JPH05506857A - Styryl-Substituted Monocyclic and Bicyclic Heteroaryl Compounds that Inhibit EGF Receptor Tyrosine Kinase - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Styryl-substituted monocyclic and bicyclic compounds that inhibit EGF receptor thyronone kinase heteroaryl compound field of invention FIELD OF THE INVENTION This invention relates to the inhibition of cell proliferation. More specifically, the present invention provides useful Styryl, including compounds that are inhibitors of lotine tyrosine kinase (PTK) - Use of substituted monocyclic and bicyclic heteroaryl compounds in inhibiting cell proliferation It is related to.

Normal cell regeneration requires the cell matrix to be converted into one or more growth factors, such as insulin, insulin, etc. Exposure to epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) It is believed that this is initiated by Such growth factors are typically Corresponding growth factor receptors embedded in or penetrating the cell membrane It is specific to the ta. The initiation of cell regeneration begins with a corresponding It is thought to occur when a growth factor binds to a receptor. This growth factor - Receptor binding changes the chemical characteristics of the relevant part of the receptor, molecules present within the cell, and the receptor itself undergoes phosphorylation, which is called autophosphorylation. Functions as an enzyme that catalyzes phorylation or phosphorylation of intracellular substrates. this Examples of such phosphorylating enzymes include phosphorylating enzymes that convert tyrosine amino acid residues in substrate proteins into Includes tyrosine kinases that catalyze lylation.

Many disease states are characterized by unchecked cell regeneration. These pathologies vary It is found in many types of cells and is associated with leukemia, cancer, psoriasis, atherosclerosis and reincarnation. Includes speech-related injuries, etc. Inhibition of this tyrosine kinase causes uninhibited cellular regeneration. It is believed to be useful in suppressing cell proliferation-related diseases.

Self-phosphorylation, i.e. phosphorylation of the growth factor receptor itself and intracellular groups Initiation of phosphorylation in the host host is involved in mitogenesis and cell proliferation. It is a biochemical event. Insulin receptor autophosphorylation and other receptor Phosphorylation of substrates by septa is the earliest identifiable biochemical hormonal response. It is.

Insulin receptor and epidermal growth factor (EGF) receptor proteins synkinase (PTK) activity in response to insulin and EGF generation. Loss of cell genetic material by site-directed mutagenesis impairs the biological activity of the receptor. Resulting in complete loss. This is completely undesirable. This is because Insulin is required by the body to perform other biological functions unrelated to cell growth. This is because it is what is required. Therefore, the PTK portion of the insulin receptor inhibiting the PTK portion of the εGF receptor at a concentration less than the concentration required to inhibit compounds that provide valuable agents for the selective treatment of cell proliferation-related diseases. Can be done.

reported facts U.S. Patent No. 4.678.793 and U.S. Pat. No. 4.826.984 are Styryl 4,4-dimethyl (dimethyl) as an active agent for the treatment of acne, etc. Cyclic heteroaryl) compounds are disclosed. Also, U.S. Patent No. 4 ．． 769.384 as an active agent for treating ulcers of the stomach and duodenum. discloses a pharmacological composition containing a styrylbenzimidazole compound of .

The most potent inhibitor of EGF receptor is EGF-induced in A431/clone 15 cells. inhibits developmental proliferation, but inhibits such cells when induced by other growth factors. have been reported to have little or no effect on the proliferation of. Also, Elle Bustin (erbstatin) is the EGF receptor in the membrane of A431 cells. inhibits self-phosphorylation of Low concentrations of erbstatin stimulate the EGF receptor. Although required for inhibition of autophosphorylation, higher concentrations of erbstatin Adenosine 3", 5'~monophosphate) (CAIIIP)-dependent protein required to inhibit inkinase.

Summary of the invention According to the present invention, a method for inhibiting cell proliferation in patients suffering from disorders such as those described above is provided. and the method provides for administering to the patient a protein tyrosine kinase inhibitory activity. administering a lyl-substituted heteroaryl compound, wherein the A heteroaryl group is a monocyclic ring having 1 or 2 heteroatoms or from 1 to about Bicyclic ring with 4 heteroatoms, the compound may optionally be mono- or may be poly-substituted, provided that if the ring is poly-substituted, the substitution provided that the groups have no common point of bond with the ring.

According to another aspect, the invention relates to novel compounds of the above type, the t \The substituents on the teroaryl group are not carboxyne or ester groups.

According to yet another aspect, the present invention provides a pharmacological agent in a mixture with a pharmaceutically acceptable carrier. The present invention relates to pharmaceutical compositions containing a clinically effective amount of a novel compound of the above type.

In connection with methodological aspects of the invention, compounds of formula I or pharmaceutically acceptable The above-mentioned styryl-substituted salts used in the practice of this invention Aki which constitutes a group of heteroaryl compounds Here, R3 is alkyl, -Hl-CN, -OH, -COOR, -CONRR or -C3NRR; R represents alkyl, -H or aralkyl; R1 has 1 or 2 N, O or S atoms or 1 or 2 N-oxide groups about 5 to about 7 membered monocyclic aryl ring containing, or 1 to about 4 N, O or or about 8 to about 12 membered 2-rings containing S atoms or 1 to about 4 N-oxide groups represents an aryl ring of the formula aryl ring, which ring is optionally substituted with 1 to about 3 groups R, and the substituents R, have no common point of attachment to the ring; R8 is Alkyl, -Hl-CN, -OH, -COOR, -CONRRl-C3NRR or -CH, CN, and R1, R3, R6, R7 and h are each independently Alkyl, -Hl-CN, halo, -OR, -C)10, -COOH, -NTken or its N-oxide group, -NOl, -NHCOCIl, -3R, -CF2 , -CH=CHC00H1-NHCO(CHt)xcOOH, morpholino or Represents a heteroaryl group: each R, independently represents alkyl, -CN, halo, -OR, - CH02-C0OH, -NR or its N-oxide group, -NO2, ~NHCO CI(,,-3R,-CF,,-CH=CHC00H1-NHCO(CHz)t cOOH, morpholino, heteroaryl group, or R8 and R7 are - together. -CH, CHt-1-C) I2C) ItCH2- or the group -C starting from R3 ON) can represent I-.

