to prepare a dispersion of the above-mentioned pharmaceutical compound, surfactant and acid (base) and mix to obtain a physical mixture of the product and the organic polymer.

Yet another process for preparing the present compositions is to prepare a dispersion of the pharmaceutical compound, the acid (base) and the selected organic polymer by dissolving them in a solvent, followed by removal of the solvent and mixing the resulting product with the surfactant at elevated temperature. It is within the skill of the skilled artisan to select the most appropriate parameters and equipment for the above procedure.

The skilled artisan will appreciate that the particle size, particle size distribution, crystallinity and morphology of the resulting powder will depend on the process of preparation and that specific requirements may be met by adjusting process parameters such as temperature, nozzle size, nozzle shape, gas flow during spraying.

The pharmaceutical composition of the present invention may be formulated into a suitable dosage form.

Thus, in the foregoing the invention provides a formulation containing a therapeutically effective amount of the composition.

For example, if the drug is delivered in standard capsules (e.g., a 900mg capacity glass thermoplastic system as described herein, with a desired drug loading of 100 mg/capsule), the amounts and properties of the other composition components will need to be selected to produce a preferred drug dissolution profile, typically requiring the use of a smaller amount of organic polymer, e.g., 20-50mg, and the ratio of acid (base) to surfactant can be set as required for the dissolution profile, e.g., 200-400mg surfactant corresponds to 450-650mg acid (base).

In addition to the pharmaceutical compound, organic polymer, acid (base) and surfactant, the composition of the present invention may contain other conventional pharmaceutical adjuvants such as sweeteners, colorants, antioxidants, fillers, glidants, lubricants, fats, waxes, coating solutions, dispersants, suspending agents (e.g., the composition is coated with a gastric acid resistant material and then dispersed in water or syrup), and the like. Such ingredients are typically present in small proportions, e.g., 0.01% to 10% by mass (compared to the sum of the masses of acid (base), surfactant, drug compound and organic polymer), and thus can be mixed directly with the drug compound. However, when the compositions of the present invention are encapsulated or otherwise disposed in a carrier (e.g., a liquid, solid, or semi-solid matrix), the proportion of such excipients (e.g., coating materials, encapsulating materials, dispersion media, etc.) may be smaller or larger, e.g., 5-95%, and not directly mixed with the pharmaceutical compound.

The product may be hygroscopic and thus may give a sticky feel when touched by hand due to absorption of moisture from the skin. It is therefore desirable to coat the product to prevent water uptake during processing. Such coatings may take the form of capsules (as described above), tablet coatings, protective films or wet coatings, removable water-resistant wraps. Tablet coatings may be applied in a conventional manner, may be dissolved in the mouth or stomach (e.g., sugar or sugar/beeswax coatings), or may be coated with a polymer resistant to gastric acid (e.g., with a coating of a polymer resistant to gastric acid when drug uptake in the small intestine is desiredGastric acid resistant Eudragit produced by GmbH^TMCoated products). The protective film or wrap is used in conjunction with topical application of the product, such as absorption through the skin or toes or nails. In this case, the composition pad is placed between the upper protective layer having adhesive properties and the lower removable layer. Examples of topical application forms applied to the nails and adjacent tissues are the treatment of fungal infections, see US-A-5182914.

The composition may also contain a suitable lubricant, such as sodium stearate, to avoid stickiness.

When the product is formulated in a specific manner, e.g. spray drying, the particles may be contained in a sealed delivery device (e.g. a spray device or a powder device such as an inhaler) for oral, nasal or topical administration of the particles. Alternatively, it can be encapsulated or mixed with filler such as lactose, starch, and microcrystalline cellulose, and the obtained mixture is tableted. In any case, the particles may require one or more coatings, such as delayed release or extended release formulations.

However, it is generally preferred to formulate the product as discrete doses and therefore require protective coatings such as capsules, coated tablets or film-coated single doses.

The compositions of the present invention may be formulated for convenient topical application or for administration into a completely empty body cavity, such as the nose, lungs, mouth, ear, stomach, rectum or vagina. Although more particularly capsules and coated tablets are preferred for patches and powders, topical administration forms include patches, tablets, troches, lozenges, earplugs, nasal plugs, coated tablets, capsules, suppositories, chewable tablets, gels, powders, granules, syrups and dispersions. The dosage form depends on the pharmaceutical compound and the treatment environment, as well as the class size of the patient.