The invention also provides novel compounds within the scope of the compounds and pharmaceutical compositions of the invention. The compound is represented by the above general formula r, where Rt is alkyl, -CN, -COOR , -CONRR or -CNRR: R is alkyl, -H or aralkyl R2 represents an about 5 to about 7 membered atom containing 1 or 2 N, 0 or S atoms. a monocyclic aryl ring, or about a monocyclic aryl ring containing from 1 to about 4 N, 0 or S atoms. Represents an 8- to about 12-membered bicyclic aryl ring, optionally containing 1 to about 3 members. may be substituted with a group R, and the substituent R9 is a common bond to the ring. No point; R8 is alkyl, -H, -COOR, -CONRRl-CSNRR or -CHtCN, where R4 and are each independently alkyl, -Hl-CN , halo, -OR, -CHOl-COOH, -NRRl-NO7, -NHCOC )1. , -SR, -CF,, -CH=CHC00H1-N)ICO(CHt)t cOOH represents a morpholino or heteroaryl group: R5, R7 and rJR8 each independently dialkyl, -Hl-CN, -OR, -C)10, -COOH, -N) ICOCH, -3R, -CF2. -CH=CHC001(,-N)IC O(CH,)tcOOH, represents a morpholino or heteroaryl group, provided that R4, A small number of R5, R6, R2 and or R6 cannot be -OR if R7 or R1 is -OR; each R3 are independently alkyl, -CN, halo, -OR, -CI(0, -NRRl-NO2 , -NHCOCHs, -5R, -CF,, -C) I=CHC00H1-NHCO (C)! 2) Represents 2COOH, morpholino, heteroaryl group, or R8 and R 2 means - together with -CH, CH2-1-CH2CHtCH, - or starting from R1 represents a group -CONH-.

Compounds within the scope of the invention are substrates of the tyrosine kinase domain of the EGF receptor. It also shows specific affinity for PDGF receptor kinase. inhibits the EGF receptor kinase and also inhibits the EGF receptor kinase. Effectively inhibits GF-dependent autophosphorylation.

Detailed description of the invention As used above and throughout this disclosure, the following terms refer to should be understood to have the following meanings:

"Alkyl" means a saturated aliphatic hydrocarbon having about 1 to about 6 carbons. It can be straight chain or branched containing atoms.

"Lower alkyl" means a group as defined above having from 1 to about 4 carbon atoms, directly Can be chained or branched, e.g. methyl, ethyl, propyl, isopropyl, butyl It can be ethyl, isobutyl, 5ec-butyl or tert-butyl.

"Alkoxy" means an alkyl-oxy group, and this "alkyl" is defined as It's like that. A lower alkoxy group is preferred. Examples are methoxy, ethoxy , n-propoxy, 1-propoxy and n-butoxy.

"Aryl" means an unsaturated or partially unsaturated ring system, with preferred aryl Ryl groups are pyridyl and indolyl.

“Acyl” is an organic acid derived from an organic acid or carboxylic acid by removing its acidic hydroxyl group. A preferred acyl group is a lower alkyl carboxylic acid group, e.g. Examples are acetyl and propionyl groups. Also preferred is a benzoyl group.

"Halo J means halogen. Preferred halogens are chlorine, bromine and fluorine. It is.

Preferred aralkyl groups are benzyl and phenethyl groups.

Therapeutically useful PTK-inhibiting compounds include EGF-recebuta tyrosine kinase (EGF RK) but not adenosine triphosphate (ATP). It is considered.

The ATP-competing PTK-inhibitors quercetin and genistein tein) inhibits other protein kinases and is highly cytotoxic as a result. It is. As a test of selectivity, insulin receptor kinase (IRK) and and/or inhibits EGFRK better than it inhibits PDGF receptor kinase. Compounds that do this are extremely valuable.

The solubility of the compounds of the invention in both water and mildly hydrophobic solvents is It is theorized that this would increase the probability of permeation through the cell membrane. However, various defects The soluble compound showed significant EGFRK inhibitory activity in the inhydrotest.

Further preferred compounds useful in the practice of this invention are those of formula I above. includes. Here, R1 is -CN, -COOR, -COOH or -C3N RR represents lower alkyl, -H or aralkyl, R2 is 1 or a 6-membered monocyclic aryl ring containing two N, O or S atoms, or 9- or 10-membered bicyclic aryl group containing 1 to 4 N, 0 or S atoms represents a ring which is optionally substituted with 1 to about 3 groups R1 , the substituent R9 has no common point of attachment to the ring, and R3 is -H: R4, R6, R6, R and each independently represent lower argyl, -H1 lower argyl; Represents lucoquine or 10H, provided that the least of R4, R3, R,, Rt and R6 Both of them are not -H, and R4, R3, or R6 is a lower atom of R7 or R8. When it is alkoxy, it can be a lower alkoxy, and R4 and h are independent may be halo, and each R9 independently represents lower alkyl, halo, lower alkoxy, -OH or 0” or a pharmaceutically acceptable salt thereof.

More preferred compounds for use in the practice of this invention have the following formulas II and III: Includes those represented by or pharmaceutically acceptable salts thereof: 8 Here, R1, R4, R3, R6, R7, R8 and Pan are as described just before this. and RIG represents -H, alkyl, aralkyl, or a group represented by the following formula: .

Even more preferred compounds are those of the above formulas II and III, where Rt is -CN; -COOR or -CONRR: R1, R8, R6, R7 and U'R, Each independently represents lower alkyl, -H1 lower alkokene or -DH, with the proviso that R4 , R3, R6, R1 and section are not -H, and R9, R3 or Ro is lower alkoxy when R7 or R8 is lower alkoxy. cannot exist, and R4 and H2 may independently be halo (:R is lower alkyl Or, it is a compound representing -H and having no substituent R.

The most preferred compound is the above formula II, in which R1 is -CN, and R3, R1 Oo masu.

each independently represents -H, and R1 and R6 each independently represent alkyl, halo, - It is a compound representing OR or -CF.

Compounds of the invention are useful as free bases, salts and hydrates. all of these Any shape is within the scope of the invention. Acid addition salts can be formed, but are simply the most convenient It is only an advantageous form of use, and in reality, the use of the salt form is ultimately inferior to the use of the base form. Equals use. Acids that can be used to prepare acid addition salts preferably include the free base and A pharmaceutically acceptable salt when combined, i.e. an anion, is the pharmaceutical dosage of the salt. is harmless to animal organs and as a result the inherent advantageous properties of the free base are Includes those that form salts that are not impaired by side effects attributed to anions. do. Although pharmaceutically acceptable salts of the basic compound are preferred, certain salts themselves may Even if the salt is desired only as a product, e.g. for purposes of purification and identification. or if the salt is formed only by ion-exchange techniques, the salt is pharmaceutically acceptable. as a source of the free base form when used as an intermediate in the preparation of salts. Any acid addition salt is useful.

Pharmaceutically acceptable salts within the scope of this invention include the following acids, such as hydrochloric acid, sulfuric acid, phosphoric acid. and inorganic acids such as sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malon acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene Derived from organic acids such as sulfonic acid, cyclohexylsulfamic acid, and quinic acid Includes salt.

Corresponding acid addition salts are hydrochloride, sulfate, phosphate, and sulfamate, respectively. , acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate salt, benzenesulfonate, p-toluenesulfonate, soclohexyl Contains rufumate and quinate.

Acid addition salts of the compounds of this invention can be prepared by converting the free base into an aqueous or aqueous solution containing a suitable acid. alcohol solution or other suitable solvent and then evaporate the solvent. or by reacting the free base with an acid in an organic solvent. It can be prepared by In the latter case, the salt can be separated directly or The salt can be obtained by concentrating the solution.