Furthermore, the present invention includes the pharmaceutical composition or pharmaceutical dosage form mentioned above for use in the prevention, treatment and diagnosis of diseases of the human or animal body.

The invention also includes pharmaceutical compositions of oral pharmaceutical formulations for mass production for therapeutic use in mammals, characterised in that the formulations can be administered at any time of the day without interference from food intake.

Alternatively, or in other words, the invention also relates to the use of a pharmaceutical composition as described above for the manufacture of an oral pharmaceutical preparation for administration to a mammal for therapeutic effect, characterized in that the preparation can be taken at any time without food influence.

The invention encompasses a method of prophylaxis, treatment or diagnosis of the human or animal body comprising administering a therapeutically or diagnostically effective pharmaceutical composition according to the invention.

The invention also encompasses a pharmaceutical package suitable for commercial sale comprising a container, and an oral dosage form as claimed in any one of claims 16 to 18 and accompanying written matter accompanying the package that writes that dosage form for use without restriction with or without food.

The invention will now be further described by way of the following non-limiting examples.

Example 1

The following compositions were prepared according to the invention:

composition 1

Cisapride 114mg

Tartaric acid 35.6mg

Lutrol^TM F68 457mg

Composition 2

Cisapride 114mg

Tartaric acid 10mg

Lutrol ^TM F68 457mg

Preparation of composition 1

114mg of cisapride and 457mg of Lutrol^TMF68 was dissolved in 1.14g of acetone. 35.6mg of tartaric acid was dissolved in 1.90ml of ethanol and the resulting solution was added to an acetone solution. The resulting mixture was dried under vacuum at 85 ℃. The residue was ground, dried under vacuum at 80 ℃ and then ground.

Preparation of composition 2

The procedure was followed for the preparation of composition 1 except 10g of tartaric acid was dissolved in 53.3ml of ethanol.

Determination of in vitro dissolution profiles for compositions 1 and 2 were prepared by placing compositions 1 and 2, respectively, containing 5.7mg cisapride in 10ml of a pH 6.8 buffer as defined in the United states Pharmacopeia (pH 6.8 buffer in the United states Pharmacopeia by mixing 6.805g KH₂PO₄109.5ml of a 0.2N NaOH solution and 700ml of distilled water were mixed in a1 liter beaker and stirred until completely dissolved, and the resulting mixture was diluted to 1 liter with distilled water), and the measured dissolution percentage of cisapride was measured as a function of time at 37 deg.C (by a magnetic stirring method, the dissolved concentration of cisapride was measured by a UV method).

The results are shown in Table 7.

TABLE 7

Percentage of cisapride in solution

Time composition 1 composition 2

0 0 0

5 1.68 98.15

30 1.51 98.33

60 1.47 98.15

120 1.45 98.24

Composition 2 is significantly more rapidly dissolved than composition 1. Thus, the addition of a significant amount of acid to the composition can increase the solubility of the pharmaceutical compound, which has a higher bioavailability.

Example 2

A gelatin capsule was prepared containing the following composition:

composition 3

R103757^＊ 100mg

Citric acid 500mg

Cremophor RH 40 250mg

Methocel^TM E5 50mg

^＊R103757 represents (-) - [2S- [ 2. alpha., 4. alpha. (S)^＊)]]-4- [4- [4- [4- [ [2- (4-chlorophenyl)]-2- [ [ (4-methyl-4-hydro-1, 2, 4-triazol-3-yl) thio ] thio]Methyl radical]-1, 3-dioxolan-4-yl]Methoxy radical]Phenyl radical]-1-piperazinyl]Phenyl radical]-2, 4-dihydroxy-2- (1-methylpropyl) -3H-1, 2, 4-triazol-3-one.

The composition is prepared by mixing 500mg of R103757, 2.5g of citric acid, and 250mg of Methocel^TME5 and 1250mg Cremophor RH40 were dissolved in 2.5ml ethanol. After complete dissolution, the solution was poured into a teflon resin tray and placed in a drying oven for vacuum drying at 80 ℃ for 2 h. The residue was pulverized and filled into gelatin capsules (No. 0 capsules) in a dose corresponding to 100mg of R103757.