Compounds useful in the pharmaceutical compositions and method aspects of the invention can be prepared using known methods, e.g. Nebenagel shrinkage as described, for example, in U.S. Pat. No. 3,149,148. It can be prepared by a synthesis reaction.

The compounds of the present invention can be prepared using ammonia or parrot, -CH, -R, Knebenagel of substituted benzaldehydes with active methylene compounds of The product of the invention is obtained by coagulation. If substitution of the group R1 is desired, the corresponding using a ketone starting material. The reaction temperature and reaction temperature are within the range of 25°C to reflux temperature. The reaction time varies depending on the materials used in the condensation.

The compounds of the present invention are commercially available, known in the literature, or known in the literature. It can be manufactured by the following method. For example, U.S. Patent No. 4.600.71.2 provides formula I above. , R1 is a cyano group, R7 is pyridyl, R3 and Discloses a fungicide in which 8 is chlor. U.S. Patent No. 3.337.565 and No. 3.337.568, in the above formula (■), even if ifR is a cyano group or or a hydroxyl group, R2 is pyridyl, and R2 is a hydroxyl group. discloses compounds that inhibit the metabolism of certain carbohydrates. U.S. Patent No. 3.196 ．． No. 1.58 is the above formula (2), even if l'iR+ is a cyano group and R2 is a pi Discloses an adrenocortical inhibitor which is lysyl and R1 or R is 71. Ru. U.S. Patent No. 3.157.663 discloses that in the above formula and R2 is pyridyl and R6, R1 or R1 is an amino or nitro group. Discloses an adrenocortical inhibitor. Buu-Hoi etc. are J, CheIIl, Soc, (C), 1969゜1) 11.2069-70 1. Conversion of 2-noarylacrylonitrile to 3-arylcoumarins (wherein the 2-aryl group has an alkoxy substituent).

The above publications disclose several compounds of the type that can be used in the methodological aspects of the invention. The use of such compounds for cell proliferation purposes is completely prohibited. Not fully disclosed.

Various substituents on the phenyl and heterocyclic rings or chains of the compound of general formula (III) R, R, , R, R4, R3, R8 and above can be present in the starting compound, or After the formation of the condensation product, a public It can be added using knowledgeable methods. When the substituent itself is reactive, the substituent itself is reactive. The body can be protected according to techniques known in the art. Various protecting groups known in the art can be used. Can be used.

Many examples of these possible groups can be found in T., W. Green, "In Organic Synthesis". Protective Groups in Organic 5ynthesis) J = 198L Found at John Wiley & Sons be able to. For example, adding a nitro group to an aromatic ring by nitration, Converting the tro group to another group, e.g. by reduction to an amino group, and converting the amino group to a diamino group. It can be converted to 71 ports by zoization and substitution of the diazo group. Friedel-Crauff Acylation allows substitution of an acyl group onto an aryl group. The acyl group is then can be addressed by various methods including Lefou-Kishner reduction and Talemensen reduction. can be converted into an alkyl group. Alkylation of amino groups to form mono- and di-alkylated kylamino groups can be formed, and mercapto and hydroxyl groups can be alkylated to It can form an ether. The primary alcohol is oxidized with an oxidizing agent known in the art. can form carboxylic acids or aldehydes. It also oxidizes secondary alcohols. can form ketones. In addition, the tertiary amino group can be treated with a known oxidizing agent, such as water peroxide. can be converted to the corresponding N-oxide with hydrogen and peracid. In this way, place Use conversion or exchange reactions to convert entire molecules of starting materials, intermediates, or final products. Various substituents can be provided.

Compounds within the scope of the invention have significant activity as protein tyrosine kinase inhibitors. In connection with the treatment of sclerosis, some people may, for example, consider genetic, environmental or medical history factors. It may be considered that there is a high risk for this reason. Compounds within the scope of the invention 1 to prevent or delay the occurrence or recurrence of a condition, or to Can be used to treat.

The compounds of the present invention can be administered in a variety of ways that are compatible with the selected route of administration, i.e., oral or parenteral administration. It can be administered to mammalian hosts in the form of Parenteral administration here refers to intravenous, intramuscular , subcutaneous, intraocular, intrasynovial, transcutaneous, intraocular, sublingual, and buccal administration, etc. It also includes topical administration meridians such as inhalation and aerosol to the eyes, skin debris, and eyes. bulbar, rectal and nasal inhalation and rectal systemic route )including.

The active compound may be present, for example, with an inert diluent or with an assimilable edible carrier. Both can be administered orally or enclosed in hard or soft shell gelatin capsules. Alternatively, it can be compressed into tablets or even incorporated directly into a therapeutic diet. Oral therapeutic dosage For administration, the active compound may be formulated with excipients to form orally ingestible tablets, buccal tablets, etc. As tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Can be used. Such compositions or preparations contain at least 0.1% of active compound. should be The proportions of active ingredients in the compositions and formulations can vary and may Advantageously, it may range from about 2 to about 6 times the weight of the dosage unit. Such therapeutic The amount of active ingredient in useful compositions is such that a suitable dosage will be obtained. present invention Preferred compositions or formulations include oral dosage units containing about 1 to io00 m of active compound. It is prepared so that the content is within the range of g.

The tablets, troches, pills, capsules, etc. may also contain the following ingredients: . i.e. binders such as gum tragacanth, acacia, cornstarch or Gelatin, excipients such as dicalcium phosphate; disintegrants such as corn starch Potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and Sweeteners such as sucrose, lactose or saccharin can be added and Flavoring agents such as peppermint oil of wintergreen or cherry flavor may be added.

When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. I can do it. Various other materials may act as coatings or otherwise modify the physical form of the dosage unit. It can exist to improve. For example, tablets, pills or capsules may contain shellac, sugar Alternatively, it can be coated with both of these. syrups or elixirs are Active compounds, sucrose as sweetener, methyl and propyl as preservatives Contains parabens, dyes and fragrances, such as cherry or orange flavor can. Of course, any materials used in the preparation of any dosage unit form are should be pharmaceutically pure and substantially non-toxic in the amounts used. Furthermore, the activity The sex compounds can be formulated into sustained release formulations and formulations.

The active compounds can also be administered parenterally or intraperitoneally. Free base also prepares a solution of the active compound as a pharmaceutically acceptable salt in hydroxypropylcell. It can be prepared as an aqueous solution mixed appropriately with a surfactant such as loin. glycerol , liquid polyethylene glycol, mixtures thereof, and dispersants dispersed in the composition were also prepared. can. Under normal conditions of storage and use, these preparations inhibit the growth of microorganisms. Contains preservatives to prevent

Dosage forms suitable for injectable use are sterile aqueous solutions or dispersions, or sterile injectable solutions or Includes sterile powders for extemporaneous preparation of dispersions. In all these cases The dosage form should be sterile and fluid to the extent that easy syringability exists. Should. It must be stable under the manufacturing and storage conditions and must be stable under the conditions of manufacture and storage. must be preserved against the contaminating action of microorganisms such as bacteria and fungi. carrier For example, water, ethanol, polyols (e.g. glycerol, propylene) liquid polyethylene glycol, etc.), suitable mixtures thereof, and It may be a solvent or dispersion medium containing oil or the like. Appropriate fluidity is determined by e.g. In the case of dispersants, maintaining a specified particle size, and using surfactants. It can be maintained depending on the purpose. Suppression of microbial action is achieved using various antibacterial agents and antifungal agents. Fungicides such as parabens, chlorobutanol, phenol, sorbic acid 1. Chime This can be achieved by Rosal et al. In many cases, isotonic agents such as sugars or salts Preferably, it contains sodium chloride. The long-term absorption of injectable compositions is Obtained by the use of retarders such as aluminum monostearate and gelatin be able to.