In vitro dissolution profile of composition 3% drug was dissolved at 0, 5, 15, 30, 45 and 65 minutes by UV measurement (using paddle method in usp, apparatus 2, 100rpm) in 600ml 0.1N HCl at 37 ℃.

The results are shown in Table 8.

TABLE 8

Composition 3

Percent amount of R103757 in solution

Time sample 1 sample 2

0 0 0

5 14.94 14.34

15 62.70 59.10

30 94.32 93.12

45 101.64 102.06

60 102.84 103.14

Example 3

A gelatin capsule was prepared containing the following composition:

composition 4

R112625^＊ 100mg

Citric acid 325mg

Polyethylene glycol monododecaneether 23325 mg

Methocel^TM E5 25mg

^＊R112625 represents (+) - (trans) -4- [1- [3, 5-bis (trifluoromethyl) benzoyl]-2- (phenylmethyl) -4-piperidinyl]-N- (2, 6-dimethylphenyl) -1-piperazineacetamide.

The composition is prepared by mixing 1g R112625, 3.25g citric acid and 250mg Methocel at 70 deg.C^TME5 was dissolved in 6ml ethanol. 3.25g of polyethylene glycol monododecyl ether 23 was added to the above solution, and stirring was continued. After complete dissolution, the solution was poured into a teflon resin tray and placed in a drying oven for vacuum drying at 80 ℃ for 2 h. The residue was pulverized and filled into gelatin capsules (No. 0 capsules) according to the corresponding dosage of 100mgR 112625.

The in vitro dissolution profile of composition 4 was determined in the same manner as composition 3.

The results are shown in Table 9.

TABLE 9

Composition 4

Percent amount of R112625 in solution

Time sample 1

0 0

5 10.98

15 51.87

30 80.82

45 97.08

60 101.91

Example 4

Stability determination

A gelatin capsule was prepared containing the following composition:

composition 5

R112625 100mg

Citric acid 325mg

Cremophor RH40 325mg

Methocel^TM E5 25mg

The composition was prepared by the same method as in example 3.

Composition 5 capsules were stored at room temperature for 1 month. The dissolution rate measurement method was the same as that of composition 3.

The results are shown in Table 10.

Watch 10

Composition 5

Percent amount of R112625 in solution

Measurement at time 0 and measurement after standing for 1 month

0 0 0

5 9.26 9.75

15 43.74 44.16

30 78.13 80.22

45 92.64 99.09

60 101.64 102.39

The above results demonstrate the stability of the compositions of the present invention.

Example 5

Quick-release/sustained-release preparation

The following compositions were prepared according to the invention:

composition 6

R165335^＊ 50mg

Citric acid 500mg

CremophorRH40 250mg

Composition 7

R165335^＊ 50mg

Citric acid 500mg

Cremophor RH40 250mg

Polyox^TM WSR 303 30mg

Composition 8

R165335 50mg

Citric acid 500mg

Cremophor RH40 250mg

Polyox^TM WSR 303 50mg

^＊R165335 represents 4- [ [ 6-amino-5-bromo-2- [ (4-cyanophenyl) ammonia]-4-pyridines]Oxy radical]3, 5-dimethylphenylcyanide.

Composition 6 was prepared by adding 5000mg of R165335 to acetone at 60 ℃ while adding 50g of citric acid and stirring continuously until complete dissolution. Then 25g Cremophor RH40 was added to the solution. After dissolution, the solution was poured into a teflon resin pan and placed in a drying oven for vacuum drying at 80 ℃ for 2 hours. The residue obtained is comminuted. Compositions 7 and 8 were prepared by adding small amounts of Polyox to composition 6 at the same prescribed levels^TM WSR 303。

In vitro dissolution profiles for compositions 6, 7 and 8 the percent dissolution of the drug compound was measured by UV method at 37 ℃ for 0, 5, 15, 30, 45, 60, 360 minutes (according to the United states Pharmacopeia basket method, apparatus 1, speed 100rpm) by placing a composition containing 50mg of R165335 in a blue pan in 0.01N HCl 900ml containing 2.5% sodium lauryl sulfate as dissolution medium.

The results are shown in Table 11.