Sterile injectable solutions contain a predetermined amount of the active compounds along with various other ingredients enumerated above. Both are prepared by blending in a suitable solvent and then sterilizing by filtration. . Generally, dispersants involve incorporating the various sterile active ingredients into a sterile vehicle. The vehicle is prepared by a basic dispersion medium and an appropriate selection from those listed above. Contains other necessary ingredients. For sterile powders for the preparation of sterile injectable solutions, preferred The preparation method is vacuum drying and freeze-drying, and the method uses pre-sterilized and filtered solutions. provides a powder of the active ingredient and any additional prescribed ingredients.

The therapeutic compounds of this invention, alone or in combination with pharmaceutically acceptable carriers such as those described above, administered to mammals in parallel. The compounding ratio of the compound depends on its solubility and chemical properties. determined by the quality, route of administration chosen and standard pharmaceutical practice.

The dose of the therapeutic agent of the present invention that is most suitable for prevention or treatment depends on the mode of administration, the selected will vary depending on the particular compound and the physiological characteristics of the particular patient being treated. . In general, use lower doses initially and, if necessary, to optimize efficacy under the circumstances. Gradually increase in small amounts until . According to physiological studies using rats, humans The therapeutic dose of phthalate is generally about 0.01 to about 100 μg/kg per day (body weight). weight) or about 0.4 to about IOg or/and more, but per day It may also be administered as a unit of one to several different doses. Oral administration is higher Requires higher doses and is thought to correlate with therapeutic activity in other animals Also includes pharmacological testing procedures. In Examples 1-13 below, compounds within the scope of the invention exemplify something. In Examples IA and IB, R1 is a cyano group and R2 is a pyridyl group. and R4 and 'cFR6 are chloro. In Example 2 , prepare the N-oxide of the compound of Example IA. In Example 3, R1 is shear , R7 is a pyridyl group, and R2 and R3 are methoxy groups. Illustrate. In Example 4, Rt is a cyano group, R7 is a pyridyl group, and R4 and Examples of compounds in which the group and the group are t-butyl groups are shown below. In Example 5, R is a cyano group The following is an example of a compound in which R7 is an indolyl group, and R1 and R1 are a methoxy group. do. In Example 6, R is a cyano group, R2 is an indolyl group, R4 and is a methoxy group and R1 is a 4-nitrophenylsulfonyl group as an example. Show. In Example 7, R1 is a cyano group, R7 is a pyridyl group, and R4 and and R5 are methoxy groups. In Example 8, R is a cyano group , Rt is a pyridyl group, and R4 and h are methoxy groups. In Example 8, R is a cyano group, R7 is a pyridyl group, and R1 and L are t-butyl groups. Ru. In Example IO, R4 is a cyano group, R7 is a pyrinol group, and R4 and The above is a trifluoromethyl group. In Example II, R1 is a cyano group, R2 is a pyrinol group, and R1 and R8 are metquin groups. Example 12 to 5 , R1 is a cyano group, R2 is an indolyl group, and R1 and R6 are trifluoro. It is a lomethyl group. In Example 13, R1 is a cyano group and R2 is indolyl group, and R4 and 9 are t-butyl groups. Example I4 is within the scope of the invention. 1 is an illustration of various compounds.

400g (2,3M) of 3,5-dichlorobenzaldehyde was added to 11.4A of free 283.5g (2.4M) of 3-pyrinolacetic acid was added to a solution dissolved in water and ethanol. tonitrile and 720.9 g of CO.

was added. A solid precipitate formed 2 minutes after the addition of K, CO,. This reaction mixture The mixture was stirred for about 2.5 hours. Add water (22,91) to this stirred reaction mixture did. After stirring for 1 hour, the mixture was filtered and the resulting filter cake was dissolved in water ( 1, washed with Ojl, dried and recrystallized from isopropanol. 534g Trans-2-(3 -pyridyl)-3-(3,5-dichlorophenyl)-2-propenenitrile Ta.

3,0g (17,1m) of 3,5-dichlorobenzaldehyde was added to 200ml of Add 1.83 ml (17,111'l+) to the solution dissolved in absolute ethanol and stirred. To 3-pyridylacetonitrile and 1 equivalent (2.38 g) of CO, was added did. The reaction flask is equipped with a reflux condenser and the stirred reaction mixture The material was refluxed for 2 hours, filtered, and concentrated. The generated residue was analyzed on silica gel. Purified by flash chromatography, eluting with 4:l hexane/ethyl acetate. cis- and trans-2-(3-pyridyl)-3 (3°5-dichloro A mixture of (lophenyl)-2-propenenitrile was obtained.

Example 2 trans-2-(3-pyridyl)-3-<3.5-dichlorophenyl )-2-propenenitrile N-oxide The compound prepared in Example IA (1.0 g; 3.6 mM) was added to 30 ml of CH,C m-chloroperbenzoic acid (m-CPB) dissolved in a stirred, water-cooled solution. A solution of (0.63 g; 3.6 tm) dissolved in 20 ml of C) I, C12 was dripped. After stirring for about 1 hour, a white solid precipitated from the reaction solution. This anti The reaction mixture was stirred overnight and then an additional 1 equivalent of m-CPBA (0.63 g) was added. added. The reaction mixture was stirred for several hours, filtered and the resulting filter cake was Washed with H, C12. The combined CH,Cl2 solution was diluted twice with 10% NaHCO, Wash with solution, dry Mg5O,) and concentrate under vacuum to give m, p, 252 Obtained 0.8 g (75%) of the title compound as a white solid at °C (decomposed).

2,0g (12,0d) of 3,4-dimethoxybenzaldehyde was added to 75ml of 1. Dissolved in absolute ethanol and stirred the solution. , 2 of 56g (13.3m) - Add pyridylacetonitrile and 12 drops of piperidine. This anti-2Fla Sco is equipped with a condenser and drying tube (using anhydrous Ca5Os). The reaction system is stirred and heated. After refluxing for 6 hours, the reaction system was cooled to room temperature. , - Stir overnight (16 hours). Remove the solvent on a rotary evaporator, The resulting residue is purified by flash chromatography on silica gel. . For elution use 4·1 hexane/ethyl acetate. The resulting yellow solid is aceto Recrystallization from hexane gives 2-(2-pyrinol) with a melting point of 11.2-114°C. )-3-(3,4-dimethoxyphenyl)-2-propenenitrile is obtained.

75 m 1.1.9g (10.1mM ) of 2-pyridylacetonitrile and 12 drops of piperidine. This anti The reaction flask is equipped with a condenser and a drying tube (using anhydrous Ca5Oa). Then, the reaction system is stirred and heated. After refluxing for 8 hours, the inverse 2 system was allowed to reach room temperature. Cool and stir overnight (16 hours). Remove the solvent using a rotary evaporator. The resulting residue was purified by flash chromatography on silica gel. make 98:2 hexane/ethyl acetate is used for elution. Colorless solid obtained was washed with cold ether-hexane to give 2-(2-pyridyl), mp 90-93°C. -3-(3,5-di-t-butylphenyl)-2-propenenitrile is obtained.

2.0g (12.0 bacteria) 3.4-dimethoxybenzaldehyde was added to 75ml of free 2.07g (13.3mM) of 3- indolyl acetonitrile and 1°83 g (13,3 d) of anhydrous potassium carbonate Add rum. This reaction flask has a condenser and a drying tube (anhydrous Ca5 The reaction system is stirred and heated. Refluxed for 24 hours Thereafter, the reaction system is cooled to room temperature. The reaction mixture was filtered to remove the salts and filtered. -Remove the solvent using a tally evaporator. The resulting residue was evaporated onto silica gel. Purify by flash chromatography. Total of 1 hexane/ethyl acetate for elution use. When the resulting yellow solid is recrystallized from acetone-hexane, the melting point 1.39-141”C 2-(3-indolyl)-3-(3,4-dimethoxy Phenyl)-2-propenenitrile is obtained.

The following compounds can be prepared following the procedures of Examples 3-5.

Example 6 2-[1-(4-nitrophenylsulfonyl)indol-3-yl]-3-( 3,4-dimethoxyphenyl)-2-propenenitrile m, p, 204-2 06℃ Example 7 2-(3-pyridyl)-3-(3,4-dimethoxyphenyl)-2-propenyl Trill m, p, 112-115℃ Example 8 2-(3-pyridyl)-3-(3,5-dimethoxyphenyl)-2-propenyl Trill: m, p, 1.03-105℃ Example 9 2-(4-pyridyl)-3-(3,5-di-t-butylphenyl-2-prope Nitrile tn, p, 105-107℃ Example 10 2-(2-pyrinol)-3-[3,5-bis(trifluoromethyl)phenyl] -2-propenenitrile/ILp, 101-103°C Example 11 2-(4-pyridyl)-3-(3,5-dimethoxyphenyl)-2-propenyl Trill: m, p, +35-137℃ Example I2 2-(3-indolyl)-3-[3,5-bis(trifluoromethyl)phenyl ]-2-Propenenitrile m, p, 222-223°C Example 13 2-(3-indolyl)-3-(3,5-di-t-butylphenyl)-2-pro Pennitrile: m, I), 134-136°C Example 14 3.4 of Example 3 ~ Dimethoxybenzaldehyde was replaced with the compound in Table 1 below. and replacing 2-pyridylacetonitrile with the compounds in Table 2 below: The corresponding product is obtained.

Table 1 Table 2 3,4.5-trimethoxybenzaldehyde 2-pyridylacetamide 4-meth Toxybenzaldehyde 2-pyridylacetic acid 3-methoxybenzaldehyde methyl 2-pyridyl acetate 3.4-dihydroxybenzaldehyde 3-pyridyl acetate Cetamide 3.4-Dimethylbenzaldehyde Methyl 3-bilidyl acetate 4- Acetylaminobenzaldehyde 4-pyridylacetamide 4-methylthiobenza rudehyde methyl 4-pyridyl acetate 3-chloropenzaldehyde 6-methy -2-pyridylacetonitrile 4-chloropenzaldehyde 4-methyl-2- Pyridylacetonitrile 3-fluorobenzaldehyde 6-chloro-2-pyridi Acetonitrile 4-fluorohensaldehyde 4=carboethoxy-2-pyri Nolaceto 3-nitrohensaldehyde nitrile 4-Nitropenzaldehyde 2-chenylacetonitrile 4-morpholinobenza Rudehyde 2-imidazolylacetonitrile 4-carpoetquin henzaldehyde 2-quinolyl acetonitrile 3-carpoetquin benzaldehyde 3-furyl Acetonitrile 2,4-difluorobensaldehyde 3-(2H-chromene)i Ruace[・nitrile 2,4-dimethquine henzaldehyde methyl 2-pyrimidine Acetate 3.5-t-butylbenzaldehyde 3-tmethylaminopyri 3.4-dimethoxybenzaldehyde 3-(2H-pyranyl)acetonitrile 3.5-noprobylbenzaldehyde 2-pyridylacetonitrile 3.4-n Brobylbenzaldehyde 3-pyridylacetonitrile 2,5-nomethylbenza Rudehyde 4-pyridylacetonitrile 2.5-dimethoxybenzaldehyde 3 -Indolylacetonitrile 3-trifluoromethylbenzaldehyde 2-ben Zothiazolylacetonitrile 3,5-ditrifluoromethylben 1-isoquino Lylacetonitrile saldehyde 3-benzothiazinyl acetonitrile 3-ri0 rho 5-methoxybenzaldehyde 2-chloro-4-methoxybenzaldehyde 3- Chloro-4-methoxybenzaldehyde 3,5-dichloroacetophenone 2.4-dichloroacetophenone 3.4-dichloroacetophenone Compounds of the present invention are subjected to various biological tests, and the results are not useful. Correlates with reproductive activity. These tests test the EGF receptor of the compounds described herein. Ptakinase, PDGF receptor kinase and insulin receptor kinase Useful for determining inhibitory activity.

Purification of EGF-receptor A method for purifying EGF-receptors was described by Yarden and Nyurennnnoya. and Schlessinger). 8 A431 cells Grow in 0cm'' confluent culture bottles (2 x 107 cells/bottle). Washed twice with PBS, 1. , harvested in PBS containing 1I EDTA (37° C for 1 hour) and centrifuged at 600 g for 10 minutes. 2x10' 1 tnl of cold solubilized Banff Y-(50 cSt Hepes) buffer per cell. 7, I) l(7,6; 1%h Triton X-100; 150nllllNaC1; 5mtil EGTA: 1 incense fil PMS F; 50gg/ml Aprotinin: 25 ts Benzamidine: 5gg/ml Leupepti solubilized for 20 minutes at 4°C in do. After centrifugation at 100,000 g for 30 minutes, the supernatant was transferred to IEJA-agarose. onto a column (filled with 100 μl of resin per 2 x 10’ cells) and heated to 4°C. Shake for 2 hours. Unabsorbed substances were removed and the resin was washed with HTN buffer (50r rM Hepes, pH 7,6; 0.1% Triton X-100; 150011 114 NaCl) twice and I containing 1 M NaCl (2× in TN buffer). TNG buffer (50-Hebes, pH 7,6; 0.1% Tri x-100; 150mM NaCl and 10% glycerol) twice Wash. This EGF-receptor was mixed with 0.5M N-acetyl-D- HTNG bag containing glucose amine (200 μI per 2X10' cells) Elute with fur. The eluted material was stored in aliquots at -70°C and used. TMrNG buffer (50mM Tris-Mes buffer y, p) before I7.6; 0.1% Triton X-1oo; 15001M NaCl and dilute with 10% glycerol).