TABLE 11

Composition 5

Percent amount of R165335 in solution

Time composition 6 composition 7 composition 8

0 0 0 0

5 22.86 8.42 4.12

15 65.88 20.03 7.45

30 95.82 35.96 12.17

45 100.18 47.89 16.67

60 100.70 58.24 24.07

75 69.65 29.52

90 78.24 35.25

105 84.73 40.61

120 90.35 47.00

150 101.01 56.28

180 101.90 65.30

240 79.29

300 93.45

360 100.70

From the results listed in table 11, it can be concluded that the composition of the present invention can achieve sustained release of the dissolution rate of the composition by adding an organic polymer to the composition.

Composition 6 was also tested for stability. The composition was left at room temperature for 8 months, and the content of R165335 in the composition was measured by high performance liquid chromatography. After 8 months, the amount of R165335 in the composition can still reach 98.5%, demonstrating the stability of the composition.

Example 6

In vivo studies

The following compositions were prepared

Composition 9

R165335 125mg

492mg of citric acid

Cremophor RH40 242mg

Methocel^TM E5 42mg

Composition 10

R278474^＊ 50mg

Citric acid 500mg

Tocopherol TPGS 250mg

Methocel^TM E5 25mg

R278474^＊Represents 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl]Ammonia]-2-pyrimidinyl]Amino group]And (3) phenyl cyanide.

Composition 9 was prepared by adding 500mg of R165335 to 5ml of tetrahydrofuran (solution A) at boiling point. 1996.6mg of citric acid, 966mg of Cremophor RH40 and 166.66mg of Methocel^TME5 was added to 4ml of ethanol (solution B) at 80 ℃. Solution a was added to solution B with constant stirring. The resulting solution was poured into a teflon resin pan and placed in a drying oven for vacuum drying at 80 ℃ for 2 hours. The residue was ground and filled into gelatin capsules (No. 0) for in vivo studies.

Composition 10 was prepared by mixing R278474300mg, 3g citric acid and 150mg Methocel^TME5 was added to 70 ℃ ethanol. The solution was dried under vacuum at 85 ℃ for 1 hour to remove the solvent. 3g of the residue obtained are mixed with 1.304g of tocopherol TPGS at 80 ℃.

R165335 Male beagle dogs were orally administered at a dose of 10mg/kg according to a capsule containing composition 9 and a PEG400 solution of R165335 (10mgR165335/ml PEG 400). Two beagle dogs were tested for each formulation. The plasma concentration of R165335 within 32 hours after oral administration was determined by HPLC method. The results are shown in Table 12.

R278474 Male beagle dogs were orally administered at a dose of 5mg/kg according to a capsule containing composition 10 and a PEG solution of R278474 (40mg R278474/ml PEG 400). Two beagle dogs were tested for each formulation. Plasma concentrations of R278474 were measured by LC-MS over 72 hours after oral administration. The results are shown in Table 13. Table 14 shows Cmax, Tmax, and AUC after administration of PEG400 solution and composition 10 capsules_{0 to 72 hours}。

TABLE 12

NQ: it cannot be quantified.

Watch 13

NQ: can not quantify

TABLE 14

Mean value of	PEG400 solution	Composition 10
			Cmax(ng/ml)	341	1144.50
Tmax(h)	4	5
			AUC0-72h(ng·h/ml)	8359	31008

The above results clearly show that composition 10 has better efficacy than its PEG400 solution. Composition 10 had a higher pharmacokinetic profile than the PEG400 solution.

Example 7

The effect of surfactants on solubility and stability under supersaturated conditions.

A2.5% (w/v) aqueous solution of hydroxypropyl-beta-cyclodextrin (HP. beta. CD) at 37 deg.C [1], 2.5% (w/v) tocopherol TPGS [2] in 0.01N HCl, 2.5% (w/v) cremophor RH40[3], 2.5% (w/v) sodium lauryl sulfate [4] or 2.5% (w/v) PEG4000[5] was prepared.

To 10ml of the above solution was added dropwise, while stirring, a concentrated solution (100mg/ml) of R278474 or R165335 in N, N-dimethylformamide until precipitation of the drug compound was observed. After 5, 30, 60 and 120 minutes, the concentration (mg%) of the dissolved R278474 or R165335 (i.e., the mg amount of the dissolved drug in 100ml of the solvent) was measured. The results are shown in Table 15.

Watch 15

^＊NM means not measurable

The results in table 15 clearly show that the surfactant can increase the solubility more greatly (create a supersaturated environment) than cyclodextrins such as HP β CD, cosurfactants such as PEG 4000. The results also indicate that the surfactant can maintain this supersaturated environment for a period of time.

Claims (49)

1. A semi-solid or solid pharmaceutical composition comprising an alkaline pharmaceutical compound, vitamin E TPGS and a physiologically acceptable water-soluble acid, characterized in that the ratio of acid to pharmaceutical compound is at least 1: 1 by weight, wherein the alkaline pharmaceutical compound is 4- [ [4- [ [4- (2-cyanovinyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile.

2. The composition according to claim 1, wherein the basic pharmaceutical compound, vitamin E TPGS and the acid are intimately mixed.

3. A composition according to any preceding claim, characterised in that the physical state of the composition is a solid dispersion.

4.A composition according to claim 1 or 2, wherein the acid is selected from citric acid, fumaric acid, tartaric acid, maleic acid, malic acid, succinic acid, oxalic acid, malonic acid, benzoic acid, mandelic acid and ascorbic acid.

5.A composition according to claim 4, wherein the acid is citric acid.

6. The composition according to claim 1 or 2, further comprising an organic polymer.

7. The composition according to claim 6, wherein the polymer is selected from the group consisting of:

-alkyl celluloses,

-hydroxyalkyl celluloses, such as,

-hydroxyalkyl alkylcelluloses,

-carboxyalkylcelluloses, such as cellulose esters,

alkali metal salts of carboxyalkylcelluloses,

-carboxyalkylalkylcelluloses,

-carboxyalkylcellulose esters of cellulose,

-a group of starches,

-a pectin-based gum,

-a derivative of chitin, wherein the chitin is a derivative of chitin,

-heparin and heparinoids,

-a polysaccharide group,

-polyacrylic acids and salts thereof,

polymethacrylic acids and salts thereof, methacrylic acid ester copolymers,

-a polyvinyl alcohol (PVA),

polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone and vinyl acetate,

polyoxyalkylenes.

8. The composition according to claim 7, wherein the alkylcellulose is methylcellulose; the hydroxyalkyl cellulose is selected from hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses are selected from hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; the carboxyalkyl cellulose is carboxymethyl cellulose; the alkali metal salt of carboxyalkyl cellulose is sodium carboxymethyl cellulose; the carboxyalkyl alkylcellulose is carboxymethyl ethyl cellulose; the pectin is carboxymethyl amylopectin sodium; the chitin derivative is chitosan; polysaccharides are selected from alginic acid and its alkali metal and ammonium salts, carrageenan, galactomannan, tragacanth, agar, gum arabic, guar gum and xanthan gum; or polyoxyalkylenes selected from polyoxyethylene and polyoxypropylene and copolymers of oxyethylene and oxypropylene.

9. A composition according to claim 7, wherein the polyoxyalkylene is selected from poloxamers and poloxamines.

10. A composition according to claim 6, wherein the polymer has an apparent viscosity of from 1 to 100mPa.s, dissolved as a 2% aqueous solution at 20 ℃.

11. A composition according to claim 6, wherein the polymer is hydroxypropylmethylcellulose.

12. A composition according to claim 6 which provides sustained release of the drug characterised in that it comprises a water-soluble polymer having an apparent viscosity of greater than 1,000mPa.s when dissolved in a 2% aqueous solution at 20 ℃.

13. A composition according to claim 1 or 2, wherein the pharmaceutical compound is only slightly soluble in water.

14. The composition according to claim 1 or 2, wherein the vitamin E TPGS is present in a concentration of 1-70% by weight relative to the total weight of the vitamin E TPGS, acid and drug.

15. The composition according to claim 14, wherein the vitamin E TPGS is present at a concentration of 5-55% by weight relative to the total weight of the vitamin E TPGS, acid and drug.

16. The composition according to claim 15, wherein the vitamin E TPGS is present in a concentration of 10-50% by weight relative to the total weight of the vitamin E TPGS, acid and drug.

17. A composition according to claim 1 or 2, wherein the weight ratio of vitamin E TPGS to drug is in the range of 100: 1 to 1: 5.

18. The composition according to claim 17, wherein the weight ratio of vitamin E TPGS to drug is in the range of 50: 1 to 1: 2.

19. The composition according to claim 18, wherein the weight ratio of vitamin E TPGS to drug is in the range of 10: 1 to 1: 1.