EGFR kinase-catalyzed phosphorylation of poly(GAT) and its inhibition W GA-purified EGFR (0.25 μg/assay) was incubated at 4°C for 20 min at 5°C. EGF ([1,85 gM ) to pre-activate. This assay consists of Mg(Ac)t(60 reagents), [γ-”P] ATP (125gM, 2-5μCi/assay), poly(GATXo, 06 25■/m170, 125 mg/ml, 0.25 mg/ml) and 6 Begin by adding a mixture containing a seed concentration (two cases each) of inhibitor. This assay 1 degree is 22°C, and the formation of phosphorylated copolymer is linear up to 20 minutes. I understand that there is something. The final concentration of PTK inhibitors tested was in water or ethanol. is dissolved in a mixture of ethanol and water not exceeding 4% during the assay. 4xma The presence of ethanol in the assay has no effect on EGFR kinase activity. Don't lose it. The concentration of EGF in the assay was 300 nM in a final volume of 4 μl. Ru. 5. After IO or 20 minutes, cut 25 μm aliquots into 3-on fibers. applied to Tutman filter paper and then a cold 1. Soak in OXTcA. - After washing at 4°C overnight, dry the cut filter paper and p Cerenkov radiation if! 11. Ru. The poly(GAT) dependence of the concentration is Michaelian. Calculated per unit of GIuaAIasTyr (GAT): 0,076 +0.007mg/ml or 0.069±0.0070Xvte. Poly (G AT) Graphically depicts this EGF response to phosphorylation. For this assay The Km for ATP was found to be 2.9 μM.

Time dependence of autophosphorylation of EGF-receptor from A431 cells Purified EGF-Recebu 9 (0.5 μg/7 assays) was incubated at 4°C for 20 minutes. Activate with F (800 nM). This reaction is &(g(Ac)*(60ran),T ris-Mes buffer.

pH7,6 (50rrM) and [”PIATP (20uM: 5μCi/hot The process is initiated by the addition of This reaction was carried out at 4°C or 15°C and Sodium silsulfate (SDS) sample buffer (10% glycerol, 50% ris, pH 6, 8, 5% β-mercaptoethanol and 3X 5DS) Stop by addition. These samples were run on an 8%-3OS polyacrylamide gel (S DS-PAGEX 30% acrylamide and 0,8% bis(acrylamide) prepared from 0.375M (1DTris, pH 8.8, O, IS SDS , 0.05% (7) TEMED 0.461) Contains ammonium persulfate ). Dry this gel and perform autoradiography. Performed using Agfa Curix RP2 X-ray film. Ru. The relevant radioactive band portions are cut out and counted in Cerenkov mode. self The rapid phase of phosphorylation continues the experiment for an additional 10 minutes. First 10 at 15℃ The extent of phosphorylation completed with -s is 1/3 of the total self-phosphorylation signal. This probably reflects phosphorylation of the first site on the receptor. Dew. Therefore, this 10-s r#JI interval is important for performing subsequent self-phosphorylation experiments. selected for.

Self-phosphorylated ATP- and MCF-dependent WGA-purified E from A431 cells GF-receptor (0,5 μg/assay) was incubated with EGF (0,5 μg/assay) for 20 min at 4°C. 85ttM). The reaction was carried out at 15°C and Mg(Ac)t(6 0rrM), Tris-Mes buffer y, pH 7,6 (50 crystal 1), [”P IATP (without carrier, 5 μCi/assay) and increasing concentrations of unreleased The injection is initiated by the addition of JTP. This reaction is completed after 10-s in the SO3 sample buffer. Stop by adding buffer. These samples were mixed with 6% SDS polyacrylamide. Run it on a gel. The gel was dried and subjected to autoradiography as described above. put on. The relevant radioactive band portions are cut out and counted in Cerenkov mode.

It was found that ATP 1 measured in this manner was 7.2 μM.

EGFRK autophosphorylation using a 10-s assay protocol. Measure F concentration dependence.

Rat liver membranes were described by Cuatreeasas. It is prepared from 6-day rat liver. Insulin purified by WGA The receptor is prepared according to the method of Zick et al. Purified with WGA Rat liver 1nsRK (1,25Mg) was added to 330nM insulin. in the presence or absence of 50mM Tris-Mes buffer, 1 pH 7,8 Preincubate for 30 minutes at 22°C. This assay was performed at 22°C. treatment, Mg(Ac)t (60mM), NaVO5 (40uM), [γ-”PIA TP (1,25 MM; 3-5 μCi/assay) and poly(G T) Begin by adding a mixture containing [poly(G1.uJyr)]. inhibition When treating agents, the poly(GT) is always added in an appropriate concentration. This app The final concentration of insulin in the cells is 125 nM. Full details of the assay The product is 40μI. After 20 minutes, a 30-μl aliquot was added to a 3-m Cold 1.00ml solution containing 0.01M sodium persulfate was applied onto filter paper. oXTcA medium Soak in. - After washing at night, dry the filter paper and measure Cerenkov radiation. Counting is performed by In5RK-catalyzed phosphorylation of poly(GT) Caelis follows Menten's kinetics.

Inhibition of EGFR autophosphorylation A431 cells were grown to confluence on human fibronectin-coated tissue culture dishes. .

After two washes with ice-cold PBS, the cells were washed with lysis buffer (50 hebes, pI (7, 5, 150 m1 Nacl 1.5 dl: ~ fgc l 2, l mM EGTA, 10% glycerol, 1% dryide:, /X-1oo,] n14 PMSF, l mg/ml aprotinin, l mg/ml leupepti by adding 500 μl/dish and incubating for 5 minutes at 4°C. Dissolved. After EGF stimulation (500 Mg/lO min at 37°C), immunoprecipitation Tests were performed using anti-EGF-R (Ab108) to autophosphorylate the samples. Reactions (50 μm aliquots, 3 μCi [γ-32P]ATP) in 2 or 1 Run for 2 min at 4°C in the presence of 0 MM of compound. This reaction is carried out by high-temperature electrophoresis. The reaction was stopped by the addition of dynamic sample buffer. 5DS-PAGE analysis (7.5% e ls) and then subjected to autoradiography, and the reaction was recorded on X-ray film. It was quantified by scanning with ``notmet, lj-''. Selective inhibition of compounds of the invention To test for sex, the procedure was changed to include PI) GF stimulation instead of EGF stimulation. Use and repeat. rIcsoJ, as used below, refers to means the concentration of inhibitor (μM) at which the rate of self-phosphorylation is halved compared to the value Ru. Preferably, the value of IC3, for EGF is less than that for PDGF. This indicates the EGF specificity of the inhibitory compound. this test The results are summarized in Table 3 below.

Table 3 Example IC,. (μM) 6 20 > 50 7 0.4 30 The results of this assay indicate that the compounds of the invention inhibit PDGF receptor kinase. It has been shown that EGF receptor kinase is inhibited better than that of EGF receptor kinase.

Inhibition of cell proliferation measured by inhibition of DNA synthesis with human fibronectin (10M (by incubating 70.5 ml/well for 30 minutes at room temperature). 05 ml per well in a coated 24-well Costar dish. Cells were seeded at cell densities. The cells were grown to confluence for 2 days.

D! medium containing 0.5 bovine serum! , grown for 36-48 h in place of lEM, then The cells were treated with PDGF, EGF (Toyobo, New York, NY; 20Mg/ml) or serum (10% bovine serum, Fe2) and various of the inhibitory compound at a concentration of .

[0.5 μC of 3H1 thymidine (NEN, Poston, MA) after 16-24 hours. i/ml and incubated for 2 hours. Remove TCA precipitable substances quantified using a reaction counter). The results of this assay are summarized in Table 4 below. Ta. As used below, rlc50J is defined as [ 3H] refers to the concentration of inhibitor (nM) at which thymidine uptake is halved. Fe2 IC for PDGF, since it contains a wide range of growth factors. The value of is for Fe2 This value should be lower than that of the compound of the present invention as a universal inhibitor. Indicates that it does not work.

2 30±17 100 3 14±IO27+5% @IμM4 9±2500 6 1? 15) f @ l ttM cell culture Cells named HER14 and rA721A (=DK) were cultured with endogenous EGF-cyclase. -1 = pig-deficient NIH 3T3 cells (clone 2.2) (C, fly ring ( Fryling), NC1, obtained from NTH), which lacks tyrosine kinase activity. cDNA construct of new wild-type EGF-receptor or mutant EGF-receptor Here, each Lys721 in the ATP-binding site is an Ala residue. prepared by transfection with (transformed). All cells were 1. DMEM containing 0% bovine serum (Hyclone, Logan, USA) It was grown in the state of Thailand.

The results obtained with the above experimental method demonstrate that the compounds within the scope of the present invention are useful proteins. Demonstrates tyrosine kinase inhibitory properties.

Comparative example The following comparative examples demonstrate the improved cell proliferation of the compounds of the present invention compared to conventional compounds. Explain anti-reproductive properties. Comparative Example C-1 describes the preparation of a prior art compound ( In this compound, R7 is a cyano group, R7 is a pyridyl group, and R5 and chloro are ). The inhibitory activity of the compounds of Examples IA and 2 was compared with the compound prepared in Comparative Example C-1. Compare with the inhibitory activity of the compound.

2.4-dichloropenzaldehyde (5.0 g; 29 mM) and 3-pyridyl acetate Tonitrile (3.05ml; 29mM) in 150ml of absolute ethanol To the dissolved and stirred solution was added 3.95 g of 2COs. Approximately 15 minutes After stirring for a while, a white solid precipitated from the reaction mixture. This reaction mixture was heated overnight. Stir and filter. The resulting filter cake was washed with absolute ethanol and CH2 Dissolved in Cl. The CHtCb solution was filtered and concentrated under vacuum. the resulting white The colored solid was recrystallized from 3-2 hexane/ethyl acetate to yield 6.0 g of the title compound. (76%).

Comparative Example C- The values were compared with those of the prior art compound prepared in 1. This EGFR self-phosphorylation Inhibition was assessed similarly to the procedure described above. The results are reported in Table 5 below.

These results indicate that the compound of Example IA is more potent than the compound of Comparative Example C-1. It has been proven to be an inhibitor of EGF-receptor kinase. This invention For a particular compound (Example IA), the test results indicate that this compound It can be seen that it has better activity than the corresponding N-oxide.

abstract A method of inhibiting cell proliferation in a patient suffering from a cell proliferation-related disorder, the method comprising: Including the use of substituted heteroaryl compounds, the heteroaryl group being I or 2 a monocyclic ring having 1 to about 4 heteroatoms or a dicyclic ring having from 1 to about 4 heteroatoms. is a cyclic ring, and the compound may be optionally mono- or polysubstituted. , provided that when the ring is polysubstituted, the substituent is have nothing in common, one substituent on the heteroaryl group of the compound is carboxy or ethyl ster group) and pharmaceutical compositions containing said compound.

international search report “　’-””-PCT/L”91102603IIlle1-drunk■＾””’- ”’rI+-:Q+ InQth1PCT/US91102603 continued from Vr, 0BSERVAT 085 WEERE UNXTY OF I) fVDJTION XS LACjING PCT/US91102603 Detailed Reasons for Holding Lack 6f Unity of! engineering innovation

Claims (1)