20. A pharmaceutical dosage form comprising a therapeutically effective amount of a pharmaceutical composition as defined in any preceding claim.

21. A dosage form according to claim 20 suitable for topical administration or administration to an external drainage body cavity.

22. A dosage form according to claim 20 suitable for topical administration or administration to the nose, lung, mouth, ear, stomach, rectum or vagina.

23. The dosage form of claim 21 or 22, wherein the composition is filled into standard capsules or mixed with a filler and compressed into tablets.

24. A pharmaceutical composition according to claim 1 or 2 for the preparation of a pharmaceutical dosage form for oral administration to a mammal in need of such treatment, characterized in that said dosage form can be administered at any time of the day independently of the food intake of said mammal.

25. Use of a pharmaceutical composition according to any one of claims 1 to 19 for the preparation of a pharmaceutical dosage form for oral administration to a mammal in need of such treatment, characterized in that said dosage form can be used at any time of the day independently of the food intake of said mammal.

26. A pharmaceutical package suitable for sale on the market comprising a container, a dosage form as claimed in any one of claims 20 to 23, and accompanying said package non-limiting written information on whether said dosage form can be taken with food.

27. A process for preparing a composition according to any one of claims 1 to 19, which process comprises: dissolving a basic pharmaceutical compound, vitamin E TPGS, a physiologically acceptable water soluble acid, and optionally a physiologically acceptable water soluble organic polymer in a solvent; removing the solvent from the resulting solution; optionally shaping the resulting product into a desired shape; and optionally coating the resulting product with a physiologically acceptable coating material, the basic pharmaceutical compound being 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile.

28. The process according to claim 27, wherein the solvent is removed by spray drying.

29. The method according to claim 27, wherein the solvent is removed by freeze drying.

30. The method according to claim 27, wherein the solvent is a supercritical fluid.

31. A method according to claim 30, wherein the supercritical fluid is removed by depressurisation.

32. A method according to claim 30 or 31, wherein the supercritical fluid technique is RESS (rapid expansion of supercritical solution) or PGSS (precipitation of gas saturated solution).

33. A method according to claim 27 wherein a supercritical fluid is added in addition to the solvent.

34. The method according to claim 33, wherein the supercritical fluid technology is GAS (GAS anti-solvent crystallization), SEDS (supercritical fluid enhanced solution dispersion), ASES (aerosol solvent extraction system), SAS (supercritical anti-solvent method), or PCA (anti-solvent compression precipitation method).

35. A process according to claim 27, wherein the solution is coated, sprayed or granulated on a suitable carrier, followed by evaporation of the solvent.

36. The process according to claim 35, wherein the solution is granulated on a suitable carrier and the solvent is evaporated.

37. A method according to claim 35 or 36, wherein the solvent is evaporated by drying at elevated temperature and/or drying under vacuum or application of microwaves.

38. The process according to claim 35 or 36, wherein the carrier is microcrystalline cellulose, pyrogenic SiO₂Or an inert core.

39. The process according to claim 38, wherein the support is pyrogenic SiO₂。

40. The process according to claim 35, wherein the process is carried out in a high shear granulator.

41. The process according to claim 27, wherein the process is carried out in an extruder.

42. A process according to claim 41, wherein a solution of the components of the composition is granulated on a suitable carrier and the moistened powder is pressed.

43. A process for the preparation of a composition according to any one of claims 1 to 19, which process comprises co-melting a basic pharmaceutical compound, vitamin E TPGS, a physiologically acceptable water-soluble acid and optionally a physiologically acceptable water-soluble organic polymer; optionally shaping the resulting product into a desired shape; and optionally coating the resulting product with a physiologically acceptable coating material, the basic pharmaceutical compound being 4- [ [4- [ [4- (2-cyanoethenyl) -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile.

44. The method of claim 43, wherein the eutectic operation is performed with a melt extruder.

45. A process according to claim 43 wherein the melt is granulated, sprayed or coated on a suitable carrier.

46. A process according to claim 45, wherein the melt is granulated on a suitable carrier.

47. A process according to claim 45 or 46, wherein the carrier is microcrystalline cellulose, pyrogenic SiO₂Or an inert core.

48. The process according to claim 47, wherein the support is pyrogenic SiO₂。

49. A process according to claim 45 wherein the process is carried out in a high shear granulator.