[Claims] 1. A method of inhibiting cell proliferation in a patient suffering from a cell proliferation-related disorder, the method comprising: administering to a patient a pharmacologically effective amount of a styryl-substituted heteroaryl compound; and the heteroaryl group of the compound is a monomer having 1 or 2 heteroatoms. a cyclic ring or a bicyclic ring having from 1 to about 4 heteroatoms, the compound may optionally be mono- or polysubstituted, provided that the ring is polysubstituted. specified, the substituents have no bond in common with the ring. The above method as a sign. 2. A styryl-substituted heteroaryl compound, wherein the heteroaryl A monocyclic ring having 1 or 2 heteroatoms or 1 to about 4 heteroatoms. is a bicyclic ring having a ro atom, and the compound is optionally mono- or polysubstituted. The substituent on the heteroaryl group of the compound may be carboxy or not an ester group, provided that if the ring is polysubstituted, the substituent is The above-mentioned compound is characterized in that it has no bonding points in common with the ring. 3. A pharmacologically effective amount of the claimed item in admixture with a pharmaceutically acceptable carrier In patients suffering from cell proliferation-related disorders characterized by containing the compound described in item 2. A pharmacological composition that inhibits cell proliferation. 4. In a mixture with a pharmaceutically acceptable carrier, a compound of the following formula or Pharmaceutically acceptable salts thereof: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [Here, R1 is alkyl, -H, -CH, -OH, -COOR, -CONRR or -CSNRR; R represents alkyl, -H or aralkyl; R2 is containing 1 or 2 N, O or S atoms or 1 or 2 ruoxide groups about 5 to about 7 membered monocyclic aryl rings, or 1 to about 4 N, O or S about 8 to about 12 membered bicyclic aryls containing atoms or 1 to about 4 ruoxide groups represents a ring, which ring is optionally substituted with 1 to about 3 groups R9. Often the substituents R9 have no common point of attachment to the ring; R3 is alkyl , -H, -CN, -OH, -COOR, -CONRR, -CSNRR or -C H2CN, R4, R5, R6, R7 and Ra are each independently alkyl, - H, -CH, halo, -OR, -CHO, -COOH, -NRR or its N-O Oxide group, -NO2, -NHCOCH3, -SR, -CF3, -CH=CHCO OH, -NHCO(CH2)2COOH, morpholino or heteroaryl group each R9 is independently alkyl, -CN, halo, -OR, -CHO, -COOH, -NRR or its N-oxide group, -NO2, -NHCOCH3, -SR, - CF2, -CH=CHCOOH, -NHCO(CH2)2COOH, Morpholino , heteroaryl group or ▲Mathematical formula, chemical formula, table, etc.▼ and R3 and R7 are -CH2CH2-, -CH2CH2CH2- or or can represent a group -CONH- starting from R3] Claim 1 comprising administering to said patient a pharmacologically effective amount of said compound. the method of. 5. A compound represented by the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ where R1 is alkyl, -CN, -COOR, -CONRR or -CSNRR represents; R represents alkyl, -H or aralkyl; R2 represents 1 or 2 N , about 5 to about 7 membered monocyclic aryl ring containing O or S atoms, or 1 about 8 to about 12 membered bicyclic arylphosphorus containing about 4 N, O or S atoms represents a ring which is optionally substituted with 1 to about 3 groups R9; The substituents R9 have no common point of attachment to the ring; R3 is alkyl, -H , -COOR, -CONRR, -CSNRR or -CH2CN; and R6 are each independently alkyl, -H, -CM, halo, -OR, -CHO, -C OOH, -NRR, -NO2, -NHCOCH3, -SR, -CF3, -CH= CHCOOH, -NHCO(CH2)2COOH, morpholino or heteroaryl R5, R7 and R3 are each independently alkyl, -H, -CN, -OR, -CHO, -COOH, -NHCOCH3, -SR, -CF3, -CH =CHCOOH, -NHCO(CH2)2COOH, morpholino or heteroaryl represents a group with the proviso that R4, R5. At least two of R6, R7 and R8 are -H and R4, R5 or R6 is - when R or R8 is -OR. cannot be OR; each R9 is independently alkyl, -CN, halo, -OR, -CHO , -NRR, -NO2, -NHCOCH3, -SR, -CF3, -CH=CHC OOH, -NHCO(CH2)2COOH, morpholino, heteroaryl group or ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ and R3 and R7 together represent -CH2CH2, -CH2CH2CH2- or represents a group -CONH- starting from R3. 6. Pharmacological compositions for inhibiting cell proliferation in patients suffering from cell proliferation-related disorders , as a mixture with a pharmaceutically acceptable carrier, as defined in claim 5. The above-mentioned pharmaceutical composition, characterized in that it contains a compound in a pharmacologically effective amount. 7. In the general formula according to claim 5, R1 is -CN, -COOR, - CONRR or -CSNRR; R is lower alkyl, -H or aralkyl; a 6-membered monocyclic atom in which R2 contains 1 or 2 N, O or S atoms; Reel ring, or 9 or 10 containing 1 to 4 N, O or S atoms a membered bicyclic aryl ring, the ring optionally containing from 1 to about 3 groups R9. Optionally substituted, the substituent R9 has no common point of attachment to the ring. ; R3 is -H; R4, R5, R6, R7 and R8 are each independently lower alkali; Kyl, -H, lower alkoxy or -OH, with the proviso that R4, R5, R6, R7 and at least two of R6 are not -H, and R4, R5 or R6 is R7 or when R8 is lower alkoxy, it cannot be lower alkoxy, and R4 and R6 may independently be halo; each R9 may independently be lower alkyl, halo; b, lower alkoxy, -OH or ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound according to claim 5, which is 8. Compound according to claim 7 represented by the following formula: ▲ Numerical formula, chemical formula, table There are etc.▼ 9. Compound according to claim 7 represented by the following formula: ▲ Numerical formula, chemical formula, table There are etc.▼ here, R10 is -H, alkyl, aralkyl, or a group represented by the following formula: ▲Numerical formula, There are academic formulas, tables, etc.▼ represents. 10. In the general formula according to claim 8, R1 is -CN, -COOR or or -CONRR; R4, R5, R6, R7 and R8 are each independently lower Represents alkyl, -H, lower alkoxy or -OH, provided that R4, R5, R6, At least two of R7 and R8 are not -H, and R4, R5 or R6 is When R7 or R8 is lower alkoxy, it cannot be lower alkoxy, R4 and R6 may also independently be halo; R is lower alkyl or -H and has no substituent R9; thing. 11. In the general formula according to claim 9, R1 is -CN, -COOR or or -CONRR; R4, R5, R6, R7 and R8 are each independently lower Represents alkyl, -H, lower alkoxy or -OH, provided that R4, R5, R6, At least two of R7 and R8 are not -H, and R4, R5 or R6 is When R7 or R8 is lower alkoxy, it cannot be lower alkoxy, Furthermore, R4 and R6 may each independently be halo; R is lower alkyl or -H; and has no substituent R9; Compound. 12. The following general formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [Here, R1 is -CN, and R5, R7 and R8 each independently represent -H. , and R4 and R6 each independently represent alkyl, halo, -OR or -CF3. The compound according to claim 5, which is a compound represented by the following. 13. The compound is 2-(3-pyridyl)-3-(3,5-dichlorophenyl)- 13. The compound according to claim 12, which is 2-propenenitrile. 14. The compound is 2-(2-pyridyl)-3-(3,4-dimethoxyphenyl) 11. The compound according to claim 10, which is -2-bropenitrile. 15. If the compound is 2-(2-pyridyl)-3-(3,5-di-t-levtylfe 13. The compound according to claim 12, which is (nyl)-2-propenenitrile. 16. The compound is 2-(3-indolyl)-3-(3,4-dimethoxyphenyl )-2-bropennitrile Compound 17 according to claim 11. Applicability The compound is 2-(3-pyridyl)-3-(3,4-dimethoxyphenyl)-2-bro 11. The compound according to claim 10, which is a pennitrile. 18. The compound is 2-(3-pyridyl)-3-(3,5-dimethoxyphenyl) 13. The compound according to claim 12, which is -2-bropenitrile. 19. The compound is 2-(4-pyridyl]-3-(3.5-di-t-butylphenyl) 13. The compound according to claim 12, which is (l)-2-bropenenitrile. 20. If the compound is 2-(3-indolyl)-3-(3,5-di-t-butylphenate) 12. The compound according to claim 11, which is (nyl)-2-propenenitrile. 21. The compound is 2-[1-(4-nitrophenylsulfonyl)indole-3 -yl]-3-(3,4-dimethoxyphenyl)-2-propenenitrile A compound according to claim 9. 22. Claim 2 of the pharmacologically effective amount for patients suffering from cell proliferation-related disorders. A method of inhibiting cell proliferation in a patient comprising administering a compound as described. 23. comprising administering the composition according to claim 3 to a patient suffering from psoriasis. A method for treating psoriasis in such patients. 24. The composition according to claim 3 in patients suffering from atherosclerosis. A method of treating atherosclerosis in a patient comprising administering.